Thyroid and Parathyroid Diseases Medical and Surgical Management

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Thyroid and Parat hyroid Diseases Medical and Surgical Managem ent Second Edition

David J. Terr is, MD, FACS Professor of Otolaryngology–Head an d Neck Surgery Surgical Director, GRU Thyroid an d Parathyroid Cen ter Georgia Regents Un iversit y Augusta, Georgia William S. Du ke, MD Assistan t Professor of Otolaryn gology–Head an d Neck Surger y Associate Surgical Director, GRU Thyroid an d Parathyroid Cen ter Georgia Regents Un iversit y Augusta, Georgia

Th iem e New York • Stuttgart • Delh i • Rio de Jan eiro

Th iem e Medical Publish ers, In c. 333 Seven th Aven ue New York, New York 10001 Executive Editor: Tim othy Y. Hiscock Man aging Editor: J. Ow en Zurh ellen IV Associate Man aging Editor: Ken n eth Schubach Director, Editorial Ser vices: Mar y Jo Casey In tern ation al Production Director: An dreas Sch abert Vice Presiden t, Editorial an d E-Product Developm en t: Vera Spilln er In tern ation al Marketing Director: Fion a Hen derson In tern ation al Sales Director: Louisa Turrell Director of Sales, North Am erica: Mike Rosem an Sen ior Vice Presiden t an d Ch ief Operatin g Of cer: Sarah Van derbilt Medical Illustrators: Em ily Ciosek & Th om son Digital Presiden t: Brian D. Scan lan Cover illustration by Em ily Ciosek Librar y of Con gress Cat alogin g-in -Pu blicat ion Dat a Thyroid an d parathyroid diseases : m edical an d surgical m an agem en t / [edited by] David J. Terris, W illiam S. Duke. – 2n d edition . p. ; cm . In cludes bibliograph ical referen ces an d in dex. ISBN 978-1-62623-008-8 (h ardcover : alk. paper) – ISBN 978-162623-009-5 (e-book) I. Terris, David J., editor. II. Duke, W illiam S., editor. [DNLM: 1. Thyroid Diseases–surger y. 2. En docrin e Surgical Procedures–m eth ods. 3. Parathyroid Diseases–surgery. W K 280] RD599 617.4'4–dc23 2015009874

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Cont ent s Forew ord by Orlo H. Clark . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi Cont ribut ors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xii Part 1. Anat om y, Physiology, and Pat hology of t he Thyroid Com part m ent 1.

The Hist ory and Evolution of Techniques for Thyroid Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Sara L. Richer, Dipti Kamani, Radu Mihai, Anatoly P. Romanchisen, and Gregory W. Randolph

2.

Developm ent al and Surgical Anat om y of t he Thyroid Com part m ent . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Alice L. Tang and David L. Steward

3.

Physiology of t he Thyroid Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 David S. Rosenthal and Kenneth H. Hupart

4.

Physiology of t he Parat hyroid Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Carlos M. Isales and Wendy B. Bollag

5.

Thyroid and Parat hyroid Pat hology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Paul W. Biddinger and Yuri E. Nikiforov

Part 2. Thyroid Diseases 6.

Thyroid Im aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Bruce Curtiss Gilbert and Ramon E. Figueroa

7.

Benign Disease of t he Thyroid Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Maisie L. Shindo

8.

Medical Managem ent of Benign Thyroid Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Jacqueline Jonklaas

9.

Malignant Disease of t he Thyroid Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 Jaime L. Wiebel and Megan R. Haymart

10.

Molecular Advances in t he Diagnosis and Treat m ent of Thyroid Cancer . . . . . . . . . . . . . . . . . . . . . . . 87 Susan J. Hsiao and Yuri E. Nikiforov

11.

Medical Managem ent of Aggressive Di erent iat ed Thyroid Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Sara Ahmadi and R. Michael Tuttle

12.

Medical Managem ent of Medullary and Anaplast ic Thyroid Cancer . . . . . . . . . . . . . . . . . . . . . . . . . 102 Victor J. Bernet and Robert C. Smallridge

Part 3. Surgical Managem ent of Thyroid Diseases 13.

Convent ional Thyroidect om y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Gerard Doherty

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Contents

14.

Minim ally Invasive Thyroid Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 Paolo Miccoli and Gabriele Materazzi

15.

Rem ot e Access Thyroid Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Katrina Chaung and William S. Duke

16.

Subst ernal Goit er . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Sara L. Richer, Brian Hung-Hin Lang, Chung-Yau Lo, Dipti Kamani, and Gregory W. Randolph

17.

Surgical Managem ent of Medullary Thyroid Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 Jennifer Yu and Je rey F. Moley

18.

Surgical Managem ent of Anaplast ic Thyroid Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Brian R. Untch and Luc G. T. Morris

19.

Surgical Managem ent of t he Cent ral Neck Com part m ent for Di erent iat ed Thyroid Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 Salem I. Noureldine and Ralph P. Tufano

20.

Surgical Managem ent of t he Lat eral Neck in Thyroid Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Daniel Kwon and Alfred Simental, Jr.

Part 4. Parat hyroid Diseases 21.

Pat hophysiology of t he Parathyroid Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172 Brendan C. Stack, Jr. and Galimat Khaidakova

22.

Parat hyroid Carcinom a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 Jason P. Hunt and Richard B. Cannon

23.

Parat hyroid Im aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Rosemarie Metzger and Mira Milas

24.

Renal Hyperparat hyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 Steven R. Bomeli and David J. Terris

Part 5. Surgical Managem ent of Parat hyroid Diseases 25.

Convent ional Parat hyroidect om y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 Jennifer Leonard and Geo rey B. Thompson

26.

Minim ally Invasive Parat hyroidect om y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 William S. Duke and David J. Terris

27.

Int raoperat ive Parat hyroid Horm one Assay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Latha V. Pasupuleti and James A. Lee

28.

Radioguided Parat hyroid Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 Sarah C. Oltmann and Herbert Chen

29.

Reoperat ive Parat hyroid Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 David J. Terris and William S. Duke

viii

Contents

Part 6. Special Topics 30.

Com plicat ions of Thyroid and Parathyroid Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 Michele N. Minuto and Emanuela Varaldo

31.

Int raoperat ive Nerve Monit oring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 Dipti Kamani, Rahul Modi, and Gregory W. Randolph

32.

O ce-Based Ult rasonography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 David L. Steward and Russell B. Smith

33.

Out pat ient Endocrine Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 Michael C. Singer and David J. Terris

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275

ix

Forew ord I w as h on ored to be asked by Dr. David J. Terris an d Dr. W illiam S. Duke to w rite th is Forew ord for th e secon d edition of th eir superb book Thyroid a nd Pa ra thyroid Disea ses: Medica l a nd Surgica l Ma na gement. Th e rst edition h ad been publish ed in 2008, an d m uch n ew in form ation is curren tly available w arran tin g th e publication of th is n ew edition . Th e editors of th e book are experien ced thyroid an d parathyroid surgeon s w h o h ave recru ited a talen ted group of auth ors w ith exten sive experien ce in th e m edical an d surgical m an agem en t of thyroid an d parathyroid disorders. Th e book in cludes six ch apters con cern in g th e basic scien ce an d clin ical aspects of thyroid an d parathyroid disorders. It is w ell organ ized an d presen ts n ew in form ation regardin g th e m olecular biology, physiology, im aging, in dication s for operat ion , an d n ew m edical an d surgical treatm en ts. Thyroid n odules are com m on , an d palpable n odules occur in about 4 percen t of th e populat ion . Thyroid can cer is th e m ost rapidly in creasin g can cer in th e USAan d Europe, th e sixth m ost com m on can cer in w om en , an d th e secon d m ost com m on can cer in w om en un der 40 years of age. Because of detect ion by ult rasoun d or by oth er scan s don e for n on -thyroid reason s, th ere is a m arked in crease in th e iden ti cation of thyroid can cer. Con troversy con tin ues regardin g th e exten t of thyroidectom y an d n ode resect ion for low risk papillar y thyroid can cers an d even for w h eth er thyroid resection is n ecessar y for patien ts w ith sm all (less th an 1 cm ) tum ors. Thyroid an d parathyroid operation s h ave advan ced im pressively durin g th e past 150 years. Today m in im ally invasive thyroid an d parathyroid operation s are bein g don e routin ely. Th e death rate from thyroidectom y h as decreased from about 40 percen t in 1850 w h en th e Fren ch Academ y of Medicin e con dem n ed thyroid operation s to less th an on e

x

percen t curren tly. New ly developed m olecular studies are h elpin g to determ in e w h eth er in determ in ate thyroid n odules w arran t rem oval. Min im ally invasive procedures an d rem ote access surger y are bein g perform ed by som e expert surgeon s in th is eld. In m edical cen ters in Japan som e patien ts w ith sm all papillar y thyroid can cers are bein g follow ed w ith out rem oval. In th ese cases tum or grow th or th e developm en t of n odal m etastases is un com m on . Most patien ts h aving thyroid an d parathyroid operat ion s are disch arged w ith in on e day of thyroidectom y or parathyroidectom y. Serious com plication s follow in g thyroid an d parathyroid operat ion s in clude postoperative bleedin g, recurren t lar yn geal or extern al lar yn geal n er ve injur y or perm an en t hypoparathyroidism . Th e com plicat ion rate by experien ced surgeon s is less th an on e percen t. Sin ce th e rst NIH guidelin es m eeting in 1990 regardin g th e m an agem en t of patien ts w ith “asym ptom atic” hyperparathyroidism , m ore eviden ce supports surgical correct ion of th is disorder even w h en th ere are few or n o apparen t adverse clin ical m an ifestation s. Dr. Terris an d Dr. Duke an d th eir colleagues h ave don e a great ser vice to th e en docrin e surgical com m un it y an d th eir patien ts by editin g an outstan din g book th at is up to date regarding all aspects of thyroid an d parathyroid disorders. Alth ough fu rth er n ew in form at ion an d t reatm en ts w ill certain ly occur, th eir book is an excellen t reference an d re ects today’s state of th e art regarding th e m an agem en t of patien ts w ith thyroid an d parathyroid disorders. Orlo H. Cla rk, MD, FACS Emer itus Professor of Surger y Universit y of Ca lifornia Sa n Fra ncisco Sa n Fra ncisco, Ca lifornia

Preface After n early a h un dred years of essen tially un ch anged m an agem en t strategies, th e disciplin e of h ead an d neck en docrin e surgery sudden ly experien ced revolution ar y ch an ges at th e t urn of th e cen tur y, prom ptin g th e publication of th e rst edition of Thyroid a nd Pa ra thyroid Disea ses: Medica l a nd Surgica l Ma nagement, w h ich in troduced cuttin g edge advan ces in thyroid an d parathyroid surger y to audien ces aroun d th e w orld. Just six years later, m any of th e n ovel tech n iques in troduced in th e rst edition are n ow routin ely in corporated in both tertiary an d com m un it ybased pract ices, an d th e w h eels of in n ovation h ave con tin ued to t urn . Th is secon d edition is th erefore a respon se to th ese con tin ued in n ovation s, as w ell as a re ection of our grow in g un derstan din g of th e com plex path ophysiology of th e thyroid an d parathyroid glan ds. All ch apters are eith er n ew or com pletely rew rit ten , yet w e h ave en deavored to m ain tain th e straigh tforw ard an d readable st yle of th e in itial w ork.

Several n ew topics an d con cepts are in troduced, represen tin g im port an t in form ation th at is crit ical to providin g stateof-th e-art care for patien ts w ith thyroid an d parathyroid disease. Th ese topics in clude m olecular advan ces in th e m an agem en t of thyroid disease, em erging n er ve m on itorin g tech n iques, m odern application of rapid in traoperative assessm en t of parathyroid h orm on e levels, evolvin g cen tral n eck im aging, an d rem ote access en docrin e surger y, an d th ey are explored in detail by in tern ation al th ough t leaders from m ult iple disciplin es w h o com plem en t crit ical review of th e curren t m edical literature w ith a w ealth of person al experien ce. It is w ith great pleasure th at w e presen t th is second edition of Thyroid a nd Pa ra thyroid Disea ses. We h ope th at th is w ork in spires an d guides ever y provider, from m edical st uden t to season ed en docrin e pract ition er, in th eir effort to provide th e h igh est qualit y care to th ose in n eed.

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Cont ribut ors Sara Ah m ad i, MD, ECNU Assistan t Professor Depart m en t of Medicin e Un iversit y of Texas Health Scien ce Cen ter San An ton io, Texas Vict or J. Bern et , MD Ch air, Division of En docrin ology Mayo Clin ic Assistan t Professor Mayo Clin ic College of Medicin e Jacksonville, Florida Pau l W. Bid d in ger, MD Professor of Path ology Ch ief, Sect ion of An atom ic Path ology Medical College of Georgia Georgia Regen ts Un iversit y Augusta, Georgia Wen d y B. Bollag, Ph D Professor of Physiology Georgia Regen ts Un iversit y Research Career Scien tist Ch arlie Norw ood VA Medical Cen ter Augusta, Georgia

William S. Du ke, MD Assistan t Professor of Otolaryn gology–Head an d Neck Surger y Associate Surgical Director, GRU Thyroid an d Parathyroid Cen ter Georgia Regen ts Un iversit y Augusta, Georgia Ram on E. Figu eroa, MD, FACR Professor of Radiology Ch ief of Neuroradiology Sect ion Departm en t of Radiology an d Im aging Georgia Regen ts Un iversit y Augusta, Georgia Br u ce Cu r t iss Gilber t , MD Assistan t Professor of Neuroradiology Georgia Regen ts Un iversit y Augusta, Georgia

Steven R. Bom eli, MD Clin ical In structor of Otolar yngology–Head an d Neck Surger y GRU Thyroid an d Parathyroid Cen ter Georgia Regen ts Un iversit y Augusta, Georgia

Megan R. Haym ar t , MD Assistan t Professor of Medicin e Division of Metabolism , En docrin ology, an d Diabetes an d Hem atology/On cology Un iversit y of Michigan An n Arbor, Mich igan

Rich ard B. Can n on , MD Depart m en t of Otolar yn gology–Head an d Neck Surger y Un iversit y of Utah Health Scien ces Cen ter Salt Lake Cit y, Utah

Su san J. Hsiao, MD, Ph D Assistan t Professor of Path ology an d Cell Biology at CUMC Colum bia Un iversit y Medical Cen ter New York, New York

Kat rin a Ch au n g, MD Ear, Nose an d Th roat Cen ters of Texas Dallas, Texas

Jason P. Hu n t , MD, FACS Director, Head an d Neck Surger y Associate Professor of Otolaryngology–Head an d Neck Surger y Un iversit y of Utah Health Scien ces Cen ter/Hun tsm an Can cer In stit ute Salt Lake Cit y, Utah

Herber t Ch en , MD, FACS Professor of Surgery Ch airm an , Departm en t of Surger y Fay Fletch er Kern er En dow ed Ch air Un iversit y of Alabam a-Birm in gh am (UAB) Sch ool of Medicin e Surgeon -in -Ch ief UAB Medicin e Birm in gh am , Alabam a

xii

Gerard M. Doh er t y, MD Utley Professor an d Ch air of Surger y Professor of Medicin e Boston Un iversit y Surgeon -in -Ch ief, Boston Medical Cen ter Boston , Massach usetts

Contributors

Ken n et h H. Hu p ar t , MD, FACP Ch airm an of Medicin e Con ey Islan d Hospital Brooklyn , New York Clin ical Associate Professor of Medicin e Albert Ein stein College of Medicin e Bron x, New York Af liate Full Clin ical Professor St. Joh n’s Un iversit y College of Ph arm acy an d Allied Health Profession s Queen s, New York Carlos M. Isales, MD Professor of Neuroscien ce an d Regen erative Medicin e, Orth opaedic Surgery, Medicin e an d Cell Biology an d An atom y Vice-Ch air, Departm en ts of Neuroscien ce an d Regen erat ive Medicin e an d Orth opaedic Surgery Georgia Regen ts Un iversit y Augusta, Georgia Jacqu elin e Jon klaas, MD, Ph D Associate Professor of Medicin e Director, Clin ical Research Un it Georgetow n Un iversit y Wash ington, DC Dip t i Kam an i, MD Director of Research Division of Thyroid an d Parathyroid Surger y Departm en t of Otolar yn gology Massach usetts Eye & Ear In rm ar y Boston, Massach usetts Galim at Kh aid akova, MD Departm en t of Gen eral Surger y Un iversit y of Arkan sas for Medical Scien ces Little Rock, Arkan sas Dan iel Kw on , MD Ch ief Residen t, Otolaryngology–Head an d Neck Surger y Lom a Lin da Un iversit y Sch ool of Medicin e Lom a Lin da, Californ ia Brian Lan g, MBBS(Hon s), MS(HK), FRACS, FCSHK, FHKAM Clin ical Associate Professor an d Ch ief, Division of En docrin e Surger y Departm en t of Surger y Un iversit y of Hon g Kon g Queen Mary Hospital Hon g Kon g, Ch in a

Jam es A. Lee, MD Associate Professor of Surger y Colum bia Un iversit y Medical Cen ter New York, New York Jen n ifer Leon ard , MD, Ph D Sen ior Residen t Departm en t of Surger y Mayo Clin ic Roch ester, Min n esota Ch u n g-Yau Lo, MS, FRCS (Ed in .), FACS Hon orar y Professor Departm en t of Surger y Th e Un iversit y of Hon g Kon g Queen Mar y Hospital Hon g Kon g, Ch in a Gabriele Materazzi, MD Departm en t of Surger y Un iversit y of Pisa Pisa, Italy Rosem arie Met zger, MD, MPH, FACS Staff, Sect ion of En docrin e Surger y En docrin ology an d Metabolism In stit ute Clevelan d Clin ic Clevelan d, Oh io Surgical Director Thyroid Cen ter Clevelan d Clin ic Florida Weston , Florida Paolo Miccoli, MD Departm en t of Surger y Un iversit y of Pisa Pisa, Italy Rad u Mih ai, MD, Ph D, FRCS Con sultan t En docrin e Surgeon Hon orar y Sen ior Clin ical Lecturer Departm en t of En docrin e Surger y Oxford Un iversit y Hospitals NHS Trust Ch urch ill Can cer Cen tre Oxford, Un ited Kin gdom Mira Milas, MD, FACS Professor of Surger y Director of En docrin e Surger y Departm en t of Surger y Oregon Health & Scien ce Un iversity Portlan d, Oregon

xiii

Contributors

Mich ele N. Min u to, MD, Ph D Assistan t Professor of Surger y Depart m en t of Surgical Scien ces Un iversit y of Gen oa Gen oa, Italy Rah u l Mod i, MBBS, MS Clin ical Research Fellow Division of Thyroid an d Parathyroid Surger y Depart m en t of Otolar yn gology Massach usetts Eye & Ear In rm ar y Boston, Massach usetts Assistan t Professor Depart m en t of Otolar yn gology–Head an d Neck Surger y Bh arat i Vidyapeeth Deem ed Un iversit y Medical College Pun e, Mah arash tra, In dia Jeffrey F. Moley, MD Professor of Surgery Ch ief, En docrin e an d On cologic Surgery Associate Director, Th e Alvin J. Sitem an Can cer Cen ter Wash ington Un iversit y Sch ool of Medicin e St. Louis, Missouri Lu c G.T. Morr is, MD, MSc, FACS Adler Jun ior Facult y Ch air Head an d Neck Ser vice Depart m en t of Surger y Mem orial Sloan Ketterin g Can cer Cen ter New York, New York Yu ri E. Nik iforov, MD, Ph D Professor of Path ology Vice Ch air for Molecular Path ology Director, Division of Molecular & Gen om ic Path ology Depart m en t of Path ology Un iversit y of Pittsburgh Pittsburgh , Pen n sylvan ia Salem I. Nou reld in e, MD Postdoctoral Fellow Division of Head an d Neck En docrin e Surger y Depart m en t of Otolar yn gology–Head an d Neck Surger y Joh n s Hopkin s Un iversit y Sch ool of Medicin e Baltim ore, Mar ylan d Sarah C. Olt m an n , MD Assistan t Professor Depart m en t of Surger y Un iversit y of Texas South w estern Medical Cen ter Dallas, Texas

xiv

Lat h a V. Pasu pu let i, MD En docrin e Surgery Fellow Clin ical In structor in Surgery Colum bia Un iversit y Medical Cen ter/NY Presbyterian Hospital New York, New York Gregor y W. Ran d olp h , MD, FACS, FACE Director, Gen eral Division an d Thyroid an d Parathyroid Surgical Division s Massach usetts Eye & Ear In rm ar y Mem ber, En docrin e Surgical Ser vice Massach usetts Gen eral Hospital Associate Professor of Otology an d Lar yngology Har vard Medical Sch ool Boston , Massach usetts Sara L. Rich er, MD, FACS North east Medical Group Bridgeport, Con n ect icut An atoly P. Rom an ch ish en , MD, Ph D, MScD Professor of Surger y an d On cology Ch ief of Hospital Surgery Departm en t of Sain t-Petersburg State Pediatric Medical Un iversit y Ch ief of Sain t-Petersburg Cen ter of En docrin ology an d On cology Hon ored Doctor of Russian Federation Sain t Petersburg, Russia David S. Rosen t h al, MD, FACP, FACE Zaki Hossein Cen ter for Hyperten sion , Diabetes, an d Vascular Disease Division of En docrin ology, Diabetes, an d Metabolism Nassau Un iversit y Medical Cen ter East Meadow, New York Assistan t Professor of Clin ical Medicin e (En docrin ology) Th e State Un iversit y of New York Stony Brook, New York Assistan t Clin ical Professor St . Joh n’s Un iversit y College of Ph arm acy an d Allied Health Profession s Queen s, New York Maisie L. Sh in d o, MD, FACS Professor an d Director, Head an d Neck En docrin e Surger y Departm en t of Otolaryngology–Head an d Neck Surgery Oregon Health & Scien ce Un iversit y Portlan d, Oregon Alfred Sim en t al Jr., MD, FACS Ch airm an , Otolaryn gology–Head Neck Surger y Lom a Lin da Un iversit y Sch ool of Medicin e Lom a Lin da, Californ ia

Contributors

Mich ael C. Sin ger, MD, FACS Director, Division of Thyroid an d Parathyroid Surger y Departm en t of Otolar yn gology–Head an d Neck Surger y Hen r y Ford Health System Detroit, Mich igan Rober t C. Sm allridge, MD Deput y Director, Mayo Clin ic Can cer Cen ter Alfred D. an d Audrey M. Petersen Professor of Can cer Research Professor of Medicin e Mayo Clin ic Jacksonville, Florida Ru ssell B. Sm it h , MD Professor of Otolaryn gology-Head an d Neck Surgery Un iversit y of Nebraska Medical Cen ter Om ah a, Nebraska Bren d an C. St ack Jr., FACS, FACE Professor UAMS Thyroid Cen ter Departm en t of Otolar yn gology–Head an d Neck Surger y Un iversit y of Arkan sas for Medical Scien ces Little Rock, Arkan sas David L. Stew ard , MD Professor Departm en t of Otolar yn gology–Head an d Neck Surger y Un iversit y of Cin cin n ati College of Medicin e Cin cin n ati, Oh io Alice L. Tan g, MD Departm en t of Otolar yn gology–Head an d Neck Surger y Un iversit y of Cin cin n ati College of Medicin e Cin cin n ati, Oh io David J. Terr is, MD, FACS Professor of Otolaryn gology–Head an d Neck Surger y Surgical Director, GRU Thyroid an d Parathyroid Cen ter Georgia Regen ts Un iversit y Augusta, Georgia

Ralp h P. Tu fan o, MD, MBA, FACS Ch arles W . Cum m ings MD Professor Co-Director, Joh n s Hopkin s Hospital Multidisciplin ar y Thyroid Tum or Cen ter Director, Division of Head an d Neck En docrin e Surgery Departm en t of Otolaryngology–Head an d Neck Surgery Th e Joh n s Hopkin s Un iversit y Sch ool of Medicin e Baltim ore, Mar ylan d R. Mich ael Tu t t le, MD En docrin ology Ser vice Professor of Medicin e Joan an d San ford I. Weill Medical College of Corn ell Un iversit y Mem orial Sloan Ketterin g Can cer Cen ter New York, New York Br ian R. Un t ch , MD Gastric an d Mixed Tum or Ser vice Head an d Neck Ser vice Departm en t of Surger y Mem orial Sloan Ketterin g Can cer Cen ter New York, New York Em an u ela Varald o, MD Assistan t Professor of Surgery Un iversit y of Gen oa Gen oa, Italy Jaim e L. Wiebel, MD Fellow in Metabolism , En docrin ology, an d Diabetes Un iversit y of Mich igan An n Arbor, Mich igan Jen n ifer Yu , MD Departm en t of Surger y Barn es-Jew ish Hospital Wash in gton Un iversit y School of Medicin e St . Louis, Missouri

Geoffrey B. Th om pson , MD Professor of Surgery Sen ior Associate Dean of Facult y Affairs Mayo Medical School Sect ion Head, En docrin e Surgery Mayo Clin ic Roch ester, Min n esota

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Part 1

1

Anat om y, Physiology, and Pat hology of t he Thyroid Com part m ent

2

The History and Evolution of Techniques for Thyroid Surgery

2

Developm ental and Surgical Anatom y of the Thyroid Com partm ent

8

3

Physiology of t he Thyroid Gland

16

4

Physiology of t he Parathyroid Glands

24

5

Thyroid and Parathyroid Pat hology

31

Anatom y, Physiology, and Pathology of the Thyroid Com part m ent

1 The Hist ory and Evolut ion of Techniques for Thyroid Surgery Sara L. Richer, Dipti Kamani, Radu Mihai, Anatoly P. Romanchisen, and Gregory W. Randolph

1.1 Int roduct ion Thyroidectom y h as evolved from a barbaric, h igh -m ortalit y procedure to an elegan t operat ion , th e epitom e of th e surgeon ’s art. It w as prim arily th e pion eerin g w ork of Koch er, rew arded w ith th e 1908 Nobel Prize, th at catalyzed th is evolution . Th is ch apter review s th e evolution of thyroidectom y, from th e bloody goiter resection of th e early cent uries to th e in n ovative, patien t-cen tered, refin ed thyroidectom y of today.

1.2 The Norm al and Enlarged Thyroid: Init ial Misunderst andings Th e in itial in terest in th e thyroid glan d w as fostered by th e large glan ds en dem ic in th e first an d second cent uries. Goiters (Latin gutt ur = th roat) w ere recogn ized in Ch in a as early as 2700 BC an d th en again by th e Rom an s in th e Alps in th e first 3 cen turies AD. Th e n orm al thyroid glan d w as n ot recogn ized un til th e Ren aissan ce. Aroun d 1500 Leon ardo da Vin ci drew th e thyroid as a globular, bilobate struct ure, w h ich h e regarded as t w o glan ds, fillin g th e em pty spaces in th e n eck. In 1543 An dreas Vesalius of Padua described tw o “glan dulae laryn ges” w h ich, h e th ough t , lubricated th e lar yn x. Barth olom aeus Eustach ius of Rom e, w h o also described th e adren al glan ds, described a sin gle “glan dulam thyroideam ” (Latin for “sh ield-sh aped”) w ith an isth m us con n ectin g its lobes, but h is w ork w as n ot publish ed un til th e 18th cen tur y. In 1656 Th om as Wh ar ton of Lon don described an d n am ed “glan dula thyroidoeis.” Th e on set of goiter in th e youn g adult at th at tim e led to speculation th at goiter form ation w as associated w ith sexual m aturit y. In th e late 18th cen tur y m icroscopy revealed colloid-filled vesicles w ith in th e glan d. Caleb Hillier Parr y of Bath , En glan d, w h o also described exoph th alm ic goiter, speculated th at th e thyroid provided a reser voir to preven t engorgem en t of th e brain .1,2

1.3 Set ons, Boot laces, and Prison: Early Days of Thyroid Surgery Celsus an d Galen h ave been credited w ith operatin g on goiters in th e first an d secon d cent uries, but it w as n ot un til AD 500 in Bagh dad th at Abdul Kasan Kelebis Abis perform ed th e first recorded goiter excision . Roger Frugardi, in th e Italian Sch ool of Salern o, provided th e first credible description of operation for goiter in approxim ately 1170. At th is tim e, if a large goiter failed to respon d to m edication (in cluding iodin e-con tain in g m arin e products), t w o seton s w ere in serted at righ t an gles, w ith th e h elp of a h ot iron , an d m an ipulated tow ard th e surface t w ice daily un t il th ey h ad cut th rough th e flesh . An oth er tech n ique for goiters th at projected an teriorly consisted of m akin g a skin in cision , grasping th e tum or w ith a h ook, th en dissectin g th e skin from th e goiter. Th e exposed pedun culated portion of th e goiter w ould be

2

ligated en m asse w ith a bootlace an d rem oved. Durin g such procedures th e patien ts w ere tied dow n to a table an d h eld firm ly. In 1718 Germ an surgeon s w rote an accoun t of thyroid surgery th at di ered little from th at of Frugardi’s. In 1646, Wilh elm Fabricus reported th e first thyroidectom y usin g a scalpel. Th is tech n ical advan ce w as iron ically an d un fortu n ately associated w ith a poor outcom e. Th e patien t died an d th e surgeon w as im prison ed. Pierre-Joseph Desault of Paris is th e first surgeon to publish an accoun t of a successful rem oval of a goiter, w h ich h e perform ed in 1791. He used a vert ical in cision to isolate an d ligate th e superior an d in ferior thyroid arteries before cutt in g th em an d dissectin g th e thyroid from th e t rach ea usin g th e scalpel. He packed th e w oun d, w h ich suppurated an d h ealed in a m on th . Guillaum e Dupuytren follow ed in Desault’s footsteps an d in 1808 perform ed th e first “total thyroidectom y.” Attem pts to suppress th e glan d by ligation of th e superior thyroid artery w ere first used by William Blizzard in 1811. Alth ough relatively sim ple due to th e lateral approach , th is operation fell in to disuse because of its m in im al lon g-term ben efit. In th e m id-19th cen tur y, William Halsted of Baltim ore, in h is m on um en tal Opera t ive Stor y of Goitre, could t race accoun ts of on ly 8 thyroid operation s in w h ich a scalpel h ad been used betw een 1596 an d 1800, an d on ly 69 furth er cases un til 1848. In th e 1850s, a variety of in cision s w ere perform ed for thyroidectom y: lon gitudin al, oblique, Y-sh aped. After th e skin in cision , m ost surgeon s perform ed blun t dissect ion , an d th eir control of bleedin g w as in adequate. Despite sign ifican t perioperative blood loss, bloodlettin g w as perform ed for postoperative com plication s. Typically th e w oun d w as left open , an d th e dead spaces w ere packed or left to fill w ith blood. At th is t im e th e m ortalit y after thyroid surgery w as as h igh as 40%. Not surprisin gly, th e Fren ch Nation al Academ y of Medicin e con dem n ed any operative procedures on th e thyroid glan d, an d Sam uel David Gross, a prom in en t Am erican surgeon , w rote in 1866, “No h on est an d sen sible surgeon w ould ever en gage in it!” Th rough out m ost of th e 19th century th e results of thyroid operation s w ere so poor th at m ost surgeon s restricted th eir practice to ver y sim ple procedures, w h ich could be grouped in th ree categories: 1. Non cuttin g operation s: seton s an d bristles w ere in serted, an d cysts w ere pun ct ured an d injected w ith iodin e or oth er irritan ts. Death s from h em orrh age, in flam m ation , or air em bolus w ere n ot un com m on . 2. En ucleat ion an d bootlace ligation of goiters. 3. Cutt in g operat ion s w ith rem oval of thyroid t issue: th ese t yp ically in cluded ligation of thyroid arteries an d division of superficial m uscles an d fascia.

1.4 The 19t h Cent ury Revolut ion: Kocher’s Thyroidect om y Th e 19th cen tur y m arked a revolut ion in all fields of surgery, triggered by th e in troduct ion of gen eral an esth esia an d asept ic

The History and Evolution of Techniques for Thyroid Surgery

Fig. 1.1 Nikolai Pirogoff.

tech n ique. In 1846, William Morton’s dem on st ration of eth er’s e cacy at Massach usetts Gen eral Hospital m arked th e begin n in g of surgical an esth etics. Th e first recorded thyroid operation w ith an esth esia w as perform ed in 1847 3 , w h en Nikolai Pirogo , of Sain t Petersburg, Russia, em ployed eth er for a thyroid operation on a 17-year-old girl, w h ose cen tral goiter com pressed th e trach ea ( Fig. 1.1). Despite such progress, m any surgeon s at th is t im e cont in ued to m an age pat ien ts w ith out an esth esia. On e of th e m ost distin guish ed surgeon s of th e 19th cent ur y, Albert Th eodor Billroth , w as involved in th e n ew era of thyroid surgery ( Fig. 1.2). In th e early 1860s, w h ile h oldin g th e ch air of surgery in Zurich , h e perform ed 20 thyroidectom ies. Billroth , described by William Halstead as a rapid thyroid operator, courageously reported h is in itial results, docum en tin g a 40% m ortalit y rate due to in t raoperative h em orrh age an d postoperative sepsis. After aban don in g thyroid surgery for m ore th an a decade, h e w as again att racted to th is field w h ile w orkin g in Vien n a. By th en an tisepsis h ad becom e m ore establish ed, an d h e ach ieved an im pressive m or talit y rate of on ly 8% for thyroidectom y. Billroth’s tech n ique at th at tim e involved division of th e stern ocleidom astoid m uscle, in cision an d drain age of any thyroid cysts, arterial ligation , an d th e use of an eur ysm al n eedles for con trollin g h em orrh age. Despite Billroth’s pion eerin g w ork, Th eodor Koch er’s n am e dom in ates th e h istor y of thyroid surgery ( Fig. 1.3). Koch er’s 1872 appoin tm en t as ch air of surgery in Bern , Sw itzerlan d, m arks th e begin n in g of an illustrious career, durin g w h ich

Fig. 1.2 Albert Theodor Billroth. (Used with perm ission from Randolph GW. Surgery of the Thyroid and Parathyroid Glands. New York, NY: Elsevier; 2003)

h e perform ed m ore th an 5,000 thyroidectom ies. Kocher represen ted a n ew st yle of thyroid surgeon . With m eticulous atten tion to th e details of surgical tech n ique, h em ostasis, an d an tisepsis, h e reported a reduct ion in m ortalit y from m ore th an 12% in th e 1870s to 0.2% in 1898. Kocher’s im portan t con tribution s to thyroid surgery in clude th e con cept of total thyroidectom y, capsular dissection , an d th e dem on st rated ben efit of bein g a h igh -volum e surgeon . All of th ese con cepts rem ain im portan t in th e m odern era. Subtotal thyroidectom y w as th e m ain stay operation prior to Kocher’s realization th at th is subtotal operat ion led to goiter recurren ce. His capsular dissection , w ith its em ph asis on precise dissect ion an d m eticulous h em ostasis, w as a gran d ch ange from th e earlier bloody, barbaric surgery. With experien ce an d atten tion to detail, h e w as able to spare th e recurren t lar yngeal n erve an d parathyroid glan ds, despite th e un kn ow n fun ct ion of th ese struct ures at th e tim e.4,5 Koch er’s tech n iqu e involved a collar in cision , w h ich bears h is n am e t od ay. He also con t ribu t ed t o t h e u n d erst an d in g of t hyroid p hysiology. His obser vat ion s of “cach exia st r u m ip riva,” th e con sequ en ces of t otal rem oval of t h e t hyroid glan d , con tribu ted to th e recogn ition th at th e thyroid is essen tial for n orm al grow t h , d evelop m en t , an d m et abolism . In 1908, Dr. Koch er w as aw ard ed t h e Nobel Pr ize for m ed icin e for h is w ork on th e p h ysiology, p ath ology, an d su rger y of th e thyroid glan d .

3

Anatom y, Physiology, and Pathology of the Thyroid Com part m ent

1.6 Refinem ent of Thyroidect om y in t he 21st Cent ury Fortun ately, issues of postoperative m ortalit y are n o lon ger central to thyroidectom y. Th e tech n ically ch allen ging issues in thyroid surgery are dom in ated by postoperat ive hypocalcem ia an d voice ch anges. Th e cosm etic outcom e h as also becom e of in creasin g im portan ce for a public w ith h igh expectation s for aesth etic, n o-risk surger y. Advan ced en ergy devices an d in traoperative n er ve m on itorin g h ave replaced th e seton s of old. Th e tren d tow ard m in im ally invasive surgical approach es an d patien t selection for thyroid can cer operation s are n ow th e topics of debate.

1.7 Out com es

Fig. 1.3 Theodor Kocher. (Used with perm ission from Randolph GW. Surgery of the Thyroid and Parathyroid Glands. New York, NY: Elsevier; 2003)

1.5 The 20t h Cent ury: Mat urit y of Thyroid Surgery In th e late 1890s, European advan ces in thyroid surgery w ere adopted in th e Un ited States by William Halsted of Baltim ore, th e Mayo broth ers of Roch ester, George Crile of Clevelan d, an d Fran k Lah ey of Boston . Th e w ell-kn ow n m edical clin ics th at bear th eir n am es w ere in itially fin an cially fueled by h igh -volum e thyroid surgery, m ade safe an d pract ical th rough th e tech n iques of Kocher. At th e turn of th e 20th cent ury, Th om as Peel Dun h ill of Melbourn e began w ork on th e t reatm en t of thyrotoxicosis. He in troduced th e tech n ique of total lobectom y w ith con tralateral subtotal thyroidectom y, subsequen tly referred to as th e Dun h ill procedure. He advocated pericapsular dissection perform ed in a staged m an n er un der local an esth esia, an d later un der ligh t gen eral an esth esia. He ach ieved a m ortality of on ly 3% w h ile operatin g on severely thyrotoxic patien ts. In Lon don , th e sam e operation at th is t im e w as associated w ith 30% m ortalit y. In terestin gly, at th e t im e of Dun h ill’s in itial presen tat ion of results in th ese patien ts to th e Royal Societ y of Medicin e in Lon don , th e society’s ch airm an w as Jam es Berr y, w h o described th e eponym ous ligam en t th at overlies th e recurren t lar yn geal n er ve close to its en t ry poin t in to th e lar yn x. After th e First World War, Dun h ill m oved to Lon don . In 1919, th e Br it ish Jour na l of Surger y publish ed h is sem in al article providin g a detailed surgical tech n ique for thyroidectom y, w h ich rem ain s true to form today.6 In th at sam e year, Sist run k described h is radical operation for thyroglossal tract lesion s, in cludin g th e resection of th e m iddle th ird of th e hyoid bon e.

4

Postoperative hypocalcem ia an d tetany w ere recogn ized as early as th e m id-19th cen tur y, an d th e careful capsular dissection in troduced by Koch er h as h elped to reduce its in ciden ce. Data h ave sh ow n th at surgeon s perform in g m ore th an 100 thyroid surgeries yearly h ave superior outcom es.7 In today’s literature, perm an en t hypoparathyroidism occurs in less th an 2% of patien ts operated on by h igh -volum e surgeon s. Iden tification of th e recurren t laryn geal n erve (RLN) durin g thyroidectom y h as been advocated for m ore th an 2 decades, fin ally putt in g to rest Crile’s doctrin e of vulnerabilit y, w h ich h eld th at a dissected n er ve w as an injured n er ve. Th e RLN m ust be iden tified an d traced up to th e en t r y poin t in th e lar yn x for on e to ascertain th at th e n erve h as n ot been dam aged durin g th e procedure. In traoperative n eural m on itorin g can provide addition al in traoperative fu n ct ion al in form ation an d h as application in n eural iden tification , aids in n eural dissect ion , an d provides progn ostic in form ation regarding postoperative fun ction .8 An injur y rate of 1 to 5% is gen erally quoted in expert series, alth ough th is likely un derestim ates th e rates of paralysis occurrin g w h en qualit y registers repor t on all surgeon s’ results.

1.8 Modern Day Technology Th e grow in g un derstan din g of th e thyroid glan d, surroun din g struct ures, an d postoperat ive m an agem en t push ed th e envelope in regard to n ew surgical tech n iques. After th e adven t of laparoscopic abdom in al surgery th e public desired m in im ally invasive tech n iques w ith th e thyroid as w ell. En ergy devices, such as th e Harm on ic Scalpel (Eth icon En doSurgery) or Ligasure system s (Covidien ), are lin ked w ith n ew er, m in im al-access approach es. Vessel cont rol can be ach ieved w ith th ese devices, alon g w ith sh orter operat ive tim e, decreased m ean in traoperative blood loss, an d less postoperat ive pain .9,10 To im prove n er ve outcom es, surgeon s h ave em ployed m agn ifyin g len ses, an d even a surgical m icroscope, to facilitate accurate dissection in th e vicin it y of th e RLN, w ith th e proper in ten t to decrease tran sien t n er ve palsies.11 Th e en doscope provides an oth er tool for m agn ification . Terris et al w ere able to dem on strate a ver y low rate of n er ve injur y w ith th e en doscope, likely because of th e m agn ified visualization.12 Th e in traoperative n er ve m on itor h as been used for th e past 2 decades in thyroid an d parathyroid surgery an d is in creasin gly em ployed by surgeon s today. Recen tly, cont in uous vagal

The History and Evolution of Techniques for Thyroid Surgery m on itorin g h as been sh ow n to be safe an d to preven t RLN paralysis.13,14 As th e surgeon recogn izes elect rom yograph ic ch anges from th e con tin uous m on itorin g, th e surgical m an euver can be aborted prior to n er ve dam age. Preser vation of th e extern al bran ch of th e superior lar yngeal n er ve (EBSLN) h as recen tly gain ed atten tion because injury m ay be a com m on ly un derestim ated m orbidit y follow in g thyroid surgery. Th e t radition al n er ve m on itor can be safely used for EBSLN m appin g, im provin g th e rate of iden tification w ell beyon d visualization alon e.15,16 Im proved surgeon aw aren ess an d a n ew en dotrach eal tube m ay h elp facilitate preservation an d decrease postoperative con cern s about vocal perform an ce.17

w as h igh er, postoperat ive pain in th e first an d second days after surgery w as low er, th e postoperative h ospital stay w as sh orter, an d th ere w ere n o sign ifican t di eren ces in com plication s com pared w ith th ose un dergoing conven t ion al thyroidectom y. Th is tech n ique h as been sh ow n to be as e ective as conven t ion al thyroid surgery at rem ovin g thyroid can cer.19

Endoscopic Thyroid Surgery

Decades after th e adven t of laparoscopic abdom in al surgery, several en th usiasts h ave explored th e possibilit y of using sim ilar equipm en t an d tech n iques durin g thyroid surgery. Min im ally invasive thyroid surgery seeks to provide a safe an d e ect ive operation th rough a sm aller in cision . With avoidan ce of drain use an d less postoperat ive pain , even outpatien t surgery h as been perform ed. Tw o path s em erged from th e adven t of m in im ally invasive thyroidectom y. On e is a truly m in im ally invasive approach th rough video-assisted or n on en doscopic tech n iques, an d an oth er involves rem ote access tech n iques, w h ich are n ot truly m in im ally invasive because th ey involve exten sive dissection , but th ey avoid th e cervical scar.

Purely en doscopic n eck surgery w as first repor ted by Gagn er for parathyroid surgery.20 His cen tral en doscopic approach used a 5 m m in cision m ade slightly an terior to th e stern al n otch w ith CO2 in su ation at 8 to 12 m m Hg pressure an d addition al t rocars at th e m idlin e an d SCM border. Sign ifican t im provem en ts in en doscopic in strum en tation (e.g., m in iscopes, m in iature in strum en ts) h ave en couraged oth ers to adopt th ese en doscopic tech n iques for thyroidectom y. In Marseille, an en doscopic thyroidectom y based on a lateral approach w as used, sim ilar to th at used for m in im ally invasive parathyroidectom y.21 A plan e w as developed betw een th e carotid sh eath laterally and th e strap m uscles m edially, allow in g exposure for iden tificat ion of th e RLN an d parathyroid glan ds.21 Th e in d ication s for en d oscop ic thyroid ect om y h ave exp an d ed as rep or ts h ave been p u blish ed on its u se for bilateral n eck exp lorat ion , lym p h n od e d issect ion in th e cen tral an d lateral com p ar t m en ts, an d thyroid n od u les greater th an 3 cm .22,23,24,25,26 Th e ap p licat ion s for en d oscop ic su rger y w ill likely con t in u e to in crease as m ore su rgeon s ad op t t h e tech n iqu e in h igh -volu m e cen ters.

Minim ally Invasive Approaches

Ext racervical Thyroidect om y

Min im ally invasive open surgery involves a cen tral cervical in cision sm aller th an Koch er’s 6 cm in cision but usin g tech n iques sim ilar to th ose of th e conven tion al operation , aided by en ergy devices for m eticulous h em ostasis. Placem en t of in cision s in n atural skin creases can im prove th e cosm et ic result. In Sidn ey, Delbridge described th e tech n ique for m in im alaccess thyroidectom y (MAT) as an exten sion of th e approach used for m in im ally invasive parathyroidectom y. In sh ort, a 2.5 cm lateral tran sverse in cision is m ade directly over th e n odule or over th e m iddle of th e thyroid lobe, straddlin g th e m edial m argin of th e stern ocleidom astoid (SCM) m uscle. Th e SCM is th en retracted laterally, an d th e space posterior to th e strap m uscles is open ed to expose th e thyroid glan d. Th is w as presen ted as a safe an d feasible surgical procedure th at provides an altern ative to open thyroid surger y in appropriately selected cases.

Th e desire to avoid n eck scars after thyroidectom y h as en couraged som e auth ors to use in cision s placed outside th e cer vical region . Th ese various approach es in clude ch est/breast, axillary, com bin ed axillar y an d areolar, postauricular, or oral cavit y access poin ts.27,28,29 Th ese approaches are n ot m in im ally invasive; th ey all require a great am oun t of dissection , but th ey do avoid a n eck scar. In itially favored in Asian societies because of a cultural aversion to n eck scars an d th e predom in an ce of hypertroph ic scarrin g, North Am erican centers h ave attem pted th ese procedures to appeal to patien ts n ow seekin g “scarless” surgery. Th ese rem ote access approaches w ere in itially en doscopically assisted, but th ey h ave n ow in corporated robot ic tech n iques. In 2000, Oh gam i an d colleagues described a rem ote-access h em ithyroidectom y usin g CO2 in su ation an d en doscopes th rough in cision s on th e parastern al border of on e breast an d alon g th e superior m argin s of both areolas.30 Th e breast w as subject to hypertroph ic scarrin g, an d oth er access poin ts w ere sough t . Ikeda an d colleagues described th e en doscopic axillar y approach in 2001.31 Th is approach takes sign ifican tly lon ger th an conven t ion al thyroidectom y, an d th e n arrow operative field an d poten tial m orbidit y related to CO2 in su ation are som e of th e lim itation s.30 Th e use of th e da Vin ci surgical robot (In tuit ive Surgical, In c.) w as first described in 2009 in South Korea by Kan g 32 an d colleagues.33 Th is uses th e axillar y approach in a m an n er sim ilar to th e endoscopic tran saxillar y approach an d w as in itially em braced w ith en th usiasm in North Am erica. How ever,

1.8.1 What Is Minim ally Invasive Thyroid Surgery?

Video -Assist ed Thyroidect om y In 1998, in Pisa, Miccoli in troduced th e m in im ally invasive video-assisted thyroidectom y (MIVAT or VAT). Th is gasless procedure is carried out th rough a 15 m m cent ral in cision above th e stern al n otch . A 5 m m 30° en doscope is in serted th rough th e skin in cision . Dissection is perform ed un der en doscopic vision usin g conven t ion al an d en doscopic in strum en ts an d tech n iques. Nodules sm aller th an 35 m m an d early-stage papillary carcin om a are am en able to th is operative tech n ique.18 Reports of MIVAT revealed th at pat ien ts’ satisfaction w ith th eir scars

5

Anatom y, Physiology, and Pathology of the Thyroid Com part m ent because of econ om ic consideration s an d com plication s, such as excessive blood loss, brach ial plexus injur y, an d esophageal perforation s, th is approach w as largely aban don ed in th e Un ited States. A relatively n ew addition to thyroid surger y approach es is th e robotic facelift thyroidectom y. Th is avoids th e cervical scar an d w as foun d to be safe an d feasible in experien ced h an ds. Patien t select ion is im portan t because th e thyroid disease sh ould be un ilateral, w ith out thyroiditis or con cern in g m align an cy.34 Alth ough a lon ger operat ion th an conven tion al thyroidectom y, th e cosm etic outcom e h as been favorable.

Pat ient Select ion Th ere is debate about w h ich patien ts sh ould un dergo surgical in terven tion . Previously, thyroid lobectom y w as un dertaken for in determ in ate n odules on fin e-n eedle aspiration . New gen etic expression classificat ion h as decreased th e n um ber of patien ts un dergoing lobectom y for diagn ostic purposes an d w ill likely con tin ue to do so.35 As th e in ciden ce of sm all papillar y carcin om as h as in creased w orldw ide an d th e n um ber of thyroidectom ies h as in creased, patien t select ion h as n ow begun w ith som e patien ts optin g for observation rath er th an surgical in terven tion .36 Certain ly th e obser vation of th ese in determ in ate an d m align an t n odules w ill con tin ue to be th e focus of furth er study. Many pat ien ts readily prefer an d seek out “m inim ally invasive” or “sm all in cision ” surgery because th ey in tr in sically assum e th at such option s, if bein g o ered, are as safe as or safer th an th e previous stan dard approach es an d are of proven ben efit. Th e safety profiles of th ese m in im ally invasive tech n iques m ust contin ue to be scrut in ized as th e m odern thyroid surgeon pion eers n ew tech n iques. Th e w ords of Th eodor Billroth rem ain as valid as ever: “On ly th e m an w h o is fam iliar w ith th e art an d scien ce of th e past is com peten t to aid in its progress in th e fut ure.”37

References [1] Slough CM Jr, Ran dolph GW, Lore JM, Rom an ch isen AP, Eds. History of thyroid an d parathyroid surgery. In : Ran dolph GW , ed. Surgery of th e Thyroid an d Parathyroid Glan ds. 1st ed. Ph iladelph ia, PA: Saun ders; 2003:3–11 [2] Welbourn e R. Th e History of En docrin e Surgery. New York, NY: Praeger; 1990 [3] Rom an sch ishen AF, Vabalayte KV, Tovbin a MH. Russian con tribution in thyroid surger y: m ore th an a centur y in th e sh ade. World J Surg Oct2013; 37 (10); 2343–2347 [4] Kopp P. Th eodor Koch er (1841–1917) Nobel prize cen ten ar y 2009. Arq Bras En docrin ol Metabol 2009; 53(9); 1176–1180 [5] Gem senjäger, E (n .d.). European Th yroid Association - Mileston es - Th eodor Koch er (1841-1917). Retrieved Novem ber 14, 2014: w w w.eurothyroid.com / about/m et/koch er.h tm l [6] Dun h ill TP. A discussion on partial thyroidectom y un der local an aesthesia, w ith special referen ce to exoph th alm ic goitre: an address in troductor y to a discussion on th e subject . Proc R Soc Med 1912; 5; 61–69 [7] Stavrakis AI, Ituar te PH, Ko CY, Yeh MW . Surgeon volum e as a predictor of outcom es in in patien t an d outpatien t en docrin e surgery. Surgery 2007; 142 (6); 887–899, discussion 887–899 [8] Ran dolph G. Surgical An atom y of Recurren t Lar yn geal Nerve. Ph iladelph ia, PA: Saun ders; 2003 [9] Casadei R, Peren ze B, Calculli L, Min n i F, Con ti A, Marran o D. [“Forgotten ” goiter: clin ical case an d review of th e literature][in Italian ] Ch ir Ital 2002; 54(6); 855–860

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[10] Cordón C, Fajardo R, Ram írez J, Herrera MF. A ran dom ized, prospect ive, parallel group study com parin g th e Harm on ic Scalpel to elect rocautery in thyroidectom y. Surgery 2005; 137(3); 337–341 [11] Seven H, Calis AB, Vural C, Turgut S. Microscopic thyroidectom y: a prospective con trolled trial. Eur Arch Otorh in olar yn gol 2005; 262(1); 41–44 [12] Terris DJ, An derson SK, Watts TL, Ch in E. Lar yn geal n er ve m on itorin g an d m in im ally invasive thyroid surgery: com plem en tary tech n ologies. Arch Otolar yn gol Head Neck Surg 2007; 133(12); 1254–1257 [13] Sch n eider R, Przybyl J, Pliquett U, et al. A n ew vagal an ch or elect rode for realtim e m on itorin g of th e recurren t laryn geal n er ve. Am J Surg 2010; 199(4); 507–514 [14] Ph elan E, Schn eider R, Loren z K, et al. Con tin uous vagal IONM preven ts recurren t lar yn geal n er ve paralysis by revealin g in itial EMG ch anges of im pen din g n europraxic injur y: a prospect ive, m ulticen ter study. Lar yn goscope Jun e2014; 124(6); 1498–1505 [15] Poten za AS, Ph elan EA, Cern ea CR, et al. Norm ative in tra-operative elect rophysiologic w aveform an alysis of superior lar yn geal n erve extern al bran ch an d recurren t lar yn geal n er ve in patien ts un dergoin g thyroid surgery. World J Surg 2013; 37(10); 2336–2342 [16] Barczyń ski M, Kon turek A, Stopa M, Hon ow ska A, Now ak W . Ran dom ized con trolled trial of visualization versus n eurom on itorin g of th e extern al bran ch of th e superior lar yn geal n er ve durin g thyroidectom y. World J Surg 2012; 36(6); 1340–1347 [17] Darr EA, Tufano RP, Ozdem ir S, Kam an i D, Hurw itz S, Ran dolph G. Superior lar yn geal n erve quan titative in traoperative m on itorin g is possible in all thyroid surgeries. Lar yn goscope April2014; 124(4); 1035–1041 [18] Miccoli P, Min uto MN, Galleri D, Puccin i M, Bert i P. Extent of surgery in thyroglossal duct carcin om a: reflect ion s on a series of eigh teen cases. Thyroid 2004; 14(2); 121–123 [19] Miccoli P, Elisei R, Materazzi G, et al. Min im ally invasive video-assisted thyroidectom y for papillary carcinom a: a prospective study of its com pleten ess. Surgery 2002; 132(6); 1070–1073, discussion 1073–1074 [20] Gagn er M. En doscopic subtotal parathyroidectom y in patien ts w ith prim ar y hyperparathyroidism . Br J Surg 1996; 83(6); 875 [21] Palazzo FF, Sebag F, Hen r y JF. En docrin e surgical tech n ique: en doscopic thyroidectom y via th e lateral approach . Surg En dosc 2006; 20(2); 339–342 [22] Miccoli P, Elisei R, Bert i P, et al. Video assisted prophylactic thyroidectom y an d cen tral com part m en t n odes clearan ce in tw o RET gene m utation adult carriers. J En docrin ol Invest 2004; 27(6); 557–561 [23] Miccoli P, Bert i P, Materazzi G, Am brosin i CE, Fregoli L, Don atin i G. En doscopic bilateral n eck exploration versus quick in traoperative parath orm on e assay (qPTHa) durin g en doscopic parathyroidectom y: A prospect ive ran dom ized trial. Surg En dosc 2008; 22(2); 398–400 [24] Bellan ton e R, Lom bardi CP, Ra aelli M, Bosch erin i M, Alesin a PF, Prin ci P. Cen tral n eck lym ph n ode rem oval durin g m in im ally invasive video-assisted thyroidectom y for thyroid carcin om a: a feasible an d safe procedure. J Laparoen dosc Adv Surg Tech A 2002; 12(3); 181–185 [25] Lom bardi CP, Ra aelli M, Prin ci P, De Crea C, Bellan ton e R. Min im ally invasive video-assisted fun ct ion al lateral n eck dissection for m etastatic papillar y thyroid carcin om a. Am J Surg 2007; 193(1); 114–118 [26] Lai SY, Walvekar RR, Ferris RL. Min im ally invasive video-assisted thyroidectom y: expan ded in dication s an d on cologic com pleten ess. Head Neck 2008; 30(11); 1403–1407 [27] Duke WS, Terris DJ. Altern ative approach es to th e thyroid glan d. En docrin ol Metab Clin North Am 2014; 43(2); 459–474 [28] Ch an taw ibul S, Lokech areon larp S, Pokaw atan a C. Total video en doscopic thyroidectom y by an axillar y approach . J Laparoen dosc Adv Surg Tech A 2003; 13(5); 295–299 [29] Akasu H, Sh im izu K, Kitagaw a W , Ish ii R, Tan aka S. Evaluation of an altern ative, subclavicular approach to thyroidectom y. Med Sci Mon it 2002; 8(11); CS80–CS82 [30] Oh gam i M, Ish ii S, Arisaw a Y, et al. Scarless en doscopic thyroidectom y: breast approach for better cosm esis. Surg Laparosc En dosc Percutan Tech 2000; 10 (1); 1–4 [31] Ikeda Y, Takam i H, Niim i M, Kan S, Sasaki Y, Takayam a J. En doscopic thyroidectom y by th e axillar y approach . Surg En dosc 2001; 15(11); 1362–1364 [32] Kan g SW, Jeon g JJ, Nam KH, et al. Robot-assisted en doscopic thyroidectom y for thyroid m align an cies usin g a gasless tran saxillary approach . J Am Coll Surg 2009; 209(2); e1–e7 [33] Duke WS, Ch aung K, Terris DJ. Con tem porary surgical tech n iques. Otolaryn gol Clin North Am 2014; 47(4); 529–544

The History and Evolution of Techniques for Thyroid Surgery [34] Terris DJ, Sin ger MC, Seybt MW . Robotic facelift thyroidectom y: II. Clin ical feasibility an d safety. Lar yn goscope 2011; 121(8); 1636–1641 [35] Duick DS, Klopper JP, Diggan s JC, et al. Th e im pact of ben ign gene expression classifier test results on th e en docrin ologist-patien t decision to operate on patien ts w ith thyroid n odules w ith in determ in ate fin e-n eedle aspiration cytopath ology. Thyroid 2012; 22(10); 996–1001

[36] Ito Y, Miyauchi A, In oue H, et al. An observation al tr ial for papillar y thyroid m icrocarcin om a in Japan ese patien ts. World J Surg 2010; 34(1); 28–35 [37] Clarebrough J. Histor y of early cardiac surgery in Australia Heart Lun g Circ Oct2003; 12(Suppl 1); S15–S20

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Anatom y, Physiology, and Pathology of the Thyroid Com part m ent

2 Developm ent al and Surgical Anat om y of t he Thyroid Com part m ent Alice L. Tang and David L. Steward

2.1 Int roduct ion Cen tral n eck surgery can be com plicated by congen ital an om alies, n eoplastic con dition s, an d ectopia. A fun dam en tal un derstan din g of th e em br yological developm en t of struct ures w ith in th e thyroid com partm en t is param oun t for perform in g safe cent ral n eck surgery, an d surgeon s w h o operate in th is region sh ould be facile in exercisin g applied em br yology to th e ben efit of th eir patien ts.

2.2 Em bryology of t he Thyroid Gland Th e thyroid glan d, w h ich is th e first en docrin e organ in th e body to form , begin s its developm en t durin g th e th ird w eek of gestation . It results from th e fusion of t w o struct ures: th e m edial an d lateral thyroid an lages. Th e m edial thyroid an lage is

derived from th e prim itive ph ar yn x. Th e lateral thyroid an lages arise from n eural crest cells th at form em br yon ic tran sien t struct ures called th e ultim obran chial bodies. Parafollicular cells (C cells) also origin ate from th e paired ultim obran chial bodies.1,2,3,4 Th e m edial thyroid an lage begin s its form ation from a diverticulum (eith er sin gle or paired), w h ich form s im m ediately caudal to th e prim ordium of th e tongue (t uberculum im par). Developm en t of th is struct ure occurs betw een th e second an d th ird ph ar yn geal arch at th e foram en cecum an d origin ates from an invagin at ion of epith elial cells from th e floor of th e prim itive ph ar yn x ( Fig. 2.1). After th is in itial invagin ation , th e m edial thyroid an lage takes form an d begin s its descen t by pen etratin g th e un derlying m esoderm durin g th e fifth to seven th w eek of gestation . At about th e sam e tim e of descen t, th e hyoid bon e, derived from th e first ph ar yn geal pouch , begin s to take form from th e con den sat ion an d ch on drification of th e m esoderm . Of part icular im portan ce is th e route of th e m edial Fig. 2.1 Em bryological origin of the thyroid gland, showing the thyroid diverticulum forming caudal to the tuberculum im par.

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Developm ental and Surgical Anatom y of t he Thyroid Com part m ent

Fig. 2.2 Route of norm al thyroid m igration from its em bryological origin at the foram en cecum to its final position in the anterior neck.

thyroid an lage m igration an d its relat ion sh ip to surroun din g struct ures ( Fig. 2.2). Th e m edial thyroid an lage begin s posteriorly an d m ost com m on ly con tin ues an terior to th e hyoid an d prim ordial ph ar yngeal gut. Durin g th e m igration , th e m edial thyroid an lage rem ain s attach ed to th e base of th e tongue by a con tin uous lum en , th e thyroglossal duct .5 As th e em br yo en lon gates an d un dergoes di eren tiat ion , th is origin al diver ticulum breaks in t w o, an d th e proxim al part retract s an d disappears. By th e seven th w eek of gestation , th e prim itive thyroid glan d reach es its fin al dest in ation an terior to th e t rach ea betw een th e secon d an d fift h trach eal rin g. Th e thyroglossal duct loses its lum en by th e eigh th w eek as th e thyroid reach es its n orm al position .2,3,6 Alth ough th e m edial thyroid an lage cont ributes to th e bulk of th e thyroid glan d, th e paired lateral thyroid an lages (form ed from th e ultim obran chial bodies) con tribute a sm all but im portan t portion of th e fin al thyroid glan d. Durin g th e fifth w eek of developm en t , at th e level betw een th e fourth an d fifth ph aryn geal pouch es, cells detach from th e ph ar yngeal w all an d fuse w ith th e posterior aspect of th e m ain body of th e thyroid as it descen ds in to th e n eck. Th ese cells origin ate from n eural crest cells an d di eren t iate in to th e parafollicular cells (C cells), w hich secrete calciton in .2 Ult im ately, th e fusion betw een th e m edial thyroid an lage an d th e paired lateral thyroid an lages produces th icken in gs of th e glan d kn ow n as th e t ubercles of Zuckerkan dl. Th e tu bercles of Zuckerkan dl serve as con sisten t lan dm arks for th e recurren t lar yn geal n er ve (RLN), w h ich m ostly run s m edial an d deep to th e t ubercles on both sides.7 Thyroid follicles begin to form at 8 w eeks of gestation from epith elial plates. After in itial form ation , grow th con tin ues by buddin g or division of prim ar y follicles. By th e four th m on th ,

follicles can be seen at various stages of developm en t, an d durin g th is tim e th ey experien ce th e greatest grow th in n um ber. Colloid is visible durin g th e 12th w eek of gestation . Iodide is in corporated in to th e follicles to m ark th e begin n in g of thyroid h orm on e syn th esis, w h ich is th en secreted in to th e fetal circulatory system .3,6 Th e n orm al adult thyroid glan d w eigh s approxim ately 10 to 20 g an d is t ypically located an terior to th e trach ea, m idw ay betw een th e thyroid cartilage an d th e suprastern al n otch . A fibrous capsule developed from th e deep cervical fascia envelopes th e glan d by dividing in to an an terior an d a posterior sh eath . Th e thyroid glan d is furth er covered an teriorly by superficial cervical fascia, strap m uscles, an d th e platysm a. Laterally, th e deep cer vical fascia is loosely adh eren t to th e glan d. On th e posterior por tion of th e glan d, th e deep cervical fascia conden ses to form a th ick suspen sor y ligam en t (ligam en t of Berr y), w h ich causes th e thyroid to be stron gly fixed to th e trach ea an d lar yn x. In e ect , th is suspen sor y ligam en t facilitates th e m ovem en t an d elevation of th e glan d as seen durin g sw allow in g. Th e fin al thyroid glan d con sists of t w o lobes, w h ich lie on both sides of th e t rach ea, w ith a cent ral m idlin e isth m us conn ectin g th e lobes. Th e lobes are t ypically 4 cm from superior to in ferior, 2 cm in w idth , an d 2 to 4 cm in th ickn ess. Th e isth m us usually m easures 1.25 cm . Thyroid disease w ill often sign ifican tly ch ange th ese dim en sion s. A pyram idal lobe is presen t in about 50% of people an d is usually con n ected to th e isth m us or on e of th e lobes.4,8

2.3 Congenit al Thyroid Anom alies Ectopic thyroid tissue is fun ct ion in g thyroid t issue th at exists at any poin t alon g th e path of m igration oth er th an th e t ypical location an terior to th e trach ea. Th e m ajorit y of aberran t thyroid t issue resides in th e m idlin e of th e n eck alon g th e thyroglossal tract. Lateral n eck ectopia is rare an d is th ough t to be derived from abn orm al lateral thyroid an lage m igration . Ectopic thyroid tissue is reported to occur in 1 of 100,000 to 300,000 people w ith out thyroid disease, an d in approxim ately 1 of 4,000 to 8,000 patien ts w ith thyroid disease. Fem ales h ave a h igh er predilection for thyroid ectopia th an m ales.9,10

2.3.1 Lingual Thyroid Th e lingual thyroid is relatively rare an d, because th e m ajorit y of cases are asym ptom atic, th e true in ciden ce is n ot kn ow n . Alth ough rare, th is en tit y accoun ts for 90% of all ectopic thyroid tissue.9 Lin gual thyroid results w h en th e m edial thyroid an lage fails to m igrate in feriorly in to th e n eck. In 70% of cases, a lin gual thyroid is associated w ith th e absen ce of th e n orm al cervical thyroid. If both location s h ave thyroid tissue presen t, usually th e lingual thyroid is th e on ly fun ct ion al tissue. Most patien ts presen t w ith an asym ptom atic m ass at th e back of th e tongue, an d th e diagn osis is confirm ed w ith a radioisotope scan sh ow in g in creased uptake in th e foram en cecum .4,8,9,10 Th e lin gual thyroid is usually associated w ith hypothyroidism given th at fun ction al ectopic thyroid tissue is usually un able to m eet th e physiological dem an ds of th e body. As a result, th e lin gual thyroid can hypertroph y from thyroid-stim ulat in g h orm on e stim ulation an d becom e sym ptom atic, provokin g dysph agia, dysphon ia, dyspn ea, or a sen sation of ch okin g.5 Adults can

9

Anatom y, Physiology, and Pathology of the Thyroid Com part m ent experien ce sleep apn ea an d respirator y di cult y, an d in ch ildren th e presence of a large base of tongue lin gual thyroid can cause upper airw ay obstruct ion requirin g surgical rem oval. In gen eral, th ough , asym ptom at ic lin gual thyroid tissue can be left alon e w ith out th e n eed for surgical in terven t ion . Th e lin gual thyroid h as a low in ciden ce of m align an t conversion , w ith pap illar y thyroid carcin om a bein g th e m ost com m on to develop.11

2.3.2 Thyroglossal Duct Rem nant Th e t hyroglossal d u ct u su ally oblit erates by t h e eigh t h w eek of d evelop m en t , bu t rem n an t s of t h is at t en u ated lu m en can p ersist in to ad u lth ood .12 Th ese rem n an t s can p resen t as a cyst or a sin u s tract th at can d evelop anyw h ere alon g th e cou rse of th e d escen t of th e thyroid an lage. An om alies of th e t hyroglossal d u ct are t h e m ost com m on congen it al n eck m asses in ch ild ren . Th e m ost com m on presen tin g sym ptom is a n on ten der palpable n eck m ass.13 Th e lesion s usually appear in th e m idlin e or just o th e m idlin e betw een th e hyoid bon e an d th e isth m us of th e thyroid an d m easure approxim ately 2.5 to 3 cm .12 A thyroglossal duct cyst m ay n ot be apparen t un til it becom es in fected or spon tan eously ruptures, usually after an upper respirator y tract in fect ion . Th ere does n ot appear to be a gen der predilection , an d m ost patien ts w ill presen t before age 20.12 Because th e thyroglossal duct cyst is usually firm ly fixed to the hyoid bon e an d tongue m usculature, sw allow in g w ill classically raise th e n eck m ass in a predictable fash ion . Historically, thyroglossal duct cysts w ere treated w ith in cision an d drain age. Recurren ce rates w ith th is m eth od of treatm en t w ere > 50%.13 Curren tly, th e stan dard treatm en t for a thyroglossal duct cyst is th e Sistrun k procedure, in w h ich th e cyst is m eticulously dissected out alon g w ith th e cen tral portion of th e hyoid bon e, w h ere th e cyst is an ch ored, an d a cu of tissue at th e base of th e tongue. Th is exten sive dissection reduces th e recurren ce rate to aroun d 5%.13 Postoperat ive in fection s are associated w ith h igh er recurren ce rates.13 Thyroid carcin om a can develop w ith in a cyst, especially if th e in dividual h as received low -dose irradiation to th e h ead an d n eck region in th e past. Th us all specim en s sh ould un dergo h istological exam in ation .

vessels on th e con tralateral side th rough th e isth m us an d w ith th e in ferior thyroid artery (ITA). Th e ITA h as a variable distribution an d is absen t on on e side (usually th e left) in approxim ately 0.2 to 6% of cases.16 After bran ch ing from th e thyrocervical t run k o th e subclavian artery, it ascen ds posterior to th e carotid sh eath an d h as a variable relation sh ip w ith th e sym path etic ch ain . Prior to en terin g th e glan d, th e ITA divides in to an upper an d a low er bran ch.15,17 Th e upper bran ch goes to th e posterior aspect of th e glan d, an d th e low er bran ch to th e low er pole of th e glan d. Th ere can be an astom oses w ith th e STA as w ell as w ith th e con tralateral ITA across th e m idlin e. An aberran t ITA (thyroid im a artery) is an in con sisten t vessel arisin g from th e aortic arch or th e brach ioceph alic, righ t com m on carotid, or in tern al th oracic artery.4 Wh en presen t, it usually arises on th e righ t side, ascen ding in fron t of th e trach ea. Th e thyroid glan d is drain ed by large vein s th at exhibit exten sive cross fillin g from both sides of th e thyroid th rough a valveless ven ous plexus ( Fig. 2.3).18 On each side of th e glan d, th ree vein s arise: th e superior, m iddle, an d in ferior thyroid vein s. Con tralateral thyroid vein s join th rough th e con n ective tissue of th e lobules of th e glan d and an astom ose beh in d th e capsule. Th e superior thyroid vein , w hich drain s th e upper t w o-th irds of th e ipsilateral thyroid lobe, accom panies its correspon din g artery an d em erges from th e upper pole of th e thyroid. It prim arily em pt ies in to th e in tern al jugular; h ow ever, in som e cases th e superior thyroid

2.4 Vascular Supply of t he Thyroid 2.4.1 Thyroid Gland Vasculat ure Th e thyroid is an extrem ely vascular glan d. Its m ain arterial blood supply com es from th e paired superior an d in ferior thyroid arteries. Th e origin of th e superior thyroid artery (STA) is variable but m ost com m on ly w ill arise from th e extern al carotid artery.4,14 It can also arise from th e bifurcation of th e com m on carotid artery an d in tern al carotid artery, alth ough th is is seen less frequen tly.14 Th e STA travels alon g th e extern al surface of th e in ferior con strictor m uscle an d en ters in to th e thyroid glan d posterom edially near th e upper pole of th e lobe.4,15 Th e artery m ay bran ch prior to en terin g th e thyroid glan d. Gupta et al proposed a sim ple classification of STA bran ch ing pattern s: t ype I (t w o m ajor bran ch es), t ype II (trifurcat ion of th e artery), an d t ype III (n o bran ch ing follow in g its origin from th e com m on carotid).14 If th e STA trifurcates, th ese bran ch es m ay join w ith

10

Fig. 2.3 Venous drainage of the thyroid gland. In addition to the superior, m iddle, and inferior thyroid veins, there is an extensive network of valveless veins within the gland that connect the t wo lobes.

Developm ental and Surgical Anatom y of t he Thyroid Com part m ent vein w ill term in ate in to th e lin guofacial t run k an d com m on facial vein .19 Th e m iddle thyroid vein is present in approxim ately 38% of dissected lobes an d in 62% of pat ien ts.20 In th eir prospective study of 394 consecut ively dissected thyroid lobes Dion igi et al foun d th at th e m iddle thyroid vein is m ore likely to be presen t in patien ts w ith hyperthyroidism an d large goiters.20 Th e auth ors advise th at positive iden tification of th e m iddle thyroid vein s in th ese particular situation s can preven t in adver ten t injur y an d excessive bleedin g. Like th e superior thyroid vein , th e m iddle thyroid vein t ypically drain s th e superior t w o-th irds of th e thyroid in to th e in tern al jugular vein (a few cen tim eters below th e superior thyroid vein ) after crossing th e com m on carotid artery an teriorly.18 Th e m iddle thyroid vein is m ore com m on ly foun d on th e righ t side.20 Th e paired in ferior thyroid vein s em erge from th e low er portion of th e glan d an d h ave abun dan t cross fillin g w ith th e con tralateral vein . Krausen w rote th at th ese vein s are th e “ultim ate guardian s of th e trach ea” because th is plexus of vein s in th e pretrach eal fat is frequen tly th e source of bleedin g durin g an d after an terior n eck surgeries.21 Th ere can be a variable n um ber of bran ch es (at least on e an d up to five) from th e in ferior thyroid vein , an d th ese bran ch es can term in ate in to th e left brach ioceph alic vein , th e righ t brach ioceph alic vein , or both vessels.19,21 Th ese vein s can form a con fluen ce to drain in to th e thyroid im a vein th at ultim ately w ill flow in to th e in n om in ate vein .21

2.4.2 Lym phat ics Th e e eren t lym ph atic vessels of th e thyroid travel alon g w ith th e ven ous drain age of th e glan d. Th ere are specific drain age pattern s for th e superior, lateral, an d in ferior portion s of th e glan d. Th e lym ph atics from th e superior portion of th e glan d an d th e isth m us drain in to th e Delph ian , or prelar yngeal, lym ph n odes an d th e jugular lym ph n odes. Th e lym ph atics from th e lateral port ion of th e glan d drain alon g w ith th e m iddle thyroid vein th rough lym ph n ode levels II th rough IV. Th e lym ph atics drain in g th e in ferior portion of th e glan d follow th e in ferior thyroid vein s an d drain to pretrach eal, paratrach eal (level VI), an d low er jugular (level IV) region s as w ell as th e level VII n odes in th e an terior m ediastin um ( Fig. 2.4). Th e thyroid glan d also h as an in traglan dular lym ph atic n etw ork th at con n ects th e t w o lobes of th e glan d. Th is subcapsular n et w ork facilitates th e spread of tum or w ith in th e glan d.

2.5 The Recurrent and Superior Laryngeal Nerves 2.5.1 Recurrent Laryngeal Nerve Iden tification of th e recurren t an d superior lar yngeal n er ves is a cardin al prin ciple durin g cen tral n eck surgery. A com plete un derstan din g of th ese n er ves an d th eir relation sh ip to n earby struct ures is n ecessar y to avoid in adverten t injur y th at can h ave tem porary or perm an en t con sequen ces, in cluding dysph on ia, dysphagia, an d dyspnea. Origin at in g from th e m edulla oblon gata, th e vagus n er ve begin s its course by exitin g th e skull th rough th e jugular

Fig. 2.4 Lym phatic net work of the thyroid gland. Lym phatic drainage parallels the venous drainage of the gland.

foram en . As th e vagus n er ve traverses th e n eck, th e superior lar yngeal n er ve (SLN) an d th e RLN bran ch o to in n er vate th e lar yn x. Th e course of th e RLN is determ in ed by th e descen t of th e h eart an d great vessels durin g em br yological developm en t . On th e righ t side, th e recurren ce of th e n er ve loops aroun d th e fourth arch (righ t subclavian arter y) th en ascen ds th e n eck to in n er vate th e lar yn x.4 In rare cases, if th e righ t fourth arch is absorbed, th e righ t RLN does n ot get pulled dow n in to th e ch est an d th us passes directly in to th e lar yn x (n on recurren t lar yngeal n er ve).22 In n orm al developm en t, th e righ t RLN exits th e vagus at or just superior to th e level of th e subclavian artery.23 After its recurren ce aroun d th e subclavian artery, th e righ t RLN travels cran ially tow ard th e t rach eoesoph ageal groove but gen erally does n ot reside in th e groove un til its m ost distal segm en t.22,23 Th e left RLN bran ch es from th e vagus as it en ters th e th orax. It th en recurs aroun d th e sixth aort ic arch (ligam en tum arteriosum ) an d travels superiorly tow ard th e t rach eoesoph ageal groove. It travels eith er on th e trach ea, in th e trach eoesoph ageal groove, or in th e adjacen t fat an d conn ect ive tissue.4,23 Th e RLN en ters th e lar yn x posterior to th e cricothyroid join t an d provides m otor, sen sor y, an d parasym path etic in n er vation . Motor in n er vation is provided by th e an terior bran ch of th e RLN, w h ich in n er vates th e thyroar yten oid, lateral cricoar yten oid, posterior cricoar yten oid, an d tran sverse ar yten oid m uscles. Th e on ly lar yngeal m uscle n ot in n ervated by th e RLN is th e cricothyroid m uscle. Sen sor y in n ervation is provided by th e posterior bran ch of th e RLN, w h ich supplies sen sation to th e vocal cords an d to th e subglottic region .22,24 Bran ch ing

11

Anatom y, Physiology, and Pathology of the Thyroid Com part m ent pattern s prior to en terin g th e lar yn x can var y.22 Ardito et al foun d th at 27.6% rem ain un bran ch ed alon g th e RLN en tire course, w h ereas 70.6% bifurcated an d a sm aller proportion of n er ves trifurcated durin g its ascen t.24 Kan dil et al prospect ively evaluated 137 RLNs in traoperatively an d foun d th at, overall, on ly 34% h ad extralar yn geal bifurcation w ith m otor fibers exclusively located in th e an terior branch an d sen sor y fibers in th e posterior bran ch .25 Th e RLN exhibits variabilit y in its course, an d m ost an atom ists describe th ese variation s relative to th ree key lan dm arks: th e ITA, th e trach eoesoph ageal groove, an d Berr y’s ligam en t. The relation sh ip of th e RLN to th e ITA is often used w h en tr yin g to iden tify th e n erve, despite th e great variabilit y in th is relation sh ip. Th e artery t ypically arises lateral to th e n er ve an d th en courses m edial to th e glan d. In early studies, Hollin sh ead dem on strated th at, on th e righ t side, th e RLN passed betw een th e m ain or m in or bran ch es of th e ITA 50% of th e t im e an d posterior to th e artery approxim ately 25% of th e tim e.26 On th e left side, th e RLN passed posterior to th e ITA 50% of th e t im e an d passed an terior to th e artery in 10 to 12%of cases.26 Subsequen t studies h ave reported m ore variabilit y betw een th ese t w o im portan t struct ures. A study of 21 cadavers by Mon fared et al foun d th at, on th e righ t side, th e RLN w as seen to pass betw een ITA bran ch es in 50% of cadavers, deep to th e ITA in 28% of cases, an d an terior to th e ITA in 21% of cases.23 On th e left side, it w as seen to pass deep to th e ITA in 50% of cadavers, in betw een ITA bran ch es in 28% of cases, an d an terior to th e ITA in 21% of cases.23 In an updated in traoperative series by Ardito et al, th e auth ors observed th at, in 61%, th e righ t RLN w as deep to th e ITA, 12% traveled in fron t of th e ITA, an d 27% w en t betw een bran ch es of th e ITA.24 On th e left side, 77.4% w ere deep, 20.5% w ere betw een th e bran ch es, an d 1.9% passed in fron t of th e ITA.24 It is clear from th ese studies th at th e relat ion sh ip betw een th e RLN an d ITA is h igh ly in con sisten t, an d surgeon s sh ould be aw are th at, alth ough th e ITA can be used as a lan dm ark, its relation sh ip w ith th e RLN is quite variable. Th e RLN’s course in relation to th e trach eoesoph ageal groove is m ore variable on th e righ t side th an on th e left.24 Th e RLN also h as a relat ion sh ip w ith Berr y’s ligam en t an d passes th rough it in 25% of cases an d deep to it 75% of cases.27 Despite th ese variation s, th e m ost con sisten t location of th e RLN is n ear its in sertion . Th e studies of Sh in do et al exam in ed h ow best to locate th e RLN surgically.28 Th eir approach w as to locate th e RLN distally as it approach ed th e cricothyroid join t, iden tifyin g th e n er ve just below Berr y’s ligam en t . Th e study sh ow ed th at, durin g th e in itial search for th e distal segm en t of th e RLN, th e dissection of th e righ t RLN can be directed tow ard a trian gle located 15 to 45° from th e t racheoesoph ageal groove w h ere th e n er ve can be expected to be foun d 78% of th e tim e.28 On th e left side, th e n er ve w as foun d in th e area of a 0 to 30° an gle to th e trach eoesoph ageal groove in 77%of cases.28 A n on recurren t lar yngeal n er ve can result secondar y to a vascular an om aly as m en tion ed previously. Durin g em br yological developm en t, th ere are m ultiple vascular con sequen ces th at result if a segm en t of th e fourth aortic arch disappears: a leftsided aort ic arch w ith a righ t subclavian artery, th e absen ce of th e in n om in ate artery, an d a retroesoph ageal subclavian artery.6,29 As a result, th e arterial segm en t aroun d w h ich th e righ t RLN recurs is absen t, leadin g to bran ch ing of th e n er ve

12

from th e vagus in th e cervical region var yin g from th e level of th e superior lobe to th e thyroid cart ilage.4,6 Th is is a rare variation , occurrin g in approxim ately 0.63% of patien ts on th e righ t an d 0.04% of pat ien ts on th e left .29 Diagn osis is m ade preoperatively, eith er in ciden tally on ch est X-ray, ultrasoun d, CT scan , or barium sw allow, or by suspicion , w ith a clin ical h istory of im pairm en t w ith sw allow in g (called dysph agia lusoria).

2.5.2 Superior Laryngeal Nerve After th e vagus n erve exits th e jugular foram en , on e of its first bran ch es is th e SLN. Th e SLN origin ates from th e n odose gan glion an d travels in feriorly posterior to th e in tern al carotid artery. About 1.5 cm caudal to th e bifurcation of th e com m on carotid artery, th e SLN divides in to an in tern al bran ch (IBSLN) an d an extern al bran ch (EBSLN).30 Th e IBSLN en ters th e lar yn x by passing th rough th e thyrohyoid m em bran e an d provides sen sation to th e port ion of th e lar ynx above th e vocal folds. Th e EBSLN provides m otor in n er vation to th e cricothyroid m uscle. Th e cricothyroid m uscle produces a rockin g m otion at th e cricothyroid join t, in creasin g th e tension in th e vocal ligam en ts an d raisin g th e vocal pitch . Dam age to th e EBSLN causes a subtle ch ange in vocal pitch an d a decreased vocal ran ge.31 Th e course of th e EBSLN is h igh ly variable, both in its relation to th e STA an d th e in ferior con strictor m uscle. Multiple classification system s h ave been publish ed regarding th is relat ion sh ip, in cluding th e Cern ea classification , th e Kiern er classification , and th e Friedm an classification .32,33,34 Stu dies by Cern ea et al describe th e classification sch em e as follow s: t ype 1, th e EBSLN crosses th e STA > 1 cm cran ial to th e upper pole of th e thyroid, t ype 2A crosses th e STA < 1 cm cran ial to th e upper edge of th e thyroid glan d, an d t ype 2B crosses th e superior thyroid pedicle below th e edge of th e upper border of th e superior pole.32 Follow in g th e publication of th e Cern ea classification , Kiern er et al added a fourth t ype, w h ich describes th e EBSLN as run n ing dorsally to th e superior thyroid pole ( Fig. 2.5).34,35 Th e studies of Friedm an et al describe th e variable course of th e EBSLN in relation to th e in ferior con strictor m uscle an d th e classifcation is based on th e term in al aspect of th e EBSLN.33 In th ese studies, th e EBSLN is classified in to th ree t ypes. Type 1 run s its en tire course superficial or lateral to th e in ferior con strictor, descen din g w ith th e STA un t il it term in ates in to th e cricothyroid m uscle. Type 2 pen etrates th e in ferior con strictor in th e low er portion of th e m uscle ~ 1 cm proxim al to th e in ferior con strictor–cricothyroid jun ct ion . Type 3 travels its en t ire course un der th e in ferior con strictor to th e cricothyroid m uscle after diving un dern eath its m ost superior fibers of th e con strictor ( Fig. 2.6).33 Positive iden tification of th e EBSLN durin g thyroid surgery can avoid un in ten tion al injur y an d h as been sh ow n to reduce th e in ciden ce of perm an en t voice ch anges.31 Iden t ification of th e SLN can be ach ieved by approach ing th e lar yn x w ith in “Joll’s space”—th e stern othyroid-lar yn geal triangle.30 To ach ieve visualization of th is space, th e superior thyroid pole is retracted in feriorly an d laterally. Th e space is th en defin ed by th e cricothyroid m uscle m edially, th e retracted superior pole laterally, an d th e stern othyroid m uscle an teriorly. With delicate dissection in to th is space, th e EBSLN can be exposed, visualized, an d preserved.31 Th e n er ve is usually seen run n in g alon g th e in ferior con strictor m uscles or piercin g th e cricothyroid m uscle.

Developm ental and Surgical Anatom y of t he Thyroid Com part m ent

Fig. 2.5 Kierner classification of the possible courses of the external branch of the superior laryngeal nerve (EBSLN).

Fig. 2.6 (a) Type 1 variant of the course of the external branch of the superior laryngeal nerve (EBSLN). EBSLN courses superficial to the inferior constrictor m uscle. (b) Type 2 variant: EBSLN courses underneath the inferior constrictor m uscle for part of its course. (c) Type 3 variant: EBSLN courses entirely deep to the inferior constrictor m uscle.

2.6 The Parat hyroid Glands 2.6.1 Em bryology of t he Parat hyroid Glands Begin n in g in th e fifth w eek of em br yological developm en t, th e parathyroid glan ds start to form from th e en doderm of th e th ird an d fourth ph ar yn geal pouch es. Th e superior parathyroid glan ds are derived from th e fourth ph ar yn geal pouch , m igratin g a sh or t distan ce m edially an d in feriorly to ultim ately reside n ear th e dorsal aspect of th e superior thyroid lobe on each side.

Th e in ferior parathyroid glan ds sh are an em br yological origin w ith th e thym us glan d. From th e th ird ph ar yn geal pouch, th e ven tral aspect of th e pouch w ill form th e thym us glan d, w h ereas th e dorsal aspect of th e pouch form s th e in ferior parathyroid glan ds. Togeth er, th e prim ordial thym us an d in ferior parathyroid glan ds, kn ow n as th e thym ic parathyroid, m igrate m edially an d in feriorly a lon ger distan ce tow ard th e superior m ediastin um . Th e t w o struct ures even tually separate as th e thym us en ters th e an terior m ediastin um .15 Th e in ferior parathyroid glan ds settle at th e level of th e in ferior thyroid lobe on each side at th e posterior an d lateral aspect of th e thyroid glan d.

13

Anatom y, Physiology, and Pathology of the Thyroid Com part m ent

Fig. 2.7 The m ost com mon location of the superior parathyroid (a) and the inferior parathyroid glands (b). Shaded areas detail the m ost com m on distribution sites of the glands.

2.6.2 Locat ion of Parat hyroid Glands and Anom alous Developm ent Superior parathyroid glan ds are m ore con sisten t in th eir location given th eir sh orter m igration pat tern . In a dissection of 160 cadavers, Wan g evaluated th e location s of n orm al parathyroid glan ds. Th e m ost com m on location is at th e cricothyroid jun ction posteriorly (77%).15,36 In th is location , th e superior parathyroid glan ds ten d to be in a 2 cm diam eter area centered 1 cm above th e in tersection of the RLN an d ITA.15 Th e superior glan d m igration pattern s exten d to retroph ar yn geal, retrolar yn geal, retroesoph ageal, an d posterior m ediastin um location s. Parathyroid glan ds m ay be ectopically located w ith in th e thyroid glan d itself. An in trathyroid ectopic location is defin ed as a parathyroid glan d surroun ded on all sides by thyroid tissue. Th is in trathyroid localization occurs m ost likely due to superior parathyroid fusion w ith th e ultim obran chial bodies durin g em br yological developm en t.6 Because of th e distan ce th e in ferior parathyroid glan ds m ust m igrate, th ere is greater variabilit y in th eir location an d a h igh er degree of ectopia th an w ith th e superior glan ds. Approxim ately 61% of th e in ferior parathyroid glan ds are foun d in ferior, lateral, or p osterior to t h e low er p ole of t h e t hyroid glan d .37 In t h e Wan g series, th e m ost com m on locat ion w as fou n d t o be an t erior or p ost erolat eral t o t h e su rface of t h e low er p ole of t h e thyroid (42%).36 Becau se vessels are p rom in en t in th is region , in ferior p arathyroid glan d s ten d to be h id d en by th ese st r u ct u res. Th e in ferior p arat hyroid glan d s are also com m on ly fou n d in th e t hyrothym ic ligam en t or t h e cer vical p ort ion of t h e t hym u s. As p reviou sly stated , t h e in ferior glan d s m igrate w it h t h e t hym us. Th e d escen t of th e t hym u s exten d s from t h e an gle of th e m an d ible to th e p ericard iu m , an d ectop ic in ferior glan d s can lie anyw h ere alon g th at p ath of d escen t. If th e in ferior glan d s fail to sep arate from th e thym u s d u rin g t h eir d escen t or sep arat ion is d elayed , th e

14

in ferior glan d s m ay h ave ect op ic locat ion s w it h in th e su p erior m ed iastin u m ( Fig. 2.7).36 Certain m igration ch aracteristics are often obser ved th at can h elp to iden tify superior an d in ferior glan ds. Th e plan e of th e parathyroid glan d in relation to th e RLN is on e such ch aracteristic.38 Th e superior parathyroid glan ds are located dorsal to th e RLN, and th e in ferior parathyroid glan ds are ven tral to th e RLN. Supern um erar y parathyroid glan ds result secon dary to accessory parathyroid fragm en ts, w h ich occur w h en th e ph ar yn geal pouch es separate from th e ph aryn x. Th ey are m ost often foun d at th e level of th e low er poles of th e thyroid lobes or in th e thym us. Supern um erar y parathyroid glan ds m ay also be situated in th e m iddle m ediastin um at th e level of th e aortopulm on ary w in dow or lateral to th e jugulocarotid axis. Such location s are m ost likely secon dar y to fragm en tation of th e superior parathyroid rath er th an m igration of path ological parathyroid tissue. In travagal parathyroid tissue h as also been docum en ted w ith a frequency of ~ 6%.39

2.6.3 Parat hyroid Gland Anat om y Norm al parathyroid glan ds t ypically w eigh 55 to 60 m g an d are approxim ately 3 to 8 m m .4 Th e parathyroid glan d is often oval sh aped w ith a yellow -brow n color. Parathyroid vascular supply is prim arily from th e ITA. Alth ough th ere is a w ide variation in th e location of th e parathyroid glan ds, th ey are gen erally sym m etric, w ith 80% sym m etr y for th e superior parathyroid glan ds an d 70% for th e in ferior parathyroid glan ds.37

2.7 The Thym us Th e thym us is derived from th e ven tral w in g of th e th ird ph aryn geal pouch an d m igrates in to th e m ediastin um durin g developm en t . Due to th is m igration , accessory thym ic t issue can be foun d in th e n eck anyw h ere alon g its path of descen t ,

Developm ental and Surgical Anatom y of t he Thyroid Com part m ent from th e superior th oracic apert ure to th e thyroid cartilage or h igh er. Th e thym us con tin ues to grow th rough ch ildh ood un til pubert y. By adulth ood, th e glan d h as atroph ied con siderably an d can be di cult to locate an d iden tify.

References [1] De Felice M, Di Lauro R. Thyroid developm en t an d its disorders: genetics an d m olecular m ech anism s. En docr Rev 2004; 25(5); 722–746 [2] Lan gm an J, Sadler T. Lan gm an’s Medical Em br yology. Philadelph ia, PA: Lippin cott W illiam s & W ilkin s; 2000 [3] Organ GM, Organ CH, Jr. Thyroid glan d an d surgery of th e thyroglossal duct: exercise in applied em br yology. World J Surg 2000; 24(8); 886–890 [4] Moh ebati A, Sh ah a AR. An atom y of thyroid an d parathyroid glan ds an d n eurovascular relation s. Clin An at 2012; 25(1); 19–31 [5] Baugh m an RA. Lin gual thyroid an d lin gual thyroglossal tract rem n an ts. A clin ical an d h istopath ologic study w ith review of th e literature. Oral Surg Oral Med Oral Path ol 1972; 34(5); 781–799 [6] Ran dolph G. Surgery of th e Thyroid an d Parathyroid Glan ds. Ph iladelph ia, PA: Elsevier; 2013 [7] Gauger PG, Delbridge LW , Th om pson NW, Crum m er P, Reeve TS. In ciden ce an d im portan ce of th e tubercle of Zuckerkan dl in thyroid surgery. Eur J Surg 2001; 167(4); 249–254 [8] Han sen JT. Surgical an atom y an d em br yology of th e low er n eck an d superior m ediastin um . In : Falk SA, ed. Th yroid Disease - En docrin ology, Surgery, Nuclear Medicin e, an d Radioth erapy. Ph iladelph ia: Lippin cott-Raven ; 1997: 15-27 [9] Guerra G, Cin elli M, Mesolella M et al. Morph ological, diagn ostic an d surgical features of ectopic thyroid glan d: a review of literature. In t J Surg 2014; 12(1) Suppl 1; S3–S11 [10] Ibrah im NA, Fadeyibi IO. Ectopic thyroid: etiology, path ology an d m an agem en t. Horm on es (Ath ens) 2011; 10(4); 261–269 [11] Hari CK, Kum ar M, Abo-Kh atw a MM, Adam s-William s J, Zeitoun H. Follicular varian t of papillar y carcin om a arisin g from lin gual thyroid. Ear Nose Th roat J 2009; 88(6); E7 [12] Wam pler HW , Krolls SO, Joh n son RP. Th yroglossal-tract cyst. Oral Surg Oral Med Oral Path ol 1978; 45(1); 32–38 [13] Roh of D, Hon in gs J, Th eun isse HJ, et al. Recurren ces after thyroglossal duct cyst surgery: results in 207 con secutive cases an d review of th e literature. Head Neck 2014 [14] Gupta P, Bh alla AS, Th ulkar S, et al. Variation s in superior thyroid arter y: A selective an giograph ic study. In dian J Radiol Im aging 2014; 24(1); 66–71 [15] Fan cy T, Gallagh er D, III, Horn ig JD. Surgical an atom y of th e thyroid an d parathyroid glan ds. Otolaryn gol Clin North Am 2010; 43(2); 221–227, viivii. [16] Hun t PS, Poole M, Reeve TS. A reappraisal of th e surgical an atom y of th e thyroid an d parathyroid glan ds. Br J Surg 1968; 55(1); 63–66 [17] Rossi P, Trach t DG, Ruzicka FF. Th yroid an giography—tech n iques, an atom y an d in dication s. Br J Radiol 1971; 44(528); 911–926 [18] Doppm an JL, Melson GL, Even s RG, Ham m on d W G. Select ive superior an d in ferior thyroid vein cath eterization . Invest Radiol 1969; 4(2); 97–99 [19] Wafae N, Hirose K, Fran co C, et al. Th e an atom y of th e h um an thyroid vein s an d its surgical application . Folia Morph ol (Warsz) 2008; 67(4); 221–225

[20] Dion igi G, Con giu T, Rovera F, Bon i L. Th e m iddle thyroid vein : an atom ical an d surgical aspects. World J Surg 2010; 34(3); 514–520 [21] Krausen AS. Th e in ferior thyroid vein s—th e ultim ate guardian s of th e trach ea. Lar yn goscope 1976; 86(12); 1849–1855 [22] Stein berg JL, Kh an e GJ, Fern an des CM, Nel JP. An atom y of th e recurren t laryn geal n er ve: a redescription . J Lar yn gol Otol 1986; 100(8); 919–927 [23] Mon fared A, Gort i G, Kim D. Microsurgical an atom y of th e lar yn geal n er ves as related to thyroid surgery. Lar yn goscope 2002; 112(2); 386–392 [24] Ardito G, Revelli L, D’Alatri L, Ler ro V, Guidi ML, Ardito F. Revisited an atom y of th e recurren t lar yn geal n erves. Am J Surg 2004; 187(2); 249–253 [25] Kan dil E, Abdel Kh alek M, Aslam R, Friedlan der P, Bellow s CF, Slakey D. Recurren t laryn geal n er ve: sign ifican ce of th e an terior extralar yn geal bran ch . Surgery 2011; 149(6); 820–824 [26] Hollin sh ead W . An atom y for Surgeon s, Volum e 1: Head an d Neck. New York, NY: Harper & Row ; 1968 [27] Lore J. Surgery of th e thyroid glan d. In : Ten ta L, Keyes G, eds. Sym posium on surgery of th e thyroid an d parathyroid glan ds. Philadelph ia, PA: W B Saun ders; 1980:69–83 [28] Sh in do ML, Wu JC, Park EE. Surgical an atom y of th e recurren t lar yn geal n er ve revisited. Otolaryn gol Head Neck Surg 2005; 133(4); 514–519 [29] Hen ry JF, Audi ret J, Den izot A, Plan M. Th e n on recurren t in ferior lar yn geal n er ve: review of 33 cases, in cluding tw o on th e left side. Surgery 1988; 104 (6); 977–984 [30] Barczyń ski M, Ran dolph GW, Cern ea CR, et al. In tern ation al Neural Mon itorin g Study Group. Extern al bran ch of th e superior laryn geal n erve m on itorin g durin g thyroid an d parathyroid surgery: In tern ation al Neural Mon itorin g Study Group stan dards guidelin e statem en t. Lar yn goscope 2013; 123 Suppl 4; S1–S14 [31] Kark AE, Kissin MW , Auerbach R, Meikle M. Voice ch anges after thyroidectom y: role of th e extern al lar yn geal n erve. Br Med J (Clin Res Ed) 1984; 289 (6456); 1412–1415 [32] Cern ea CR, Ferraz AR, Furlan i J, et al. Iden tification of th e extern al bran ch of th e superior lar yn geal n er ve durin g thyroidectom y. Am J Surg 1992; 164(6); 634–639 [33] Friedm an M, LoSavio P, Ibrah im H. Superior lar yn geal n er ve iden tification an d preservation in thyroidectom y. Arch Otolaryn gol Head Neck Surg 2002; 128(3); 296–303 [34] Kiern er AC, Aign er M, Burian M. Th e extern al bran ch of th e superior lar yn geal n er ve: its topograph ical an atom y as related to surger y of th e n eck. Arch Otolar yn gol Head Neck Surg 1998; 124(3); 301–303 [35] Cern ea CR, Nish io S, Hojaij FC. Iden tification of th e extern al bran ch of th e superior lar yn geal n erve (EBSLN) in large goiters. Am J Otolaryn gol 1995; 16 (5); 307–311 [36] Wan g C. Th e an atom ic basis of parathyroid surgery. An n Surg 1976; 183(3); 271–275 [37] Akerström G, Malm aeus J, Bergström R. Surgical an atom y of h um an parathyroid glan ds. Surgery 1984; 95(1); 14–21 [38] Pyrtek L, Pain ter RL. An an atom ic study of th e relation sh ip of th e parathyroid glan ds to th e recurren t lar yn geal n er ve. Surg Gyn ecol Obstet 1964; 119; 509– 512 [39] Lack EE, Delay S, Lin n oila RI. Ectopic parathyroid tissue w ith in th e vagus n er ve. In ciden ce an d possible clin ical sign ifican ce. Arch Pathol Lab Med 1988; 112(3); 304–306

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Anatom y, Physiology, and Pathology of the Thyroid Com part m ent

3 Physiology of t he Thyroid Gland David S. Rosenthal and Kenneth H. Hupart

3.1 Int roduct ion Th e m ature thyroid glan d lies an teriorly, in feriorly, an d laterally to th e lar yn geal thyroid cart ilage in th e n eck. Th e sh ape of th is cartilage, rem in iscen t to som e of an an cien t Greek sh ield (thureos), is th e source of th e n am e thyroid, w h ich w as used for th e first tim e in 1656 by Th om as Wh ar ton .1 Alth ough Graves’ disease fin din gs w ere first docum en ted at th e en d of th e 18th an d begin n in g of th e 19th cen turies, it w as only n ear th e close of th e 19th cent ur y, w ith th e publication of th e report of th e Myxoedem a Com m ission of th e Royal Society of Lon don ,2 th at th e thyroid glan d’s fun ction began to be un derstood. Th e concept th at a ver y sm all glan d w as capable of producin g an “in tern al secretion ” th at could regulate an im al an d h um an m etabolism stem s from th is period. We n ow kn ow th at th e thyroid glan d concen trates iodide, syn th esizes an d stores th e iodin e-rich h orm on es tetraiodothyron in e, also referred to as thyroxin e an d l-thyroxin e (T4), an d triiodothyron in e (T3), an d releases th em in to th e circulation by h igh ly regulated processes. Th ese h orm on es h ave e ects in m ost cells of th e body, controllin g oxidative m etabolism an d th e expression of m any gen es th at are specific to di eren tiated cells. Th is ch apter review s th e physiology of th e thyroid, from its cell struct ure an d organ ization , to its cellular processes an d th e regulation of its secretion . It also in troduces h ow th e m easurem en t of h orm on es from th e thyroid axis can aid in th e diagnosis of thyroid diseases, an d review s h ow special circum stan ces in n orm al physiology, such as aging, pregn an cy, an d diet, can a ect th e fun ct ion of th e thyroid h orm on e axis an d th e tests th at w e use to m easure th at fun ct ion .

3.2 The Cellular St ruct ure of t he Thyroid Th e secretory fun ct ion s of th e thyroid are carried out by t w o distin ct cell t ypes of di erin g origin . Th e classic thyroid h orm on es T3 an d T4 are products of th e follicular cells. Th ese are em br yologically derived from th e en doderm of th e prim it ive foregut in th e region of th e posterior ph ar yn x at th e base of th e tongue. Th ey m igrate to th eir m ature position alon g a tubular stalk, th e thyroglossal duct , w h ich ultim ately is reabsorbed an d disappears.3 Follicular cells, th e bulk of th e thyroid secretor y cell population , form follicles th at are th e basic secretory an d storage un its for thyroid h orm on e. Follicles are com posed of tigh tly adh eren t cuboidal to colum n ar epith elial cells, w h ich form a “picket fen ce” str uct ure aroun d a lum en . Each cell is orien ted w ith a basolateral m em bran e adjacen t to th e m icrovasculature an d an apical border com posed of m icrovilli (th e “brush border”) exten din g in to th e lum en . Th e m icrovilli in crease th e surface area betw een th e cells an d th e lum en , w h ich con tain s thyroglobulin. It is h ere th at iodide (I– ), w h ich h as been concen trated w ith in th e follicular cell cytoplasm , is com bin ed w ith th e thyroglobulin to form th e active thyroid h orm on es ( Fig. 3.1). In terspersed betw een th e follicles are th e parafollicular C cells, w h ich produce th e calcium -m odulatin g h orm on e calciton in . Em br yologically, C cells are of n eural crest origin . Th ey form bilaterally from th e ultim obran chial bodies, w h ich are derived from th e fourth ph ar yn geal pouch es an d th en m igrate to lie in th eir m ature position betw een th e follicles (see Fig. 3.1).4

Fig. 3.1 Cellular architecture of the thyroid. (a) Low-power hem atoxylin-eosin (H&E)-stained view of thyroid showing follicles with central colloid and thyroid capsule. (b) Medium -power H&E stained view of thyroid. Note varying sized follicles com posed of a single layer of epithelial cells surrounding a central colloid m atrix containing thyroglobulin. C cells lie in the interfollicular zones. (Courtesy of Lester Freedman, MD, Department of Pathology, Nassau Universit y Medical Center.)

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Physiology of t he Thyroid Gland

3.3 Thyroid Horm one Synt hesis and Release Thyroid h orm on es are th e on ly iodin e-con tain in g h um an h orm on es an d require an adequate dietary supply of th is environ m en tally scarce elem en t for th eir biosyn th esis. Iodide (I– ) is th e essen tial rate-lim itin g substrate for thyroid h orm on ogen esis. Soph isticated biom ech an ism s h ave evolved for th e uptake an d con cen t ration of iodide in to th e thyroid follicular cell, its in sertion in to t yrosin e to form m on o- an d diiodot yrosin e (MIT an d DIT) an d th eir subsequen t coupling in to th e thyroid h orm on es T3 an d T4 ( Fig. 3.2). Th e sodium (Na)/iodide sym porter (NIS), a 643 am ino acid 108 kDa dim erized t ran sm em bran e glycoprotein , is located at th e basolateral m em bran e of th e thyroid follicular cell adjacen t to th e m icrovasculature.5,6 It is an aden osin e t riph osph ate (ATP)-driven active tran sport protein th at sim ultan eously tran sports Na + an d I– (in a 2:1 ratio) in to th e cytoplasm . Th is con cen t rates I– again st an electroch em ical gradien t an d results in an in tra- to extracellular I– con cen t ration ratio of up to 40:1.7 NIS activit y, dem on strable as early as th e on set of fetal thyroid h orm on ogen esis at about th e 12th w eek of gestation ,8 is stim ulated by thyrotropin -stim ulat in g h orm on e (TSH) of pituitar y origin an d in h ibited by an ion s, such as th iocyan ate (SCN – ) an d perch lorate (CLO4 – ).9 Im portan tly, w h en excessive iodin e exposure leads to h igh in trathyroidal I– con cen t ration s, a block of I–

oxidation an d organ ification occurs, leadin g to reduced h orm on e syn th esis (th e Wol –Ch aiko e ect).10 It h as been proposed th at th is sam e in creased in trathyroidal I– concen tration also in h ibits NIS act ivit y, resultin g in decreased I– t ran sport in to th e cytoplasm , th ereby reducin g in trathyroidal I– levels an d en ablin g an “escape” from th e Wol –Ch aiko e ect.11 In th is m an n er, I– itself is able to autoregulate NIS act ivit y. Wh ile crucial to thyroid fun ction , NIS activit y h as also been iden tified in oth er tissues, such as th e lactat in g breast , salivar y glan ds, stom ach , an d sm all in testin e.9 NIS-m ediated iodin e uptake an d con cen tration w ith in th e follicular cell is th e basis for thyroid radioiodin e diagnost ic testin g as w ell as treatm en t of th ose differen tiated thyroid can cers expressin g adequate NIS act ivit y. Recen t reports h ave suggested th at facilitation of radioiodin e treatm en t by upregulation of poor NIS expression m ay be possible in som e tum ors w ith the use of t yrosin e kin ase in h ibitors.12 From th e follicular cell cytoplasm , I– is furth er t ran slocated across th e apical cell brush border m em bran e in to th e follicular lum en . Th e ch aracterization of th e apical m em bran e tran sporter(s) is yet to be fully defin ed but is th ough t to involve th e tran sm em bran e tran sporter pen drin (also kn ow n as th e sodium -in depen den t ch loride/iodide transporter),13 a 780 am in o acid 115 kDa glycoprotein , an d possibly oth er anion tran sport ch ann els, such as an oct am in -1.14 As is true for NIS, pen drin act ivit y is stim ulated by TSH. Mutation s in th e gen e en coding pen drin h ave been lin ked to Pen dred syn drom e of

Fig. 3.2 Iodoam ines in thyroid horm one synthesis. Tyrosine residues in the follicular thyroglobulin colloid are iodinated at the 3- and 5positions of their phenyl rings by oxidation and organification of I– catalyzed by TPO in the presence of H2O2 to form inactive MIT and DIT. TPO then further couples MIT and DIT by placing an ether bond between t wo rings into the active thyroid horm ones T3 and T4. H2 O2, hydrogen peroxide; TPO, thyroperoxidase; MIT, monoiodotyrosine; DIT, diiodot yrosine; T3, triiodothyronine; T4, tetraiodothyronine, l-thyroxine.

17

Anatom y, Physiology, and Pathology of the Thyroid Com part m ent goiter, hypothyroidism , sen sorin eural h earin g loss, an d im paired I– organ ification .15,16 With in th e lum en at th e apical border, I– is oxidized an d th en organ ified 17 on to t yrosyl residues at th eir 3- an d 5-ph enyl rin g position s w ith in th e colloid m atrix, w h ich is com posed of th e rough en doplasm ic reticulum (RER)-processed 660 kDa dim erized glycoprotein thyroglobulin .18 Th is oxidation an d organ ification is catalyzed by th e h em e-con tain ing apical en zym e thyroperoxidase (TPO) in th e presen ce of hydrogen peroxide (H2 O2 ), resultin g in th e form ation of th e biologically in active MIT an d DIT.19 Th e required H2 O2 is gen erated by th e calcium depen den t 180 to 190 kDa glycoprotein dual oxidases DUOX1 an d DUOX2, w h ich are co-localized w ith TPO at th e apical border.20,21 DUOX act ivit y is upregulated by TSH an d low I– con cen tration s an d dow n regulated by h igh I– con cen tration s. Th is h as been proposed as a part ial explan ation of th e Wol –Ch aiko ph en om en on .22 TPO th en fur th er catalyzes th e coupling of MIT an d DIT by placin g an eth er bon d betw een t w o ph enyl rin gs, form in g th e act ive thyroid h orm on es T3 an d T4, w h ich are still attach ed to th e thyroglobulin protein backbon e.17 TPO en zym atic act ivit y is also stim ulated by TSH, w h ereas it is in h ibited

by th e an tithyroid th ion am ide drugs propylth iouracil (PTU), m eth im azole (MMI), an d its m etabolic precursor carbim azole (CBZ).23 Th is th ion am ide in h ibit ion of TPO activit y form s th e basis for th e oral an tithyroid drug treatm en t of hyperthyroidism . Th e iodothyron in es (T3, T4, MIT, an d DIT) rem ain stored w ith in th e thyroglobulin colloid reservoir un t il n eeded an d are th en brough t in to th e cytoplasm by en docytosis an d proteolytically hydrolyzed w ith in lysosom es. Th e resultin g T3 an d T4 are secreted in to th e vasculature th rough th e basolateral m em bran e by th e active tran sm em bran e m on ocarboxylate tran sporter 8 (MCT8).24 MCT8 is expressed in m any tissues, in cluding thyroid, brain, kidn ey, h eart , an d skeletal m uscle. Th e Allan –Hern don –Dudley syn drom e of m en tal retardation , hypoton ia/dyston ia, an d abnorm al thyroid h orm on e levels h as been lin ked to a loss-of-fun ction m utation in th e gen e en codin g MCT8.25,26 Th ose MIT an d DIT residues rem ain in g in th e cytoplasm un dergo deh alogenation by th e en zym e DEHAL1, w ith th e liberated I– recycled in to th e colloid for furth er h orm on ogen esis.27 Th e com plex in tracellular path w ays accom plish ing th ese tasks are sh ow n sch em at ically in Fig. 3.3.

Fig. 3.3 Intracellular pathways for the synthesis and release of thyroid horm one by follicular cells. The basolateral m em brane of the follicular cell abuts the m icrovasculature, whereas the apical brush border faces the follicle lum en containing the colloid m atrix. The colloid contains TG, which had originated in the ER before being transported into the lum en. NIS, at the basolateral m em brane, actively concentrates I– from the blood across the membrane into the cytoplasm, from where it is transported by pendrin and anoctamin-1 across the apical brush border. This enables intralum inal oxidation of I– , catalyzed by TPO in the presence of H2 O2, and its subsequent TPO-mediated organification onto t yrosyl m oieties within the TG, form ing MIT and DIT. TPO further couples MIT and DIT into the active thyroid hormones T3 and T4. These are stored within the colloid until needed, at which tim e they are brought back into the cytoplasm by endocytosis and proteolytically hydrolyzed by lysosom es into T3 and T4 secretory products. These are actively transported across the basolateral m em brane into the microvasculature by MCT8. I– resulting from dehalogenation of residual MIT and DIT reenters the cytoplasm ic I– pool for reuse. TG, thyroglobulin; ER, endoplasm ic reticulum ; NIS, sodium /iodide sym porter; TPO, thyroperoxidase; MIT, m onoiodot yrosine; DIT, diiodotyrosine; T3, triiodothyronine; T4, tetraiodothyronine, l-thyroxine; MCT8, m onocarboxylate transporter 8.

18

Physiology of t he Thyroid Gland T4 an d T3 are secreted by th e thyroid in m olar proportion s variously calculated as 14:1,28 or m ore recen tly as 17:1.29 How ever, th is direct thyroidal secretion accoun ts for on ly 20% (~ 6 µg) of th e circulatin g T3, w h ereas th e oth er 80% (~ 25 µg) is th e result of periph eral conversion of T4 to T3 by 5´-deiodin ation of T4.28

3.4 Thyroid Horm one Deiodinat ion Secreted T4 m ay be con sidered a proh orm on e an d is conver ted to th e act ive T3 form by deiodin ation at th e 5´ position on its outer ph enyl rin g. Th is is accom plish ed by th e selen odeiodin ases type 1 (D1) an d, m ore robustly, by th e h igh er-a n it y t ype 2 (D2). Deiodin ation at th e 5 position on th e in n er rin g is accom plish ed by t ype 3 (D3), an d to a lesser exten t by D1, an d leads to th e in active m olecule reverse T3 ( Fig. 3.4). Th ese sign ifican tly tissue-specific deiodin ases m ain tain thyroid h orm on e h om eostasis an d regulate thyroid-m ediated in t racellular activit y. Th ey are all struct urally sim ilar m em bran e-boun d protein s of 29-33 KDa. D1 an d D3 h ave a t ran sm em bran e dom ain at th e cell surface, w h ereas D2 is located at th e en doplasm ic reticulum . All h ave th eir fun ction ally act ive cen ters in the cytosol. D1

is presen t in several tissues, such as liver, kidn ey, thyroid, an d pituitar y, but it is n ot presen t in th e cen tral n er vous system (CNS). D2 activit y is presen t in th e CNS as w ell as in th e periph eral tissues, such as thyroid, h eart, skeletal an d vascular sm ooth m uscle, kidn eys, placen ta, an d pan creas. D3 is foun d in th e CNS as w ell as placen tal an d fetal tissues.30,31,32 Alterat ion s in deiodin ase activities are th ough t to play an im portan t role in such path ophysiological con dition s as th e n on thyroidal illn ess syn drom e.

3.5 Thyroid Horm one Regulat ion As already n oted, alth ough T4 is th e m ain secretor y product of th e thyroid glan d, T3 is respon sible for th e cellular act ion s of thyroid h orm on es. Th e n uclear thyroid h orm on e receptors h ave 10- to 15-fold h igh er a n it y for T3 th an T4, an d th e bin din g of T3 to th e receptor isoform expressed in a particular cell t ype drives th e upregulation or dow n regulation of th e tran scription of specific gen es.33 Th e products of th ese gen es govern th e cellular respon ses to thyroid h orm on es, as w ell as th e regulation of th e syn th esis an d release of thyroid h orm on e. Th e hypoth alam us respon ds to th e am bien t thyroid h orm on e state in a classical negative h om eostatic feedback loop by regulatin g its secretion of thyrotropin -releasing h orm on e (TRH).

Fig. 3.4 Pathways of thyroid hormone selenodeiodinase–m ediated activation and deactivation. Secreted T4 (tetraiodothyronine, l-thyroxine) is converted to the active T3 (triiodothyronine) form by deiodination at the 5´ position on its outer phenyl ring. This is accom plished by the selenodeiodinases t ype 1 (D1) and t ype 2 (D2). Deiodination at the 5 position on the inner ring is accom plished by t ype 3 (D3) and D1.

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Anatom y, Physiology, and Pathology of the Thyroid Com part m ent Th e cell bodies of TRH-secretin g n euron s are localized in th e paraven tricular n ucleus of th e hypoth alam us. Th eir n erve en din gs secrete TRH in to th e portal vein in th e hypoth alam ic m edian em in en ce for t ran sport to th e pituitar y glan d. Th is hypoth alam ic TRH respon se is regulated by T3, w h ich is derived m ore from region al in tracellular deiodin ation of T4 th an from circulatin g T3 an d is prin cipally m ediated by th e β2 T3 n uclear receptor.34 In th is w ay, th e in creased level of T4 in hyperthyroidism poten tly dow n regulate th e syn th esis an d secretion of TRH, w h ereas th e decreased level in hypothyroidism result in en h an ced TRH release. Th e target for TRH is a cell m em bran e–based receptor on th e TSH-producin g cells, th e thyrotroph s, located in th e an terom edial port ion of th e pituitar y glan d—also part of th e n egative feedback con trol m ech an ism . TRH rapidly stim ulates TSH syn th esis an d release. Th is e ect of TRH on th e thyrotroph s is m odulated by both T4 an d T3. In hyperthyroidism , th e stim ulatory e ect of TRH on th e thyrotroph s is dow n regulated, an d TSH release decreases an d m ay cease. Th e TSH m olecule, a 28 kDa glycoprotein , is com posed of a specific β subun it th at is un ique to TSH, an d an α subun it th at is com m on to th e oth er dim eric glycoprotein h orm on es—lutein izing h orm on e (LH), follicle-stim u latin g h orm on e (FSH), an d h um an ch orion ic gon adotropin (h CG) ( Fig. 3.5).35

3.6 Laborat ory Assessm ent of Thyroid St at e Laborator y testin g is used to screen for thyroid glan d dysfun ction , diagnose or con firm th e presen ce of hypothyroidism or hyperthyroidism , or m on itor a patien t’s respon se to thyroid disease treatm en t . Testin g strategies are determ in ed by th e goal of perform in g th e test an d can in clude serum m easurem en ts of thyroid h orm on es an d TSH, n uclear m edicin e tests, im agin g studies, an d assessm en t for th e presen ce of an tithyroid autoan tibodies. Alth ough T3 is th e form of thyroid h orm on e th at bin ds to th e thyroid n uclear receptor an d is respon sible for thyroid biological respon ses, m easurin g its serum concen tration to determ in e thyroid fu n ct ion can be m isleadin g. Circulat in g T3 h as a sh orter h alf-life (1 day) th an does T4 (7 days), an d its concen tration is frequen tly t ran sien tly low ered by sign ifican t in tercurren t n on thyroidal illn esses, w h ich m ay lead to m isin terpretat ion of a patien t’s thyroid state.36 T4 is th e m ain secretor y product of th e thyroid glan d an d th e m ost com m on ly prescribed agen t for th e treatm en t of hypothyroidism . In addition , because of its lon ger serum h alf-life, its con cen t ration is m ore stable th an th at of T3. Sim ilar to T3, its con cen t ration is a ected by th e presen ce of oth er diseases, but th is occurs to a lesser degree. Thyroid h orm on es are h igh ly boun d to th eir circulatin g carrier protein s: thyroxin e-bin din g globulin (TBG), h um an serum album in (HSA), an d t ran sthyretin (TTR). On ly 0.02% of serum T4 an d 0.3% of serum T3 exists in th e un boun d an d th erefore m etabolically act ive form . Hen ce, in addition to th e presence of thyroid disease, alterat ion s in th e con cen t ration of th ese thyroid h orm on e–bin din g protein s can sign ifican tly a ect th e serum concen tration of thyroid h orm on es.37,38 Th is h as led to th e developm en t of readily available assays th at m easure th e concen tration of free T4. Th ese assays

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Fig. 3.5 The hypothalam ic–pituitary–thyroid negative feedback loop. Hypothalam ic thyrotropin-releasing horm one (TRH) stimulates pituitary thyrotrophs to secrete thyrotropin-stim ulating hormone (TSH), which stim ulates thyroidal hormone synthesis and secretion. The secreted T4 (tetraiodothyronine, l-thyroxine) and T3 (triiodothyronine) regulate secretory function at both the hypothalamic and pituitary levels in a classical negative feedback loop: downregulating as T4 and T3 levels increase and upregulating as their levels decrease.

h ave im portan tly supplem en ted th e m easurem en t of total seru m T4 an d T3 in m any clin ical circum stan ces. Wh ile th e m easurem en t of free T4 is often m ore clin ically usefu l in assessing a pat ien t’s thyroid state th an em ployin g assays for total T4, total T3, or free T3, th ere are still im portan t lim itation s. Many com m ercially available assays for free T4 em ploy specific m eth ods, w h ich perform di eren tly w h en applied to clin ical situation s th at greatly a ect eith er th e con cen tration s of th e thyroid-bin din g protein s or th eir bin din g a n ities for thyroid h orm on es. Exam ples in clude in creased protein bin din g due to elevation s of TBG occurrin g in pregn an cy, in w om en treated w ith oral estrogen s or con traceptives, an d in ch ron ic liver disease; in h erited variation s in TBG levels; in creased p rotein -bin d in g a n it y for T4 as in fam ilial d ysalbu m in em ic hyp er t hyroxin em ia; or w it h crit ical in t ercu rren t n on t hyroid al illn ess. Even m ore t ech n ically d em an d in g, less w id ely available assays, w h ich em p loy equ ilibriu m d ialysis t o m easu re free T4, m ay n ot p erform reliably in all of th ese circu m stan ces.39,40 Th e n orm al ran ge for serum thyroid h orm on e concen tration s in h um an s is very large. Typically, th e upper lim it of n orm al is 150% h igh er th an th e low er lim it of th e n orm al ran ge. Th e set poin t about w h ich any in dividual regulates T4/free T4 varies

Physiology of t he Thyroid Gland little d u rin g a lifetim e. It th erefore follow s th at, in an in d ivid u al in w h om th e T4/free T4 is u su ally in th e h igh er p ar t of t h e n orm al ran ge, hyp othyroid ism can resu lt in a low er T4/ free T4 th at is st ill in t h e n orm al ran ge. In a sim ilar fash ion , hyp er t hyroid ism m ay cau se a d ou blin g of an in d ivid u al’s seru m T4/free T4 con cen tration , yet th is also m ay be w ith in th e n orm al ran ge. TSH an d free T4 levels vary inversely in a log-lin ear relation sh ip,41 an d, con sequen tly, as a sin gle test for thyroid fun ction , TSH is th e m ost reliable. In th e presence of hyperthyroidism , TSH serum con cen t ration s are decreased below n orm al an d are often suppressed below th e assay’s detect ion lim it. Sim ilarly, w h en prim ary hypothyroidism is present, even to a m ild degree, serum TSH is elevated. How ever, w h en secondar y hypothyroidism is presen t an d th e problem lies in eith er th e hypoth alam us or th e pituitar y, profoun d hypothyroidism m ay be presen t, yet serum TSH is reported as bein g n orm al or low. Th erefore, care m ust be exercised in relying on on e blood test to diagnose thyroid disease. Th ere are n um erous circum stan ces in w h ich th e serum TSH con cen tration m ay n ot correlate w ith th e clin ical state. In critically ill patien ts treated w ith dopam in e agon ists, or w h en th erapy requires th e use of h igh -dose glucocorticoids, pituitary TSH release m ay be in h ibited, even in th e face of hypothyroidism .42 Durin g severe n on thyroidal illn ess com plex ch anges occur at all levels of th e hypoth alam ic–pituitar y–thyroid (HPT) axis, producin g ch anges in thyroid h orm on e m easurem en ts th at m ake clin ical evaluation di cult. Seru m levels of T4 an d T3 m ay fall profoun dly w h ile th ose of reverse T3 rise. Wh en patien ts recover from such illn esses as in fect ion or sh ock, or th ey im prove after h avin g m ajor surgery, serum TSH m ay be tran sien tly elevated for several w eeks as th e serum con cen t ration s of T4 an d T3 return to n orm al.36 Up to on e-th ird of patien ts w ith acute psych iatric illn ess m ay presen t w ith alterat ion s in TSH an d thyroid h orm on e levels. Th ese are usually tran sien t an d n orm alize over several days to a few w eeks as th e psych iatric illn ess rem its. Th e path ophysiology is poorly un derstood, but alteration s in th e HPT axis h ave been proposed.43 Recen t sch olarsh ip h as iden tified th at th e “n orm al” ran ge for TSH m ay var y w ith age, gen der, an d eth n icit y. In older patien ts w ith out eviden ce of thyroid disease, elevation s of TSH in to th e range th at h as t ypified m ild hypothyroidism m ay be seen . Th is h as prom pted proposals to ch ange th e w ay th at TSH is in terpreted an d alter th e th resh old for in itiat in g th erapy.44 In addition , th e ran ge of TSH in pregn an t w om en di ers from th e ran ge in oth er adults. As previously n oted, th e struct ure of h CG is sim ilar to th at of TSH, w ith both sh arin g a com m on α subun it. Con sequen tly, w h en h CG is presen t in ver y h igh concentration , as it is in pregn an cy, it bin ds to th e TSH receptor on th e thyrotroph cell surface an d m im ics th e act ion of TSH. As a result , thyroid h orm on e secretion is stim ulated an d pituitar y TSH secretion is reduced. Th is results in a low ered “n orm al” TSH ran ge in pregn an cy.45,46 Given th e lim itation s of th e clin ical laborator y w h en applied to thyroid assessm en t, it is reason able to com bin e th e m easurem en t of TSH w ith on e or m ore oth er tests, such as T4 or free T4, w hen diagn osing thyroid disease or evaluatin g a patien t w h o requires h ospitalizat ion . How ever, w h en follow in g a stable patien t for th e adequacy of thyroid h orm on e replacem en t, m easurem en t of serum TSH alon e m ay su ce.

Screen in g apparen tly n orm al adult patien ts for thyroid disease w ith blood tests is a con troversial practice th at h as been advocated by som e 47 an d determ in ed n ot to be cost-e ect ive by oth ers.48,49 Also con troversial is th e value of un iversal or sim ply targeted screen in g for thyroid dysfun ction of w om en in early pregn an cy to reduce th e risk of pregn an cy com plication s an d of fetal CNS developm en tal defects. St udies to date rem ain in con clusive,50,51 an d relevan t guidelin es m ake n o recom m en dation s for or again st th is practice.46 Greater agreem en t exits in favor of screen in g populat ion s at in creased risk, such as older adults w h o m ay n ot m an ifest th e usual sign s an d sym ptom s of thyroid disease.52 Screen in g n ew born s for th e presen ce of congen ital hypothyroidism by m easurin g TSH is w idely accepted. Program s th at m easure TSH in all n eon ates are con sidered to h ave alleviated sign ifican t su erin g by preven t in g th e severe cogn itive im pairm en t , deafn ess, an d m utism th at t ypify th is disease w h en it is not t reated soon after birth .53

3.7 Drugs A ect ing Thyroid Funct ional St at us Many drugs used in clin ical pract ice h ave sign ifican t e ects on thyroid fun ct ion al status. Som e, such as proton pum p in h ibitors, H2 receptor an tagon ists, an d an tacids, reduce gast ric acidit y, th ereby reducin g absorption of thyroid h orm on es, w h ereas oth ers (bile acid sequestran ts, calcium , iron , alum in um hydroxide, sucralfate) reduce absorption by in creasin g h orm on e bin din g in th e in testin e. Activation of th e h epatic cytoch rom e P450 system by ph enytoin , rifam pin , carbam azepin e, an d barbiturates results in an in creased m etabolic clearan ce rate of thyroid h orm on e. Th e cardiac an tiarrhyth m ic am iodaron e is an iodin erich (37% by w eigh t) lipoph ilic agen t w ith a lon g h alf-life of 40 to 60 days, an d it h as poten t ially profoun d an d variable thyroidal e ects. Its h igh iodin e conten t can result in an organ ification block (th e Wol –Ch aiko e ect), an d it also h as an tagon istic act ion at th e thyroid h orm on e receptor (perhaps sign ifican t for its an tiarrhyth m ic e ect), in h ibits D1 act ivit y, an d h as a follicular cell cytotoxic e ect . Con sequen tly, hypothyroidism h as been reported in 5 to 15% of pat ien ts given am iodaron e. Thyrotoxicosis h as been iden tified in up to 12% of treated pat ien ts an d h as been divided in to t ypes 1 (in troduct ion of a large iodin e load in to a pat ien t w ith preexistin g thyroidal auton om y—th e Jod-Basedow e ect) an d 2 (cytotoxic destructive thyroiditis). Lith ium can m im ic th e Wol –Ch aiko e ect because it is concen trated by follicular cells, in h ibits th e release of thyroidal iodin e, an d th ereby in creases in trathyroidal iodin e levels. Th e resultin g dow n regulation of thyroid h orm on e syn th esis an d secretion m ay cause hypothyroidism . Tran sien t thyrotoxicosis due to a cytotoxic destruct ive thyroiditis h as also been described. Tyrosin e kin ase in h ibitors m ay in crease h epat ic clearan ce of thyroid h orm on e. Th is m ay require in creased treatm en t doses in thyroidectom ized or previously hypothyroid patien ts an d m ay lead to hypothyroidism in euthyroid patien ts as a result of dest ructive thyroiditis (som et im es w ith an early thyrotoxic ph ase) an d possibly by decreasin g thyroidal blood flow by in h ibit ion of vascular en doth elial grow th factor recep tors (VEGFRs). Im m un e suppressors, such as alem tu zum ab (used in th e t reatm en t of m ultiple sclerosis) an d h igh act ivit y an tiret roviral th erapy (HAART), h ave been reported to in duce

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Anatom y, Physiology, and Pathology of the Thyroid Com part m ent clin ical Graves’ disease. Cytokin es, such as in terferon -α an d in terleukin -2, h ave been associated w ith both autoim m un e an d cytotoxic destruct ive thyroid e ects resultin g in tran sien t or perm an en t hypothyroidism , tran sien t thyrotoxicosis, or Graves’ disease.54

3.7.1 Genet ic and Molecular Cont rol of Thyrocyt e Grow t h Recen t years h ave seen m ajor advan ces in th e un derstan din g of th e gen et ic an d m olecular con trol of thyrocyte grow th , di eren t iation , proliferation , an d sur vival. A cascade of t yrosin e protein kin ases h as been sh ow n to be cent ral to th is regulator y m ech an ism .55,56 Th e RET (rearran ged durin g tran sfect ion ) proto-on cogen e is situ ated on th e lon g arm of ch rom osom e 10 an d con tain s 21 exon s. It codes for th e t ran sm em bran e receptor

t yrosin e kin ase RET, w h ich is th e gateway to th e m itogen -act ivated protein kin ase (MAPK) / extracellular sign al-regulated kin ase (ERK) path w ay. Act ivation of RET by bin din g of on e of its grow th -stim u latin g or cytokin e ligan ds to th e extracellular dom ain of th e receptor results in ph osph orylation of t yrosin e residues in th e in tracellular dom ain an d in itiates a cascade of subsequen t ph osph orylation even ts, tran sducin g a dow n st ream sign al regulatin g cell grow th . Th e first of th ese involves th e RAS viral on cogen e fam ily of 21 kDa protein kin ases (H-RAS, N-RAS, an d K-RAS). Th ese are act ivated by ph osph orylation of th eir com pon en t guan osin e diph osph ate (GDP) m oieties to guan osin e triph osph ate (GTP). Subsequen t sign alin g occurs by activatin g ph osph orylation s of th e dow n stream RAF fam ily of protoon cogen e serin e/th reon in e t yrosin e kin ases (A-RAF, B-RAF, an d C-RAF), MEK (also kn ow n as MAPK kin ase or MAPKK), an d ERK. Act ivated ERK th en tran slocates in to th e n ucleus, w h ere it m odulates tran scription factors, such as PAX8 (paired dom ain tran scription factor 8), an d h orm on e receptors, such as PPARγ (peroxisom e proliferator–act ivated receptor γ), w h ich are im portan t to thyroid h orm on e biosyn th esis as w ell as cell grow th , sur vival, an d apoptosis. A secon d path w ay tran sm it tin g an d m odulatin g th e sign al for con trol of cell grow th begin s w ith ph osph at idylin ositol-3 kin ase (PI3K). Th is in itiates th e P13K/AKT/m TOR viral on cogen e t yrosin e kin ase cascade.57 PI3K is activated both directly by th e tran sm em bran e receptor kin ase RET an d in directly by RAS, w h ereas it is dow n regulated by PTEN-m ediated deph osph orylation ( Fig. 3.6). Iden tifyin g th ese path w ays an d un derstan din g th e im portan ce th at poin t m utation s an d gen e fusion s (rearran gem en ts) of th eir com pon en ts play in can cer developm en t an d progression h ave led to m ajor advan ces in th e diagn osis 58,59,60,61,62 an d targeted treatm en t 56,63,64 of thyroid can cer. See Ch apter 10 for fur th er detailed discussion of th is subject .

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Fig. 3.6 Pathways of intracellular t yrosine kinase signal transduction, modulating cell growth, proliferation, and survival. Ligands of the transm em brane RET t yrosine kinase initiate phosphorylation cascades, such as the MAPK (RAS→RAF→MEK→ERK) and the PI3K (PI3K→AKT→m TOR) pathways, modulating nuclear transcription factors for cell growth and survival. PTEN expression inhibits PI3K activit y. (Courtesy of Dr. Yuri Nikiforov, Departm ent of Pathology, Universit y of Pittsburgh.)

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[40] Th ien pon t LM, Van Uytfangh e K, Poppe K, Velken iers B. Determ in ation of free thyroid h orm on es. Best Pract Res Clin En docrin ol Metab 2013; 27(5); 689– 700 [41] Spen cer CA, LoPresti JS, Patel A, et al. Application s of a n ew ch em ilum in om etric thyrotropin assay to subn orm al m easurem en t. J Clin En docrin ol Metab 1990; 70(2); 453–460 [42] Haugen BR. Drugs th at suppress TSH or cause cen tral hypothyroidism . Best Pract Res Clin En docrin ol Metab 2009; 23(6); 793–800 [43] Dickerm an AL, Barn h ill JW . Abn orm al thyroid fun ct ion tests in psych iatric patien ts: a red h err in g? Am J Psych iatr y 2012; 169(2); 127–133 [44] Boucai L, Hollow ell JG, Surks MI. An approach for developm en t of age-, gender-, an d eth n icity-specific thyrotropin referen ce lim its. Th yroid 2011; 21(1); 5–11 [45] Pan esar NS, Li CY, Rogers MS. Referen ce in tervals for thyroid h orm on es in pregn an t Ch in ese w om en . An n Clin Bioch em 2001; 38(Pt 4); 329–332 [46] Stagn aro-Green A, Abalovich M, Alexan der E, et al. Am erican Th yroid Association Taskforce on Th yroid Disease Durin g Pregn an cy an d Postpar tum . Guidelin es of th e Am erican Th yroid Association for th e diagn osis an d m an agem en t of thyroid disease durin g pregn an cy an d postpar tum . Thyroid 2011; 21(10); 1081–1125 [47] Laden son PW , Sin ger PA, Ain KB, et al. Am erican Thyroid Association guidelin es for detect ion of thyroid dysfun ction . Arch In tern Med 2000; 160(11); 1573–1575 [48] Gaiton de DY, Row ley KD, Sw een ey LB. Hypothyroidism : an update. Am Fam Physician 2012; 86(3); 244–251 [49] Helfan d M U.S. Preven tive Ser vices Task Force. Screen ing for subclin ical thyroid dysfun ct ion in n on pregn an t adults: a sum m ar y of th e eviden ce for th e U.S. Preven tive Ser vices Task Force. An n In tern Med 2004; 140(2); 128–141 [50] Negro R, Schw artz A, Gism on di R, Tin elli A, Man gieri T, Stagn aro- Green A. Un iversal screen ing versus case fin din g for detect ion an d treatm en t of thyroid h orm on al dysfun ction durin g pregn an cy. J Clin En docrin ol Metab 2010; 95(4); 1699–1707 [51] Lazarus JH, Bestw ick JP, Ch an n on S, et al. An ten atal thyroid screen ing an d ch ildh ood cognitive fun ction . N Engl J Med 2012; 366(6); 493–501 [52] Baskin HJ, Cobin RH, Duick DS, et al. Am erican Association of Clin ical En docrin ologists. Am erican Association of Clin ical En docrin ologists m edical guidelin es for clin ical practice for th e evaluation an d treatm en t of hyperth yroidism an d hypothyroidism . En docr Pract 2002; 8(6); 457–469 [53] Rose SR, Brow n RS, Foley T et al. Am erican Academ y of Pediatrics. Sect ion on En docrin ology an d Com m ittee on Gen etics, Am erican Th yroid Association . Public Health Com m ittee, Law son Wilkin s Pediatric En docrin e Society. Update of n ew born screen in g an d th erapy for congenital hypothyroidism . Pediatrics 2006; 117(6); 2290–2303 [54] Barbesin o G. Drugs a ectin g thyroid fun ction . Th yroid 2010; 20(7); 763–770 [55] Nikiforova MN, Nikiforov YE. Molecular diagn ostics an d predictors in thyroid can cer. Th yroid 2009; 19(12); 1351–1361 [56] Liebn er DA, Sh ah MH. Th yroid can cer: path ogen esis an d targeted th erapy. Th er Adv En docrin ol Metab 2011; 2(5); 173–195 [57] Xin g M. Gen etic alteration s in th e ph osph atidylin ositol-3 kin ase/Akt path w ay in thyroid can cer. Thyroid 2010; 20(7); 697–706 [58] Alexan der EK, Ken n edy GC, Baloch ZW , et al. Preoperative diagn osis of ben ign thyroid n odules w ith in determ in ate cytology. N En gl J Med 2012; 367(8); 705–715 [59] Hodak SP, Rosen th al DS Am erican Th yroid Association Clin ical A airs Com m ittee. In form ation for clin ician s: com m ercially available m olecular diagn osis testin g in th e evaluation of thyroid n odule fin e-n eedle aspiration specim ens. Thyroid 2013; 23(2); 131–134 [60] Bern et V, Hupart KH, Parangi S, Woeber KA. AACE/ACE disease state com m en tar y: m olecular diagn ostic testin g of thyroid n odules w ith in determ in ate cytopath ology. En docr Pract 2014; 20(4); 360–363 [61] Nikiforova MN, Wald AI, Roy S, Durso MB, Nikiforov YE. Targeted n ext-gen eration sequen cin g pan el (ThyroSeq) for detect ion of m utation s in thyroid can cer. J Clin En docrin ol Metab 2013; 98(11); E1852–E1860 [62] Nikiforov YE, Cart y SE, Ch iosea SI, et al. High ly accurate diagn osis of can cer in thyroid n odules w ith follicular n eoplasm /suspicious for a follicular n eoplasm cytology by ThyroSeq v2 n ext-gen eration sequen cin g assay. Can cer 2014; 120(23); 3627–3634 [63] Xin g M, Haugen BR, Sch lum berger M. Progress in m olecular-based m an agem en t of di eren tiated thyroid can cer. Lan cet 2013; 381(9871); 1058–1069 [64] Brose MS, Nuttin g CM, Jarzab B, et al. DECISION investigators. Sorafen ib in radioactive iodin e-refractor y, locally advan ced or m etastatic di eren tiated thyroid can cer: a ran dom ised, double-blin d, ph ase 3 trial. Lan cet 2014; 384 (9940); 319–328

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Anatom y, Physiology, and Pathology of the Thyroid Com part m ent

4 Physiology of t he Parat hyroid Glands Carlos M. Isales and Wendy B. Bollag

4.1 Int roduct ion Calcium is on e of th e m ost tigh tly regulated ion s in th e body, h igh ligh tin g its crit ical role in ever yth in g from in tracellular sign alin g to m uscular con tract ion . Th us, even sm all deviation s in calcium values outside th e n orm al ran ge usually sign ify som e un derlyin g path ology. Disorders involving hypercalcem ia are m ore com m on th an th ose involving hypocalcem ia because of all of th e com pen sator y system s th at respon d to a drop in seru m calcium . In an out pat ien t sett in g th e m ost com m on cause of hypercalcem ia is prim ar y hyperparathyroidism . Th e diagnosis of early prim ar y hyperparathyroidism in creased dram atically w ith th e adven t of autom ated m ultiple sam ple blood ch em istr y an alysis. Th e corollary of th is fact is th at w e rarely en coun ter pat ien ts as dram atic as Captain Martell anym ore.1 Th erefore, to be able to better diagnose an d treat patien ts w ith diseases of th e parathyroid glan d, w h o often do n ot h ave sign ifican t clin ical sign s or sym ptom s, it is im portan t to h ave a clear

un derstan din g of th e factors involved in th e regulation an d secretion of parathyroid h orm on e (PTH) to avoid m isdiagn osis.

4.2 Hist ory Th e com parative an atom ical description an d n am in g of parathyroid glan ds are credited to San dstroem in 1880,2,3 w h o exam in ed th e n ecks of h um an s an d oth er m am m als (dog, cat, rabbit, h orse, an d ox) for th e glan ds h e even tually n am ed glan dulae parathyroidea 4 ( Fig. 4.1). As a m edical studen t in th e Depart m en t of An atom y in th e Un iversit y of Uppsala h e exam in ed th e n ecks of h um an cadavers an d iden tified th e sam e organ s h e h ad observed in an im als in 43 of 50 cadavers: “Foun d on both sides of th e inferior border of th e thyroid an organ of th e size of a sm all pea w h ich judgin g from its exterior, did n ot appear to be a lym ph glan d, or an accessor y thyroid glan d an d w h ich upon h istological exam in ation sh ow ed a rath er peculiar struct ure.”4 At th at t im e on ly t w o parathyroid glan ds w ere Fig. 4.1 Tim eline illustrating the m ajor discoveries related to the parathyroid glands, parathyroid horm one and vitam in D. 1,25(OH)2D3 , 1,25-dihydroxyvitam in D3 ; CaSR, calcium -sensing receptor; OFC, osteitis fibrosa cystica; PT, parathyroid; PTH, parathyroid horm one; PTHrP, parathyroid horm one–related protein; VDR, vitam in D receptor.

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Physiology of the Parat hyroid Glands recogn ized to be present in hum ans. Interestingly, the descrip tion of parathyroid glands as distin ct organs in anim als had been m ade as far back as 1852 by Ow en, w ho identified “a sm all com pact yellow glandular body attached to the thyroid” in the Indian rhinoceros.2,5 A potential role of these organs w as not clear until the French physiologist Eugene Gley dem onstrated that tetany did not occur after thyroidectom y in experim ental anim als if the parathyroid glands w ere excluded.4 However, it w as felt that the parathyroid gland’s role w as to rem ove toxins (such as m ethyl guanidine) from the body and that it w as the accum ulation of these toxins that w as precipitating the tetany.6 It w as not until alm ost 20 years later that MacCallum and Voegtlin dem onstrated that rem oval of the parathyroid glands w as associated w ith hypocalcem ia and that infusion of calcium prevented tetany.6,7 A conn ect ion betw een overproduct ion of PTH an d a specific disease w as proposed in 1915 w h en th e path ologist Friedrich Schlagen h aufer, based on t w o autopsies h e w as perform in g on patien ts w ith hyperparathyroidism , speculated th at an en larged parathyroid glan d (aden om a) could result in parathyroid bon e disease (osteitis fibrosa cystica).4,6 Subsequen tly, in 1925 th is hypoth esis w as put to th e test w h en Dr. Felix Man dl successfully rem oved an en larged parathyroid glan d in a patien t, w ith m arked im provem en t in th e accom panyin g bon e disease.6 Aroun d th is tim e, Fuller Albrigh t an d colleagues at th e Massachusetts Gen eral Hospital began careful m etabolic studies to characterize calcium an d ph osph ate turn over.8,9,10,11,12 A New En glan d sea captain by th e n am e of Ch arles Martell h ad developed severe parathyroid bon e disease an d w as operated on by Dr. Edw ard Rich ardson , h ead of th e Depar tm en t of Surger y at th e Massach usetts Gen eral Hospital. No abn orm al parathyroid tissue w as located in th e n eck despite repeated surgeries. Dr. Oliver Cope, th en a surgical residen t, un dertook a study on n orm al variation s in th e parathyroid glan ds. In 1932, Dr. Edw ard Ch urch ill, togeth er w ith Dr. Cope, in Captain Martell’s seven th surgery, exten ded th e in cision to th e ch est w ith a sternotom y an d successfully rem oved a parathyroid aden om a from th e m ediastin um .13 Un fort un ately, Captain Martell w en t on to die from ren al failure related to kidn ey ston e disease from th e m any years of severe hyperparathyroidism . Durin g th at tim e, w ork w as also proceeding on th e purification of parathyroid h orm on e (called “parathyrin ” at th at tim e).

Han son ,14 an d later Collip,15 w ere able to successfully m ake a purified extract of PTH from bovin e parathyroids. Jam es Collip, w h o h ad previously assisted in th e preparation of an in sulin extract w ith Drs. Ban tin g an d McLeod, dem on st rated th at adm in istration of h is extract successfully preven ted th e developm en t of tetany in a pat ien t.16 Furth er ch aracterization of th e PTH m olecule required m ore pure preparation s, w h ich w as even tually accom plish ed by Aurbach 17 an d Rasm ussen an d Craig 18 in 1959.

4.3 Parat hyroid Physiology Evolution arily, parathyroid glan ds are kn ow n to be present in am ph ibian s an d m am m als but n ot fish . In view of calcium ’s m ultiple essen tial roles in th e body, it h as been hypoth esized th at, as organ ism s m igrated from th e ocean (w ith a h igh calcium conten t) to lan d th ey required a m ech an ism for regulatin g th is key ion , an d th us th ose organ ism s th at developed parathyroid glan ds w ere at a selective advan tage.19 In h um an s, th e parathyroid glan ds develop from th e en doderm of th e th ird an d fourth ph ar yn geal pouch es. A key tran scription factor in th e developm en t of th e parathyroid glan ds is Gcm -2.20 Th is tran scription factor appears to be exclusively expressed in th e parathyroid glan ds. Phylogen etic studies h ave also sh ow n it to be expressed in ph ar yn geal pouch es in fish (from w h ich th e in tern al gill buds develop).21 Th us Grah am et al22 speculate th at th e evolution of th e parathyroid glan ds w as a n atural progression from th e gills in fish to th eir presen t form and th us th e reason for th e glan ds’ location in th e n eck.

4.3.1 Calcium Recept ors Calcium is th e key regulator of PTH secretion . Un til recen tly, it w as n ot clear h ow th is cation regulated PTH secretion . It is n ow kn ow n th at th ere is a distin ct calcium receptor th at belon gs to th e G-protein coupled seven -t ran sm em bran e-dom ain receptor fam ily.23 In addition to th e ch ief cells in th e parathyroid glan d, th e calcium receptor is expressed in m ultiple oth er tissues, in cluding C cells in th e thyroid, kidn ey, bon e cells, cart ilage, in testin e, placen ta,24 brain , lun g, an d keratin ocytes,25 w h ere it plays a key role in regulatin g calcium balan ce ( Fig. 4.2).

Fig. 4.2 The calcium-sensing receptor is widely expressed and can bind other ligands besides calcium . Parathyroid hormone (PTH) secretion from the parathyroid gland is negatively regulated by ionic calcium concentration. As calcium drops, PTH secretion increases rapidly within a narrow range. cAMP, cyclic adenosine monophosphate; CaSR, calcium -sensing receptor; ERK, extracellular signal-regulated kinase; PKC, protein kinase C; PLC, phospholipase C; PTH, parathyroid hormone.

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Anatom y, Physiology, and Pathology of the Thyroid Com part m ent Alth ough th is receptor h as th e h igh est a n it y for calcium , it w ill also bin d oth er polyvalen t cation s, like m agn esium , an d arom atic am in o acids, such as L-ph enylalan in e an d L-tr yptoph an .26 In fact , th e presence of th e calcium receptor on an tral G cells (w h ich secrete gast rin ), gast ric parietal cells (w h ich secrete acid), an d ren al cort ical th ick ascen ding lim b cells (w h ich regulate urin ar y calcium ) m ay explain w hy in gestion of protein or am in o acids results in in creased gastrin , acid secretion , an d urin ary calcium excret ion , respect ively.26 Bin din g of calcium to th e calcium receptor in th e parathyroid glan ds results in suppression of PTH secretion . Stim ulation of PTH secretion because of hypocalcem ia follow s a sigm oidal cur ve, w ith large in creases in PTH secretion occurrin g w ith on ly sm all drops in serum calcium . Th e parathyroid t issue expresses ver y h igh levels of th e calcium receptor, an d calcium bin din g results in activation of ph osph oin osit ide-specific ph osph olipase C (PI-PLC) an d activation of protein kin ase C (PKC). In addition to th is sign al tran sd uct ion path w ay, calcium bin din g to its receptor also act ivates th e ph osph olipase A2 (PLA2 ), ph osph olipase D (PLD), an d m itogen -activated protein kin ase (MAPK) path w ays. Th ese calcium receptor–regulated proliferative path w ays h ave a m ajor im pact on parathyroid cell m itosis. Un der n orm al con dition s th ere is ver y little proliferative act ivit y in parathyroid t issue; h ow ever, hypocalcem ia m arkedly stim ulates parathyroid cell division , as seen in patien ts w ith ren al failure. Calcium receptor bin din g in parathyroid tissue also activates th e in h ibitory G protein (Gi) an d in h ibits adenylate cyclase an d low ers cyclic aden osin e m on oph osph ate (cAMP) levels. In terestin gly, th ese sign al t ran sduct ion path w ays can also be m odulated by oth er cation s. It h as lon g been kn ow n th at hypom agn esem ia in h ibits PTH secretion . It h as recen tly been sh ow n th at th is hypom agnesem ic-in duced in h ibition of PTH secretion is secondar y to an in creased activation of th e ph osph oin ositide path w ay an d greater in h ibit ion of cAMP.

4.3.2 Parat hyroid Horm one St ruct ure and Secret ion PTH is syn th esized in th e ch ief cells as a larger peptide th at is 115 am in o acids lon g (pre-pro PTH), an d is th en cleaved in th e en doplasm ic reticulum to a peptide th at is 90 am in o acids in len gth (pro-PTH). Fin ally, 6 addition al am in o acid residues are rem oved in th e Golgi com plex to result in an 84-am in o-acid peptide (PTH1–84) stored in secretor y vesicles for im m ediate release. Th e am in o portion of th e m olecule (1–34) h as been con sidered to h ave full biological act ivit y. Th e first th ree am in o acids of th e peptide are essen tial for activatin g adenylate cyclase. Am in o acids 24 to 32 provide PTH w ith its am ph iph ilic alph a h elical conform ation , w h ich is im portan t in PTH receptor bin din g an d PKC activation .27 Carboxy-term in al fragm en ts distal to am in o acids 1 to 34 (i.e., 35–84) w ere n ot con sidered to h ave any biological activit y, even th ough th is portion of th e m olecule is h igh ly conser ved. More recen t studies h ave dem on strated, h ow ever, th at carboxy-term in al PTH fragm en ts do h ave specific cellular e ects. Th ere is at present n o consen sus con cern in g th e im portan ce of th ese e ects in term s of eith er th e cell biology or th e physiology of PTH act ion . PTH secretion is prim arily regulated by th e calcium concen tration via th e calcium receptor as already discussed. Th e

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parathyroid glan d is prim ed to secrete PTH ton ically, an d it is calcium bin din g th at in h ibits th is PTH secretion . Durin g prolon ged hypocalcem ia (lastin g > 1 h ), PTH degradation is m arkedly reduced. If th e hypocalcem ia persists, ultim ately th ere is proliferation an d hyperplasia of th e parathyroid tissue. Th e form of PTH secreted can var y accord in g t o calciu m levels. For exam p le, u n d er n orm ocalcem ic con d it ion s PTH is p red om in an t ly secreted from t h e p arat hyroid glan d s as t h e in t act m olecu le (PTH1–84), w h ich is t h en p rocessed in t h e liver an d kid n eys in t o a n u m ber of fragm en t s t h ough t to be biologically in er t . Un d er h yp ercalcem ic con dit ion s t h e p rop or t ion of carboxy-t erm in al fragm en ts (PTH7–84, PTH24– 84; PTH28–84; PTH34–84; PTH37–84, an d PTH43–84) secreted by t h e p arat hyroid glan d in creases, an d PTH1–84 d ecreases. In addition to hypocalcem ia, hyperph osph atem ia also stim ulates PTH secret ion in vitro th rough a decrease in cytosolic PLA2 activit y. Ph osph ate stim ulates PTH gen e expression by decreasin g th e degradation of th e PTH tran script. It w ould also appear th at 1,25-dihydroxyvitam in D3 decreases PTH secretion an d in h ibits parathyroid glan d hyperplasia.

4.3.3 Parat hyroid Horm one Recept ors Th e classic act ion s of PTH on kidn ey an d bon e are m ediated by th e am in o-term in al 1–34 residues of th e m olecule th rough a seven -tran sm em bran e-dom ain G-protein -coupled receptor, PTH1 R. Th is receptor couples to both adenylyl cyclase an d PIPLC. A secon d putative receptor for PTH w as clon ed from a rat cerebral cortex cDNA librar y.28 Th e am in o acid sequen ce sh ares 51% am in o acid h om ology w ith PTH1 R. Th is PTH2 R is distributed less w idely th an PTH1 R an d is foun d predom in an tly in th e brain an d pan creas, w ith lesser expression in th e placen ta an d testis. Th e PTH2 R binds PTH(1–34) preferen tially over parathyroid h orm on e–related peptide (PTHrP1–36) an d appears to act ivate th e adenylyl cyclase sign al tran sd uct ion path w ay at relatively low con cen tration s of PTH (betw een 10 – 10 an d 10 –9 M). How ever, th is receptor does n ot respon d to com parable doses of PTHrP. How ever, PTH2 R appears to h ave a h igh er a n it y for th e tuberoin fun dibular peptide (TIP34) th an for PTH. Th us, PTH2R m ay be a m isn om er because it w ould appear th at th is is n ot a true PTH receptor an d m ay act ually be a TIP receptor. A th ird putative PTH receptor w as iden tified in zebrafish an d h as h om ology to PTH1 R. How ever, th ere does n ot appear to be a h um an h om ologue, an d th is receptor (PTH3R) m ay h ave evolved th rough gen e duplication . Th us, even th ough th ree putative PTH receptors h ave been iden tified (PTH1R–PTH3R), on ly PTH1 R appears to be a true PTH receptor. An addition al putative carboxy-term in al PTH receptor w as ch aracterized by In om ata et al.29 Usin g radiolabeled C-term in al PTH fragm en ts for bin din g an d cross-lin kin g studies, th ese investigators ch aracterized t w o protein s of 90 an d 40 kDa in size in a rat osteosarcom a cell lin e (ROS 17/2.8). Th ese putative receptors dem on st rate a h igh er a n it y for C-term in al fragm en ts of PTH (PTH19–84; PTH39–84; PTH53–84) th an for Nterm in al fragm en ts of PTH or for C-term in al fragm en ts of PTHrP. Carboxy-term in al PTH fragm en ts do n ot bin d to PTH1 R an d do n ot elevate cellular cAMP levels.

Physiology of the Parat hyroid Glands

Fig. 4.3 Target tissues for parathyroid horm one (PTH). PTH receptors are present in m any tissues, although bone and kidney are the m ain classical targets. In the kidney, PTH increases 1-alpha hydroxylase activit y and synthesis of 1,25-dihydroxyvitamin D3 . It also decreases urinary calcium excretion and increases urinary phosphate excretion. In the bone it predominantly targets the osteoblasts and secondarily the osteoclasts. Ca, calcium ; PTH, parathyroid hormone.

4.4 Parat hyroid Horm one Target Organs 4.4.1 PTH Act ions in t he Kidney PTH h as m ultiple action s in th e kidn ey, in cluding decreasin g ph osph ate an d bicarbon ate reabsorption in th e proxim al t ubule an d in creasin g calcium reabsorption in th e distal tubule ( Fig. 4.3). Because of th ese PTH act ion s in th e kidn ey th e m ost com m on elect rolyte abn orm alit ies in p rim ar y hyp erp arathyroid ism are hyp ercalcem ia w ith hyp op h osp h atem ia an d a hyp erch lorem ic m et abolic acid osis. Abou t 50% of p at ien t s w it h p rim ar y hyp erp arat hyroid ism h ave a seru m p h osp h oru s level < 2.5 m g/d L, an d 40% of p at ien t s h ave a ch lorid e level > 107 m Eq/L.30 PTH also in creases th e act ivit y of th e 25-hyd roxyvitam in D 1-alp h a hyd roxylase en zym e in t h e m it och on d ria of t h e p roxim al t u bu le cells. Th is en zym e conver t s circu lat in g 25hyd roxyvit am in D to t h e act ive 1,25-d ih d yroxyvit am in D m etabolite, w h ich in tu r n in creases calciu m absorp tion in th e sm all in t est in e by in creasin g t h e levels of an in t est in al calciu m -bin d in g p rotein .31 In ad equ ate levels of vit am in D resu lt in p oor in test in al calcium absorp t ion from t h e d iet, an d even t h e sm all am ou n t s of t h e ion lost in t h e u rin e can n ot be rep laced . PTH secret ion rem ain s h igh in an attem p t to com p en sate, resu ltin g in th e p rogressive d rain in g of calciu m from t h e bon e reser voir in an at t em p t t o m ain t ain seru m calciu m levels. Th is loss of calciu m resu lts in p oorly m in eralized

Fig. 4.4 Vitam in D generation and m etabolism . Solar irradiation converts 7-dehydrocholesterol (7-DHC) in the skin to previtamin D3 (preD3 ), which then thermally rearranges to vitam in D3 . Vitam in D3 leaves the skin and is transported throughout the body bound to the serum protein, vitam in D binding protein (DBP). Vitam in D is hydroxylated in the liver to inactive 25-hydroxyvitam in D3 [25(OH)D3 ] by the enzym e 25-hydroxylase (CYP2R1) and then to the active m etabolite 1,25-dihydroxyvitam in D3 [1,25(OH)2 D3 ] by the 1αhydroxylase (CYP27B1) enzym e in the kidney. It should be noted that the skin itself also expresses the 25-hydroxylase and 1-hydroxylase enzymes and so can produce active 1,25-dihydroxyvitam in D3 ; however, the skin does not seem to contribute to the system ic levels of 1,25-dihydroxyvitam in D3 , although this sterol horm one does appear to serve a paracrine role to regulate skin cell (keratinocyte) growth and differentiation.

bon es an d is term ed ricket s in t h e you n g, or ost eom alacia in ad u lt s. Vitam in D can be obtain ed from exposure of th e skin to ultraviolet B radiation in sun ligh t ( Fig. 4.4) or from th e diet. Ultraviolet irradiation of 7-dehydroch olesterol (provitam in D) in th e skin ph otolyzes th is sterol to previtam in D, a th erm odyn am ically un stable com poun d th at rapidly converts to vitam in D, an d is th en circulated in th e bloodstream boun d to vitam in D– bin din g protein .32,33,34 Vitam in D can also be obtain ed from dietary an im al an d plan t sources. Circulatin g vitam in D is m etabolized in th e liver to 25-hydroxyvitam in D, an in active m etabolite th at is th en converted to active 1,25-dihydroxyvitam in D in th e kidn ey un der th e cont rol of PTH. Historically, th e abilit y to obtain vitam in D from t w o sources (th e diet or sun exposure) w as a source of con fusion an d debate am on g scien tists at th e tim e. Betw een th e 1600s an d th e 1900s, th e in dustrial revolution, w ith its in creased pollution , urban ization , an d overall decreased solar exposure, led to an in creasin g prevalen ce of rickets in ch ildren , such th at, at th e tu rn of th e 19th cent ury, ~ 90% of ch ildren on autopsy presen ted w ith th e disease.32,33 As early as 1822, Sn iadecki origin ally proposed th at rickets w as due to lack of sun ligh t,32,34 an d th is idea w as

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Anatom y, Physiology, and Pathology of the Thyroid Com part m ent supported alm ost 7 decades later in th e epidem iological studies of Palm .32,34 From about 1919 to 1922 various research ers w ere able to dem on st rate th at exposure to radiation from a m ercury vapor quartz lam p or th e sun could cure rickets.32,33,34,35 Durin g th is sam e t im e several investigators also sh ow ed th at rach itic an im al m odels could be cured by adm in istration of cod liver oil, w h ich is n ow kn ow n to be h igh in vitam in D. By about 1925 th e con fusion about w h eth er rickets could be cured by direct exposure to th e sun or a dietary factor w as resolved by studies of th eir com m on m ech an ism of act ion , leadin g to th e fort ification of m ilk products w ith vitam in D an d virtually eradicating rickets.32,33 Neverth eless, th ere is an on goin g debate about th e exact requirem en ts for th is im portan t sterol, w ith question s about its poten t ial ben eficial e ects on t issues an d organ s in addition to bon e. Th e In stit ute of Medicin e (IOM) h as recen tly am en ded its recom m en ded vitam in D requirem en t to 600 in tern ation al un its for adults aged 19 to 70, statin g th at th is am oun t seem s to fu lly protect bon e h ealth an d in dicatin g th at th e data for e ects on oth er tissues are equivocal.36 Neverth eless, th ere are som e scien tists w h o feel th at th e IOM did n ot properly evaluate all of th e data,37 an d m ore research is n eeded.36

4.4.2 PTH Act ions on Bone PTH h as com plex e ects on th e bon e ( Fig. 4.3). PTH receptors are present on bon e-form in g cells, osteoblasts, an d in th e osteoblast precursors, m esen chym al stem cells. In pat ien ts w ith lon g-stan din g hyperparathyroidism th ere is an in crease in th e n um ber of cells th at break dow n bon e, osteoclasts, but th is appears to be an in direct e ect m ediated by release of soluble factors from th e osteoblast in respon se to PTH. Osteoclast n um ber an d activit y are regulated by th e balan ce betw een factors th at stim ulate osteoclast ic m aturation , such as receptor act ivator of n uclear factor-κB ligan d (RANKL), an d th ose factors th at in h ibit osteoclastic developm en t , such as osteoprotegerin (OPG), w h ich is a soluble decoy receptor for RANKL. Both of th ese factors are produced by osteoblasts, an d PTH favors th e product ion of RANKL over OPG, th us in creasin g th e n um ber an d act ivity of osteoclasts.31 On th e oth er h an d, PTH in creases th e n um ber of osteoblasts by decreasin g osteoblast apoptosis 38,39 an d in creases th e product ion of grow th factors, such as in sulin -like grow th factor 1 (IGF-1), by osteoblasts.40,41 Th e fact th at th e an abolic e ect of PTH predom in ates is eviden ced by th e fact th at PTH is curren tly used for th e treatm en t of osteoporosis, alth ough th e key di eren ce seem s to be th at, in prim ar y hyperparathyroidism , PTH levels are elevated in a sustain ed m an n er, w h ereas PTH, w h en used for treatm en t of osteoporosis, is adm in istered in an in term itten t fash ion .

4.4.3 PTH Act ions on Nonclassical Target Organs For m any years, th e exclusive target cells for PTH act ion w ere th ough t to be th ose in several segm en ts of th e proxim al an d distal ren al tubules an d certain bon e cells.42,43 How ever, m ore recen t w ork h as led to th e discover y th at th ere are e ects of PTH on a variety of oth er cells, in cluding cardiac m yocytes,

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adren al glom erulosa cells,44 vascular en dothelial cells,45 an d vascular sm ooth m uscle cells.44,46,47 It w as in itially th ough t th at PTH m igh t be a vasoconstrictor because th ere is a h igh er in ciden ce of essen tial hyperten sion in patien ts w ith prim ary hyperparathyroidism an d because parathyroidectom y in spon tan eously hyperten sive rats (SHR) preven ts th e developm en t of hyperten sion . How ever, investigators foun d th at if PTH w as in fused in vivo, th e h orm on e caused sm ooth m uscle relaxation ,48 an d if PTH w as in fu sed in to an im als or h um an s, th ere w as an in itial rapid (th ough t ran sien t) fall in blood pressure. Th e in itial hypoten sive e ect is seen w ith am in o term in al PTH fragm en ts (1–34), is m ost e ective w h en th e m uscle is precon tracted, an d is predom in an tly a cAMP, an d n ot a n itric oxide cyclic guan osin e m on oph osph ate-m ediated, relaxation. PTH h as also been reported to block L-t ype calcium ch an n el curren t in a n eural cell lin e, suggestin g an altern ate possible m ech an ism for its abilit y to in duce sm ooth m uscle relaxat ion .49 PTH recep tors h ave been sh ow n to be present in vascular en dothelial cells,45 an d PTH can m odulate secretion of th e poten t vasocon strictor en doth elin -1. Th us som e of th e discrepan cies in th e observation s of PTH e ects on m uscle an d vasculature m ay relate to di eren ces in direct PTH e ects on sm ooth m uscle versus in direct e ects th rough en doth elial cells. Th e closely related m olecule PTHrP also appears to be a poten t vasorelaxan t,50 an d it is possible th at th e act ion of PTH on sm ooth m uscle relaxation is m ediated th rough a PTHrP receptor. PTHrP m RNA an d th e protein itself are kn ow n to be presen t in vascular sm ooth m uscle an d en doth elial cells. Th erefore, it h as been proposed th at PTHrP m ay be a vasodilatory paracrin e factor secreted to regulate sm ooth m uscle con tract ion .51,52,53,54 PTH h as also been sh ow n to poten tiate an gioten sin II–stim ulated aldosteron e secretion in vitro an d th us plays a role in th e h igh er in ciden ce of h igh blood pressure seen in patien ts w ith prim ary hyperparathyroidism , alth ough h igh PTH con cen tration s w ere used in th e publish ed studies. It is possible th at th is PTH e ect is seen in vivo on ly in situation s of sustain ed elevation s of PTH, such as in prim ar y hyperparathyroidism .

4.5 Conclusion Calcium regulation is exquisitely regulated in vivo, w ith sm all ch anges in serum calcium leadin g to large ch anges in PTH secretion , an d addition al ch anges in calcium h an dlin g by th e kidn ey an d in testin e. Because of th e evolut ion ar y t ran sition from a calcium -rich ocean environ m en t to a calcium -poor lan d environ m en t , th e h um an body contain s m ultiple h om eostatic m ech an ism s to protect again st hypocalcem ia; th us th is is a relatively rare occurren ce. Hypercalcem ic disorders on th e oth er h an d are com m on an d m ay ran ge from ben ign to m align an t processes involving th e parathyroid glan ds. Th e presen t availabilit y of agen ts th at m odify calcium bin din g to its receptor in th e parathyroid glan d (calcilytic or calcim im etic agen ts), parathyroid glan d grow th an d proliferation (vitam in D an alogues), or parathyroid h orm on e processing m akes it essen tial for th e clin ician to h ave a clear un derstan din g of th e n orm al physiological regulation of PTH secretion to m ake m ore ration al th erapeutic decision s.

Physiology of the Parat hyroid Glands

4.6 Acknow ledgm ent Dr. Isales’s w ork is supported in part by fun din g from th e Nation al In stit ute of Health (NIA # P01AG036675). Dr. Bollag is supported by a VA Research Career Scien tist Aw ard. Th e con ten ts of th is art icle do n ot represen t th e view s of th e Departm en t of Veteran s A airs or th e Un ited States Govern m en t.

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Anatom y, Physiology, and Pathology of the Thyroid Com part m ent [51] Hon go T, Kupfer J, En om oto H, et al. Abun dan t expression of parathyroid h orm on e-related protein in prim ar y rat aor tic sm ooth m uscle cells accom panies serum -in duced proliferation . J Clin Invest 1991; 88(6); 1841–1847 [52] Okan o K, Wu S, Huan g X, et al. Parathyroid h orm on e (PTH)/PTH-related protein (PTHrP) receptor an d its m essen ger ribon ucleic acid in rat aortic vascular sm ooth m uscle cells an d UMR osteoblast-like cells: cell-specific regulation by an gioten sin-II an d PTHrP. En docrin ology 1994; 135(3); 1093–1099

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[53] Pirola CJ, Wan g HM, Strgacich MI, et al. Mech anical stim uli in duce vascular parathyroid h orm on e-related protein gen e expression in vivo an d in vitro. En docrin ology 1994; 134(5); 2230–2236 [54] Rian E, Jem tlan d R, Olstad OK, et al. Parathyroid h orm on e-related protein is produced by cultured en doth elial cells: a possible role in an giogen esis. Bioch em Biophys Res Com m un 1994; 198(2); 740–747

Thyroid and Parathyroid Pathology

5 Thyroid and Parat hyroid Pat hology Paul W. Biddinger and Yuri E. Nikiforov

5.1 Int roduct ion

5.2.2 Thyroidit is

Th e thyroid an d parathyroid glan ds are suscept ible to a n um ber of path ological processes, in cluding developm en tal, in flam m atory, autoim m un e, an d n eoplastic con dition s. A fun dam en tal un derstan din g of thyroid an d parathyroid path ology is critical in coun selin g an d m an aging patien ts w ith th ese diseases.

Chronic Lym phocyt ic Thyroidit is (Hashim ot o’s or Aut oim m une Thyroidit is)

5.2 Thyroid Pat hology 5.2.1 Developm ent al Lesions of t he Thyroid Ectopic thyroid tissue is usually found m edially along the em bryological m igration track of the m edial anlage between the base of tongue and the norm al thyroid location. Most cases of ectopia involve the tongue and are asym ptom atic. However, lingual ectopia can be sym ptom atic due to m ass e ect, and m ost sym ptom atic cases lack other functional thyroid tissue.1 Rare cases of carcinom a arising in lingual thyroids have been reported.2 Thyroglossal duct cysts develop from rem n an ts of th e thyroglossal duct , typically in th e m idlin e of th e n eck betw een th e foram en cecum an d th e thyroid. Cysts usually con tain m ucoid or gelat in ous m aterial, but thyroid tissue is usually n ot grossly iden tifiable. Th e lin ing of th ese cysts ran ges from ciliated epith elium to sim ple cuboidal or stratified squam ous cells. Colloidcontain ing follicles are seen in about 50% of cases.3 Fin e-n eedle aspiration (FNA) gen erally yields sparsely cellular specim en s w ith foam y or h em osiderin -lad en m acroph ages in a backgroun d of am orph ous m aterial. Ciliated or squam ous cells m ay be seen , but thyroid follicles are un com m on fin din gs in FNAs. Cysts m ay becom e in fected or m ay rarely un dergo m align an t tran sform ation . Most cases of m align an cy are papillar y thyroid carcin om as (PTCs).2

Ch ron ic lym ph ocytic thyroiditis (CLT), altern atively kn ow n as Hash im oto’s thyroidit is or autoim m un e thyroiditis, is an autoim m un e disorder an d th e m ost com m on clin ically sign ifican t form of thyroiditis. It is ch aracterized by dest ruction of follicular cells, w h ich , over tim e, can result in hypothyroidism . Th e path ogen esis of CLT is in com pletely un derstood, but both cellm ediated an d h um oral m ech an ism s appear to be involved, probably in duced by th e in teraction of gen etic an d environ m en tal factors.4 CLT is t ypically associated w ith di use thyroid en largem en t, gen erally, t w o to four tim es n orm al size. Thyroid t issue is usually paler th an its n orm al red-brow n color due to lym ph ocyt ic in filtration an d loss of follicular t issue. Glan ds m ay sh ow accen tuated lobulation . Histologically, th e m ost ch aracteristic feature is in filtration by lym ph ocytes an d plasm a cells ( Fig. 5.1). Th e lym ph oplasm acyt ic in filtration is di use but variable in its in ten sity an d e acem en t of th e follicles. Lym phoid germ in al centers are an oth er ch aracteristic feature. Variable n um bers of follicular epith elial cells exh ibit en largem en t an d abun dan t, fin ely gran ular eosin oph ilic cytoplasm , know n as on cocyt ic or Hü rth le cell m etaplasia. Th is appearan ce is caused by abun dan t cytoplasm ic m itoch on dria. On cocytic follicular cells m ay also sh ow n uclear en largem en t an d prom in en t n ucleoli. Varian ts of CLT in clude fibrous, fibrous atrophy, toxic (h ash itoxicosis), an d juven ile, th ough m ost cases of CLT h ave sligh t to m oderate fibrosis. Th e fibrous varian t usually exh ibits som e degree of thyroid en largem en t associated w ith m arked deposition of den se fibrous tissue an d follicular atrophy. Fibrosis is lim ited to th e thyroid, in contrast to th e extrathyroidal fibrosis

Fig. 5.1 Chronic lym phocytic thyroiditis. (a) Lym phoplasm acytic infiltrate, germ inal center, follicular atrophy, and oncocytic m etaplasia. (b) High-power view of oncocytic m etaplasia. (Hem atoxylin-eosin stain)

31

Anatom y, Physiology, and Pathology of the Thyroid Com part m ent of invasive fibrous (Riedel’s) thyroidit is. Squam ous m etaplasia is m ore com m on an d prom in en t com pared to classic CLT. Som e cases m ay represen t im m un oglobulin G4 (IgG4)-related sclerosin g disease involving th e thyroid.5 Th e fibrous atrophy varian t is h istologically sim ilar to th e fibrous varian t but is distin guish ed by th e sm all size of th e thyroid. Wh eth er th e fibrous atrophy varian t represen ts progression of th e fibrous varian t an d/or classic form of CLT or h as a distin ct path ogen ic m ech an ism is un clear at th is tim e. CLT m ay be associated w ith hyperthyroidism , a con dition referred to as h ash itoxicosis. Thyroids w ith th is con dition gen erally exhibit classical ch anges of CLT w ith variable degrees of follicular epith elial hyperplasia.6

Subacut e Granulom at ous Thyroidit is (Subacut e or de Quervain’s Thyroidit is) Subacute gran ulom atous thyroiditis (SGT) is ch aracterized by th e presen ce of epith elioid m acroph ages (h istiocytes) an d variable n um bers of m ultin ucleated gian t cells. Th is condition h as a variet y of altern ate n am es, in cluding de Quer vain ’s, subacute, pain fu l subacute, post viral, an d gian t cell thyroiditis. SGT appears to be th e result of a system ic illn ess, w ith viral in fect ion bein g th e leadin g suspect, alth ough con clusive eviden ce is lackin g at th is tim e. Th e thyroid glan d is usually en larged to about t w ice its n orm al size. Th e en largem en t m ay be asym m etric, an d a sm all percen tage of cases present as a solitar y n odule.7 Durin g th e early, usually hyperthyroid, stage of disease th e thyroid sh ow s follicular dam age w ith loss of epith elium an d colloid. Acute an d ch ron ic in flam m ator y cells are present w ith in residual follicles an d in terfollicular areas. Over tim e gran ulom atous an d ch ron ic in flam m ation w ith variable degrees of fibrosis predom in ate.8 Distin ct gran ulom ata or lym ph oid follicles are usually n ot seen ; in stead gian t cells are foun d aroun d disrupted follicles. Th e in flam m ator y an d repair process m ay be h eterogen eous w ith areas of active in flam m at ion coexistin g w ith areas of fibrosis.

Acut e Thyroidit is Acute, or suppurative, thyroiditis is ch aracterized by a predom in an tly n eutroph ilic in flam m atory in filtrate. Th is is a rare form of thyroiditis, usually caused by bacterial in fect ion arisin g elsew h ere in th e n eck an d secondarily involving th e thyroid. In ch ildren , acute thyroiditis is usually associated w ith a pyriform sin us fistula.9

Invasive Fibrous Thyroidit is (Riedel’s Thyroidit is) Invasive fibrous thyroiditis (IFT), also kn ow n as Riedel’s, fibrosin g, or sclerosing thyroiditis, is a rare disease ch aracterized by progressive fibrosis of th e thyroid. A ected glan ds are extrem ely firm an d adh eren t to perith yroidal tissues due to fibrosis exten ding beyon d th e thyroid. Th e thyroid paren chym a is e aced by ch ron ic in flam m ation an d fibrosis, w ith absen ce or m arked atrophy of follicles. Lym ph ocytes an d plasm a cells are th e predom in an t in flam m ator y cells. Occlusive vasculit is of sm all- to m edium -sized vein s is a dist in ct ive feature. FNA is alm ost alw ays n on diagn ostic due to acellular or paucicellular

32

specim en s. Th e presen ce of IgG4-posit ive plasm a cells an d association w ith oth er fibroin flam m ator y disorders suggest th at IFT m ay be a m an ifestation of IgG4-related sclerosin g disease.10

5.2.3 Goit er Goiter is a n on specific term m ean in g en largem en t of th e thyroid an d en com passes m ultin odular, en dem ic, dysh orm on ogen etic, di use toxic, an d am yloid goiter. Th ese en tit ies, w ith th e except ion of am yloid goiter, are associated w ith hyperplast ic ch anges of th e follicles.

Mult inodular Goit er (Nodular Hyperplasia) Multin odular goiter (MNG) is a com m on con dition ch aracterized by en largem en t of th e thyroid glan d w ith variable am oun ts of n odularit y. MNG is also kn ow n as n odular hyperplasia, n odular goiter, colloid goiter or n odule, aden om atoid n odule or hyperplasia, an d oth er com bin ation s of th ese term s. Th e term n odular hyperplasia reflects h istopath ologic ch anges seen in th is con dition an d is often used in th e path ological description an d diagn osis. Sporadic an d en dem ic MNG h ave com parable path ological features. En dem ic goiter is usually due to dietary iodin e deficien cy.11 Sporadic cases h ave a n um ber of possible path ogen ic m ech an ism s, in cluding in dividual dietary iodin e deficien cy, excessive in gestion of goitrogen ic foods, m edication s, in creased thyroid-stim ulatin g h orm on e (TSH) secretion , an d con stitu tive activation of follicular cells due to som atic m utation s of th e TSH receptor gen e.12 Iden t ifyin g a specific cause m ay be di cult, if n ot im possible, because m ost cases of MNG appear to be due to com plex in teraction betw een m ultiple gen es an d various environ m en tal factors. Con gen ital defects in th e path w ays of thyroid h orm on e syn th esis an d release can result in dysh orm on ogen etic goiter an d associated hypothyroidism . MNG is ch aracterized by thyroid en largem en t th at can ran ge from m ild to m assive. Most cases h ave m ultiple n odules eviden t grossly, alth ough early cases m ay lack distin ct n odularit y or on ly h ave a sin gle m acroscopic n odule. Thyroid en largem en t m ay be sym m etric or asym m etric. Th e section ed surfaces t ypically h ave a n odular, h eterogen eous appearan ce. Som e areas h ave a sem itranslucen t appearan ce due to abun dan t colloid, w h ereas oth er foci exh ibit h em orrh age, fibrosis, cystic degen eration , an d/or calcificat ion . Nodules m ay appear part ially en cap sulated by fibrous tissue. Microscopically, follicles exh ibit variable sizes an d sh apes, ran ging from sm all w ith m in im al colloid to ver y large w ith abun dan t colloid ( Fig. 5.2). Som e path ologists use th e term aden om atous n odule to refer to a n odule w ith h igh cellularit y due to a m icrofollicular or solid grow th pattern , an d th e term colloid n odule for a n odule w ith abun dan t colloid an d a low den sit y of follicular cells. Th e follicular epith elium varies from flatten ed to cuboidal or colum n ar an d focally m ay exh ibit on cocyt ic or clear cell features. Follicles m ay contain papillar y-like in foldin g of epithelium , som etim es raisin g con cern for papillar y carcin om a. Foci of h em orrh age an d fibrosis are com m on an d m ay be associated w ith dystroph ic calcification . FNA t ypically yields a m ixture of colloid an d ben ign -appearin g follicular cells. Follicular cells are usually arran ged in even ly spaced m on olayer sh eets. Macroph ages are com m on ly seen an d m ay contain h em osiderin .

Thyroid and Parathyroid Pathology

Fig. 5.2 Multinodular goiter (nodular hyperplasia). (a) Macrofollicles with abundant colloid. (b) Area with follicles ranging from m acrofollicular to m icrofollicular with scant colloid. (Hem atoxylineosin stain)

Endem ic Goit er

Toxic MNG is a com plication of MNG in w h ich on e or m ore n odular collect ion s of follicular cells secrete an excessive am oun t of thyroid h orm on e. A ected glan ds are grossly com parable to n on toxic MNG. Microscopically, on e or m ore n odules m ay sh ow features of hyperfun ct ion , in cluding tall follicular cells, papillar y-like in foldin gs, an d scan t, w ater y colloid w ith periph eral scallopin g. Defin itive diagnosis depen ds on clinical an d laboratory fin din gs of hyperthyroidism .

by excessive product ion of thyroid h orm on e an d di use hyperplasia w ith en largem en t of th e thyroid. DTH is associated w ith extrathyroidal lesion s, in cluding in flam m at ion of th e orbital t issues, kn ow n as Graves’ oph th alm opathy, an d excessive accum ulation of glycosam in oglycan s in th e skin , kn ow n as m yxedem a. DTH is caused by autoant ibodies attach ing to th e TSH recep tor (TSHR) on follicular cells. Th e autoan tibodies act ivate th e receptor an d stim ulate thyroid h orm on e syn th esis an d secretion in addition to proliferation of th e follicular epith elium . A com bin ation of gen etic susceptibilit y an d on e or m ore environ m en tal triggers appears to result in th is autoim m un e disorder.4 Thyroid glands are m ild to m oderately enlarged, usually in a sym m etrical m anner. Untreated cases have a dark red appearance due to high vascularity, w hereas treated cases appear lighter and m ore sim ilar to norm al thyroid due to decreased vascularit y and the presence of m ore colloid. The classic m icroscopic appearance is di use hyperplasia, w ith follicles lined by tall colum nar cells that exhibit papillary-like infolding into the central space ( Fig. 5.3). Untreated cases contain very little colloid. Som e form of therapy precedes resect ion of m ost cases, resulting in reduct ion of the hyperplastic changes and an increase in the am ount of colloid. The regression of hyperplastic changes is t ypically incom plete, w ith scattered areas of follicular hyperp lasia still present. Variable num bers of lym phocytes are seen in the interfollicular strom a. Radioiodine m ay cause nuclear atypia that, in som e cases, suggests papillary carcinom a. A case of t reated DTH m ay be in terpreted as MNG or CLT by a path ologist un aw are of th e clin ical diagn osis an d prior treatm en t. Nodular lesion s are foun d in 10 to 25% of thyroids w ith DTH, an d m ost are ben ign w ith features of follicular hyperplasia or colloid n odule. How ever, about 10 to 20% of n odules are foun d to h ave carcin om a, usually papillar y carcin om a, an d th e overall in ciden ce of carcin om a associated w ith DTH is in th e 1 to 9% ran ge.15,16

Di use Toxic Hyperplasia (Graves’ Disease)

5.2.4 Thyroid Neoplasia

Di use toxic hyperplasia (DTH), also kn ow n as Graves’ disease or di use toxic goiter, is an autoim m un e disorder ch aracterized

Thyroid n eoplasia is classified in to th ree gen eral categories of prim ary epith elial, n on epith elial, an d secon dary (m etastatic)

En dem ic goiter refers to thyroid en largem en t th at occurs in a sign ifican t port ion of a region or populat ion . A com m on criterion is 5% or m ore of ch ildren aged 6 to 12 h avin g thyroid en largem en t.13 Th e path ological features of en dem ic goiter are com parable to those of MNG.

Dyshorm onogenet ic Goit er Dysh orm on ogen etic goiter results from a gen et ic defect th at in terrupts any on e of th e steps of thyroid h orm on e syn th esis. Excess TSH, released to tr y to correct th e prim ary hypothyroidism , leads to en largem en t of th e thyroid glan d. Dysh orm on ogen etic goiter is grossly in distin guish able from MNG, an d th eir m icroscopic features overlap. A feature favorin g dysh orm on ogen etic goiter is pron oun ced hyperplasia w ith a predom in an tly solid or m icrofollicular pattern th rough out th e en tire glan d, n ot just th e n odules.14 Colloid is usually absen t or m in im al, an d follicular cells frequently sh ow m arked n uclear at ypia. Th ese fin din gs in th e thyroid of a ch ild or youn g adult are suspicious for dysh orm on ogen etic goiter, but defin itive diagnosis w ill depen d on clin icopath ologic correlation an d con firm atory an cillar y studies.

Toxic (Hyperfunct ioning) Mult inodular Goit er

33

Anatom y, Physiology, and Pathology of the Thyroid Com part m ent

Fig. 5.3 Graves’ disease (diffuse toxic hyperplasia). (a) Untreated with high vascularit y and scant, watery colloid. (b) Treated with reduced vascularity and accum ulation of colloid. (Hem atoxylin-eosin stain)

tum ors. Th e World Health Organ ization classifies thyroid tum ors as follow s 17 : ● Thyroid carcin om as ○ Papillary carcin om a ○ Follicular carcin om a ○ Poorly di eren tiated carcin om a ○ Un di eren tiated (an aplastic) carcin om a ○ Squam ous cell carcin om a ○ Mucoepiderm oid carcin om a ○ Sclerosing m ucoepiderm oid carcin om a w ith eosin oph ilia ○ Mucin ous carcin om a ○ Medullar y carcin om a ○ Mixed m edullar y an d follicular cell carcin om a ○ Spin dle cell tum or w ith thym us-like di eren tiat ion ○ Carcin om a sh ow in g thym us-like di eren tiat ion ● Thyroid aden om a an d related tum ors ○ Follicular aden om a ○ Hyalin izing trabecular tum or ● Oth er thyroid t um ors ○ Teratom a ○ Prim ar y lym ph om a an d plasm acytom a ○ Ectopic thym om a ○ An giosarcom a ○ Sm ooth m uscle t um ors ○ Periph eral n er ve sh eath t um ors ○ Paragangliom a ○ Solitar y fibrous tum or ○ Follicular den drit ic cell tum or ○ Lan gerh an s cell h istiocytosis ● Secon dary (m etastatic) tum ors Most thyroid n eoplasm s are prim ar y epith elial tu m ors derived from follicular epith elium , w ith a sm all fract ion origin at in g from C cells. Great strides h ave been m ade in un derstan din g the m olecular gen etics of thyroid n eoplasia, an d th is subject is addressed in Ch apter 9.

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Papillary Thyroid Carcinom a PTC is a w ell-di eren t iated m align an t tum or of thyroid follicular cells defin ed by ch aracteristic n uclear features. A papillar y grow th pattern is frequen tly seen but is n ot required for th e diagn osis. PTC is th e m ost com m on t ype of thyroid can cer, accoun tin g for 85 to 90% of cases in th e Un ited States.18 Th e vast m ajorit y of tum ors are sporadic cases, w ith on ly a sm all port ion bein g due to germ lin e m utation s.19 Preexistin g solitar y thyroid n odules an d/or aden om as an d m ultin odular goiter are risk factors for PTC, possibly due to an in creased cell proliferation rate in aden om as an d hyperplast ic n odules an d RAS gen e m utation s in follicular aden om as th at m ay predispose to m align an t t ran sform ation .20 Grossly, m ost PTCs appear as a discrete but ill-defin ed n odule w ith irregular borders. A capsule is t ypically absen t, but som e tum ors m ay be w ell dem arcated or en capsulated, w ith th e except ion of th e follicular varian t. Tum ors ran ge in appearan ce from tan -brow n to gray-w h ite an d from firm an d solid to m ore friable w ith cystic spaces. Irregularly sh aped areas of fibrosis are frequen t. Spon tan eous n ecrosis an d h em orrh age are rare but m ay be seen after FNA. Multifocal t um ors are fairly com m on . PTC can exh ibit a variety of pattern s. Microscopically, m ost PTCs sh ow a papillar y grow th pat tern ch aracterized by fin e, fin gerlike stran ds of fibrovascular strom a covered by n eoplastic epith elial cells, usually form in g a sin gle layer. Th is pattern is com m on ly adm ixed w ith a variable proportion of n eoplastic follicles. Approxim ately t w o-th irds of tum ors h ave th is predom in an tly papillar y grow th , w h ereas about on e-th ird exhibit a predom in an tly follicular arch itecture ( Fig. 5.4).21 Papillar y carcin om as can h ave oth er grow th pattern s, in cludin g solid an d trabecular, but th ese rarely predom in ate. Despite th ese h istological fin din gs, th e diagn osis of PTC is depen den t on ch aracteristic n uclear features, n ot grow th pattern . Th ese features in clude n uclear en largem en t, overlapping,

Thyroid and Parathyroid Pathology

Fig. 5.4 Papillary thyroid carcinom a. (a) Papillary and (b) follicular growth patterns. (Hem atoxylineosin stain)

Fig. 5.5 Nuclear features of papillary thyroid carcinom a. (a) Nuclear hypochrom asia, enlargem ent, and overlapping. (b) Irregular nuclear m em brane contours. (c) Nuclear grooves (arrows). (d) Nuclear pseudoinclusion (arrow). (Hem atoxylin-eosin stain)

hypoch rom asia, irregular con tours, grooves, an d pseudoin clusion s ( Fig. 5.5). In som e PTCs all of th e n uclear features are readily iden tifiable. Oth ers exh ibit m ost , but n ot all, of th ese features, or th ey are foun d focally. Th ere is n o con sen sus on h ow m any n uclear features are su cien t for th e diagnosis an d h ow w idespread th ey sh ould be, but m ost exh ibit at least four. Non e of th ese features are path ogn om on ic for PTC, an d a sin gle feature m ay be seen in a variety of ben ign lesion s. True n uclear pseudoin clusion s h ave a relatively h igh specificit y, but th ey are

th e least com m on feature an d absen t in a sign ifican t proportion of PTCs. Psam m om a bodies are distin ctive lam in ated calcification s th at are foun d in about h alf of all PTCs.21,22 Psam m om a bodies are par ticularly abun dan t in th e di use sclerosin g varian t of PTC, an d t rue psam m om a bodies are exceedingly rare in lesion s oth er th an PTC. PTC FNA specim en s con tain follicular cells arran ged in papillae an d/or m on olayers. Th e cells exh ibit th e ch aracteristic

35

Anatom y, Physiology, and Pathology of the Thyroid Com part m ent

Fig. 5.6 Cytological features of papillary thyroid carcinom a. (a) Papillary tissue fragment (DiffQuik stain). (b) Psam mom a bodies associated with m alignant cells (hematoxylin-eosin stain). (c) Nuclear grooves and finely textured chromatin (arrow) (Papanicolaou stain). (d) Nuclear pseudoinclusion (arrow) (hem atoxylin-eosin stain).

n uclear features already n oted ( Fig. 5.6). Th e am oun t of colloid is variable, an d som etim es psam m om a bodies are seen . Multifocal disease m ay represen t eith er m ultiple in depen den t prim ar y t um ors or in traglan dular dissem in ation from a sin gle prim ar y t um or. Lym ph atic invasion is frequen tly seen , w h ereas blood vessel invasion is ver y un com m on . Extrathyroidal exten sion of tum or m ay be m in im al or exten sive. Min im al extrathyroidal exten sion in cludes in filtration of perith yroidal skeletal m uscle or th e areas surroun din g sizable vascular struct ures or n er ves.23 Wh eth er a m in im al presen ce in perith yroidal adipose tissue qualifies as extrathyroidal exten sion is som ew h at con troversial. Exten sive extrathyroidal exten sion is defin ed as involvem en t of th e adjacen t viscera (laryn x, trach ea, an d/or esoph agus), recurren t lar yn geal n erve, carotid artery, m ediastin al blood vessels, or subcutan eous soft tissues, an d som e auth ors also in clude involvem en t of adjacen t skeletal m uscle in th is category. Exten sive extrathyroidal invasion m ay be associated w ith a poorer progn osis.24

5.3 Variant s of Papillary Carcinom a PTC h as m ore th an 10 di eren t h istological varian ts, m ost of w h ich are rare. Th e m ost com m on is papillar y m icrocarcin om a, defin ed by th e World Health Organ ization (WHO) classification as PTC, w h ich is both ≤ 1 cm in diam eter an d foun d in ciden tally.17 Many m icrocarcin om as are iden tified on ly m icroscopically, an d th ey can exh ibit papillar y, follicular, or a m ixed grow th pattern .

36

Follicular varian t PTC (FVPTC) is an oth er com m on varian t ch aracterized by an exclusive or predom in an tly follicular grow th pattern , a lack of w ell-form ed papillae, an d th e presen ce of diagnost ic n uclear features of PTC. Th is is a distin ct varian t of papillar y carcin om a w ith a n um ber of ch aracteristic m olecular an d biological features, som e of w h ich overlap w ith follicular tu m ors. FVPTC is frequen tly w ell circum scribed an d som etim es en capsulated. Most of th e ch aracteristic n uclear features of PTC are presen t, part icularly n uclear en largem en t, ch rom atin clearin g, an d irregularit y of n uclear con tours. Oth er n uclear features are t ypically less abun dan t th an in classic pap illar y carcin om a. Im m un oh istoch em ical stain in g, particularly for HBME-1, m ay be h elpful w h en positive to distin guish FVPTC from a follicular aden om a or carcin om a. En capsulated subt ypes of follicular varian t are gen erally in dolen t tum ors w ith a low rate of distan t m etastasis.25 Th e tall cell varian t is ch aracterized by a predom in an ce (> 50%) of tum or cells w ith a h eigh t at least th ree tim es th e w idth ( Fig. 5.7a). Th e tall cell varian t h as a poorer progn osis w ith a sign ifican tly h igh er rate of lym ph n ode an d distan t m etastases an d low er 5-year disease-specific sur vival.26,27 Tum ors w ith a tall cell com pon en t < 50% are design ated as “pap illar y carcin om a w ith tall cell features.” Th e sign ifican t of a m in or tall cell com pon en t is un certain at th is tim e, but it too m ay be a m arker of m ore aggressive beh avior com pared to PTC w ith out tall cell features. Addition al varian ts in clude solid, di use sclerosing, colum n ar cell, on cocyt ic, Warth in -like, clear cell, cribriform -m orular, an d th ose w ith prom in en t h obn ail cells or fasciitis-like strom a. Th e solid varian t h as a predom in an tly (> 50%) solid, trabecular, or

Thyroid and Parathyroid Pathology

Fig. 5.7 Variants of papillary thyroid carcinom a. (a) Tall cell variant. (b) Solid variant. (c) Diffuse sclerosing variant with m arked fibrosis, lym phocytic infiltration, and num erous psam m om a bodies. (Hem atoxylin-eosin stain)

n ested pattern ( Fig. 5.7b). Di use sclerosin g varian t is ch aracterized by di use glan dular involvem en t, den se fibrosis, n um erous psam m om a bodies, exten sive lym ph ocyt ic in filtration , an d frequen t squam ous m etaplasia ( Fig. 5.7c). Colum n ar cell varian t is an aggressive form of PTC ch aracterized by elon gated, pseudostratified, an d often hyperch rom atic n uclei w ith a variet y of grow th pattern s. Th e cribriform -m orular varian t h as a frequen t association w ith fam ilial aden om atous polyposis.28

5.3.1 Follicular Adenom a and Carcinom a Follicular aden om a (FA) is a ben ign , en capsulated, n on invasive tum or origin atin g from thyroid follicular cells, an d follicular carcin om a (FC) is a m align an t, w ell-di eren t iated t um or of thyroid follicular cells th at lacks th e diagnost ic n uclear features of PTC. Most FAs an d FCs are solitar y n odules th at are clearly dem arcated from th e surroun din g thyroid tissue by a w ellform ed fibrous capsule. Carcin om as are distin guish ed from aden om as by invasive grow th th rough th e capsule or in to blood vessels located in or periph eral to th e capsule ( Fig. 5.8). Eith er is a su cien t criterion for m align an cy. Invasive grow th is n ot grossly iden tifiable in th e vast m ajorit y of cases. Wh en grossly iden tifiable, invasion m ay be focal in an en capsulated tu m or or w idespread in a tu m or th at h as little or n o capsule. FAs an d FCs exhibit arch itectural an d cytological features th at are dist in ct from th e surroun din g thyroid paren chym a. A variet y of m icroscopic pattern s can be seen , in cludin g m icrofollicular, solid/trabecular, n orm ofollicular, an d m acrofollicular. Microfollicular is th e m ost frequen t pattern , but m ultiple

pattern s in a given t um or are com m on . FCs ten d to be m ore cellular th an FAs, but cellularit y per se is n ot a di eren tiatin g feature. Nuclei are usually sm all to m edium , roun d w ith sm ooth con tours, un iform , an d n orm och rom atic or hyperch rom atic. Occasion ally, cells w ith large an d h igh ly irregular n uclei m ay be foun d in eith er FAs or FCs. Mitotic figures are rarely seen in aden om as, an d m ost carcin om as h ave low act ivit y (up to 1–2 per 10 h igh -pow er fields) w ith th e exception of areas of recen t FNA. Necrosis an d m ore frequen t m itoses suggest th e em ergen ce of poorly di eren tiated thyroid carcin om a.29 Assessm en t for capsular an d an gioinvasion can be ch allengin g due to a n um ber of factors, in cluding in frequen t foci an d a n um ber of real an d artifact ual ch anges th at m im ic invasion . One exam ple is prior FNA th at results in pseudoinvasive alteration s of th e capsule. Th e exten t of vascular invasion appears to be sign ifican t because invasion of four or m ore blood vessels is associated w ith an in creased rate of tu m or recurren ce an d/or tum or-related m ortalit y.30,31 FAs an d FCs h ave a n um ber of m icroscopic varian ts. On cocytic varian ts (Hü rth le cell) are com m on an d are ch aracterized by cells th at are larger th an t ypical n eoplastic follicular cells an d h ave gran ular eosin oph ilic cytoplasm due to abun dan t m itoch on dria ( Fig. 5.9). At least 75% of th e cells sh ould be on cocyt ic to qualify as th is varian t. Th e criteria for m align an cy are th e sam e as for conven t ion al FC. W h eth er on cocyt ic tum ors sh ould be considered varian ts of FAs an d FCs or distin ct varian ts is a subject of debate, an d fut ure classification m ay ch ange. Th e term oncocyt ic is recom m en ded in stead of Hürthle cell.17 Oth er m icroscopic varian ts of follicular n eoplasia in clude clear, m ucin ous, an d sign et rin g cells.

37

Anatom y, Physiology, and Pathology of the Thyroid Com part m ent

Fig. 5.8 Minim ally invasive follicular thyroid carcinom a showing (a) capsular and (b) vascular invasion. (Hematoxylin-eosin stain)

5.3.3 Poorly Di erent iat ed Carcinom a

Fig. 5.9 Oncocytic follicular thyroid neoplasm showing abundant granular eosinophilic cytoplasm . (Hem atoxylin-eosin stain)

5.3.2 Hyalinizing Trabecular Tum or Hyalin izing trabecular tum or (HTT) is a rare n eoplasm of follicular cell derivation . Th e t um or is t ypically w ell circum scribed, is som etim es en capsulated, an d h as a solid or vaguely lobulated cut surface. Th ese tu m ors lack blood vessel or capsular invasion . Microscopically th ey h ave a prom in en t trabecular pattern , an d th e in tratrabecular strom a con tain s abun dan t eosin oph ilic hyalin e m aterial. Th e cells m ay h ave a polygon al, oval, spin dled, or fusiform sh ape. Th e n uclei are roun d to oval an d often h ave irregular con tours, in tran uclear grooves, an d pseudoin clusion s. Scattered calcification s are frequen t, but t rue psam m om a bodies are less com m on . Th e tum or cells are stron gly positive for thyroglobulin , thyroid tran scription factor (TTF-1), an d low m olecular w eigh t cytokeratin s an d n egative for calciton in an d calciton in gen e-related peptide. Th e m align an t poten t ial of HTT is extrem ely low.32 Surgical excision of a n on invasive HTT sh ould be curative, even if on ly a lobectom y is perform ed.

38

Poorly di eren tiated carcin om a (PDC) is a m align an t t um or of follicular cell origin th at occupies an in term ediate position m orph ologically an d beh aviorally betw een w ell-di eren tiated thyroid carcin om as an d an aplastic carcin om a. Th e 2004 WHO classification of thyroid t um ors recognizes PDC as a specific en t it y ch aracterized by solid, trabecular, or in sular arch itecture; in filtrative grow th ; n ecrosis; an d vascular invasion .17 Th e Turin con sen sus criteria, subsequen tly developed by an in tern ation al group of thyroid path ologists, are (1) solid/trabecular/in sular arch itectural pattern , (2) lack of w ell-developed n uclear features of papillar y carcin om a, an d (3) on e of th e follow in g: (3a) convoluted n uclei, (3b) tu m or n ecrosis, or (3c) th ree or m ore m itoses per 10 h igh -pow er fields.29 PDCs t ypically exh ibit grossly overt in filtration , often w ith extrathyroidal exten sion . Som e t um ors sh ow partial en capsulation , but com plete an d in tact capsules are rare. Th e cut surface is solid, tan to w h ite-tan , an d frequen tly variegated due to foci of h em orrh age an d n ecrosis. Areas of w ell-di eren tiated follicular or papillary carcin om a m ay be seen in cont in uit y w ith PDC. PDC h as a relatively m on oton ous cell population , lackin g th e m arked pleom orph ism or h igh ly atypical n uclei of an aplastic carcin om a. PDCs also retain di use im m un oreactivit y for cytokeratin an d TTF-1, an d at least focal positivit y for thyroglobulin , in contrast to an aplastic carcin om a. PDC is distin guish ed from m edullar y carcin om a by th e lack of im m un ostain in g for calciton in .

5.3.4 Anaplast ic (Undi erent iat ed) Carcinom a An aplastic thyroid carcin om a (ATC) is a h igh ly aggressive m align an t tum or of follicular cell derivation but is ch aracteristically devoid of m orph ological an d im m un oph en ot ypic m arkers of thyroid origin . An altern ate term is undi erentia ted ca rcinoma . Most ATCs are th ough t to develop th rough dedi eren t iation of w ell-di eren t iated or poorly di eren tiated thyroid carcin om as.

Thyroid and Parathyroid Pathology

Fig. 5.10 Anaplastic carcinoma. (a) Spindle cell pattern. (b) Pleom orphic giant cell pattern. (c) Squamoid pattern. (Hem atoxylin-eosin stain)

ATC is t ypically a w idely in filtrative m ass th at e aces th e thyroid glan d an d exten ds in to adjacen t extrathyroidal tissue. Th e cut surface usually h as a variegated appearan ce w ith m ultiple foci of h em orrh age an d n ecrosis. Com m on m icroscopic features in clude w idely invasive grow th , tum or n ecrosis, m arked n uclear pleom orph ism , an d h igh m itotic act ivity. ATCs usually exh ibit on e or a m ixture of spin dle cell, pleom orph ic gian t cell, or squam oid cell pattern s ( Fig. 5.10).33 Variably sized areas of w ell-di eren tiated or poorly di eren tiated carcin om as are frequen tly foun d in association w ith ATC. The proport ion of ATC in a given tum or m ay in fluen ce progn osis w ith lon ger survival in th ose cases w h ere ATC com prises only a sm all com pon en t of an oth erw ise w ell-di eren t iated papillar y or follicular carcin om a.33

5.3.5 Medullary Carcinom a Medullar y thyroid carcin om a (MTC) is a m align an t t um or of th e thyroid glan d th at exhibits C-cell di eren tiation . In th e Un ited States, MTC accoun ts for ~ 2% of thyroid m align an cies.18 About 75% of cases are sporadic, w ith th e rem ain der h eritable due to a germ lin e m utation of th e RET (rearran ged durin g tran sfect ion ) gen e.34 Th e th ree subt ypes of h ereditar y disease are en com passed by m ultiple en docrin e n eoplasia t ype 2A (MEN2A), m ultiple endocrin e n eoplasia t ype 2B (MEN2B), an d fam ilial m edullar y thyroid carcin om a (FMTC). MEN2A is th e m ost com m on of th e th ree subt ypes, accoun tin g for about 75 to 90% of fam ilial cases, w ith FMTC an d MEN2B accoun tin g for about 15% an d 5% of cases, respect ively.34,35 MTCs t ypically h ave w ell-defin ed borders but lack en capsulation an d are usually foun d in th e m iddle region s of th e lateral lobes. Tum or is lim ited to on e lobe in m ost sporadic cases, but

bilateral disease is iden tifiable in m ost h ereditar y cases, part icularly if resection w as n ot perform ed early in life.36 Microscopically, MTCs exh ibit a broad ran ge of grow th pattern s an d cytological features ( Fig. 5.11). Th e m ost com m on grow th pattern is solid, w ith sh eets an d n ests of cells separated by fibrovascular strom a. Th is in terven in g strom a appears hyalin ized in m any cases due to am yloid deposition . Cells are usually roun d to oval but frequen tly h ave a polyh edral, an gulated, or spin dle sh ape. A n um ber of varian ts h ave been reported, in cludin g tum ors com posed predom in an tly of on cocytic, spin dle, squam ous, sm all, gian t, m ucin ous, or m elan otic cells. Th e variet y of h istopath ologic m an ifestation s of MTC can prove ch allengin g, but positive im m un ostain in g for calciton in facilitates th e diagn osis in th e vast m ajorit y of cases. A sm all n um ber of m ixed m edullary an d follicular an d m ixed m edullar y an d papillar y carcin om as h ave been reported. Diagn osis of th e form er is problem atic in th e absen ce of m etastatic lesion s w ith m ixed features. Th e term mixed medulla r y a nd pa pilla r y ca rcinoma is reserved for tu m ors th at exh ibit an in t im ate adm ixture of th e t w o t ypes, n ot for separate coin ciden tal tum ors.

5.3.6 Prim ary Thyroid Lym phom a Prim ar y thyroid lym ph om as (PTLs) are defin ed by th e absen ce of system ic disease. Alm ost all PTLs arise in th e settin g of ch ron ic lym ph ocyt ic (Hash im oto’s) thyroiditis.37 Alm ost all PTLs are B-cell lym ph om as, th e m ajorit y bein g of th e di use large Bcell lym ph om a (DLBCL) subt ype, w ith m ost of th e rem ain der bein g extran odal m argin al zon e lym ph om a of m ucosa-associated lym ph oid t issue (MALT lym ph om a).37,38 A sign ifican t n um ber of MALT lym ph om as coexist w ith DLBCL. Grossly, PTLs var y

39

Anatom y, Physiology, and Pathology of the Thyroid Com part m ent

Fig. 5.11 Medullary thyroid carcinom a with (a) round cell, (b) polygonal cell, and (c) spindle cell m orphology. (d) Am yloid deposition. (Hematoxylin-eosin stain)

w idely in size at th e tim e of diagn osis. Th ey m ay appear as on e or m ore n odules or as a m ass com pletely e acin g on e or both lobes. Th e cut surface t ypically appears solid an d grayish -w h ite to ligh t tan . Foci of h em orrh age, n ecrosis, an d cystic degen eration m ay be seen . Histological classification uses th e sam e m orph ological an d im m un oh istochem ical criteria as n ode-based lym ph om as.

struct ure. Metastatic t um or can ran ge from m icroscopic deposits in lym ph ovascular spaces to grossly apparen t m asses. Th e kidn ey (ren al cell carcin om a), lun g, breast , an d gastroin testin al tract are th e m ost frequen t prim ar y sites.39 Diagn osis of m etastatic t um or is usually establish ed by basic histological features an d pan els of im m un ostain s com bin ed w ith clin ical h istor y an d/or im aging studies.

5.3.7 Rare Prim ary Thyroid Tum ors

5.4 Parat hyroid Pat hology

Th e W HO classification of thyroid tum ors recogn izes a n um ber of rare prim ar y tu m ors an d t um or-like lesion s of th e thyroid.17 Rare tum ors w ith epith elial di eren tiation in clude squam ous cell carcin om a, m ucoepiderm oid carcin om a, sclerosing m ucoepiderm oid carcin om a w ith eosin oph ilia, m ucin ous carcin om a, spin dle cell tum or w ith thym us-like di eren t iation , an d carcin om a sh ow in g thym us-like di eren tiation . Oth er rare prim ar y thyroid t um ors an d t um or-like condition s in clude an giosarcom a, teratom a, sm ooth m uscle tum ors, periph eral n er ve sh eath tum ors, paragangliom a, solitar y fibrous tum or, follicular den dritic cell tum or, Lan gerh an s cell h istiocytosis, Rosai–Dorfm an ’s disease, an d ectopic thym om a.

5.4.1 Parat hyroid Hyperplasia

5.3.8 Secondary (Met ast at ic) Thyroid Tum ors Secon dary, or m etastatic, t um ors of th e thyroid glan d are defin ed as bein g th e result of lym ph atic or h em atogen ous spread from a distan t site, n ot direct exten sion from an adjacen t

40

Parathyroid hyperplasia is an in crease in th e n um ber of paren chym al cells, m an ifested by in creased size an d w eigh t of a glan d. Hyperplasia can occur prim arily or be secon dar y to a disorder stim ulatin g parathyroid h orm on e secret ion , m ost com m on ly ch ron ic ren al failure. Th e total w eigh t of n orm al parathyroid glan ds is usually 80 to 90 m g, an d an in dividual glan d w eigh in g m ore th an 40 m g can be con sidered abn orm al.40 Hyperplastic glan ds ten d to becom e m ore irregular in sh ape, but th e degree of glan dular en largem en t can var y in a given case. Con sequen tly, gross diagn osis m ay be problem atic. Microscopic exam in ation reveals an in crease in paren chym al cells, w ith a relative decrease in strom al adipose tissue in m ost cases. Most n orm al parathyroid glan ds con tain about 20% strom al adipose tissue,40 but th e w ide variation in th e am oun t an d distribution of th is strom al adipose tissue in n orm al glan ds m akes evaluation of borderlin e en larged glan ds ch allengin g. Ch ief cells usually accoun t for m ost of th e in creased paren chym al m ass, but in creased n um bers of on cocyt ic an d clear cells

Thyroid and Parathyroid Pathology

Fig. 5.12 Parathyroid adenoma. (a) Low-power photom icrograph showing rim of norm al parathyroid (upper region). (b) Medium -power photom icrograph showing uniform, cytologically bland cells of adenom a. (Hem atoxylin-eosin stain)

m ay also be seen . Hyperplasia can be di use or n odular, an d grow th pattern s in clude solid, trabecular, an d acin ar. Hyperplastic cells are usually com parable to n orm al cells, an d m itoses are rare. Occasion ally n uclear pleom orph ism is seen but it h as n o clin ical sign ifican ce. Th e h istological features of prim ar y, secon dary, an d tert iary hyperplasia overlap.

5.4.2 Parat hyroid Neoplasia Parat hyroid Adenom a Parathyroid aden om a is a ben ign n eoplasm predom in an tly com posed of ch ief cells, th ough on cocyt ic cells, tran sit ion al on cocyt ic cells, or a com bin ation of th ese cell t ypes m ay be ad m ixed w it h t h e ch ief cells or p resen t in segregated n ests.17 Ad ip ose cells are absen t or ver y sparse. Most ad en om as ran ge bet w een 200 an d 1,000 m g in w eigh t , h ave a t h in cap su le, an d var y from t an t o red d ish -brow n in color. A rim of n orm al p arathyroid tissu e m ay be seen at th e p erip h er y an d ser ve as a u sefu l d iagn ost ic aid ( Fig. 5.12). Th e h istological grow t h p attern can var y from solid to n od u lar w ith trabecu lar, follicu lar, an d /or acin ar su bp attern s. Mitotic act ivit y is absen t or ver y low . Nu clear p leom orp h ism is seen occasion ally, bu t it is n ot in d icat ive of m align an cy. Histological varian t s in clud e on cocytic, w ater-clear, an d at yp ical ad en om a. Lip oad en om a is an oth er varian t , w it h abu n d an t ad ip ose t issu e an d scat t ered p aren chym al cells. Som e con sid er lip oad en om a t o be a h am ar t om a. Th e m ajor di eren tial diagn osis of aden om a is parathyroid hyperplasia. En largem en t of t w o or m ore glan ds favors hyperplasia. Th e presen ce of an appreciable am oun t of strom al adipose cells favors hyperplasia, w h ereas a periph eral rem n an t of n orm ocellular parathyroid tissue supports aden om a. Histological di eren tiat ion of a m icroaden om a from n odular hyperplasia, particularly on th e basis of a sm all biopsy, m ay be ver y di cult if n ot im possible. Fort un ately, in traoperative parathyroid h orm on e testin g h as obviated th e n eed for m ost of th ese m icroscopic ch allenges.

Parat hyroid Carcinom a Parathyroid carcin om as are rare, m align an t n eoplasm s th at exh ibit overlapping features w ith parathyroid aden om a. Carcin om as ten d to be larger an d often adh eren t to adjacen t structures. Diagn osis of carcin om a is depen den t on fin din g m etastatic lesion s or invasive grow th h istologically. Invasive grow th sh ould be un equivocal an d on e or m ore of th e follow in g: (1) tran scapsular grow th in to adjacen t tissues, (2) vascular invasion of capsular or extracapsular vessels, an d (3) perin eural space invasion .17 Oth er h istological fin din gs m ay in clude elevated m itotic activit y, fibrous trabeculae, an d n uclear pleom orph ism , but th ese h ave n ot proven to be reliable criteria, an d n eoplasm s w ith th ese features are gen erally called atypical aden om as. A n um ber of proliferative m arkers an d im m un oh istoch em ical profiles h ave been studied, but th ese too h ave n ot proven to be defin itive in di eren tiat in g carcin om as from aden om as.

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Anatom y, Physiology, and Pathology of the Thyroid Com part m ent [9] Pearce EN, Farw ell AP, Braverm an LE. Th yroiditis. N En gl J Med 2003; 348 (26); 2646–2655 [10] Ston e JH, Zen Y, Desh pande V. IgG4-related disease. N En gl J Med 2012; 366 (6); 539–551 [11] Li M, East m an CJ. Th e ch angin g epidem iology of iodin e deficien cy. Nat Rev En docrin ol 2012; 8(7); 434–440 [12] Kroh n K, Fü h rer D, Bayer Y, et al. Molecular path ogen esis of euthyroid an d toxic m ultin odular goiter. En docr Rev 2005; 26(4); 504–524 [13] Allen L, de Ben oist B, Dary O, Hurrell R, Eds. Guidelin es on food fortification w ith m icron utrien ts. Gen eva: World Health Organ ization ; 2006 [14] Gh ossein RA, Rosai J, He ess C. Dysh orm on ogen etic Goiter: A Clin icopath ologic Study of 56 Cases. En docr Pathol 1997; 8(4); 283–292 [15] Kraim ps JL, Bouin -Pin eau MH, Mathon n et M, et al. Multicen tre study of thyroid n odules in patien ts w ith Graves’ disease. Br J Surg 2000; 87(8); 1111– 1113 [16] Stocker DJ, Burch HB. Th yroid can cer yield in patien ts w ith Graves’ disease. Min er va En docrin ol 2003; 28(3); 205–212 [17] DeLellis RA, Lloyd RV, Heitz PU, En g C, Eds. World Health Organ ization Classification of Tum ours. Path ology an d Gen etics of Tum ours of En docrin e Organ s. Lyon : IARC Press; 2004 [18] How lader NNA, Krapch o M, Garsh ell J, et al. Cron in KA (eds). SEER Can cer Statistics Review, 1975–2011, Nation al Can cer In stit ute. Beth esda, MD, h ttp:// seer.can cer.gov/csr/1975_2011/, based on Novem ber 2013 SEER data subm ission , posted to th e SEER w eb site, April 2014 [19] Nosé V. Fam ilial thyroid can cer: a review. Mod Path ol 2011; 24 Suppl 2; S19– S33 [20] Fagin JA. Min ireview : bran ded from th e start-distin ct on cogen ic in itiatin g even ts m ay determ in e tum or fate in th e thyroid. Mol En docrin ol 2002; 16(5); 903–911 [21] Carcangiu ML, Zam pi G, Pupi A, Castagnoli A, Rosai J. Papillar y carcin om a of th e thyroid. A clin icopath ologic study of 241 cases treated at th e Un iversit y of Floren ce, Italy. Can cer 1985; 55(4); 805–828 [22] Aden iran AJ, Zh u Z, Gan dh i M, et al. Correlation betw een gen etic alteration s an d m icroscopic features, clin ical m an ifestation s, an d progn ostic ch aracteristics of thyroid papillary carcinom as. Am J Surg Path ol 2006; 30(2); 216–222 [23] Seethala RJAS, Carty SE, Hodak SP, et al. Protocol for th e Exam in ation of Specim en s From Patien ts w ith Carcin om as of th e Th yroid Glan d. College of Am erican Path ologists; 2014 [24] Rivera M, Ricarte-Filho J, Tuttle RM, et al. Molecular, m orph ologic, an d outcom e an alysis of thyroid carcin om as according to degree of extrathyroid exten sion . Thyroid 2010; 20(10); 1085–1093 [25] Vivero M, Kraft S, Barletta JA. Risk stratification of follicular variant of papillar y thyroid carcin om a. Thyroid 2013; 23(3); 273–279

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[26] Morris LG, Sh ah a AR, Tuttle RM, Sikora AG, Gan ly I. Tall-cell variant of papillar y thyroid carcinom a: a m atch ed-pair an alysis of sur vival. Th yroid 2010; 20 (2); 153–158 [27] Gh ossein RA, Leboeuf R, Patel KN, et al. Tall cell varian t of papillar y thyroid carcinom a w ith out extrathyroid exten sion : biologic beh avior an d clin ical im plication s. Th yroid 2007; 17(7); 655–661 [28] Ito Y, Miyauchi A, Ish ikaw a H, et al. Our experien ce of treatm en t of cribriform m orular varian t of papillar y thyroid carcin om a; di eren ce in clin icopath ological features of FAP-associated an d sporadic patien ts. En docr J 2011; 58(8); 685–689 [29] Volan te M, Collin i P, Nikiforov YE, et al. Poorly di eren tiated thyroid carcin om a: th e Turin proposal for th e use of un iform diagn ostic criteria an d an algorith m ic diagn ostic approach . Am J Surg Path ol 2007; 31(8); 1256–1264 [30] Gh ossein RA, Hiltzik DH, Carlson DL, et al. Progn ostic factors of recurren ce in en capsulated Hurth le cell carcin om a of th e thyroid glan d: a clin icopath ologic study of 50 cases. Can cer 2006; 106(8); 1669–1676 [31] Ito Y, Hirokaw a M, Masuoka H, et al. Progn ostic factors of m in im ally invasive follicular thyroid carcin om a: exten sive vascular invasion sign ifican tly a ects patien t progn osis. En docr J 2013; 60(5); 637–642 [32] Nosé V, Volan te M, Papott i M. Hyalin izing trabecular tum or of th e thyroid: an update. En docr Pathol 2008; 19(1); 1–8 [33] Sm allridge RC, Ain KB, Asa SL, et al. Am erican Thyroid Association An aplastic Thyroid Can cer Guidelin es Taskforce. Am erican Thyroid Association guidelin es for m an agem en t of patien ts w ith an aplastic thyroid can cer. Thyroid 2012; 22(11); 1104–1139 [34] Kram pitz GW , Norton JA. RET gene m utation s (gen otype an d ph en otype) of m ultiple en docrin e n eoplasia type 2 an d fam ilial m edullary thyroid carcin om a. Can cer 2014; 120(13); 1920–1931 [35] Molin e J, En g C. Multiple en docrin e n eoplasia type 2: an over view. Gen et Med 2011; 13(9); 755–764 [36] Kloos RT, En g C, Evan s DB, et al. Am erican Th yroid Association Guidelin es Task Force. Medullar y thyroid can cer: m an agem en t guidelin es of th e Am erican Th yroid Association . Thyroid 2009; 19(6); 565–612 [37] Stein SA, Wartofsky L. Prim ar y thyroid lym ph om a: a clin ical review. J Clin En docrin ol Metab 2013; 98(8); 3131–3138 [38] Derrin ger GA, Th om pson LD, From m elt RA, Bijw aard KE, He ess CS, Abbon dan zo SL. Malign an t lym ph om a of th e thyroid glan d: a clin icopath ologic study of 108 cases. Am J Surg Path ol 2000; 24(5); 623–639 [39] Mogh addam PA, Corn ejo KM, Kh an A. Metastatic carcinom a to th e thyroid glan d: a sin gle in stitut ion 20-year experien ce an d review of th e literature. En docr Path ol 2013; 24(3); 116–124 [40] Lloyd RVDB, Youn g W F Jr. En docrin e Diseases. Atlas of Non tum or Path ology, First Series, Fascicle 1. Wash in gton , DC: Am erican Registr y of Pathology; 2002

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12 Medical Managem ent of Medullary and Anaplastic Thyroid Cancer

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6 Thyroid Im aging Bruce Curtiss Gilbert and Ramon E. Figueroa

6.1 Int roduct ion Im aging of th e thyroid is an im portan t com plem en t to th e clin ical exam in ation an d laborator y an alysis in th e evaluation of thyroid disease. Ult rasoun d (US) is th e prim ary m odalit y to evaluate thyroid an d visceral space path ology.1,2 How ever, cross-section al m odalit ies, such as com puted tom ography (CT) an d m agn etic reson an ce im aging (MRI), m ay play an im portan t secon dary role. Th e thyroid glan d is often visualized on routin e n eck, ch est, or cervical spin e CT an d MRI exam ination s. Kn ow ledge of th e n orm al thyroid appearan ce as seen w ith th ese im aging m odalities en ables on e to recognize in cidentally im aged disease processes. Nuclear scin tigraphy plays an im portan t role in th e thyroid fun ct ion al evaluation . Th is ch apter discusses th e various im aging m odalit ies available for evaluation of thyroid disease, th e n orm al im aging appearan ce of th e thyroid, an d th e im agin g ch anges in thyroid disease states.

6.2 Im aging Modalit ies of t he Thyroid 6.2.1 Ult rasound Over th e past 4 decades, US h as becom e th e preferred diagn ostic im aging tool for evaluatin g thyroid disease. Th e glan d’s superficial location in th e an terior n eck an d th e h igh im agin g resolution of m odern t ran sducers m ake US an ideal tool for thyroid im agin g. US provides an accurate assessm en t of glan d size an d paren chym al h om ogen eit y w ith out th e adverse e ects of ion izing radiation or th e h igh costs of oth er im agin g m odalit ies. Th e m ost frequen t in dicat ion s for thyroid US evaluation in clude a palpable n eck m ass in th e visceral space, an in ciden tal thyroid abn orm alit y detected by oth er im aging m odalit ies (such as CT an d MRI), screen in g h igh -risk patien ts for occult m align an cy, evaluating for region al n odal m etastases in patien ts w ith suspected or proven thyroid carcin om a prior to thyroidectom y, an d screen in g th e thyroid bed in post thyroidectom y pat ien ts.2,3 US exam in ation em ploys a lin ear-array, h igh -frequen cy 7.5 to 15 MHz t ran sducer, w ith th e n eck in hyperexten sion . Each lobe of th e thyroid is im aged in lon gitudin al an d t ran sverse plan es usin g both B m ode an d color Doppler US. Th e average adult thyroid m easures 4 to 6 cm in cran iocaudal len gth an d 1.3 to 1.8 cm in an teroposterior an d t ran sverse dim en sion s. Th e n orm al an teroposterior th ickn ess of th e isth m us is up to 3 m m .4 Th e n orm al thyroid h as a h om ogen eous backgroun d of m edium -level to h igh -level ech ogen icit y (un iform ly hyperech oic relative to th e adjacen t strap m uscles) surroun ded by an echogen ic fibrous capsule. Th e thyroid capsule allow s for clear delin eation of th e thyroid from adjacen t struct ures of th e visceral space ( Fig. 6.1a). Color Doppler im agin g m ay be used to evaluate th e vascularit y of th e thyroid as w ell as thyroid n odules, w h ich m ay be h elpful in determ in in g m align an cy. Th e routin e thyroid US also evaluates th e n orm al adjacen t an atom ical structures of th e visceral n eck, such as th e com m on carotid arteries, jugular vein s, cervical esoph agus, parathyroid glan ds, an d

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lym ph n odes. Fam iliarit y w ith th e n orm al son ograph ic appearan ce of th ese adjacen t struct ures m ay preven t m isin terpretation of n orm al an atom ical struct ures as thyroid path ology. Poten t ial lim itation s of US in clude th e h igh degree of operator depen den ce an d th e in abilit y to adequately evaluate th e retrotrach eal region an d th e superior m ediastin um .1

6.2.2 CT and MRI CT an d MRI h ave lim ited abilit y to directly evaluate int rathyroid path ology due to poor capacit y to discrim in ate ben ign an d m align an t disease. How ever, CT an d MRI h ave im portan t adjun ct ive roles for staging advan ced thyroid can cer by iden tification of extracapsular exten sion of disease in to adjacen t structures, such as th e esophagus, trach ea, laryn x, m usculature, an d vasculature. Th ey are also im por tan t for evaluatin g direct exten sion of disease in to th e m ediastin um or retrotrach eal region , as w ell as to iden tify both region al lym ph n odes an d distal m etastases, providin g relevan t in form ation th at can im pact surgical m an agem en t. Th ey m ay also h ave specific roles in cases of m ultin odular goiter to evaluate for retrostern al exten sion of disease an d trach eal deviation or com pression .5,6 Due to its h igh iodin e con ten t, th e n orm al thyroid h as in creased atten uation com pared to th e adjacen t m usculature, w ith a den sit y of 80 to 100 Houn sfield un its.4,5 Con trast-en h an ced CT di usely in creases th e atten uat ion of th e thyroid due to stron g uptake of iodin ated contrast, providin g addition al in form ation about thyroid lesion s ( Fig. 6.1b). How ever, iodinated contrast should be avoided if functional nuclear im aging is desired or in the w orkup of di erentiated thyroid carcinom a (unless the inform ation obtained from the addition of contrast is expected to significantly alter the patient’s m anagem ent) because a large iodine thyroid gland load m ay persist for up to 6 w eeks and interfere w ith radioactive iodine uptake. As an alternative, MRI w ith gadolinium m ay be perform ed in conjunct ion w ith nuclear scintigraphy because gadolinium does not a ect iodine uptake or organification by the thyroid. The thyroid is im aged by MRI using an anterior neurovascular neck coil centered over the thyroid. Multiple pulse sequences can be obtained through the gland, including sagittal and axial T1 precontrast, axial T2 fast spin-echo w ith fat saturation, and postgadolinium axial and coronal T1 w ith fat saturation. The thyroid gland is hom ogeneous in signal and slightly hyperintense com pared to neck m usculature on T1 im aging. On T2w eighted im aging, the thyroid is hom ogeneously hyperintense to neck m usculature ( Fig. 6.1c). It dem onstrates a di use hom ogeneous pattern of enhancem ent on postcontrast im aging.

6.2.3 Nuclear Scint igraphy Nuclear scin tigraphy plays an im portan t role in th e evaluation of thyroid disease, providin g a reflect ion of th e fu n ct ion al state of th e thyroid glan d as w ell as th e physiological state of any struct ures w ith in th e glan d, such as a thyroid n odule. In dication s for thyroid scin tigraphy in clude evaluation of th e size an d

Thyroid Im aging

Fig. 6.1 Normal thyroid. (a) Transverse ultrasound im age of norm al thyroid (black star) shows homogeneously increased echogenicit y compared with the overlying strap muscle (SM). The echogenic capsule (white arrow) separates the thyroid from adjacent visceral space structures. T, trachea; E, esophagus; C, com m on carotid arteries. (b) Axial contrast-enhanced computed tom ographic im age shows norm al hom ogeneous enhancem ent throughout the thyroid, slightly less dense than the internal jugular veins (black star). The internal jugular vein is visible (black star). T, trachea; SM, strap muscle; C, comm on carotid artery; E, esophagus. (c) Axial T2-weighted m agnetic resonance im aging shows norm al thyroid with hom ogeneous, slightly hyperintense signal com pared to strap muscle (SM). The right com m on carotid flow void is seen (white star). T, trachea; E, esophagus; V, cervical vertebral body. (d) Norm al anteroposterior scintigraphic thyroid image shows diffuse and hom ogeneous radiotracer uptake.

location of thyroid tissue, thyroid evaluation w h en clin ical laboratory tests suggest abn orm al thyroid fun ct ion , evaluation of patien ts at risk for thyroid n eoplasm , assessm en t of fun ct ion of thyroid n odules, an d evaluation of congen ital thyroid abn orm alities. Thyroid uptake m easurem en ts are obtain ed for di eren tiation of hyperthyroidism from form s of thyrotoxicosis an d for calculatin g I-131 doses in patien ts to be treated for hyperthyroidism w ith thyroid ablative th erapy. W h ole body im aging is perform ed to iden tify th e presen ce an d location of residual thyroid t issue after thyroidectom y or ablative th erapy for thyroid carcin om a an d for iden tifyin g iodin e avid m etastases from thyroid carcin om a.6 Th e t w o m ain isotopes for thyroid scin tigraphy are tech n etium -99 m (Tc-99m ) pertech n etate an d iodin e 123 (I-123). Tc99 m pertech n etate is trap ped by th e thyroid, w h ereas I-123 is trapp ed an d organ ified. On e dist in ct advan tage of I-123 over Tc-99 m is in th e evaluation of thyroid n odules, in particular w hen a thyroid n odule appears “w arm ” by Tc-99 m . If “cold” on I-123, th is is con sidered a discordan t n odule requirin g furth er

w orkup an d possible thyroid fin e-n eedle aspiration (FNA). I123 also h as an advan tage over Tc-99 m in iden tifyin g an d localizing ectopic thyroid tissue because th ere is sign ifican tly less backgroun d act ivit y w ith in th e h ead an d n eck w h en com pared to Tc-99 m .5,7,8 Wh eth er im aged w ith Tc-99 m pertech n etate or I-123, th e n orm al thyroid sh ow s h om ogen eous radion uclide uptake through out th e glan d ( Fig. 6.1d). Radioactive iodin e uptake m ay be m easured at 4 an d 24 h ours w ith n orm al values of 5 to 15% an d 8 to 35%, respect ively. Th e use of iodin e-con tain ing supplem en ts or certain m edication s can poten tially a ect iodin e uptake an d in corporation by th e thyroid glan d. Most centers recom m en d a low -iodin e diet for 7 to 14 days prior to radioiodin e adm in istration .

6.3 Congenit al Anom alies of t he Thyroid Gland Un derstan din g congen ital an om alies of th e thyroid glan d requires a lim ited review of thyroid em br yology. Th e m edian

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Thyroid Diseases

Fig. 6.2 Ectopic thyroid. (a) Coronal com puted tom ographic im age shows nodular ectopic thyroid tissue (white arrows) within the superior mediastinum . Norm al thyroid (black star). (b) Lingual thyroid. Nodular hyperdense ectopic thyroid tissue (white star) in the floor of the m outh is consistent with lingual thyroid, supplied by a tortuous lingual artery (white arrow).

an lage of th e thyroid glan d arises from en doderm al cells origin atin g from th e th ird bran ch ial pouch in th e floor of th e prim itive ph ar yn x, at th e tongue base. Th e glan d m igrates dow nw ard from th e ton gue base, passing an terior to th e hyoid bon e an d thyroid cartilage, to its fin al dest in ation an terior to th e secon d an d th ird t rach eal rin gs in th e low er n eck. Th e thyroid rem ain s attach ed to th e ton gue base by th e thyroglossal duct , an epith elial-lin ed tube th at elon gates durin g descen t an d even tually degen erates prior to defin itive thyroid form ation . Th e m edian an lage form s th e h orm on e-secretin g follicular cells of th e thyroid. Th e calciton in -secret in g parafollicular C cells are form ed by th e lateral an lages, w h ich are derived from th e fourth an d fift h bran chial pouch es. With in th e in frahyoid n eck, th e lateral an lages fu se w ith th e m edian an lage to form th e bilobed thyroid.9,10

6.3.1 Ect opic Thyroid Tissue Failure or abn orm al descen t of th e thyroid glan d alon g its n orm al path w ay m ay occur durin g th e fetal period, resultin g in ectopic thyroid tissue at any location alon g th e path w ay of descen t . Clin ically apparen t thyroid ectopia is rare, occurrin g in 1 in 3,000 to 1 in 10,000 people; h ow ever, autopsy series suggest a m uch h igh er prevalen ce, ran ging from 7 to 10%.11,12 Alth ough 90% of ectop ic thyroid tissu e occu rs at th e tongu e base an d arises from t h e m ed ian an lage, ect op ic thyroid t issu e m ay also be id en t ified in t h e lateral n eck, lar yn x, esop h agu s, m ed iast in u m , p ericard iu m , or h ear t ( Fig. 6.2a). Rare n on cer vical an d n on m ed iast in al locat ion s of ect op ic t hyroid t issu e h ave also been d escribed in t h e gallblad d er, p or t a h ep at is, sm all bow el, p an creas, an d ad ren al glan d s. Ect op ic t hyroid is vu ln erable to any d isease p rocess th at m ay occu r w it h in t h e n orm ally located t hyroid glan d ; h ow ever,

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d evelop m en t of m align an cy is con sid ered rare. W h en tu m or d oes arise w ith in ectop ic thyroid tissu e, it is rep or ted as p ap illar y carcin om a in > 90% of cases.12,13 Wh en thyroid ectopia is iden tified, patien ts sh ould un dergo fur th er evaluation for th e presen ce of n orm ally located thyroid tissue prior to surgical excision of ectopic thyroid, to avoid an acute thyroid in su cien cy. Oth er th an lackin g th e t ypical bilobed appearan ce, ectopic thyroid t issue appears as n orm al thyroid t issue by all im aging m odalities. Nuclear scin tigraphy dem on st rates uptake of radiotracer in th e ectopic thyroid as w ell as in th e orth otopic tissue. Th e m ost com m on US im agin g findin g is th e absen ce of n orm al orth otopic thyroid t issue. How ever, carefu l evaluation of th e n eck at th e ton gue base or alon g th e expected t rack of thyroid descen t m ay reveal a roun d, w ell-circum scribed m ass iden tical to th e expected echogen icity of n orm al thyroid tissue. Ectopic thyroid glan d detected by n on contrast CT w ill presen t as a hyperden se n odular m ass w ith respect to th e adjacen t m usculature, sh ow in g in ten se en h an cem en t after in traven ous adm in istration of iodin ated contrast. MRI presen ts thyroid ectopia as a n odular m ass, T1 isoin ten se to m ildly hyperin ten se in sign al com pared to m uscle, m ildly T2 hyperin ten se, an d w ith a variable pattern of en h an cem en t on postgadolin ium im aging. Detect ion of n odules or goitrous en largem en t in th e ectopic thyroid t issue m ay also in crease th e diagn ostic confiden ce. Lin gual thyroid is th e m ost com m on form of thyroid ectopia.14 Th e ectopic t issue at th e base of th e tongue m ay ran ge from m icroscopic to several cen tim eters ( Fig. 6.2b). Clin ical sym ptom s are often related to grow th of th e ectopic thyroid t issue, includin g dysphagia, dysph on ia, cough , an d foreign body sen sation . How ever, patien ts m ay be asym ptom atic, w ith in ciden tal detect ion by clin ical exam or im agin g for n on thyroidrelated purposes.

Thyroid Im aging cyst carcin om as, w ith < 5% bein g of squam ous cell origin . Th e average patien t age for TGD cyst carcin om a developm en t is 39 years, w ith th e squam ous cell t ype occurrin g at an average age of 54 years. US is th e m odalit y of ch oice for in itial im aging assessm en t of a suspected TGD cyst. On US, TGD cysts m ay h ave a variable ech ogen icit y pat tern based on in trin sic fluid protein con ten t . Th e m ost com m on presentation s in clude a w ell-circum scribed an ech oic cyst or a pseudosolid appearan ce w ith a h eterogen eous echo pat tern (m ore com m on ly seen in ch ildren ). Posterior acoustic en h an cem en t (in creased ech ogen icit y deep to th e cyst) is a cystic ch aracteristic fin din g; h ow ever, th is m ay be subtle in th e sett in g of a pseudosolid lesion . Th e presence of th ick w alls or in tern al septa often correlates w ith in tern al in flam m ation . CT presen ts TGD cysts as w ell-circum scribed, th in -w alled m idlin e lesion s w ith m ucoid atten uation , usually at or below th e level of th e hyoid bon e ( Fig. 6.3a). In creased com plexit y of th e lesion , w ith th icken in g an d en h an cem en t of cyst w alls, septation s, an d in creased cyst atten uation , suggests cyst in flam m ation or in fect ion . TGD cysts m ay appear on MRI scan s as sim ple cysts, dem on st ratin g low in t rin sic T1 an d h igh T2 sign al, th ough in trin sic protein /thyroglobulin con ten t m ay elicit h igh T1 an d h igh T2 sign al. Iden tification of a soft tissue n odule w ith in a TGD cyst sh ould raise concern for carcin om a, especially in th e presen ce of calcification ( Fig. 6.3b). Th e m ain di eren tial con sideration s of TGD cysts in clude a bran ch ial cleft cyst, derm oid, an d h em an giom a, an d an en larged lym ph n ode.

6.4 Benign Diseases of t he Thyroid Most ben ign disease processes th at a ect th e thyroid glan d are diagn osed by clinical fin din gs an d do n ot require im aging. How ever, several ben ign disease processes of th e thyroid h ave a ch aracteristic appearan ce on im agin g.

6.4.1 Graves’ Disease Fig. 6.3 Thyroglossal duct cyst. (a) A m idline cystic m ass (white arrow) is seen along the inferior m argin of the hyoid, proven to be thyroglossal duct (TGD) cyst. (b) A different patient with a TGD cyst with an irregular enhancing nodule of its posterior cyst wall (white arrow), proven to be squam ous cell carcinom a.

6.3.2 Thyroglossal Duct Cyst Thyroglossal duct (TGD) cyst is th e m ost com m on m idlin e con gen ital n eck m ass, arisin g secon darily to failure of com plete regression of th e TGD.15 Sim ilarly to ectopic thyroid tissue, a TGD cyst m ay arise anyw here alon g th e descen t path w ay of th e m edian an lage, from th e base of th e tongue to th e suprastern al region . Most lesion s presen t in ch ildh ood or in youn g adults as an en largin g pain less m ass, w ith 60 to 80% associated w ith th e hyoid bon e. Ectopic thyroid t issue w ith in th e cyst w all is seen in up to 5.7% of cases.16 TGD cysts can be com plicated by in flam m ation an d h em orrhage, w h ich m ay be associated w ith pain . Carcin om a arisin g in a TGD cyst is rare, occurrin g in 0.7 to 1% of TGD cysts, w ith 90% arisin g from a thyroid tissue rem n an t. Papillar y carcin om a represen ts approxim ately 94% of TGD

Graves’ disease is th e m ost com m on cause of hyperthyroidism in th e Un ited States. It is an autoim m un e process in w h ich patien ts develop autoan tibodies again st thyroid-stim ulatin g h orm on e (TSH) receptors, thyroglobulin , an d thyroperoxidase. TSH receptor an tibodies result in receptor stim ulation , leadin g to glan dular grow th , in creased vascularit y, an d in creased product ion of thyroid h orm on e. On gray-scale US, th e thyroid is en larged an d d i u sely hyp oech oic; h ow ever, n orm al ech ogen icit y m ay be p resen t.17,18 On color Dop p ler im agin g, th e thyroid sh ow s m arked ly in creased vascu larit y th rough ou t th e t hyroid p aren chym a, resu ltin g in t h e “t h yroid st or m ” p at t ern ( Fig. 6.4a,b). Peak systolic velocit y m easurem en ts of th e in ferior thyroid or in t raparen chym al arteries are m arkedly in creased in Graves’ disease, w h ich is h elpful in distin guish in g it from Hash im oto’s disease an d thyrotoxicosis. CT an d MRI h ave lim ited usefuln ess in evaluation of Graves’ disease, sh ow in g an en larged thyroid w ith possible visualization of a pyram idal lobe or prom in en t in trathyroidal vasculature.19 Thyroid scin tigraphy sh ow s a di usely en larged glan d w ith in creased thyroid uptake. A pyram idal lobe m ay also be iden tified on scin tigraph ic im aging ( Fig. 6.4c). Radioactive iodin e

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Thyroid Diseases

Fig. 6.4 Graves’ disease. (a) Transverse gray-scale ultrasound shows a diffusely enlarged thyroid with decreased echogenicit y equal to and slightly less than strap m uscle (SM). (b) Color Doppler im aging with a “thyroid storm ” pattern of diffuse increased vascularit y throughout the gland. (c) Anteroposterior scintigraphic im age with homogeneously increased tracer uptake with the pyram idal lobe (white arrow) arising from the junction of the isthmus and the left lobe. (d) Coronal com puted tom ography showing enlargem ent of the extraocular m uscle bellies.

uptake (RAIU) is elevated at 24 h ours (> 35%), alth ough a varian t form , Graves’ disease w ith rapid iodin e t urn over, m ay sh ow n orm al RAIU at 24 h ours but elevated RAIU at 4 to 6 h ours (> 20%).8 An extrathyroidal m an ifestat ion of Graves’ disease is thyroidassociated orbitopathy. Its diagn osis is prim arily clin ical; h ow ever, im agin g m ay be perform ed in un cert ain cases.20 CT an d MRI are th e prim ar y im aging m odalit ies, classically show in g proptosis w ith expan sion of th e in traorbital fat an d enlargem en t of th e extraocular m uscle bellies, but n ot th eir ten don s. Th e in ferior rect us is m ost com m on ly a ected, follow ed by th e m edial rectus an d superior m uscle com plex. Bilateral involvem en t occurs in approxim ately 90%of cases ( Fig. 6.4d).

6.4.2 Hashim ot o’s Disease Hash im oto’s disease is an autoim m un e thyroiditis result in g from glan dular in filtration by T an d B lym ph ocytes, possibly stim ulated by an environ m en tal trigger. Autoant ibodies to th e TSH receptor, thyroglobulin an d thyroid peroxidase, are produced by B cells, w h ereas T cells con tribute to local paren chym al destru ction . Th e n et e ect is an in itial thyrotoxicosis follow ed by ch ron ic hypothyroidism . Hash im oto’s disease is th e m ost com m on cause of hypothyroidism in th e Un ited States, a ect in g at least 2% of all w om en .21 On US, th e thyroid is

48

en larged w ith di use h eterogen eous hypoech oic pattern outlin in g echogen ic in tern al septation s. A h igh ly diagn ostic son ograph ic feature for Hash im oto’s disease is th e presen ce of m ultiple hypoech oic m icron odules, ran gin g from 1 to 7 m m in size ( Fig. 6.5a).22 Color Doppler im aging m ay sh ow m ild to m arkedly in creased vascularit y as also seen in Graves’ disease. On CT, th e thyroid m ay be di usely en larged w ith a h eterogen eous, hypoden se atten uation pat tern . Hash im oto’s disease scin tigraph ic fin din gs are n on specific, w ith a h eterogen eous, patchy radiotracer activit y th at m ay ran ge from un iform ly in creased act ivit y to severely decreased radiotracer uptake.23 Hash im oto’s thyroidit is h as a stron g association w ith lym ph om a. Th e presen ce of a rapidly grow in g focal hypoden se m ass w ith m argin s exten din g beyon d th e n orm al thyroid con tour sh ould raise suspicion for lym ph om a ( Fig. 6.5b). Lym ph om a ten ds to be less invasive th an prim ary thyroid carcin om a an d usually lacks calcification s or cystic degen eration , w h ich h elps to distin guish it from thyroid carcin om a or goiter.24

6.4.3 Toxic Aut onom ous Nodule Toxic autonom ous n odule (Plum m er’s disease) occurs w h en on e or m ore thyroid n odules produce an excess of thyroid

Thyroid Im aging

Fig. 6.6 Toxic autonom ous nodule. Anteroposterior iodine 123 scintigraphic scan im age shows a large, hot nodule in the left thyroid m id to lower lobe with right lobe (white star) and left lobe upper pole photopenia.

h orm on e released in to th e system ic circulation . Th e proposed etiology is a som atic m utation of th e TSH receptor gen e of a thyroid aden om a causin g th e un regulated production an d release of thyroid h orm on e.7 Thyroid scin tigraphy sh ow s in creased act ivit y w ith in th e auton om ous fun ction in g n odule (“h ot n odule”) again st a backgroun d of fain t or absen t glan d activit y from th e lack of TSH stim ulation of n orm al thyroidal tissue ( Fig. 6.6). Th e RAIU is usually m ildly elevated or n orm al. Historically, h ot n odules are con sidered ben ign ; h ow ever, som e case series h ave foun d a prevalen ce of carcin om a w ith in h ot n odules of approxim ately 3.1%. If suspicious US ch aracteristics are iden tified or th ere is grow th of a h ot n odule over t im e, th en USguided FNA sh ould be con sidered.25 Th e preferred th erapy for a toxic n odule is ablation w ith I-131, w h ich is preferen tially con cen trated in th e hyperfun ct ion in g n odule rath er th an in th e n orm al thyroid glan d.

w h ich are n on fun ction in g, usually providin g for a balan ced state of thyroid h orm on e product ion an d th us n orm al thyroid fun ction (n on toxic goiter). A toxic goiter often occurs w h en th ere is an excess of thyroid h orm on e product ion resultin g in hyperthyroidism . Sporadic goiter occurs in approxim ately 5% of the U.S. population, w ith m ost patients presenting w ith a neck m ass. US show s an enlarged thyroid gland w ith m ultiple nodules of various sizes ( Fig. 6.7a). The nodules are often hypoechoic w ith intern al com plex/septated cystic areas corresponding to internal degeneration and hem orrhage. Intrinsic com et tail artifact secondary to colloidal degeneration and shadow ing secondary to dystrophic calcifications m ay also be seen. CT and MRI are indicated to assess substernal disease extension and tracheal or esophageal com pression ( Fig. 6.7b,c).26 The thyroid m ay be di usely or asym m etrically enlarged and nodular, w ith individual nodules on CT varying from intensely enhancing to hypodense secondary to internal necrosis ( Fig. 6.7d). Variable fluid com position w ith in th e n odules causes a w ide ran ge of im agin g appearan ces by MRI. Th e RAIU in th e settin g of toxic m ultin odular goiter is usually n orm al or sligh tly elevated. Scin tigraph ic fin din gs in clude an en larged thyroid w ith global h eterogen eous radiotracer uptake, in cluding both h ot an d cold n odular areas. Th e presence of a solitar y cold n odule in th e settin g of a m ultin odular glan d sh ould be considered suspicious because th e can cer rate in th is settin g is sim ilar to th at of a n orm al glan d. US-guided FNA sh ould be con sidered in th e settin g of a solitar y cold n odule or dom in an t/en largin g n odule in a m ultin odular goiter.5,7

6.4.4 Mult inodular Goit er

6.4.5 Riedel’s Thyroidit is

A m ultin odular goiter is an en larged thyroid con tain ing several n odules, som e of w h ich are hyperfun ction in g an d som e of

Riedel’s thyroiditis, also kn ow n as invasive fibrous thyroiditis, is ch aracterized by thyroid glan d destruct ion w ith replacem en t of

Fig. 6.5 Hashim oto’s thyroiditis. (a) Transverse ultrasound im age showing m ultiple bilateral hypoechoic m icronodules (white arrows) in the setting of Hashim oto’s disease. (b) A patient with a history of Hashim oto’s disease and a right hem ithyroidectom y presents with a large m ass (black star) extending beyond the norm al gland m argins and displacing adjacent anatomical structures without invasion, which was proved to be prim ary thyroid lym phom a.

49

Thyroid Diseases

Fig. 6.7 Thyroid goiter. (a) Transverse ultrasound im age shows m arkedly enlarged thyroid with diffuse heterogeneous and nodular echogenicit y. (b) Patient with goiter (black star) presenting with marked tracheal com pression (arrow) requiring em ergent thyroidectomy. (c) Gross surgical specim en from thyroidectomy in (b). (d) Coronal com puted tomography shows a m arkedly enlarged thyroid with heterogeneous attenuation and large cystic bilateral nodules.

th e n orm al paren chym a w ith den se fibrosis, w h ich m ay exten d beyon d th e m argin s of th e thyroid capsule in to th e adjacen t soft tissue struct ures of th e n eck.27 Th e clin ical presen tat ion m ay in clude hypothyroidism , hypoparathyroidism , or sym ptom s from com pression on adjacen t struct ures, such as th e recurren t lar yngeal n er ve. Malign an cy m ay be suspected clin ically due to a firm , en larged thyroid. Th e thyroid m ay be en larged, hypoech oic, an d hypovascular on US.28 On CT th e thyroid m ay be diffusely hypoden se w h ere th ere is di use glan d involvem en t. How ever, if th ere is residual n orm al tissue on a backgroun d of fibrosis, th e glan d m ay h ave a m ore h eterogen eous appearan ce. Extracapsular in filtration in to adjacen t n eck struct ures m ay be presen t ( Fig. 6.8). MRI sh ow s the glan d as T1 iso- to hypoin ten se an d T2 hypoin ten se, w ith decreased en h an cem en t. Both th e clin ical an d th e im agin g appearan ce can be suspicious for an aggressive m align an t process. If Riedel’s thyroiditis is

50

suspected, an open surgical biopsy sh ould be con sidered to exclude m align an cy.

6.5 Thyroid Nodules Thyroid n odules are com m on in th e adult population , foun d in up to 60% of adults in som e autopsy series.29 Th e in ciden ce of thyroid n odules h as steadily in creased over th e last 3 decades, predom in an tly as a result of im agin g. Th e inciden tal nodule (in ciden talom a) is an asym ptom atic thyroid lesion discovered on an im agin g exam in ation perform ed for reason s un related to th e thyroid glan d, reported in up to 9% of carotid US exam in ation s, 16% of CT an d MRI exam in ation s, an d 3% of positron em ission tom ograph ic (PET) scan s. Th e risk of m align an cy of th e in ciden tal thyroid n odule is n ot in sign ifican t, w ith studies sh ow in g m align an cy rates ran gin g from 8.6 to 29%.30 Th erefore,

Thyroid Im aging

Fig. 6.8 Riedel’s thyroiditis. Axial com puted tom ography with contrast shows diffuse enlargement of the thyroid with m arkedly decreased attenuation and lack of enhancem ent. Note infiltration of the adjacent anatom ical structures with encasem ent of the comm on carotid arteries (red stars).

evaluation of th e in ciden talom a is an im portan t aspect of patien t care. High -resolution US is th e preferred im aging m odalit y for evaluation an d ch aracterization of th e thyroid in ciden talom a. Son ograph ic features of thyroid n odules th at raise suspicion for m align an cy in clude th e presen ce of m icrocalcification s, eviden ce of local invasion or n odal m etastasis, n odules th at are taller th an w ide in th e t ran sverse plan e, an d m arked hypoechogen icity. Alth ough a sin gle suspicious son ograph ic feature m ay be of lim ited value, t w o son ograph ic sign s of m align an cy correlate w ith an in creased risk of can cer. Patien ts w ith decreased TSH levels m ay un dergo I-123 thyroid scin tigraphy to evaluate for a hyperfun ct ion al n odule, w h ich is rarely m align an t an d h istorically precludes th e n eed for addition al testin g.30 Microcalcification s m ost com m on ly occur in th e settin g of papillar y carcin om a. Nodules w ith m icrocalcification s h ave pun ctate (< 1 m m ) hyperech oic foci on US, w ith or w ith out posterior acoustic sh adow in g, represen tin g in tran odular psam m om a bodies ( Fig. 6.9a). Macrocalcification s, in cluding rim calcification s, m ay also be seen associated w ith thyroid n odules in both ben ign an d m align an t processes. Th e presence of an in com plete rim of

Fig. 6.9 Suspicious thyroid nodules. (a) Longitudinal thyroid ultrasound (US) im age shows clusters of hyperechoic m icrocalcifications (black stars) in the m id to inferior pole of the thyroid in this patient with papillary carcinom a. (b) Longitudinal thyroid US image shows hypoechoic papillary carcinom a (white star) within the inferior pole, extending beyond the normal contour of the thyroid with loss of norm al interface bet ween the thyroid and overlying strap muscle. Microcalcifications are present. Norm al interface and thyroid capsule are visible (white arrows). (c) Transverse US im age of hypoechoic papillary carcinoma (white star) with “taller than wide” nodule dim ensions. (d) Longitudinal US image with ovoid solid nodule with incom plete and irregular hypoechoic rim (white arrows). (e) Same solid nodule with central vascularity by color Doppler imaging, proven to be invasive follicular carcinoma at surgery.

51

Thyroid Diseases sim ilar-appearin g n odules lackin g suspicious im aging ch aracteristics ( Fig. 6.10a).4 In a m ultin odular thyroid, it is essen tial to evaluate each in dividual n odule for suspicious son ograph ic features. Th e 2009 Am erican Thyroid Association (ATA) m an agem en t guidelin es for thyroid nodules recom m en d FNA for n odules > 5 m m in h igh -risk patients an d suspicious son ograph ic features ( Fig. 6.10b).32 Som e studies h ave sh ow n th at adh eren ce to such clin ical guidelin es ach ieves th e goal of diagn osing clin ically sign ifican t can cers an d avoidin g un n ecessary procedures in patien ts w ith benign n odules.33 In ciden talom as detected by PET/PET-CT deserve special m en tion . Approxim ately 3% of PET scan s h ave in ciden tally detected focal PET avidit y associated w ith thyroid n odules, w ith som e studies sh ow in g up to on e-th ird of th ese lesion s provin g to be m align an t. At th is tim e n o stan dard uptake value (SUV) cuto is establish ed th at is safe to exclude or suspect m align an cy. Th erefore all PET avid n odules, regardless of size, sh ould un dergo evaluation an d fin e n eedle aspirat ion .34

6.6 Malignant Disease of t he Thyroid Gland

Fig. 6.10 Benign thyroid nodule. (a) Transverse ultrasound (US) im age with heterogeneous isoechoic nodule with complete peripheral hypoechoic halo (red arrowheads), proven to be follicular hyperplasia by US-guided fine-needle aspiration (FNA). (b) US-guided 20-gauge core biopsy using a parallel technique in a patient with t wo previous nondiagnostic FNAs. The hyperechoic needle (white arrow) is seen traversing the nodule.

calcification or hypoech ogen icit y periph eral to th e rim calcification favors a m align an t process. Extracapsular exten sion of a n odular thyroid m ass in to th e adjacen t soft tissues is a h igh ly specific sign of m align an cy. Th is m ay be subtle, w ith n odule m argin s exten din g sligh tly beyon d th e thyroid capsule, or it m ay be overt , w ith gross invasion of adjacen t an atom ical structures ( Fig. 6.9b,c). A cervical lym ph n ode m etastasis is also a h igh ly specific sign of thyroid m align an cy, com m on ly iden tified w ith papillar y an d m edullar y carcin om as. Abn orm al lym ph n odes m ay sh ow in creased size, loss of fatt y h ilum , in tern al cystic ch ange, calcification , an d in creased vascularit y th rough out th e lym ph n ode, rath er th an cen trally w ith in th e h ilum . Metastatic lym ph n odes associated w ith papillar y carcin om a m ay appear cystic on US an d are easily m istaken for a cystic thyroid n odule. Less specific ultrasoun d features of a m align an t thyroid n odule in clude th e lack of a com plete hypoechoic h alo, irregular m argin s, an in t rin sic solid com pon en t, or in creased cen tral vascularit y ( Fig. 6.9d,e).31 US features of a ben ign n odule in clude a un iform hypoech oic h alo aroun d th e n odule periph er y, a predom in an tly cystic n odule, an avascular n odule, an d an en larged thyroid w ith m ultiple

52

Thyroid carcin om a is th e m ost rapidly in creasin g m align an cy in th e Un ited States. How ever, despite th e sign ifican t rise in th e n um ber of di eren tiated thyroid carcin om as over th e last decades, th e m ortalit y rate h as n ot sign ifican tly risen .35 Statistically, m ost thyroid m align an cies are papillar y carcin om a, represen tin g approxim ately 80%of all cases of thyroid carcin om a. Follicular cell an d m edullar y can cers accoun t for approxim ately 10 to 20% an d 6 to 8%, respect ively. Aggressive an aplastic carcin om a accoun ts for on ly 1 to 2% of thyroid m align an cies, yet is respon sible for approxim ately 39% of thyroid can cer–related death s.36 Alth ough th ere are n o specific im aging fin din gs for th e di eren t t ypes of thyroid carcin om a, th e in itial US im aging h elps w ith staging of thyroid carcin om a by assessing tu m or size, extrathyroidal exten sion of disease, an d th e presen ce of lym ph n ode m etastasis.

6.6.1 Di erent iat ed Carcinom as Papillary can cer m ost com m on ly presents in youn g w om en in th e th ird to fifth decades of life. In papillary carcin om a, careful US exam in ation of th e lym ph n ode ch ain s sh ould be perform ed because region al lym ph n ode m etastases at th e tim e of diagnosis occur in 25 to 80% of pat ien ts.37 An exten sive in trathyroidal lym ph atic n et w ork allow s for tum or spread w ith in th e glan d. In traglan dular m etastases are present in 80% of papillar y thyroid carcin om a at h istological diagn osis, accoun tin g for th e 5 to 20% reported recurren ce rates in patien ts un dergoing partial thyroidectom y.38 About 10% of pat ien ts sh ow distan t m etastases, m ost com m on ly to th e lun gs, bon es, or cent ral n ervous system . Follicular carcinom a is th e second m ost com m on thyroid m align an cy, usually present in g in th e fourth to sixth decades of life as a solitar y thyroid m ass. In con trast to papillar y thyroid carcin om a, m ultifocal disease an d region al lym ph n ode m etastases are m uch less com m on . Alth ough involvem en t of region al lym ph n odes is n ot as com m on as in papillary carcin om a, it is a poor progn ostic in dicator, im plyin g extrathyroidal exten sion

Thyroid Im aging

Fig. 6.11 Follicular carcinom a with m etastasis. (a) Asym m etric left thyroid lobe m ass (red asterisk) with extracapsular extension to the retrotracheal space, proven to be a follicular carcinom a. (b) Axial computed tom ography at upper thorax shows a left chest wall m etastasis (white arrow).

of disease. A h em atogen ous pat tern , rath er th an lym ph atic dissem in ation , is m ore com m on ly seen in follicular carcin om a, resu ltin g in d istan t m etastases to th e lu n gs, bon es, an d cen t ral n er vou s system , w h ich also im p ly a p oor p rogn osis ( Fig. 6.11). In patien ts w ith di eren tiated carcin om as, h igh -resolution US often ser ves as th e on ly preoperative im aging exam in ation prior to thyroidectom y. Patien ts w ith m ore aggressive form s of di eren tiated carcin om a, clin ical fin din gs suggestive of invasion of local struct ures, or exten sive lym ph n ode disease m ay ben efit from adjun ct cross-sect ion al im aging w ith CT or MRI to fur th er ch aracterize involvem en t of adjacen t struct ures an d to allow for m ore accurate preoperative plan n in g ( Fig. 6.12). Lym ph n ode m etastases are also better assessed by CT an d MRI in areas poorly visualized by US, such as th e retroph ar yn geal an d m ediastin al spaces. In t h e set t in g of d i eren tiated carcin om a, w h ole-body rad ioiod in e scan n in g m ay be p erform ed several w eeks p ostthyroid ect om y t o assess for rem n an t t hyroid t issu e, evalu ate for fu n ction in g m et astatic d isease, h elp d eterm in e th erap eu tic rad ioiod in e d ose, an d reveal altered biod ist ribu t ion ( Fig. 6.13). Th e ATA recom m en ds a w h ole-body scan prior to ablation w h en th e volum e of rem n an t thyroid is un able to be defin ed by US or by surgical repor t, or if th e w h ole-body scan m ay alter

Fig. 6.12 Papillary carcinom a with tracheal invasion. (a) Hypodense right thyroid lobe mass (black star) with intrinsic calcification and invasion of the right tracheal wall. (b) Coronal im age shows tum or on both sides of the tracheal rings (red arrowheads) consistent with tracheal invasion. Note pretracheal lym ph node m etastasis (white arrow).

th erapeutic radioiodin e dosage or th e decision to treat w ith radioiodin e ablation th erapy.36 Studies h ave sh ow n th at I-131 th erapy reduces th e risk of locoregion al recurren ce, an d th is th erapy h as becom e th e stan dard adjun ct ive t reatm en t in subsets of patien ts w ith di eren tiated thyroid can cer. Th e ATA recom m en ds ablation of th e thyroid rem n an t in patien ts w ith T3 tum ors or lym ph n ode disease an d select ive ablation in patien ts w ith in trathyroidal lesion s m easurin g 1 to 2 cm in size. Sh ort-term follow -up w ith physical exam in ation , recom bin an t TSH-stim ulated thyroglobulin m easurem en ts, an d n eck US serve as th e in itial 6 m on th follow -up for th e m ajorit y of postsurgical an d postablation pat ien ts. After thyroidectom y an d

53

Thyroid Diseases

Fig. 6.13 Follicular carcinom a. (a) An 11-year-old child with follicular carcinom a of the right thyroid lobe (white arrow), stomach (black star). Iodine131 whole-body scan shows diffuse activit y in the lungs (white arrowheads) consistent with m etastatic disease. (b) Postthyroidectom y scan shows m ultiple lung m etastases (white arrowheads) and cervical adenopathy (arrow).

rem n an t ablation , on ly m in im al ech ogen ic t issue sh ould be iden tified w ith in th e thyroid bed, likely represen tin g n orm al con n ective t issue an d scar t issue. Th e presen ce of solid or m ixed solid an d cystic soft tissue in th e thyroid bed is con cern in g for disease recurren ce ( Fig. 6.14a). Recurren t tum or often dem on strates hyper vascularit y, an d use of color Doppler im aging in th ese cases m ay be h elpful in distin guish in g recurren t disease from postoperative abscess, gran ulom a, or ch anges in th e m usculature. In th e sett in g of elevated thyroglobulin levels, US is 96% sen sitive in detect ion of locoregion al disease. How ever, 20% of th e population w ill h ave a posterosuperior trun k of th e thyroid lym ph atic path w ay th at drain s in to th e lateral retroph ar yn geal n odes, w h ich are poorly evaluated by US ( Fig. 6.14b).39 In th e situation of elevated stim ulated thyroglobulin an d n egative n eck US, radioactive iodin e w h ole-body im agin g m ay be perform ed. MRI or CT m ay also be considered for im proved anatom ical evaluation for m etastat ic retroph ar yn geal, retrotracheal, or m ediastin al m etastases. Elevated thyroglobulin levels w ith a n egative radioiodin e w h ole-body scan m ay represen t dedi eren t iation of thyroid carcin om a cells in to a m ore aggressive form of disease. In th is settin g, fludeoxyglucose (FDG)-PET/ CT is ben eficial for disease localization w ith reported sen sitivit y for disease detect ion ran ging from 70 to 95% an d fin din gs alterin g pat ien t clin ical m an agem en t in 20 to 40% of cases. FDG-PET/ CT fin din gs also provide progn ostic in form ation , w ith a greater n um ber of positive lesion s an d h igh er stan dardized uptake values im plyin g poorer patien t progn osis.40

54

6.6.2 Medullary Carcinom a Medullar y carcin om a arises from calciton in -producing parafollicular C cells. Approxim ately 25% of m edullar y carcin om as occur as par t of an in h erited gen et ic disorder (fam ilial autosom al dom in an t m edullar y thyroid carcin om a or m ultip le en docrin e n eoplasia t ype 2A an d 2B [MEN 2A an d 2B] syn drom es). Medullar y carcin om a m ay be detected early in th ese patien ts by follow in g screen in g calciton in levels. How ever, th e sporadic form of disease represen ts th e m ajorit y of cases, w ith patien ts often detected late w ith a firm palpable thyroid n odule, often w ith lym ph n ode m etastases (35 to 50%).41 Alth ough th ere is m uch overlap w ith di eren tiated carcin om a by US, m edullar y carcin om a m ay dem on strate a h igh er propen sit y for in trin sic cyst form ation an d m ore h om ogen eous echogen icit y in solid com pon en ts of th e lesion .42 On CT scan , m edullar y carcin om a usually appears as a w ell-circum scribed m ass w ith h eterogen eous atten uation ( Fig. 6.15a). Radioiodin e scin tigraphy or th erapy is n ot useful in th e settin g of m edullar y carcin om a because th ese lesion s do n ot concen trate iodin e. Surgical resection is th e m ain stay of treatm en t . Serum calciton in levels are m on itored after surgery to evaluate for tum or recurren ce. Patien ts w ith detectable calcitonin levels < 150 pg/m L often h ave locoregion al disease an d sh ould un dergo h igh -resolution n eck US for detect ion of local recurren ce or lym ph n ode m etastases. Calciton in levels > 150 pg/m L in crease th e likelih ood of distan t m etastatic disease. In addition to n eck US, oth er diagn ostic im aging m odalit ies, such as chest CT w ith

Thyroid Im aging

Fig. 6.14 Postthyroidectom y ultrasound (US). (a) Transverse US im age showing no thyroid tissue rem nant in the thyroid bed (white star). However, a hyperechoic nodule (white arrow) along the posterolateral aspect of the com m on carotid artery is proven to be a lym ph node m etastasis. (b) Axial com puted tom ography shows an enlarged hyperenhancing m ass (white arrow) in the left retropharyngeal space in this patient with papillary carcinoma, consistent with lym ph node m etastasis.

con trast an d liver MRI, m ay be con sidered. Reported sen sitivit y of FDG-PET/CT for m edullar y carcin om a is 78% ( Fig. 6.15b).43

6.6.3 Hürt hle Cell Carcinom a Hü rth le cell carcin om a (HCC), w h ich accoun ts for 3 to 5% of thyroid can cers, is considered by som e to be a varian t of follicular carcin om a an d by oth ers as a distin ct en t it y. HCC is m ore aggressive th an papillar y an d follicular carcin om a, w ith h igh er

Fig. 6.15 Medullary thyroid carcinom a. (a) Hypodense nodule (black arrow) with coarse calcification in the left thyroid lobe. Notice the m etastatic level 4 lym ph node (black star) with an im aging appearance sim ilar to that of the intrathyroid m ass. (b) Positron em ission tom ographic scan of the sam e patient showing glucose uptake in the thyroid m ass (black star) as well as in num erous pathological lym ph nodes (black arrows).

rates of lym ph n ode an d distan t m etastases an d a 10-year relative sur vival rate of approxim ately 76%.4 US im aging features do n ot di eren tiate HCC from oth er thyroid n eoplasm s. As w ith follicular n eoplasm s, US-guided FNA can n ot di eren tiate Hü rth le cell aden om a from HCC. Th is distin ction can be m ade on ly by tum or capsule evaluation s. High-resolution US sh ould

55

Thyroid Diseases of th e thyroid capsule is com m on ly presen t on US. CT scan s sh ow m ixed areas of hypoden sit y an d hyperden sit y th at often represen t n ecrosis an d h em orrh age, w ith about 65% of an aplastic carcin om as sh ow in g in trin sic calcification s ( Fig. 6.16). MRI often reveals a h eterogen eous T1 an d T2 sign al w ith a m oderate to m arked postgadolin ium en h an cem en t pattern . CT an d/or MRI exam in ation s sh ould in clude th e en tire n eck an d upper ch est to fully evaluate th e exten t of disease an d evaluate for lym ph n ode m etastasis. FDG-PET/CT is in dicated w ith an aplastic carcin om a because th ese lesion s do n ot con cen trate iodin e an d presen t w ith distan t m etastatic disease in approxim ately 40% of patien ts. FDG-PET/CT is also recom m en ded ever y 3 to 6 m on th s post treatm en t as a guide to furth er th erapies.45,46

References Fig. 6.16 Anaplastic carcinom a. Large heterogeneous m ass arising from the right lobe of thyroid with infiltration of the larynx (white star) and com m on carotid artery encasem ent (black arrow).

be perform ed for detect ion of m etastatic cer vical n odes. Th e utilit y of radioiodin e im aging an d th erapy is lim ited because HCC often does n ot concen trate iodin e. Th e m ain stay of treatm en t is aggressive surgical rem oval, an d HCC respon ds poorly to ch em oth erapy an d radiation .44 In th e post thyroidectom y patien t w ith elevated thyroglobulin levels, th ere is a role for FDGPET/CT, w ith som e studies sh ow in g sen sitivit y an d specificit y up to 95%.

6.6.4 Poorly Di erent iat ed Thyroid Carcinom a and Anaplast ic Thyroid Carcinom a Poorly di eren tiated an d an aplastic carcin om as h ave a m ore aggressive clin ical course com pared w ith th e previously discussed thyroid can cers. Poorly di eren tiated carcin om a likely represen ts an in term ediate step in th e t ran sition of di eren tiated carcin om a in to an aplastic carcin om a. It often m ain tain s m arkers of its follicular cell origin , con cen t ratin g iodin e in 85% of cases, an d is pron e to radioiodin e im agin g an d ablat ion treatm en t. Conversely, an aplastic carcin om a is an extrem e un di eren t iated form of thyroid carcin om a th at is un able to take up iodin e or produce thyroglobulin . Alth ough a rare tum or, it accoun ts for a large percen tage of thyroid-related death s, w ith m edian patien t sur vival after diagn osis of approxim ately 5 m on th s. Patien ts are usually older an d m ay h ave a h istory of thyroid goiter. Th e tum or m ay arise de n ovo or represen t a progressive dedi eren tiation of a preexistin g di eren tiated thyroid carcin om a. Patien ts often presen t w ith a large, h ard thyroid m ass w ith sym ptom s related to com pression or invasion of adjacen t struct ures. US t ypically sh ow s a 5 to 10 cm hypoech oic m ass, often w ith in trin sic cystic areas an d hyperech oic calcification s. US is also used to evaluate th e cen tral an d lateral n odal com partm en ts because approxim ately 40% of patien ts h ave lym ph n ode disease at diagn osis. Mass exten sion beyon d th e n orm al m argin s

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[1] Patel BN, Kam aya A, Desser TS. Pitfalls in son ograph ic evaluation of thyroid abn orm alities. Sem in Ultrasoun d CT MR 2013; 34(3); 226–235 [2] Ch audh ar y V, Ban o S. Thyroid ultrasoun d. In dian J En docrin ol Metab 2013; 17(2); 219–227 [3] ACR-AIUM-SPR-SRU. Practice Guidelin es for th e Perform an ce of a Thyroid an d Parathyroid Ultrasoun d Exam in ation . Am erican College of Radiology, Am erican In stitu te of Ultrasoun d in Medicin e, Society of Pediatric Radiology, Society of Radiologists in Ultrasoun d, 2013. [4] Nach iappan AC, Metw alli ZA, Hailey BS, Patel RA, Ostrow ski ML, W yn n e DM. Th e thyroid: review of im aging features an d biopsy tech n iques w ith radiologic-path ologic correlation . Radiograph ics 2014; 34(2); 276–293 [5] Loevn er LA, Kaplan SL, Cun n an e ME, Moon is G. Cross-sect ion al im aging of th e thyroid glan d. Neuroim agin g Clin N Am 2008; 18(3); 445–461, vii [6] ACR-SNM-SPR. Pract ice Guidelin e for th e Perform an ce of Thyroid an d Scin tigraphy an d Uptake Measurem en ts. Am erican College of Radiology, Society of Nuclear Medicin e an d Molecular Im aging, Society of Pediatric Radiology, 2009. [7] In tenzo CM, Dam HQ, Man zon e TA, Kim SM. Im aging of th e thyroid in ben ign an d m align an t disease. Sem in Nucl Med 2012; 42(1); 49–61 [8] Griggs W S, Divgi C. Radioiodin e im aging an d treatm en t in thyroid disorders. Neuroim agin g Clin N Am 2008; 18(3); 505–515, viii [9] Policen i BA, Sm oker W R, Reede DL. An atom y an d em bryology of th e thyroid an d parathyroid glan ds. Sem in Ultrasoun d CT MR 2012; 33(2); 104–114 [10] Zan der DA, Sm oker WR. Im aging of ectopic thyroid tissue an d thyroglossal duct cysts. Radiograph ics 2014; 34(1); 37–50 [11] Altay C, Erdoğan N, Karasu S, et al. CT an d MRI fin din gs of developm en tal abn orm alities an d ectopia varieties of th e thyroid glan d. Diagn In terv Radiol 2012; 18(4); 335–343 [12] Noussios G, An agnostis P, Goulis DG, Lappas D, Natsis K. Ectopic thyroid tissue: an atom ical, clin ical, an d surgical im plication s of a rare en tit y. Eur J En docrin ol 2011; 165(3); 375–382 [13] Goldstein B, Westra WH, Califano J. Multifocal papillar y thyroid carcin om a arisin g in a lin gual thyroid: a case report. Arch Otolaryn gol Head Neck Surg 2002; 128(10); 1198–1200 [14] Am r B, Mon ib S. Lin gual thyroid: A case report . In t J Surg Case Rep 2011; 2 (8); 313–315 [15] Allard RH. Th e thyroglossal cyst. Head Neck Surg 1982; 5(2); 134–146 [16] Kutuya N, Kurosaki Y. Son ograph ic assessm en t of thyroglossal duct cysts in ch ildren. J Ultrasoun d Med 2008; 27(8); 1211–1219 [17] Boi F, Loy M, Piga M, Serra A, Atzen i F, Mariotti S. Th e usefuln ess of conven tion al an d ech o colour Doppler son ography in th e di eren tial diagn osis of toxic m ultin odular goitres. Eur J En docrin ol 2000; 143(3); 339–346 [18] Vitti P, Rago T, Man cusi F, et al. Th yroid hypoech ogen ic pattern at ultrason ography as a tool for predict in g recurren ce of hyperth yroidism after m edical treatm en t in patien ts w ith Graves’ disease. Acta En docrin ol (Copen h ) 1992; 126(2); 128–131 [19] Julian o AF, Cun n an e MB. Ben ign con dition s of th e thyroid glan d. Sem in Ultrasoun d CT MR 2012; 33(2); 130–137 [20] Parm ar H, Ibrah im M. Extrathyroidal m an ifestation s of thyroid disease: thyroid oph th alm opathy. Neuroim agin g Clin N Am 2008; 18(3); 527–536, viii–ix [21] Pearce EN, Farw ell AP, Braverm an LE. Th yroiditis. N En gl J Med 2003; 348 (26); 2646–2655

Thyroid Im aging [22] An derson L, Middleton W D, Teefey SA, et al. Hash im oto thyroiditis: Part 1, son ograph ic an alysis of th e n odular form of Hash im oto thyroiditis. AJR Am J Roen tgen ol 2010; 195(1); 208–215 [23] Zen gi A, Karaden iz M, Dem irpolat G, Akgun A, Karakose S, Yilm az C. Hypothyroid Hash im oto’s thyroiditis w ith scin tigraph ic an d color flow doppler son ography features m im ickin g a h ot n odule. In tern Med 2009; 48(4); 231–234 [24] Sakorafas GH, Kokkoris P, Farley DR. Prim ar y thyroid lym ph om a diagn ostic an d th erapeutic dilem m as. Surg On col 2010; 19; 124–129 [25] Mirfakh raee S, Math ew s D, Peng L, Woodru S, Zigm an JM. A solitar y hyperfun ct ion in g thyroid n odule h arborin g thyroid carcin om a: review of th e literature. Th yroid Res 2013; 6(1); 7 [26] Pollard DB, Weber CW, Hudgin s PA. Preoperative im aging of thyroid goiter: h ow im aging tech n ique can in fluen ce an atom ic appearan ce an d create a poten tial for in accurate in terpretation . AJNR Am J Neuroradiol 2005; 26(5); 1215–1217 [27] Hen n essey JV. Clin ical review : Riedel’s thyroiditis: a clin ical review. J Clin En docrin ol Metab 2011; 96(10); 3031–3041 [28] An n aert M, Th ijs M, Sciot R, Decallon n e B. Riedel’s thyroiditis occurrin g in a m ultin odular goiter, m im ickin g thyroid can cer. J Clin En docrin ol Metab 2007; 92(6); 2005–2006 [29] Jin J, McHen r y CR. Th yroid in ciden talom a. Best Pract Res Clin En docrin ol Metab 2012; 26(1); 83–96 [30] Ch aikh outdin ov I, Mitzn er R, Golden berg D. In ciden tal thyroid n odules: In ciden ce evaluation , an d outcom e. Otolaryn gol Head Neck Surg 2014; 150(6); 939–942 [31] Papin i E, Pacella CM, Hegedus L. Diagn osis of en docrin e disease: thyroid ultrasoun d (US) an d US-assisted procedures: from th e sh adow s in to an array of application s. Eur J En docrin ol 2014; 170(4); R133–R146 [32] Cooper DS, Doh erty GM, Haugen BR, et al. Am erican Thyroid Association (ATA) Guidelin es Taskforce on Thyroid Nodules an d Di eren tiated Thyroid Can cer. Revised Am erican Thyroid Association m an agem en t guidelin es for patien ts w ith thyroid n odules an d di eren tiated thyroid can cer. Thyroid 2009; 19(11); 1167–1214 [33] Hobbs HA, Bah l M, Nelson RC, et al. Applyin g th e society of radiologists in ultrasoun d recom m en dation s for fin e-n eedle aspiration of thyroid n odules: e ect on w orkup an d m align an cy detect ion . AJR 2014: 602–07

[34] Bertagn a F, Treglia G, Piccardo A, Giubbin i R. Diagn ostic an d clin ical sign ifican ce of F-18-FDG-PET/CT thyroid in ciden talom as. J Clin En docrin ol Metab 2012; 97(11); 3866–3875 [35] Pacin i F, Castagn a MG, Brilli L, Pen th eroudakis G ESMO Guidelin es Working Group. Thyroid can cer: ESMO Clin ical Pract ice Guidelin es for diagn osis, treatm en t an d follow -up. An n On col 2010; 21 Suppl 5; v214–v219 [36] Ram os CO, Mirasol RC. US guidan ce im proves diagn ostic yield an d accuracy of fin e n eedle aspiration biopsy of thyroid n odules in detectin g m align an cy. Thyroid Disorders Th er 2014; 3; 2 [37] Aiken AH. Im aging of thyroid can cer. Sem in Ultrasoun d CT MR 2012; 33(2); 138–149 [38] Loevn er L. Surgical Approach es in Th yroid Can cer: Wh at th e radiologist n eeds to kn ow Neuroim agin g Clin N Am 2008; 18; 445–562 [39] Otsuki N, Nish ikaw a T, Iw ae S, Saito M, Moh ri M, Nibu K. Retroph aryn geal n ode m etastasis from papillar y thyroid carcinom a. Head Neck 2007; 29(5); 508–511 [40] Abrah am T, Sch öder H. Th yroid can cer—in dication s an d opport un ities for positron em ission tom ography/com puted tom ography im agin g. Sem in Nucl Med 2011; 41(2); 121–138 [41] Sippel RS, Kun n im alaiyaan M, Ch en H. Curren t m an agem en t of m edullary thyroid can cer. On cologist 2008; 13(5); 539–547 [42] Lee S, Sh in JH, Han BK, Ko EY. Medullary thyroid carcinom a: com parison w ith papillary thyroid carcin om a an d application of curren t son ograph ic criteria. AJR Am J Roen tgen ol 2010; 194(4); 1090–1094 [43] Can cer MT. Man agem en t Guidelin es of th e Am erican Thyroid Association 2009; 19; 6 [44] Can n on J. Th e sign ifican ce of h urth le cells in thyroid disease. On cologist 2011; 16(10); 1380–1387 [45] Am erican Th yroid Association Guidelin es for Man agem en t of Patien ts w ith An aplastic Thyroid Can cer Thyroid 2012; 22(11); 1104–1139 [46] Treglia G, An n un ziata S, Salvatori M, et al. Th e Role of F-18-FDG PET in Aggressive Histological Subt ypes of Th yroid Can cer: An Over view, In tern ation al Journ al of En docrin ology 2013, Art icle ID 856189, 6 pages

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Thyroid Diseases

7 Benign Disease of t he Thyroid Gland Maisie L. Shindo

7.1 Int roduct ion Ben ign thyroid diseases com prise both n odular diseases an d in flam m ator y thyroid condition s. Nodular diseases can be categorized as solitar y thyroid n odules an d m ultin odular goiters. Th e term goiter is used to describe a path ological en largem en t of th e thyroid glan d. Goiters can be classified as di use or n odular, toxic or n on toxic. Toxic condition s of th e thyroid are th orough ly review ed in Ch apter 8. In flam m atory thyroid condition s in clude autoim m un e thyroiditis, subacute thyroiditis, an d Riedel’s thyroiditis. Th e prevalen ce of clin ically eviden t thyroid n odules is approxim ately 5%, depen din g on age, sex, an d geography.1 In autopsy series th e prevalen ce of solitar y n odules is approxim ately 10%, an d of thyroid n odularit y it is as h igh as 50%.2 In recen t years im aging m odalities h ave becom e m ore ubiquitous an d sen sitive in m edicin e, resultin g in seren dipitous discover y of asym ptom at ic un expected thyroid n odules, referred to as in ciden talom as. With th e routin e use of im aging m odalities, such as ultrasoun d (US), com puted tom ography (CT), m agnetic reson an ce im aging (MRI), an d positron em ission tom ography (PET), th e in ciden ce of thyroid in ciden talom as w ill likely be sim ilar to th e prevalen ce of n odules foun d on autopsy. US can detect thyroid n odules in 19 to 68% of ran dom ly selected in dividuals.3,4 Th e in ciden ce of m align an cy in a solitar y n odule ran ges from 10 to 40%, depen din g on th e age, sex, ch aracteristics of th e nodule, selective criteria for surgery, an d presen ce of risk factors.5,6,;7,8 In evaluatin g a thyroid n odule, a com plete h istory sh ould be elicited regardin g factors th at m ay predict th e risk of m align ancy, such as voice ch ange, h em optysis, rapid grow th , h istor y of ch ildh ood h ead an d n eck irradiation , total body irradiat ion for bon e m arrow tran splan tation , exposure to ion izing radiation in ch ildh ood or adolescen ce, an d thyroid m align an cy in first-degree relatives.5,7,8,9,10 Radiation exposure can be from prior h ead an d n eck irradiation for lym ph om a or ben ign con dition s (acn e, thym us, en larged aden oids, t in ea capitis),11,12 total body irradiation for bon e m arrow t ran splan tation ,13,14 an d exposure to fallout, such as from th e Ch ern obyl in ciden ts, part icularly in th ose un der 15 years of age.15,16,17 A review of th e patien t’s fam ily h istory is im portan t for assessing th e risk factor for thyroid can cer. Th e probabilit y of a patien t w ith a thyroid n odule h avin g a m align an cy is estim ated to be approxim ately 38% w h en t w o first-degree fam ily m em bers are a ected, an d is even h igh er w h en th ree or m ore are a ected.18 It is also im portan t to be aw are th at n odular thyroid diseases m ay be associated w ith various h ereditar y syn drom es, particularly w h en present at a younger age. Fam ilial aden om atous polyposis is an autosom al dom in an t disease caused by m utation of the APC gen e an d is ch aracterized by polyposis of th e colon , epiderm oid cysts of th e skin , desm oid tum ors of th e abdom in al w all, retin al pigm en ted epith elium , an d thyroid carcin om a. A sm all subset of th ese patien ts presen t w ith osteom as, referred to as Gardn er’s syn drom e. Thyroid carcin om as occur in 1 to 2% of th ese patien ts an d are usually papillar y carcin om a.19,20 Cow den’s disease is an autosom al dom in an t disease ch aracterized by tum ors of th e thyroid, breast, colon ,

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en dom etrium , an d brain , an d h am ar tom as an d t um ors of th e skin . Th e thyroid abn orm alities m ay present in ch ildh ood as m ultin odular goiters, m ultifocal follicular aden om as, an d aden om atous n odules.20,21 Carn ey’s com plex is an autosom al dom in an t m ultiple n eoplasia syn drom e due to m utation in th e PRKAR1A gen e con sistin g of spott y skin pigm en tation , m yxom as, en docrin e tum ors, an d sch w an n om as.22 Multiple en docrin e organ s are a ected, result in g in thyroid t um ors; prim ar y pigm en ted n odular adren ocort ical disease, w h ich can result in Cush in g’s syn drom e; prolact in -producin g pituitar y t um ors; testicular tum ors causin g precocious pubert y; an d ovarian tum ors.22 Up to 75% of pat ien ts w ith Carn ey’s com plex h ave m ultiple thyroid n odules, an d som e m ay also present w ith thyroid m align an cy.22 Skin m an ifestation s in clude spott y pigm en ted skin lesion s, blue n evi, an d café au lait spots. Th e m yxom as can involve th e h eart , breast, an d skin .22 Pen dred syn drom e is an autosom al recessive disease m an ifestin g as a com bin ation of goiter an d congen ital deafn ess. Goiters m ay be presen t from ch ildh ood to early adolescen t years. Th e gen etic defect w ith th is disease h as been sh ow n to be a m utation of th e PDS (SLC26A4) gen e on ch rom osom e 7q22–31.1.23 In t h e evalu at ion of n od u lar t hyroid d isease, t h e h ead an d n eck exam in at ion sh ou ld in clu d e t h e ch aract erist ics of th e t hyroid glan d an d an assessm en t for lym p h ad en op at hy an d cran ial n er ve fu n ct ion , p ar ticu larly vocal cord m obilit y. A thyroid n od u le associated w ith ip silateral vocal cord p aralysis is h igh ly su sp iciou s for a m align an cy. In t h e rare p atien t w h o m ay also h ave h em op tysis, flexible lar yn goscopy sh ou ld be p erform ed to assess lar yn geal p ath ology an d to exam in e th e u p p er trach ea for p resen ce of trach eal in vasion from a thyroid m align an cy.

7.2 Evaluat ion and Managem ent of Solit ary Thyroid Nodules Th e n atural course of thyroid n odules is n ot fully un derstood. On e lon g-term study sh ow ed th at 23% of thyroid n odules ultim ately in creased in size.24 Th e m ost im portan t goal in th e diagn ostic evaluation of a thyroid n odule is to exclude m align an cy. Because thyroid n odules are quite prevalen t, in cluding n on palpable on es foun d in ciden tally, th e ch allenge for th e clin ician is in decidin g w h ich n odules n eed to be biopsied or surgically excised an d w h ich on es can be observed. Serum thyroid-stim ulatin g h orm on e (TSH) sh ould be th e in itial first test in th e evaluation of n odular thyroid disease.5 US is also an im portan t in itial test. It is excellen t for detection an d ch aracterization of thyroid n odules an d th us is an adjun ct to th e physical exam in ation .5,25,26,27 Thyroid son ography provides ver y useful m an agem en t in form ation th at in cludes accurate m easurem en t of th e size of th e n odule; w h eth er th e n odule is purely cystic, solid, or m ixed; w h eth er oth er n on palpable n odules are presen t; an d w h eth er th ere are fin din gs in dicatin g a m align an cy, such as m icrocalcificat ion s an d irregular m argin s, in tran odular hypervascularit y, an d m arked hypoech ogen icit y.27,28,29 A thyroid uptake scan for solitar y n odules is n ot particularly useful un less

Benign Disease of the Thyroid Gland th e TSH level is suppressed (i.e., below n orm al ran ge). In w h ich case, a thyroid uptake scan can be obtain ed to see if th e n odule is hyperfun ction in g, in dicative of a toxic sin gle aden om atous n odule. Fin e-n eedle aspiration (FNA) is a ver y im portan t an d usefu l tool in th e diagn ostic evaluation of solitar y n odules.7,30 In gen eral, a solitar y n odule requires h istological evaluation , eith er by FNA or surgical excision , w h en associated w ith risk factors for m align an cy. Th ese factors in clude rapid en largem en t, associated lym ph aden opathy, associated vocal cord paralysis, prior radiation exposure, age over 60 or un der 20, an d a fam ily h istory of thyroid can cer in a first-degree relative. Th e in ciden ce of m align an cy in a solitar y n odule in ch ildh ood is greater th an th at in adults an d h as been reported to be as h igh as 50%.11,31,32,33 Th erefore, serious con sideration sh ould also be given to biopsy or surgical excision of thyroid n odules detected durin g ch ildh ood, particularly if th ey are > 1.5 cm an d solid. Solid thyroid n odules in pat ien ts over 65 years of age h ave a h igh er risk of bein g m align an t. Furth erm ore a h igh er percen tage of th e m align an cies in th is age group ten d to be of th e m ore aggressive t ype.6,34,35 In a study of 21,748 patien ts w ith thyroid n odules w h o un derw en t US-guided FNA an d surgical path ological correlation in 3,629 patien ts, 37% of th e n odules occurrin g in th ose over age 65 w ere foun d to be m align an t, an d up to 36% of th e m align an cies w ere diagnosed as an aplastic or m etastatic.6 Th erefore, a cytological or path ological diagnosis is w arran ted in elderly patien ts w h o presen t w ith a n ew thyroid n odule, particularly if it is rapidly grow in g. Son ograph ic evaluation of th e an terior cer vical lym ph n ode (cen tral an d bilateral) com partm en ts sh ould be perform ed w h en ever thyroid n odules are detected.7 If US detects cervical lym ph n odes th at are son ograph ically suspicious for thyroid can cer, FNA of th e suspicious lym ph n ode sh ould be perform ed. In ciden talom as pose a m an agem en t dilem m a. Nodules w ith son ograph ic fin din gs suspicious for m align an cy as discussed earlier sh ould be biopsied.28,36 It h as been suggested by several auth ors as w ell as th e Am erican Thyroid Association (ATA) Task Force on Thyroid Nodules an d Di eren tiated Thyroid Can cer th at, in th e absen ce of clin ical risk factors for m align an cy, risk stratification of a thyroid n odule base on a con stellation of US fin din gs w ould h elp triage w h ich n odules sh ould be biopsied an d w h ich sh ould n ot.7,36,37,38,39 Th e 2014 ATA guidelin es recom m en d ch aracterizin g th e pattern of US fin din gs an d stratifyin g th e n odules in to ben ign or suspicious.7 Purely cystic n odules are con sidered ben ign an d do n ot require a biopsy. Suspicious fin din gs are risk stratified in to h igh , in term ediate, low, an d very low suspicion categories based on w h eth er th ey are solid or cystic, th eir echogen icity, an d th e presen ce of on e or m ore of th e follow in g w orrisom e features: m icrocalcificat ion s, a taller th an w ide sh ape, rim calcification s w ith a sm all extrusive soft tissue com pon en t, an d extrathyroidal extension . Hypoech oic solid n odules w ith or w ith out a cystic com ponen t exh ibitin g on e or m ore of th ese w orrisom e features are con sidered h igh risk (70–90% risk of m align an cy) an d sh ould be biopsied if > 1 cm . Hypoech oic solid n odules w ith out th ese w orrisom e features carry a m uch low er risk of m align an cy (10–20%); biopsy of such lesion s sh ould be con sidered if th ey are > 1 cm . Nodules th at are isoech oic, hyperech oic, or part ially cystic w ith eccen t ric solid areas th at do n ot exh ibit any of th e w orr isom e features are considered low risk (5–10% risk of m align an cy), an d th us biopsy can be con sidered w h en th e n odules are > 1.5 cm . Mixed cystic solid n odules w ith

a spon giform appearan ce stron gly correlate w ith ben ign it y, an d FNA can be w ith h eld un til th ey are > 2 cm . Oth er laborator y tests con sidered in th e evaluation of a thyroid n odule in clude serum calciton in an d thyroglobulin levels. A seru m calciton in level sh ould be obtain ed if th ere is a fam ily h istory of m edullary thyroid carcin om a, or if th e FNA of th e n odule reveals atypical sm all roun d cells or spin dle cells, w h ich are n ot t ypical of cells derived from a follicular origin . Serum thyroglobulin is n ot ver y h elpful as a diagn ostic tool. An elevated thyroglobulin level itself is n ot in dicative of a thyroid m align an cy because ben ign con dition s, such as an aden om atous n odule or a recen t FNA, can cause elevation of serum thyroglobulin . How ever, sh ould th e n odule turn out to be a follicular cell–derived thyroid carcin om a, a n orm al preoperative level obtain ed prior to FNA m ay be in dicative of a n on thyroglobulin -secretin g t um or, w h ich m ay guide th e m eth odology of subsequen t can cer sur veillan ce. Thyroid FNA cytological fin din gs are gen erally repor ted usin g th e Bethesda System for Report in g Thyroid Cytopath ology.40,41 Th e Beth esda System recogn izes six diagn ostic categories: (I) n on diagn ostic/un satisfactory; (II) ben ign ; (III) atypia of un determ in ed sign ifican ce/follicular lesion of un determ in ed sign ifican ce (AUS/FLUS); (IV) follicular n eoplasm /suspicious for follicular n eoplasm (FN), a category th at also en com passes th e diagn osis of Hü rth le cell n eoplasm /suspicious for Hü rth le cell n eoplasm ; (V) suspicious for m align an cy (SUSP), an d (VI) m align an t. A n on diagn ostic FNA results from poor preservation of th e specim en or low cellularit y obtain ed from th e aspiration , w h ich can occur for several reason s, in cludin g sm all n odules, den sely fibrotic or calcified n odules, cystic n odules, an d operator in experien ce. Th e diagnostic yield of FNA can be im proved w h en perform ed un der US guidan ce.42,43 Furth erm ore, w ith US guidan ce, sm all, n on palpable n odules can be biopsied w ith h igh yield. Th e rate of n on diagn ostic aspiration can be furth er reduced to < 2% w h en th e biopsy is perform ed un der US guidan ce w ith on -site cytological preparation w h ere cytotech n ologists or cytopath ologists can provide im m ediate feedback on w h eth er or n ot th e aspirate is su cien tly cellular.6,44,45 Thyroidectom y sh ould be recom m en ded if th e FNA cytology is con sisten t w ith or suspicious for a m align an cy. Th e risk of m align an cy in an in determ in ate n odule (Beth esda classification s III an d IV) ran ges from 20 to 30%.46,47,48 With in determ in ate cytology, th e option s are surgical excision for defin itive diagn osis, or testin g th e FNA w ith th e Afirm a Gen e Expression Classifier (GEC), w h ich evaluates m RNA expression of 167 gen es.49 Th e GEC h as been sh ow n in a m ulti-in st itut ion al study to h ave a n egative predict ive value of 95%, an d a 37% positive predict ive value. Th is m ean s th at if th e GEC is n on suspicious, th e risk of m align an cy is 5%; h ow ever, if it is suspicious, th e risk of m align an cy is on ly 37%; th us it is considered a rule-out test. Th e decision is n ot as straigh tforw ard w h en th e FNA cytology is n on diagn ostic. Repeat FNA or surgery sh ould be recom m en ded if th e cytologically n on diagn ostic n odule is solid, depen ding on th e clin ical an d US suspicious features. Th e patien t’s age an d un derlyin g m edical con dition also n eed to be factored in to th e decision m akin g. In youn g patien ts w ith large n odules, particularly if th ey are solid or dem on st rate som e atypia, surgical excision for defin itive diagn osis an d lon g-term treatm en t is preferred over observation . In elderly patien ts w ith

59

Thyroid Diseases th is scen ario, if th e pat ien t h as little or n o an esth etic risks, surgical excision sh ould be con sidered. How ever, in th ose w ith sign ifican t com orbidities, it w ould be appropriate to repeat th e FNA an d closely obser ve th e n odule.50 Cystic n odules are diagnostically ch allen ging because aspiration of th e fluid usually yields a hypocellular specim en . Th e risk of m align an cy in cystic thyroid n odules am on g adults ran ges from approxim ately 15 to 30%, sim ilar to th at of solid n odules, and th e risk a of false-n egative aspirate is h igh .51,52,53 Th e recom m en dation form ulated by th e ATA is th at cystic n odules w h ich repeatedly yield n on diagnostic aspirates n eed surgical excision or close obser vation w ith fastidious follow -up an d repeat FNA.7 A cystic n odule con tain ing a large solid com pon en t, particularly w ith m icrocalcification s, or w ith an irregular an d fin gerlike pedun culated m ass exten din g in to th e lum en , is suspicious for a cystic papillar y carcin om a.54,55 If th e in itial FNA of a cystic n odule w ith th ese US ch aracteristics is n on diagn ostic, eith er th e FNA sh ould be repeated w ith US guidan ce an d on -site cytologic evaluation , or surger y sh ould be recom m en ded. Wh en perform in g FNA on a cystic n odule, th e diagn ostic yield can be im proved by first aspiratin g th e fluid con ten t an d th en reaspiratin g un der US guidan ce th e rem ain ing cyst w all or solid com pon en t.55,56,57 A cystic thyroid n odule associated w ith cystic lym ph aden opathy in th e paratrach eal region is stron gly suggestive of cystic papillary thyroid carcin om a an d sh ould be t reated as such un til proven oth erw ise. FNA of th e thyroid n odule an d cystic n ode, particularly if perform ed un der US an d cytological guidan ce, sh ould confirm th e diagnosis. A cystic thyroid n odule associated w ith cystic lym ph aden opathy in th e lateral n eck is m ore ch allengin g in term s of establish ing a cytological diagn osis because th e aspirate from th e lym ph n ode can be hypocellular or can m im ic lesion s of n on thyroid origin , such as a bran ch ial cleft cyst.52,58 In th at settin g, th e fluid from th e lym ph n ode aspiration can be sen t for a thyroglobulin level; if elevated, it w ould be diagn ostic of cystic papillar y carcin om a; h ow ever, a n orm al level does not exclude m align an cy. Measurin g th e thyroglobulin level in th e fluid obtain ed from FNA of a cystic thyroid n odule is generally n ot h elpful because it can also be elevated in a ben ign n odule. If FNA of a thyroid n odule associated w ith cystic cervical lym ph aden opathy can n ot establish a diagn osis, surgery w ith frozen sect ion is w arran ted.

7.3 Nodular Goit ers Nodular goiters en com pass several di eren t path ological con dition s, in cluding hyperthyroidism , hypothyroidism , autoim m un e thyroiditis, an d m align an cy. In th e absen ce of such con dition s, it constitutes an en t it y described as sim ple n odular goiter, often in terch angeably term ed m ultin odular goiter. Multin odular goiter is th e m ost com m on en docrin e disorder w orldw ide. Goiters can occur en dem ically an d sporadically. An en dem ic goiter is on e th at occurs in a region , such as th e An des an d Pyren ees, w h ere its prevalen ce in ch ildren 6 to 12 years of age is > 5%.59 Sporadic goiter is on e th at occurs in a n on en dem ic region in a euthyroid in dividual.

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7.3.1 Pat hogenesis Th e etiology of n odular goitrous en largem en t is m ultifactorial an d can be categorized in to environ m en tal an d gen etic.59,60 Iodin e deficien cy is th e m ost com m on environ m en tal factor con tribut in g to form ation of en dem ic goiters.61 Iodin e deficien cy a ects th e organ ificat ion step in thyroxin syn th esis, resultin g in in adequate thyroid h orm on e product ion , w h ich leads to in creased TSH product ion by th e pituitar y. TSH stim ulation ultim ately causes grow th of thyroid follicles an d glan dular en largem en t. On ce iodin e w as supplem en ted in th e diet as iodized salt, th e prevalen ce of goiters decreased sign ifican tly in m any parts of th e w orld. Alth ough iodin e deficien cy m ay also be a cause of goiters in n on en dem ic region s, th e etiology in m ost cases of sporadic goiters is un clear. Various natural substan ces th at in terfere w ith th e iodin e-trappin g m echan ism h ave been im plicated in th e developm en t of goiters.62 Som e of th ese n atural goitrogen s, such as cyanogen ic glycosides an d th iocyan ates, are foun d in vegetables; oth ers are foun d in grass an d w eeds, w h ich are th en t ran sm itted th rough cow s an d an im als th at con sum e th em . Fem ale sex is also associated w ith in creased risk of n odular goiter form ation . Oth er etiologies th at h ave been im plicated in developm en t of goiters are sm okin g,59,63,64 m edication s,65 an d low selen ium level.66 Rarely, iodin e excess h as also been advocated as a cause of goiter. Gen etics h as also been im plicated in th e form ation of nodular goiters.67,68,69,70,71 Im m un ogen ic stim ulation h as also been speculated to be a poten t ial cause of goiter form ation . Im m un oglobulin s th at can stim ulate grow th of thyroid follicles in vitro h ave been detected in pat ien ts w ith both toxic an d n on toxic n odular goiters 72,73 ; h ow ever, th eir role in developm en t of th ese goiters h as yet to be clearly establish ed. Regardless of th e thyrotroph ic stim ulatin g agen t , be it TSH or im m un oglobulin , th e in itial respon se in th e thyroid is di use en largem en t. With ch ron ic stim ulat ion , various areas of th e glan d con tin ue to proliferate at di eren t rates. Som e areas w ill becom e hypofun ction al, w h ereas oth ers m ay becom e hyperfun ct ion al. Th e in creased t issue m ass is also m odulated by apoptosis, resultin g in death of thyrocytes an d involut ion in som e areas. Th e apop tosis is th ough t to be m ediated by th e Fas an tigen .74

7.3.2 Pat t erns of Grow t h Th e n atural h istory of un treated euthyroid m ultin odular goiters can be som ew h at variable.75,76 Som e w ill con tin ue to grow in volum e, up to 20% in a year, w h ile rem ain in g euthyroid.76 As grow th con tin ues, th e en largin g thyroid glan d can exten d outside of th e thyroid bed an d spread in feriorly to th e m ediastin um or posteriorly alon g th e sides or beh in d th e ph ar yn x. Chin an d colleagues studied th e pattern s of grow th on CT scan s in 190 pat ien ts w ith goiters.77 Th ey reported th at in 44% of th e patien ts th e goiters spread outside of th e thyroid bed. Th irt yseven percen t of th e goiters dem on st rated exten sion in to th e m ediastin um , an d 7 percent exten ded alon g or beh in d th e ph ar yn x. Of th ose th at exten ded in to th e m ediastin um , all exten ded in to th e an terior com part m en t, an d 7% exten ded in to th e posterior com partm en t .

Benign Disease of the Thyroid Gland

7.3.3 Evaluat ion and Managem ent of Nont oxic Goit ers Approach es to th e m an agem en t of n on toxic goiters di er con siderably am on g physician s of th e sam e specialt y an d di eren t specialties, betw een di eren t con tin en ts, an d for youn g versus old patien ts. North Am erican clin ician s use serum TSH (100%), follow ed by FNA an d thyroid US, w ith th e m ajorit y em ployin g US guidan ce for FNA. Thyroid uptake scin tigraphy an d serum calciton in levels are used less frequen tly by North Am erican clin ician s com pared to European clin ician s. Th ere is also con siderable disagreem en t am on g clin ician s on th e m an agem en t of n on toxic goiters. In th e sam e sur vey reported by Bon n em a et al78 on e-th ird preferred observation , w h ereas approxim ately h alf used levothyroxin e, despite a lack of eviden ce from prospective clin ical trials dem on st ratin g th e value of levothyroxin e th erapy. Seven t y-eigh t percen t recom m en ded surgery if rapid grow th is observed, an d 69% recom m en ded surgery for com pressive sym ptom s. Surgery w as also preferred by approxim ately tw o-th irds of th e clin ician s if th ere is a h istory of prior h ead an d n eck radiation or a fam ily h istory of thyroid m align an cy. With out a un iform con sen sus in approach es to th e m an agem en t of n on toxic goiters, a logical approach w ould be to base th e decision on th e presen ce or absen ce of dom in an t n odules, an d w h eth er or n ot th e goiter is in creasin g in size or causin g com pression . Th e patien t’s age an d sex, h istory of rapid grow th , prior h ead an d n eck irradiation exposure, an d fam ily h istory of thyroid m align an cy also n eed to be factored in to th e decision .

Noncom pressive Goit ers In the absence of any associated risk factors for m alignancy, sm all, nontoxic goiters w ith sm all nodules can generally be observed w ith periodic thyroid sonogram s. Nodules should be biopsied w hen grow th is observed. Dom inant nodules in a m ultinodular goiter, particularly if they are hypofunctional, should undergo FNA. Guidelines on w hen to biopsy a thyroid nodule have been discussed in the previous section on solitary nodules. In the presence of tw o or m ore thyroid nodules > 1 cm , those w ith a suspicious sonographic appearance should be aspirated preferentially. If none of the nodules has a suspicious sonographic appearance and m ultiple sonographically sim ilar nodules are present, the largest nodule (> 2 cm ) should be biopsied.7 In recen t years th e use of eth an ol inject ion for lon g-term m an agem en t of cystic n odular goiters h as been advocated by som e as an altern ative to surgical excision . With th is tech n ique, th e cyst is decom pressed un der US guidan ce an d h igh ly concen trated (i.e., 95%) eth an ol is injected. Several studies h ave sh ow n th at volum e reduct ion by as m uch as 95% can be ach ieved, w ith low recurren ce rates.79,80,81,82,83 Som e h ave even advocated th at cysts up to 40 m L can be successfully t reated.81 Wh en com parin g th e tech n iques of sim ply inject in g eth an ol in to th e cyst, versus aspiratin g th e cyst first th en inject in g th e eth an ol, th e cure an d com plication rates are sim ilar w ith both techn iques; in fact, th e patien ts prefer on ly on e n eedle pun ct ure, an d th e t im e of procedure is sh orter w ith out aspiration of th e cyst.80 Cysts w ith

h igh viscosity ten d to be di cult to treat. For th ese t ypes of cysts, Zielezn ik an d colleagues advocate a t w o-stage eth an ol injection tech n ique w h ere eth an ol is injected in to th e cyst un der US durin g th e first procedure an d left for 2 w eeks, w h ich h elps reduce th e viscosity. In th e second stage, th e th in n er fluid is aspirated an d 95% eth an ol is reinjected un der US.84 Th e auth ors reported a 92% reduct ion in volum e an d n o recurren ce. Th e th erapeutic use of eth an ol inject ion for thyroid n odules rem ain s con troversial. Opin ion s ran ge from th ose w h o believe th at th is is still an investigative tech n ique to oth ers w h o use it select ively in pat ien ts w h o can n ot un dergo surgery to those w h o use it routin ely.59,80,85,86 Alth ough th is h as becom e a popular prim ary treatm en t m odalit y for thyroid cysts an d toxic aden om atous n odules in Europe an d Asia, th is procedure is gen erally n ot favored as th e prim ary treatm en t of ch oice in th e Un ited States.

Com pressive and Subst ernal Goit ers W h en n odular goiters becom e su cien tly large, th ey can cause deviation or com pression of th e aerodigestive tract. With furth er exten sion in feriorly, th ey can advan ce in to th e m ediastin um an d becom e substern al goiters. Lah ey an d Sw in ton defin ed a substern al goiter as a “glan d in w h ich th e greatest diam eter of th e in t rath oracic m ass by roen tgen ogram is w ell below th e upper apertu re of th e th oracic cage m ade by th e stern um , first rib, an d vertebral bodies.”87 Th e in ciden ce of substern al goiter in th e gen eral population based on screen in g ch est Xray is 0.02%to 0.5%.88,89 Several classification system s h ave been proposed for substern al goiters. Higgin s origin ally described a classification system based on th e percen tage of th e goiter in th e n eck versus th e th orax.90 He classified a goiter as in trath oracic if at least four-fifth s of th e glan d lies in th e th orax. In addition , h e described substern al (par t or all of th e glan d exten din g below th e stern um ) an d/or subclavicular (part or all of th e glan d exten din g below th e clavicle) com pon en ts. An oth er classification w as developed by Coh en an d Ch o based on th e percen tage of th e m ediastin al com pon en t of th e substern al goiter. Grade I is defin ed as up to 25% of th e goiter in th e ch est, grade II is defin ed as 26 to 50%, grade III is defin ed as 51 to 75%, an d grade IV is defin ed as > 75%.91 Com pressive cervical an d substern al goiters can grow considerably for years before causin g any sym ptom s. Wh en su cien tly large, th ey can im pinge on th e trach ea an d cause deviation or n arrow ing of th e trach eal lum en . Man y patien ts w ith trach eal n arrow ing are asym ptom atic, but som e m ay experien ce dyspnea. Patien ts w ith t rach eal deviation are usually asym ptom atic. Large goiters can also im pinge on th e esoph agus an d cause dysphagia. Substern al goiters can occasion ally im pinge on th e in trath oracic great vessels an d cause ven ous obstru ct ion . Wh en ven ous com pression is severe, it can im pede ven ous outflow from th e h ead an d n eck, result in g in facial er yth em a w h en arm s are raised above th e h ead, kn ow n as Pem ber ton’s sign . In th ose w h o are sym ptom at ic from a substern al goiter th e m ost com m on com pressive m an ifestation is dyspnea (48–67%), follow ed by dysph agia (26–53%), an d stridor (11– 17%).92,93,94,95,96

61

Thyroid Diseases

Fig. 7.1 Substernal goiter with mild tracheal narrowing and com pression.

Levothyroxin e th erapy is recom m en ded in a patien t w ith n on toxic m ultin odular goiter w ith hypothyroidism , an d in th is settin g, radioact ive iodin e ablation h as been associated w ith a 40 to 60% reduct ion in volum e w ith in 2 years of th erapy.97,98 Recom bin an t h um an TSH h as also been sh ow n to en h an ce radioact ive iodin e uptake in euthyroid goiters.99,100,101 It h as also been sh ow n to reduce th e dose of radioactive iodin e n eeded for e ect ive ablation an d im prove its lon g-term e ectiven ess.99,100,102 Despite th e fact th at radioactive iodin e h as been sh ow n to be e ect ive in reducin g th e volum e of goiters,97,98,99,100,101 thyroidectom y is th e preferred defin itive t reatm en t m odalit y for youn g patien ts w ith cervical an d substern al goiters, especially w h en com pressive. Th e decision for thyroidectom y is n ot as straigh tforw ard in th e elderly w ith such goiters because of associated com orbidities. Rapid en largem en t of a goiter in an elderly patien t is w orrisom e for a thyroid m align an cy an d th erefore requires at least FNA, if n ot thyroidectom y. Observation is a reason able approach for th e asym ptom atic elderly patien t w ith a cer vical or substern al com pressive goiter th at is kn ow n to h ave been presen t for years w ith very little ch ange in size an d degree of com pression . Com pressive goiters th at are in ciden tally discovered on im aging studies perform ed for som e oth er reason , h ow ever, pose a m anagem en t dilem m a in elderly patien ts. In th is situation , if th e pat ien t is asym ptom at ic an d radiograph s dem on strate on ly m ild to m oderate trach eal deviation or n arrow in g ( Fig. 7.1), observation w ith FNA of th e dom in an t n odule(s) is a reason able approach . If th e patien t is experien cin g dysph agia or sh ort n ess of breath , it is im portan t to di eren tiate if th eir sym ptom s are act ually due to com pression by th e goiter or due to som e oth er con dition s th at frequen tly coexist in th is age group, such as congestive h eart failure, cricoph ar yn geal spasm , or esoph ageal dysm otilit y. Pulm on ary fun ct ion s tests w ith flow loops m ay occasion ally be h elpful if extrath oracic obst ruction is seen , but a n orm al flow loop does n ot n ecessarily exclude sym ptom at ic t rach eal com pression . An esoph agram , if it dem on strates extrin sic com pression , m ay also provide suppor tive eviden ce th at th e goiter is causin g dysph agia. How ever, a n orm al study does not n ecessarily m ean th at th e goiter is n ot th e cause of th e dysph agia. Non con t rast CT of th e n eck an d ch est is h elpful in assessin g th e exten t of substern al exten sion

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Fig. 7.2 Substernal goiter with significant extension below the aortic arch and into the posterior m ediastinum. A, aortic arch; G, substernal goiter.

( Fig. 7.2), th e degree of trach eal com pression , or if th e goiter is actually com pressin g on th e esoph agus to h elp determ in e if th e patien t w ould truly ben efit from thyroidectom y. For routin e im aging of th e thyroid, in traven ous con trast is un n ecessary an d sh ould be avoided because th e glan d is often w ell visualized on CT. Th us, in an elderly patien t w ith a large com pressive goiter (in trath oracic or cer vical) an d sym ptom s of com pression , such as dysph agia, dyspnea, an d facial ven ous congestion , in th e absen ce of oth er con curren t condition s th at can explain th ese com pressive sym ptom s, subtotal or n ear-total thyroidectom y sh ould be recom m en ded, provided th e pat ien t’s an esth etic risks are low. Oth erw ise, radioact ive iodin e can be used, w h ich h as been sh ow n to decrease up to 50% of th e goiter size.97,98,99

7.4 Inflam m at ory Thyroid Condit ions Thyroiditis can be classified as (1) ch ron ic, w h ich en com passes Hash im oto’s thyroiditis (HT) an d Riedel’s strum a; (2) subacute, w h ich in cludes gran ulom atous an d lym ph ocyt ic pain less thyroidit is; an d (3) acute suppurative, w h ich is exceedin gly rare.

7.4.1 Hashim ot o’s Thyroidit is By far, th e m ost com m on of all in flam m ator y thyroid disorders, HT a ect s approxim ately 2% of th e gen eral population . It is ch aracterized by lym ph ocyt ic in filtration of th e thyroid glan d, follow ed by a gradual dest ruction an d fibrous replacem en t of th e thyroid paren chym a. Patien ts m ay or m ay n ot develop a goiter. Th e prin cipal bioch em ical ch aracteristic of th e disease is th e presen ce of thyroid autoant ibodies in th e patien ts’ sera again st t w o m ajor thyroid an tigen s, thyroid peroxidase (TPO) an d thyroglobulin (Tg). TPO an tibodies are presen t in m ore th an 90% of pat ien ts w ith HT, w h ereas approxim ately 80% w ill h ave positive Tg an tibodies.103 Alth ough both an tibodies are m arkers for th is disease, th ey are likely n ot th e prim ar y path ogen esis. It is likely th at T-cell-m ediated cytotoxicit y an d act ivation of apoptotic path w ays in fluen ce th e disease. Un like Tg an tibodies, TPO an tibodies can act ivate com plem en t an d are able to cause dam age to thyroid cells due to an tibody-depen den t cell

Benign Disease of the Thyroid Gland cytotoxicit y.104 A com plex in teraction betw een gen etic an d n on gen etic factors presum ably results in en h an ced thyroid an tigen presen tation an d reduced im m un e toleran ce leadin g to thyroid dest ruction an d clin ical disease. Multiple susceptibilit y gen es m ay be involved in th e disease developm en t, som e of w h ich are also com m on for oth er autoim m un e diseases, w h ereas oth ers are specific for thyroid autoim m un it y. Th e gen e for Tg, located on chrom osom e 8q24, as w ell as various im m un eregulator y gen es, such as HLA, CTLA-4, an d PTPN22, h ave all been sh ow n to be associated w ith developm en t of HT, alon g w ith Graves’ disease an d oth er autoim m un e diseases. Th e VDR gen e, also associated w ith various autoim m un e diseases, such as t ype 1 diabetes or Addison’s disease, is also an oth er HT predisposing gen e. Cytokin e gen es, such as IFN-γ, IL-4, or TGF-β, in dicate th e association w ith th e developm en t an d severit y of HT.105 Histologically, th e glan d is in filtrated w ith a polym orph ous population of lym ph ocytes, an d destruct ion of thyroid follicles and form ation of lym ph oid follicles is seen . Un like pain less lym ph ocyt ic thyroiditis (see Subacute Pain less Lym ph ocyt ic Thyroiditis), oxyph ilic (Hü rth le cell) ch anges an d areas of glan dular fibrosis are also seen . Th e clin ical presen tation varies, depen din g on th e stage at th e tim e of presen tation . Th e patien t m ay be com pletely asym ptom atic or presen t w ith sym ptom s of hypothyroidism . Th e glan d is gen erally en larged, sym m etric, an d finely n odular w ith out any discrete palpable n odules. Rarely, th e patien t m ay present w ith pain , an d th e glan d m ay be ten der to palpation , m im ickin g th e clin ical features of subacute thyroiditis.106,107 Thyroid h orm on e levels w ill also var y at th e tim e of presen tation . Th ey m ay be n orm al w ith a n orm al TSH (euthyroid), low w ith an elevated TSH (hypothyroid), or n orm al w ith an elevated TSH (subclin ically hypothyroid). Th e clin ical course of HT is variable. Up to 50% of th e patien ts can becom e subclin ically hypothyroid an d 5 to 40% can becom e clin ically hypothyroid, em phasizing th e im portan ce of follow in g thyroid fun ction tests in th ese patien ts.108,109,110 Treatm en t for ch ron ic autoim m un e thyroiditis depen ds on th e results of th e thyroid fun ction tests. Pat ien ts w ith overt hypothyroidism are t reated w ith levothyroxin e. Th e dose is age depen den t . TSH levels sh ould be m on itored, an d th e dose sh ould be adjusted to m ain tain levels w ith in th e referen ce ran ge. Patien ts w ith HT h ave a h igh er frequen cy of oth er autoim m un e disorders, such as adren al in su cien cy, diabetes m ellitus, Sjögren’s syn drom e, celiac disease, rh eum atoid arth ritis, an d lupus er yth em atosus. Th ey also h ave an in creased risk of developin g B-cell lym ph om a of th e thyroid.111,112,113 Rapid grow th in th e settin g of HT sh ould alert th e clin ician to th e possibility of thyroid lym ph om a.

7.4.2 Subacut e Painless Lym phocyt ic Thyroidit is Th ere are t w o form s of pain less thyroiditis, sporadic an d postpartu m , both sh arin g ver y sim ilar features. It is ch aracterized by destruct ion of th e thyroid glan d by lym ph ocytes, absen ce of pain , an d tem porar y thyroid dysfun ct ion . It is m uch m ore com m on in w om en . Th e etiology is un cert ain , but it is clear th at th e im m un e system is involved because it h as been foun d in patien ts w ith a w ide variety of autoim m un e diseases. HLA-DR3 is presen t in in creased frequen cy in both sporadic an d postpartum form s.114 In addition to HLA-DR3, HLA-DR5 is also

in creased in frequen cy in postpartum thyroiditis.114 Histologically, th e glan d is prom in en tly in filtrated w ith lym ph ocytes, an d areas of follicle destruction are prom in en t.115 Clin ically, th e patien t t ypically passes th rough four ph ases: thyrotoxic, euthyroid, hypothyroid, an d euthyroid. Th e in itial thyrotoxicosis is caused by a release of preform ed h orm on e an d n ot because of sustain ed overproduct ion of th e h orm on e, an d th erefore is n ot true hyperthyroidism . It t ypically lasts 3 to 6 m onth s but m ay persist for 1 year.109 Sym ptom s are gen erally m ild, alth ough in som e cases th ey m ay be severe en ough to require h ospitalization . Th e in itial thyrotoxic ph ase of post partum thyroidit is is usually m ilder th an sporadic thyroiditis. Th e glan d is usually sym m etrical an d m ay be sligh tly to m oderately en larged. It is com pletely pain less to palpation . Thyroid fun ct ion tests w ill reflect th e degree of hypo- or hyperthyroidism at th e t im e of testin g. Th e thyroglobulin levels are elevated, as are an tim icrosom al an tibodies. Unlike subacute gran ulom atous thyroiditis, th e er yth rocyte sedim en tation rate is gen erally n orm al. Iodin e131 uptake is low, usually below 5%. Because th e hyperthyroid ph ase of th e disease is usually tran sien t an d m ild in n ature, m ost patien ts do n ot require treatm en t . If th e cardiac sym p tom s are prom in en t, th ey can be con trolled w ith beta-blockers.

7.4.3 Subacut e Granulom at ous Thyroidit is Also kn ow n as pain ful thyroiditis an d gran ulom atous thyroiditis, th is disorder is ch aracterized by sudden on set of an terior n eck pain , localized over th e thyroid glan d, w h ich m ay radiate to on e or both ears or jaw s. It m ay be associated w ith an teceden t viral illn ess. Th ere is a fem ale prepon deran ce. Th e patien ts frequen tly report m alaise, w eakn ess, an d fatigue as w ell as sym ptom s of thyrotoxicosis, such as palpitation s, n er vousn ess, trem or, h eat in toleran ce, an d w eigh t loss. Th e m ost prom in en t physical fin din g is an en larged thyroid glan d th at is exquisitely ten der to palpation . Frequen tly, patien ts presen t w ith tachycardia an d hyperpyrexia, w ith th e tem perature elevated up to 102° F. Th e er yth rocyte sedim en tation rate is con sisten tly h igh , an d th e w h ite blood cell coun t m ay be elevated. Thyroid fun ct ion tests m ay be n orm al, elevated, or low, depen din g on th e stage of th e disease at th e t im e of presen tation . Sim ilar to pain less thyroidit is, pat ien ts w ill go th rough th e in itial ph ases of thyrotoxicosis for 1 to 3 m on th s, w h ich is a result of release of stored thyroid h orm on es from acute dest ruction of th e thyroid paren chym a. Subsequen t to th at th ey becom e euthyroid. In severe cases, after return in g to a euthyroid state th e patien t can th en develop hypothyroidism , w h ich usually lasts 2 to 6 m on th s. Th is ph ase is usually tran sien t , w ith approxim ately 90% of th e patien ts recoverin g an d return in g to a euthyroid state. Path ologically, th e thyroid is in filtrated w ith n eutroph ils, lym ph ocytes, an d large m on ocytes. Multin uclear gian t cells w ith gran ulom a form ation are also seen . Thyroid follicles becom e hyperplast ic, an d areas of follicular disruption are seen . In th e late stage of th e disease, follicular regen eration is eviden t w ith on ly m in im al fibrosis.

7.4.4 Acut e Suppurat ive Thyroidit is Th is rare en tit y usually occurs from a bacterial in fect ion , an d rarely from a n on bacterial in fect ion , of th e thyroid. It ten ds to

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Thyroid Diseases a ect a youn ger age group in th e 30 to 40 ran ge, an d n ot in frequen tly a ects ch ild ren . Th e in fection m ay reach th e glan d via blood, lym ph atics, or direct ly th rough a persisten t thyroglossal d uct or a n earby in tern al fistu la, su ch as a pyriform sin u s fistula. History of an an teceden t in fect ion , su ch as ph ar yn gitis, can frequen tly be elicited. Patien ts t ypically p resen t w ith sym ptom s ver y sim ilar to subacute thyroiditis, in th at th ere is usually an terior n eck p ain an d fever. Th e patien t m ay experien ce dysph agia, an d left un treated m ay progress to dyspn ea. Physical fin din gs in clude tendern ess over th e thyroid w ith localized er yth em a an d w arm th . Pyriform sin us fist ula sh ould be in cluded in th e di eren t ial d iagn osis in ch ildren .116 Th e w h ite blood cell coun t is usu ally elevated. Th e bacterial path ogen s in clu de Sta phylococcus, Streptococcus, an d a variet y of gram -n egative organ ism s, particu larly oral p ath ogen s.117,118,119 Non bacterial in fection of th e thyroid glan d is ver y rare but can result from Aspergillus, Coccidioides, an d Ca ndida .117 Treatm en t consists of app rop riate an tim icrobial th erapy an d an algesics.

7.4.5 Riedel’s St rum a Also kn ow n as invasive fibrous thyroiditis or Riedel’s thyroiditis, th is exceedin gly rare disorder is ch aracterized by in ten se in filtration of th e thyroid paren chym a by in flam m ator y cells an d subsequen t replacem en t by den se fibrosis an d collagen .120 It is n ot a prim ar y disorder of th e thyroid but involves th e thyroid an d represen ts part of a system ic disease. It m ay a ect on ly th e thyroid glan d or m ay also involve oth er sites, such as th e m ediastin um , retroperiton eum , orbit, an d biliary t ract. It gen erally a ect s w om en in th e fourth to fifth decade of life. Patien ts t ypically present w ith a pain less thyroid m ass th at feels h ard an d fixed . W it h tim e t h e fibrosis w ill exten d beyon d t h e thyroid cap su le an d in filt rate in to th e su r rou n d in g st ru ctu res, in clu d ing t h e st rap m u scles. Vascu lit is an d p h lebitis m ay also be seen . Thyroid fu n ct ion t est s w ill reflect eu t hyroid ism in ap p roxim at ely t w o-t h ird s of p at ien t s; h ow ever, t h ey m ay also reveal hyp othyroid ism w h en th e glan d is su cien tly rep laced by th e fibroid t issu e. Th e clin ical p resen t at ion m ay be con fu sed w ith an aggressive thyroid m align an cy, su ch as an ap lastic carcin om a. Im aging st u d ies an d FNA can h elp d i eren tiate th e t w o. Un like th e CT fin d in gs of m ost thyroid m align an cies, t h e t hyroid glan d w ith Ried el’s ap p ears as an in filt rat ive m ass t h at is isod en se w it h t h e n eck m u scles, hyp od en se w ith th e n orm al thyroid tissu e, an d n on en h an cin g w it h con t rast .121 Recen tly im m u n oglobu lin G4 (IgG4) is t h ough t t o p lay a role in d evelop m en t of Ried el’s t hyroid it is based on fin d in gs of in filt rat ion by IgG4 con t ain in g lym p h op lasm acytic cells, lead in g to fibrosis.122 Th is con d it ion is ben ign an d u su ally self-lim it ing. How ever, as it p rogresses an d en cases t h e t rach ea, t h e p at ien t m ay d evelop d ysp n ea. If sym ptom at ic, a w edge resection of t h e isth m u s an d in ser t ion of t rach eotom y can be p erform ed . High -d ose glu cocor t icoid an d levot hyroxin e treat m en t h as been rep or ted t o be e ect ive for red u cin g t h e sym pt om s from Ried el’s.123 Tam oxifen , m ycop h en olate m ofetil, an d rit u xim ab h ave also been sh ow n t o be e ect ive in red u cin g t h e m ass e ect on t h e air w ay.123,124,125

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Thyroid Diseases [77] Ch in SC, Rice H, Som PM. Spread of goiters outside th e thyroid bed: a review of 190 cases an d an an alysis of th e in ciden ce of th e various exten sion s. Arch Otolaryn gol Head Neck Surg 2003; 129(11); 1198–1202 [78] Bon n em a SJ, Ben n edbaek FN, Laden son PW, Hegedü s L. Man agem en t of th e n on toxic m ultin odular goiter: a North Am erican sur vey. J Clin En docrin ol Metab 2002; 87(1); 112–117 [79] Guglielm i R, Pacella CM, Bian ch in i A, et al. Percutan eous eth anol inject ion treatm en t in ben ign thyroid lesion s: role an d e cacy. Thyroid 2004; 14(2); 125–131 [80] Kim DW, Rh o MH, Kim HJ, Kw on JS, Sun g YS, Lee SW . Percutan eous eth anol inject ion for ben ign cystic thyroid n odules: is aspiration of eth anol-m ixed fluid advan tageous? AJNR Am J Neuroradiol 2005; 26(8); 2122–2127 [81] Del Prete S, Caraglia M, Russo D, et al. Percutan eous eth an ol inject ion e cacy in th e treatm en t of large sym ptom atic thyroid cystic n odules: ten -year follow -up of a large series. Th yroid 2002; 12(9); 815–821 [82] Lee SJ, Ah n IM. E ect iven ess of percutaneous eth an ol inject ion th erapy in ben ign n odular an d cystic thyroid diseases: lon g-term follow -up experien ce. En docr J 2005; 52(4); 455–462 [83] Valcavi R, Frasoldati A. Ultrasoun d-guided percutaneous eth an ol inject ion th erapy in thyroid cystic n odules. En docr Pract 2004; 10(3); 269–275 [84] Zieleźn ik W, Kawczyk-Krupka A, Barlik MP, Cebula W, Sieroń A. Modified percutan eous eth an ol inject ion in th e treatm en t of viscous cystic thyroid n odules. Thyroid 2005; 15(7); 683–686 [85] Freitas JE. Th erapeutic option s in th e m an agem en t of toxic an d n on toxic n odular goiter. Sem in Nucl Med 2000; 30(2); 88–97 [86] Kun ori T, Sh inya H, Satom i T, et al. Man agem en t of n odular goiters an d th eir operative in dication s. Surg Today 2000; 30(8); 722–726 [87] Lah ey FH, Sw in ton MW . In trath oracic goiter. Surg Gyn ecol Obstet 1934; 59; 627–637 [88] Reeves TS, Rundle FF, Hale JB, et al. Th e investigation an d arran gem en t of in trath oracic goiter. Surg Gyn ecol Obstet 1962; 115; 222–229 [89] Reeve TS, Rubinstein C, Rundle FF. In trath oracic goitre: its prevalen ce in Sydn ey m etropolitan m ass radiography sur veys. Med J Aust 1957; 44(5); 149– 156 [90] Higgin s CC. In trath oracic goiter. Arch Surg 1927; 15; 895–912 [91] Coh en JP, Ch o HT. Surgery for substern al goiter. In : Freidm an M, ed. Operative Tech niques in Otolaryn gology an d Head an d Neck Surgery. Ph iladelph ia: W B Saun ders; 1994; 118–25 [92] New m an E, Sh ah a AR, Sm ith JC, Sm ith MM, Day TA, Burkey BB. Substern al goiter. J Surg On col 1995; 60(3); 207–212 [93] Pulli RS, Con iglio JU. Surgical m an agem en t of th e substern al thyroid glan d. Lar yn goscope 1998; 108(3); 358–361 [94] Torre G, Borgon ovo G, Am ato A, et al. Surgical m an agem en t of substern al goiter: an alysis of 237 patien ts. Am Surg 1995; 61(9); 826–831 [95] San ders LE, Rossi RL, Sh ah ian DM, W illiam son W A. Mediastin al goiters. Th e n eed for an aggressive approach . Arch Surg 1992; 127(5); 609–613 [96] Sin gh B, Lucen te FE, Sh ah a AR. Substern al goiter: a clin ical review. Am J Otolar yn gol 1994; 15(6); 409–416 [97] Wesche MFT, Tiel-V Buul MM, Lips P, Sm its NJ, Wiersin ga W M. A ran dom ized trial com parin g levothyroxin e w ith radioactive iodin e in th e treatm en t of sporadic n on toxic goiter. J Clin En docrin ol Metab 2001; 86(3); 998–1005 [98] Bon n em a SJ, Hegedü s L. Radioiodin e th erapy in ben ign thyroid diseases: e ects, side e ects, an d factors a ectin g th erapeutic outcom e. En docr Rev 2012; 33(6); 920–980 [99] Fast S, Nielsen VE, Grupe P, et al. Prestim ulation w ith recom binan t h um an thyrotropin (rh TSH) im proves th e lon g-term outcom e of radioiodin e th erapy for m ultin odular n on toxic goiter. J Clin En docrin ol Metab 2012; 97(8); 2653– 2660 [100] Nieuw laat W A, Huysm an s DA, van den Bosch HC, et al. Pretreatm en t w ith a sin gle, low dose of recom binan t h um an thyrotropin allow s dose reduct ion of radioiodin e th erapy in patien ts w ith n odular goiter. J Clin En docrin ol Metab 2003; 88(7); 3121–3129 [101] Huysm ans DA, Nieuw laat WA, Erdtsieck RJ, et al. Adm inistration of a sin gle low dose of recom binan t h um an thyrotropin sign ifican tly en h an ces thyroid radioiodide uptake in n on toxic n odular goiter. J Clin En docrin ol Metab 2000; 85(10); 3592–3596

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[102] Fast S, Hegedü s L, Grupe P, et al. Recom bin an t h um an thyrotropin -stim ulated radioiodin e th erapy of n odular goiter allow s m ajor reduction of th e radiation burden w ith retained e cacy. J Clin En docrin ol Metab 2010; 95(8); 3719– 3725 [103] Ch en AY, Bern et VJ, Carty SE, et al. Surgical A airs Com m ittee of th e Am erican Th yroid Association . Am erican Thyroid Association statem en t on optim al surgical m an agem en t of goiter. Th yroid 2014; 24(2); 181–189 [104] McLach lan SM, Rapoport B. W h y m easure thyroglobulin autoan tibodies rath er th an thyroid peroxidase autoan tibodies? Thyroid 2004; 14(7); 510– 520 [105] Zaletel K, Gaberšček S. Hash im oto’s Thyroiditis: From Gen es to th e Disease. Curr Gen om ics 2011; 12(8); 576–588 [106] Sh igem asa C, Ueta Y, Mitan i Y, et al. Ch ron ic thyroiditis w ith pain ful ten der thyroid en largem ent an d tran sien t thyrotoxicosis. J Clin En docrin ol Metab 1990; 70(2); 385–390 [107] Ish ih ara T, Mori T, Waseda N, Ikekubo K, Akam izu T, Im ura H. Histological, clin ical an d laborator y fin din gs of acute exacerbation of Hash im oto’s thyroiditis—com parison w ith th ose of subacute gran ulom atous thyroiditis. En docrin ol Jpn 1987; 34(6); 831–841 [108] Hayash i Y, Tam ai H, Fukata S, et al. A lon g term clin ical, im m un ological, an d h istological follow -up study of patien ts w ith goitrous ch ron ic lym ph ocytic thyroiditis. J Clin En docrin ol Metab 1985; 61(6); 1172–1178 [109] Woolf PD. Thyroiditis. In : Thyroid Disease, Falk SA, ed., Lippin cott-Raven Publish er, Philadelph ia, PA, 1997, Ch apter 21, 393–410 [110] Mäen pää J, Raatikka M, Räsän en J, Taskin en E, Wager O. Natural course of juven ile autoim m une thyroiditis. J Pediatr 1985; 107(6); 898–904 [111] Holm LE, Blom gren H, Löw h agen T. Can cer risks in patien ts w ith ch ron ic lym ph ocytic thyroiditis. N En gl J Med 1985; 312(10); 601–604 [112] Kato I, Tajim a K, Suchi T, et al. Ch ron ic thyroiditis as a risk factor of B-cell lym ph om a in th e thyroid glan d. Jpn J Can cer Res 1985; 76(11); 1085–1090 [113] Rizvi AA. Prim ar y Th yroid Lym ph om a: Review of Clin ical Features an d Diagn ostic Evaluation . En docrin ologist 2004; 14(3); 144–147 [114] Farid NR, Haw e BS, Walfish PG. In creased frequen cy of HLA-DR3 an d 5 in th e syn drom es of pain less thyroiditis w ith tran sien t thyrotoxicosis: eviden ce for an autoim m un e aetiology. Clin En docrin ol (Oxf) 1983; 19(6); 699–704 [115] Mizukam i Y, Mich igish i T, Non om ura A, et al. Postpartum thyroiditis. A clin ical, h istologic, an d im m un opath ologic study of 15 cases. Am J Clin Path ol 1993; 100(3); 200–205 [116] Miyauchi A, Matsuzuka F, Kum a K, Takai S. Piriform sin us fistula: an un derlyin g abn orm alit y com m on in patien ts w ith acute suppurative thyroiditis. World J Surg 1990; 14(3); 400–405 [117] Berger SA, Zon szein J, Villam en a P, Mitt m an N. In fectious diseases of th e thyroid glan d. Rev In fect Dis 1983; 5(1); 108–122 [118] Jen g LB, Lin JD, Ch en MF. Acute suppurative thyroiditis: a ten -year review in a Taiw an ese h ospital. Scan d J In fect Dis 1994; 26(3); 297–300 [119] Mush arrafieh UM, Nassar NT, Azar ST. Acute Suppurative Thyroiditis: A Forgotten En tit y: Case Report an d Literature Review . En docrin ologist 2002; 12 (3); 173–177 [120] Sch w aegerle SM, Bauer TW , Esselstyn CB, Jr. Riedel’s thyroiditis. Am J Clin Path ol 1988; 90(6); 715–722 [121] Ozgen A, Cila A. Riedel’s thyroiditis in m ultifocal fibrosclerosis: CT an d MR im aging fin din gs. AJNR Am J Neuroradiol 2000; 21(2); 320–321 [122] Pusztaszeri M, Tripon ez F, Pach e JC, Bon giovan n i M. Riedel’s thyroiditis w ith in creased IgG4 plasm a cells: eviden ce for an un derlyin g IgG4-related sclerosin g disease? Thyroid 2012; 22(9); 964–968 [123] Lo JC, Loh KC, Rubin AL, Ch a I, Green span FS. Riedel’s thyroiditis presen ting w ith hypothyroidism an d hypoparathyroidism : dram atic respon se to glucocort icoid an d thyroxin e th erapy. Clin En docrin ol (Oxf) 1998; 48(6); 815–818 [124] Levy JM, Hasn ey CP, Friedlan der PL, Kan dil E, Occh ipin ti EA, Kah n MJ. Com bin ed m ycoph en olate m ofetil an d predn ison e th erapy in tam oxifen - an d predn ison e-resistan t Reidel’s thyroiditis. Th yroid 2010; 20(1); 105–107 [125] Soh SB, Ph am A, O’Heh ir RE, Ch erk M, Topliss DJ. Novel use of rit uxim ab in a case of Riedel’s thyroiditis refractory to glucocort icoids an d tam oxifen . J Clin En docrin ol Metab 2013; 98(9); 3543–3549

Medical Managem ent of Benign Thyroid Disease

8 Medical Managem ent of Benign Thyroid Disease Jacqueline Jonklaas

8.1 Hypot hyroidism Hypothyroidism is a con dition ch aracterized by decreased thyroid h orm on e product ion . Th e particular bioch em ical profile is determ in ed by th e en docrin e glan d in itially respon sible for th e failu re t o m ain t ain ad equ ate t hyroid h orm on e levels, w it h a raised seru m thyroid -stim u latin g h orm on e (TSH) level in d icatin g p rim ar y hyp othyroid ism an d a low or in ap p rop riately n orm al seru m TSH level ch aracterizing secon d ar y hyp ot hyroid ism . Th e clin ical syn d rom e is n otable for w id e-ran gin g sym pt om s associated w it h t hyroid h orm on e d eficien cy at th e level of all t issu es an d organ system s ( Fig. 8.1). Secon d ar y hyp ot hyroid ism is also likely t o be accom p an ied by sign s an d sym pt om s of p itu it ar y d ysfu n ct ion . Myxed em a com a can resu lt from organ system d ecom p en sation , gen erally after lon g-st an d in g h yp othyroid ism .

8.1.1 Prim ary Hypot hyroidism Failure of th e thyroid glan d itself causes prim ar y hypothyroidism . Th e m ost com m on cause in th e Un ited States is lym ph ocyt ic in filtration of th e thyroid glan d associated w ith autoim m un e thyroid disease (Hash im oto’s thyroiditis), w h ich h ad a prevalen ce of 5.13% in on e population -based study.1 Oth er causes of prim ar y hypothyroidism are destruct ion of thyroid tissue by surgery, radioiodin e th erapy, extern al beam radiation , or in filtrative diseases. Subclin ical hypothyroidism , in w h ich thyroid h orm on e levels are still m ain tain ed in th e n orm al ran ge, is th e m ore com m on abn orm alit y (4–8% of th e U.S. pop ulation ), com pared w ith overt hypothyroidism , w h ich occurs in 0.3 to 0.4% of th e population .2,3 Iodin e deficien cy, w h ile com m on as a cause of hypothyroidism in in lan d region s of Africa (e.g., Eth iopia, Algeria, an d Sudan ), an d m oun tain ous areas (e.g., th e An des an d th e

Fig. 8.1 Organ system s affected by thyroid horm one dysfunction.

Him alayas), is an un com m on cause of hypothyroidism in th e Un ited States. Oth er un com m on causes of prim ar y hypothyroidism in clude goitrogen s, en zym e deficien cies, an d thyroid agen esis.

Diagnosis An elevated serum TSH indicates reduced thyroid horm one feedback on the pituitary thyrotropes, w hich secrete TSH, and is the cardinal feature of prim ar y hypothyroidism . Many patients w ill have a free thyroxine (T4) level w ithin the norm al range and few sym ptom s of hypothyroidism . With progression of hypothyroidism , the free T4 concentration w ill drop below the norm al level. Thyroidal horm one production w ill shift tow ard greater am ounts of tri-iodothyronine (T3); thus T3 concentrations w ill often be m aintained in the norm al range in spite of a low T4.4 If the disease is not recognized, serum T3 levels w ill also progressively fall below the norm al range. Sym ptom s of hypothyroidism include fatigue, w eight gain, depression, exercise intolerance, cold intolerance, dry skin, coarse hair, constipation, and im paired m entation. Clinical features of m yxedem a com a include hypotherm ia, bradycardia, and altered sensoriu m ranging from dim inished consciousness to com a.

Treat m ent Th e goal of th erapy for hypothyroidism is to reverse th e m yriad sym ptom s of thyroid h orm on e deficien cy an d th e accom panyin g bioch em ical abn orm alities. Levothyroxin e (LT4) is th e m ain stay of th erapy an d is easily adm in istered, e cacious, an d in expen sive, an d it am eliorates th e sym ptom s of hypothyroidism in th e vast m ajorit y of cases.5 Approxim ately 75% of an oral dose of LT4 is absorbed, w ith im paired absorption bein g associated w ith close proxim it y to m eals, m edication s th at adsorb th e LT4, an d m edication s th at decrease gast ric acidit y, to n am e but a few culprits.5 Seru m TSH can be ch ecked approxim ately 6 w eeks after in itiatin g or ch angin g an LT4 dose, w h en a steady state h as been reach ed, an d th e LT4 can be tit rated up or dow n if th e TSH is above or below th e referen ce in terval, respect ively. Alth ough m any practit ion ers w ill attem pt to ach ieve a serum TSH w ith in th e ran ge of 1 to 2 m IU/L in order to replicate th e values seen in a populat ion free of thyroid disease,2 th ere is curren tly little eviden ce to support th at th is approach im proves patien ts’ sym ptom s or w ell-bein g.6,7 How ever, m ost experts agree on ver y specific TSH goals w h en hypothyroidism is bein g treated in th e pregn an t population . TSH referen ce in tervals are 0.1 to 2.5 m IU/L durin g th e first t rim ester, 0.2 to 3 m IU/L durin g th e secon d trim ester, an d 0.3 to 3 m IU/L durin g th e th ird trim ester, an d treatm en t to keep th e seru m TSH w ith in th ese values is gen erally en dorsed.8 Modified, h igh er TSH targets m ay also be appropriate for older age groups. Iatrogen ic thyroid disease sh ould be avoided due to th e atten dan t risks, but several studies suggest th at th is goal m ay n ot be ach ieved in as m any as 40% of patien ts.2,3,9 Th ere h as been a tren d to in itiate hypothyroidism th erapy for m ilder disease in recen t years, th us placin g m ore in dividuals at risk for

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Thyroid Diseases iatrogen ic thyroid disease.10 In addition , th ere is a h igh rate of LT4 in itiat ion in older age groups, poten tially exposing th ese in dividuals w h o m ay h ave addition al m edical problem s to risks of overt reatm en t.11 A subset of th ose treated w ith LT4 th erapy w ill contin ue to h ave residual sym ptom s, such as fatigue, w eigh t gain , an d im paired w ell-bein g, despite full resolution of th eir bioch em ical abn orm alities.5 Th e thyroid glan d usually cont ributes about 20% of circulating serum T3 levels.12 Anim al studies have dem onstrated closer replication of norm al T4 and T3 levels in serum and tissues during intravenous LT4 and liothyronine (LT3) infusion com pared w ith LT4 alone.13,14 Based on these findings, it has been hypothesized that com bination therapy w ith both LT4 and LT3 m ay provide greater patient satisfaction. Obtaining proof of th is con cept, h ow ever, has been an elusive goal. Despite 13 trials w ith various regim en s of com bin ation th erapy, superiorit y of com bin ation th erapy h as n ot been con sisten tly sh ow n .5,15,16,17 Th e preferen ce for T3 th erapy n oted in som e of th ese trials could poten tially in dicate an un recogn ized param eter or en d poin t a ected by th e T3-con tain ing com bin ation . How ever, it sh ould be em ph asized th at m ost trials h ave been of sh ort duration (~ 8–16 w eeks) an d h ave targeted m iddle-aged w om en . Th erefore, lon g-term risk an d ben efits h ave n ot been assessed, especially in older age groups. Oth er sh ortcom in gs of th is body of eviden ce in clude h eterogen eit y of study design an d results an d var yin g an d n onvalidated en d poin ts 5 ( Table 8.1). A sin gle ran dom ized trial of desiccated thyroid extract com pared w ith LT4 sh ow ed an average w eigh t loss of 3 lb w ith th e extract an d preferen ce for th e extract in 49% of studied patien ts.18 A sm all, ran dom ized cross-over trial of th ree tim es daily LT4 com pared w ith LT3 illustrated th e difficulties in adh erin g to a th rice daily regim en , an d dem on strated a m odest w eigh t loss an d im proved LDL ch olesterol w ith th e T3 regim en .19 Myxedem a com a sh ould be treated w ith in traven ous LT4 to ensure adequate absorption in th e sett in g of im paired gast roin testin al fu n ct ion in g.5 A loadin g dose of LT4, adjusted for th e w eigh t of th e patien t, is in dicated to en sure both reoccupation of depleted protein -bin din g sites an d an in crem en tal in crease in serum free T4 levels. Con com itan t use of in traven ous LT3 is recom m en ded by som e expert s.

Table 8.1 Issues a ecting the assessment of combination therapy trials for hypothyroidism treatm ent Heterogeneit y of study design Diverse causes of hypothyroidism Different dosing regim ens used Different outcomes m easures Different duration of treatm ent Other design problem s Non-validated outcom e measures Carryover effects in som e studies Overtreatm ent not explored Men and the elderly not studied Het erogeneit y of study results End of study TSH differences between groups Values the same versus higher versus lower in T3 group T3 and FT3 differences between groups Values the same versus higher in T3 group Health related qualit y of life or m ood Superiority of combination therapy on multiple measures in two trials versus superiority of combination therapy on a minority of measures in two trials versus no superiority of combination therapy in eight trials Neurocognitive functioning Superiority of combination therapy on multiple measures in one trial versus superiority of combination therapy on a minority of measures in one trial versus no superiority of combination therapy in eight trials Treatm ent preference in five blinded, cross-over design trials Combination therapy preferred in four trials (128 patients) versus no treatment preference between groups in one trial (101 patients) Exam ined in t wo blinded, parallel design trials Combination therapy preferred in one trial (130 patients) versus no preference in other trial (573 patients) Abbreviations: TSH, thyroid-stim ulating horm one; T3, tri-iodothyronine; FT3, free T3. Source: Adapted from Jonklaas J, Bianco AC, Bauer AJ, et al. 2014 Guidelines for the Treatm ent of Hypothyroidism: Prepared by the Am erican Association Taskforce on Thyroid Horm one Replacem ent. Thyroid 2014; 24: 1670-1751.

8.1.2 Secondary Hypot hyroidism Adequate TSH stim ulation is required for norm al thyroid function. Thyrotrope insu ciency due to pituitary tum ors, pituitary surgery, pituitary irradiation, or pituitary hem orrhage is associated w ith thyroid atrophy and secondary hypothyroidism . Secondary hypothyroidism is considerably less com m on than prim ary hypothyroidism , w ith a prevalence of 1:80,000 to 1:120,000.20

Diagnosis Hypothyroidism in patien ts w ith pituitar y disease is ch aracterized by low or n orm al serum TSH con cen tration s. A serum TSH con cen t ration in th e n orm al ran ge is clearly in appropriate if th e patien t also h as a low free T4.

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Treat m ent As is th e case w ith prim ar y hypothyroidism , LT4 is th e recom m en ded treatm en t for secon dary hypothyroidism . Because th e seru m TSH concen tration can n ot be used to m ake th erapeut ic adjustm en ts, th e serum free T4, com bin ed w ith n on thyroid an alytes, such as serum lipids an d patien t sym ptom s, m ust suffice.5 Several studies h ave attem pted to determ in e th e optim um seru m free T4 in t reated pat ien ts, an d based on th ese studies it seem s reason able to keep th e free T4 in th e upper h alf of th e referen ce in ter val based on successful reversal of th e sym ptom s of hypothyroidism an d favorable e ects on th e lipid profile an d body com position .21

Medical Managem ent of Benign Thyroid Disease

Thyrotoxicosis results w h en tissues are exposed to excessive levels of thyroid h orm on es, eith er T4, T3, or both . With appropriate n egative feedback on th e pituitar y thyrotropes, thyroid auton om y is accom panied by low erin g of th e serum TSH con cen t ration . In cont radistin ct ion , thyrotrope autonom y is ch aracterized by both elevated serum TSH an d elevated thyroid h orm on e con cen t ration s. As is th e case w ith hypothyroidism , th e sym ptom s are due to th e e ects of thyroid h orm on e on m ultiple organ system s an d tissues ( Fig. 8.1). Thyroid storm occurs w h en th ere is failure to com pen sate for th ese system ic deran gem en ts. Th e prevalen ce of hyperthyroidism in th e U.S. population w as 1.3% in th e th ird Nation al Health an d Nutrition Exam in ation Sur vey (NHANES III), w ith 0.75% bein g subclin ical disease an d 0.55% overt hyperthyroidism .2

Graves’ disease is th e m ost com m on cause of hyperthyroidism in iodin e-su cien t count ries, in w h ich it accoun ts for about 80% of cases. W h en coun tries w ith iodin e su cien cy are com pared to th ose w ith iodin e deficien cy, th e in ciden ce of Graves’ disease is greater in th e form er an d th e in ciden ce of toxic m ultin odular goiter is greater in th e lat ter.24 Graves’ hyperthyroidism results from th e action of TSAbs, w h ich are directed again st th e thyrotropin receptor on th e surface of th e thyroid cell. Havin g boun d to th e receptor, th ey in duce thyrocyte proliferation an d hyperfun ct ion by activatin g th e adenylyl cyclase sign alin g path w ay in th e sam e m an n er as TSH.25 Autoan tibodies th at react w ith orbital m uscle an d fibroblast tissue in th e skin are respon sible for th e extrathyroidal m an ifestat ion s of Graves’ disease.22 In terestin gly, th e extrathyroidal disorders m ay n ot appear at th e sam e t im e as th e hyperthyroidism but m ay precede or follow th e hyperthyroidism .

8.2.1 Di use Goit er

8.3.1 Diagnosis

A di use goiter can be respon sible for excessive production of thyroid h orm on es eith er due to stim ulation of th e glan d by thyroid autoant ibodies, such as thyroid-stim ulatin g an tibodies (TSAbs), as occurs in Graves’ disease, or to stim ulation by TSH, as occurs w ith developm en t of a TSH-secret in g aden om a ( Fig. 8.2).

Laborator y testin g in Graves’ disease is ch aracterized by sup pressed or un detectable TSH due to n egative feedback by elevated levels of thyroid h orm on e actin g on th e pituitary. In m ild Graves’ disease th at h as resulted on ly in subclin ical hyperthyroidism , th e thyroid h orm on e levels w ill rem ain w ith in th e n orm al ran ge. Overt hyperthyroidism w ill be ch aracterized by fran kly elevated thyroid h orm on e con cen t ration s due to an in crease in th e overall h orm on e product ion rate. Sym ptom s in clude tachycardia, hyperdefecation , proxim al m uscle w eakn ess, trem ors, an d h eat in toleran ce. Th ere is often a disproportion ate in crease in serum T3 relative to serum T4 due to th e stim ulation of th e t ype 2 deiodin ase by TSAb.26 Th e disproportion ate product ion of T3 can result in a T3 thyrotoxicosis in w h ich on ly th e serum T3 con cen tration is in creased. If th e patien t is n ot pregn an t or lactatin g, a 24-h our radioact ive iodin e uptake (RAIU) sh ould be obtain ed if th ere is any diagn ostic un cert ain t y. An in creased RAIU docum en ts th at th e thyroid glan d is in appropriately usin g th e iodin e to produce m ore

8.2 Hypert hyroidism

8.3 Graves’ Disease Graves’ disease is an autoim m un e condition th at t ypically in cludes hyperthyroidism an d di use thyroid en largem en t. Th ere is also accom panyin g oph th alm opathy (orbitopathy) in som e patien ts, w ith at least 50% h avin g som e m ild sym ptom s of eye disease an d approxim ately 5% h avin g severe oph th alm op athy.22,23 Less com m on ly th ere m ay also be Graves’ derm opathy (pretibial m yxedem a) an d thyroid acropachy. Graves’ derm op athy is n oted on physical exam in ation in about 13% of th ose w ith severe oph th alm opathy.22

Fig. 8.2 Evaluation algorithm for a diffuse goiter. TSH, thyroid-stim ulating horm one; RAIU, radioactive iodine uptake; US, ultrasound.

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Thyroid Diseases Table 8.2 Com parison of thionamides Characteristic

Methim azole

Propylthiouracila

Serum half-life

4–6 h

75 m in

Dosing

Daily

Two to three tim es a day

Com pliance

Easier

More difficult

Response time (for patient to become euthyroid)

Faster

Slower

Inhibition of T4 to T3 conversion

No

Yes

Side effects

Dose related

Less dose related

Nature of hepatotoxicit y

Cholestatic injury

Hepatocellular injury

Recom m ended use in pregnancy

Second, third trimester

First trim ester

Incidence of teratogenicit y

Probably higher

Probably lower

Spectrum of teratogenic effects

“MMI-em bryopathy” (choanal atresia, om phalocele, esophageal atresia, om phalom esenteric duct anom alies)

Face and neck m alform ations

Effect on subsequent RAI

May reduce efficacy

Reduces efficacy

Abbreviation: MMI, m ethimazole; RAI, radioactive iodine; T3, tri-iodothyronine; T4, thyroxine. a Propylthiouracil is no longer considered a first-line agent.

thyroid h orm on e at a tim e w h en th e patien t is thyrotoxic. In con trast, a low RAIU is suggestive of dam aged thyroid tissue th at is n ot able to tran sport iodin e. A h om ogen eous pattern of uptake is consisten t w ith th e gen eralized glan dular stim ulation ch aracteristic of Graves’ disease. Thyroid storm ensues w hen the patien t is no longer able to com pensate for the e ects of th e persistent in creases in thyroid horm one levels and is characterized by hyperth erm ia an d altered sensoriu m , w ith resultant features such as severe tachycardia, h eart failure, agitation, disorientation , m ania, com a, n ausea, vom iting, volum e depletion, diarrhea, jaundice, an d fever.

8.3.2 Treat m ent To treat Graves’ disease, dual th erapy to reduce th e tissue e ects of th e excessive thyroid h orm on e an d also to low er th e thyroid h orm on e levels is n eeded. Beta-blockers ser ve to reduce th e tachycardia an d trem ulousn ess an d to decrease th e patien t’s sym ptom s. A th ion am ide is concurren tly used to reduce fur th er thyroid h orm on e syn th esis. Th e th ion am ides approved for use in th e Un ited States are m eth im azole (MMI) an d propylth iouracil (PTU) ( Table 8.2). Both of th ese agen ts preven t th e in corporation of iodin e in to t yrosin e residues an d in h ibit th e coupling of iodotyrosin e residues. Th ey are both w ell absorbed from th e gast roin testin al tract an d are actively concen trated w ith in th e thyroid glan d.27 Th is lat ter feature accoun ts for th e fact th at, despite th eir sh ort plasm a h alf-lives, MMI, an d som etim es even PTU, can e ectively be given as a sin gle daily dose. In itial doses for th erapy w ith MMI are 10 to 30 m g/d, som etim es given in tw o divided doses. In it ial doses for th erapy w ith PTU ran ge from 150 to 300 m g/d, often given in th ree divided doses. Patien ts w ith severe hyperthyroidism m ay require larger in itial doses,28 an d m ay also respon d better if th e dose is divided. Th e m axim al blockin g doses of PTU an d MMI are 1,200 m g an d 120 m g daily,

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respect ively. On ce th e in t rathyroidal pool of thyroid h orm on e is reduced an d n ew h orm on e syn th esis is su cien tly blocked, clin ical im provem en t sh ould en sue. MMI m ay be associated w ith a m ore rapid ach ievem en t of euthyroidism th an PTU.29 Usually w ith in 4 to 8 w eeks of in itiat in g th erapy, sym ptom s w ill dim in ish , an d circulatin g thyroid h orm on e levels w ill return tow ard n orm al. At th is tim e a taperin g regim en can be started. Ch an ges in dose for each drug sh ould be m ade on a m on th ly basis, because th e en dogen ously produced T4 w ill reach a n ew steady-state con cen t ration in th is in terval. E ective daily m ain ten an ce doses for PTU an d MMI var y w idely, but t ypical ran ges are 100 to 150 m g an d 5 to 15 m g, respect ively. Side e ects can occur in approxim ately 5 to 25% of th ose treated w ith th ion am ides, depen din g on th e th orough n ess of th e docum en tation an d th e doses used. With MMI, th e side e ects gen erally appear to be dose related, w h ereas th ey ten d to be m ore idiosyn cratic w ith PTU ( Table 8.2). Min or adverse react ion s, w h ich occurred in about 5% of pat ien ts in on e literature review,30 in cluded rash es, arth ralgias, fevers, an d gastroin testin al sym ptom s. Rash es m ay som etim es regress spon tan eously. Leukopen ia m ay also occur. Th e leukopen ia is often tran sien t , m ay be con fused w ith th e m ild leukopen ia seen in Graves’ disease itself,31 an d is n ot usually a predictor of subsequen t agran ulocytosis. Agran ulocytosis is seen m ore frequen tly at h igh er doses of th ion am ides an d m ay be a direct toxic e ect follow in g con cen t ration of th e drug w ith in gran ulocytes or an im m un e-m ediated process, or it m ay h ave a dual path ogen esis. Agran ulocytosis often occurs w ith in th e first 3 m on th s of th erapy, but its on set is sudden an d m ay n ot be detected w ith m on itorin g of com plete blood coun ts.32 Th e developm en t of agran ulocytosis is h eralded by fever, m alaise, oroph ar yn geal in fect ion , an d a gran ulocyte coun t of < 500/ m m 3 ; h en ce th e recom m en dation th at patien ts discon tin ue th erapy an d con tact th eir physician w h en flulike sym ptom s, such as fever, m alaise, or sore th roat, develop. Supportive care

Medical Managem ent of Benign Thyroid Disease w ith an tibiotic th erapy is critical for th e recover y of a ected patien ts. Use of colony-stim ulatin g factors h as n ot been sh ow n to speed recover y or sh orten h ospital stay in a ran dom ized trial.33 Neverth eless, th ese agen ts are gen erally recom m en ded, particularly in pat ien ts w ith poor progn ostic factors.34 Patien ts w h o h ave su ered th is side e ect sh ould n ot be reexposed to eith er th ion am ide because th e agranulocytosis m ay be im m un ologically m ediated an d th us could recur w ith eith er drug. Hyperth yroidism m ay be associated w ith abn orm al liver tests, w ith 14 to 23% of hyperthyroid patien ts h avin g t ran sam in ase elevation s in on e sm all study.35 Use of MMI an d PTU m ay also be associated w ith tran sam in ase elevation s,28,36 as can be seen in 6 to 9% of MMI-treated pat ien ts an d 26% of patien ts treated w ith PTU. A study of PTU th erapy reported in 1993 suggested th at in itial en zym e elevation s even tually n orm alize in m ost patien ts w ith con tin ued th erapy.37 Th e auth ors suggested th at subclin ical liver injur y is com m on an d th at PTU th erapy could be con tin ued w ith caution in th e absen ce of sym ptom s an d hyperbiliru bin em ia.37 How ever, m ore substan tial h epatotoxicit y m ay also occur, an d PTU is n o lon ger considered a firstlin e drug ( Table 8.2). Th e liver injur y seen w ith PTU seem s to be h epatocellular in n ature.30,38,39 A literat ure review perform ed in 1997 docum en ted 49 cases of serious h epatoxicit y: 28 cases associated w ith PTU use an d 21 cases associated w ith MMI use.40 Accom panyin g th e h epatoxicit y w ere seven death s in th e PTU-treated group an d th ree deaths in th e MMI-treated group. Th e dose or durat ion of th ion am ide t reatm en t did n ot appear to predict th e outcom e.40 A m ore recen t an alysis of 20 years of PTU use in th e Un ited States revealed th at 22 adults h ad developed severe h epatoxicit y leadin g to n in e death s an d five liver tran splan ts.41 Th e risk of th is com plication w as greater in ch ildren (1:2,000) th an in adults (1:10,000). Fin ally, an an alysis of data reported to th e Food an d Drug Adm in istration (FDA) from 1982 to 2008 foun d th at toxicit y in ch ildren w as gen erally related to h igh er doses of PTU an d th at toxicit y in both ch ildren an d adults w as associated w ith th erapy lastin g m ore th an 4 m on th s in duration .42 In ligh t of such eviden ce for h epatotoxicit y, PTU carries a black box w arn in g. It h as been recom m en ded th at PTU n ot be con sidered as first-lin e th erapy in eith er adults or ch ildren . On e except ion in cludes th e first t rim ester of pregn an cy, w h en th e risk of MMI-in duced em br yopathy m ay exceed th at of PTU-in duced h epatotoxicit y. Oth er exception s in clude in toleran ce to MMI an d thyroid storm . MMI use can also be associated w ith severe h epatotoxicit y. Based on an im al studies th e toxicit y of MMI to th e liver m ay be due to th e form ation of N-m ethylth iourea.43 From a review of cases of MMI-in duced h epatotoxicit y, it appears th at th e n ature of th e liver injur y w as ch olestatic in m any of th ese cases.44 Older patien t age an d h igh er drug doses appeared to be risk factors for h epatotoxicit y. Th ere are som e special con sideration s regardin g m edical treatm en t of hyperthyroidism durin g pregn an cy ( Table 8.2). Alth ough h istorically both th ion am ides w ere th ough t to be safe durin g pregn an cy, MMI h as n ow been clearly lin ked to em br yopathy, in cluding trach eoesoph ageal fistulas an d ch oan al atresia.45 PTU w as th en con sidered th e preferred an tith yroidal agen t durin g pregn an cy un til th e in ciden ce of its h epatotoxicit y w as fully appreciated. At th is jun ct ure m ost clin ician s recom m en d use of PTU durin g th e first trim ester of pregn an cy w h en organ ogen esis is occurrin g, w ith subsequen t consideration of

tran sit ion to MMI for th e rem ain der of pregn an cy based on th e avoidan ce of th e greater h epatotoxicit y risk of PTU.8 Th is approach m ay m in im ize th e congen ital m alform ation s associated w ith MMI an d th e len gth of exposure to PTU. Support in g th is approach , a recen t Japan ese study 46 reported th at th e in ciden ce of m ajor an om alies associated w ith first t rim ester MMI use w as 4.1%, com pared w ith 1.9% in the PTU-treated group. Th e an om alies associated w ith MMI included aplasia cutis, om ph alocele, om ph alom esen teric duct an om aly, an d esoph ageal atresia. How ever, w orr yin gly, an analysis of data from a Dan ish registr y sh ow ed sim ilar rates of an om alies w h en MMI or carbim azole (9.1%) versus PTU (8%) w ere used durin g early pregn an cy.47 Th e m ain di eren ce betw een th e t w o drug classes w as th e spectrum of an om alies, w h ich consisted of m alform ation s in th e face an d n eck region w ith PTU an d ch oan al atresia, esoph ageal atresia, om ph alocele, om ph alom esen teric duct an om alies, and aplasia cut is w ith MMI. Mild hyperthyroidism is w ell tolerated by both m oth er an d fetus, so th e con cern s about th ion am ide use durin g pregn an cy, an d th e un resolved issues about th eir safety, un derscore th e n eed to use th e low est e ective dose th at w ill m ain tain th e thyroid h orm on e levels in th e upper part of th e n orm al ran ge. As w as discussed previously for serum TSH values, total an d free thyroid h orm on es h ave referen ce in tervals th at are specific for pregn an cy.8 Total thyroid h orm on e values are in creased by approxim ately 50%.48 Free T4 values are usually low er th an n on pregn an t values but di er greatly betw een various im m un oassays 48,49 an d m ass spectrom etr y assays.50 Th ese caveats sh ould be con sidered w h en adjustm en ts are bein g m ade in th ion am ide dose. As is th e case for pregn an cy, th e low est e ective th ion am ide dose sh ould also be used durin g lactation . Both MMI an d PTU are excreted in th e breast m ilk of th ion am idetreated n ursin g m oth ers, an d usin g th e th ion am ide in divided doses adm in istered after each feedin g is recom m en ded.8 Non m edical m an agem en t option s for th e treatm en t of Graves’ hyperthyroidism in clude radioiodin e th erapy an d surgery. If pretreatm en t w ith th ion am ides is used prior to radioactive iodin e th erapy, th ere can be a decrease in th e e cacy of th e radioiodin e th erapy.51 How ever, som e in dividual studies h ave n ot sh ow n th at MMI w as associated w ith treatm en t failures after radioiodin e therapy. Prior sur veys of pract icing physician s in North Am erica h ave sh ow n a preferen ce for usin g radioiodin e th erapy to treat pat ien ts w ith un com plicated Graves’ disease. How ever, a sur vey con ducted in 2011 sh ow ed a tren d for in creasin g use of thion am ide th erapy. In fact, 40.5% of physician s in dicated th eir choice of th ion am ide th erapy for an in dex patien t, com pared w ith 30% in 1990.52 A study of prescription s w rit ten for MMI an d PTU durin g th e period 1991 to 2008 revealed a n in efold in crease in an n ual MMI prescript ion s, com pared w ith a 19% in crease in an n ual PTU prescription s.53 Th e n um ber of MMI prescription s exceeded th e n um ber of PTU prescription s from 1996 onw ard. Study of future tren ds w ill sh ed ligh t on w h eth er th is apparen t tren d to favor ph arm acological th erapy for Graves’ disease w ill be m itigated by con cern for th e adverse e ects of th ese drugs. Th e corn erston e of treatin g thyroid storm is m ultim odalit y th erapy w ith a th ion am ide, beta-blockers, in organ ic iodide, an d glucocorticoids, alon g w ith appropriate supportive care an d treatm en t of precipitatin g condition s in an in ten sive care un it settin g.38

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Thyroid Diseases

8.4 TSH-Secret ing Pit uit ary Adenom a Pituit ar y tum ors th at overproduce fun ct ion al TSH are quite rare, represen tin g 0.5 to 3% of all pituitar y aden om as.54 Th ese tum ors can be diagnosed at any age but are t ypically diagnosed in th e 30- to 60-year age group, an d are sligh tly m ore frequen t in w om en (fem ale to m ale ratio of 1.35:1).55 Hyperth yroidism en sues w h en th ese sporadically occurrin g tum ors produce TSH th at is un respon sive to n orm al feedback con trol. Th us th e obvious presen tat ion is th at of a goiter an d thyrotoxicosis. In addition , th ere m ay be com prom ise of oth er pituitar y fun ction an d visual field defects. Th e clin ical pict ure m ay be furth er com plicated if th ere is cosecret ion of prolactin or grow th h orm on e by th e tu m or.

8.4.1 Diagnosis Criteria for th e diagn osis of TSH-in duced hyperthyroidism in clude (1) eviden ce of periph eral hyperm etabolism , (2) di use thyroid glan d en largem en t, (3) elevated free thyroid h orm on e levels, an d (4) elevated or in appropriately “n orm al” serum TSH con cen t ration s.54,55 Because th e pituitar y glan d is extrem ely sen sitive to even m in im al elevation s of circulatin g thyroid h orm on es, a “n orm al” or elevated TSH level in any thyrotoxic patien t in dicates the in appropriate production of TSH. Th e distin ction betw een Graves’ disease an d a TSH-secret in g pituitar y aden om a is easily m ade, as lon g as th e serum TSH con cen t ration is considered. Failure to n ote th at a h allm ark of Graves’ disease is a low or un detectable TSH can lead to in ap propriate th erapy, in th e form of radioiodin e th erapy or thyroidectom y, bein g em ployed. Because TSH-secretin g aden om as retain a m in or degree of respon siven ess to th e n egative feedback from elevated thyroid h orm on e levels, th is th erapy can result in un in h ibited grow th of th e pituitar y aden om a.55 How ever, th e di eren tial diagn osis for a thyrotoxic patien t w ith a goiter an d a n orm al or m ildly elevated serum TSH con cen tration also in cludes pituitar y resistan ce to thyroid h orm on e

(PRTH). Th is con dition can be dist in guish ed from a TSH-secretin g aden om a based on several features, w h ich n eed to be in terpreted togeth er.54 Lack of TSH respon se to TRH inject ion (n ow n ot usually used due to lack of availabilit y of TRH) favors a TSH-secret in g adenom a. A pituitar y aden om a iden tified on MRI scan favors a TSH-secreting aden om a. An elevated alph a subun it or alph a-subun it:TSH ratio favors a TSH-secretin g tu m or (TSHom a).54

8.4.2 Treat m ent Th e treatm en t of ch oice for a TSH-secreting pituitar y aden om a is tran ssph en oidal (or subfron tal) resection of th e tum or. If a cure is n ot ach ieved by surgery, oth er option s in clude targeted radioth erapy an d m edical m an agem en t w ith som atostatin an alogues an d dopam in e agon ist th erapy.54 Tem porizing t reatm en t w ith beta-blockers an d th ion am ides w ill h elp reduce thyrotoxic sym ptom s an d is th us useful to restore euthyroidism before surgical rem oval of th e aden om a.

8.5 Toxic Nodular Disease Toxic n odular disease in cludes both toxic aden om a an d toxic m ultin odular goiter (MNG) ( Fig. 8.3). Th e path ogen esis of th ese en t ities is th ough t to be sim ilar: di use hyperplasia caused by goitrogen ic stim uli, leadin g to m utation s an d clon al expan sion of ben ign n eoplasm s.56 Th e fun ction al status of th e n odule(s) depen ds on th e n ature of th e un derlying m utation s, w h eth er activatin g (such as TSH receptor m utation s) or in h ibitory. Thyrotoxicosis occurs w h en a su cien t m ass of auton om ous follicles gen erates en ough thyroid h orm on e to exceed th e n eeds of th e patien t.

8.6 Toxic Adenom a An auton om ous thyroid n odule is a discrete thyroid m ass w h ose fun ction is in depen den t of pituitar y an d TSH control. Th e prevalen ce of toxic aden om a ran ges from about 2 to 9% of

Fig. 8.3 Evaluation algorithm for a thyroid nodule or m ultinodular goiter. FNA, fine-needle aspiration; MNG, m ultinodular goiter; RAIU, radioactive iodine uptake; TSH, thyroid-stim ulating hormone; US, ultrasound.

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Medical Managem ent of Benign Thyroid Disease thyrotoxic patients, and depends on iodine availability and geographic location. Toxic adenom as are benign tum ors that produce thyroid horm one. They arise from gain-of-function som atic m utations of the TSH receptor or, less com m only, the Gα protein, such that the cyclic adenosine m onophosphate (cAMP) cascade is act ivated and there is increased grow th and function of the follicular cells.56 More than a dozen TSH receptor m utations have been described.57 This is in contrast to the situation w ith Graves’ disease w here the hyperthyroidism is m ediated by an activating antibody. These nodules are referred to as toxic adenom as, or hot nodules, because of their elevated uptake on a radioiodine thyroid scan, w ith decreased uptake in the surrounding thyroid tissue due to suppression by the autonom ously functioning area. The am ount of thyroid horm one produced by an autonom ous nodule is m ass related. Therefore, hyperthyroidism usually occurs w ith larger nodules (i.e., > 3 cm in diam eter). Patients older than 60 years are up to 60% m ore likely to be thyrotoxic from autonom ous nodules than are younger patients (12%).58

8.6.1 Diagnosis Laborator y data sh ow in g hyperthyroidism com bin ed w ith physical exam in ation fin din gs suggestive of a thyroid n odule support th e diagnosis of a toxic aden om a. A radioiodin e uptake an d scan w ill sh ow th e discrete area of iodin e uptake represen tin g th e auton om ously fu n ct ion in g thyroid tissue. Laboratory fin din gs ran ge from subclin ical hyperthyroidism th rough to overt hyperthyroidism , gen erally proport ion al to th e size of th e toxic aden om a. Th ere are m any reports of isolated elevation of serum T3 in patien ts w ith autonom ously fun ct ion in g n odules. Th erefore, if th e FT4 level is n orm al, a T3 level m ust be m easured to rule out T3 toxicosis. Autonom ous fun ction can even be presen t w h en th e TSH is n orm al due to com pen sator y suppression of th e rem ain der of th e thyroid. If desired, th e diagn osis can be con firm ed by a failure of th e auton om ous n odule to decrease its iodin e uptake durin g exogen ous T3 adm in istration su cien t to suppress TSH.

8.6.2 Treat m ent Surgical resection , radioact ive iodin e ablat ion , th ion am ides, an d percutan eous eth an ol inject ion are treatm en t option s for toxic aden om a,59 but, because th ion am ides do n ot h alt th e proliferative process in th e n odule, defin itive th erapies are recom m en ded.38 It h as been hypoth esized th at subleth al radiation doses received by th e surroun din g n on -n odular thyroid tissue durin g radioact ive iodin e th erapy of toxic n odules m ay lead to in duction of thyroid can cer, but gast ric can cer appears to be th e m align an cy m ost associated w ith radioactive iodin e th erapy of toxic n odular disease.60 An auton om ously fun ct ion in g n odule, if n ot large en ough to cause thyrotoxicosis, can often be observed con servatively w ith out th erapy. Eth an ol ablation m ay be associated w ith pain an d dam age to surroun din g extrathyroidal tissues, lim itin g its acceptan ce in in stit ut ion s w ith out expert ise in its use.

8.7 Toxic Mult inodular Goit er In toxic MNGs, follicles w ith auton om ous fun ction coexist w ith n orm al or even n on fun ction in g follicles. Th e path ogen esis

of MNG is t h ough t t o be sim ilar t o t h at of t oxic ad en om a.56 Thyrotoxicosis in an MNG occu rs w h en a su cien t m ass of au t on om ou s follicles gen erat es en ough t hyroid h orm on e t o exer t n egative feed back on th e p itu it ar y an d low er th e seru m TSH. Th is t yp e of hyp er t hyroid ism d evelop s in sid iou sly over a p eriod of several years an d p red om in an tly a ect s old er in d ivid u als w it h lon g-st an d in g goit ers.58 Th e p at ien t’s com p lain ts of w eigh t loss, d ep ression , an xiet y, an d in som n ia m ay be at t ribu t ed t o old age,61 an d t h eir p resen t at ion in an eld erly p atien t w ith an MNG calls for th e exclu sion of u n recogn ized t hyrotoxicosis.

8.7.1 Diagnosis Physical exam in at ion is usually n otable for an en larged glan d w ith an irregular contour due to th e un derlying n odules. Nodules larger th an 1 to 1.5 cm m ay be palpable depen din g on th e con tours of th e glan d an d th e patien t’s h abit us. Laborator y evaluation of thyroid fun ction sh ow s thyrotoxicosis th at m ay be subclin ical or over t. Th e thyrotoxicosis m ay in corporate a pattern of predom in an t elevation of seru m T3. Thyroid autoan tibodies are gen erally n egative. A thyroid scan an d uptake w ill sh ow discrete areas of auton om ously fun ct ion in g thyroid t issue in term ixed w ith hypofun ct ion ing areas represen tin g th e sup pressed extran odular tissue.62 If discrete cold n odules are docum en ted, th ese sh ould be ch aracterized by ultrason ography an d biopsied based on th eir features an d size (discussed in th e section addressin g euthyroid MNG).

8.7.2 Treat m ent Th e preferred t reatm en t for toxic MNG is radioiodin e th erapy or surgery because th ese select ion s usually provide defin itive th erapy.38 Surger y is usually selected for youn ger pat ien ts an d patien ts in w h om large goiters im pinge on vital struct ures. Th ion am ide th erapy can be used, but , again , th is ch oice does n ot address the un derlyin g proliferative process w ith its n atural h istory of progression over tim e. Altern atively, percutan eous injection of 95% eth an ol h as also been used to destroy sin gle or m ultin odular aden om as, w ith a 5-year success rate approach ing 80%.

8.8 Eut hyroid Goit er Patien ts w h o are euthyroid m ay also h ave di use thyroid en largem en t or sin gle or m ultiple n odules. Man agem en t of diffuse goiter is directed at m on itorin g grow th , trackin g th e proxim it y of thyroid tissue to vital struct ures in th e n eck an d ch est, an d lim itin g any com pressive sym ptom s. Man agem en t of n odules is directed at selectin g n odules th at require biopsy to rule out m align an cy ( Fig. 8.2 an d Fig. 8.3).

8.9 Di use Goit er An en larged thyroid glan d is gen erally th ough t of as on e th at is estim ated to h ave a w eigh t > 20 g, or docum en ted to h ave dim en sion s > 4 to 5 cm in len gth an d 2 to 3 cm in w idth . Wh en such a glan d does n ot, in fact , h arbor any n odules, or on ly subcen tim eter n odules are n oted, a di use goiter is present .

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Thyroid Diseases Physical exam in ation is disappoin tin gly in accurate for th e assessm en t of w h eth er an apparen tly di use thyroid glan d en largem en t is in fact an MNG h arborin g n on palpable n odules. Th e abilit y to palpate n odules depen ds on th eir size, th eir location w ith in th e thyroid glan d, th e an atom y of th e pat ien t’s n eck, an d th e t rain in g of th e exam in er. Ult rason ography is critical in th is regard an d w ill docum en t w h eth er n odules are actually presen t in a glan d th at appears di usely en larged ( Fig. 8.2).

8.9.1 Diagnosis A di use goiter exists w h en th e thyroid is en larged in th e absen ce of discrete n odules. If a serum TSH level in dicates hypothyroidism or hyperthyroidism , evaluation for Hash im oto’s thyroidit is or Graves’ disease, respectively, is in dicated. In a euthyroid patien t, Hash im oto’s thyroiditis m ay n everth eless be presen t an d can be recogn ized by th e altered thyroid glan d ech otext ure seen on ultrason ography an d th e presence of circulatin g thyroid peroxidase an tibodies. Rapid en largem en t of a goiter, particularly in th e settin g of Hash im oto’s thyroiditis, m ay h erald th e developm en t of lym ph om a.

8.9.2 Treat m ent Many di use goiters m ay n eed n o treatm en t at all, on ce hypothyroidism , hyperthyroidism , an d m align an cy h ave been ruled out. Wh en th e pat ien t is euthyroid, th erapy is based on th e n eed to reduce th e goiter size due to m ass-related sym ptom s such as dysphagia. If th ere are com pressive sym ptom s or com prom ise of vital struct ures, surgical in terven tion is in dicated. TSH-suppressive LT4 th erapy can be given to patien ts w ith n odular thyroid disease an d di use goiter. Th e ration ale for suppression th erapy is to reduce TSH secretion because TSH stim ulation prom otes grow th an d fun ct ion of th e abn orm al thyroid tissue. How ever, such m an agem en t, oth er th an for patien ts w ith elevated TSH levels, is quite con troversial. Doses of thyroid h orm on e su cien t to suppress TSH levels m ay slow goiter grow th or cause som e degree of sh rin kage, an d overall di use goiters m ay respon d better to such th erapy th an n odular goiters.63 How ever, in gen eral, suppression th erapy for di use goiter is in adequate to address m ass e ect , does n ot persist beyon d th e period of LT4 t reatm en t, an d exposes th e pat ien t to th e risks of iatrogen ic hyperthyroidism .63,64,65

8.10 Mult inodular Goit er As described for toxic MNGs, th e auton om ous areas w ith in a euthyroid MNG m ay be com pen sated for by suppression of surroun din g tissue, such th at th e pat ien t retain s n orm al overall thyroid fu n ct ion an d h as a n orm al serum TSH. Altern atively n odular areas m ay be hypofun ct ion in g an d, again , th e patien t m ay rem ain euthyroid. Ult rason ography is crit ical w h en n odules are present to docum en t th e n um ber of n odules, th eir size, th eir location , an d th eir ch aracteristics ( Fig. 8.3).

8.10.1 Diagnosis In a euthyroid (or hypothyroid) pat ien t, diagn ostic studies w ould focus on ultrason ograph y to docum en t th e size an d

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ch aracteristics of th e n odules presen t w ith in th e goiter. Fin en eedle aspiration of th e n odules is pursued based on th e size of th e n odule an d th e ultrasoun d ch aracteristics. Ultrasoun d ch aracteristics th at h ave been used, an d th at h ave var yin g degrees of sen sitivit y an d specificit y for predictin g m align an cy, in clude m icrocalcificat ion s, absen ce of h alo, irregular m argin s, hypoech ogen icit y, an d in creased vascularit y.66 Nodules w ith w orrisom e ch aracteristics m erit biopsy at sm aller dim en sion s th an n odules w ith a m ore ben ign appearan ce.67 To illustrate th is concept, th e suggested size criterion for biopsy of n odules w ith m oderately an d h igh ly suspicious features is 1 cm or greater, w h ereas n odules w ith ultrasoun d ch aracteristics th at are of a low degree of suspicion are n ot recom m en ded for biopsy un less th ey are 1.5 cm or larger, an d spon giform nodules do n ot m erit biopsy un less th ey are at least 2 cm .67 Som e studies,68 but n ot all studies,69 suggest th at patien ts w ith MNG h ave th e sam e risk of m align an cy as th ose w ith solitar y thyroid n odules. Th us biopsy of on ly th e “dom in an t” n odule m ay n ot detect an existin g thyroid can cer, an d targetin g th e m ost suspicious n odules is crit ical. Wh en som e n odules w ith in an MNG are autonom ous, a thyroid scan can be correlated w ith th e ultrason ograph ic fin din gs in order to focus biopsy e orts on isofun ct ion in g or hypofun ction in g areas. Man agem en t of thyroid n odules sh ow n to be m align an t is usually surgical. Nodules w ith ben ign cytology can be m on itored, w ith th e follow -up sch edule bein g determ in ed by th e degree of suspicion suggested by th e ultrasoun d features.67 As discussed elsew h ere in th is volum e, n odules w ith Beth esda categories of follicular n eoplasm , atypia of un determ in ed sign ifican ce, an d follicular lesion s of un determ in ed sign ifican ce m ay, after appropriate discussion w ith th e pat ien t, be subject to m olecular testin g in order to facilitate m an agem en t decision s.

8.10.2 Treat m ent Man agem en t of thyroid n odules sh ow n to be m align an t is usually surgical. On ce m align an cy h as been ruled out in a euthyroid patien t w ith an MNG or a sin gle n odule, th e n odules are m on itored. Nodules th at in crease in size by 20% in t w o dim en sion s or by 50% in volum e durin g follow -up w arran t a repeat biopsy. A n odule “calculator” is available on th e Am erican Thyroid Association w ebsite (h tt p://w w w.thyroid.org/thyroid-physician sprofession als/calculators/). Even if th e absen ce of m align an cy h as been convin cin gly dem on strated, surgery m ay be n eeded to reduce th e goiter size due to m ass-related sym ptom s such as dysphagia. Doses of thyroid h orm on e su cien t to suppress TSH levels m ay slow goiter grow th or cause som e degree of sh rin kage, but in gen eral, suppression th erapy for n odular disease is quite con troversial, as it is for di use goiter. Som e clin ician s rarely recom m en d or use such th erapy; oth ers w ill recom m en d a trial of LT4 as suppressive th erapy in selected patien ts. Th e conclusion s of th ree m eta-an alyses w ere th at suppressive th erapy for n odules w as associated w ith a sm all decrease in n odule grow th ,70 a statistically n on sign ifican t reduct ion in n odule grow th ,71 an d a sign ifican t reduct ion in n odule grow th th at w as reduced w ith longer-term treatm en t .72 Radioactive iodin e th erapy, often assisted by recom bin an t h um an TSH, h as been used to reduce th e size of large goiters, in cluding th ose w ith substern al exten sion .73 Th is th erapy h as been favored for patien ts w h o are older or h ave m edical con dition s th at m ake

Medical Managem ent of Benign Thyroid Disease surgery a less attractive option . A 35 to 50% reduct ion in n odule size is gen erally ach ieved over a 1- to 2-year tim e fram e. Tem porar y sw ellin g of th e thyroid t issue an d thyroiditis w ith hyperthyroidism can occur w ith in a few days an d a few w eeks after radioiodin e adm in istration , respect ively, but usually th ese side e ects are n ot of a m agnitude th at precludes use of th is th erapy.

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ran dom ized, double-blin d, crossover study. J Clin En docrin ol Metab 2013; 98 (5); 1982–1990 Celi FS, Zem skova M, Lin derm an JD, et al. Metabolic e ects of liothyron in e th erapy in hypothyroidism : a ran dom ized, double-blin d, crossover trial of liothyron in e versus levothyroxin e. J Clin En docrin ol Metab 2011; 96(11); 3466–3474 Lan ia A, Persan i L, Beck-Peccoz P. Cen tral hypothyroidism . Pituitar y 2008; 11 (2); 181–186 Slaw ik M, Klaw itter B, Meiser E, et al. Th yroid h orm on e replacem ent for central hypothyroidism : a ran dom ized con trolled trial com parin g t w o doses of thyroxin e (T4) w ith a com bin ation of T4 an d triiodothyron in e. J Clin En docrin ol Metab 2007; 92(11); 4115–4122 Bah n RS. Graves’ oph th alm opathy. N En gl J Med 2010; 362(8); 726–738 Seigel SC, Hodak SP. Thyrotoxicosis. Med Clin North Am 2012; 96(2); 175– 201 Laurberg P, Pedersen KM, Vestergaard H, Sigurdsson G. High in ciden ce of m ultin odular toxic goitre in th e elderly population in a low iodin e in take area vs. h igh in ciden ce of Graves’ disease in th e youn g in a h igh iodin e in take area: com parative sur veys of thyrotoxicosis epidem iology in East-Jutlan d Den m ark an d Icelan d. J In tern Med 1991; 229(5); 415–420 Rapoport B, McLach lan SM. Th e thyrotropin receptor in Graves’ disease. Thyroid 2007; 17(10); 911–922 Ito M, Toyoda N, Nom ura E, et al. Type 1 an d type 2 iodothyron in e deiodin ases in th e thyroid glan d of patien ts w ith 3,5,3´-triiodothyron in e-predom in an t Graves’ disease. Eur J En docrin ol 2011; 164(1); 95–100 March an t B, Alexan der W D, Robertson JW , Lazarus JH. Con cen tration of 35Spropylth iouracil by th e thyroid glan d an d its relation sh ip to an ion trappin g m ech anism . Metabolism 1971; 20(11); 989–999 Nakam ura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Ham ada N. Com parison of m eth im azole an d propylth iouracil in patien ts w ith hyperth yroidism caused by Graves’ disease. J Clin En docrin ol Metab 2007; 92(6); 2157–2162 Okam ura K, Iken oue H, Sh iroozu A, Sato K, Yosh in ari M, Fujish im a M. Reevaluation of th e e ects of m ethylm ercaptoim idazole an d propylth iouracil in patien ts w ith Graves’ hyperthyroidism . J Clin En docrin ol Metab 1987; 65(4); 719–723 Cooper DS. Th e side e ects of an tith yroid drugs. En docrin ologist 1999; 9; 457–476 Eakin DL, Peake RL, Weiss GB. E ect of th erapy on th e n eutropen ia of hyperthyroidism . South Med J 1983; 76(3); 335–337, 340 Nakam ura H, Miyauch i A, Miyaw aki N, Im agaw a J. An alysis of 754 cases of an tith yroid drug-in duced agran ulocytosis over 30 years in Japan . J Clin En docrin ol Metab 2013; 98(12); 4776–4783 Fukata S, Kum a K, Sugaw ara M. Gran ulocyte colony-stim ulatin g factor (GCSF) does n ot im prove recover y from an tith yroid drug-in duced agran ulocytosis: a prospect ive study. Thyroid 1999; 9(1); 29–31 An drès E, Maloisel F, Zim m er J. Th e role of h aem atopoietic grow th factors gran ulocyte colony-stim ulatin g factor an d gran ulocyte-m acroph age colonystim ulatin g factor in th e m an agem en t of drug-in duced agran ulocytosis. Br J Haem atol 2010; 150(1); 3–8 Gü rlek A, Coban kara V, Bayraktar M. Liver tests in hyperth yroidism : e ect of an tith yroid th erapy. J Clin Gastroen terol 1997; 24(3); 180–183 Otsuka F, Noh JY, Ch in o T, et al. Hepatotoxicit y an d cutan eous reaction s after an tith yroid drug adm in istration . Clin En docrin ol (Oxf) 2012; 77(2); 310–315 Liaw YF, Huan g MJ, Fan KD, Li KL, Wu SS, Ch en TJ. Hepatic injur y durin g propylth iouracil th erapy in patien ts w ith hyperth yroidism . A coh ort study. An n In tern Med 1993; 118(6); 424–428 Bah n RS, Burch HB, Cooper DS, et al. Am erican Thyroid Association . Am erican Association of Clin ical En docrin ologists. Hyperthyroidism an d other causes of thyrotoxicosis: m an agem en t guidelin es of th e Am erican Thyroid Association an d Am erican Association of Clin ical En docrin ologists. En docr Pract 2011; 17 (3); 456–520 Cooper DS. Hyperthyroidism . Lan cet 2003; 362(9382); 459–468 W illiam s KV, Nayak S, Becker D, Reyes J, Burm eister LA. Fift y years of experien ce w ith propylth iouracil-associated h epatotoxicity: w h at h ave w e learn ed? J Clin En docrin ol Metab 1997; 82(6); 1727–1733 Bah n RS, Burch HS, Cooper DS, et al. Th e Role of Propylth iouracil in th e Man agem en t of Graves’ Disease in Adults: report of a m eetin g join tly spon sored by th e Am erican Th yroid Association an d th e Food an d Drug Adm in istration . Thyroid 2009; 19(7); 673–674 Glin oer D, Cooper DS. Th e propylth iouracil dilem m a. Curr Opin En docrin ol Diabetes Obes 2012; 19(5); 402–407 Heidari R, Babaei H, Egh bal M. Mech an ism s of m ethim azole cytotoxicit y in isolated rat h epatocytes. Drug Ch em Toxicol 2013; 36(4); 403–411

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Thyroid Diseases [44] Woeber KA. Meth im azole-in duced h epatotoxicit y. En docr Pract 2002; 8(3); 222–224 [45] Clem en ti M, Di Gianan ton io E, Pelo E, Mam m i I, Basile RT, Ten con i R. Meth im azole em bryopathy: delin eation of th e ph en otype. Am J Med Gen et 1999; 83(1); 43–46 [46] Yosh ih ara A, Noh J, Yam aguch i T, et al. Treatm en t of graves’ disease w ith an tith yroid drugs in th e first trim ester of pregn an cy an d th e prevalen ce of congen ital m alform ation . J Clin En docrin ol Metab 2012; 97(7); 2396–2403 [47] An dersen SL, Olsen J, Wu CS, Laurberg P. Birth defects after early pregn an cy use of an tith yroid drugs: a Danish n ationw ide study. J Clin En docrin ol Metab 2013; 98(11); 4373–4381 [48] Lee RH, Spen cer CA, Mestm an JH, et al. Free T4 im m un oassays are flaw ed durin g pregn an cy. Am J Obstet Gyn ecol 2009; 200(3); 260.e1–260.e6 [49] Bliddal S, Feldt-Rasm ussen U, Boas M, et al. Gestation al age-specific referen ce ran ges from di eren t laboratories m isclassify pregn an t w om en ’s thyroid status: com parison of tw o lon gitudin al prospective coh ort studies. Eur J En docrin ol 2014; 170(2); 329–339 [50] Kah ric-Jan icic N, Soldin SJ, Soldin OP, West T, Gu J, Jon klaas J. Tan dem m ass spectrom etr y im proves th e accuracy of free thyroxin e m easurem en ts durin g pregn an cy. Th yroid 2007; 17(4); 303–311 [51] Walter MA, Briel M, Ch rist- Crain M, et al. E ects of an tith yroid drugs on radioiodin e treatm en t: system atic review an d m eta-analysis of ran dom ised con trolled trials. BMJ 2007; 334(7592); 514 [52] Burch HB, Burm an KD, Cooper DS. A 2011 sur vey of clin ical practice pattern s in th e m an agem en t of Graves’ disease. J Clin En docrin ol Metab 2012; 97(12); 4549–4558 [53] Em ilian o AB, Govern ale L, Parks M, Cooper DS. Sh ifts in propylth iouracil an d m eth im azole prescribin g practices: an tith yroid drug use in th e United States from 1991 to 2008. J Clin En docrin ol Metab 2010; 95(5); 2227–2233 [54] Beck-Peccoz P, Lan ia A, Beckers A, Ch atterjee K, Wem eau JL. 2013 European thyroid association guidelin es for th e diagn osis an d treatm en t of thyrotropin -secretin g pituitar y tum ors. Eur Thyroid J 2013; 2(2); 76–82 [55] Beck-Peccoz P, Persan i L, Man n avola D, Cam pi I. Pituitar y tum ours: TSHsecretin g aden om as. Best Pract Res Clin En docrin ol Metab 2009; 23(5); 597– 606 [56] Kroh n K, Fü h rer D, Bayer Y, et al. Molecular path ogen esis of euthyroid an d toxic m ultin odular goiter. En docr Rev 2005; 26(4); 504–524 [57] Kroh n K, Pasch ke R. Som atic m utation s in thyroid n odular disease. Mol Gen et Metab 2002; 75(3); 202–208 [58] Ham burger JI. Evolution of toxicit y in solitary n on toxic auton om ously fun ction in g thyroid n odules. J Clin En docrin ol Metab 1980; 50(6); 1089–1093

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[59] Yan o Y, Sugin o K, Akaish i J, et al. Treatm en t of auton om ously fun ct ion in g thyroid n odules at a sin gle in stit ution : radioiodin e th erapy, surgery, an d eth anol inject ion th erapy. An n Nucl Med 2011; 25(10); 749–754 [60] Metso S, Auvin en A, Huh tala H, Salm i J, Oksala H, Jaatin en P. In creased can cer in ciden ce after radioiodin e treatm en t for hyperthyroidism . Can cer 2007; 109 (10); 1972–1979 [61] Cam pbell AJ. Thyroid disorders in th e elderly. Di culties in diagn osis an d treatm en t. Drugs 1986; 31(5); 455–461 [62] In tenzo CM, dePapp AE, Jabbour S, Miller JL, Kim SM, Capuzzi DM. Scin tigraph ic m an ifestation s of thyrotoxicosis. Radiograph ics: a review publication of th e Radiological Society of Nor th Am erica In c 2003; 23; 857–869 [63] Ross DS. Thyroid h orm on e suppressive th erapy of sporadic n on toxic goiter. Thyroid 1992; 2(3); 263–269 [64] Bergh out A, Wiersin ga W M, Drexh age HA, Sm its NJ, Touber JL. Com parison of placebo w ith L-thyroxin e alon e or w ith carbim azole for treatm en t of sporadic n on -toxic goitre. Lan cet 1990; 336(8709); 193–197 [65] Wesche MF, Tiel-V Buul MM, Lips P, Sm its NJ, W iersinga W M. A ran dom ized trial com parin g levothyroxin e w ith radioactive iodin e in th e treatm en t of sporadic n on toxic goiter. J Clin En docrin ol Metab 2001; 86(3); 998–1005 [66] Bah n RS, Castro MR. Approach to th e patien t w ith n on toxic m ultin odular goiter. J Clin En docrin ol Metab 2011; 96(5); 1202–1212 [67] Haugen BR, Alexan der E, Bible KC, et al. Am erican Thyroid Association Man agem en t Guidelin es for Patien ts w ith Thyroid Nodules an d Di eren tiated Thyroid Can cer. Thyroid 2015 [68] Marqusee E, Ben son CB, Frates MC, et al. Usefuln ess of ultrason ography in th e m an agem en t of n odular thyroid disease. An n In tern Med 2000; 133(9); 696– 700 [69] Brito JP, Yarur AJ, Prokop LJ, McIver B, Murad MH, Mon tori VM. Prevalen ce of thyroid can cer in m ultin odular goiter versus sin gle n odule: a system atic review an d m eta-analysis. Thyroid 2013; 23(4); 449–455 [70] Zelm an ovitz F, Gen ro S, Gross JL. Suppressive th erapy w ith levothyroxin e for solitar y thyroid n odules: a double-blin d con trolled clin ical study an d cum ulative m eta-analyses. J Clin En docrin ol Metab 1998; 83(11); 3881–3885 [71] Castro MR, Caraballo PJ, Morris JC. E ectiven ess of thyroid h orm on e suppressive th erapy in ben ign solitar y thyroid n odules: a m eta-analysis. J Clin En docrin ol Metab 2002; 87(9); 4154–4159 [72] Sdan o MT, Falciglia M, Welge JA, Stew ard DL. E cacy of thyroid h orm on e suppression for ben ign thyroid n odules: m eta-an alysis of ran dom ized trials. Otolaryn gol Head Neck Surg 2005; 133(3); 391–396 [73] Bon n em a SJ, Fast S, Hegedü s L. Th e role of radioiodin e th erapy in ben ign n odular goitre. Best Pract Res Clin En docrin ol Metab 2014; 28(4); 619–631

Malignant Disease of the Thyroid Gland

9 Malignant Disease of t he Thyroid Gland Jaime L. Wiebel and Megan R. Haymart

9.1 Int roduct ion Thyroid m align an cies are gen erally classified as di eren tiated thyroid can cer (in cludin g papillar y an d follicular h istology), m edullar y thyroid can cer, or an aplastic thyroid can cer. Each categor y varies drastically in overall progn osis as w ell as in th erapeutic option s. Alth ough localized di eren tiated thyroid can cer h as a 10-year disease-specific sur vival th at exceeds 90%, an aplastic thyroid can cer h as a life expectan cy on th e order of m on th s.1,2 Thyroid can cer is becom ing in creasin gly com m on . Over th e past 3 decades, th e in ciden ce of thyroid can cer in th e Un ited States h as n early tripled.3 Th is ch apter review s th e evaluation of thyroid n odules, clinical ch aracteristics of thyroid m align an cies, th e in itial evaluation of patien ts w ith thyroid can cer, clin ical staging, an d postoperative m an agem ent.

9.2 Thyroid Nodules A thyroid n odule is a dist in ct area on radiological im aging th at is di eren t from th e surroun din g thyroid paren chym a. Most cases of di eren tiated thyroid can cer presen t as a thyroid n odule th at m ay h ave been discovered by th e patien t, durin g a physical exam , or in ciden tally on im agin g. All patien ts w ith thyroid n odules sh ould be assessed for risk factors for thyroid can cer, such as prior radiation exposure or a fam ily h istory of thyroid can cer or thyroid can cer syn drom e in a first-degree relative.4 Th e evaluation of a thyroid n odule begin s w ith m easurem en t of th e thyroid-stim ulatin g h orm on e (TSH). If th e TSH level is n orm al or elevated, addition al evaluation sh ould be un dertaken . A diagn ostic ultrasoun d sh ould be perform ed on all patien ts suspected of h avin g a thyroid n odule. As sh ow n in Table 9.1, sonograph ic ch aracteristics con cern in g for m align an cy in clude in creasin g size of th e n odule, solid n odules, hypoech oic ech ogen icit y, in creased in tern al vascularit y, irregular borders, Table 9.1 Ultrasound characteristics of thyroid nodules Ultrasound characterist ic

Suggests benign

Suggests m alignant

Densit y

Cystic

Solid

Echogenicity

Iso- or hyperechoic

Hypoechoic

Vascularit y

None or peripheral

Central

Calcifications

None or rim

Micro or course

Size

< 1 cm

> 2 cm

Shape

Flat (width > height)

Round (height > width)

Borders

Well circum scribed

Irregular

None or flat with intact fat t y hilum

Round, loss of fat t y hilum , intranodal cystic com ponents, m icrocalcifications

Lym phadenopathy

Sources: Smith-Bindm an et al,5 Papini et al,6 Leboulleux et al.58

presen ce of m icrocalcification s, an d presen ce of abn orm al lym ph n odes.5,6 Path ological evaluation for m align an cy begin s w ith fin e-n eedle aspiration (FNA) of th e n odule. In dication s for FNA are largely based on th e size of th e n odule. In pat ien ts w ith a h igh risk h istory (radiation exposure, previous thyroid can cer, fam ily h istory of thyroid can cer), n odules as sm all as 5 m m can be considered for biopsy. In pat ien ts w ith gen eral risk, n odules ≥ 1 cm should be biopsied if th ere are any con cern in g ultrasoun d features, an d ben ign -appearin g n odules > 1.5 to 2 cm sh ould undergo biopsy.7 Studies h ave foun d low er rates of n on diagn ostic an d false-n egative biopsies w h en FNA is perform ed un der ultrasoun d guidance.8,9 Th e cytopath ology results from th e FNA sh ould be classified un der th e Bethesda system in to on e of th e follow in g path ological categories: ben ign , follicular lesion of un determ in ed sign ificance/at ypia of un determ in ed sign ifican ce (FLUS/AUS), follicular neoplasm , suspicious for m align an cy, or m align an t w ith correspon din g reported risks of m align an cy of < 1%, 5 to 10%, 20 to 30%, 50 to 75%, an d 100%, respect ively.10 In adequate specim en s are categorized as n on diagnost ic; th e rate of m align an cy in th ese n odules is m ore varied, but on e series foun d a 5% m align an cy rate.11 FNA sam ples w ith ben ign cytology do n ot require any fur th er im m ediate action . Follow -up ultrasoun d can be obtain ed 6 to 18 m on th s after th e biopsy to en sure stabilit y of th e n odule.12 FNA sam ples th at are n on diagn ostic sh ould be repeated because up to 76% of solid n odules w ill yield a diagn ostic cytology specim en on ultrasoun d-guided FNA.11 Lesion s w ith cytology suspicious for m align an cy or m align an t sh ould gen erally un dergo surgical excision w ith h em ithyroidectom y or thyroidectom y. Lesion s w ith cytology positive for follicular n eoplasm or Hü rth le cell n eoplasm gen erally un dergo surgical resection .13 Nodules w ith FLUS/AUS present a clin ical ch allenge. Th e reported rate of m align an cy in th is group is low at 5 to 10%, but som e studies h ave suggested th at it varies from center to cen ter, w ith m align an cy rates as h igh as 25% at com preh en sive can cer cen ters.14 Repeat FNA sh ould be con sidered because ben ign or h igh er-acuit y cytology w ill be obtain ed about 50% of th e tim e on second biopsy.15 A large portion of patien ts w ith in determ in ate lesion s (FLUS/AUS an d follicular n eoplasm ) w ill h ave ben ign path ology, so un iversal excision results in a large n um ber of un n ecessary surgeries. Determ in in g w h ich pat ien ts are m ost likely to h ave m align an cy is a grow in g area of research . Th e presen ce of gen etic m utation s com m on ly associated w ith thyroid can cer, such as RET/PTC an d BRAF, is in dicative of m align an cy.16,17,18 Addition ally, a gen e expression classifier w as recen tly in t roduced to iden tify ben ign thyroid n odules, but its use in clin ic pract ice is n ot yet routin e.19

9.3 Di erent iat ed Thyroid Cancer Di eren t iated thyroid can cer (DTC) origin ates from follicular epith elial cells w ith in th e thyroid. It is, by far, th e m ost prevalen t form of thyroid can cer an d carries th e best progn osis.20 Can cers are t ypically classified by th eir h istological appearan ce

77

Thyroid Diseases Table 9.2 Poor prognostic indicators in di erentiated thyroid cancer Increasing patient age Distant m etastasis Extrathyroidal extension (macroscopic > m icroscopic) Cervical lym ph node m etastasis (lateral > central) Capsular invasion Lym phovascular invasion Increasing tumor size Aggressive histologic subt ype (i.e., tall cell, diffuse sclerosing) Sources: Lundgren et al,25 Banerjee et al, 22 Kim et al. 69

in to papillary, follicular, or Hü rth le cell carcin om as. Papillar y thyroid carcin om as (PTCs) accoun t for approxim ately 85% of th is group, follicular can cers m ake up 12%, an d about 3% h ave Hü rth le cell h istology.21 Progn ost ic in dicators in DTC are sum m arized in Table 9.2. Thyroid can cer is un ique in th at patien t age is a h igh ly im portant prognostic indicator for risk of death.22,23 Tum or characteristics w ith poor prognostic features include increasing size of the tum or, capsular invasion, extrathyroidal extension into surrounding tissues, and the presence of lym ph node or distant m etastasis.24,25 PTC has a tendency to spread by lym ph node m etastasis; in fact, m ore than 50% of patients w ith PTC and clinically uninvolved lym ph nodes w ill have m icrom etastases at the tim e of initial surgery.26 In addition, specific histological findings, such as lym phovascular invasion, abundant m itosis, and extensive tum or necrosis have been associated w ith an increased risk of recurrent and m etastatic disease and poor clinical outcom es.27,28 PTC is categorized in to several h istologic subt ypes; som e com m on ly en coun tered subt ypes in clude follicular varian t , tall cell varian t, an d di use sclerosing.29 Th e follicular varian t of PTC carries a sim ilar progn osis to conven t ion al PTC. How ever, it can be di cult to di eren tiate from follicular aden om as an d follicular carcin om as, so it can present a diagn ostic ch allenge.29 Th e tall cell an d di use sclerosing varian ts are associated w ith a w orse progn osis.30 Pat ien ts w ith tall cell varian t h ave been described to experien ce h igh er rates of recurren ce an d m etastatic disease, especially in th ose over th e age of 50 years.31,32 Th e di use sclerosin g varian t of PTC is often en coun tered in pediatric pat ien ts (41.2% of PTC in on e series), an d is associated w ith a low er recurren ce-free sur vival.33 Th e previously discussed h igh -risk h istopath ologic fin din gs are often presen t in th ese aggressive subt ypes. Alth ough it appears patien ts w ith follicular can cer are m ore likely to presen t w ith m etastatic disease, the progn osis for follicular thyroid can cer is sim ilar to th at for PTC w h en con trollin g for stage at diagn osis.23,34 In con trast to PTC, w h ich ten ds to m etastasize to cervical lym ph n odes, follicular can cers are m ore likely to spread h em atogenously.35 Histological specim en s are often classified by th e degree of invasion : m in im ally invasive invades on ly in to th e capsule, an d w idely invasive invades th rough th e capsule. Patien ts w ith m in im ally invasive follicular can cers h ave an excellen t progn osis.36 Som e auth ors h ave suggested addin g a m oderately invasive category th at in cludes

78

tum ors w ith an gioinvasion , because th ese patien ts h ave a sligh tly w orse progn osis com pared to th ose w ith m in im ally invasive disease.37 Outcom es for patien ts w ith follicular carcin om a are depen den t on th e degree of invasion seen on h istology, as w ell as age an d in itial tum or stage. Patien ts w ith h igh ly invasive tum ors ten d to h ave oth er poor progn ostic factors, such as older age, distan t m etastasis, an d in com plete resection , so th e degree of invasiven ess h as n ot been sh ow n to be an in depen den t risk factor.38 Hü rth le cell carcin om a is a rare tum or th at is classified as a varian t of follicular can cer. Classically th ough t to be a m ore aggressive t um or th an PTC an d follicular can cer, m ore recen t data suggest th at th e outcom es for Hü rth le cell carcin om a are sim ilar to th ose for follicular can cers.39,40 Wh en com pared to a population of m ostly PTC, h ow ever, th e overall an d disease-specific sur vival are low er for pat ien ts w ith Hü rth le cell carcin om a.41 Like oth er w ell di eren tiated can cers, outcom es are ver y dependen t on in itial stage an d invasiven ess of th e tum or.39 Addition ally, Hü rth le cell tu m ors are often less iodin e avid com pared to oth er di eren tiated tum ors.42

9.3.1 Genet ics of Di erent iat ed Thyroid Cancer Several gen etic m utation s h ave been associated w ith tum or developm en t in di eren tiated thyroid can cer. Th e m ost exten sively studied are th e RET/PTC, BRAF V600E, RAS, an d PAX8/ PPARG m utation s. RET/PTC rearran gem en ts result in activation of th e RET proto-on cogen e an d h ave been described in up to 43% of papillar y thyroid can cers.43 Activation of th e RET protoon cogen e h as been associated w ith prior radiation exposure. Recen tly, RET/PTC m utation s h ave been described in follicular aden om as an d oth er ben ign thyroid path ologies, an d w h en presen t are associated w ith an in creased rate of grow th .44 Mutation in th e BRAF gen e, resultin g in con stit utive act ivation of BRAF kin ase, h as been lin ked to developm en t of PTC an d poorly di eren tiated thyroid can cers.45 Th e BRAF m utation , w h ich h as been described in 50 to 90% of conven tion al PTC, is associated w ith older age, lym ph n ode m etastasis, distan t m etastasis, recurren ce, an d persisten t disease.46,47 How ever, because of its h igh prevalen ce, use of BRAF positivit y h as been di cult to in tegrate in to clin ical pract ice. Coexistent m utation s in BRAF an d RET/PTC h ave been described in up to 13% of PTC an d w ere m ore com m on in advan ced stages of disease.48 Mutation s in th e four RAS proto-on cogen es, HRAS, KRASA, KRASB, an d NRAS, result in a conform ation al ch ange to th eir active form an d prom ote dow n stream grow th e ects. RAS m utation s h ave been foun d to h ave a h igh prevalen ce in follicular aden om as an d follicular varian ts of PTC.49,50 Th ey are associated w ith w orse outcom es in papillar y thyroid can cer an d poorly di eren tiated thyroid can cers.51,52 PAX8/PPARG is a fusion gen e, often th e result of a t(2;3)(q13; p25) ch rom osom al tran slocation . Con stitut ive act ivation in thyroid cells leads to th e overexpression of PPARG an d consequen t loss of th e n orm al in h ibition of cell proliferation an d in duction of apoptosis. Th e loss of th ese fun ct ion s results in un con trolled cell grow th .53 Th e PAX8/PPARG fusion gen e is a com m on gen et ic abn orm alit y seen in approxim ately 50% of follicular aden om as an d 35% of follicular carcin om as.54,55

Malignant Disease of the Thyroid Gland

9.3.2 Preoperat ive Evaluat ion If m align an cy h as been confirm ed by FNA, or is h igh ly suspected, th en an ultrasoun d of th e thyroid an d lateral n eck sh ould be obtain ed prior to any surgical in terven t ion . Cer vical lym ph n ode involvem en t is estim ated to occur in 20 to 50% of cases of di eren tiated thyroid can cer.24 Patien t outcom es are h igh ly a ected by th e com pleten ess of th e resection , in cluding cervical lym ph n odes, so it is im portan t to iden tify patien ts w ith eviden ce of lym ph n ode m etastasis for optim al surgical plan n in g.56,57 On ultrasoun d im aging, involved lym ph n odes ten d to h ave loss of th e fatt y h ilum , a roun ded sh ape, hypoech ogen icit y, cystic ch ange, in creased periph eral vascularit y, an d m icrocalcification s.58 Th e location of th e lym ph n ode is also im portan t; lym ph n odes located in th e low er portion of th e n eck are m ore likely to be a ected th an lym ph n odes in th e upper por tion of th e n eck, w here th ey are m ore likely to be react ive.59 How ever, n on e of th ese criteria are su cien tly sen sitive or specific to defin itively iden tify cervical m etastasis. Th erefore, all abn orm al-appearin g lym ph n odes sh ould un dergo FNA biopsy if it w ill ch ange surgical m an agem en t. Th e lym ph n ode aspirates m ay also be sen t for thyroglobulin to in crease th e diagn ostic accuracy of detect in g m etastatic DTC.60 Th e sen sitivit y of oth er im aging m odalities, such as com puted tom ography (CT), m agn etic reson an ce im agin g (MRI), an d positron em ission tom ography (PET), for abn orm al n eck lym ph n odes is low er th an n eck ultrasoun d an d, th erefore, n ot routin ely recom m en ded in th e preoperative evaluation .61

9.3.3 Staging Stagin g for di eren tiated thyroid can cer is gen erally perform ed usin g th e Am erican Join t Com m ittee on Can cer’s (AJCC) TNM staging system .62 Th is is th e m ost un iversally accepted stagin g system an d is required for can cer regist ries. Stage is based first on patien t age because older patien ts h ave a h igh er risk of death from thyroid can cer th an youn ger patien ts.23 Patien ts un der th e age of 45 h ave stage I disease if th ere is n o eviden ce of distan t m etastasis an d stage II disease if th ere is eviden ce of distan t m etastasis. For patien ts over th e age of 45, stage I disease is defin ed as tum or < 2 cm w ith out lym ph n ode or distan t m etastasis. Stage II disease is a tum or 2 to 4 cm w ith out lym ph n ode or distan t m etastasis. Stage III disease is a tum or that is > 4 cm or h as m in im al extrathyroidal exten sion , or th e presence of m etastasis to th e cen tral lym ph n ode com partm en t. Stage IV is divided in to th ree substages: IVa is a tum or th at invades th rough th e thyroid capsule or t um or w ith lateral com partm en t lym ph n ode m etastasis; IVb is a tu m or th at invades in to th e prevertebral fascia or en cases th e carotid artery or m ediastin al vessels; IVc is a t um or w ith eviden ce of distan t m etastasis. Th e AJCC staging system addresses a patien t’s risk of death due to di eren tiated thyroid can cer but w as n ot developed to determ in e th e patien t’s risk of recurren ce, w h ich causes sign ifican t m orbidit y in patien ts. Th us it is suggested th at risk of recurren ce be classified in to h igh , in term ediate, an d low risk of recurren ce.7 High -risk patien ts h ave m acroscopic tum or invasion th rough th e capsule, in com plete tum or resection , or distan t m etastatic disease. In term ediate-risk pat ien ts dem on st rate m icroscopic t um or invasion th rough th e capsule, cervical

lym ph n ode m etastasis, aggressive h istology (i.e., tall cell, in sular, colum n ar cell), or vascular invasion . Low -risk patien ts h ave n o region al or distan t m etastatic disease, an d com plete tu m or resection w ith out eviden ce of capsular or vascular invasion .7

9.3.4 Post operat ive Managem ent Un der th e in fluen ce of TSH, radioactive iodin e (RAI) is taken up in to thyroid cells an d in duces cell apoptosis. RAI h as in creasin gly been adm in istered in th e treatm en t of papillar y thyroid can cer, th ough th ere is variation in its use, an d th e in dication s for th erapy rem ain a topic of debate.63 Th e m ost un iversally accepted in dication for RAI is for th e t reatm en t of distan t m etastatic thyroid can cer, especially to th e lungs.64,65,66 In addition , RAI h as been used in an adjun ct ive role to t reat can cer cells th at are suspected to be presen t after operat ive t reatm en t but are n ot clin ically apparen t. Th ere h ave been studies th at sh ow reduct ion s in th e rate of recurren ce, as w ell as all-cause m ortalit y.23,67,68 How ever, oth er studies h ave n ot confirm ed th is ben efit, especially in low -risk patien ts.69,70,71,72 Fin ally, radioiodin e h as been used to ablate th e n orm al rem n an t thyroid tissue, w h ich facilitates postoperative surveillan ce of thyroglobulin levels an d allow s th e physician to diagnose recurren ce at an earlier stage.73 Radioiodin e is n ot w ith out side e ects, m ost com m on ly salivar y glan d dam age an d obst ruction of th e n asolacrim al duct .74,75 Addition ally, after RAI, th ere appears to be a sm all risk of in creased m align an cy, especially leukem ia, w h ich is dose depen den t.76,77 Recom m en dat ion s for RAI are largely depen den t on th e risk of death an d/or recurren ce due to thyroid can cer, balan ced w ith th e in creased cost an d m orbidit y associated w ith treatm en t . For PTC, RAI is recom m en ded for all patien ts w ith eviden ce of distant m etastasis, gross extrathyroidal exten sion of th e t um or, an d tum ors > 4 cm in size. RAI m ay be in dicated in tum ors 1 to 4 cm in size w ith lym ph n ode m etastasis, lym ph ovascular invasion , or aggressive h istology, an d sh ould be con sidered on a case-by-case basis. RAI is n ot recom m en d ed in u n ifocal or m ult ifocal PTC if all foci are < 1 cm an d t h ere are n o ot h er h igh -risk feat u res. In con t rast t o PTC, follicu lar an d Hü r t h le cell can cers are con sid ered h igh er risk for recu rren ce; th erefore, alm ost all p atien t s w it h t h ese t u m ors are t reat ed w it h RAI (if iod in e avid), w ith th e exception of m in im ally invasive follicu lar carcin om a.7,78 If a patien t is determ in ed to be a can didate for RAI, th ere appear to be sim ilar results usin g thyroid h orm on e w ith draw al to in crease th e TSH versus usin g recom bin an t h um an TSH (rhTSH).79,80 Th e treatm en t dose of RAI sh ould be m in im ized to th e greatest exten t possible to preven t side e ects. For thyroid rem n an t ablation , use of 30 m Ci w as foun d to be as e ective as a h igh er dose of 100 m Ci.81 Treatm en t doses for suspected m icroscopic or m acroscopic disease are gen erally h igh er. No ran dom ized stud ies on th is topic h ave been perform ed, h ow ever, so th e treatm en t dose is largely based on physician preferen ce. Levothyroxin e m ust be used to replace physiological thyroid h orm on e levels after total thyroidectom y, but it is also often em ployed as a th erapeutic agen t . TSH receptor protein s are presen t on th e m em bran es of DTC, an d th ese cells respon d w ith accelerated cell grow th in th e presen ce of TSH. For th at reason , larger doses of levothyroxin e h ave been used follow in g prim ary

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Thyroid Diseases treatm en t for DTC to suppress th e TSH, preven tin g grow th of tum or cells. Th is practice, w h ich h as been sh ow n to reduce both m ortalit y an d recurren ce, is supported by m ost studies in th e literature, in cludin g a previous m eta-an alysis.82 Like RAI, th ese ben efits are n ot as clear in low -risk pat ien ts.72 TSH suppression is also n ot w ith out side e ects; it m ay con tribute to in creased cardiovascular m ortalit y in elderly patien ts an d fract ures in postm en opausal w om en .83,84,85 Th e physician m ust balan ce th e risks an d ben efits of TSH sup pression th erapy in each patien t. With th e in creasin g in ciden ce of low -risk DTC, con troversy rem ain s over th e degree an d duration of TSH suppression . Patien ts at in term ediate an d h igh risk for recurren ce sh ould gen erally un dergo TSH suppression to < 0.1 m U/L, w h ereas th ose at low risk for recurren ce sh ould h ave a TSH in th e 0.1 to 0.5 m U/L ran ge.7 Lon g-term TSH goals m ay be m ore relaxed, w ith a target of 0.5 to 2 m U/L in th ose at low risk for recurren ce. How ever, th ose at h igh risk sh ould con tin ue to h ave a TSH suppressed below 0.1 m U/L in th e absen ce of sign ifican t risk of side e ects.86,87 Alth ough th e risk of death from thyroid can cer is low, persisten t an d recurren t disease rem ain s a sign ifican t source of m orbidit y. Several tech n iques are em ployed to detect recurren t disease in patien ts after treatm en t of DTC. Thyroglobulin (Tg) is a protein produced on ly by thyroid cells, so its presence in blood suggests th at th ere are residual thyroid cells (eith er n orm al thyroid or DTC). It can be m easured w h ile th e patien t h as a suppressed TSH on levothyroxin e th erapy (suppressed Tg) or under levothyroxin e w ith draw al (stim ulated Tg). Altern atively, rh TSH h as also been em ployed to obtain stim ulated Tg levels.88 In a patien t w h o h as un dergon e thyroid rem n an t ablation , Tg sh ould be un detectable. Stim ulated Tg < 1 n g/m L is in dicative of rem ission , w h ereas a suppressed Tg > 1 n g/m L suggests th e presen ce of disease.89 Tg levels are m ore di cult to in terpret in a patien t w h o h as n ot un dergon e rem n an t ablation . Addition ally, som e patien ts develop Tg an tibodies, w h ich can result in a falsely low level in a pat ien t w ith recurren t disease. Th e m ost com m on area for DTC recurren ce is in th e n eck.68 Th erefore, an ultrasoun d is gen erally obtain ed 6 to 12 m on th s after th erapy to determ in e if th ere are any suspicious-appearin g lym ph n odes. Con cern in g lym ph n odes sh ould un dergo FNA biopsy. An iodin e-131 (I-131) diagn ostic scan can also be perform ed, especially in patien ts w ith m ildly elevated Tg levels (suppressed Tg > 1 n g/m L or stim ulated Tg > 2 n g/m L) an d a n orm al n eck ultrasoun d; h ow ever, it is of little utilit y in patien ts w ith un detectable thyroglobulin levels.90 In patien ts w ith a n egative I-131 scan an d sign ifican tly elevated stim ulated Tg (> 5–10 n g/m L), a PET scan m ay be useful to detect n on iodin e avid disease.91,92 Tum or ch aracteristics can be used to estim ate th e risk of recurren ce, discussed earlier in th is ch apter. Addition ally, patien t respon se to in itial th erapy is predict ive of th e likelih ood of recurren ce an d can th erefore be used to “restage” patien ts.93 In on e study, pat ien ts at low risk for recurren ce h ad a 3% rate of recurren t disease in th e 2 years after treatm en t , w h ereas th ose at in term ediate risk h ad a 21% rate an d th ose at h igh risk h ad a 68% rate. In th e coh ort w h o dem on st rated an excellen t respon se to th erapy (stim ulated Tg < 1 n g/m L, n egative n eck ultrasoun d), th e risk of recurren ce w as 2% in th e low -risk group, 2% in th e in term ediate-risk group, an d 14% in th e h igh -risk group. Altern atively, th e cohort w h o h ad an in com plete respon se to

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th erapy (suppressed Tg > 1 n g/m L, stim ulated Tg > 10 n g/m L, risin g Tg level or eviden ce of struct ural disease on im agin g) h ad a 13% recurren ce rate in th e low -risk group, 41% in th e in term ediate group, an d 79% in th e h igh -risk group.

9.4 Medullary Thyroid Cancer Medullar y thyroid can cer (MTC) arises from th e calciton in secretin g parafollicular C cells of th e thyroid glan d, w h ich are derived from th e n eural crest durin g developm en t . Medullar y thyroid can cer accoun ts for < 4% of all cases of thyroid can cer diagn osed in th e Un ited States.21 Overall sur vival rates in MTC are 80 to 85% at 5 years an d 70 to 75% at 10 years.94 Few er th an 50% of patien ts w ith MTC are cured after surgical resection ; h ow ever, even in th e presen ce of residual disease, th e 10-year sur vival is approxim ately 70%.95 Th e stron gest predictors of decreased sur vival are older age at diagn osis, exten t of th e prim ar y t um or, n odal disease, an d distan t m etastasis.94,96,97

9.4.1 Genet ics of Medullary Thyroid Cancer MTC is often associated w ith a gen etic abn orm alit y in th e RET proto-on cogen e; an estim ated 20 to 25% of MTC is associated w ith th e autosom al dom in an t gen etic syn drom es of m ultiple en docrin e n eoplasia (MEN) 2A, MEN 2B, an d fam ilial MTC.98,99 Table 9.3 discusses clin ical ch aracteristics of MTC syn drom es. RET germ lin e m utation s associated w ith in h erited can cer syn drom es lead to overexpression of th e Ret protein in all t issues an d are, th erefore, associated w ith oth er tum ors, such as ph eoch rom ocytom a an d parathyroid aden om as.100 Altern atively, som atic RET m utation s are present in 40 to 50% of sporadic cases of MTC an d are associated w ith an advan ced stage at diagn osis an d low er lon g-term sur vival.101 Th e m ost com m on gen et ic syn drom e associated w ith MTC is MEN 2A. MEN 2A is associated w ith developm en t of ph eoch rom ocytom a in up to 68% of patien ts an d prim ar y hyperparathyroidism in 15 to 30%.95,102 Pen et ran ce in MEN 2A is n ot 100%, but an estim ated 90% of MEN 2A gen e carriers w ill develop bioch em ical eviden ce of MTC by age 31, an d 60% of patien ts w ill develop clin ical disease by age 70.103 Fam ilial MTC is con sidered a clinical varian t of MEN 2A, w h ere m ultiple fam ily m em bers h ave been diagn osed w ith MTC, but th ere is n o h istory of ph eoch rom ocytom a or prim ar y hyperparathyroidism .104 It can be di cult at t im es to di eren t iate MEN 2A from fam ilial MTC; m isdiagn osis of fam ilial MTC risks failure to appropriately screen for ph eoch rom ocytom a. MEN 2B is n ot as com m on as MEN 2A but is associated w ith m ore aggressive disease. Patien ts un iversally develop MTC, often at a m ore advan ced stage an d earlier in life.105,106 Ph eoch rom ocytom a is described in up to 28% of patien ts a ected by MEN 2B.107 Patien ts w ith MEN 2B h ave extraen docrin e m an ifestation s, such as m arfan oid h abit us, gan glion eurom atosis of th e gut an d oral m ucosa, an d m edullated corn eal n erve fibers. Up to 90% of pat ien ts h ave a colon ic disturban ce; m ost presen t w ith ch ron ic constipation , but a sign ifican t n um ber w ill also develop m egacolon requirin g surgical in terven t ion .108 All patien ts diagn osed w ith MTC sh ould un dergo germ lin e screen in g for a RET m utation . Th e presen ce of specific RET

Malignant Disease of the Thyroid Gland Table 9.3 Genetic syndromes in m edullary thyroid cancer MEN 2A

MEN 2B

Fam ilial MTC

Associated disorders

Pheochrom ocytom a and prim ary hyperparathyroidism

Pheochromocytoma, marfanoid habitus, neurogangliomas, m egacolon, m edullated corneal nerve fibers

None

MTC characteristics

Most com mon, 80% of genetic MTC

Youngest age at diagnosis, m ost aggressive

Variant of MEN 2A

Prophylactic thyroidectom y

Before 5 years old

Before 1 year old

Before 5 years old

Need to test fam ily members

Yes, at age 3–5 years

Yes, preferably at birth

Yes, at age 3–5 years

Abbreviations: MEN, m ultiple endocrine neoplasia; MTC, m edullary thyroid cancer. Source: Am erican Thyroid Association Guidelines Task Force, Thyroid, 2009.

m utation s m ay require sur veillan ce an d treatm en t for ph eoch rom ocytom a or prim ar y hyperparathyroidism . Addition ally, th e presen ce of a germ lin e m utation in th e RET proto-on cogen e n ecessitates screen in g of first-degree relatives.109 It is recom m en ded th at ch ildren of patien ts w ith MEN 2A an d fam ilial MTC un dergo RET testin g at 3 to 5 years of age, an d th ose th at test positive sh ould h ave a prophylactic thyroidectom y by th e age of 5.110,111 For ch ildren of paren ts w ith MEN 2B, testin g sh ould be don e as soon as possible an d thyroidectom y sh ould be perform ed by 1 year of age, th ough MTC h as been repor ted in ch ildren as young as 2 m on th s old.112,113

9.4.2 Preoperat ive Evaluat ion For patien ts suspected of h avin g MTC, th e preoperative evaluation begin s w ith a n eck ultrasoun d to evaluate for eviden ce of lym ph n ode m etastasis; th is sh ould in clude th e cen tral an d lateral lym ph n ode com partm en ts.114 Ult rasoun d h as th e h igh est sen sitivit y to detect m etastatic lym ph n odes in th e n eck.115 All patien ts sh ould also un dergo serum testin g for calcium , calciton in , carcin o-em bryon ic an tigen (CEA), an d RET m utation , if n ot already don e. Patien ts w ith elevated plasm a calciton in levels above 400 pg/m L sh ould un dergo evaluation for m etastat ic disease w ith CT scan of th e n eck an d ch est, as w ell as t riple-ph ase liver CT scan or MRI of th e liver, to evaluate for eviden ce of m etastatic disease prior to surgical in terven tion .116 Patien ts w ith h ereditar y t um or syn drom es sh ould also un dergo evaluation for prim ary hyperparathyroidism an d ph eoch rom ocytom a. If th ere is elevated calcium on preoperative testin g, con sisten t w ith prim ar y hyperparathyroidism , a subtotal p arat hyroid ect om y or fou r-glan d resect ion w it h aut ograft sh ou ld be p erfor m ed at t h e sam e t im e.117,118 Any p atien t w ith su sp ected or con firm ed MEN sh ou ld also h ave evalu at ion for p h eoch rom ocyt om a p rior t o any su rgical in t er ven tion . Th is can be d on e w it h m easu rem en t of p lasm a m etan ep h rin es or 24-h ou r u rin ar y m etan ep h rin es.119 Alth ough bioch em ical screen in g is th e stan d ard ap p roach , im aging of t h e abd om en w it h ou t evid en ce of an ad ren al n od u le ru les ou t p h eoch rom ocytom a.120 If t h ere is evid en ce of p h eoch rom ocytom a, th is sh ou ld be treated p rior to resection of MTC becau se hyp er t en sive crisis associated w it h u n t reat ed p h eoch rom ocytom a d u rin g su rgical p roced u res is associated w it h a h igh m or t alit y.121

9.4.3 St aging Like di eren tiated thyroid can cer, stagin g for MTC is also based on th e AJCC TNM staging system .62 Stage I disease is defin ed as a tu m or < 2 cm w ith out eviden ce of lym ph n ode m etastasis or distan t m etastatic disease; th is group is fur th er subcategorized in to stage IA for tum ors < 1 cm an d stage IB for t um ors 1 to 1.9 cm . Stage II disease is defin ed by a tum or 2 to 4 cm w ith out eviden ce of lym ph n ode m etastasis or m etastat ic disease. Stage III disease is any tum or over 4 cm , m icroscopic eviden ce of cap sule invasion , or th e presence of cent ral com part m en t lym ph n ode m etastasis. Stage IV disease is subcategorized in to th ree groups: stage IVA disease is tum or w ith m acroscopic invasion th rough th e capsule, or cervical or m ediastin al lym ph n ode m etastasis; stage IVB is tum or th at invades in to prevertebral fascia or en cases th e carotid artery or m ediastin al vessels; stage IVC disease is defin ed as distan t m etastasis.

9.5 Anaplast ic Thyroid Cancer An aplastic thyroid can cer (ATC) is con sidered th e m ost aggressive form of th e prim ar y thyroid m align an cies. It accoun ts for < 2% of all thyroid can cers in th e Un ited States, but h as th e w orst progn osis, w ith a m edian survival of 3 to 5 m on th s an d a 1-year sur vival of 20%.122 ATC h as been associated w ith iodin e deficien cy. Th e in cidence of ATC h as fallen in several coun tries, w h ich h as been attributed in part to th e in stit ution of dietary iodin e supplem en tation .123,124,125 In con trast to th e di eren tiated thyroid can cers, ATC tu m ors are rapidly grow in g an d often presen t w ith sym ptom s due to local invasion , such as dysph agia, dyspn ea, an d h oarsen ess.126 ATC often arises from a preexistin g di eren tiated thyroid cancer, an d th e t w o often coexist in th e path ological specim en .127,128 Com m on t ypes of di eren tiated can cers foun d w ith ATC are tall cell varian t of papillar y carcin om a, follow ed by follicular carcin om a an d Hü rth le cell carcin om a.129 Som e studies h ave suggested th ere is im proved survival w h en on ly a sm all portion of th e tum or h as an aplastic features in a backgroun d of di eren tiated thyroid can cer, term ed in ciden tal ATC.130,131,132 Oth er im portan t progn ost ic features in ATC in clude exten t of disease, size of th e prim ar y tum or, an d patien t age.1,133 Addition ally, patien ts w h o un dergo com plete surgical resection appear to h ave im proved sur vival.134,135

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Thyroid Diseases Table 9.4 Preoperative evaluation in patients with suspected anaplastic thyroid cancer Test

Indication

Basic m etabolic panel (including calcium)

Hypercalcemia due to PTHrP production, or hypocalcem ia due to destruction of parathyroid glands

Com plete blood count

Leukocytosis due to chem okine production or infection; poor prognostic indicator

Thyroid function tests

Thyrotoxicosis or hypothyroidism due to gland destruction

Ultrasound of neck

Extrathyroidal extension of tumor, presence of abnormal lym ph nodes

Cross-sectional im aging of neck (usually CT) Evaluate resectabilit y of lesion PET scan

Evaluate for distant m etastasis

Abbreviations: CT, com puted tom ography; PET, positron em ission tom ography; PTHrP, parathyroid horm one–related peptide. Source: Smallridge et al.55

9.5.1 Genet ics of Anaplast ic Thyroid Cancer ATC tum ors are often an euploid an d associated w ith com plex ch rom osom al deletion s an d rearran gem en ts.136,137 Addition ally, loss of h eterozygosit y h as been dem on st rated at the site of several t um or suppressor gen es, w h ich supports th e hypoth esis th at ATC arises from preexistin g di eren tiated thyroid can cer.138 Mutation s associated w ith di eren tiated thyroid can cer, such as BRAF an d RAS, are th ough t to occur early in th e thyroid can cer developm en t an d predispose to dedi eren t iation .139 Mutation s in gen es such as p53 an d β-ca tenin, th ough t to be th e “secon d h it” causin g dedi eren t iation , are com m on ly en coun tered in an aplastic thyroid can cer.140,141 Mutation s in p53 an d β-ca tenin are n ot specific to thyroid t issues an d are seen in m any oth er m align an cies.142,143,144 BRAF an d RAS m utation s are m ore com m on ly associated w ith thyroid m align an cies but can be seen in oth er m align an cies, such as m elan om a an d h em atologic can cers.145,146 RET/PTC an d PAX8/PPARG m utation s are fairly specific for thyroid tissues but are un com m on ly en coun tered in ATC.147,148 Alth ough th ese m utation s provide poten tial targets for fut ure m olecular th erapies, th ey are n ot curren tly required for diagnosis of ATC.

9.5.2 Preoperat ive Evaluat ion As sum m arized in Table 9.4, patien ts con firm ed or suspected to h ave ATC sh ould h ave a basic laborator y evaluation , in cluding a com plete m etabolic pan el (in cluding calcium an d ph osph oru s), com plete blood coun t, an d thyroid fun ct ion tests prior to any surgical in ter ven t ion . Leukocytosis m ay suggest an un derlyin g in fect ion , or severe leukocytosis m ay be due to product ion of cytokin es by th e tum or itself.149,150 Th e presence of leukocytosis is a poor progn ost ic in dicator.131 Preoperative thyroid fun ction testin g is im portan t because large t um ors m ay replace n orm al thyroid t issue, causin g hypothyroidism . Altern atively, ATC h as also been associated w ith thyrotoxicosis secon dar y to thyroidit is.151 Hypercalcem ia due to production of parathyroid h orm on e–related peptide h as been described.152 As in oth er thyroid m align an cies, ultrasoun d of th e n eck is usefu l to ch aracterize th e thyroid tu m or, as w ell as th e presen ce of any abn orm al lym ph n odes. Th e exten t of t um or invasion and resectabilit y of th e lesion sh ould be assessed w ith crosssect ion al im aging, m ost com m on ly CT scan . It is crit ical to

determ in e exten sion of th e t um or in to adjacen t t issues of th e n eck, as w ell as th e presen ce of lym ph n odes in areas n ot w ell visualized by ultrasoun d, such as th e paraph aryngeal space.153 CT scan can also be used to evaluate for distan t m etastases, m ost com m on ly in th e ch est an d abdom en . PET scan m ay h ave h igh er sen sitivit y for distan t m etastases th an oth er im aging m odalities.154 Due to th e rapid grow th of th ese t um ors, surgical in terven tion sh ould n ot be sign ifican tly delayed to obtain addition al preoperative im aging.

9.5.3 St aging Like oth er thyroid m align an cies, staging for ATC is also based on th e AJCC TNM staging system .62 Due to its poor progn osis, ATC is un iversally defin ed as stage IV at th e t im e of diagn osis. Tum ors th at are con fin ed to th e thyroid glan d, w ith or w ith out lym ph n ode m etastasis, are stage IVA. Stage IVB t um ors invade in to th e adjacen t tissues an d m ay h ave lym ph n ode m etastases but n o distan t m etastases. Stage IVC is distan t m etastatic disease. Addition ally, because th e extent of surgical resection is a sign ifican t progn ostic factor, th e AJCC also developed a residual tum or classification . R0 is n o residual tum or, R1 is m icroscopic residual t um or, an d R2 is m acroscopic residual tum or. Patien ts w ith R0/R1 disease after surgical resection h ave sign ifican tly lon ger sur vival, especially in studies th at h ave evaluated adjun ct ive ch em oth erapy an d radiation .134,135 How ever, it is di cult to assess th e e cacy of ch em oth erapy or radiation because th ese tr ials are n ot ran dom ized. Patien ts w ho un dergo ch em oth erapy or radiation are likely to h ave im proved fun ction al status at baselin e, an d lack of ran dom ization fails to con trol for th is sign ifican t confoun der. To date, th ere are n o ran dom ized, con trolled trials for treatm en t of ATC.155 Th e overall poor progn osis for ATC, an d th e m argin al treatm ent ben efit of curren t th erapies sh ould be discussed w ith th e patien t; palliative care is an option th at sh ould be con sidered for all patien ts.133,156

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Progn ostic sign ifican ce of FDG PET/CT on th e follow -up of patien ts of di eren tiated thyroid carcin om a w ith n egative 131I w h ole-body scan an d elevated thyroglobulin levels: correlation w ith clin ical an d h istopath ologic ch aracteristics an d lon g-term follow up data. Clin Nucl Med 2012; 37(10); 953–959 [93] Tuttle RM, Tala H, Sh ah J et al. Estim atin g risk of recurren ce in di eren tiated thyroid can cer after total thyroidectom y an d radioactive iodin e rem n an t ablation : usin g respon se to th erapy variables to m odify th e in itial risk estim ates predicted by th e n ew Am erican Th yroid Association staging system . Thyroid 2010; 20(12); 1341–1349 [94] Cupisti K, Wolf A, Ra el A, et al. Lon g-term clin ical an d bioch em ical follow -up in m edullar y thyroid carcinom a: a sin gle in stitut ion ’s experien ce over 20 years. An n Surg 2007; 246(5); 815–821 [95] Modiglian i E, Coh en R, Cam pos JM, et al. Progn ostic factors for sur vival an d for bioch em ical cure in m edullary thyroid carcin om a: results in 899 patien ts. Th e GETC Study Group. Groupe d’étude des tum eurs à calciton in e. Clin En docrin ol (Oxf) 1998; 48(3); 265–273 [96] Rom an S, Lin R, Sosa JA. Progn osis of m edullary thyroid carcinom a: dem ograph ic, clin ical, an d path ologic predictors of survival in 1252 cases. Can cer 2006; 107(9); 2134–2142 [97] Esfan diari NH, Hugh es DT, Yin H, Ban erjee M, Haym art MR. Th e e ect of exten t of surgery an d n um ber of lym ph n ode m etastases on overall sur vival

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in patien ts w ith m edullary thyroid can cer. J Clin En docrin ol Metab 2014; 99 (2); 448–454 Pelizzo MR, Bosch in IM, Bern an te P, et al. Natural h istory, diagn osis, treatm en t an d outcom e of m edullary thyroid can cer: 37 years experien ce on 157 patien ts. Eur J Surg On col 2007; 33(4); 493–497 Bergan t D, Hocevar M, Besic N, Glavac D, Korosec B, Caserm an S. Hereditary m edullar y thyroid can cer in Sloven ia—genotype-ph en otype correlation s. Wien Klin Woch ensch r 2006; 118(13–14); 411–416 Math ew CG, Ch in KS, Easton DF, et al. A lin ked genetic m arker for m ultiple en docrin e n eoplasia t ype 2A on ch rom osom e 10. Nature 1987; 328(6130); 527–528 Elisei R, Cosci B, Rom ei C, et al. Progn ostic sign ifican ce of som atic RET on cogen e m utation s in sporadic m edullary thyroid can cer: a 10-year follow -up study. J Clin En docrin ol Metab 2008; 93(3); 682–687 Iih ara M, Yam ash ita T, Okam oto T, et al. A n ationw ide clin ical sur vey of patien ts w ith m ultiple en docrin e n eoplasia t ype 2 an d fam ilial m edullary thyroid carcinom a in Japan . Jpn J Clin On col 1997; 27(3); 128–134 Easton DF, Pon der MA, Cum m ings T, et al. Th e clin ical an d screen in g age-aton set distribution for th e MEN-2 syn drom e. Am J Hum Gen et 1989; 44(2); 208–215 Kloos RT, En g C, Evan s DB, et al. Am erican Th yroid Association Guidelin es Task Force. Medullar y thyroid can cer: m an agem en t guidelin es of th e Am erican Th yroid Association . Thyroid 2009; 19(6); 565–612 O’Riordain DS, O’Brien T, Weaver AL, et al. Medullary thyroid carcinom a in m ultiple en docrin e n eoplasia t ypes 2A an d 2B. Surgery 1994; 116(6); 1017– 1023 Brauckh o M, Gim m O, Weiss CL, et al. Multiple en docrin e n eoplasia 2B syn drom e due to codon 918 m utation : clin ical m an ifestation an d course in early an d late on set disease. World J Surg 2004; 28(12); 1305–1311 Mach ens A, Brauckh o M, Holzh ausen HJ, Th an h PN, Leh n ert H, Dralle H. Codon -specific developm en t of ph eoch rom ocytom a in m ultiple en docrin e n eoplasia type 2. J Clin En docrin ol Metab 2005; 90(7); 3999–4003 O’Riordain DS, O’Brien T, Crott y TB, Gh arib H, Gran t CS, van Heerden JA. Multiple en docrin e n eoplasia type 2B: m ore th an an en docrin e disorder. Surgery 1995; 118(6); 936–942 Mulligan LM. From gen es to decision s: evolvin g view s of gen otype-based m an agem en t in MEN 2. Can cer Treat Res 2004; 122; 417–428 Fran k-Raue K, Buh r H, Dralle H, et al. Lon g-term outcom e in 46 gene carriers of h ereditar y m edullar y thyroid carcinom a after prophylactic thyroidectom y: im pact of in dividual RET genotype. Eur J En docrin ol 2006; 155(2); 229–236 Skin n er MA, Moley JA, Dilley WG, Ow zar K, Deben edetti MK, Wells SA, Jr. Prophylactic thyroidectom y in m ultiple en docrin e n eoplasia typ e 2A. N Engl J Med 2005; 353(11); 1105–1113 Un ruh A, Fitze G, Jän ig U, Bielack S, Loch bü h ler H, Coerdt W. Medullar y thyroid carcinom a in a 2-m on th -old m ale w ith m ultiple en docrin e n eoplasia 2B an d sym ptom s of pseudo-Hirsch sprun g disease: a case report . J Pediatr Surg 2007; 42(9); 1623–1626 van Heurn LW, Sch aap C, Sie G, et al. Predictive DNA testin g for m ultiple en docrin e n eoplasia 2: a th erapeutic ch allenge of prophylactic thyroidectom y in ver y youn g ch ildren. J Pediatr Surg 1999; 34(4); 568–571 Moley JF, DeBen edetti MK. Pattern s of n odal m etastases in palpable m edullar y thyroid carcin om a: recom m en dation s for exten t of n ode dissection . An n Surg 1999; 229(6); 880–887, discussion 887–888 Giraudet AL, Van el D, Leboulleux S, et al. Im aging m edullary thyroid carcin om a w ith persisten t elevated calciton in levels. J Clin En docrin ol Metab 2007; 92(11); 4185–4190 Mach ens A, Schn eyer U, Holzh ausen HJ, Dralle H. Prospects of rem ission in m edullar y thyroid carcinom a accordin g to basal calcitonin level. J Clin En docrin ol Metab 2005; 90(4); 2029–2034 van Heerden JA, Ken t RB, III, Sizem ore GW , Gran t CS, ReMin e W H. Prim ar y hyperparathyroidism in patien ts w ith m ultiple en docrin e n eoplasia syn drom es. Surgical experien ce. Arch Surg 1983; 118(5); 533–536 Herfarth KK, Bartsch D, Doh er ty GM, Wells SA, Jr, Lairm ore TC. Surgical m an agem en t of hyperparathyroidism in patien ts w ith m ultiple en docrin e n eoplasia type 2A. Surgery 1996; 120(6); 966–973, discussion 973–974 Saw ka AM, Jaesch ke R, Sin gh RJ, Youn g WF, Jr. A com parison of bioch em ical tests for ph eoch rom ocytom a: m easurem en t of fraction ated plasm a m etan eph rin es com pared w ith th e com bination of 24-h our urin ar y m etaneph rin es an d catech olam in es. J Clin En docrin ol Metab 2003; 88(2); 553–558 Gim en ez-Roqueplo AP, Caum on t-Prim A, Houzard C, et al. EVA Investigators. Im aging w ork-up for screen ing of paragangliom a an d ph eoch rom ocytom a in SDHx m utation carriers: a m ulticen ter prospect ive study from th e PGL. J Clin En docrin ol Metab 2013; 98(1); E162–E173

[121] O’Riordan JA. Ph eoch rom ocytom as an d an esthesia. In t An esthesiol Clin 1997; 35(4); 99–127 [122] Sm allridge RC, Coplan d JA. An aplastic thyroid carcin om a: path ogen esis an d em ergin g th erapies. Clin On col (R Coll Radiol) 2010; 22(6); 486–497 [123] Bach er-Stier C, Riccabon a G, Tötsch M, Kem m ler G, Oberaign er W , Mon cayo R. In ciden ce an d clin ical ch aracteristics of thyroid carcinom a after iodin e prophylaxis in an en dem ic goiter coun tr y. Thyroid 1997; 7(5); 733–741 [124] Dijkstra B, Prich ard RS, Lee A, et al. Ch an ging pattern s of thyroid carcin om a. Ir J Med Sci 2007; 176(2); 87–90 [125] Passler C, Sch euba C, Prager G, et al. An aplastic (un di eren tiated) thyroid carcin om a (ATC). A retrospective an alysis. Lan gen becks Arch Surg 1999; 384(3); 284–293 [126] Bi on i M, Garritan o S, Scipion i P, Colan gelo M, De Meo D, Mon ti M. Man agem en t of acute clin ical presen tation of an aplastic thyroid can cer. A di cult ch oice. An n Ital Ch ir 2013; 84(2); 187–191 [127] Ven katesh YS, Ordon ez NG, Schultz PN, Hickey RC, Goepfert H, Sam aan NA. An aplastic carcinom a of th e thyroid. A clin icopath ologic study of 121 cases. Can cer 1990; 66(2); 321–330 [128] Nish iyam a RH, Dun n EL, Th om pson NW. An aplastic spin dle-cell an d gian tcell tum ors of th e thyroid glan d. Can cer 1972; 30(1); 113–127 [129] Albores-Saavedra J, Hern an dez M, San ch ez-Sosa S, Sim pson K, An geles A, Hen son DE. Histologic varian ts of papillar y an d follicular carcin om as associated w ith an aplastic spin dle an d gian t cell carcin om as of th e thyroid: an an alysis of rh abdoid an d thyroglobulin in clusion s. Am J Surg Path ol 2007; 31(5); 729–736 [130] Aldin ger KA, Sam aan NA, Iban ez M, Hill CS, Jr. An aplastic carcin om a of th e thyroid: a review of 84 cases of spin dle an d gian t cell carcin om a of th e thyroid. Can cer 1978; 41(6); 2267–2275 [131] Sugitan i I, Kasai N, Fujim oto Y, Yan agisaw a A. Progn ostic factors an d th erapeutic strategy for an aplastic carcin om a of th e thyroid. World J Surg 2001; 25 (5); 617–622 [132] Sugin o K, Ito K, Mim ura T, et al. Th e im portan t role of operation s in th e m an agem en t of an aplastic thyroid carcinom a. Surgery 2002; 131(3); 245–248 [133] Haym art MR, Ban erjee M, Yin H, Worden F, Griggs JJ. Margin al treatm en t ben efit in an aplastic thyroid can cer. Can cer 2013; 119(17); 3133–3139 [134] Sw aak-Kragten AT, de W ilt JH, Sch m itz PI, Bon ten bal M, Leven dag PC. Multim odality treatm en t for an aplastic thyroid carcin om a—treatm en t outcom e in 75 patien ts. Radioth er On col 2009; 92(1); 100–104 [135] Haigh PI, Ituar te PH, Wu HS, et al. Com pletely resected an aplastic thyroid carcin om a com bined w ith adjuvant ch em oth erapy an d irradiation is associated w ith prolon ged sur vival. Can cer 2001; 91(12); 2335–2342 [136] Ekm an ET, Wallin G, Bäckdah l M, Löw h agen T, Auer G. Nuclear DNA con ten t in an aplastic gian t-cell thyroid carcin om a. Am J Clin On col 1989; 12(5); 442– 446 [137] Miura D, Wada N, Ch in K, et al. An aplastic thyroid can cer: cytogen etic pattern s by com parative genom ic hybridization . Thyroid 2003; 13(3); 283–290 [138] Hun t JL, Tom etsko M, LiVolsi VA, Sw alsky P, Fin kelstein SD, Barn es EL. Molecular eviden ce of an aplastic tran sform ation in coexistin g w ell-di eren tiated an d an aplastic carcin om as of th e thyroid. Am J Surg Path ol 2003; 27(12); 1559–1564 [139] Kon do T, Ezzat S, Asa SL. Path ogenetic m ech anism s in thyroid follicular-cell n eoplasia. Nat Rev Can cer 2006; 6(4); 292–306 [140] Fagin JA, Matsuo K, Karm akar A, Ch en DL, Tan g SH, Koe er HP. High prevalen ce of m utation s of th e p53 gen e in poorly di eren tiated h um an thyroid carcinom as. J Clin Invest 1993; 91(1); 179–184 [141] Garcia-Rostan G, Tallin i G, Herrero A, D’Aquila TG, Carcan giu ML, Rim m DL. Frequen t m utation an d n uclear localization of beta-caten in in an aplastic thyroid carcin om a. Can cer Res 1999; 59(8); 1811–1815 [142] Muller PA, Vousden KH. Mutan t p53 in can cer: n ew fun ction s an d th erapeutic opport un ities. Can cer Cell 2014; 25(3); 304–317 [143] Fassn ach t M, Kroiss M, Allolio B. Update in adren ocortical carcinom a. J Clin En docrin ol Metab 2013; 98(12); 4551–4564 [144] Klaus A, Birch m eier W . W n t sign allin g an d its im pact on developm en t an d can cer. Nat Rev Can cer 2008; 8(5); 387–398 [145] Voskoboyn ik M, Arken au HT. Com bin ation th erapies for th e treatm en t of advan ced m elanom a: a review of curren t eviden ce. Bioch em Res In t 2014; 2014; 307059 [146] Ebi H, Faber AC, En gelm an JA, Yan o S. Not just gRASpin g at flaw s: fin din g vuln erabilities to develop n ovel th erapies for treatin g KRAS m utan t can cers. Can cer Sci 2014; 105(5); 499–505 [147] Marotta V, Guerra A, Sapio MR, Vitale M. RET/PTC rearran gem en t in ben ign an d m align an t thyroid diseases: a clin ical stan dpoin t. Eur J En docrin ol 2011; 165(4); 499–507

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Thyroid Diseases [148] Carpi A, Mech an ick JI, Saussez S, Nicolin i A. Th yroid tum or m arker gen om ics an d proteom ics: diagn ostic an d clin ical im plication s. J Cell Physiol 2010; 224 (3); 612–619 [149] Fujita T, Ogasaw ara Y, Naito M, Doih ara H, Sh im izu N. An aplastic thyroid carcin om a associated w ith gran ulocyte colony-stim ulatin g factor: report of a case. Surg Today 2006; 36(1); 63–67 [150] Sato T, Om ura M, Saito J, et al. Neutroph ilia associated w ith an aplastic carcin om a of th e thyroid: production of m acroph age colony-stim ulatin g factor (M-CSF) an d in terleukin -6. Thyroid 2000; 10(12); 1113–1118 [151] Alagöl F, Tan akol R, Boztepe H, Kapran Y, Terzioglu T, Dizdaroglu F. An aplastic thyroid can cer w ith tran sien t thyrotoxicosis: case report an d literature review. Th yroid 1999; 9(10); 1029–1032 [152] Iw ai H, Oh n o Y, Aoki N. An aplastic thyroid carcinom a w ith h um oral hypercalcem ia of m align an cy (HHM): an autopsy case report . En docr J 2004; 51(3); 303–310

[153] Loevn er LA, Kaplan SL, Cun n an e ME, Moon is G. Cross-sect ion al im aging of th e thyroid glan d. Neuroim agin g Clin N Am 2008; 18(3); 445–461, viivii. [154] Poisson T, Dean dreis D, Leboulleux S, et al. 18F-fluorodeoxyglucose positron em ission tom ography an d com puted tom ography in an aplastic thyroid can cer. Eur J Nucl Med Mol Im aging 2010; 37(12); 2277–2285 [155] Sm allridge RC, Ain KB, Asa SL, et al. Am erican Thyroid Association An aplastic Thyroid Can cer Guidelin es Taskforce. Am erican Thyroid Association guidelin es for m an agem en t of patien ts w ith an aplastic thyroid can cer. Thyroid 2012; 22(11); 1104–1139 [156] Sugitan i I, Miyauchi A, Sugin o K, Okam oto T, Yosh ida A, Suzuki S. Progn ostic factors an d treatm en t outcom es for an aplastic thyroid carcin om a: ATC Research Con sort ium of Japan coh ort study of 677 patien ts. World J Surg 2012; 36(6); 1247–1254

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Molecular Advances in t he Diagnosis and Treat m ent of Thyroid Cancer

10 Molecular Advances in t he Diagnosis and Treat m ent of Thyroid Cancer Susan J. Hsiao and Yuri E. Nikiforov

10.1 Int roduct ion Sign ifican t w ork h as been don e over th e last few decades to illum in ate th e gen etic basis of thyroid n eoplasia. Th ese e orts, accelerated in recen t years by th e availabilit y of in creasin g am oun ts of data gen erated th rough n ext-gen erat ion sequen cin g tech n ologies, h ave led to th e elucidation of th e can cer gen es un derlyin g th e path ogen esis of th e m ajorit y (> 90%) of thyroid tum ors. In deed, thyroid t um ors are am on g th e few tum ors in w h ich th is level of un derstan din g h as been ach ieved to date. Th is kn ow ledge (1) allow s th e accurate diagn osis of t um or, (2) aids in tum or classification , (3) provides guidan ce in th e clin ical m an agem en t of patien ts w ith thyroid tum ors, (4) o ers poten tial targets for th erapy, an d (5) form s a fram ew ork for future discoveries of n ew can cer gen es or biom arkers. Th is ch apter review s th e m olecular m ech an ism s un derlying thyroid can cer, w h ich prim arily involve th e m itogen -act ivated protein kin ase (MAPK) an d ph osph at idylin ositol 3-kin ase (PI3K) path w ays. Recen t data from studies exam in ing m ultiple gen es m utated in thyroid can cer as w ell as data from m ore th an 400 thyroid carcin om as sequen ced by Th e Can cer Gen om e Atlas in itiative suggest th at, for m ost w ell-di eren t iated follicular cell–derived thyroid tum ors, a single m utation in a driver gen e is su cien t for tum or developm en t . Aggressive or poorly di eren t iated t um ors, on th e oth er h an d, are m ore likely to h ave m ultiple m utation s. Th ese addition al acquired m utation s are likely late even ts th at prom ote tum or progression an d aggressiven ess. Oth er m olecular alteration s are foun d t ypically on ly in ben ign n odules, an d can be h elpful in di eren tiatin g tu m or from ben ign disease. In addition to playin g a role in thyroid can cer diagn osis, m olecular fin din gs are in creasin gly bein g used to determ in e surgical m an agem en t of thyroid n odules, or, in th e case of

fam ilial m edullar y thyroid can cer, to determ in e th e n eed for prophylact ic surgery. Exam ples of h ow m olecular fin din gs can be used to guide m edical an d surgical m an agem en t of patien ts as w ell as poten tial targeted th erapies w ill also be discussed in th is ch apter.

10.2 Gene Alt erat ions in Thyroid Disease Th e gen et ic lan dscape of di eren t t ypes of thyroid t um ors in cludes gen et ic alteration s th at occur in di eren t t um or t ypes an d alteration s th at are specific for certain t ypes of thyroid tum ors ( Fig. 10.1).

10.2.1 Papillary Thyroid Cancer Papillary thyroid can cer (PTC) is th e m ost com m on type of thyroid can cer, accoun tin g for approxim ately 80% of all thyroid m align an cies an d 90% of thyroid can cers in ch ildren . Most pap illary thyroid can cers are associated w ith a low m ortalit y rate, w ith a sur vival rate of > 98%.1 How ever, approxim ately 10% of patien ts w ill h ave recurren t disease.2 A com m on m olecular alteration , seen in approxim ately 45% of papillar y thyroid can cers, is m utation of th e BRAF gen e.1,3 BRAF is a serin e-th reon in e kin ase th at fun ct ion s in th e MAPK path w ay. BRAF is activated by RAS. Activated BRAF th en act ivates MEK, leadin g to dow n st ream act ivation of e ectors in th e MAPK path w ay. BRAF is t ypically act ivated by poin t m utation , w ith th e BRAF V600E m utation seen in m ore th an 98% of cases. Th e BRAF K601E m utation can be seen in 1 to 2% of cases, an d oth er BRAF m utation s, such as sm all in -fram e in ser tion s or deletion s, accoun t for th e rem ain der.4,5,6,7 In addition to poin t

Fig. 10.1 Com m on gene m utations and gene fusions in different thyroid tumors. (Data from Nikiforova MN, Nikiforov YE. Molecular diagnostics and predictors in thyroid cancer. Thyroid. 2009;19[12]:1351–1361, and references described in text.)

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Thyroid Diseases m utation s an d in sertion or deletion m utation s, BRAF m ay be activated as a result of ch rom osom al rearran gem en t, such as on e leadin g to a fu sion of BRAF to AKAP9 (A kin ase protein an ch or 9).8 Th e AKAP9–BRAF fusion is seen in up to 11% of cases associated w ith radiation exposure but is un com m on in sporadic papillar y can cers.8 Specific t ypes of PTC are associated w ith di eren t BRAF m utation s. Th e BRAF V600E m utation is seen m ost frequen tly in classical an d tall-cell varian ts of PTC an d th e BRAF K601E m utation is frequen tly seen in th e follicular varian t of PTC.9,10,11 An oth er im portan t alteration in PTC involves fusion of th e RET (rearran ged durin g tran sfection ) gen e w ith oth er part n er gen es. Th e RET gen e is a receptor t yrosin e kin ase, an d t ypically th e 3´ portion of RET en coding th e t yrosin e kin ase dom ain is involved in on cogen ic fu sion s w ith th e 5´ portion of partn er gen es.12,13 Several t ypes of RET rearran gem en ts, term ed RET/ PTC, h ave been described.14,15,16,17,18,19,20,21,22 Of th ese RET/PTC rearran gem en ts, th e m ost com m on t ypes are RET/PTC1 (w h ich is form ed by th e fusion of RET w ith CCDC6) an d RET/PTC3 (w h ich is form ed by th e fusion of RET w ith NCOA4).14,15 RET/PTC rearran gem en ts are foun d in approxim ately 10 to 20% of PTC cases.23,24 Tum ors carr yin g RET/PTC rearran gem en t are usually classic PTC, alth ough th ese rearran gem en ts h ave been observed in oth er varian ts of PTC.25,26,27 RET/PTC rearran gem en ts are t yp ically foun d m ore com m on ly in ch ildren an d youn g adults, an d in association w ith radiation exposure.28,29,30 Th e RAS gen es (HRAS, NRAS, an d KRAS) also play a role in PTC. RAS protein s are G protein s th at fun ct ion in sign alin g to th e MAPK an d PI3K path w ays. RAS m utation s are m ore t ypically associated w ith follicular can cers an d w ill be discussed in furth er detail later in th e ch apter, but RAS m utation s also accoun t for 10 to 20% of PTCs.31,32,33 RAS m utation s are seen alm ost exclusively in th e follicular varian t of PTC, in con trast to oth er m utation s, such as BRAF V600E, w h ich are rarely foun d in th is varian t of PTC.34 Rearran gem en ts involving th e NTRK gen es accoun t for up to 5% of PTCs. NTRK1 an d NTRK3 are m em bers of th e n eurotroph ic receptor t yrosin e kin ase fam ily of gen es, an d th eir fu sion s also act ivate th e MAPK sign alin g path w ay. To date, th ree fusion partn ers, TPM3, TPR, an d TFG, h ave been iden tified for NTRK1, an d on e fusion partn er, ETV6, h as been iden tified for NTRK3.35,36,37,38,39 Th ese rearran gem en ts m ay occur in h igh er frequen cies in patien ts w ith radiation exposure.8,39,40 Rearran gem en ts involving th e ALK gen e, particularly STRN-ALK, occur in approxim ately 1% of PTCs.41

10.2.2 Follicular Thyroid Tum ors Follicular thyroid carcin om as, in cluding th e conven tion al an d on cocyt ic (Hü rth le cell) t ypes, accoun t for 10 to 15% of thyroid can cers. Follicular thyroid aden om a is a ben ign t um or belon gin g to th is group. Poin t m utation s in RAS gen es (HRAS, NRAS, an d KRAS), w h ich typically occur in codon s 12, 13, an d 61, are foun d in 40 to 50% of follicular carcin om as an d in 20 to 40% of follicular aden om as.31,32,33 Of th e RAS gen es, th e m ost com m on ly m utated is NRAS codon 61, follow ed by HRAS codon 61, an d th en KRAS codon s 61 and 12/13. A recen t study of 204 thyroid n odules foun d th at n odules w ith KRAS codon 12/13 m utation h ad a low er risk of carcin om a (41.7%) th an n odules w ith NRAS codon 61 m utation (86.8% risk) or HRAS codon 61

m utation (95.5% risk), an d fu rth erm ore th at KRAS codon 12/13 m utation w as associated w ith on cocyt ic ch ange.42 An oth er im portan t alteration in follicular thyroid t um ors involves rearran gem en t of th e PAX8 an d PPARG gen es. PAX8 is a paired dom ain tran scription factor an d PPARG is a n uclear h orm on e receptor. Th e PAX8/PPARG rearran gem en t h as been reported in 30 to 40% of follicular carcin om as.43,44,45 Th is rearran gem en t is also presen t at low er frequen cies in on cocytic (Hü rth le) cell carcin om as, in th e follicular varian t of PTC, an d in follicular aden om as.43,44,45,46,47 Gen es involved in th e PI3K/AKT sign alin g path w ay h ave also been im plicated in follicular tum ors. Aberran t sign alin g of th e PI3K/AKT path w ay m ay be due to act ivation of upstream regulators, m ay result from activatin g m utation s in PIK3CA an d AKT1, or m ay result from in act ivation of PTEN, w h ich n egatively regulates th is path w ay. PIK3CA is a catalytic subun it of PI3Ks and is t ypically activated by m utation s in exon 9 an d exon 20. Mutation of PIK3CA h as been reported in 6 to 13% of follicular carcin om as.48,49,50 PTEN m utation m ay occur as germ lin e or som atic even ts; germ lin e PTEN m utation s can cause follicular tum ors in patien ts w ith PTEN h am artom a syn drom e, an d som atic PTEN m utation s can be seen in both follicular thyroid tum ors an d follicular aden om as.49,50,51,52,53

10.2.3 Poorly Di erent iat ed and Anaplast ic Thyroid Cancer Poorly di erentiated thyroid carcinom as are partially dedi erentiated cancers, w hereas anaplastic (undi erentiated) carcinom as lose entirely the phenotypical features of thyroid and even epithelial di erentiation. It is thought that m ost poorly di erentiated and anaplastic carcinom as arise via dedi erentiation of a w ell-di erentiated cancer. Both w ell-di erentiated and poorly/ undi erentiated com ponents are often seen in these tum ors, and both com ponents often share m utations in RAS or BRAF. RAS m utation s h ave been reported in 25 to 30% of poorly differen tiated carcin om as an d 40 to 50% of an aplastic carcin om as, w h ereas BRAF m utation h as been reported in 10 to 15% of poorly di eren tiated carcin om as an d 20 to 30% of an aplastic carcin om as. Poorly di eren tiated or an aplastic tum ors w ith RAS or BRAF m utation often h arbor oth er m utation s as w ell, w h ich contribute tow ard tum or dedi eren t iation . Th e m ost com m on addition al m utation s involve th e TP53 an d CTNNB1 gen es. TP53 is a t um or suppressor w ith roles in DNA repair, cell cycle regulation , an d apoptosis. Most m utation s in TP53 are poin t m utation s w ith in th e DNA bin din g dom ain . TP53 m utation s h ave been seen in 20 to 30% of poorly di eren tiated carcin om as an d 70 to 80% of an aplastic carcin om as.54,55,56,57,58 CTNNB1 (beta-caten in ) is a gen e involved in th e Wn t sign alin g path w ay. Typically, m utation s in CTNNB1 occur at ph osph or ylation sites, result in g in stabilization of th e protein an d in creased sign alin g. Mutation s in CTNNB1 h ave been reported in 25% of poorly di eren tiated carcin om as an d 60 to 70% of an aplastic carcin om as.59,60 ALK fusion s are foun d in 5 to 10% of th ese tum ors an d result in con stitu tive activation of ALK kin ase.41 Th e PI3K path w ay also plays a role in th ese tu m ors. Mutation s in PIK3CA h ave been obser ved in 10 to 20% of an aplastic carcin om as.48,49 In addition , on e study reported th e presen ce of AKT1 m utation in m etastatic poorly di eren tiated carcin om a.61

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Molecular Advances in t he Diagnosis and Treat m ent of Thyroid Cancer Recen tly, t w o m utation s in th e prom oter region of telom erase (TERT) h ave been described in thyroid can cer. Telom erase is a reverse tran scriptase th at fun ction s to m ain tain telom ere length an d is frequen tly expressed in tu m or cells.62 Th ese TERT prom oter m utation s, c.–124C> T (C228T) an d c.–146C> T (C250T), w ere first described in m elan om a an d w ere foun d to in crease prom oter activit y.63,64 In thyroid can cer, th ese m utation s w ere detected in follicular cell–derived thyroid can cers (but n ot in m edullary carcin om a), an d w ere presen t at th e h igh est frequen cy in poorly di eren tiated an d an aplastic carcin om as.65,66,67,68

10.2.4 Medullary Thyroid Cancer Medullar y thyroid carcin om a arises from C (parafollicular) cells an d accoun ts for approxim ately 3 to 4% of thyroid can cers.1 Th e m ajorit y of m edullar y carcin om as are sporadic, but m edullar y carcin om a m ay also arise in m ultip le en docrin e n eoplasia t ype 2A or 2B (MEN2A or MEN2B) syn drom e, or in fam ilial m edullar y thyroid carcin om a (FMTC). Medullar y carcin om as th at develop in th e con text of fam ilial syn drom es t ypically are m ulticen tric an d occur in youn ger patien ts. RET gen e m utation is com m on ly foun d in both fam ilial an d sporadic m edullary thyroid carcin om a. In cont rast to papillary thyroid can cer, w h ere th e 3´ port ion of th e RET gen e is activated via ch rom osom al rearran gem en t, in m edullar y thyroid carcin om as, RET is act ivated by poin t m utation . In sporadic m edullary carcin om as, th e m ost com m on m utation is RET M918 T.69,70 Th e M918 T m utation is located w ith in th e t yrosin e kin ase dom ain an d results in altered substrate specificit y.71 Th e M918 T m utation is also seen in > 90% of m edullary carcin om as arisin g in MEN2B syn drom e.70,72,73,74 In MEN2A an d FMTC, RET m utation s usually occur at cystein e residues in th e cystein e-rich extracellular dom ain . In MEN2A, th is com m on ly involves codon 634, w h ereas in FMTC, oth er cystein e residues can be involved.75,76 Mutation of a cystein e residue in th e extracellular dom ain con fers th e m utan t RET protein th e abilit y to un dergo ligan d-in depen den t dim erization w ith an oth er m utan t RET protein . More recen t studies h ave sh ow n th at RAS m utation s also occur in sporadic m edullar y thyroid carcin om as, an d are m utually exclusive w ith RET m utation s.77,78,79 HRAS an d KRAS m utation s occur in approxim ately 8% of th ese tum ors, w h ich ten d to beh ave less aggressively.78

10.2.5 Genet ic Alt erat ions in Hyperfunct ioning Thyroid Nodules Hyperfun ction in g (h ot) thyroid n odules, w h ich on h istopath ologic exam in ation m ay be diagn osed as follicular aden om as, hyperplast ic n odules, or, rarely, follicular carcin om as, often carr y m utation s in thyroid-stim ulatin g h orm on e receptor (TSHR) or GNAS. TSHR en codes a m em bran e receptor w h ose activit y is m ediated by G protein s. Activatin g m utation s in TSHR h ave been reported in 50 to 80% of n odules.80,81 Th ese m utation s are t ypically located in th e extracellular and tran sm em bran e dom ain s of TSHR. GNAS en codes an alph a subun it of h eterotrim eric G protein com plexes, an d th us fun ct ion s dow n stream of TSHR. Activatin g m utation s of GNAS, w h ich m ostly occur in codon s 201 an d 227, h ave been seen in 3 to 6% of

hyperfun ct ion in g n odules.82,83,84 Alth ough TSHR m utation s at specific h otspots m ay also be seen in thyroid carcin om as, in a lim ited series of cases, all n odules w ith GNAS m utation w ere ben ign .53 Th us GNAS m utation m ay be a un ique m arker of ben ign n odules.

10.2.6 Addit ional Molecular Alt erat ions in Thyroid Cancer m iRNA Expression in Thyroid Carcinom as A m icro RNA (m iRNA) is a sm all, n on codin g RNA th at fu n ct ion s in regulatin g gen e expression . m iRNAs bin d to th e 3´ un tran slated region of target m RNAs an d cause degradation or tran slation in h ibit ion . Several m iRNAs h ave been iden tified in m iRNA m icroarray studies an d foun d to be recurren tly up - or dow n regulated in thyroid carcin om a. In PTC, m any m iRNAs h ave been iden tified, but som e of th e best ch aracterized in clude m iR-187, -221, -222, an d -146b, w h ich h ave been foun d to be sign ifican tly overexpressed in tum or t issue in several studies.85,86,87,88 m iR-146b upregulation h as been associated w ith advan ced tum ors, extrathyroidal exten sion , an d poor progn osis.89,90 In follicular carcin om as, m iR-221, -222, an d -146b as w ell as m iR-182, -183, -96, -874, an d -449a w ere reported to be upregulated, an d m iR-542–5p, -574–3p, -455–3p, -455–5p, -199a-5p, -199a-3p, an d 125a-3p w ere dow n regulated.86,91,92,93 In terestin gly, di eren tial expression of m iR-885–5p w as observed betw een conven t ion al an d on cocyt ic follicular carcin om as.93 A n um ber of m iRNAs w ere foun d to be altered in poorly di eren tiated an d an aplastic thyroid carcin om as.86,94,95

Met hylat ion in Thyroid Carcinom as DNA m ethylat ion t ypically occurs on cytosin e residues in CpG islan ds (region s w ith a h igh occurren ce of CpG din ucleotides), w h ich t ypically are located in gen e prom oters. Hyperm ethylation of prom oters m ay result in silen cin g of t um or suppressor gen es, an d, conversely, hypom ethylation can result in in creased tran scription of on cogen es. In addition , hypom ethylat ion is th ough t to lead to ch rom osom e in stabilit y. In PTC, hyperm ethylat ion of several gen es h as been observed, in cluding tissue in h ibitor of m etalloprotein ases 3 (TIMP3), SLC5A8, death-associated protein kin ase 1 (DAPK1), an d TSHR.96,97,98,99 Methylat ion of th ese gen es w as observed in association w ith the BRAF V600E m utation .99 Th ese gen es fun ct ion in several cellular path w ays: DAPK1 is a calm odulin -depen den t serin e th reon in e kin ase w ith roles in apoptosis; SLC5A8 is an iodide, m on ocarboxylate, an d sh ort-ch ain fatt y acid t ran sporter; an d TSHR is thyroid-stim ulatin g h orm on e receptor. TIMP3 fun ction s by bin din g to th e m etalloprotein ase zin c cofactor, th ereby in act ivatin g m etalloprotein ase. Studies h ave suggested th at silen cin g of th e TIMP3 gen e an d the subsequen t loss of m etalloprotein ase in h ibition are associated w ith extrathyroidal invasion an d lym ph n ode m etastasis.99 In follicular thyroid t um ors, hyperm ethylation of gen es, in cluding PTEN an d RASSF1, h ave been reported.98,100,101,102 Alteration s of th e PI3K-AKT path w ay, in w h ich PTEN fun ct ion s, are com m on in follicular tu m ors. RASSF1 is a gen e related to th e RAS gen es an d h as roles in cell cycle regulation an d apoptosis.

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Thyroid Diseases PTEN an d RASSF1 hyperm ethylat ion h ave been seen in both follicular thyroid tum ors an d ben ign lesion s, such as follicular aden om as an d hyperplastic n odules.98,100,101,103 Altered DNA m ethylation pattern s h ave been seen in poorly di eren tiated an d an aplastic thyroid carcin om as as w ell. Som e eviden ce exists th at, com pared to w ell-di eren t iated thyroid carcin om as, an aplastic thyroid carcin om as ten d to h ave aberran t gen e prom oter hypom ethylat ion rath er th an hyperm ethylation .104

10.3 Ut ilit y of Molecular Test ing in Diagnosis, Managem ent , and Therapy 10.3.1 Molecular Diagnost ics in Indet erm inat e Cyt ology Thyroid Nodules Th e diagn osis of thyroid can cer th rough th e use of ultrasoun d exam in ation an d cytological exam in ation of cells obtain ed by fin e-n eedle aspiration (FNA) t ypically diagnoses th e m ajorit y of thyroid n odules as ben ign or m align an t .105,106 How ever, in approxim ately 20 to 30% of n odules, cytological analysis of th e cells results in an in determ in ate classificat ion .107,108 Th ese in determ in ate categories in clude at ypia of un determ in ed sign ifican ce or follicular lesion of un determ in ed sign ifican ce (AUS/ FLUS) (Beth esda categor y III), follicular n eoplasm or suspicious for a follicular n eoplasm (FN/SFN) (Beth esda categor y IV), an d suspicious for m align an cy (SUSP) (Beth esda category V).107,109 Th e risk of m align an cy is 5 to 15% in th e AUS/FLUS category; 15 to 30% in th e FN/SFN category, an d 60 to 75% in th e SUSP category.109 How ever, on surgical resection , on ly 10 to 40% of in determ in ate n odules are m align an t.105,110,111 Molecular testin g of in determ in ate cytology thyroid n odules o ers th e abilit y to correctly iden tify an d diagnose m align an cies, in cludin g low -grade m align an cies, an d to classify m align an cies based on likelih ood of progression or aggressive beh avior. In evaluatin g th e utilit y of any test, com parison s of sen sitivit y, specificit y, positive predictive value (PPV), an d n egative predictive value (NPV) are im portan t . A test th at is useful to rule out m align an cy sh ould h ave a h igh sen sitivit y (percen tage of correctly iden tified positives) an d a h igh NPV (percen tage of patien ts w ith a n egative test result w h o do n ot h ave th e disease). To rule in m align an cy, a test w ith h igh specificit y (percen tage of correctly iden tified n egatives) an d h igh PPV (percen tage of pat ien ts w ith a positive test result w h o h ave th e disease) sh ould be used. It is im portan t to n ote th at, w h ile sen sitivit y an d specificit y of a test reflect test perform an ce, NPV and PPV can var y based on th e prevalen ce (or pretest probabilit y) of m align an cy. In clin ical practice, prevalen ce of m align an cy m ay ch ange n ot on ly based on th e patien t population but also by in stit ut ion al variation s in m align an cy rates conferred by each cytological diagnosis.

Approaches t o Molecular Test ing Many di eren t diagn ostic tools h ave been used in in determ in ate cytology thyroid n odules in an attem pt to better classify th ese n odules. Th ese diagnost ic tools w ere developed based on

kn ow ledge accum ulated about m ech an ism s un derlying thyroid tum origen esis an d in clude im m un oh istochem ical m arkers, m iRNAs, gen e m utation s/rearran gem en ts, an d gen e expression m arkers.105,106,111,112 Alth ough all of th ese tools h ave been sh ow n to h ave ut ilit y as diagn ostic m arkers, th e t w o t ypes of m olecular m arkers curren tly bein g used in clinical pract ice are gen e m utation s/rearran gem en ts an d gen e expression m arkers, an d w ill be discussed in fu rth er detail. Gen e m utation /rearran gem en t testin g is bein g o ered in in stit ut ion s an d com m ercial laboratories as single-gen e testin g or pan el testin g, an d a gen e expression pan el is curren tly o ered com m ercially.

Gene Mutation/Rearrangem ent Test ing Th e m olecular gen etics of thyroid t um ors are ver y w ell ch aracterized, w ith m any m utation s an d rearran gem en ts th at are specific for m align an cy. Th e sin gle gen e m utation BRAF V600E is sp ecific an d h as a h igh PPV for m align an cy, an d t est in g for t h is m u t ation h as been sh ow n t o in crease t h e sen sit ivit y of FNA biop sies.111,113,114 Mu t at ion s in t h e RAS gen es h ave a low er PPV for m align an cy of 74 to 87%.110,115,116 Th is is d u e t o t h e occu rren ce of RAS m u t at ion s in ben ign follicu lar ad en om as. How ever, alth ough follicu lar ad en om as are ben ign , som e stu d ies h ave fou n d evid en ce t h at RAS m u tat ion s in follicu lar ad en om as are p recan cerou s ch anges th at m ay p rogress t o m align an cy.117,118,119,120 In creased sen sitivit y an d specificit y from sin gle-gen e testin g can be ach ieved by usin g m ultigen e pan els. A m ultigen e pan el consistin g of th e seven (or eigh t) m ost com m on ly altered gen es (BRAF, KRAS, HRAS, NRAS, PAX8/PPARG, RET/PTC1, RET/PTC3 [and TRK rearran gem en t]) h as been dem on strated to provide h igh specificit y an d PPV for can cer detect ion in th ree prospective studies.114,118,119 With th e seven gen e pan el for m olecular testin g, h igh NPV (94%) w as ach ieved for AUS/FLUS cytology n odules; th ough low er NPV w as seen in FN/SFN an d SUSP n odules.110 Advan ces in tech n ology h ave m ade it possible to test for m ore gen e m utation s usin g th e lim ited am oun t of DNA available in FNA biopsy specim en s. Next-gen eration sequen cing (NGS) platform s allow h igh -th rough put, m assively parallel n ucleic acid sequen cing, an d h igh ly sen sitive an d quan titative assessm en t of th e m utan t allele ( Fig. 10.2). NGS h as been in creasin gly in tegrated in to clin ical use for m olecular testin g as an e cien t an d cost-e ective w ay of an alyzin g m ultiple gen es in on e react ion ( Fig. 10.3). Expan ded diagn ostic pan els are expected to furth er in crease sen sitivit y an d NPV, as w as sh ow n in a recen t report of an NGS thyroid gen e m utation pan el th at in cluded > 60 gen es an d gen e fusion s.121 Th is pan el expan ded from th e previously described seven -gen e pan el to also test for m utation s in h otspots of RET, GNAS, TSHR, CTNNB1, TP53, AKT1, PTEN, PIK3CA, an d TERT, an d 42 t ypes of rearran gem en ts involving RET, BRAF, PPARG, NTRK1, NTRK3, ALK, an d THADA. In FN/SFN cytology thyroid n odules, th e 60-gen e pan el sh ow ed h igh sen sitivit y (90%), specificit y (93%), PPV (83%), an d NPV (96%) for can cer detect ion .121 An addition al advan tage of NGS-based m utation al an alysis is th e abilit y to detect th e presen ce of m ultiple m utation s. Alth ough th e m ajorit y of thyroid n odules w ith m utation s h ave only a sin gle m olecular alteration , in a sm all n um ber of cases, m ultiple m utation s m ay be presen t.121,122 Th us iden tification of

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Fig. 10.2 Quantitative detection of a BRAF V600E m utation by next-generation sequencing. View of sequence alignm ents in the Integrative Genom ics Viewer (IGV) (Broad Institute) showing m utant sequencing reads (arrows) in a sam ple obtained by thyroid fine-needle aspiration.

m olecular alteration s can be useful diagnostically, but fin din g m ultiple m utation s in a thyroid n odule m ay h ave progn ost ic im plication s as w ell an d w ill be discussed in furth er detail.

Gene Expression Markers A gen e expression pan el is curren tly bein g com m ercially o ered as Afirm a (Veracyte). Usin g m RNA expression profiles of a proprietary set of 142 gen es, in determ in ate thyroid n odules are classified in to eith er a ben ign or a suspicious category.123 In an in dustr y-spon sored, m ulti-in stit ution al, prospective, doubleblin d study, th is gen e expression classifier w as foun d to dem on strate a h igh NPV in AUS/FLUS (95%), FN/SFN (94%), an d SUSP (85%) cytology n odules.105 How ever, th e PPV in all in determ in ate cytology categories w as low er, reported as 38% in AUS/ FLUS n odules, 37% in FN/SFN n odules, an d 76% in SUSP n odules.105 A recen t sm aller, in depen den t study usin g th e Afirm a gen e expression classifier in AUS/FLUS an d FN n odules foun d a sign ifican tly low er PPV of 16%.124 As w ith all tests, th e NPV of th e gen e expression classifier w ill vary w ith disease prevalen ce. In th e origin al validation study, th e disease prevalen ce w as 24% in AUS/FLUS n odules, 25% in FN/SFN n odules, an d 62% in SUSP n odules.105 In a separate study in w h ich th e disease prevalen ce in in determ in ate n odules

(AUS/FLUS an d FN/SFN) w as 33%, th e NPV w as foun d to be 89.6%.125

10.3.2 Molecular Diagnost ics and Managem ent of Thyroid Nodules and Tum ors Typically, pat ien ts w ith AUS/FLUS n odules un dergo a repeat FNA, w h ereas surgical lobectom y is recom m en ded for patien ts w ith FN/SFN n odules, an d total thyroidectom y is recom m en ded for patien ts w ith SUSP n odules.109,126 According to Am erican Thyroid Association guidelin es, m olecular m arkers m ay be con sidered for patien ts w ith in determ in ate n odules to h elp guide m an agem en t.126 A n egative result in m olecular tests w ith a h igh NPV, for exam ple, th e 60-gen e pan el or Afirm a gen e expression classifier, reduces th e risk of m align an cy to levels sim ilar to th e risk of a n odule w ith ben ign cytology.105,121 Th us th ese patien ts m ay be able to avoid un n ecessary surgery. Alth ough m ost diagnost ic lobectom ies are perform ed for ben ign thyroid n odules, in 10 to 40% of cases, th e n odule is foun d to be m align an t.105,127,128 If a patien t w h o h as un dergon e surgical lobectom y h as a t um or > 1 cm in size, a com pletion thyroidectom y is usually perform ed. In th ese cases, preoperative

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Fig. 10.3 Progress in composition of m ultigene m utational panels. A seven-gene panel developed in 2007 covered m utations and rearrangements accounting for 65% of thyroid tum ors; by 2013 with new genes identified and the availabilit y of next-generation sequencing technologies, a 15-gene panel was developed to encom pass m utations in approxim ately 80% of thyroid tum ors. By 2014, further advances in knowledge and technology allowed the m olecular testing of 60 gene mutations and rearrangem ents, involved in 91% of thyroid tum ors.

m olecular testin g usin g a m olecular test w ith h igh PPV could be ben eficial in reducin g th e n eed for a t w o-step surgery. Gen e m utation pan els h ave been consisten tly sh ow n to h ave h igh specificit y an d h igh PPV.110,115,116,121 A positive result in a gen e m utation pan el (w ith th e possible exception of gen es th at m ay be m utated in ben ign lesion s, such as RAS or TSHR), w ould be an in dication for a total thyroidectom y rath er th an an in itial lobectom y follow ed by a com pletion lobectom y. Use of a seven gen e m utation pan el w as recen tly reported to be e ect ive in reducin g th e n um ber of t w o-step surgeries.129 In th is study of a series of 471 in determ in ate n odules, th e auth ors foun d th at patien ts w h o did n ot un dergo gen e m utation m arker testin g w ere 2.5-fold m ore likely to n eed a t w o-step surgery.129 In pediatric patien ts, w h ere in determ in ate cytology n odules m ay accoun t for up to 38% of n odules, sim ilar results w ere seen .130 In a sm all series of cases, gen e m utation pan el testin g w as used to guide surgical m an agem en t an d preven t t w o-step surgeries in 60% of cases.127 Molecular m arkers can also provide valuable progn ostic in form ation . Patien ts w ith m olecular alteration s ch aracteristic of aggressive tum ors could poten tially ben efit from a m ore exten sive in itial resection th at in cludes cen tral com partm en t lym ph n ode dissection , as w ell as close clin ical follow -up postsurgery. Th e BRAF V600E m utation w as on e of th e first m utation s studied as a m olecular m arker for aggressive tu m ors, an d testin g of FNA biopsies for th e BRAF V600E m utation h as been show n to h ave ut ilit y in preoperative risk stratification .128 Many studies h ave exam in ed th e association of th e BRAF V600E m utation w ith aggressive tum or features, such as extrathyroidal invasion , lym ph n ode m etastasis, an d t um or recurren ce. A m eta-an alysis of th ese studies foun d th at th e presen ce of th e BRAF V600E m utation w as sign ifican tly associated w ith tum or recurren ce or persisten t disease (25% of BRAF V600E–positive tum ors vs. 13% of BRAF V600E–n egative tum ors).131 Th e presen ce of th e BRAF V600E m utation in papillary thyroid carcin om as h as also been sh ow n to be associated w ith a sm all but

significantly increased risk of m ortality (5% of BRAF V600E–positive tum ors vs. 1% of BRAF V600E–negative tum ors).132 Thus BRAF V600E–positive tum ors tend to show m ore aggressive features and have increased risk of recurrence and m ortality. However, m ost BRAF V600E tum ors w ill not recur, and overall survival rem ains high in patients regardless of BRAF m utational status. These findings suggest that use of the BRAF V600E m utation alone is not specific as a m arker of aggressive tum or behavior. TP53 is an im portan t tum or suppressor w ith roles in cell cycle regulation an d apoptosis. Mutation of TP53 frequen tly occurs in poorly di eren tiated an d an aplastic thyroid can cer an d is an im portan t even t in thyroid tu m or dedi eren t iation .54,55 Th us th e presen ce of TP53 m utation suggests an aggressive tu m or. How ever, TP53 m utation s h ave also been reported in som e w ell-di eren t iated carcin om as; th us th e specificit y of TP53 m utation for aggressive t um ors sh ould be ch aracterized furth er.53 More recent studies have suggested that, rather than the presence of a single genetic alteration, the presence of m ultiple driver m utations m ay be a m ore specific m arker of aggressive tum or behavior. Coexisting m utations in early driver genes, such as BRAF or RAS, along w ith m utation in genes such as PIK3CA, AKT1, or TP53, w hose m utation is thought to be a late event, have been reported in poorly di erentiated and anaplastic carcinom as.48,49,133 New er genetic panels, run on NGS platform s, are ideally suited to interrogate tum ors for the presence of m ultiple m utations. In one reported NGS-based analysis, 4% of thyroid carcinom as had m ore than one m utation, and these tum ors w ith m ultiple m utations tended to display aggressive features.53 An oth er prom ising progn ostic m olecular m arker is m utation of th e TERT prom oter region at c.–124C> T (C228T) or c.– 146C> T (C250T). Th ese m utation s h ave been reported in 7 to 22% of w ell-di eren t iated papillar y an d follicular carcin om as, but th ey occur at a h igh er frequen cy (29–52%) in poorly di eren t iated an d an aplastic thyroid carcin om as.65,66,67,68 TERT prom oter m utation s w ere foun d to be associated w ith persisten t disease, m etastatic disease, an d in creased m ortalit y.68 An association of TERT prom oter m utation s w ith th e presen ce of th e BRAF V600E m utation h as also been observed in som e studies, suggestin g an in terplay betw een both gen es th at m ay con trib ute tow ard aggressive t um or beh avior.65,67 Fin ally, m utation s in RET detected in a thyroid n odule m ay be usefu l as an in dication for germ lin e testin g. Specific m utation s in RET are ch aracteristic of patien ts w ith fam ilial form s of m edullar y thyroid carcin om a; for exam ple, in MEN2A, 90% of m utation s occur at codon 634.70,74,75 Kn ow ledge of germ lin e RET m utation s h as im plication s for in traoperative m an agem en t of parathyroid glan ds, for sur veillan ce an d m an agem en t of oth er tum ors, an d for screen in g an d prophylactic thyroidectom y of fam ily m em bers.69 For PTEN, m utation s m ay be seen in both ben ign an d m align an t n odules, an d m any di eren t m utation s in PTEN h ave been reported for PTEN h am artom a syn drom e.49,50,51,52,53 Th us detect ion of PTEN m utation in a n odule w ould n ot n ecessarily be an in dication for germ lin e testin g un less th ere w as an appropriate clin ical con text.

10.3.3 Molecular Diagnost ics and Target ed Therapy For m ost w ell-di eren tiated thyroid tu m ors, surgical resection is th e prim ar y th erapy. How ever, in advan ced disease thyroid

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Molecular Advances in t he Diagnosis and Treat m ent of Thyroid Cancer kin ase in h ibitor), an d sun itin ib (a m ulti–t yrosin e kin ase in h ibitor).136,137,138 Crizotin ib an d oth er ALK in h ibitors m ay be explored in patien ts w ith advan ced thyroid can cer positive for STRN-ALK or oth er ALK fusion s.41,139,140 In advan ced m edullary can cer, t w o FDA-approved targeted th erapies are available: van detan ib an d cabozan tin ib. Th ese are m ulti–t yrosin e kin ase in h ibitors w ith activit y again st RET. Both van detan ib an d cabozan tin ib th erapy w ere sh ow n in ph ase 3 trials to sign ifican tly im prove progression -free sur vival over placebo-treated patien ts.141,142

10.4 Conclusion

Fig. 10.4 Thyroid tumor therapies target components of the MAPK and PI3K/AKT pathway. Therapeutics acting on receptor t yrosine kinases include vandetanib and cabozantinib, which are m ulti–t yrosine kinase inhibitors with activit y against RET that are FDA approved in the treatment of advanced m edullary thyroid cancer, sorafenib (a m ulti– t yrosine kinase inhibitor), which is FDA approved for the treatm ent of progressive differentiated thyroid carcinom a refractory to radioactive iodine treatm ent, as well as other t yrosine kinase inhibitors currently under investigation, including pazopanib and sunitinib. Other targeted therapeutics that have shown promising results in clinical trials target BRAF (vem urafenib and dabrafenib), or inhibit MEK (tram etinib and selum etinib).

tum ors m ay h ave distan t m etastases, m ay be in operable, or m ay be refractor y to radioactive iodin e th erapy. For th ese patien ts, lim ited th erapeutic option s are available. Advan ces in our un derstan din g of th e gen etic ch anges un derlyin g m ost thyroid can cers h as iden tified poten t ial targets for th erapy. Th erapies curren tly available as w ell as th ose un der investigation target com pon en ts of th e MAPK an d PI3K/AKT path w ays, w h ich are act ivated in m ost thyroid tum ors ( Fig. 10.4). Th e FDA recen tly approved sorafen ib (a m ulti-t yrosin e kin ase in h ibitor) for th e treatm en t of locally recurren t or m etastatic, progressive di eren tiated thyroid carcin om a refractory to radioact ive iodin e t reatm en t. In a ran dom ized, double-blin d, m ulticen ter, ph ase 3 trial, sorafen ib w as sh ow n to sign ifican tly in crease progression -free sur vival over placebo.134 Several oth er poten t ial th erapies are curren tly bein g investigated for di eren t iated thyroid can cers. Vem urafen ib an d dabrafenib are BRAF in h ibitors th at are FDA approved for th e treatm en t of m etastatic m elan om a. A ph ase 1 trial of vem urafen ib in patien ts w ith m etastatic papillary thyroid can cer h as sh ow n prom ising results.135 Curren t ph ase 2 trials are un der w ay exam in ing th e e ect of vem urafen ib an d dabrafen ib (w ith or w ith out th e MEK in h ibitor tram etin ib). Oth er th erapies th at h ave sh ow n prom isin g results in ph ase 2 trials of di eren tiated thyroid can cers in clude selum etin ib (a MEK in h ibitor), pazopan ib (a t yrosin e

Most of th e gen etic alteration s un derlying thyroid can cer involve dysregulation of th e MAPK or PI3K/AKT path w ays. As of today, gen etic ch anges in > 90% of thyroid can cers h ave been iden tified. Elucidation of th e gen etic m ech an ism s of can cer developm en t h as led to m any pract ical application s. Molecular diagn ostics are in creasin gly bein g in corporated in to routin e clin ical care to guide diagn osis, surgical m an agem en t, an d th erapy. Future advan ces w ill be th rough im proved sequen cing tech n ology. NGS-based testin g of expan ded pan els of gen es h as been sh ow n to sign ifican tly im prove th e sen sitivit y an d specificit y in th e diagnosis of thyroid can cer from th e lim ited sam ples obtain ed by FNA biopsy. As th e tech n ology im proves an d costs of testin g decrease, routin e use of th ese tools w ill allow m ore detailed ch aracterization of th e m olecular profiles of thyroid tum ors. Each m olecular profile w ill likely be associated w ith di eren t risks of tum or progression , recurren ce, or m or talit y, an d w ill likely require specific surgical m an agem en t or th erapy. Th us in corporation of m olecular fin din gs w ill be essen tial in o erin g th e patien t w ith a thyroid n odule t ruly person alized m edical care.

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Gen es Can cer 2011; 2(1); 46–55 [92] Weber F, Teresi RE, Broelsch CE, Frilling A, Eng C. A lim ited set of h um an MicroRNA is deregulated in follicular thyroid carcinom a. J Clin En docrin ol Metab 2006; 91(9); 3584–3591 [93] Dettm er M, Vogetseder A, Durso MB, et al. MicroRNA expression array iden tifies n ovel diagn ostic m arkers for conven tion al an d on cocytic follicular thyroid carcin om as. J Clin En docrin ol Metab 2013; 98(1); E1–E7 [94] Braun J, Hoan g-Vu C, Dralle H, Hü ttelm aier S. Dow n regulation of m icroRNAs directs th e EMT an d invasive poten tial of an aplastic thyroid carcin om as. On cogen e 2010; 29(29); 4237–4244 [95] Dettm er MS, Perren A, Moch H, Kom m in oth P, Nikiforov YE, Nikiforova MN. MicroRNA profile of poorly di eren tiated thyroid carcinom as: n ew diagn ostic an d progn ostic in sigh ts. J Mol En docrin ol 2014; 52(2); 181–189 [96] Xin g M, Usadel H, Coh en Y, et al. Methylation of th e thyroid-stim ulating h orm on e receptor gene in epith elial thyroid tum ors: a m arker of m align an cy an d a cause of gene silen cing. Can cer Res 2003; 63(9); 2316–2321 [97] Porra V, Ferraro-Peyret C, Duran d C, et al. Silen cin g of th e tum or suppressor gen e SLC5A8 is associated w ith BRAF m utation s in classical papillar y thyroid carcinom as. J Clin En docrin ol Metab 2005; 90(5); 3028–3035 [98] Hoque MO, Rosen baum E, Westra WH, et al. Quan titative assessm en t of prom oter m ethylation profiles in thyroid n eoplasm s. J Clin En docrin ol Metab 2005; 90(7); 4011–4018 [99] Hu S, Liu D, Tufan o RP, et al. Association of aberran t m ethylation of tum or suppressor genes w ith tum or aggressiven ess an d BRAF m utation in papillary thyroid can cer. In t J Can cer 2006; 119(10); 2322–2329 [100] Alvarez-Nuñ ez F, Bussaglia E, Mauricio D, et al. Thyroid Neoplasia Study Group. PTEN prom oter m ethylation in sporadic thyroid carcinom as. Thyroid 2006; 16(1); 17–23 [101] Hou P, Ji M, Xin g M. Association of PTEN gen e m ethylation w ith gen etic alteration s in th e ph osph atidylinositol 3-kin ase/AKT sign alin g path w ay in thyroid tum ors. Can cer 2008; 113(9); 2440–2447 [102] Pfeifer GP, Dam m an n R. Methylation of th e tum or suppressor gene RASSF1A in h um an tum ors. Bioch em istr y (Mosc) 2005; 70(5); 576–583 [103] Brow n TC, Juh lin CC, Healy JM, Prasad ML, Korah R, Carling T. Frequen t silen cin g of RASSF1A via prom oter m ethylation in follicular thyroid hyperplasia: a poten tial early epigenetic susceptibilit y even t in thyroid carcin ogen esis. JAMA Surg 2014; 149(11); 1146–1152 [104] Rodríguez-Rodero S, Fern án dez AF, Fern án dez-Morera JL, et al. DNA m ethylation sign atures iden tify biologically distin ct thyroid can cer subtypes. J Clin En docrin ol Metab 2013; 98(7); 2811–2821 [105] Alexan der EK, Ken n edy GC, Baloch ZW , et al. 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Thyroid Diseases [107] Baloch ZW . LiVolsi VA, Asa SL, et al. Diagn ostic term in ology an d m orph ologic criteria for cytologic diagn osis of thyroid lesion s: a syn opsis of th e Nation al Can cer In stitu te Th yroid Fin e-Needle Aspiration State of th e Scien ce Con feren ce. Diagn Cytopath ol. Jun 2008;36(6):425–437 [108] Oh ori NP, Sch oedel KE. Variability in th e atypia of un determ in ed sign ifican ce/ follicular lesion of un determ in ed sign ifican ce diagn osis in th e Beth esda System for Reportin g Th yroid Cytopath ology: sources an d recom m en dation s. Acta Cytol 2011; 55(6); 492–498 [109] Ali SZ, Cibas ES. Th e Beth esda System for Reportin g Thyroid Cytopath ology. New York: Sprin ger; 2010 [110] Nikiforov YE, Oh ori NP, Hodak SP, et al. Im pact of m utation al testin g on th e diagn osis an d m an agem en t of patien ts w ith cytologically in determ in ate thyroid n odules: a prospective an alysis of 1056 FNA sam ples. J Clin En docrin ol Metab 2011; 96(11); 3390–3397 [111] Kim SW, Lee JI, Kim JW, et al. BRAFV600E m utation an alysis in fin e-n eedle aspiration cytology specim ens for evaluation of thyroid n odule: a large series in a BRAFV600E-prevalen t population . J Clin En docrin ol Metab 2010; 95(8); 3693–3700 [112] Keutgen XM, Filicori F, Crow ley MJ, et al. A pan el of four m iRNAs accurately di eren tiates m align an t from ben ign in determ in ate thyroid lesion s on fin e n eedle aspiration . Clin Can cer Res 2012; 18(7); 2032–2038 [113] Zatelli MC, Trasforin i G, Leon i S, et al. BRAF V600E m utation an alysis in creases diagn ostic accuracy for papillar y thyroid carcinom a in fin e-n eedle aspiration biopsies. Eur J En docrin ol 2009; 161(3); 467–473 [114] March etti I, Lessi F, Mazzan ti CM, et al. A m orph o-m olecular diagn osis of pap illar y thyroid carcinom a: BRAF V600E detect ion as an im portan t tool in preoperative evaluation of fin e-n eedle aspirates. Thyroid 2009; 19(8); 837–842 [115] Can tara S, Capezzon e M, March isotta S, et al. Im pact of proto-on cogen e m utation detect ion in cytological specim ens from thyroid n odules im proves th e diagn ostic accuracy of cytology. J Clin En docrin ol Metab 2010; 95(3); 1365– 1369 [116] Nikiforov YE, Stew ard DL, Robin son -Sm ith TM, et al. Molecular testin g for m utation s in im provin g th e fin e-n eedle aspiration diagn osis of thyroid n odules. J Clin En docrin ol Metab 2009; 94(6); 2092–2098 [117] Burn s JS, Blaydes JP, Wrigh t PA, et al. Stepw ise tran sform ation of prim ar y thyroid epith elial cells by a m utan t Ha-ras on cogen e: an in vitro m odel of tum or progression . Mol Carcin og 1992; 6(2); 129–139 [118] Fagin JA. Min ireview : bran ded from th e start-distin ct on cogen ic in itiatin g even ts m ay determ in e tum or fate in th e thyroid. Mol En docrin ol 2002; 16(5); 903–911 [119] Nikiforov YE, Oh ori NP. Follicular carcin om a. In : Nikiforov YE, Biddinger PW , Th om pson LDR, eds. Diagn ostic path ology an d m olecular gen etics of th e thyroid. 2n d ed. Ph iladelph ia: Lippin cott W illiam s & W ilkin s; 2012:152–182 [120] Zh u Z, Gan dh i M, Nikiforova MN, Fisch er AH, Nikiforov YE. Molecular profile an d clin ical-path ologic features of th e follicular varian t of papillary thyroid carcinom a. An un usually h igh prevalen ce of ras m utation s. Am J Clin Path ol 2003; 120(1); 71–77 [121] Nikiforov YE, Cart y SE, Ch iosea SI, et al. High ly accurate diagn osis of can cer in thyroid n odules w ith follicular n eoplasm /suspicious for a follicular n eoplasm cytology by ThyroSeq v2 n ext-gen eration sequen cin g assay. Can cer 2014; 120(23); 3627–3634 [122] Dettm er M, Perren A, Moch H, Kom m in oth P, Nikiforov YE, Nikiforova MN. Com preh en sive MicroRNA expression profilin g iden tifies n ovel m arkers in follicular varian t of papillar y thyroid carcin om a. Thyroid 2013; 23(11); 1383–1389 [123] Ch udova D, W ilde JI, Wan g ET, et al. Molecular classification of thyroid n odules usin g h igh -dim en sionalit y gen om ic data. J Clin En docrin ol Metab 2010; 95(12); 5296–5304 [124] McIver B, Castro MR, Morris JC, et al. An in depen den t study of a gene expression classifier (Afirm a) in th e evaluation of cytologically in determ in ate thyroid n odules. J Clin En docrin ol Metab 2014; 99(11); 4069–4077

[125] Harrell RM, Bim ston DN. Surgical Utilit y of Afirm a: E ects of High Can cer Prevalen ce an d On cocytic Cell Types in Patien ts w ith In determ in ate Thyroid Cytology. En docr Pract 2013; 20(4); 1–16 [126] Cooper DS, Doh erty GM, Haugen BR, et al. Am erican Thyroid Association (ATA) Guidelin es Taskforce on Thyroid Nodules an d Di eren tiated Thyroid Can cer. Revised Am erican Thyroid Association m an agem en t guidelin es for patien ts w ith thyroid n odules an d di eren tiated thyroid can cer. Thyroid 2009; 19(11); 1167–1214 [127] Bur yk MA, Mon aco SE, W itch el SF, et al. Preoperative cytology w ith m olecular an alysis to h elp guide surgery for pediatric thyroid n odules. In t J Pediatr Otorh in olar yn gol 2013; 77(10); 1697–1700 [128] Xin g M, Clark D, Guan H, et al. BRAF m utation testin g of thyroid fin e-n eedle aspiration biopsy specim ens for preoperative risk stratification in papillary thyroid can cer. J Clin On col 2009; 27(18); 2977–2982 [129] Yip L, W h arr y LI, Arm stron g MJ, et al. A clin ical algorith m for fin e-n eedle aspiration m olecular testin g e ect ively guides th e appropriate exten t of in itial thyroidectom y. An n Surg 2014; 260(1); 163–168 [130] Mon aco SE, Pantan ow itz L, Kh albuss W E, et al. Cytom orph ological an d m olecular genetic fin din gs in pediatric thyroid fin e-n eedle aspiration . Can cer Cytopath ol 2012; 120(5); 342–350 [131] Tufan o RP, Teixeira GV, Bish op J, Carson KA, Xin g M. BRAF m utation in papillar y thyroid can cer an d its value in tailorin g in itial treatm en t: a system atic review an d m eta-analysis. Medicin e (Baltim ore) 2012; 91(5); 274–286 [132] Xin g M, Alzah ran i AS, Carson KA, et al. Association betw een BRAF V600E m utation an d m ortalit y in patien ts w ith papillar y thyroid can cer. JAMA 2013; 309(14); 1493–1501 [133] Liu Z, Hou P, Ji M, et al. High ly prevalen t genetic alteration s in receptor t yrosin e kin ases an d ph osph atidylin ositol 3-kin ase/akt an d m itogen -activated protein kin ase path ways in an aplastic an d follicular thyroid can cers. J Clin En docrin ol Metab 2008; 93(8); 3106–3116 [134] Brose MS, Nuttin g CM, Jarzab B, et al. DECISION investigators. Sorafen ib in radioactive iodin e-refractor y, locally advan ced or m etastatic di eren tiated thyroid can cer: a ran dom ised, double-blin d, ph ase 3 trial. Lan cet 2014; 384 (9940); 319–328 [135] Kim KB, Caban illas ME, Lazar AJ, et al. Clin ical respon ses to vem urafen ib in patien ts w ith m etastatic papillary thyroid can cer h arborin g BRAF(V600E) m utation . Thyroid 2013; 23(10); 1277–1283 [136] Carr LL, Man ko DA, Goulart BH, et al. Ph ase II study of daily sun itin ib in FDG-PET-positive, iodin e-refractor y di eren tiated thyroid can cer an d m etastatic m edullary carcinom a of th e thyroid w ith fun ct ion al im agin g correlation . Clin Can cer Res 2010; 16(21); 5260–5268 [137] Bible KC, Sum an VJ, Molin a JR, et al. En docrin e Malign an cies Disease Orien ted Group. Mayo Clin ic Can cer Cen ter. Mayo Ph ase 2 Con sort ium . E cacy of pazopan ib in progressive, radioiodin e-refractor y, m etastatic di eren tiated thyroid can cers: results of a ph ase 2 con sortium study. Lan cet On col 2010; 11 (10); 962–972 [138] Hayes DN, Lucas AS, Tanvetyanon T, et al. Ph ase II e cacy an d ph arm acogen om ic study of Selum etin ib (AZD6244; ARRY-142886) in iodin e-131 refractory papillar y thyroid carcinom a w ith or w ith out follicular elem en ts. Clin Can cer Res 2012; 18(7); 2056–2065 [139] Pérot G, Soubeyran I, Ribeiro A, et al. Iden tification of a recurren t STRN/ALK fusion in thyroid carcin om as. PLoS ONE 2014; 9(1); e87170 [140] Dem eure MJ, Aziz M, Rosen berg R, Gurley SD, Bussey KJ, Carpten JD. W h olegen om e sequen cing of an aggressive BRAF w ild-type papillar y thyroid can cer iden tified EML4-ALK tran slocation as a th erapeutic target. World J Surg 2014; 38(6); 1296–1305 [141] Elisei R, Schlum berger MJ, Mü ller SP, et al. Cabozan tin ib in progressive m edullar y thyroid can cer. J Clin On col 2013; 31(29); 3639–3646 [142] Wells SA, Jr, Robin son BG, Gagel RF, et al. Van detan ib in patien ts w ith locally advan ced or m etastatic m edullar y thyroid can cer: a ran dom ized, doubleblin d ph ase III trial. J Clin On col 2012; 30(2); 134–141

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Medical Managem ent of Aggressive Di erentiat ed Thyroid Cancer

11 Medical Managem ent of Aggressive Di erent iat ed Thyroid Cancer Sara Ahmadi and R. Michael Tuttle

11.1 Int roduct ion Alth ough patien ts w ith thyroid can cer presen t w ith eith er in term ediate- or low -risk disease th at is ver y e ectively treated w ith thyroid surgery (w ith or w ith out th e addition of radioactive iodin e [RAI]), as m any as 10 to 15% of patien ts h ave advan ced disease th at is m an ifest eith er by distan t m etastases or locally aggressive disease. Distan t m etastases can occur durin g follow -up in 6 to 20% of patien ts w ith thyroid can cer an d can be seen in 3 to 15% of patien ts at th eir presen tation .1,2,3,4,5,6,7,8,9 In locally advan ced disease, th e prim ar y clin ical m an agem en t issues relate to invasion of m ajor cervical structures (vessels, esophagus, trach ea, lar yn x, recurren t laryn geal n er ves). In distan t m etastases, th e m an agem en t issues are often related to local com pressive sym ptom s if m etastatic foci are located n ear (or in ) m ajor n eurovascular struct ures or th e aerodigestive t ract , or as an im pen din g (or act ual) path ological bon e fract ure. Alth ough advan ced disease can m an ifest eith er at th e t im e of in itial presen tation or durin g follow -up, th e basic m an agem en t prin ciples rem ain th e sam e. Man agem en t of advan ced disease is ideally un dertaken in th e con text of a fun ction al, in tegrated team , because the care of th ese patien ts usually requires com plex decision m akin g an d a w ide array of poten t ial th erapies. Treat m en t option s for advan ced disease can be divided in to localized th erapies directed tow ard on e or m ore in dividual tum or foci or system ic th erapies design ed to treat m ore w idespread disease. A w ide variety of localized th erapies are curren tly available an d in clude option s such as exten sive surgery or focused surgical m etastasectom y, extern al beam radiation th erapy (EBRT), em bolization , an d radiofrequen cy ablation .10 In m ost clin ical situation s, a biopsy of th e suspected m etastatic foci is n eeded to confirm th e diagn osis prior to proceeding w ith localized th erapies. Alth ough thyroid-stim ulatin g h orm one (TSH) suppression an d RAI th erapy h ave been th e m ain stays of system ic th erapy for m ore th an 50 years, recen t studies h ave dem on st rated clin ical e cacy of several oral kin ase in h ibitors in th e treatm en t of RAI refractor y thyroid can cer.

11.2 Localized Therapies in Advanced Thyroid Cancer In patien ts w ith advan ced thyroid can cer, localized th erapies are valuable tools to address m align an t foci th at arise in critical location s an d are at h igh risk of causin g sign ifican t m orbidit y or m ortalit y secon dary to t um or in filtration or com pression of vital struct ures if n ot treated expeditiously.11 In fact, t reatm en t of disease at th ese critical location s takes preceden ce over thyroidectom y an d RAI th erapy. Exam ples of critical location s in clude th e brain , n eurovascular struct ures (e.g., spin e m etastases; m ajor disease in th e n eck, upper m ediastin um , or base of th e skull; or m etastases causin g superior ven a cava syn drom e), m ajor airw ays (e.g., trach ea, lar yn x, m ajor bron ch i), or bon e

w ith im pen din g (or previous) path ological fracture. In addition to avertin g local sym ptom s th at could develop from t um or progression , directly treating th ese lesion s before usin g RAI th erapy m ay preven t m orbidit y related to sw ellin g th at can occur in som e of th ese m etastatic foci w ith an in crease in TSH (eith er en dogen ous or exogen ous TSH). Th e ch oice of a specific localized th erapy is depen den t on tum or size, tum or location , an d preferen ces of th e pat ien t an d disease m an agem en t team .

11.2.1 Localized Therapy for Dist ant Met ast ases Localized th erapies are ver y frequen tly used in th e m an agem en t of bon e m etastases from thyroid can cer. Bon e m etastases occur in 2 to 13% of all patien ts w ith di eren tiated thyroid can cer an d are associated w ith poor clin ical outcom e an d sign ifican t m orbidit ies, in cludin g path ological fract ure, severe pain , an d im m obilit y.12 Surgical m etastasectom y is th e preferred treatm en t option for bon e m etastases th at are associated w ith struct ural in stabilit y or are in critical location s th at m ay cause n eurovascular com prom ise. A retrospective study of 109 patien ts w ith bon e m etastases from thyroid can cer reported th at com plete resection of bon e m etastases in young patien ts is associated w ith a sign ifican t im provem en t in survival.13 EBRT is th e preferred t reat m en t op tion for bon e m etastases th at are struct urally stable but are causin g pain , in creasin g in size, or located w h ere progressive grow th could cause local com pressive sym ptom s or struct ural in stabilit y. Alth ough em bolization of tum or vasculature can be used for pain cont rol, it is m ore often used prior to surgical resection of bon e lesion s because th ese m etastatic foci ten d to be very vascular an d pron e to in traoperative bleedin g. Radiofrequen cy ablation h as been predom in an tly used to treat liver m etastasis from thyroid cancer, but it h as also been reported to reduce th e pain from thyroid can cer skeletal m etastases.14,15,16 Brain m etastases origin at in g from di eren tiated thyroid carcinom a are un com m on . Th ey are usually foun d in th e settin g of w idespread distan t m etastases an d associated w ith a ver y poor progn osis.17,18,19 On ce iden tified, h igh -dose glucocorticoids are usually recom m en ded to decrease th e surroun din g edem a. Th en th e preferred treatm en t option is surgical resection of th e m etastatic lesion un less th e lesion s are very sm all an d/or m ultifocal.20,21 Stereotactic radiation can be an e ective treatm en t if few er th an 3 to 5 sm all lesion s are presen t, w h ereas w h ole brain radiation is required for m ore n um erous lesion s.17 Localized th erapies can also be e ective t reat m en t option s for disease involving th e airw ays. Bron ch oscopy w ith laser th erapy can be e ect ively used to t reat in t ralum in al disease. En dobron ch ial sten ts are occasion ally used to m ain tain paten t airw ays. Because postobstruct ive pn eum on ia is a com m on cause of death in advan ced thyroid can cer, localized th erapies to preven t or alleviate com pression of m ajor bron ch i can decrease m orbidit y. Depen din g on th e size of th e lesion ,

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Thyroid Diseases location of lesion s, an d clin ical condition of th e patien t, addition al option s in clude surgical resection of m etastatic lesion s or focused EBRT. Alth ough n ot com m on ly perform ed, resection of in dividual dom in an t m etastatic lesion s in th e lun g or liver can be considered in pat ien ts in w h om th e rem ain der of th e disease is relatively stable. Even th ough m etastasectom y is n ot curative, resection of a dom in an t progressive m etastatic lesion m ay obviate th e n eed for system ic th erapies for m on th s to years.

11.2.2 Localized Therapy for Advanced Disease in t he Neck In patien ts present in g w ith locally advan ced thyroid can cer, th e treatm en t option s m ay exten d beyon d total thyroidectom y an d RAI ablation . Con sideration sh ould be given to EBRT in all patien ts w ith clin ically eviden t gross extrathyroidal exten sion .22,23,24 It is im portan t to balan ce th e poten tial for locoregion al con trol w ith th e w ell-described lon g-term com plication s of EBRT (part icularly w h en used in conjun ction w ith RAI) of den tal decay, trach eal sten osis, esophageal strict ure, osteon ecrosis, fibrosis, an d xerostom ia.2 Th ere is con sen sus th at EBRT can provide e ect ive locoregion al control for gross residual disease th at can n ot be surgically rem oved. Curren t available radioth erapy tech niques such as in ten sit y-m odulated radiation th erapy (IMRT) h as m ade it possible to give a h igh er dose of EBRT safely w ith out exceeding th e toleran ce of surroun din g crit ical struct ures.25,26,27 How ever, th e role of EBRT as adjuvan t th erapy in patien ts th at h ad all clin ical eviden ce of locally invasive disease surgically rem oved is m uch m ore con troversial.26,27,28,29,30 In th e absen ce of gross residual disease, w e usually reserve EBRT for use in older patients (> 50 y) w ith tum ors that are likely to be RAI refractory (e.g., Hürthle cell carcinom a, poorly di erentiated thyroid cancer, tall cell variants) w ho w e feel are at high risk of early locoregional disease recurrence that m ay not be am enable to additional surgery in the future. In younger patients, especially those w ith tum ors that are likely to be RAI responsive (classic papillary thyroid cancer, follicular thyroid cancer), we seldom use EBRT as adjuvant therapy but rather follow w ith close crosssectional im aging, reserving EBRT for the very few younger patients that develop rapid structural disease recurrence that cannot be adequately treated w ith additional surgery or RAI. EBRT is also considered in th e recurren t disease settin g if th e gross recurren t disease can n ot be surgically resected or if th e exten t of resection required w ould result in rem oval of str uctures th at is un acceptable to th e patien t (e.g., laryn gectom y). How ever, surgical resection rem ain s th e prim ar y treatm en t m odalit y for recurren t thyroid can cer in th e n eck an d is associated w ith th e best locoregion al con trol in m ost sett in gs.

11.3 Syst em ic Therapies in Advanced Thyroid Cancer Alth ough localized th erapies are frequen tly e ective at m an agin g in dividual m etastatic lesion s, system ic th erapies are often required in patien ts w ith m ore w idespread disease. Over tim e, th ese system ic th erapy option s h ave becom e m ore diverse an d m ore e ect ive.

11.3.1 TSH Suppressive Therapy w it h Levot hyroxine Di eren t iated thyroid can cer cells express th e TSH receptor an d respon d to TSH stim ulation by in creasin g th e expression of several thyroid-specific protein s an d th e rates of cell grow th . TSH suppression by usin g supraphysiological doses of levothyroxin e is usually used in patien ts w ith thyroid can cer to decrease th e risk of recurren ce.11 Both th e 2009 an d th e 2015 Am erican Thyroid Association (ATA) m an agem en t guidelin es recom m en ded in itial TSH sup pression to < 0.1 m IU/L in h igh - an d in term ediate-risk thyroid cancer patien ts an d a TSH betw een 0.1 an d 0.5 m IU/L in low risk patien ts. In lon g-term follow -up, th e TSH goals are based on an in tegration of th e patien t’s respon se to th erapy classification w ith th e pat ien t’s com orbid con dition s th at could be associated w ith an in creased risk of prolon ged aggressive TSH suppression . In th e absen ce of com orbid con dition s, a TSH goal of 0.5 to 2 m IU/L is recom m en ded in patien ts w ith out eviden ce of disease (excellen t respon se). How ever, in pat ien ts w ith structurally or bioch em ically in com plete respon ses to th erapy, a TSH goal of < 0.1 m IU/L is recom m en ded un less com orbidities th at in crease th e risk of com plication s from TSH suppression (e.g., post m en opausal w om en , un derlying h eart disease, osteopen ia/ osteoporosis, atrial fibrillat ion ) are present , in w h ich cases TSH levels as h igh as 0.1 to 0.5 m IU/L are con sidered appropriate.11,31

11.3.2 Radioact ive Iodine Therapy RAI treatm en t is on e of th e m ain t reatm en ts in patien ts w ith m etastatic di eren tiated thyroid can cer. Avidit y to RAI is directly related to th e degree of di eren tiation of thyroid can cer, an d th is is directly related to th e age of th e pat ien ts. Loss of RAI avidit y occurs w h en thyroid can cer un dergoes dedi eren tiat ion an d is associated w ith poor outcom e. Many studies h ave sh ow n both a h igh er rate of RAI avidit y in younger patien ts (< 45 y) an d a better progn osis in younger patien ts w ith sm all-volum e RAI avid distan t m etastases.2,9,32,33 Furth erm ore, t um ors h arborin g RAS driver m utation s are m ore likely to be RAI avid th an tum ors w ith BRAF m utation s.34,35,36 Conversely, extrapulm on ar y m etastases (e.g., brain an d bon e m etastases) are associated w ith a poor progn osis an d are less respon sive to RAI t reat m en t.2,5,6,7,9,32,33 Un fortun ately, m any of th e aggressive thyroid can cers h ave poorly di eren tiated or tall cell varian t h istology th at usually do n ot con cen trate RAI w ell. Tum ors w ith rem ain in g fun ction al di eren tiation for thyroglobulin syn th esis an d iodin e uptake h ave low glucose m etabolism an d are 18-fludeoxyglucose positron em ission tom ography (FDG-PET) n egative. Tum ors th at dedi eren t iate an d lose th e abilit y to uptake iodin e-131 ( 131 I) an d syn th esize thyroid h orm on e sh ow h igh glucose m etabolism an d are FDG-PET positive.37 High rates of FDG uptake an d a h igh volum e of FDG-avid disease are poor progn ostic factors. Th ese patien ts are less likely to respon d to RAI an d h ave a h igh er m ortalit y.38,39 Alth ough RAI is usually in e ect ive in aggressive thyroid can cer, th ere are w ell-described cases of aggressive t um ors respon din g to RAI. Th erefore, it is critical th at th e determ in ation of w h eth er or n ot RAI is likely to be ben eficial be carefully m ade. Over th e years, several defin ition s for RAI refractory

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Medical Managem ent of Aggressive Di erentiat ed Thyroid Cancer disease h ave been developed for use in th is critical m an agem en t decision . We con sider patien ts to be defin itively RAI refractory (m ore th an 95% probabilit y th at RAI w ill produce n o clin ically m ean in gful e ect) in th e follow in g cases: ● Direct lesion al dosim etr y m easurem en ts of th e m etastatic foci in dicate th at th erapeutic doses of RAI can n ot be ach ieved usin g eith er collim ated uptake in th e selected region s of in terest or iodin e-124 PET scan n in g.40 ● A n egative post th erapy RAI scan is obtain ed after an appropriately perform ed adm in istration of > 30 m Ci 131 I follow in g eith er thyroid h orm on e w ith draw al or recom bin an t h um an TSH preparation . ● Cum ulative RAI adm in istered activities of > 600 m Ci are required.32 ● Struct ural disease progression occurs w ith in 1 year of a prop erly adm in istered th erapeutic dose of RAI. Furth erm ore, w e con sider pat ien ts to be ver y likely to be RAI refractory (> 75–80% probabilit y th at RAI w ill produce n o clin ically m ean in gful e ect) in th e follow in g cases: ● Th e diagn ostic RAI scan is n egative in th e settin g of str uct urally iden tifiable disease.41 ● Markedly positive FDG-PET lesion s are present .39 ● Serum thyroglobulin levels rise w ith in 6 m on th s of previous RAI th erapy. Wh en evaluatin g th e e ect iven ess of previous RAI th erapies, it is im portan t to en sure th at th e prior treatm en ts w ere don e correctly. If th ere is sign ifican t con cern th at th e prior evaluation s could h ave been associated w ith acciden tal iodin e con tam in ation or in adequate TSH stim ulation , th en repeat RAI scan n in g (or possibly even addition al em pirical RAI th erapy) sh ould be stron gly considered. On e of th e m ost excitin g areas of research in thyroid can cer is the discover y th at in h ibit ion of th e BRAF/RAS/ERK m itogen -act ivated protein (MAP) kin ase path w ay can lead to redi eren t iation of thyroid can cer cells an d restore RAI avidit y in both preclin ical an d an im al studies.40,42 Sh ort-term (~ 4 w k) adm in istration of BRAF or MEK in h ibitors appear to sign ifican tly upregulate both th e sodium iodin e sym porter an d th e TSH receptor, w h ich dram atically en h an ces th e abilit y of thyroid can cer cells to concen trate RAI. Multiple clin ical t rials are un der w ay explorin g th e im pact of th is t ype of redi eren t iation th erapy in th e application of RAI th erapies.

11.3.3 Ant iresorpt ive Therapies for Bone Met ast ases In addition to th e localized th erapy option s already described, an tiresorpt ive th erapies h ave been dem on strated to be clin ically e ective in pat ien ts w ith bon e involvem en t in a variet y of solid an d liquid tu m ors.43 Th e data w ith regard to e cacy of th ese agen ts in thyroid cancer are still in com plete; h ow ever, t w o sm all studies do suggest a ben efit in thyroid can cer.44,45 Non eth eless, an t iresorptive th erapies w ith eith er a bisph osph on ate (usually in traven ous zoledron ic acid) or a receptor act ivator of n uclear factor κ B (RANK) ligan d in h ibitor (usually den osum ab) are recom m en ded for thyroid can cer patien ts w ith clin ically sign ifican t, m ultiple bon e m etastases and in patien ts th at h ave experien ced a skeletal-related even t . Skeleta l-rela ted

event (SRE) is a term used to quan tify th e m orbidit y associated w ith skeletal m etastases an d in cludes (1) spin al cord com pression , (2) path ological fracture, (3) extern al beam radiation or surgery to con trol pain or to preven t fract ure, an d (4) hypercalcem ia of m align an cy. Sm all bon e m etastases th at are n ot associated w ith cort ical bon e involvem en t, especially if RAI avid, do n ot require an tiresorptive th erapy.46 Th e optim al dosin g an d duration of treatm en t w ith an tiresorptive th erapies are n ot kn ow n .

11.3.4 Novel Syst em ic Therapies In th e past, tradit ion al ch em oth erapies w ere seldom used in advan ced thyroid can cer because of th e low respon se rate an d relatively h igh in ciden ce of side e ects.11 Th e last decade h as seen a dram atic expan sion in th e availabilit y of n ovel system ic th erapy option s for RAI refractor y thyroid can cer.47 Th e in itial prom isin g result from thyroid can cer pat ien ts en rolled in ph ase 1 trials of m ultitargeted oral kin ase in h ibitors w as verified in m ultiple ph ase 2 trials. More recen tly, both sorafen ib an d lenvatin ib h ave been dem on strated to im prove progression-free survival in prospective, ran dom ized clin ical trials.48 Curren tly sorafen ib is th e on ly Food an d Drug Adm in istration (FDA)-approved m ulti–kin ase in h ibitor for thyroid can cer. How ever, th e Nation al Com preh en sive Can cer Net w ork guidelin es n ote th at axitin ib, pazopan ib, sun itin ib, or van detin ib can be considered if clin ical trials are n ot available or appropriate.49 Furth erm ore, based on th e results of th e ph ase 3 trial, it is an ticipated th at lenvatin ib w ill be FDA approved for RAI refractory thyroid can cer in 2015. In gen eral, th ese kin ase in h ibitors often provide progression -free sur vival (usually stable struct ural disease, som etim es w ith sh rin kage of m etastatic lesion s) but h ave n ot yet been sh ow n to im prove eith er disease-specific survival or overall survival. Non eth eless, rem arkable treatm en t respon ses w ith th ese agen ts h ave been seen , w ith n um erous patien ts experien cin g prolon ged progression -free sur vival (at least 12–18 m o) w ith a side-e ect profile th at is tolerable in properly selected patien ts. Because m any patien ts w ith RAI refractor y thyroid can cer can sur vive m any years w ith on ly m in im al disease progression th at is asym ptom atic, it is im portan t to iden tify w h ich patien ts m ay or m ay n ot ben efit from an im provem en t in progression free sur vival. Th ese are com plex m an agem en t decision s th at n eed to in corporate a variety of factors related to th e tum or, th e patien t’s associated com orbidities, th e patien t’s toleran ce of side e ects an d im pact on qualit y of life, an d th e patien t preferen ces. Critical factors th at sh ould be con sidered in clude th e follow in g: ● Size of th e m etastatic lesion s: It is un usual to in itiate a n ovel system ic th erapy for lesion s < 1 cm ; h ow ever, n ot all m etastatic lesion s > 1 cm require system ic th erapy. ● Location of th e m etastatic lesion s: System ic th erapy m ay be in itiated soon er if m etastat ic lesion s are in location s w h ere con tin ued grow th w ould result in com prom ise of critical surroun din g struct ures. ● Sym ptom s: Th ese could in clude sym ptom s attr ibuted to a sign ifican t disease burden an d m ay in clude w eigh t loss, m uscle w astin g, fatigue, or oth er con stit ution al sym ptom s. ● Rate of struct ural disease progression : Tum ors th at are ver y slow ly grow in g are better can didates for observation rath er

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th an in terven t ion . How ever, w h en th e rate of progression is rapid en ough th at th e disease is likely to cause m orbidit y or m ortalit y, system ic th erapy sh ould be con sidered. Addition al m etastatic foci iden tified: Even if th e foci are sm all, th e iden tification of addition al m etastatic foci w ill lead to con sideration of system ic th erapy. Patien t preferen ce: Because n on e of th e curren tly available drugs h ave been defin itively dem on strated to im prove disease-specific sur vival, patien t preferen ce is always an im portan t con sideration . Factors such as h ow aggressive th e pat ien t w an ts th e treatm en t to be, th e patien t’s w illin gn ess to accept an d tolerate th e side e ects of th ese th erapies, an d th e patien t’s un derstan din g of both th e risks an d th e ben efits (an d costs) of th ese t reatm en ts an d th e poten t ial im pact on qualit y of life are critical issues to be carefu lly discussed.

In addition to th e n ovel system ic th erapy option s th at are curren tly available, a w ide ran ge of clin ical trials are available for patien ts w ith RAI refractory thyroid can cer. A list of available clin ical trials can be foun d on th e Web sites of th e In tern ation al Thyroid On cology Group (h ttp://w w w.itog.org/) an d th e Nation al In stit ute of Health (h tt ps://clin icaltrials.gov/).

11.4 Conclusion Th e m edical m an agem en t of aggressive di eren tiated thyroid can cer requires com plex decision m akin g w ith in put from a w ide variety of clin ical specialists. Fortun ately, ver y e ect ive localized th erapies are available to provide disease cont rol both in th e n eck an d at distan t sites. Even m ore im portan t ly, th e developm en t of a n ovel approach to redi eren t iation th erapy h olds prom ise th at RAI m ay becom e an even m ore im portan t tool in th e m an agem en t of aggressive thyroid can cer. Fin ally, th e FDA approval of n ovel agen ts for RAI refractory thyroid can cer h as provided th e first m ean in gful system ic th erapy option s beyon d RAI for patien ts w ith struct urally progressive disease th at is n ot am en able to localized th erapies.

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An n Surg 2006; 244(2); 296–304 [17] Hen riques de Figueiredo B, Godbert Y, Soubeyran I, et al. Brain m etastases from thyroid carcinom a: a retrospective study of 21 patien ts. Thyroid 2014; 24(2); 270–276 [18] Ch iu AC, Delpassan d ES, Sh erm an SI. Progn osis an d treatm en t of brain m etastases in thyroid carcin om a. J Clin En docrin ol Metab 1997; 82(11); 3637– 3642 [19] McW illiam s RR, Gian n in i C, Hay ID, Atkin son JL, Sta ord SL, Buckn er JC. Man agem en t of brain m etastases from thyroid carcinom a: a study of 16 path ologically con fir m ed cases over 25 years. Can cer 2003; 98(2); 356–362 [20] Bern ad DM, Sperduto PW , Souh am i L, Jen sen AW , Roberge D. Stereotactic radiosurger y in th e m an agem en t of brain m etastases from prim ar y thyroid can cers. J Neuroon col 2010; 98(2); 249–252 [21] Kim IY, Kon dziolka D, Niranjan A, Flickin ger JC, Lun sford LD. Gam m a kn ife radiosurger y for m etastatic brain tum ors from thyroid can cer. J Neuroon col 2009; 93(3); 355–359 [22] Esik O, Ném eth G, Eller J. Prophylactic extern al irradiation in di eren tiated thyroid can cer: a retrospective study over a 30-year observation period. On cology 1994; 51(4); 372–379 [23] Ben ker G, Olbrich t T, Reinw ein D, et al. Sur vival rates in patien ts w ith di eren tiated thyroid carcinom a. In fluen ce of postoperative extern al radioth erapy. Can cer 1990; 65(7); 1517–1520 [24] Lee N, Tuttle M. Th e role of extern al beam radiotherapy in th e treatm en t of papillar y thyroid can cer. En docr Relat Can cer 2006; 13(4); 971–977 [25] Tsan g RW , Brierley JD, Sim pson W J, Pan zarella T, Gospodarow icz MK, Sutcli e SB. Th e e ects of surgery, radioiodin e, an d extern al radiation th erapy on th e clin ical outcom e of patien ts w ith di eren tiated thyroid carcinom a. Can cer 1998; 82(2); 375–388 [26] Farah ati J, Rein ers C, Stusch ke M, et al. Di eren tiated thyroid can cer. Im pact of adjuvan t extern al radiotherapy in patien ts w ith perithyroidal tum or in filtration (stage pT4). Can cer 1996; 77(1); 172–180 [27] O’Con n ell ME, A’Hern RP, Harm er CL. Results of extern al beam radiotherapy in di eren tiated thyroid carcin om a: a retrospect ive study from th e Royal Marsden Hospital. Eur J Can cer 1994; 30A(6); 733–739 [28] Ph lips P, Han zen C, An dry G, Van Houtte P, Frü uling J. Postoperative irradiation for thyroid can cer. Eur J Surg On col 1993; 19(5); 399–404 [29] Kim TH, Yan g DS, Jun g KY, Kim CY, Ch oi MS. Value of extern al irradiation for locally advan ced papillar y thyroid can cer. In t J Radiat On col Biol Phys 2003; 55(4); 1006–1012 [30] Keum KC, Suh YG, Koom WS, et al. Th e role of postoperative extern al-beam radiotherapy in th e m an agem en t of patien ts w ith papillary thyroid can cer invadin g th e trach ea. In t J Radiat On col Biol Phys 2006; 65(2); 474–480 [31] Am erican Thyroid Association Guidelin es Taskforce on Th yroid Nodules. Differen tiated Th yroid Can cer: Revised Am erican Th yroid Association m an agem en t guidelin es for patien ts w ith thyroid n odules an d di eren tiated thyroid can cer. 2015. In press

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Medical Managem ent of Aggressive Di erentiat ed Thyroid Cancer [32] Duran te C, Haddy N, Baudin E, et al. Lon g-term outcom e of 444 patien ts w ith distan t m etastases from papillary an d follicular thyroid carcin om a: ben efits an d lim its of radioiodin e th erapy. J Clin En docrin ol Metab 2006; 91(8); 2892– 2899 [33] Nixon IJ, W h itch er MM, Palm er FL, et al. Th e im pact of distan t m etastases at presen tation on progn osis in patien ts w ith di eren tiated carcin om a of th e thyroid glan d. Thyroid 2012; 22(9); 884–889 [34] Ricarte-Filh o JC, Ryder M, Ch itale DA, et al. Mutation al profile of advan ced prim ar y an d m etastatic radioactive iodin e-refractor y thyroid can cers reveals distin ct path ogen etic roles for BRAF, PIK3CA, an d AKT1. Can cer Res 2009; 69 (11); 4885–4893 [35] Elisei R, Ugolin i C, Viola D, et al. BRAF(V600E) m utation an d outcom e of patien ts w ith papillary thyroid carcinom a: a 15-year m edian follow -up study. J Clin En docrin ol Metab 2008; 93(10); 3943–3949 [36] Sabra MM, Dom in guez JM, Grew al RK, et al. Clin ical outcom es an d m olecular profile of di eren tiated thyroid can cers w ith radioiodin e-avid distan t m etastases. J Clin En docrin ol Metab 2013; 98(5); E829–E836 [37] Fein e U, Lietzen m ayer R, Han ke JP, Held J, Wöh rle H, Mü ller-Schauen burg W . Fluorin e-18-FDG an d iodin e-131-iodide uptake in thyroid can cer. J Nucl Med 1996; 37(9); 1468–1472 [38] Wan g W , Larson SM, Fazzari M, et al. Progn ostic value of [18F]fluorodeoxyglucose positron em ission tom ographic scan n in g in patien ts w ith thyroid can cer. J Clin En docrin ol Metab 2000; 85(3); 1107–1113 [39] Wan g W, Larson SM, Tuttle RM, et al. Resistan ce of [18f]-fluorodeoxyglucoseavid m etastatic thyroid can cer lesion s to treatm en t w ith h igh -dose radioactive iodin e. Th yroid 2001; 11(12); 1169–1175 [40] Ho AL, Grew al RK, Leboeuf R, et al. Selum etin ib-en h an ced radioiodin e uptake in advan ced thyroid can cer. N En gl J Med 2013; 368(7); 623–632

[41] Sabra MM, Grew al RK, Tala H, Larson SM, Tuttle RM. Clin ical outcom es follow in g em piric radioiodin e th erapy in patien ts w ith struct urally iden tifiable m etastatic follicular cell-derived thyroid carcin om a w ith n egative diagn ostic but positive post-th erapy 131I w h ole-body scan s. Th yroid 2012; 22(9); 877– 883 [42] Ch akravarty D, San tos E, Ryder M, et al. Sm all-m olecule MAPK in h ibitors restore radioiodin e in corporation in m ouse thyroid can cers w ith con dition al BRAF activation . J Clin Invest 2011; 121(12); 4700–4711 [43] Woodw ard EJ, Colem an RE. Preven tion an d treatm en t of bon e m etastases. Curr Ph arm Des 2010; 16(27); 2998–3006 [44] Orita Y, Sugitan i I, Toda K, Man abe J, Fujim oto Y. Zoledron ic acid in th e treatm en t of bon e m etastases from di eren tiated thyroid carcin om a. Thyroid 2011; 21(1); 31–35 [45] Vitale G, Fon derico F, Mart ign etti A, et al. Pam idron ate im proves th e quality of life an d in duces clin ical rem ission of bon e m etastases in patien ts w ith thyroid can cer. Br J Can cer 2001; 84(12); 1586–1590 [46] Roben sh tok E, Farooki A, Grew al RK, Tuttle RM. Natural h istory of sm all radioiodin e-avid bon e m etastases th at h ave n o struct ural correlate on im agin g studies. En docrin e 2014; 47(1); 266–272 [47] Dadu R, Caban illas ME. Optim izin g th erapy for radioactive iodin e-refractory di eren tiated thyroid can cer: curren t state of th e ar t an d fut ure direct ion s. Min er va En docrin ol 2012; 37(4); 335–356 [48] Brose MS, Nuttin g CM, Jarzab B, et al. DECISION investigators. Sorafen ib in radioactive iodin e-refractor y, locally advan ced or m etastatic di eren tiated thyroid can cer: a ran dom ised, double-blin d, ph ase 3 trial. Lan cet 2014; 384 (9940); 319–328 [49] Nation al Com preh en sive Can cer Netw ork. h tt p://w w w.n ccn .org/profession als/physician _gls/pdf/thyroid.pdf

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Thyroid Diseases

12 Medical Managem ent of Medullary and Anaplast ic Thyroid Cancer Victor J. Bernet and Robert C. Smallridge

12.1 Int roduct ion Alth ough th e vast m ajorit y of pat ien ts w ith thyroid can cer, particularly di eren tiated thyroid can cer (DTC), do extrem ely w ell, patien ts w ith m edullar y thyroid can cer (MTC) an d an aplastic thyroid can cer (ATC) h ave a sign ifican t risk for m orbidit y an d m ortalit y related to th eir disease. ATC origin ates from follicular cells an d m any tim es arises from preexistin g DTC, particularly foci of papillar y thyroid can cer, w h ereas MTC originates from C cells, w h ich are of n eural crest origin an d t ypically reside in th e posterolateral aspect of th e thyroid glan d.1,2 C cells h ave a distin ct fun ct ion separate from thyroid follicles, producin g calciton in (Ct) an d carcin oem bryon ic an tigen (CEA) in stead of thyroid h orm on e an d thyroglobulin . MTC w as first described in 1906 as “m align an t goiter w ith am yloid.”3 ATC is an aggressive form of un di eren tiated thyroid can cer that ten ds to grow rapidly, invade local tissues, an d m etastasize early, an d it lacks th e abilit y to con cen trate iodin e. ATC cells do n ot secrete thyroglobulin an d m ost com m on ly present as a gian t cell tu m or w ith biph asic spin dle cells, alth ough several m orph ological variation s can be en coun tered. Th e treatm en t of patien ts w ith MTC an d ATC varies sign ifican tly from regim en s used to treat DTC. So m uch so, th at th e Am erican Thyroid Association provides in depen den t guidelin es for th e m an agem en t of both MTC an d ATC. Alth ough surgery plays a sign ifican t role in MTC and is som etim es in dicated in ATC, un like DTC, radioiodin e th erapy an d TSH suppression h ave n o role. In stead, th erapies such as extern al beam radioth erapy an d system ic ch em oth erapy are stan dard in cases of ATC an d frequen tly used in cases of MTC, depen din g on th e disease course. Recen t advan ces, particularly in th e area of system ic th erapy, provide h ope for con tin ued im provem en t in outcom es for patien ts w ith both MTC an d ATC, th ough th e latter is still associated w ith a soberin g m ortalit y risk.

12.2 Epidem iology MTC accoun ts for approxim ately 4% of all thyroid can cers in th e Un ited States.4 MTC prim arily occurs as sporadic disease (75%), w ith th e rem ain der represen tin g on e of th e autosom al dom in an t in h erited form s.4,5 In h erited form s of MTC in clude m ultiple en docrin e n eoplasia (MEN) t ypes 2A (80%) an d 2B (5%) as w ell as fam ilial MTC (FMTC) (15%). MEN2A is associated w ith MTC (~ 100%), ph eoch rom ocytom a (50%), an d hyperparathyroidism (30%), w h ereas MEN2B con sists of MTC (~ 100%), ph eoch rom ocytom a (50%), an d cutan eous n eurom as, w ith < 5% exh ibitin g hyperparathyroidism . Requirem en ts for FMTC, an apparen t varian t of MEN2A, in clude th e presence of MTC w ith out eviden ce for ph eochrom ocytom a an d prim ar y hyperparathyroidism . Reports do exist of fam ilies in itially categorized as h avin g FMTC later bein g foun d to h ave MEN2A upon clin ical expression of ph eoch rom ocytom a or hyperparathyroidism .6,7 Recom m en dation s var y in regard to th e n um ber of in dividuals

an d gen erat ion s th at m ust be a ected w ith MTC alon e in order to m eet th e criteria for FMTC.8,9 Th e prevalen ce of ATC varies geograph ically, ran gin g betw een 1.3 to 9.8% of all thyroid can cers, an d accoun ts for 1.7% of thyroid can cers in th e Un ited States.10 It ten ds to occur later in life, at a m edian age of 69 years, an d m ore so in w om en (65.8%).11 Data from th e Sur veillan ce, Epidem iology an d En d Results (SEER) database in dicates ATC m ay occur som ew h at m ore frequen tly in n on -Hispan ic Caucasian s, but th is fin din g requires addition al confirm ation .12 Patien ts w ith ATC m ay present w ith such fin din gs as an en largin g n eck m ass, voice ch anges (e.g., h oarsen ess or dysph on ia), dysph agia, dyspn ea, h em optysis, n eck pain , superior ven a cava syn drom e, an d distan t m etastasis.12 ATC frequen tly (> 80%) arises from an abn orm al thyroid, such as a goiter, an d can arise w ith in th e con text of a preexistin g DTC, alth ough th e reported frequen cy of th is occurren ce varies w idely (7–89%).1,2,4,13,14,15,16

12.3 Diagnosis 12.3.1 Cyt ology MTC cytology consists of polygon al-sh aped cells, eccen tric n uclei, gran ular ch rom atin , am yloid, an d azuroph ilic cytoplasm ic gran ules.17 Studies report a sen sitivit y ran ge betw een 63 an d 89% for iden tifyin g MTC by FNA cytology, an d th ere are reports of cytological m isdiagn osis.18 In m any of th ese in stan ces, cellular atypia w as n oted or an oth er form of m align an cy suspected, w ith th e diagn osis of MTC bein g appreciated on ly on surgical h istology.19 Th e presen ce of ATC can m any tim es be surm ised by th e classic clin ical presentation of a rapidly en largin g n eck m ass th at is fixed an d h ard in texture. Prom pt tissue confirm ation is essen tial. Alth ough fin e-n eedle aspiration (FNA) is t ypically h elpful in th e evaluation of thyroid n odules/m asses, in th e case of ATC, exten sive fibrosis an d cellular n ecrosis lim it th e abilit y to obtain an adequate sam ple for confirm atory diagn osis.20,21 Use of a core biopsy sh ould be pursued w h en FNA yields in adequate cellularit y, an d progression to open biopsy sh ould be con sidered if th e core biopsy is n on diagnost ic.

12.3.2 Hist ology Con firm ation of ATC by h istology can be ch allen ging because th e di eren tial diagn osis in cludes poorly di eren tiated thyroid can cer, lym ph om a, m etastases to th e thyroid, sarcom a, squam ous cell carcin om a of th e thyroid or h ead/n eck, an d Riedel’s thyroidit is.22 Addition ally, variation s in presen tin g ATC h istology in clude spin dle cell, gian t cell, squam oid, an d paucicellular form s.13,23 Detailed path ological exam in ation m ay reveal th e presen ce of areas of DTC or poorly di eren tiated thyroid can cer in con cert w ith ATC in 20 to 90% of cases.2,4,24 Wh ereas im m un ostain in g for thyroglobulin an d Ct ten d to be positive in di eren t iated an d m edullar y thyroid can cer, respect ively, such

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Medical Managem ent of Medullary and Anaplast ic Thyroid Cancer stain in g is n egative in ATC. Testin g for P53 an d pan cytokerat in is usually positive in ATC tissue. Furth erm ore, positive im m un ostain in g for E-cadh erin is com m on , w h ereas positivit y for PAX8 an d TTF-1 is considered un com m on .25

12.3.3 Biochem ical Alth ough n o blood test exists to diagn ose ATC, m easurem en t of seru m calciton in can be used to iden tify cases of MTC, w ith basal serum Ct levels > 20 to 100 pg/m L bein g suspicious for MTC.26 Serum Ct screen in g yielded an MTC prevalen ce of 0.40% in a European -based study of 10,864 patien ts w ith thyroid n odules. Ct elevation w as associated w ith a better sen sitivit y an d specificit y for MTC th an cytology as w ell as earlier diagn osis w ith im proved rem ission rates (59% vs. 2.7%; p = 0.0001).27 In th e Un ited States, Ct m easurem en t h as tradit ion ally been targeted tow ard at-risk in dividuals w ith thyroid n odules, such as th ose w ith a fam ily h istory of MTC or t ype of thyroid can cer un con firm ed, suspicious cervical lym ph aden opathy, a h istory of parathyroid-related hypercalcem ia, or suspicion for ph eoch rom ocytom a. How ever, a U.S.-based study foun d th at Ct screen in g of thyroid n odules could be cost e ect ive at $11,793 per lifeyears saved w h ile yieldin g 113,000 life-years at a cost in crease of on ly 5.3%.28 Prior to th e clin ical availabilit y of RET (rearran ged durin g tran sfect ion ) m utation testin g, stim u lated Ct levels w ere used to iden tify C cell hyperplasia an d/or MTC in at-risk in dividuals. In fusion of calcium an d/or pen tagast rin stim u lates Ct release, w ith stim u lated Ct levels > 100 to 500 pg/m L bein g suspicious for th e presence of C-cell hyperplasia an d/or MTC.29 Th e sen sitivit y an d specificit y of th is testin g is im pacted by th e specific Ct cuto levels applied.30 How ever, pen tagastrin is n o lon ger available in th e Un ited States, an d RET on cogen e m utation testin g is n ow preferred for iden tification of at-risk in dividuals. Preoperative calciton in levels do provide h elpful in form ation to guide th e exten t of preoperative staging as th e probability of extracervical disease rises w ith calciton in levels > 400 pg/m L.8

12.3.4 Mut at ional Test ing RET on cogen e m utation testin g allow s for iden tification of in dividuals w ith in h erited form s of MTC. In itial RET on cogen e testin g t ypically involves screen in g of th e m ore com m on ly a ected exon s: 8, 9, 10, 11, 13, 14, an d 16. It m ust be realized th at lack of a RET on cogen e m utation does n ot exclude in h erited form s of MTC because previously un iden tified m utation s con tin ue to be discovered.16 Th erefore, fu ll RET on cogen e sequen cing is recom m en ded w h en an in h erited form of MTC is suspected but in itial screen in g is n egative. Iden t ification of RET m utation s also h olds progn ostic value because pat ien ts w ith certain m utation s (634, 804, 883, 918) display a m ore aggressive disease course, w h ereas th ose w ith oth er m utation s (609, 620, 630, 635) display a m uch m ore in dolen t course.4 In addition to RET m utation s, HRAS an d KRAS gen e m utation s h ave been sh ow n to be presen t in cases of sporadic MTC an d im pact tum or beh avior, in cluding possibly th e respon se to targeted th erapy, such as m ultikin ase in h ibitors.31,32 Cutan eous lich en am yloidosis (CLA) is seen w ith MEN2 an d tends to involve th e T2 to T6 scapular area derm atom es. Pruritus related to CLA can precede developm en t of MTC an d, if

recogn ized, allow for early diagnosis. Hirsch sprun g’s disease (HD) can also occur an d is secon dary to a RET gen e loss-of-fun ction altered m igration of n eural crest to en teric subm ucosa.33 HD occurs in on ly about 7% of patien ts w ith MEN2A an d FMTC, an d on ly 2 to 5% of patien ts w ith HD are foun d to h ave MTC.34,35 MEN2B occurs as a de n ovo m utation in > 50% of cases, w ith th e M918 T RET m utation (exon 16) bein g foun d in > 95% an d an oth er 2 to 3% exh ibitin g th e A883F (exon 15) m utation .36 MEN2B–associated MTC ten ds to exh ibit m ore aggressive beh avior an d presen t about a decade earlier th an th at associated w ith MEN2A. MEN2B is associated w ith several ph en otypic fin din gs, in cluding Marfan oid h abitus; pectus excavatum ; pes cavus; n eurom as of th e lips, tongue, an d corn ea; an d gastroin testin al disorders, such as con stipation (som etim es com plicated by m egacolon ), vom itin g w ith dehydration , in testin al gan glion eurom atosis, an d obstruction .37 Addition al fin din gs in youn g ch ildren in clude an in abilit y to gen erate tears w h en cryin g, severe con stipation , an d feedin g-related issues.38 RET on cogen e testin g allow s for poten t ial early recognition of at-risk fam ily m em bers prior to th e developm en t of MTC, even prior to eviden ce of Ct elevation . W ith th e n atural course of MTC associated w ith various RET m utation s bein g better un derstood, th e t im ing for prophylactic thyroidectom y can be in dividualized based on th e m utation present . Th e Am erican Thyroid Association (ATA) MTC guidelin es divide RET on cogen e m utation s in to groups th at represen t severit y of disease an d expected t im e of on set.16 W ith MEN2B m utation s exh ibitin g a tren d for an aggressive disease pattern w ith early on set, surgical in terven tion sh ould be con sidered w ith in th e first year of life.39 Th ose w ith MEN2A–related m utation s w ith h igh er-risk MTC are recom m en ded to un dergo thyroidectom y w ith eviden ce of Ct elevation or prior to 5 years of age, w h ereas th ose w ith less con cern in g m utation s can poten tially be follow ed w ith serial n eck ultrasoun d (US) im agin g an d Ct levels.40 Thyroidectom y sh ould be con sidered for developm en t of Ct elevation s or in ch ildh ood w h en len gthy serial follow -up is n ot preferred by th e pat ien t an d/or paren ts.16 Ph eoch rom ocytom a screen in g sh ould begin by age 16 years. Because prim ar y hyperparathyroidism (HPT) frequen tly occurs in association w ith MEN2A kin dreds, screen in g for th is en tity sh ould occur prior to thyroid surgery. Laborator y testin g con sisten t w ith prim ar y HPT sh ould precipitate addition al evaluation for con firm at ion of th e diagnosis. Localizat ion testin g sh ould be in terpreted w ith caution because m ultiglan d disease is com m on , but n ot all involved parathyroid glan ds m ay be n oted on sestam ibi parathyroid scan n in g or n eck US. Microscopic evaluation reveals m ost ATC sam ples to be an euploid in n ature an d con tain sign ifican t abn orm alities in ch rom osom al n um bers an d struct ure.41,42 Th e eviden t m utation al progression an d evolut ion of ch rom osom al ch anges progressing from PTC to poorly di eren tiated thyroid can cer an d th en to ATC supports th e con cept of m ultistep m utation -driven dedifferen tiation .43,44,45 Mutation s com m on ly foun d in both w ell-differen tiated DTC an d ATC in clude BRAF, RAS, ph osph oin ositide3-kin ase (PIK3-α ), as w ell as RET/PTC3 rearran gem en t.46,47 In a report of 652 ATC cases, th e follow in g prevalen ce of gen etic m utation s w as n oted: RAS 60%, TP53 48%, PI3KCA 24%, BRAF 23%, PTEN 16%, an d RET/PTC 4%.48 Oth er m utation s n oted in ATC in clude axin , TP53 an d β-caten in , an aplastic lym ph om a kin ase (ALK), an d aden om atous polyposis coli (APC).26,49,50 A

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Thyroid Diseases Table 12.1 Notable cellular pathway changes evident in anaplastic thyroid cancer Function

↑ Expression

↓ Expression

Transcription

PPAR-γ, C-myc, fra1, HNF-1a, Id1, HMG1(y), YPX1

FOXE1, Pax8, NKX2–1, CBX5

Signaling

EGFR, pERK, pAKT1, CXCR4, JAK/STAT,

SOCS 1,3,5

Mitosis

Aurora kinases, k-α1 tubulin, topoisom erase-11

TACC3

Proliferation

SPAG9, OEATC-1, RBBP4, MKI67, epCAM, CD44v6, Claudin-7, ALDH1, FoxO3a, MIR-25, MIR-30d

Cell cycle

Cyclin D1, Cyclin D3, Cyclin E

p21, p27

Apoptosis

NF-κβ IAPS, DJ-1, LCN2

Bcl2, αβ-crytallin

Adhesion

β-catenin, FAK, ILK1

E-cadherin

Tum or suppression

p53, MIR-20a

p16, Rb, PTEN

Abbreviations: Abbreviations: PPAR-γ, Peroxisom e proliferator-activated receptor gam ma; C-myc, Myc proto-oncogene protein; fra1, FOS-like antigen 1; HNF-1a, Hepatic Nuclear Factor 1 Alpha; Id1, DNA-binding protein inhibitor; HMG1(y), high mobilit y group 1(y); EGFR, epiderm al growth factor receptor; pERK, phosphorylation of ERK; pAKT1, protein kinase B; CXCR4, receptor for the strom al cell– derived factor-1 (SDF-1)/CXCL12; JAK/STAT, Janus kinase/ signal transducers and activators of transcription; Aurora kinases, fam ily of serine-threonine kinases; Ka1 tubulin, a-tubulin isotype (Ka1); SPAG9, sperm associated antigen 9; OEATC-1, overexpressed in anaplastic thyroid carcinoma-1; RBBP4, Histone-binding protein RBP; MKI67, m arker of proliferation Ki67; epCAM, Epithelial cell adhesion m olecule; ALDH1, Aldehyde dehydrogenase 1; Fox-O3a, Forkhead box protein O3; MIR-25, microRNA-25; MIR-30d, m icroRNA-30d; NF-κB: nuclear factor kB; IAPS, inhibitors of apoptosis proteins; LCN2, Lipocalin-2; FAK, focal adhesion kinase; ILK1, integrit y-linked kinase; p53, cyclin-dependent kinase inhibitor; MIR-20a, MicroRNA-20a; FOXE1, forehead box E1; Pax8, paired box 8; NKX2-1, NK2 hom eobox 1; CBX5, chromosom e protein hom olog 5; SOCS, Suppressor of cytokines signaling 1, 2, 3; TACC3, transform ing acid coiled-coil 3; p21, cyclin-dependent kinase inhibitor; p27, cyclin-dependent kinase inhibitor; Bcl2, B cell lym phoma 2; E-Cadherin, Cadherins cell-cell (calcium -dependent) adhesion m olecule; Rb, Retinoblastom a; PTEN, Phosphatase and tensin hom olog (PTEN)

sign ifican t am oun t of gen e m utation s an d m icroRNA alteration s leads to protein expression ch anges im pactin g crit ical cellular roles. Th ese ch anges are sum m arized in Table 12.1.

12.3.5 St aging Stagin g for MTC is based on th e Am erican Join t Com m ittee on Can cer (AJCC).51 Stage I con sists of tum ors < 2 cm an d stage II in cludes t um ors betw een 2 an d 4 cm , both w ith out eviden ce of extraglan dular disease. Stage III en com passes any tum ors > 4 cm , level VI n odal m etastases or m icroscopic extrathyroidal invasion irrespective of tum or size. Th e presen ce of any distan t m etastases, lym ph n ode involvem en t beyon d level VI, or gross soft t issue exten sion qualifies as stage IV. Th e reported associated m ortalit y by stage is stage I, 0%; stage II, 13%; stage III, 56%; an d stage IV, 100%.52 Correct in itial stagin g of patien ts w ith ATC provides in form ation th at plays an im portan t role for both assessm en t of progn osis an d th erapeut ic decision plan n in g. All cases of ATC are con sidered stage IV an d are subdivided as follow s: IVA, prim ary tum or lim ited to thyroid; IVB, extrathyroidal exten sion ; an d IVC, distan t m etastases. Th e prepon deran ce of data in dicates th at patien ts w ith ATC ten d to present w ith m ore advan ced disease burden : stage IVC (~ 45%), IVB (~ 40%), an d IVA (~ 10%).2,53,54,55,56 Th e reported m edian sur vival in m on th s by stage are IVA, 7.3; IVB, 3.9; an d IVC, 1.7, w ith respect ive 1-year sur vival rates of 72.7%, 24.8%, an d 8.2%.2,10

12.4 Preoperat ive Assessm ent Th e surgical m an agem en t of MTC an d ATC is th orough ly review ed in Ch apters 17 an d 18, respect ively, an d th e reader is

referred to th ese section s for detailed discussion of th is area. Th is sect ion is lim ited to surgical issues pertin en t to th e discussion of m edical m an agem en t. Optim al surgical m an agem en t is essen tial in patien ts w ith MTC. MTC tum ors are kn ow n to often invade perithyroidal soft tissue struct ures an d also frequen tly spread to cen tral an d lateral cervical lym ph n odes. Th erefore, preoperative an atom ical im aging is essen tial an d in cludes detailed cervical lym ph n ode m appin g w ith n eck US or com puted tom ograph ic (CT) scan n in g, th e latter allow in g detailed central n ode assessm en t despite an in tact thyroid.57 Aerodigestive tract involvem en t can occur, an d th e presen ce of h oarsen ess, dysphagia, or oth er upper respiratory com plaints sh ould precipitate upper respiratory tract an d vocal cord visualization . Addition ally, con trast CT of th e ch est is useful for iden tification of m etastases to th e m ediastin um an d lun gs, w h ereas CT of th e abdom en an d pelvis sh ould be pursued w h en calciton in levels are > 400 pg/m L.16 Con trast-en h an ced th ree-ph ase liver CT an d m agn etic reson an ce im aging (MRI) are m ore sen sitive th an conven tion al CT for detect ion of liver m etastases. Preoperative laparoscopic liver screen in g for m icrom etastases w as advocated but n ow is rarely perform ed, because exten sive cervical m icrodissection s are n o lon ger recom m en ded given th at sustain ed clin ical ben efit w as in frequen t.58 Preoperative iden tification of MEN is im portan t because ph eoch rom ocytom a occurs in 50% of MEN2A an d MEN2B cases. Iden tification an d treatm en t of ph eoch rom ocytom a is essen tial to avoid perioperat ive m orbidit y an d m ortalit y related to th is en t it y.59 MEN-related ph eoch rom ocytom as are t ypically ben ign , m ulticen tr ic, in traglan dular, an d bilateral.60 Preoperative screen in g for ph eoch rom ocytom a m ay in clude plasm a m etan eph rin es, 24-h our urin e catech olam in es, an d m etan eph rin es w ith creatin in e or CT of th e adren al glan ds.

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Medical Managem ent of Medullary and Anaplast ic Thyroid Cancer Patien ts w ith ATC frequen tly presen t w ith sign s or sym ptom s in dicatin g upper airw ay involvem en t (h oarsen ess, stridor, dysph agia, h em optysis, etc.). Mirror or fiberoptic visualization allow s assessm en t of th e lar yn x an d vocal cords for eviden ce of invasion or vocal cord dysfun ct ion . Follow -up bron ch oscopy for fur th er trach eal in spection is recom m en ded in cases w ith eviden ce of any upper airw ay involvem en t, w h ich n ecessitates prom pt in terven t ion to secure it. In itial laborator y testin g upon diagn osis of ATC in cludes a com plete blood coun t an d m etabolic profile. Hypocalcem ia secondar y to tu m or-related hypoparathyroidism m ay be en coun tered an d, rarely, h um oral-in duced hypercalcem ia m ay occur.61,62,63 Thyroid fun ct ion status sh ould be assessed w ith TSH an d free T4 levels because hypothyroidism or thyrotoxicosis m ay be presen t.64 Im aging to assess th e prim ar y tum or an d m etastatic burden is in tegral in treatm en t plan n in g, in cludin g determ in in g th e poten tial for tum or resection . Th e preferred im aging m odalit y is 18-fludeoxyglucose positron em ission tom ography (18-FDGPET) CT scan n in g is th e preferred im agin g m odalit y for ATC cases, allow in g for both an atom ical assessm en t of th e n eck an d chest an d screen in g for extracervical 18-FDG avid m etastases. If PET-CT is un available th en cross-sect ion al im aging of th e n eck, chest, an d abdom en sh ould be obtain ed.44,65 Metastases from ATC m ay occur in th e lun gs, m ediastin um , liver, kidn eys, h eart , adren al glan ds, brain , an d bon es.22 Addition al targeted im agin g w ith n eck US an d MRI or bon e scan m ay be clin ically useful.22 Radioactive iodin e scan n in g does n ot h ave a role because ATC tum ors do n ot con cen t rate iodin e.

12.5 Treat m ent In th e context of in h erited form s of MTC, prophylactic thyroidectom y sh ould occur prior to th e expected on set of can cer based on th e RET on cogen e m utation presen t. Total thyroidectom y w ith cen tral lym ph n ode dissection is recom m en ded in patien ts > 8 years old w ith MEN2A or FMTC, an d at any age for patien ts w ith MEN2B. How ever, total thyroidectom y alon e is con sidered appropriate in ch ildren < 5 years old w ith MEN2A or FMTC w ith out cervical lym ph aden opathy.16 Patien ts w ith local cervical m etastases (≥ 10 lym ph n odes) ten d n ot to ach ieve bioch em ical cure, w ith on ly approxim ately 10% cured despite exten sive surgical in ter ven t ion s.66 How ever, pat ien ts w ith persisten t postoperative Ct elevation s exh ibit reason able sur vival rates of 80.2% at 5 years an d 70.3% at 10 years.67 Wh en MTC is diagn osed follow in g h em ithyroidectom y, com pletion thyroidectom y an d cervical lym ph n ode dissection should be considered. Poten tial in dication s for addition al surgery in clude th e presen ce of m ultifocal MTC, cervical lym ph aden opathy, an d postsurgical Ct levels. Multifocal MTC is m ore com m on in fam ilial form s (~ 75% in MEN2A) in com parison to sporadic MTC (0–22%).68 Alth ough Ct elevation s in dicate persisten t MTC, th ere is n o defin itive cuto for pursuin g addition al surgery.13 If serial follow -up is elected, Ct levels sh ould be closely m onitored, w ith any rise prom pt in g reevaluation . Wh en feasible, com plete excision of th e thyroid/an aplast ic tum or sh ould occur because sur vival is sign ifican tly im pacted by exten t of resection . Th e exten t of invasion , th e specific cervical struct ures involved, an d th e presence of distan t m etastases

are th e m ain factors th at im pact t um or resectabilit y. If surgery is deem ed appropriate, th en surgical goals in clude total thyroidectom y w ith cen tral an d lateral lym ph n ode resection . Th e degree of tum or resection is divided in to four levels: R0, n o residual tum or; R1, m icroscopic residual t um or; R2, m acroscopic residual tum or; an d RX, presen ce of residual t um or can n ot be assessed.51 Available data in dicate im provem en t in sur vival w ith com plete resection , w h eth er or n ot addition al ch em oth erapy an d/ or radioth erapy are bein g considered. Addition ally, in com plete tum or resection is preferred over lesser resection or n o surgery at all.10,44,69,70,71,72,73 In an e or t to ach ieve disease-free m argin s, en bloc resection of t um or m ay be appropriate, but tu m or debulkin g h as n ot been associated w ith an im provem en t in outcom es.22 Of in terest, n eoadjuvan t th erapy w ith com bin ation ch em oth erapy an d radioth erapy can result in origin ally un resectable tu m ors m eetin g criteria for poten t ial resection .74 Man agem en t of airw ay issues is particularly ch allen ging in patien ts w ith ATC. Alth ough avoidan ce of trach eostom y placem en t is preferred, if n ecessar y, it is best to perform th e procedure in an operatin g room un der controlled circum stan ces an d avoid em ergen t placem en t.75 To successfully place th e trach eostom y, an isth m usectom y or debulkin g of tum or an terior to th e trach ea m ay be required w h en thyroidectom y is n ot feasible.

12.5.1 Radiat ion Therapy Because C cells do n ot concen trate iodin e, postoperative radioactive iodin e (RAI) ablation is n ot used except possibly in rare occasion s w h en coin ciden t DTC is diagn osed. Th e role of extern al beam radiation th erapy (EBRT) in th e treatm en t of MTC rem ain s con troversial because prospect ive data for a sur vival ben efit are lackin g. EBRT m ay im prove local disease control, but Ct levels rarely becom e un detectable. EBRT h as n ot un iform ly been sh ow n to a ect locoregion al recurren ce rates, alth ough cases w ith persisten t m icroscopic disease, extrathyroidal exten sion , or positive lym ph aden opathy displayed a better 10-year local relapse-free rate w ith EBRT th an w ith out (86 vs. 52%; p = 0.049). Sim ilar results w ere n oted in an oth er, m uch sm aller study.76 No con sen sus exists in regard to th e use of EBRT for persistent Ct elevation follow in g successful resection of m acroscopic disease. A study of 207 patien ts w ith persisten t Ct elevation w ithout distan t m etastases revealed a reduced recurren ce rate.77 How ever, m easurable postoperative Ct levels m ay represen t eith er persisten t local m icroscopic disease or un iden tified distan t m etastases, w ith EBRT th erapy h oldin g n o sign ifican t ben efit in th e latter scen ario. Because surgical resection of recurren t MTC is an e ect ive altern ative for local con trol an d because radiation ch anges m ake future surgery m uch m ore ch allen ging, EBRT is best reserved for cases w h ere on ly in com plete resection is feasible an d gross residual disease rem ain s. Th e ATA MTC guidelin es suggest th e poten t ial use of postoperat ive adjuvan t EBRT of th e n eck or m ediastin um follow in g surgery in cases of h igh -volum e disease, part icularly w ith m icroscopically positive m argin s.17 Eviden ce of extran odal exten sion an d persisten tly m easurable Ct postoperatively are oth er possible in dication s for EBRT. Of n ote, th e latter t w o in dicat ion s are on ly supported by a grade C ratin g an d reflect expert opin ion rath er th an con clusive data.

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Thyroid Diseases EBRT plays an in tegral role in th e m an agem en t of patien ts w ith ATC. Radioth erapy can slow th e grow th of locoregion al disease, an d in com bin ation w ith prior successful surgical resection (R0 an d R1) an d ch em oth erapy is associated w ith th e best local con trol an d sur vival rates.1,54,78,79 A m ultivariate an alysis of 516 ATC cases n oted th at on ly patient age an d com bin ed surgery w ith radioth erapy w ere reliable sur vival predictors.13 Because ATC t um ors display ver y rapid grow th , hyperfraction ated or accelerated treatm en t protocols are preferred over conven t ion al tech n iques, alth ough th ese protocols are associated w ith a rise in adverse e ects.80 In ten sit y-m odulated radiation th erapy (IMRT), w h ich en ables con cen t ration of treatm en t to t um or tissue w h ile m in im izin g exposure to adjacen t n orm al tissue, is m ost com m on ly used.81,82,83 Outcom es appear to im prove w h en at least 40 Gy is delivered, as observed in t w o studies w ith exten sion in survival from 3.2 to 11.1 m on th s an d 1.7 to 5.4 m on th s.1,56 An oth er report n oted im proved m edian sur vival at 1 year (54% vs. 17%) w ith a treatm en t dose > 45 Gy.74 Th ere h as been som e debate as to w h eth er radioth erapy sh ould be delivered pre- or postoperatively.84,85,86 Th e ATA ATC guidelin es advise th at, for patien ts w ith resectable disease, radioth erapy after surgery is appropriate, an d th at treatm en t sh ould begin about 2 to 3 w eeks postoperatively to allow for resolution of sw ellin g an d adequate h ealin g.22 Available data in dicate th at better results occur w ith a com bin ation of surgery an d radiation th an radioth erapy alon e.53,54,85,87,88 How ever, in cases w h ere tum ors are un resectable, radioth erapy, particularly com bin ed w ith system ic th erapy, sh ould be con sidered in pat ien ts w h o prefer aggressive treatm en t , h ave been educated on poten tial risks an d ben efits, an d are deem ed fit to un dergo such treatm en t . Palliative radiation th erapeutic regim en s can be con sidered in pat ien ts w ith poor perform an ce status w h o are un fit for m ore aggressive in terven tion but have local sym ptom s an d are in terested in receivin g at least som e th erapy. Radiation th erapy m ay also be con sidered beyond th e region of th e n eck an d m ediastin um for distan t m etastases to location s such as th e brain or bon e.22 Com plication s from EBRT can be clin ically sign ifican t an d in clude odyn oph agia, dysphagia, an orexia w ith w eigh t loss, radiation burn s, fatigue, an d poor n utrition al state.

12.5.2 Met ast ases Approxim ately 50% of patien ts w ith MTC presen t w ith m etastases, m ost com m on ly involving cervical lym ph n odes, alth ough lun g, liver, or bon e m etastases can also be presen t. Th e risk for m etastases correlates w ith in creasin g Ct levels, ran ging from approxim ately 50% w ith Ct levels > 5,000 pg/m L to n early 100% in pat ien ts w ith Ct levels > 20,000 pg/m L.66 Brain m etastases can occur w ith eith er MTC or ATC an d carr y a sign ifican t risk for associated m orbidit y. Th e use of steroids to reduce brain edem a an d an tiseizure m edication sh ould be in dividualized an d in clude in put from n eurology an d n eurosurgery con sultan ts. Wh en feasible, surgical rem oval of brain m etastases is preferred but is n ot alw ays possible. EBRT, to in clude stereotactic radiosurger y, sh ould be con sidered for treatm en t of brain m etastases w h en resection is n ot possible.89 Distan t m etastases occur in approxim ately 65% of ATC patien ts an d can im pact th e lun gs, liver, bon es, brain , an d skin , particularly th e scalp.90 Solitar y pulm on ar y n odules are

can didates for resection or radioth erapy, w h ereas m ultiple lun g lesion s do n ot len d th em selves to such in ter ven tion . Palliative radiation is useful for treatm en t of pain fu l ch est w all or pleural-based m etastases. Liver m etastases are usually n um erous an d n ot am en able to resection , but stereotact ic radiosurgery or radiofrequen cy ablation can be con sidered select ively. Osseous m etastases, seen w ith both MTC an d ATC, m ay presen t as bon e pain or be foun d in ciden tally on im aging.91 Metastases im pact in g w eigh t-bearin g bon es require orth opedic in terven tion to preven t fract ure or to provide stabilization follow in g a fract ure. EBRT is an appropriate treatm en t consideration , especially for bon e m etastases th at are partially resectable, un resectable, th reaten n earby struct ures, or are associated w ith pain . Palliative radioth erapy is appropriate in certain circum stan ces an d t ypically con sists of a total of 2,000 to 3,000 cGy delivered over 1 to 2 w eeks.22 Addition al treatm en t option s in clude radiofrequen cy ablation , arterial em bolization , or cr yosurgery, w h ich m ay be follow ed by surgery, EBRT, or cem en tation in certain in stan ces.92 Spin e m etastases can th reaten th e spin al cord an d are an urgent m atter. Glucocorticoid th erapy to reduce in flam m ation m ay be used un til m ore defin itive th erapy w ith surgery or EBRT can occur.93 In traven ous bisph osph on ates or den osum ab h as sh ow n e ect iven ess in treatin g thyroid can cer–related bon e m etastases, th ough data are lim ited in relation to th eir use in ATC an d MTC.94,95 Metastases to th e skin occur in patien ts w ith ATC an d require path ological confirm ation w h en suspected. Alth ough FNA or core biopsy is a reason able first step, com plete excision is both diagn ostic an d th erapeutic.

12.5.3 Syst em ic Therapy For m any years, on ly t radition al ch em oth erapeutic agen ts, w h ich yielded disappoin tin g clin ical results, w ere available for treatm en t of MTC an d ATC. How ever, th e discover y of protein kin ases th at regulate cellular com m un icat ion an d processes led to th e iden tification of m ore th an 500 kin ases, som e of w h ich play an in tegral role in cellular fun ct ion , in cluding path ogen esis of thyroid can cer.96 More recen tly, substan ces im pactin g kin ase activit y h ave sh ow n th erapeutic prom ise in a grow in g am oun t of m align an cies to include both MTC an d ATC ( Table 12.2).97 Research h as revealed th at th e vascular en dothelial grow th factor receptor (VEGFR) an d epiderm al grow th factor receptor (EGFR) path w ays play an im portan t role in th e path ogen esis of MTC. Th is led to th e developm en t of t yrosin e kin ase/m ult ikin ase in h ibitors th at m odulate dysfun ct ion al kin ase path w ays. Van detin ib an d cabozan tin ib w ere approved by th e Food an d Drug Adm in istration (FDA) in April 2011 an d Novem ber 2012, respect ively, for use in patien ts w ith advan ced MTC. Th eir use h as been associated w ith im proved progression -free survival (PFS) but n ot im proved overall sur vival.32 A large study assessing cabozan tin ib th erapy (140 m g daily) in patien ts w ith advan ced, prim arily sporadic, MTC foun d a m edian PFS of 11.2 m on th s in com parison to 4 m on th s for placebo. Th e im provem en t in PFS at 1 year w as 47.2% in com parison to 7.2% in th e placebo group. An object ive respon se rate (RR) of 28% an d a partial respon se (PR) duration of 14.6 m on th s w ere n oted, as w ell as 45% an d 24% decreases in calciton in an d CEA, respect ively.98 Th e ph ase 3 evaluation of van detan ib w as perform ed prim arily in cases of sporadic an d m etastatic MTC. Van detan ib th erapy (300 m g daily) ach ieved a disease con trol

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Medical Managem ent of Medullary and Anaplast ic Thyroid Cancer Table 12.2 Potential system ic agents for treatm ents of m edullary thyroid cancer and/or anaplastic thyroid cancer Agent

Mechanism of action

MTC

ATC

Axitinib

Inhibitor of VEGFR

X

Cabozantinib

Inhibitor of c-MET and VEGFR inhibitor

X

Dacarbazine

Alkylating agent

X

Everolim us

Inhibitor of m TOR

X

Fluorouracil

Irreversible inhibition of thym idylate synthase

X

Motesanib

Inhibitor of VEGFR

X

Sunitinib

Inhibitor of VEGFR, PDGFR, KIT, RET

X

Vandetanib

Inhibitor of VEGFR, EGFR and RET-t yrosine

X

Doxorubicin

Anthracycline antibiotic

X

X

Pazopanib

Inhibitor of VEGFRs:1,2 &3; PDGFR, KIT

X

X

Sorafenib

Inhibitor of Raf-1,PDGFR,RET,KIT and VEGFR2

X

X

Carboplatin

Alkylating agent

X

Efatutazone

PPAR-γ agonist

X

Fosbretabulin

Microtubule disrupting agent

X

Im antinib

Inhibitor of Bcr-Abl, PDGFRs: α & β; KIT, RET

X

Paclitaxel

Disruption of microtubule function, m itotic inhibitor

X

Vorinostat

Inhibitor of histone deacet ylase (HDAC)

X

Abbreviations: ATC, anaplastic thyroid cancer; MTC, medullary thyroid cancer; VEGFR, vascular endothelial growth factor receptor, c-MET, hepatocyte growth factor receptor; Inhibitor of m TOR, m am malian target of rapam ycin; PDGFR, platelet-derived growth factor receptors; KIT, t yrosine kinase; RET, ret proto-oncogene; Bcr-Abl, Philadelphia translocation; HDAC, histone deacet ylase.

rate of 87%, w ith a relative RR of 45%, an im proved PFS w ith a m edian h azard ratio of 0.46 (p < 0.001), an d a declin e in calciton in an d CEA of 69% an d 52%, respect ively.32 St udies of sorafen ib (400 m g t w ice daily) th erapy in pat ien ts w ith advan ced MTC foun d an im provem en t in m edian PFS of betw een 10.5 an d 17.9 m on th s. Everolim us h as been studied in n in e patien ts w ith advan ced MTC.99 Prelim in ar y results revealed an im proved PFS of 47 w eeks for all thyroid can cer t ypes. Motesan ib ach ieved stable disease in 81% of pat ien ts w ith a durable respon se ≥ 24 w eeks in 48%. PFS w as 48 w eeks, an d calciton in an d CEA w ere reduced by 83% an d 75%, respectively.100 Im atin ib yielded stable disease (SD) in 27% of advan ced MTC cases, but n o object ive respon ses w ere n oted.101 Treatm en t w ith axitin ib ach ieved an RR of 30%, an SD in 40%, and progressive disease (PD) in 30% w ith first-lin e treatm en t , w ith th e respon se decreasin g w ith secon d- an d th ird-lin e treatm en ts.102 Pazopan ib th erapy w as associated w ith a m edian PFS of 9.4 m on th s an d overall sur vival of 19.9 m on th s.103 A sm all study of sun itin ib in MTC also yielded positive respon ses, w h ereas th erapy w ith suberan ilohydroxam ic acid (vorin ostat), a h iston e deacet ylase (HDAC) in h ibitor, did n ot yield any object ive respon se in th ree MTC patien ts.104 System ic th erapy is associated w ith risk for sign ifican t adverse e ects, w h ich n ot in frequen tly precipitate eith er a reduct ion in dose or discon tin uation of th erapy altogeth er. More com m on adverse side e ects related to system ic th erapy in clude fatigue, w eigh t loss, hyperten sion , h an d-foot syn drom e, rash , n ausea, vom itin g, diarrh ea, an d stom atit is. Van detin ib h as

been also associated w ith sign ifican t QTc in terval prolon gat ion ; th us special t rain in g is required to prescribe th is m edication . Som e positive th erapeutic e ect h as been repor ted w ith treatm en t usin g radiolabeled m olecules, such as [ 90 ytt rium DOTA]-TOC, an d radioim m un oth erapy usin g pretargeted radioim m un oth erapy (pRAIT) w ith a bispecific m on oclon al an tibody (CEA/an t i diethylen etriam in e pen taacetic acid [DPTA]-in dium BsMAb) an d iodin e-131 (131 I)-labeled bivalen t h apten , as w ell as 131 I-m etaiodoben zylguan idin e (MIBG) th erapy to a lesser exten t .105,106 How ever, adverse e ects w ere also n oted, an d th ese th erapies rem ain m ore investigation al in n ature. Ch em oth erapy, t ypically w ith radioth erapy, h as been t radition ally used in treatm en t of ATC but w ith relatively m odest success un t il th e developm en t of n ew m ultim odal regim en s. Data from Mayo Clin ic for patien ts w ith ATC t reated betw een 1949 an d 1999 revealed n o ch em oth erapy-related im provem en t in m edian sur vival.2 Th e radiosen sit izing agen ts doxorubicin an d cisplatin h ave been associated w ith variable success in treatm en t of ATC.56,63,107 More recen tly, studies h ave sh ow n a ben efit from taxan e th erapy, w ith on e study n otin g a 53% RR to paclitaxel an d an oth er reportin g a 33% RR an d 1-year sur vival of 44%.108,109 Docetaxel, an oth er taxan e, ach ieved on ly a 14% RR alon e, but adm in istered w ith IMRT a m edian sur vival > 21 m on th s w as ach ieved in five out of six patien ts.110,111 Foote et al reported a n otable respon se in 10 ATC patien ts receivin g com bin ation IMRT an d system ic th erapy, w ith stage IVA/IVB patien ts displayin g an overall sur vival of 70% at th e 1-year an d 60% at th e 2-year tim e poin ts ( Fig. 12.1).112

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Thyroid Diseases som e success h as also been ach ieved w ith som atostatin an alogue th erapy.125 Addition ally, alth ough diarrh ea is a poten tial adverse e ect of som e TKI agen ts, reduction in calciton in levels secon dary to kin ase th erapy can be associated w ith decreased diarrh ea as w ell. Data on use of clay-derived bin ders also sh ow prom ise.126

12.6 Surveillance Test ing

Fig. 12.1 Survival im provem ent in anaplastic thyroid cancer with multim odal therapy. IMRT, intensit y-m odulated radiation therapy. (Used with perm ission from Foote RL, Molina JR, Kasperbauer JL, et al. Enhanced survival in locoregionally confined anaplastic thyroid carcinom a: a single institution experience using aggressive multim odal therapy. Thyroid 2011;21:25–30.)

Th ere is a grow in g body of eviden ce for oth er poten t ial agen ts in th e treatm en t of ATC. Im atin ib, a t yrosin e kin ase in h ibitor (TKI), ach ieved a PR in 25% of cases an d SD in 50% w ith a PFS of 6 m on th s in 36%.113 An oth er study foun d th at im at in ib appears to en h an ce th e an tit um or e ect of docetaxel in ATC cell cultures.114 Sorafin ib th erapy attain ed a m edian PFS of 4.4 m on th s, w h ereas an oth er trial yielded SD in 25% an d PR in 10% w ith a m edian PFS of 1.9 m on th s.115,116 Th e respon se to fosbretabulin , a m icrotubule disruptin g agen t , h as been m ixed, ach ieving a 27% SD rate in on e study but n o ch ange in m edian sur vival in com bin ation w ith carboplatin /paclitaxel in an oth er.117,118 Testin g of efatu tazon e, a PPAR-γ agon ist, dosed orally t w ice daily w ith paclitaxel ever y 3 w eeks, ach ieved a m edian sur vival of 98 an d 138 days w ith 0.15 m g an d 0.3 m g treatm en t doses, respect ively.119 Preclin ical studies testin g Aurora-A an d Aurora-B in h ibition h ave revealed t um or in h ibition in both cell culture an d xen ograft m odels, w h ereas a com bin ation of aferin A an d sorafen ib revealed a syn ergistic apoptotic e ect on th e ATC cell lin e (SW1736).120,121,122 Studies in th e area of system ic th erapy for thyroid can cer h ave been in creasin g over th e first decade of th is cen tur y.123 At th e t im e of w rit in g, th e Nation al Can cer In stitute (NCI) Clin ical Trials Web site in cludes th ree treatm en t studies recruit in g ATC patien ts. Th ese protocols in clude a ph ase 1/2 trial com paring th e follow in g regim en s: crolibulin (EPC2407), a m icrotubulin in h ibitor, plus cisplatin ; IMRT an d paclitaxel w ith an d w ith out pazopan ib; an d efat utazon e w ith paclitaxel in com parison to paclitaxel alon e.124 At presen t, ATA ATC guidelin es recom m en d a ch em oth erapeutic regim en th at in cludes a taxan e an d/or an th racyclin e, such as doxorubicin , an d/or a platin , such as cisplat in or carboplatin .22 Alth ough diarrh ea is a poten tial adverse e ect of certain system ic th erapies, it is also en coun tered in MTC pat ien ts, related to sign ifican t calciton in elevation s. Th e diarrh ea can be relatively problem atic an d ch allengin g to cont rol in som e patien ts. Alth ough reduct ion of calciton in levels by m ean s of reducin g tum or burden is desirable, it is n ot alw ays attain able. Many patien ts respon d to treatm en t w ith an tim otilit y agen ts, an d

Th e presen tin g stage of disease, residual t um or burden follow in g surgery, presen ce of postoperative com plication s, an d in dividual patien t n eeds all im pact th e sch edule of sur veillan ce testin g. In MTC cases, Ct an d CEA levels sh ould in itially be obtain ed at 6-m on th in tervals. Testin g sh ould occur m ore frequen tly w ith eviden ce of risin g t um or m arkers, occurrin g at approxim ately on e-fourth th e sh ortest doublin g rate period. Alth ough th e fin din g of an un detectable Ct level alon g w ith n egative surveillan ce im aging is consisten t w ith lack of eviden ce for disease, cont in ued sur veillan ce is required. Th e in terval betw een sur veillan ce testin g can be broaden ed over tim e if patien ts rem ain free of eviden ce for disease. Measurable basal Ct levels leave open th e possibilit y of recurren ce, an d levels > 150 pg/m L are suggestive of th e presence of m etastatic disease. CEA levels can also be m on itored. Th e rate in rise of Ct an d CEA, also kn ow n as th e Ct an d/or CEA doublin g tim es, h as been sh ow n to be useful in predictin g both th e progression an d aggressiven ess of MTC. Ten -year sur vival correlates w ith MTC tum or m arker doublin g tim e: < 6 m on th s 8%, 6 to 24 m on th s 37%, an d > 2 years 100%.66,127 Th e ATA provides free access to an on lin e doublin g rate calculator.128 Ct elevation > 400 pg/m L or th e presen ce of cervical lym ph n ode m etastases in dicates th e n eed for addition al localization im aging. Th e ATA MTC guidelin es suggest use of cross-section al im aging, such as n eck an d ch est CT plus th ree-ph ase contrasten h an ced liver CT or MRI.16,129 A bon e scan an d/or MRI of th e spin e an d pelvis is recom m en ded for iden tifyin g bon e m etastases.130 Th ere are conflict in g data on th e usefuln ess of FDG-PET for th e detect ion of MTC m etastases. A m eta-an alysis revealed a 59% m etastasis detect ion rate (DR) by FDG-PET or PET/CT in patien ts w ith recurren t MTC (95% confiden ce in terval: 54– 63%), w ith lack of localization in approxim ately 40% of recurrent MTC.131 Results w ere m ore prom isin g for patien ts w ith seru m Ct ≥ 1,000 n g/L, CEA ≥ 5 n g/m L, calciton in -doubling tim e < 12 m on th s, or CEA doublin g-t im e < 24 m on th s, w h ich exh ibited respect ive DRs of 75%, 69%, 76%, an d 91%.44 Due to th eir relatively low sen sitivit y, im aging w ith radion uclides, such as iridiu m 111 ( 111 In )-oct reotide, tech n etium -99 m ( 99m Tc)dim ercaptosuccin ic acid ( 99m Tc-DMSA), or 131 I-labeled an ti-CEA an tibodies are n ot recom m en ded for in itial localization e orts, alth ough th ese m odalit ies can be con sidered in th e face of elevated Ct or CEA levels an d persisten tly n egative conven t ion al im aging.132 In cases w h ere local recurren ce or m etastatic disease is foun d, t um or or m etastases resection is preferred w h en feasible. Otherw ise, addition al th erapeutic option s in clude EBRT, targeted th erapy w ith radiofrequen cy ablation , arterial em bolization , cryosurgery, or system ic th erapy. Because pat ien ts w ith ATC t ypically exh ibit progression w ith in on ly a few m on th s’ tim e, in itial m on itorin g sh ould occur in 1- to 3-m on th in tervals. In cases w ith out eviden ce of

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Medical Managem ent of Medullary and Anaplast ic Thyroid Cancer progression at 1 year, th is can occur less frequen tly. 18-FDGPET scan n in g is superior to CT alon e for detect ion of m etastases an d alters t reat m en t decision m akin g in 25 to 50% of cases.44 Addition al targeted use of US an d cross-section al im aging w ith CT an d MRI can be em ployed as w ell. Because osseous ATC m etastases ten d to be osteolytic, bon e scan is of lim ited utilit y. ATC tum ors do n ot produce or secrete thyroglobulin , so its m easurem en t does n ot play a role in follow -up. In cases of progressive ATC, th e patien t an d treatm en t team n eed to con tin ually discuss an d update treatm en t goals an d th e th erapeutic plan accordingly. Also, th e n eed for involvem en t of palliative an d/or h ospice care ser vices sh ould be regularly recon sidered in such cases as w ell. Eth ical concern s can arise w h en carin g for patien ts w ith ATC an d MTC. In h erited form s of MTC are particularly com plicated. It is recom m en ded th at patien ts w ith MTC or MEN w h o are foun d to h ave a RET m utation n otify relevan t fam ily m em bers so th at coun seling an d poten t ial screen in g can occur in a prom pt m an n er. Sh ould a patien t refuse to provide such n otification to poten tially a ected fam ily m em bers, con sultation w ith th e supportin g m edical facility’s eth ics com m ittee sh ould occur. Such consultation , alon g w ith m edical-legal in put, w ill h elp determ in e th e m ost appropriate course of act ion to address such ch allengin g situ ation s.

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[63] Heym ann RS, Bren t GA, Hersh m an JM. An aplastic thyroid carcinom a w ith thyrotoxicosis an d hypoparathyroidism . En docr Pract 2005; 11(4); 281–284 [64] Alagöl F, Tan akol R, Boztepe H, Kapran Y, Terzioglu T, Dizdaroglu F. An aplastic thyroid can cer w ith tran sien t thyrotoxicosis: case report an d literature review. Th yroid 1999; 9(10); 1029–1032 [65] Bogsrud TV, Karan tan is D, Nath an MA, et al. 18F-FDG PET in th e m an agem en t of patien ts w ith an aplastic thyroid carcin om a. Thyroid 2008; 18(7); 713–719 [66] Mach ens A, Schn eyer U, Holzh ausen HJ, Dralle H. Prospects of rem ission in m edullar y thyroid carcinom a accordin g to basal calcitonin level. J Clin En docrin ol Metab 2005; 90(4); 2029–2034 [67] Modiglian i E, Coh en R, Cam pos JM, et al. Th e GETC Study Group. Progn ostic factors for sur vival an d for bioch em ical cure in m edullary thyroid carcinom a: results in 899 patien ts. Th e GETC Study Group. Groupe d’étude des tum eurs à calciton in e. 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Medical Managem ent of Medullary and Anaplast ic Thyroid Cancer [88] De Crevoisier R, Baudin E, Bach elot A, et al. Com bin ed treatm en t of an aplastic thyroid carcin om a w ith surgery, ch em oth erapy, an d hyperfract ion ated accelerated extern al radiotherapy. In t J Radiat On col Biol Phys 2004; 60(4); 1137– 1143 [89] McW illiam s RR, Gian n in i C, Hay ID, At kin son JL, St a ord SL, Bu ckn er JC. Man agem en t of brain m etast ases from t h yroid carcin om a: a st u d y of 16 p at h ologically con fir m ed cases over 25 years. Can cer 2003; 98(2); 356– 362 [90] Dah l PR, Brodlan d DG, Goelln er JR, Hay ID. Thyroid carcin om a m etastatic to th e skin : a cutan eous m an ifestation of a w idely dissem in ated m align an cy. J Am Acad Derm atol 1997; 36(4); 531–537 [91] Tickoo SK, Pittas AG, Adler M, et al. Bon e m etastases from thyroid carcinom a: a h istopath ologic study w ith clin ical correlates. Arch Pathol Lab Med 2000; 124(10); 1440–1447 [92] Wexler JA. Approach to th e thyroid can cer patien t w ith bon e m etastases. J Clin En docrin ol Metab 2011; 96(8); 2296–2307 [93] Quan GM, Poin tillart V, Palussière J, Bon ichon F. Multidisciplin ar y treatm en t an d sur vival of patien ts w ith vertebral m etastases from thyroid carcin om a. Thyroid 2012; 22(2); 125–130 [94] Vitale G, Fon derico F, Mart ign etti A, et al. Pam idron ate im proves th e quality of life an d in duces clin ical rem ission of bon e m etastases in patien ts w ith thyroid can cer. Br J Can cer 2001; 84(12); 1586–1590 [95] Aapro M, Abrah am sson PA, Body JJ, et al. Guidan ce on th e use of bisph osph on ates in solid tum ours: recom m en dation s of an in tern ation al expert pan el. An n On col 2008; 19(3); 420–432 [96] Keefe SM, Coh en MA, Brose MS. Targetin g vascular en doth elial grow th factor receptor in thyroid can cer: th e in tracellular an d extracellular im plication s. Clin Can cer Res 2010; 16(3); 778–783 [97] Kapiteijn E, Schn eider TC, Morreau H, Gelderblom H, Nortier JW, Sm it JW . New treatm en t m odalities in advan ced thyroid can cer. An n On col 2012; 23 (1); 10–18 [98] Ravaud A, de la Fouch ardière C, Asselin eau J, et al. E cacy of sun itin ib in advan ced m edullary thyroid carcin om a: in term ediate results of ph ase II THYSU. On cologist 2010; 15(2); 212–213, auth or reply 214 [99] Lim SM, Ch an g H, Yoon MJ, et al. A m ulticen ter, ph ase II trial of everolim us in locally advan ced or m etastatic thyroid can cer of all h istologic subt ypes. An n On col 2013; 24(12); 3089–3094 [100] Sch lum berger MJ, Elisei R, Basth olt L, et al. Ph ase II study of safety an d e cacy of m otesan ib in patien ts w ith progressive or sym ptom atic, advan ced or m etastatic m edullary thyroid can cer. J Clin On col 2009; 27(23); 3794–3801 [101] de Groot JW , Zon n en berg BA, van U ord-Man n esse PQ, et al. A ph ase II trial of im atin ib th erapy for m etastatic m edullar y thyroid carcin om a. J Clin En docrin ol Metab 2007; 92(9); 3466–3469 [102] Capdevila J, Perez JM, Aller J, et al. Axitin ib treatm en t in advan ced RAI-resistan t di eren tiated thyroid can cer (DTC) an d refractory m edullar y thyroid can cer (MTC). J Clin On col 2014; 32; 5s–(suppl; abstr 6027) [103] Bible KC, Sum an VJ, Molin a JR, et al. En docrin e Malign an cies Disease Orien ted Group, Mayo Clin ic Can cer Cen ter, an d th e Mayo Ph ase 2 Con sortium . A m ulticen ter ph ase 2 trial of pazopan ib in m etastatic an d progressive m edullar y thyroid carcin om a: MC057 H. J Clin En docrin ol Metab 2014; 99(5); 1687– 1693 [104] Woyach JA, Kloos RT, Rin gel MD, et al. Lack of t h erap eu t ic e ect of t h e h ist on e d eacet ylase in h ibit or vorin ost at in p at ien t s w it h m et ast at ic rad ioiod in e-refract or y t h yroid carcin om a. J Clin En d ocrin ol Met ab 2009; 94(1); 164–170 [105] Iten F, Mü ller B, Sch in dler C, et al. Respon se to [90Yttr ium -DOTA]-TOC treatm en t is associated w ith lon g-term sur vival ben efit in m etastasized m edullar y thyroid can cer: a ph ase II clin ical trial. Clin Can cer Res 2007; 13(22 Pt 1); 6696–6702 [106] Ch atal JF, Cam pion L, Kraeber-Bodéré F, et al. Fren ch En docrin e Tum or Group. Sur vival im provem en t in patien ts w ith m edullary thyroid carcin om a w h o un dergo pretargeted an ti-carcin oem br yon ic-an tigen radioim m un oth erapy: a collaborative study w ith th e Fren ch En docrin e Tum or Group. J Clin On col 2006; 24(11); 1705–1711 [107] Sh im aoka K, Sch oen feld DA, DeW ys WD, Creech RH, DeCon ti R. A ran dom ized trial of doxorubicin versus doxorubicin plus cisplatin in patien ts w ith advan ced thyroid carcinom a. Can cer 1985; 56(9); 2155–2160 [108] Ain KB, Egorin MJ, DeSim on e PA. Collaborative An aplastic Th yroid Can cer Health In terven tion Trials (CATCHIT) Group. Treatm en t of an aplastic thyroid carcinom a w ith paclitaxel: ph ase 2 tr ial usin g n in ety-six-h our in fusion . Thyroid 2000; 10(7); 587–594

[109] Higash iyam a T, Ito Y, Hirokaw a M, et al. In duct ion ch em oth erapy w ith w eekly paclitaxel adm in istration for an aplastic thyroid carcin om a. Thyroid 2010; 20(1); 7–14 [110] Troch M, Koperek O, Sch euba C, et al. High e cacy of con com itan t treatm en t of un di eren tiated (an aplastic) thyroid can cer w ith radiation an d docetaxel. J Clin En docrin ol Metab 2010; 95(9); E54–E57 [111] Kaw ada K, Kitagaw a K, Kam ei S, et al. Th e feasibility study of docetaxel in patien ts w ith an aplastic thyroid can cer. Jpn J Clin On col 2010; 40(6); 596– 599 [112] Foote RL, Molin a JR, Kasperbauer JL, et al. En h an ced sur vival in locoregion ally con fin ed an aplastic thyroid carcinom a: a sin gle-institu tion experien ce usin g aggressive m ultim odal th erapy. Thyroid 2011; 21(1); 25–30 [113] Ha HT, Lee JS, Urba S, et al. A ph ase II study of im atin ib in patien ts w ith advan ced an aplastic thyroid can cer. 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Thyroid 2014; 24(2); 232–240 [119] Sm allridge RC, Coplan d JA, Brose MS, et al. Efatutazon e, an oral PPAR-γ agon ist, in com bination w ith paclitaxel in an aplastic thyroid can cer: results of a m ulticen ter ph ase 1 trial. J Clin En docrin ol Metab 2013; 98(6); 2392–2400 [120] Libert in i S, Abagn ale A, Passaro C, et al. AZD1152 n egatively a ects th e grow th of an aplastic thyroid carcinom a cells an d en h an ces th e e ects of on colytic virus dl922–947. En docr Relat Can cer 2011; 18(1); 129–141 [121] Wun derlich A, Fisch er M, Sch lossh auer T, et al. Evaluation of Aurora kin ase in h ibition as a n ew th erapeutic strategy in an aplastic an d poorly di eren tiated follicular thyroid can cer. Can cer Sci 2011; 102(4); 762–768 [122] Coh en SM, Mukerji R, Tim m erm an n BN, Sam adi AK, Coh en MS. A n ovel com bin ation of w ith aferin A an d sorafen ib sh ow s syn ergistic e cacy again st both papillary an d an aplastic thyroid can cers. Am J Surg 2012; 204(6); 895–900, discussion 900–901 [123] Bern et V, Sm allridge R. New th erapeutic option s for advan ced form s of thyroid can cer. Expert Opin Em erg Drugs 2014; 19(2); 225–241 [124] Nation al Can cer In stit ute Clin ical Trial. h ttp://w w w.can cer.gov/clinicaltrials/ search . Accessed. Septem ber 14, 2014 [125] Vain as I, Koussis Ch , Pazaitou-Pan ayiotou K, et al. Som atostatin receptor expression in vivo an d respon se to som atostatin an alog th erapy w ith or w ith out oth er an tin eoplastic treatm en ts in advan ced m edullar y thyroid carcinom a. J Exp Clin Can cer Res 2004; 23(4); 549–559 [126] Dadu R, Hu MI, Cleelan d CS, et al. Th e E cacy of th e Natural Clay, CASAD, In Reducin g Medullar y Thyroid Can cer (MTC)-Related Diarrh ea an d Its E ects on Quality of Life (QOL): A Pilot Study. 84th An n ual Meetin g of th e Am erican Thyroid Association . Poster 166. Thyroid. 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Part 3 Surgical Managem ent of Thyroid Diseases

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13 Conventional Thyroidectomy

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14 Minim ally Invasive Thyroid Surgery

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15 Rem ot e Access Thyroid Surgery

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16 Substernal Goit er

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17 Surgical Managem ent of Medullary Thyroid Cancer

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18 Surgical Managem ent of Anaplast ic Thyroid Cancer

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19 Surgical Managem ent of the Central Neck Com partm ent for Di erentiated Thyroid Cancer

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20 Surgical Managem ent of the Lateral Neck in Thyroid Cancer

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13 Convent ional Thyroidect om y Gerard Doherty

13.1 Int roduct ion Conven tion al thyroidectom y is th e stan dard an d m ost com m on ly em ployed approach to thyroid surgery. Th is open operative approach ( Table 13.1) is un iversally applicable, w h ereas oth er approach es m ay h ave specific requirem en ts or exclusion s based on pat ien t or thyroid glan d ch aracteristics. Thyroidectom y is considered a delicate procedure based on sign ifican t tech n ical com plication s th at can create perm an en t ch anges to patien t fun ction . Th e m ost com m on of th ese are hypoparathyroidism an d n erve injur y. A clear un derstan din g of th e an atom y an d safe approach es to th e procedure are critical to m in im izing th e occurren ce of th ese com plication s.

13.2 Operat ive St eps 13.2.1 Beach Chair Posit ion and Curvilinear Skin Crease Incision General anesthesia is preferred, w ith the patient sem isupine in a partially sitting position (beach chair position), hands in the lap, and the neck gently extended by a support placed transversely beneath the shoulders. Local anesthetic techniques, w ith or w ithout concom itant sedation, can be used in selected patient circum stances. Neck extension should be lim ited to m inim ize postoperative discom fort and to keep the overlying strap m uscles relaxed. A transverse cervical incision of 4 to 5 cm in length is typical, though this m ay be longer or shorter depending upon the patient’s habitus and the size of the gland to be rem oved. For larger thyroid glands, the skin incision is rarely the lim iting factor in exposure; rather, the strap m uscles m ay im pede delivery of the gland from the w ound. An incision over the thyroid isthm us, w hich is consistently positioned one fingerbreadth below the cricoid cartilage, gives good exposure to the upper and low er poles. The incision should generally be gently curved, sym m etrical, and placed in a natural skin crease for good cosm esis.

13.2.2 St rap Muscle Separat ion and Thyroid Exposure Th e in cision is carried th rough th e subcutan eous fat an d platysm a m uscle. Subplat ysm al flaps can im prove th e m obilit y of th e Table 13.1 Sequential steps of thyroidectom y 1

Beach chair position and curvilinear skin crease incision

2

Strap m uscle separation and thyroid exposure

3

Upper pole m obilization

4

Division of superior vascular pedicle

5

Lateral dissection and middle thyroid vein division

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Recurrent laryngeal nerve and parathyroid gland identification

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Inferior vessel division and ligam ent of Berry dissection

un derlyin g m uscles an d thyroid glan d. Th e an terior jugular vein s m ay be used to defin e th e deep lim it of th e plan e of dissect ion w h en th e platysm a m uscle can n ot be easily iden tified. Th e strap m uscles are separated in th e m idlin e. Th e paired stern ohyoid an d stern othyroid m uscles are elevated an d dissected aw ay from th e thyroid capsule. Th e strap m uscles can be tran sected t ran sversely if n ecessar y to gain addition al exposure.

13.2.3 Upper Pole Mobilizat ion With th e strap m uscles an d carotid artery retracted w ith a sm all Rich ardson retractor, in ferolateral ten sion is placed on t h e u p p er p ole of t h e t hyroid lobe. Th e sp ace bet w een t h e cricothyroid m u scle an d th e m ed ial asp ect of th e u p p er p ole of th e t hyroid glan d is op en ed . Th e u p p er p ole is sep arated from t h e lar yn x by d issecting from in fer ior to su p er ior, isolatin g t h e su p er ior t hyroid vessels aw ay from t h e extern al bran ch of t h e su p erior lar yn geal n er ve (EBSLN).

13.2.4 Division of t he Superior Vascular Pedicle Th e superior pedicle m ay be divided w ith a pow ered dissection in strum en t (e.g., th e h arm on ic scalpel or an elect rosurgical device), or betw een clips or t ies. Th e vessels m ust be carefully divided adjacen t to th eir site of pen etration of th e thyroid cap sule to avoid injur y to th e EBSLN an d devascularization of a superior parathyroid glan d, w h ich can be supplied in part by th e superior thyroid artery.

13.2.5 Lat eral Dissect ion and Middle Thyroid Vein Division With th e superior pole of th e thyroid free of fascial attach m en ts, th e thyroid lobe is retracted m edially, rotatin g th e laryn x to expose th e trach eoesoph ageal groove, an d dissection com m en ces on th e lateral aspect of th e lobe. On e or m ore m iddle thyroid vein s m ay be en coun tered an d divided alon g th e lateral aspect of th e thyroid.

13.2.6 Recurrent Laryngeal Nerve and Parat hyroid Gland Ident ificat ion Th e thyroid lobe is reflected an teriorly to expose th e trach eoesoph ageal groove. Th e dissect ion is carried dow n alon g th e m edial surface of th e carotid arter y to th e prevertebral fascia. Th e in ferior thyroid artery (ITA) can be iden tified passin g deep to th e carotid in its course tow ard th e low er pole of th e thyroid. Careful dissection is n ecessary aroun d th e ITA to iden tify th e recurren t lar yngeal n er ve (RLN) as it passes un dern eath , or less com m on ly, an terior to th e artery ( Fig. 13.1). If th e RLN is n ot visible, it can usually be iden tified caudally (in previously un dissected areas) as it ascen ds in th e t rach eoesoph ageal groove. Th e ceph alad course of th e n er ve is defin ed, takin g care

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Conventional Thyroidectom y

Fig. 13.1 Reflection of the left lobe of the thyroid gland reveals the relationship of the inferior parathyroid gland, inferior thyroid artery, and left recurrent laryngeal nerve.

Fig. 13.2 The superior parathyroid gland is often tucked posterior to the upper pole, t ypically superior to the inferior thyroid artery, and posterior to the recurrent laryngeal nerve.

to preserve bran ch es th at arise proxim al to its disappearan ce un der th e caudal border of th e in ferior constrictor m uscle. Th e righ t RLN arises m ore laterally in th e ch est th an th e left , leadin g to a m ore oblique course. Th e righ t RLN can also bran ch directly from th e vagus n er ve to th e lar yn x (a “n on recurren t” n er ve). Th is varian t n erve alw ays passes posterior to th e carotid artery en route to th e lar yn x. Th e superior an d in ferior parathyroid glan ds can be preserved by dissectin g th em aw ay from th e posterior capsule of th e thyroid glan d w ith th eir vascular pedicles. Th e superior

glan ds are m ost com m on ly located on th e dorsal surface of th e thyroid lobe at th e level of th e upper t w o-th irds of th e glan d ( Fig. 13.2). Alth ough th eir location is m ore variable, th e low er glan ds usually lie caudal to th e ITA.

13.2.7 Inferior Vessel Division and Ligam ent of Berry Dissect ion W ith th e course of th e RLN directly iden tified, th e bran ch es of th e ITA are divided adjacen t to th eir en t ran ce in to th e thyroid

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Surgical Managem ent of Thyroid Diseases glan d to preserve th e parathyroid blood supply. Th e in ferior pole is th en dissected. Th e sm all arteries an d vein s in th is area are divided. Th e RLN is vuln erable to injur y in th is area if its course is n ot clear. With its upper an d low er poles free, th e thyroid lobe rem ain s fixed to th e trach ea by th e ligam en t of Berr y. Th e thyroid glan d is rolled m edially, an d w ith th e RLN separated from th e thyroid glan d an d in clear view, th e ligam en t is en circled, ligated, an d divided ( Fig. 13.3). Th e thyroid glan d can th en be dissected from th e an terior surface of th e trach ea.

13.3 Principles of Thyroid Dissect ion Th ough th e steps of dissection already detailed are applicable in m ost circum stan ces, th ey m ay require m odification in certain patien ts. Can cer or ver y large thyroid glan ds, in particular, can preven t th e perform an ce of th e operation in th e usual

Fig. 13.3 Once the superior and inferior pole vessels have been divided, the parathyroid glands have been dropped away from the posterior surface of the thyroid gland, and the recurrent laryngeal nerve (RLN) has been exposed up to the insertion into the larynx, the ligam ent of Berry can be safely divided as shown in this depiction of the dissection of the right thyroid lobe.

sequen ce. How ever, alth ough th e steps of th e operation m ay ch ange, th e prin ciples of safe dissect ion to m in im ize th e risk of dam age to adjacen t struct ures sh ould n ot ch ange ( Table 13.2).

13.3.1 Five Key Principles of Dissect ion 1. Avoid dividing any struct ures in th e trach eoesoph ageal groove un til th e n er ve is defin itively iden tified. Sm all bran ch es of th e ITA m ay seem like th ey can clearly be safely tran sected; h ow ever, th e distort ion of tum or, retract ion , or previous scar m ay lead th e surgeon to m istaken ly divide a bran ch of th e RLN. Th e iden tifyin g feature of th e RLN is th at, th e m ore it is dissected, th e m ore it looks like th e correct struct ure, based on both th e m orph ological appearan ce an d th e an atom ical course. Th e n erve can tolerate m an ipulation but n ot cut tin g. On ce cut , repair of th e n er ve is of un proven ben efit. 2. Iden tify th e n erve low in th e n eck, w ell below th e ITA, at th e level of th e low er pole of th e thyroid glan d, or below. Th is allow s dissection of th e n erve at a site w h ere it is n ot teth ered by its attachm en ts to th e lar yn x or its proxim it y to th e ITA. Traction injuries to th e n erve can occur w h en th e n er ve is m an ipulated n ear a site of fixation . 3. Keep th e n erve in view durin g th e subsequen t dissect ion of th e thyroid aw ay from th e lar yn x. On ce th e n erve is iden tified, th e dissection can gen erally proceed from in ferior to superior alon g th e n er ve, dividing th e ITA bran ches an d preservin g th e parathyroid glan ds. Th is allow s careful dissect ion of th e tissues w ith m in im al m an ipulation of th e RLN. 4. Min im ize th e use of pow ered dissect ion posterior to th e thyroid. Alth ough th e electrocauter y an d h igh -frequen cy ultrason ic scalpel are useful tools in dissect ion , th ey h ave som e risk of lateral th erm al spread, w h ich can dam age adjacen t tissues. Careful cold dissect ion an d h em ostasis w ith ligatures or clips w ill avoid th is risk. Th is is particularly im portan t at th e en t r y of th e RLN to th e laryn x, im m ediately adjacen t to th e ligam en t of Berr y an d its vessels. 5. Treat every parathyroid gland as though it w ere the last; use parathyroid autografting liberally w hen the parathyroid gland appearance is changed. It can be challenging to identify dam aged parathyroid glands. Given the very high success rate of fresh parathyroid autografting, this should be routinely used for any glands that have been com prom ised by dissection.

13.4 Thyroidect om y Com plicat ions Safe perform an ce of conven t ion al thyroidectom y requires kn ow ledge of th e poten tial com plication s of th e procedure

Table 13.2 Key principles of thyroid dissection 1

Avoid dividing any structures in the tracheoesophageal groove until the nerve is definitively identified

2

Identify the nerve low in the neck, well below the inferior thyroid artery, at the level of the lower pole of the thyroid gland, or below

3

Keep the nerve in view during the subsequent dissection of the thyroid away from the larynx

4

Minim ize the use of powered dissection posterior to the thyroid

5

Treat every parathyroid gland as though it were the last; use parathyroid autograft liberally when parathyroid gland appearance is changed

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Conventional Thyroidectom y Table 13.3 Incidence of com plications after total thyroidectomy Authors, year

Num ber of patients

Transient nerve paresis, N (%)

Perm anent nerve paresis, N (%)

Transient hypoparathyroidism , N (%)

Perm anent hypoparathyroidism , N (%)

Thom pson et al, 1978 7

165

NR

0

NR

< 2%

Farrar et al, 1980 6

29

NR

1 (3%)

2 (7%)

4 (14%)

Schroder et al, 1986 8 56

1 (2%)

0

9 (17%)

3 (6%)

Clark et al, 1988 9

160

4 (2.5%)

3 (2%)

NR

1 (0.6%)

Ley et al, 1993 10

124

1 (0.8%)

1 (0.8%)

13 (10%)

2 (1.6%)

Tartaglia et al, 2003 11

1,636

31 (1.9%)

15 (0.9%)

NR

14 (0.9%)

Rosato et al, 2004 12

9,599

195 (2%)

94 (1%)

797 (8.3%)

163 (1.7%)

Grant et al, 2010 13

420

NR

6 (1.4%)

NR

5 (1.2%)

Laird et al, 2012 14

119

2 (1.7%)

0

NR

2 (1.7%)

Abbreviation: NR, not reported.

because an ticipat ion of th ese issues is w h at in form s th e sequen ce an d prin ciples of dissect ion . Th e poten tial com plication s of thyroid operat ion s in clude th e im m ediate dan ger of cervical h em atom a, as w ell as th e m ore ch ron ic com plication s of hypoparathyroidism an d n er ve injury ( Table 13.3).

13.4.1 Neck Hem at om a A p ost op erative n eck h em atom a requ irin g reop erat ion d evelop s in abou t 1 of ever y 150 thyroid ect om ies.1,2,3,4,5 Hem at om as u su ally ap p ear w it h in t h e in it ial 6 h ou rs after t h e com p let ion of th e p roced u re, th ough th ey m ay ap p ear even later if a p at ien t is on an t icoagu lat ion . Th e h em atom a can collect eith er bet w een th e p latysm a m u scle an d th e stern ohyoid m u scles (su p erficial), or d eep to t h e st rap m u scles alon g t h e lar yn x (d eep ). Th e d eep h em atom as are t h e m ore d an gerou s becau se th ey can lead to lar yn geal ed em a an d airw ay obstru ct ion . Th e risk of cervical h em atom a h as led som e to question th e safety of outpatien t thyroidectom y because th ere is th e possibilit y of a h em atom a developin g after disch arge.1,2,3,4,5 Th e curren t experien ce by experts in th e field h as dem on st rated th at outpatien t thyroid surgery can be don e safely, th ough postoperative obser vation for several h ours m ay be con sidered in order to detect th is com plication prior to disch arge.

13.4.2 Hypoparat hyroidism Th e parathyroid glan ds are sm all, delicate struct ures th at sh are a blood supply w ith th e thyroid glan d. Th eir dim in utive size (n orm al 30–60 m g) an d fragile n ature m ake th em particularly pron e to dam age durin g thyroidectom y. Patien ts w h o h ave m arkedly dim in ish ed or absen t parathyroid fun ction after thyroidectom y h ave severe hypocalcem ia th at requires replacem en t to n orm alize. If perm an en t , th is com plication can be palliated by calcium supplem en ts, but th is requires m ultiple doses each day, an d un com fortable sym ptom s occur if doses are late or m issed. In addition , th ere is cum ulative bon e dam age over tim e.

Tem porary hypocalcem ia occurs in about 10% of patien ts after total thyroidectom y, an d perm an en t hypocalcem ia in about 1% (see Table 13.3).6,7,8,9,10,11,12,13,14 Tem porary hypocalcem ia can be severe an d m ay require in traven ous or oral sup plem en tation for th e durat ion of th e e ect . Perm an en t hypoparathyroidism requires lifelon g support w ith calcium supplem en ts an d vitam in D an alogues. Missing doses of th e supplem en ts w ill usually produce sym ptom s of var yin g severit y, w h ich , w h ile m an ageable, are often quite both ersom e for patien ts. In addition to th e discom fort an d in conven ien ce of th e supplem en ts, patien ts develop low -turn over bon e disease, w h ich resem bles osteom alacia.15 Avoidan ce of perm an en t hypoparathyroidism is far m ore desirable th an treatm en t of it. Th is can be accom plish ed by preservation of th e parathyroid glan ds on th eir n ative blood supply, or autograftin g of parathyroid tissue to a m uscular bed.16 Durin g thyroidectom y, th e blood supply to each parathyroid glan d sh ould be iden tified an d specifically con sidered durin g dissect ion . As stated earlier, every parathyroid glan d sh ould be treated as th ough it w ere th e on ly rem ain in g glan d. Durin g dissection of th e thyroid, th e ITA bran ches sh ould be divided distal to th e bran ch ing of th e parathyroid en d-arteries. Th e parathyroid glan ds can th en be m oved posteriorly in th e n eck aw ay from th e thyroid, to allow safe dissect ion of th e RLN an d thyroid attach m en ts to th e trach ea. If th e parathyroid glan ds can n ot be preserved on th eir n ative blood supply, th en tran sfer of th e glan d to a conven ien t graft in g site can m ain tain fun ct ion .16,17 For n orm al parathyroid glan ds, tran sfer to th e stern ocleidom astoid m uscle provides a conven ien t vascular bed for tran splan t. Th e parathyroid glan d m ust be reduced to pieces th at can sur vive on th e di usion of n utrien ts tem porarily w h ile n eovascular in grow th occurs over several w eeks.

13.4.3 Nerve Injuries Th ere are several n erves adjacen t to th e thyroid glan d th at can be deliberately or in adverten tly a ected durin g thyroidectom y. Th ese in clude th e RLN im m ediately adjacen t to th e thyroid, an d

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Surgical Managem ent of Thyroid Diseases th e vagus n er ve, w h ich is sligh tly m ore rem oved, but causes th e sam e sym ptom s if dam aged. Th e extern al bran ch of th e superior lar yn geal n er ve can be injured durin g dissection of th e upper pole of th e thyroid glan d, an d th e sym path etic ch ain an d stellate ganglion can be injured n ear th e posterior aspect of th e upper pole of th e glan d as w ell. Th e RLN an d th e extern al bran ch of th e superior lar yn geal n er ve are directly involved in ever y thyroidectom y. Th e RLN fibers are a part of th e vagus n er ve on each side un til th ey bran ch o in th e upper ch est, course aroun d th e ligam en tum arteriosum (left RLN) or th e subclavian artery (righ t RLN), an d back alon g th e trach eoesoph ageal groove on each side. Th ey pass betw een th e thyroid an d th e lar yn x an d in sert in th e lar yn x at th e in ferior border of th e cricoph ar yn geal m uscle. Th e n er ve often bran ches at about th e level of th e low er pole of th e thyroid an d in serts to th e laryn x as t w o or m ore adjacen t fibers; th ere is also an esoph ageal bran ch th at exten ds posteriorly from about th e level of th e thyroid low er pole. Dam age to th e RLN causes un ilateral paralysis of th e m uscles th at con trol ipsilateral vocal cord m obilit y. Un ilateral RLN injur y ch anges th e voice substan tially in m ost pat ien ts, an d also sign ifican tly a ects th e sw allow in g m ech an ism . Bilateral RLN injur y causes paralysis of both cords an d usually results in a ver y lim ited airw ay lum en at th e glottis. Patien ts w ith th is injury m ay require rein tubation to m ain tain ven t ilation . RLN paresis is usually tem porar y an d resolves over days to m on th s.6,7,8,9,10,11,12,13,14 Th ere is n o kn ow n m eth od of aidin g or speeding recovery. Avoidan ce of RLN injury is far superior to palliation . Great care m ust be taken durin g th e dissection of th e n er ve in order to protect it. In som e clin ical situation s, th e RLN is sacrificed in order to allow adequate tum or resection , but, absen t th is un usual circum stan ce, careful dissect ion can gen erally preserve cord fun ction . Th e use of n er ve stim ulators an d lar yngeal m uscle poten tial m on itors h as recen tly been investigated as a tool to tr y to lim it or avoid n er ve injuries.18,19 How ever, th e risk of n er ve injury is related to several factors, and th e data do n ot curren tly support th e use of th ese devices as stan dard of care.20,21,22,23 Th is m ay be because th ey m erely h elp to iden tify th e n er ve, w h ereas th e portion of th e operation m ost likely to produce dam age in experien ced h an ds is th e dissection of th e RLN at th e fixed poin t of th e cricoph ar yngeus. How ever, m any experienced surgeon s n ow routin ely use a n erve-m on itorin g system for a variet y of reason s, in cluding th e opport un it y to alter a plan n ed bilateral thyroidectom y if th ere is n erve dysfun ct ion on th e side dissected in itially.23 Th e extern al bran ch of th e superior lar yn geal n er ve courses adjacen t to th e superior pole vessels of th e thyroid glan d, th en separates from th e thyroid to pen etrate th e cricoph ar yn geus m uscle fascia at it superoposterior aspect. Th e n er ve supplies m otor in n ervation to th e cricothyroid m uscle. Dam age to th is n er ve ch anges th e abilit y of th e laryn x to con trol h igh -pressure phon ation , such as h igh -pitch ed sin ging (sopran o/falsetto) or yellin g.12,23,24 To avoid dam aging th e EBSLN, th e dissection of th e upper pole vessels sh ould proceed from a space w h ere th e n er ve is sequestered un der th e cricoph ar yngeal fascia, to th e superior vessels th em selves, th us safely separatin g th e n er ve from th e tissue to be divided.

References [1] Burkey SH, van Heerden JA, Th om pson GB, Gran t CS, Schleck CD, Farley DR. Reexploration for sym ptom atic h em atom as after cervical exploration . Surgery 2001; 130(6); 914–920 [2] Adler JT, Sippel RS, Sch aefer S, Ch en H. Preservin g fun ct ion an d quality of life after thyroid an d parathyroid surgery. Lan cet On col 2008; 9(11); 1069–1075 [3] Leyre P, Desurm on t T, Lacoste L, et al. Does th e risk of com pressive h em atom a after thyroidectom y auth orize 1-day surgery? Lan gen becks Arch Surg 2008; 393(5); 733–737 [4] Rosen baum MA, Haridas M, McHen r y CR. Life-th reaten in g n eck h em atom a com plicatin g thyroid an d parathyroid surgery. Am J Surg 2008; 195(3); 339– 343, discussion 343 [5] Harding J, Sebag F, Sierra M, Palazzo FF, Hen r y J-F. Thyroid surger y: postoperative h em atom a—preven tion an d treatm en t. Lan gen becks Arch Surg 2006; 391(3); 169–173 [6] Farrar W B, Cooperm an M, Jam es AG. Surgical m an agem en t of papillar y an d follicular carcinom a of th e thyroid. An n Surg 1980; 192(6); 701–704 [7] Th om pson NW , Nish iyam a RH, Harn ess JK. Th yroid carcin om a: curren t con troversies. Curr Probl Surg 1978; 15(11); 1–67 [8] Sch roder DM, Ch am bors A, Fran ce CJ. Operative strategy for thyroid can cer. Is total thyroidectom y w orth th e price? Can cer 1986; 58(10); 2320–2328 [9] Clark OH, Levin K, Zen g QH, Green span FS, Siperstein A. Th yroid can cer: th e case for total thyroidectom y. Eur J Can cer Clin On col 1988; 24(2); 305–313 [10] Ley PB, Rober ts JW, Sym m on ds RE, Jr, et al. Safety an d e cacy of total thyroidectom y for di eren tiated thyroid carcin om a: a 20-year review. Am Surg 1993; 59(2); 110–114 [11] Tartaglia F, Sgueglia M, Muh aya A, et al. Com plication s in total thyroidectom y: our experien ce an d a n um ber of con sideration s. Ch ir Ital 2003; 55(4); 499–510 [12] Rosato L, Avenia N, Bern an te P, et al. Com plication s of thyroid surgery: an alysis of a m ulticen tric study on 14,934 patien ts operated on in Italy over 5 years. World J Surg 2004; 28(3); 271–276 [13] Gran t CS, Stulak JM, Th om pson GB, Rich ards ML, Readin g CC, Hay ID. Risks an d adequacy of an optim ized surgical approach to th e prim ar y surgical m an agem en t of papillary thyroid carcinom a treated durin g 1999–2006. World J Surg 2010; 34(6); 1239–1246 [14] Laird AM, Gauger PG, Miller BS, Doh ert y GM. Evaluation of postoperative radioactive iodin e scan s in patien ts w h o un derw en t prophylactic central lym ph n ode dissection . World J Surg 2012; 36(6); 1268–1273 [15] Rubin MR, Dem pster DW, Zh ou H et al. Dyn am ic an d struct ural propert ies of th e skeleton in hypoparathyroidism . J Bon e Min er Res 2008; 23(12); 2018– 2024 [16] Olson JA, Jr, DeBen edetti MK, Baum an n DS, Wells SA, Jr. Parathyroid autotran splan tation durin g thyroidectom y. Results of lon g-term follow -up. An n Surg 1996; 223(5); 472–478, discussion 478–480 [17] Th om usch O, Mach en s A, Sekulla C, Ukkat J, Brauckh o M, Dralle H. Th e im pact of surgical tech n ique on postoperative hypoparathyroidism in bilateral thyroid surgery: a m ultivariate an alysis of 5846 con secutive patien ts. Surgery 2003; 133(2); 180–185 [18] Rea JL, Kh an A. Clin ical evoked elect rom yography for recurren t lar yn geal n erve preservation : use of an en dotracheal tube electrode an d a postcricoid surface electrode. Lar yn goscope 1998; 108(9); 1418–1420 [19] Otto RA, Coch ran CS. Sen sitivity an d specificity of in traoperative recurren t lar yn geal n erve stim ulation in predictin g postoperative n er ve paralysis. An n Otol Rh in ol Lar yn gol 2002; 111(11); 1005–1007 [20] Dralle H, Sekulla C, Loren z K, Brauckh o M, Mach en s A, Germ an ISG Germ an IONM Study Group. In traoperative m on itorin g of th e recurren t lar yn geal n erve in thyroid surger y. World J Surg 2008; 32(7); 1358–1366 [21] Dralle H, Sekulla C, Haertin g J, et al. Risk factors of paralysis an d fun ction al outcom e after recurren t laryn geal n er ve m on itoring in thyroid surgery. Surgery 2004; 136(6); 1310–1322 [22] Th om usch O, Sekulla C, Mach en s A, Neum an n H-J, Tim m erm an n W , Dralle H. Validity of in tra-operative n eurom on itorin g sign als in thyroid surgery. Lan gen becks Arch Surg 2004; 389(6); 499–503 [23] Ch an drasekh ar SS, Ran dolph GW , Seidm an MD, et al. Am erican Academ y of Otolaryn gology-Head an d Neck Surgery. Clin ical practice guidelin e: im provin g voice outcom es after thyroid surgery. Otolaryn gol Head Neck Surg 2013; 148(6) Suppl; S1–S37 [24] Stojadin ovic A, Sh ah a AR, Orliko RF, et al. Prospect ive fun ction al voice assessm en t in patien ts un dergoin g thyroid surgery. An n Surg 2002; 236(6); 823–832

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Minim ally Invasive Thyroid Surgery

14 Minim ally Invasive Thyroid Surgery Paolo Miccoli and Gabriele Materazzi

14.1 Int roduct ion Min im ally in vasive t hyroid su rger y o ers several ad van t ages over t h e t rad it ion al t hyroid ect om y p roced u re in carefu lly select ed p at ien t s. Sh or ter in cision len gt h s red u ce t h e cosm et ic im p act of t h e op erat ion . A sm aller exten t of d issect ion , t h e om ission of p ost op erat ive d rain s, an d ou t p at ien t m an agem en t st rat egies d ecrease p ost op erat ive p ain , sp eed t h e recover y p rocess, an d im p rove t h e p at ien t ’s p ost op erat ive experien ce.1,2 ,3 Tw o m in im ally invasive t hyroid ect om y p roced u res are cu rren tly p er form ed : m in im ally in vasive n on en d oscop ic t h yroid ect om y (MINET) an d m in im ally invasive vid eo -assist ed t hyroid ect om y (MIVAT). MINET is t yp ically p erform ed t h rough a 4 cm in cision , w h ereas MIVAT can be p er form ed t h rough in cision s as sm all as 1.5 cm .4 MIVAT u ses en d oscop ic assist an ce to visu alize t h e op erat ive field u n d er t h e soft tissu e en velop e; oth er w ise t h e p roced u res are id en t ical. Alt h ough t h is ch apt er focu ses on t h e MIVAT t ech n iqu e, t h e p rin cip les d iscu ssed are easily ad ap ted for t h e MINET p roced u re.

14.2 Pat ient Select ion St r ict sele ct ion cr it e r ia h ave b e e n d e scr ib e d t o im p r ove t h e ch an ce of op e r at ive su cce ss an d m in im ize com p licat ion s in MIVAT ( Tab le 1 4 .1 ).5 Pat ie n t s sh ou ld h ave b e n ign or in d e te r m in at e n od u le s < 3 t o 3 .5 cm or low - r isk p ap illar y t h yroid car cin om as < 2 cm , w it h an ove rall t h yr oid volu m e < 2 5 m L. Con t r ain d icat ion s in clu d e re cu r r e n t d ise ase , locally ad van ce d or m e t ast at ic car cin om a, an d t h yr oid it is.

14.3.1 St ep 1: Preparat ion of t he Operat ive Space Th e pat ien t, un der gen eral en dotrach eal an esth esia, is placed in a supin e position . Neck hyperexten sion h as to be avoided in order n ot to reduce th e operative space, w h ich is m ain tain ed on ly by an extern al retract ion an d n ot by m ean s of any in su ation . Furth erm ore, th is position is stron gly suggested to m in im ize cervical traum a, w h ich is on e of th e m ost im portan t con tributors to postoperative pain , part icularly in elderly patien ts, w h o often su er from cervical ailm en ts. Th e skin is protected by m ean s of a sterile film (Bioclusive, Joh n son & Joh n son ). A 1.5 cm h orizon tal skin in cision is perform ed in a skin crease approxim ately 2 cm above th e stern al n otch in th e central cervical area ( Fig. 14.1). Th e m on opolar elect rocautery blade is protected, leavin g just th e tip able to coagulate, in order to avoid any possible burn in g of th e skin or th e superficial plan es. Th e subcutan eous fat an d platysm a are carefully dissected w h ile th e m idlin e is open ed for n o m ore th an 2 cm , just en ough to allow th e en doscope an d n eedlescopic in strum en ts to en ter th e operative space. Because th e absen ce of positive pressure provided by in su ation can n ot lim it th e bleeding as in th e m ajorit y of laparoscopic procedures, particular caution is n ecessary w h en dividin g th e strap m uscles alon g th e lin ea alba so as to avoid any bleedin g durin g th is

14.3 Operat ive St eps Th e MIVAT tech n ique h as been previously described in detail6 an d is sum m arized h ere. Th e procedure con sists of both open an d en doscopic port ion s. Exten ding th e in cision sligh tly allow s th e procedure to be perform ed w ith out en doscopic assistan ce. In th ese cases (th e MINET procedure), th e en doscopic steps are perform ed un der direct visualization .

Table 14.1 Indications and contraindications for m inimally invasive video-assisted thyroidectom y Indication

Contraindication

Benign disease a

Recurrent disease (previous cervicotomy)

Graves’ disease a

Locally advanced and/or metastatic carcinom a

Indeterm inate nodule

Short neck in obese patient

“Low-risk” papillary carcinoma

Thyroiditis

a Thyroid

volume < 25 m L and nodule diam eter < 3 cm .

Fig. 14.1 Minim ally invasive video-assisted thyroidectomy is perform ed through a 1.5 cm horizontal skin incision placed in a skin crease ~ 2 cm above the sternal notch in the central cervical area.

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Fig. 14.2 (a) The strap m uscles are divided in the m idline along the linea alba to avoid any bleeding. (b) Two sm all, m odified, m iniaturized Farabeuf retractors give optimal access to the thyroid compartment.

ph ase. Tw o sm all, m odified, m in iaturized Farabeuf retractors give optim al access to th e m idlin e ( Fig. 14.2). Blun t dissection of th e strap m uscles o th e thyroid lobe is perform ed th rough th e skin in cision by gen tle retract ion an d usin g tin y spat ulas. Wh en th e thyroid lobe is alm ost com pletely dissected from th e strap m uscles, larger an d deeper retractors (stan dard Farabeuf retractors) are placed, on e ret ract in g th e thyroid lobe, and the other retract ing the neck bundle, in particular the carotid artery, w hich has to be w ell visualized before being gently retracted ( Fig. 14.3a). The m edial retractor should alm ost com pletely load the thyroid lobe; w hen the correct position is achieved, thyroid parenchym a should not be visible through the endoscope, except a m inim al portion of the posterior part of the lobe ( Fig. 14.3b). The m edial retractor basically plays the role of the hand of the assistant during a conventional thyroidectom y. Then the operative space w ill be correctly established and w ill provide an excellent access to all the critical structures during the endoscopic part of the procedure. Then a 5 m m , 30° endoscope is introduced through this cervical access. From this m om ent on the operation is perform ed endoscopically until the extraction of the lobe of the gland. Preparation of the thyrotracheal groove is com pleted using sm all (2 m m in

diam eter) instrum ents, such as spatulas, forceps, a suction spatula, and scissors, under endoscopic visualization ( Fig. 14.4).

14.3.2 St ep 2: Division of t he Main Thyroid Vessels A Harm on ic device (Eth icon En do-Surgery, In c., Blue Ash , Cin cin n ati, OH, USA) is used for alm ost all th e vascular struct ures, but , if th e vessel to be coagulated is run n ing particularly close to th e recurren t lar yn geal n er ve (RLN), th en h em ostasis is ach ieved by m ean s of sm all vascular clips applied by a disposable or reusable clip applier. Th e first vessel to be ligated is th e m iddle vein , w h en present , or th e sm all vein s betw een th e jugular vein an d thyroid cap sule. Th is provides a larger operative space an d a better retraction betw een th e carotid artery an d th e thyroid lobe, furth er exposing th e thyrotrach eal groove. Durin g th is step th e en doscope h as to be h eld w ith th e 30° tip lookin g dow nw ard an d in an orth ogon al axis w ith th e thyroid lobe an d trach ea. Th e n ext step is exposure of th e upper pedicle, w h ich m ust be carefully prepared, un til optim al visualization of th e di eren t bran ch es is ach ieved. At th is poin t th e en doscope m ust be

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Fig. 14.3 (a) Standard Farabeuf retractors are used to m aintain the operative space. One retractor is placed on the thyroid lobe and the other on the lateral neck structures. (b) When the m edial retractor is correctly placed only a m inim al portion of the thyroid lobe should be visible.

Fig. 14.4 Standard instrum ents used in m inim ally invasive video-assisted thyroid surgery.

flipped dow n side-up an d, lookin g in th e cephalic direct ion , th e upper pedicle w ill be visualized at th e top of th e screen . Th is requires a com plete rotat ion of 180°, w ith th e 30° tip lookin g upw ard an d h eld in a parallel direct ion w ith th e thyroid lobe an d trach ea, in order to better visualize th e upper port ion of th e operat ive field w h ere th e superior thyroid vein an d artery are run n in g ( Fig. 14.5). Th e upper pedicle h as to be exposed by retract in g th e thyroid lobe dow nw ard an d m edially by gen tly loadin g it w ith th e retractor an d th e assistan t spatula. In th e m ean t im e th e vessels are pulled laterally in order to provide th e correct space for th e Harm on ic scalpel to be in troduced. Th is w ill allow th e extern al bran ch of th e superior lar yn geal n erve (SLN) to be easily iden tified durin g m ost procedures ( Fig. 14.6). SLN injur y m ust be avoided an d is preven ted by keepin g th e in active blade of th e en ergy in strum en t facing th e lar yngeal m uscles so as n ot to

tran sm it excessive h eat to th is delicate struct ure. At th is poin t, division of th e upper pedicle can be perform ed w ith th e Harm on ic scalpel en bloc or select ively, depen din g on th e diam eter of th e sin gle vessels or th e an atom ical situ ation .

14.3.3 St ep 3: Ident ificat ion of t he Im port ant St ruct ures of t he Region: The Recurrent Laryngeal Nerve and t he Parat hyroids After retract in g th e thyroid lobe m edially an d ven trally, th e t ip of th e en doscope is again orien ted dow nw ard an d sligh tly m edially, an d th e deeper fascia can be open ed w ith gen tle spatula dissect ion . Th e RLN gen erally appears at th is poin t, lyin g in th e thyrotrach eal groove an d posterior to th e tubercle of

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Fig. 14.5 Endoscopic dissection of the superior vascular pedicle, revealing the vessels and superior laryngeal nerve (SLN). Fig. 14.6 Ligation of the superior vascular pedicle with a Harm onic device. SLN, superior laryngeal nerve.

preserve its sm all pedicle, an d delicately m oved aw ay from th e thyroid glan d, to avoid any dam age to its vascular support durin g th e m obilization an d extract ion of th e lobe.

14.3.4 St ep 4: Ext ract ion of t he Thyroid Lobe Out side t he Neck and Com plet ion of t he Lobect om y

Fig. 14.7 Endoscopic view of the recurrent laryngeal nerve (RLN) and parathyroid glands.

Zuckerkan dl (posterior lobe), w h ich con stitu tes an im portan t lan dm ark in th is step. Also, both parathyroid glan ds are gen erally easily visualized th an ks to th e en doscope m agn ification ( Fig. 14.7). Th eir vascular supply is preserved by selective ligation of th e bran ch es of th e in ferior thyroid artery. Durin g dissection , h em ostasis is ach ieved w ith 3 m m tit an ium vascular clips w h en dividing th e sm all vessels th at often cross th e recurren t n er ve. Th e RLN m ust be dissected an d carefully t raced un til its in sertion n ear Berr y’s ligam en t. Th is is of param oun t im portan ce in order to avoid excessive tract ion on th is delicate structure on ce th e thyroid lobe is delivered th rough th e skin in cision (follow in g step). Th e t ypical sh ape an d color are of great h elp for recogn ition of th e parathyroid glan ds, an d th ese ch aracteristics are greatly en h an ced by th e en doscopic view. On ce iden tified th e parathyroid can be gen tly dissected, w ith care to

On ce th e lobe is com pletely m obilized th e en doscope an d retractors are rem oved, an d th e surgeon delivers th e lobe th rough th e in cision . Th is is accom plish ed by grabbin g th e superior pole of th e thyroid w ith conven t ion al Kelly or Crile forceps, an d th en gen tly extract in g it th rough th e in cision by rotatin g th e en tire lobe on its lon gest axis ( Fig. 14.8). On ce th e lobe is exteriorized th e operation proceeds un der direct visualization as in open surgery. Th e lobe is freed from th e t rach ea by ligating th e sm all vessels an d dissectin g Berr y’s ligam en t. It is ver y im portan t to rech eck th e course of th e RLN at th is poin t to avoid its injur y before th e fin al step. Th e isth m us is th en dissected from th e trach ea an d divided. After com pletely exposing th e trach ea, th e lobe is fin ally rem oved by th e conven t ion al open tech n ique. Th is com pletes th e un ilateral thyroid lobectom y. In cases w h ere total thyroidectom y is n ecessary th e procedure is sim ply repeated on th e opposite side.

14.3.5 St ep 5: Access Closure Drain age is n ot n ecessar y. Th e strap m uscles are approxim ated w ith a single stitch . Th e platysm a is sutured w ith a subcuticular resorbable run n in g suture, an d th e skin is closed by m ean s of a sealan t skin glue.

14.4 Result s and Out com e Sin ce Jun e 1998, w h en th e tech n ique w as con ceived an d developed in Pisa, m ore th an 3,000 MIVATs h ave been perform ed at

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Minim ally Invasive Thyroid Surgery Table 14.2 Managem ent of hypocalcemia following thyroidectom y on the first postoperative day Sym ptom s

Treatm ent

Acute sym ptomatic

Calcium gluconate intravenously

Asym ptom atic calcium ≤ 7.5 a m g/dL

Calcium (3 g) + vitam in D (0.5 µg) orally, daily

Asym ptom atic calcium 7.5– 7.9 mg/dL

Calcium (1.5 g) orally, daily

a Normal

Fig. 14.8 The thyroid lobe is delivered through the incision to facilitate further dissection.

th e Departm en t of Surger y, Un iversit y of Pisa. In a recen tly publish ed series of n early 2,000 of th ese patien ts, th e fem ale to m ale ratio w as 5:1, w ith a m ean pat ien t age of 40.2 years (ran ge 8–85 y) an d a total thyroidectom y to h em ithyroidectom y ratio of n early 3:1.5 Th e m ean operative tim e w as 31 m in utes (ran ge 20–120 m in ) for h em ithyroidectom y an d 41 m in utes (ran ge 30– 130 m in ) for total thyroidectom y. Surgical in dicat ion s in cluded follicular lesion s, low -risk papillar y carcin om as, toxic m ultin odular goiter, Graves’ disease, an d fam ilial m edullar y carcin om a (prophylactic operat ion for RET [rearran ged durin g tran sfection ] gen e m utation carriers).5 In traoperative conversion from MIVAT to conven tion al thyroidectom y (Kocher in cision ) w as n ecessary in 1.9% of cases, prim arily due to in traoperative bleedin g, di cult dissect ion for thyroidit is, an d un expected trach eal or esoph ageal in filtration from carcin om a.5 A review of 10 years of experien ce w ith MIVAT sh ow ed th at com plication rates for laryn geal n er ve injur y, hypoparathyroidism , an d postoperative bleedin g w ere sim ilar to th ose of convention al thyroid surgery.7 A prospect ive, ran dom ized study clearly dem on st rated th at MIVAT ach ieves th e sam e clearan ce at th e thyroid bed level an d th e sam e outcom e as th e conven tion al thyroidectom y tech n ique w h en dealin g w ith low -risk papillar y carcin om a.8 At th e sam e tim e, MIVAT pat ien ts can ben efit from th e m ain advan tages of th is m in im ally invasive tech n ique: reduced postoperative pain , a faster postoperative recover y, an d an excellen t cosm et ic outcom e.

14.5 Post operat ive Care After surgery, patien ts un dergoing MIVAT require strict observation durin g th e first 5 to 10 h ours on th e w ard. Dysph on ia, airw ay obstru ct ion , an d n eck sw ellin g m ust be carefully evaluated. No drain is left, so careful sur veillan ce for postoperative

range: 8–10 m g/dL.

h em atom as is required durin g th e im m ediate postoperative period. Th e postoperat ive bleedin g risk is ver y low an d dram atically decreases after 5 h ours; th erefore, patien ts sh ould lie in bed at least for 5 to 6 h ours. Oral feedin g sh ould be avoided durin g th e sam e observation period in order to decrease th e risk of postoperat ive n ausea an d vom itin g. Pat ien ts can be disch arged th e day after surgery (in Italy, “on e day surgery” [sam e day disch arge] for thyroidectom y is n ot allow ed by law ) an d th ey can return to n orm al act ivit ies. Substitut ive th erapy w ith levothyroxin e begin n in g on th e first postoperative day is stron gly suggested, especially in cases of total thyroidectom y for carcin om a. No care is required for th e w oun d because th e glue protects th e w oun d from any m ech an ical t raum a or extern al contam in ation . Frequen tly, oral an ti-in flam m atory drugs are prescribed in th e postoperative period in order to decrease ph aryngeal an d cervical back pain (th e latter sh ould be m oderate, h ow ever, because pat ien ts un dergoing MIVAT are position ed on th e operatin g table w ith out n eck hyperexten sion ).

14.6 Managem ent of Procedure -Specific Com plicat ions In t h e sett in g of p ost op erat ive h em atom a, if com p ressive sym pt om s an d air w ay obst ru ct ion are p resen t , su rgical in t erven tion an d im m ed iate h em atom a evacu ation are stron gly recom m en d ed . Patien ts can start oral in take on th e even in g of th e day of surgery an d are disch arged th e day after surgery. On th e first an d second postoperative days, serum calcium m ust be ch ecked to con trol hypoparathyroidism by substitut ive th erapy, as described in Table 14.2. Voice im pairm en ts an d subject ive or object ive dysphon ia require im m ediate postoperat ive vocal cord evaluation by an otolar yngologist. In asym ptom atic pat ien ts, th is evaluation m ay be delayed for 3 m on th s.

References [1] Park CS, Ch un g W Y, Ch an g HS. Min im ally invasive open thyroidectom y. Surg Today 2001; 31(8); 665–669 [2] Miccoli P, Bert i P, Materazzi G, Min uto M, Barellin i L. Min im ally invasive video-assisted thyroidectom y: five years of experien ce. J Am Coll Surg 2004; 199 (2); 243–248 [3] Miccoli P, Min uto MN, Ugolin i C, Pisan o R, Fosso A, Bert i P. Min im ally invasive video-assisted thyroidectom y for ben ign thyroid disease: an eviden ce-based review. World J Surg 2008; 32(7); 1333–1340

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Surgical Managem ent of Thyroid Diseases [4] Miccoli P, Materazzi G. Min im ally invasive, video-assisted thyroidectom y (MIVAT). Surg Clin Nor th Am 2004; 84(3); 735–741 [5] Min uto MN, Bert i P, Miccoli M, et al. Min im ally invasive video-assisted thyroidectom y: an an alysis of results an d a revision of in dication s. Surg En dosc 2012; 26(3); 818–822 [6] Miccoli P, Bert i P, Ra aelli M, Con te M, Materazzi G, Galleri D. Min im ally invasive video-assisted thyroidectom y. Am J Surg 2001; 181(6); 567–570

[7] Miccoli P, Bert i P, Am brosin i CE. Perspect ives an d lesson s learn ed after a decade of m in im ally invasive video-assisted thyroidectom y. ORL J Otorh in olaryn gol Relat Spec 2008; 70(5); 282–286 [8] Miccoli P, Elisei R, Materazzi G, et al. Min im ally invasive video-assisted thyroidectom y for papillary carcinom a: a prospective study of its com pleten ess. Surgery 2002; 132(6); 1070–1073, discussion 1073–1074

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Rem ote Access Thyroid Surgery

15 Rem ot e Access Thyroid Surgery Katrina Chaung and William S. Duke

15.1 Int roduct ion Recen t tech n ological in n ovation s h ave addressed grow in g patien t in terest in reducin g th e cosm et ic im pact of surgery, leadin g to th e developm en t of altern ative approach es to thyroid surgery. Th ese approach es h ave developed alon g t w o dist in ct path w ays: m in im ally invasive tech n iques th at create sm all an terior cer vical in cision s an d rem ote access approaches th at elim in ate any an terior n eck in cision . Alth ough m in im ally invasive tech n iques result in a sm all cervical scar th at is w ell h idden in a n atural skin crease, som e patien ts regard th e prospect of any publically visible scar as un acceptable. Rem ote-access tech n iques rem ove th e in cision from th e visible portion of th e n eck an d con ceal it in a distan t, h idden location . En doscopic or robotic tech n iques are th en used to access th e thyroid com partm en t. For th e appropriate patien t w h o regards cosm esis as a priorit y, rem ote-access tech n iques can safely an d e ect ively ach ieve both th e surgical an d th e cosm etic goals.1,2

15.2 Background Th e “conven tion al” thyroidectom y tech n ique w as developed by Em il Th eodor Kocher in th e late 1800s. His m eth ods, w h ich used a 7 to 10 cm t ran sverse cervical in cision ,3 elevation of subplatysm al flaps, an d m eticulous dissection tech n iques, t ran sform ed thyroid surgery in to a procedure th at w as so safe an d un iversally accepted th at, for m ore th an 100 years, it w as perform ed on all patien ts un dergoing thyroid surgery, regardless of th eir glan d size or disease. The first endoscopic cervical surgery w as described by the Gagner group 4 in 1996 to perform a subtotal parathyroidectom y. Although this procedure exposed m any lim itations of endoscopic neck surgery, including prolonged surgical tim e, m ild hypercarbia and subcutaneous em physem a related to the CO2 insu ation, and a prolonged postoperative hospital stay, the cosm etic outcom e w as reported as excellent.5 This experience attracted the interest of surgeons and patients and suggested the possibility of alternative approaches to thyroid surgery that could m inim ize the cosm etic im pact of the procedure. Th is grow in g in terest resulted in th e developm en t of m in im ally invasive an d rem ote access approach es. Th e m in im ally invasive approach es in clude both th e m in im ally invasive videoassisted thyroidectom y (MIVAT) 6,7 an d th e m in im ally invasive n on en doscopic thyroidectom y (MINET).8 Th ese tech n iques em ploy in cision s h idden in n atural skin creases th at are sign ifican tly sm aller th an th ose used for conven t ional thyroid surgery. Th e exten t of dissection is reduced, an d th e procedure can be perform ed w ith out a drain an d on an outpatien t basis.9 Despite th e lim ited in cision len gth used in m in im ally invasive surgery an d th e predictably excellen t cosm etic results ach ieved in th e m ajorit y of pat ien ts, th ese procedures m ay result in a con spicuous an terior cervical scar th at can be di cult to cam ouflage, an un acceptable possibility for som e patien ts. To fur th er reduce th e cosm etic im pact of thyroid surgery, rem ote-access approach es w ere developed, w h ich com pletely

rem ove th e scar from th e visible portion of th e n eck an d h ide it in a concealed, distan t location . Th ese approach es prim arily em erged in Asia, w h ere poor w oun d h ealin g an d a cultural bias again st visible n eck scars are com m on .10,11 It is im portan t th at patien ts realize th at th ese approach es h ide th e scar but are n ot scarless. As a result of th e rem ote access site, a lon ger an d m ore exten sive dissection is required, an d struct ures th at are n ot usually en coun tered durin g thyroid surgery m ay be at risk w ith th ese approach es. Due to th e h eterogen eity of access sites and in str um en tation th at h as been em ployed in rem ote access procedures, it is di cult to directly com pare th e overall degree of postoperative pain or duration of recovery for th is group to th at of conven tion al thyroid surgery.12,13,14 Given th e in creased dissection exten t an d un conven t ion al an atom ical van tage poin t, th e surgeon’s experien ce an d com fort level can sign ifican tly im pact operative t im es.14,15 Th ese approach es are gen erally m ore expen sive th an conven t ion al or m in im ally invasive procedures. Curren tly, th ere are n o reim bursem en t strategies in place in th e Un ited States to o set th ese in creased costs.16,17 Addition ally, surgeon train in g an d robotic equipm en t m ay n ot be w idely available. Despite th ese ch allen ges, rem ote access procedures are an att ract ive altern ative for select pat ien ts w h o con sider any visible cervical scar an un desirable result.

15.3 Rem ot e Access Endoscopic Procedures 15.3.1 Chest /Breast Approaches Th e first com pletely rem ote access thyroidectom y w as perform ed by Oh gam i et al18 in 2000. Th e procedure used in cision s at th e parastern al border of on e breast an d alon g th e superior m argin s of both areolas. Low -pressure CO2 in su ation an d en doscopic equipm en t w ere also used to dissect across th e ch est an d gain access to th e thyroid com part m en t. Several variation s of th is tech n ique h ave been described, in cluding isolated an terior ch est w all approach es 19 as w ell as bilateral20 an d un ilateral21,22 tran sareolar approach es. Use of ch est/breast approach es are gen erally reserved for un ilateral ben ign lesion s < 3 cm an d sm all papillary thyroid carcin om as in patien ts w ith n o suspicious lym ph aden opathy or prior n eck surgery or irradiat ion .19,20,21,22 Th ese approaches avoid a visible n eck scar but h ave a n um ber of lim itation s. First , in cision s on th e an terior ch est are pron e to hypertroph ic scarrin g.23 Addition ally, in cision s on th e breast m ay be an un appealin g con sideration for North Am erican patien ts.24,25 Due to th e particular course of dissection , th e operative field is n arrow, restrict in g th e ran ge of m ovem en t of th e rigid en doscopic in strum en tation .23

15.3.2 Axillary Approaches Ikeda et al26,27 described th e en doscopic axillar y approach as an altern ative to th e an terior ch est an d breast approach es. Th e

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Surgical Managem ent of Thyroid Diseases in cision is h idden in th e axilla, an d CO2 in su ation an d en doscopic dissect ion are used to access th e thyroid com partm en t . Th e cosm etic sequelae of th is approach are less con spicuous as com pared to th ose of conven tion al surgery; h ow ever, disadvan tages in clude a sign ifican tly lon ger operatin g t im e, a n arrow operative field, th e n eed for en doscopic visualization , an d poten tial m orbidit y associated w ith CO2 in su ation .28 To avoid som e of th ese lim itation s, “gasless” rem ote tech n iques w ere developed th at used specialized retractor system s rather th an CO2 in su ation .29 Th e gasless approach h as been described for thyroidectom y an d cen tral com part m en t n ode dissection in patien ts w ith low -risk papillary thyroid carcin om a, an d postoperative thyroglobulin levels an d iodin e-131 scan s reflect acceptable on cological outcom es.29,30 Addition al experien ce an d lon ger follow -up periods w ill be n eeded to defin e th e exact in clusion criteria for th e treatm en t of m align an t disease usin g th is rem ote approach . Th e axillo-bilateral-breast approach (ABBA) 23 an d th e bilateral axillo-breast approach (BABA) 31 are am on g several hybrid en doscopic procedures developed. These tech n iques com bin e axillar y an d areolar in cision s for th e cosm etic ben efit of th e axillar y approaches w h ile gran t in g an addition al an terior ch est w orkin g port w ith out n ecessitatin g a t ran sverse parastern al scar. Several com plication s n ot t ypically lin ked to tradit ion al thyroid surgery, in cluding t ran sien t n europraxia of th e brach ial plexus 32 an d pn eum oth orax,31 h ave been reported w ith th ese approach es. Alth ough th ese en doscopic rem ote access approach es are still used in som e Asian centers, th ey h ave failed to gain sign ifican t traction in Western practices.

15.4 Rem ot e Access Robot ic Procedures To overcom e th e lim itation s of th e en doscopic approach es, in 2009 a group of surgeon s in South Korea in troduced th e con cept of robotically assisted rem ote access thyroid surgery.33 Th e in troduction of th e da Vin ci Surgical System (In tuit ive Surgical, In c.) o ers several critical advan tages over en doscopic tech nology. Th e h igh -defin ition bin ocular cam era system provides surgeon s w ith a th ree-dim en sion al view of th e operative field. Many of th e robotic in strum en ts are art iculated in such a w ay th at th ey o er as m any or m ore degrees of freedom th an th e h um an w rist can ach ieve, allow in g for im proved m obilit y in tigh t operative spaces. Th e robot also faith fully reproduces th e m ovem en ts of th e surgeon’s h an ds, perm itt in g safe dissection aroun d crit ical str uct ures. Th ese robotically assisted rem ote access procedures can be accom plish ed w ith out th e use of CO2 in su ation . Dual-in cision axillar y an d ch est w all,33 sin gle-in cision axillar y 34 an d facelift 35 approach es h ave been developed. Th e tech n ology also perm its cent ral an d lateral n eck dissection s for m align an t disease.36

15.4.1 Robot ic Axillary Thyroidect om y Th e gasless robotic axillary thyroidectom y (RAT) w as described in South Korea in 2009.13,33 Th e in itial cases w ere perform ed as dual-in cision approach es usin g a secon d parastern al in cision on th e an terior ch est w all.13,30 Ch un g et al subsequen tly refin ed

th e approach , w h ich is n ow m ost com m on ly accom plish ed th rough a sin gle axillary in cision .33,34,37 In th is tech n ique, an axillar y in cision is p erform ed , an d a soft tissu e p ocket is d evelop ed across th e an terior ch est. A sp ecially d esign ed retractor (Ch u n g retractor) m ain tain s th e p ocket, an d th e t hyroid com p ar t m en t is accessed by sep arat in g t h e stern al an d clavicu lar h ead s of t h e st ern ocleid om astoid (SCM) m u scle.30 Th e robot is in t rod u ced an d t h e glan d is rem oved . RAT h as been u sed to treat ben ign thyroid n od u les as w ell as sm all, w ell-d i eren tiat ed t hyroid can cers w it h ou t com es com p arable to treatm en t w ith con ven tion al or en d oscop ically assisted app roach es 13,15,30,38 Alth ough th is approach h as rem ain ed popular in South Korea, th e en th usiasm th at RAT in itially enjoyed in Western practices has w aned. In the United States, w here 2% of cases have required conversion to an anterior cervical approach,39,40,41 there have been a num ber of significant com plications not usually encountered in thyroid surgery, including brachial plexus injury, esophageal perforation, and significant blood loss from large-vessel injury. RAT also requires postoperative drainage and inpatient care—a step backw ard from m any of the advances achieved w ith the m inim ally invasive anterior cervical approaches.1,17,37,39,42,43 For these reasons, this procedure has been abandoned in m any Western centers.

15.4.2 Robot ic Facelift Thyroidect om y Th e robotic facelift thyroidectom y (RFT) w as developed to overcom e th e disadvan tages associated w ith RAT ( Table 15.1).35,44 In th is tech n ique, robotic assistan ce is used to rem ove th e thyroid glan d th rough a postauricular m odified facelift in cision .44 Recen t assessm en t of m ore th an 60 RFT procedures perform ed in our center foun d th is tech n ique to be safe an d clin ically feasible.39 Th ough th e first patien t received a drain an d overn igh t observation , ever y subsequen t procedure h as been perform ed on an outpatien t basis w ith out a drain . On e in ciden ce of tran sien t vocal fold w eakn ess an d t w o serom as h ave been reported, all of w h ich resolved w ith out in ter ven t ion . Th ere w ere n o cases of perm an en t recurren t lar yngeal n er ve injury or hypocalcem ia. No conversion s to an an terior cervical approach w ere required. Th is com plication profile com pares favorably to th at repor ted for RAT. Th e in itial m ean operative tim e for a lobectom y w as 157 m in utes, w h ich decreased to less th an 2 h ours w ith in creasin g surgeon experien ce.35,39 Th e RFT approach h as been replicated in at least four oth er centers w ith sim ilar safety profiles.2,35,44 Alth ough n o rem ote access procedure can be con sidered m in im ally invasive, th e exten t of dissection in RFT is approxim ately 38% less th an th at required for RAT ( Fig. 15.1).45 Th is t ran slates in to expedited recover y t im e, reduced postoperative discom fort , an d drain less outpatien t surgery.1,2,45 Th e cervical course of dissection is m ore fam iliar to th e h ead and n eck surgeon th an th at of th e tran saxillar y approach ,44 an d th e ceph alad approach allow s th e recurren t lar yn geal n erve (RLN) to be en coun tered early in dissection at its m ost constan t location , w h ich is advan tageous in preven tin g n er ve an d parathyroid glan d injur y.35,37,44 A disadvan tage of RFT is tran sien t hypesth esia in th e great auricular n er ve distribution even w h en th e n er ve is carefully preserved.44

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Rem ote Access Thyroid Surgery Table 15.1 Advantages and disadvantages associated with alternative approaches to thyroid surgery Approach

Advantages

Endoscopic

● ● ● ● ●

Disadvantages

Decreased incision length Hidden incision sites Decreased extent of dissection Drainless surgery Outpatient surgery

● ● ● ●

●

Robotic

●

Single incision site Incision hidden in rem ote location Robotic system provides binocular high-definition, threedim ensional view Robotic instrumentation allows equal or greater degrees of freedom than the hum an wrist No CO2 insufflation required

●

Does not use a head or neck incision

● ● ●

●

Axillary

● ●

● ●

● ● ● ● ●

Facelift

● ●

● ● ● ●

Anatom ical perspective familiar to the head and neck surgeon Early identification of the recurrent laryngeal nerve (RLN) helps prevent RLN and parathyroid gland injury Drainless surgery Outpatient surgery Favorable safet y profile Low rate of conversion to anterior cervical approach

15.4.3 Select ion Crit eria for RFT Robotic facelift thyroidectom y is a viable option for th e h igh ly m otivated patien t w h o places a prem ium on cosm etic outcom e. Th e pat ien t sh ould also be w illin g to accept an in creased surgical tim e, greater exten t of dissection , an d th e possibilit y of con version to an open an terior cer vical approach in return for elim in at ion of a visible n eck scar. Careful con sideration of patien t ch aracteristics sh ould also be m ade to en sure eligibilit y for RFT.1,35,39,44 Th e requirem en ts in clude a body m ass in dex < 40, th e absen ce of previous n eck surgery, an d th e lack of sign ifican t m edical com orbidities. Select ion criteria in regard to disease features 1,35,39,44 are also im portan t . Th e thyroid disease sh ould be am en able to un ilateral surgery because th e vector of approach in th is tech n ique does n ot perm it bilateral surgery. Staged bilateral surgery th rough a con tralateral in cision can be perform ed if indicated. Th e largest n odule sh ould be ≤ 4 cm in its largest dim en sion , an d th ere sh ould be n o substern al or extrathyroidal exten sion . Addition ally th ere sh ould be n o clin ically apparen t thyroiditis or lym ph aden opathy ( Table 15.2).

15.4.4 RFT Procedure and Anat om ical Landm arks Preoperat ive Considerat ions Preoperatively, th e patien t is m arked in th e uprigh t position . Th e m odified facelift in cision begin s adjacen t to th e postauricular crease an d exten ds approxim ately 1 cm in to th e occipital

●

Some techniques use CO2 insufflation Some techniques involve chest and/or breast incisions Narrow operative field Decreased range of motion of rigid endoscopic instrum entation Increased operative tim e Increased operative tim e, dependent on surgeons’ experience Increased costs com pared to traditional or endoscopic approaches Lim ited by equipment availabilit y Requires careful patient selection

2% conversion rate to anterior cervical approach Drain required Postoperative inpatient care Dissection approach unfam iliar to the head and neck surgeon Risk of brachial plexus injury, esophageal perforation, highvolume blood loss Transient great auricular nerve hypesthesia even when the nerve is preserved

h airlin e, contin uin g in feriorly as far as n ecessar y ( Fig. 15.2).1,2,35,44 An an terior cervical in cision is also m arked in th e un likely event th at conversion to an open approach is n ecessary. Lar yngeal n er ve m on itorin g is used; th erefore, a sh ort-actin g m uscle relaxan t is given durin g in duct ion , but n o paralytics are used durin g dissection . Th e patien t is in tubated w ith an electrom yograph ic en dotrach eal tube for lar yngeal n erve m on itorin g (NIM-3, Medtron ic, In c.) un der GlideScope video lar yngoscope (Verath on ) visualization to en sure appropriate placem en t. Th e operat in g table is rotated 180° from th e an esth esia team , requirin g exten sion tu bin g for th e an esth esia circuit. Upon con clusion of th e surgery, deep extubation is perform ed to m in im ize th e cough in g an d buckin g th at can occur durin g em ergen ce.1,39

Open Dissect ion Establish in g th e operat ive pocket to access th e thyroid com partm en t is essen tial for robotic excision of th e glan d. Th e m odified facelift in cision is m ade. As a subplat ysm al m usculocutan eous flap is developed, th e stern ocleidom astoid m uscle (SCM) is iden tified an d traced in feriorly to th e clavicle. Th e proper dissection plan e is superficial to th e great auricular n er ve (GAN) an d extern al jugular vein (EJV) to avoid injurin g th ese struct ures ( Fig. 15.3). Th e an terior aspect of th e GAN is usually en coun tered ~ 4 cm from th e apex of th e in cision .37 Th e EJV is usually iden tified 2 to 3 cm an terom edial from th e GAN.39 Depen din g on its position , th e EJV can be reflected dorsally, left dow n on th e SCM, or divided for im proved access.1,2,35,37,44

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Surgical Managem ent of Thyroid Diseases Th e dissection is aided by progressively deeper retract ion w ith Terris thyroid retractors (Medtron ic, In c.) an d ren al vein retractors. A m alleable retractor is used to reflect th e SCM dorsally an d laterally. Th e m uscular trian gle defin ed by th e an terior surface of th e SCM, posterior border of th e stern ohyoid m uscle, an d superior border of th e om ohyoid m uscle is delin eated.1 On average, th e om ohyoid m uscle is located 12 cm from th e apex of th e in cision .37 Th e om ohyoid is reflected ven trally w h ile th e stern ohyoid an d stern othyroid m uscles are reflected an teriorly an d m edially, exposin g th e superior pole of th e thyroid glan d

Fig. 15.2 The rem ote-access robotic m odified facelift thyroidectomy incision. (Reprinted with perm ission from Terris D, Singer MC, Seybt MW. Robotic facelift thyroidectomy: patient selection and technical considerations. Surg Laparosc Percutan Tech 2011;21[4]:237–242.)

Fig. 15.3 Dissection of the robotic facelift thyroidectom y operative pocket, revealing the great auricular nerve (black arrow) and external jugular vein (white arrow). The strap muscles are retracted ventrally. (Adapted with perm ission from Terris DT, Singer MC, Seybt MW. Robotic facelift thyroidectom y: patient selection and technical considerations. Surg Laparosc Endosc Percutan Tech 2011;21:237– 242.)

Fig. 15.1 Com parison of the extent of dissection required for the robotic axillary thyroidectomy (RAT) and robotic facelift thyroidectomy (RFT). (Reprinted with permission from Duke WS, Terris DJ. Alternative approaches to the thyroid gland. Endocrinol Metab Clin North Am 2014;43[2]:459–474)

Table 15.2 Selection criteria for robotic facelift thyroidectomy Patient factors ● ● ● ● ●

Disease factors

Highly motivated to avoid cervical scar Understands possibilit y of conversion to an anterior cervical approach American Society of Anesthesiologists class 1 or 2 No prior neck surgery or irradiation No m orbid obesit y

● ● ● ● ● ●

Extent of disease appropriate for unilateral surgery Largest nodule ≤ 4 cm No substernal extension No extrathyroidal disease extension No pathological lym phadenopathy No clinically apparent thyroiditis

Source: Adapted from Terris D, Singer MC, Seybt MW. Robotic facelift thyroidectomy: patient selection and technical considerations. Surg Laparosc Percutan Tech 2011;21(4):237–242.

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Fig. 15.4 Access to the thyroid com partm ent from a right rem oteaccess robotic facelift thyroidectomy, with the om ohyoid m uscle reflected ventrally and the sternohyoid and sternothyroid m uscles reflected anteriorly and m edially to reveal the superior aspect of the thyroid gland. (Reprinted with perm ission from Terris DJ, Singer MC, Seybt MW. Robotic facelift thyroidectomy, II: Clinical feasibilit y and safet y. Laryngoscope 2011;121[8]:1636–1641.)

( Fig. 15.4). Th rough direct visualization , th e thyroid glan d is m obilized as m uch as possible an d th e superior vascular pedicle defin ed to facilitate th e robot ic dissection .1,2,35,39,44 Fixed retractors are used to m ain tain th e operative w orkin g space. A m odified Ch un g retractor (Marin a Medical, In c.) is in troduced un dern eath th e strap m uscles to provide ven t ral retract ion . A Sin ger h ook retractor (Medt ron ic, In c.) on an adjustable Green berg Retractor arm (Codm an & Sh urtle , In c.) is applied for posterior retract ion of th e SCM.1,2,35,39

Robot ic Deploym ent After th e operative pocket is secured, th e da Vin ci Surgical System is deployed. Th e robotic pedestal is position ed on th e side con tralateral to th e dissect ion at an an gle ~ 30° from th e operatin g table. Fin e adjustm en ts are m ore easily accom plish ed by m oving th e operatin g table position rath er th an th e robot . Th ree robot ic arm s are em ployed ( Fig. 15.5). Th e cen ter cam era arm h olds a 30° dow n facing en doscope an d is position ed parallel to th e lon g axis of th e m odified Ch un g retractor w ith its arm alm ost fully exten ded to m in im ize collision s of th e elbow join t w ith th e oth er arm s. Th e dom in an t in strum en t arm h olds a Harm on ic ACE cur ved sh ears (Eth icon En dosurgery, In c.), an d th e n on dom in an t in strum en t arm h olds a Mar ylan d grasper. Th ese t w o in strum en t arm s are situ ated on eith er side of th e cen ter cam era arm an d adjusted to avoid collision s w ith th e oth er arm s.1,2,35,44

Fig. 15.5 Robotic arm s deployed along the axis of the fixed retractor system . (Reprinted with perm ission from Terris D, Singer MC, Seybt MW. Robotic facelift thyroidectomy: patient selection and technical considerations. Surg Laparosc Percutan Tech 2011;21[4]:237–242.)

w h ich allow s th e superior pole of th e thyroid to be m obilized in feriorly an d ven trally aw ay from th e in ferior con strictor. Th e extern al bran ch of th e superior lar yngeal n er ve can usually be visualized traversin g th e in ferior constrictor m uscle. Th e superior parathyroid glan d is gen erally in t im ately associated w ith th e posterior surface of th e thyroid glan d an d is carefully dissected aw ay an d preserved.1,2,35,44 Th e RLN is iden tified just proxim al to its en tran ce in to th e laryn x as it courses un dern eath th e in ferior con strictor ( Fig. 15.6) at a poin t approxim ately 1.2 cm lateral to th e m uscle origin on th e cricoid cartilage.37 By dissect in g th e RLN in feriorly for a sh ort distan ce, th e ligam ent of Berr y is exposed. Th e ligam en t of Berr y is divided w ith th e Harm on ic device w ith th e RLN un der direct visualization . Next, th e isth m us is defin ed an d divided w ith th e Harm on ic device.1,2,35,39,44 Th e lateral border of th e thyroid glan d is m obilized by blun t dissection of th e surroun din g tissues. Th e m iddle thyroid vein follow ed by th e in ferior thyroid vessels are isolated an d ligated w ith th e Harm on ic device, takin g care to iden tify an d preserve th e in ferior parathyroid glan d. At th is poin t, th e rem ain in g attach m en ts betw een th e thyroid an d an terior trach ea are divided w ith th e Harm on ic device, an d th e thyroid lobe is delivered from th e surgical pocket.1,2

Closure Meticulous h em ostasis of th e surgical field is obtain ed, an d a sh eet of Surgicel (Eth icon , In c.) is placed in th e thyroid bed. Th e deep aspect of th e in cision is closed w ith in terrupted, buried 4– 0 Vicr yl Sutures (Eth icon , In c.). Th e skin edges are sealed w ith skin adh esive an d a quarter-in ch Steri-Strip (3 M Corp .) No drain s are used.1,2

Robot ic Dissect ion Durin g th e robot ic dissection , a field surgeon is seated at th e patien t’s side an d assists th e dissect ion w ith a Terris atraum atic suct ion (Medtron ic, In c.). Th e con sole surgeon begin s by ligatin g th e superior vascular pedicle w ith th e Harm on ic device,

Post operat ive Considerat ions Because n o drain is placed after th e robot ic facelift thyroidectom y, th e pat ien t is disch arged on th e day of surgery, provided th ere are n o im m ediate postoperative com plication s or oth er

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Surgical Managem ent of Thyroid Diseases

Fig. 15.6 Retraction of the thyroid ventrally allows identification of the recurrent laryngeal nerve seen at the tip of the nerve stimulator just inferior to the inferior constrictor m uscle during robotic facelift thyroidectomy. The t wo active robotic arm s are indicated by numbers 1 and 2, respectively, on the robotic screen. (Reprinted with perm ission from Terris DJ, Singer MC, Seybt MW. Robotic facelift thyroidectomy, II: Clinical feasibilit y and safet y. Laryngoscope 2011;121[8]:1636–1641.)

m edical con train dication s. Patien ts sh ould be coun seled regardin g th e poten tial for m ild n eck edem a due to th e m ore exten sive dissection , as w ell as expected t ran sien t hypoesth esia in th e GAN distribution for several m on th s postoperatively.

15.5 Conclusion Patien t-driven desires to im prove cosm etic outcom es h ave fueled th e developm en t of altern ative approach es to thyroid surgery. Rem ote access tech n iques exch ange a visible an terior cervical scar for a distan t, con cealed scar. Alth ough all of th ese approach es involve a greater exten t of dissect ion , th e robot ic facelift thyroidectom y tech n ique can be perform ed as an outpatien t procedure w ith out th e use of a postoperative drain . Appropriate patien t counselin g an d select ion are essen tial, an d staged procedures for bilateral surgery are feasible. In th e h an ds of an experien ced surgeon , rem ote access thyroidectom y can provide carefully selected patien ts w ith a surgically soun d an d cosm et ically excellen t result th at is n ot ach ievable by oth er m eth ods of thyroid surgery.

References [1] Terris DJ, Sin ger MC, Seybt MW . Robotic facelift thyroidectom y: patien t selection an d tech n ical con sideration s. Surg Laparosc En dosc Percutan Tech 2011; 21(4); 237–242 [2] Terris DJ, Sin ger MC. Robotic facelift thyroidectom y: Facilitating rem ote access surgery. Head Neck 2012; 34(5); 746–747 [3] Pin chot S, Ch en H, Sippel R. In cision s an d exposure of th e n eck for thyroidectom y an d parathyroidectom y. Oper Tech Gen Surg 2008; 10; 63–76 [4] Gagn er M. En doscopic subtotal parathyroidectom y in patien ts w ith prim ar y hyperparathyroidism . Br J Surg 1996; 83(6); 875 [5] Naitoh T, Gagn er M, Garcia-Ruiz A, Hen iford BT. En doscopic en docrin e surgery in th e n eck. An in itial report of en doscopic subtotal parathyroidectom y. Surg En dosc 1998; 12(3); 202–205, discussion 206

[6] Miccoli P, Bert i P, Con te M, Ben din elli C, Marcocci C. Min im ally invasive surgery for thyroid sm all n odules: prelim in ar y repor t. J En docrin ol Invest 1999; 22(11); 849–851 [7] Bellan ton e R, Lom bardi CP, Ra aelli M, Rubino F, Bosch erin i M, Perilli W . Min im ally invasive, totally gasless video-assisted thyroid lobectom y. Am J Surg 1999; 177(4); 342–343 [8] Terris DJ, Seybt MW, Elch oufi M, Ch in E. Cosm etic thyroid surgery: defin in g th e essen tial prin ciples. Lar yn goscope 2007; 117(7); 1168–1172 [9] Terris DJ, Ch in E. Clin ical im plem en tation of en doscopic thyroidectom y in selected patien ts. Laryn goscope 2006; 116(10); 1745–1748 [10] McCurdy JA, Jr. Con sideration s in Asian cosm etic surgery. Facial Plast Surg Clin North Am 2007; 15(3); 387–397, viivii. [11] Duh QY. Robot-assisted en doscopic thyroidectom y: h as th e tim e com e to aban don n eck in cision s? An n Surg 2011; 253(6); 1067–1068 [12] Tan CT, Ch eah W K, Delbridge L. “Scarless” (in th e n eck) en doscopic thyroidectom y (SET): an eviden ce-based review of publish ed tech n iques. World J Surg 2008; 32(7); 1349–1357 [13] Kan g SW , Jeon g JJ, Yun JS, et al. Robot-assisted en doscopic surger y for thyroid can cer: experien ce w ith th e first 100 patien ts. Surg En dosc 2009; 23(11); 2399–2406 [14] Jackson NR, Yao L, Tufano RP, Kan dil EH. Safety of robotic thyroidectom y approach es: m eta-analysis an d system atic review. Head Neck 2014; 36(1); 137–143 [15] Lee J, Yun JH, Nam KH, Soh EY, Ch un g W Y. Th e learn in g cur ve for robotic thyroidectom y: a m ulticen ter study. An n Surg On col 2011; 18(1); 226–232 [16] Cabot JC, Lee CR, Brun aud L, et al. Robotic an d en doscopic tran saxillary thyroidectom ies m ay be cost proh ibitive w h en com pared to stan dard cervical thyroidectom y: a cost an alysis. Surgery 2012; 152(6); 1016–1024 [17] Perrier ND. W h y I h ave aban don ed robot-assisted tran saxillary thyroid surgery. Surgery 2012; 152(6); 1025–1026 [18] Oh gam i M, Ish ii S, Arisaw a Y, et al. Scarless en doscopic thyroidectom y: breast approach for better cosm esis. Surg Laparosc En dosc Percutan Tech 2000; 10 (1); 1–4 [19] Kataoka H, Kitan o H, Takeuchi E, Fujim ura M. Total video en doscopic thyroidectom y via th e an terior ch est approach usin g th e cervical region -liftin g m eth od. Biom ed Ph arm acoth er 2002; 56 Suppl 1; 68s–71s [20] Hur SM, Kim SH, Lee SK, et al. New en doscopic thyroidectom y w ith th e bilateral areolar approach : a com parison w ith th e bilateral axillo-breast approach . Surg Laparosc En dosc Percutan Tech 2011; 21(5); e219–e224 [21] Youben F, Bo W , Ch un lin Z, et al. Tran s-areola sin gle-site en doscopic thyroidectom y: pilot study of 35 cases. Surg En dosc 2012; 26(4); 939–947 [22] You ben F, Bom in G, Bo W , et al. Tran s-areola sin gle-in cision en d oscop ic t hyroid ect om y. Su rg Lap arosc En d osc Percu t an Tech 2011; 21(4); e192– e196 [23] Sh im azu K, Sh iba E, Tam aki Y, et al. En doscopic thyroid surgery th rough th e axillo-bilateral-breast approach . Surg Laparosc En dosc Percutan Tech 2003; 13(3); 196–201 [24] Yeun g GH. En doscopic thyroid surgery today: a diversit y of surgical strategies. Thyroid 2002; 12(8); 703–706 [25] Ogden J, Lin dridge L. Th e im pact of breast scarrin g on perception s of attractiven ess: an experim en tal study. J Health Psych ol 2008; 13(3); 303–310 [26] Ikeda Y, Takam i H, Niim i M, Kan S, Sasaki Y, Takayam a J. En doscopic thyroidectom y an d parathyroidectom y by th e axillar y approach . A prelim in ar y report . Surg En dosc 2002; 16(1); 92–95 [27] Ikeda Y, Takam i H, Niim i M, Kan S, Sasaki Y, Takayam a J. En doscopic thyroidectom y by th e axillar y approach . Surg En dosc 2001; 15(11); 1362–1364 [28] Ikeda Y, Takam i H, Sasaki Y, Takayam a J, Niim i M, Kan S. Clin ical ben efits in en doscopic thyroidectom y by th e axillar y approach . J Am Coll Surg 2003; 196 (2); 189–195 [29] Yoon JH, Park CH, Ch ung W Y. Gasless en doscopic thyroidectom y via an axillar y approach : experien ce of 30 cases. Surg Laparosc En dosc Percutan Tech 2006; 16(4); 226–231 [30] Kan g SW , Jeon g JJ, Nam KH, Ch an g HS, Ch ung W Y, Park CS. Robot-assisted en doscopic thyroidectom y for thyroid m align an cies usin g a gasless tran saxillar y approach . J Am Coll Surg 2009; 209(2); e1–e7 [31] Ch oe JH, Kim SW, Ch ung KW , et al. En doscopic thyroidectom y usin g a n ew bilateral axillo-breast approach . World J Surg 2007; 31(3); 601–606 [32] Bärleh n er E, Ben h idjeb T. Cer vical scarless en doscopic thyroidectom y: Axillobilateral-breast approach (ABBA). Surg En dosc 2008; 22(1); 154–157 [33] Kan g SW , Lee SC, Lee SH, et al. Robotic thyroid surgery usin g a gasless, tran saxillar y approach an d th e da Vin ci S system : th e operative outcom es of 338 con secutive patien ts. Surgery 2009; 146(6); 1048–1055

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Rem ote Access Thyroid Surgery [34] Ryu HR, Kan g SW, Lee SH, et al. Feasibility an d safety of a n ew robotic thyroidectom y th rough a gasless, tran saxillar y sin gle-in cision approach . J Am Coll Surg 2010; 211(3); e13–e19 [35] Terris DJ, Sin ger MC, Seybt MW . Robotic facelift thyroidectom y: II. Clin ical feasibility an d safety. Lar yn goscope 2011; 121(8); 1636–1641 [36] Kan g SW , Park JH, Jeong JS, et al. Prospects of robotic thyroidectom y usin g a gasless, tran saxillar y approach for th e m an agem en t of thyroid carcin om a. Surg Laparosc En dosc Percutan Tech 2011; 21(4); 223–229 [37] Sin ger MC, He ern an A, Terris DJ. Defin in g an atom ical lan dm arks for robotic facelift thyroidectom y. World J Surg 2014; 38(1); 92–95 [38] Tae K, Ji YB, Ch o SH, Lee SH, Kim DS, Kim TW . Early surgical outcom es of robotic thyroidectom y by a gasless un ilateral axillo-breast or axillary approach for papillary thyroid carcin om a: 2 years’ experien ce. Head Neck 2012; 34(5); 617–625 [39] Duke W S, Terris DJ. Robotic Thyroidectom y: Facelift Approach . Curr Surg Rep. 2014; 2; 1–36

[40] Kan dil EH, Noureldin e SI, Yao L, Slakey DP. Robotic tran saxillar y thyroidectom y: an exam in ation of th e first on e h un dred cases. J Am Coll Surg 2012; 214(4); 558–564, discussion 564–566 [41] Lin HS, Folbe AJ, Carron MA, et al. Sin gle-in cision tran saxillar y robotic thyroidectom y: ch allenges an d lim itation s in a North Am erican population . Otolaryn gol Head Neck Surg 2012; 147(6); 1041–1046 [42] Lan dr y CS, Grubbs EG, Warn eke CL, et al. Robot-assisted tran saxillar y thyroid surgery in th e Un ited States: is it com parable to open thyroid lobectom y? An n Surg On col 2012; 19(4); 1269–1274 [43] Kuppersm ith RB, Holsinger FC. Robotic thyroid surgery: an in itial experien ce w ith North Am erican patien ts. Lar yn goscope 2011; 121(3); 521–526 [44] Terris DJ, Sin ger MC. Qualitative an d quan titative di eren ces betw een 2 robotic thyroidectom y tech n iques. Otolaryn gol Head Neck Surg 2012; 147 (1); 20–25 [45] Sin ger MC, Seybt MW , Terris DJ. Robotic facelift thyroidectom y: I. Preclin ical sim ulation an d m orph om etric assessm ent. Lar yn goscope 2011; 121(8); 1631–1635

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Surgical Managem ent of Thyroid Diseases

16 Subst ernal Goit er Sara L. Richer, Brian Hung-Hin Lang, Chung-Yau Lo, Dipti Kamani, and Gregory W. Randolph

16.1 Int roduct ion In 1920, William Stuart Halsted w rote “th e extirpation of th e thyroid glan d for goiter better t ypifies perh aps m ore th an oth er operation s, th e suprem e trium ph of th e surgeon’s art.” Th e exten sion of a goiter from its origin al cervical position in to th e m ediastin um , kn ow n as substern al goiter, presen ts un ique ch allen ges for th e thyroid surgeon . Th e an atom ical distort ion , restricted surgical access of th e th oracic in let, an d un predictable vascularit y can m ake substern al goiter surgery ch allengin g an d tech n ically dem an ding. Th is ch apter review s th e defin ition , clin ical presen tat ion , an d surgical tech n ique of substern al goiter w ith an em ph asis on th e appropriate preparation for ach ievin g optim al surgical outcom es.

16.2 Definit ion and Classificat ion of a Subst ernal Goit er Th e w ord goiter is derived from th e Latin w ord gutter, m ean in g throa t, an d is an en largem en t of th e thyroid glan d. Alth ough it h as been di cult to defin e w h at con stit utes a goiter (som e h ave defin ed it based on var yin g w eigh ts or len gth s), th e defin ition of a substern al goiter is even less clear. Multiple surgeon s h ave described th e substern al goiter in di eren t w ays. Early surgeon s defin ed th e substern al goiter by position . Koch er defin ed a substern al thyroid as a glan d in w h ich som e portion rem ain s perm an en tly retrostern al, an d Crile defin ed th e substern al goiter as thyroid grow th dow n to th e aortic arch .1 Oth er position al defin ition s in clude a goiter w ith its low er position perm an en tly rem ain in g below th e stern al n otch w ith th e neck in hyperexten sion or a goiter totally or part ially located in th e m ediastin um th at in operatin g position h as its edge at least 3 cm below th e stern al m an ubrium .2,3,4 It h as also been defin ed radiograph ically as thyroid grow th to th e level of th e fourth th oracic

vertebrae on X-ray exam in ation .5 Oth er defin ition s h ave focused on th e tech n ique required to rem ove th e goiter, such as on e th at requires m ediastin al explorat ion an d dissection for rem oval.6 In a review of th e in trath oracic goiter defin ition s, th e clin ical defin ition foun d to be m ost relevan t defin ed an in trath oracic goiter as a thyroid glan d th at h as a portion w h ich rem ain s perm an en tly retrostern al on n eck exam in ation w ith out hyperexten sion .7 Th is classification can be m ade on physical exam an d w as foun d to be as sen sitive as th e oth er defin ition s for determ in in g th e presence of com pressive clin ical features an d developm en t of postoperative com plication s. In addition , several auth ors h ave o ered various classification sch em es for substern al goiter in order to object ively describe th e degree of substern al exten sion . Lah ey classified substern al goiters in to t w o grades according to th e relation sh ip to th e aor tic arch : grade I includes th ose exten din g n early to th e arch of th e aorta, an d grade II in cludes th ose exten din g to th e arch of th e aorta or beyon d.8 Higgin s described a classification sch em e based on th e percen tage of goiter in th e ch est; goiters w ith > 50% in th e n eck are substern al, th ose w ith > 50% in th e ch est are partially in trath oracic, an d th ose w ith > 80% in th e ch est are com pletely in t rathoracic.9 Sim ilarly, Coh en an d Ch o graded substern al goiters according to th e percen tage of m ediastin al or in trath oracic com pon en t of th e goiter (grade 1: 0–25%, grade 2: 26–50%, grade 3: 51–75%, grade 4: > 75%).10 A m ore practical classificat ion sch em e w ith associated an atom ical correlates is usefu l for surgical plan n in g an d is dem on strated in Table 16.1.11

16.3 Pat hogenesis of Subst ernal Goit er Th e vast m ajorit y of substern al goiters derive from a caudal m igration of cervical goiters. Th is dow nw ard m igration of th e

Table 16.1 A substernal goiter classification based on anatom ical relationships Type

Location

Anatom y

Prevalence

Approach

I

Anterior mediastinum

Anterior to great vessels, trachea, recurrent laryngeal nerve

85%

Transcervical (sternotomy, only if intrathoracic goiter diam eter is greater than thoracic inlet diam eter)

II

Posterior m ediastinum

Posterior to great vessels, trachea, recurrent laryngeal nerve

15%

As above; also consider sternotom y or right posterolateral thoracotom y if t ype IIB

IIA

Ipsilateral extension

IIB

Contralateral extension

IIB1

Extension posterior to both trachea and esophagus

IIB2

Extension bet ween trachea and esophagus

III

Isolated m ediastinal goiter

No connection to orthotopic gland; may have m ediastinal blood supply

< 1%

Transcervical or sternotom y

Source: Reproduced from Randolph 11 with permission from Saunders.

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Subst ernal Goiter cervical goiters in to th e th orax h as been attributed to a com bin ation of factors, such as th e n egative in trath oracic pressure gen erated durin g in spiration , repetitive forces of deglutit ion , th e e ect of gravit y, an d th e large poten t ial space of th e m ediastin um . Th e substern al com pon en ts ten d to m igrate an terior to th e trach ea, esoph agus, recurren t lar yn geal n er ve (RLN), an d subclavian vessels in 85 to 90% of th e cases.12,13 Th ey m ay exten d even ly on both sides or asym m etrically. Alth ough som e series rep or t ed a h igh er in cid en ce of su bstern al ext en sion on th e left sid e, ot h ers h ave rep or ted t h e op p osit e p h en om en on .6,14,15,16 In approxim ately 15% of substern al goiters, th e goiter involves th e posterior m ediastin um . Th e posterior m ediastin al goiter descen ds beh in d th e trach ea, great vessels, an d RLN. Th e thyroid surgeon m ust be aw are of th is ven tral position of th e RLN so th at it m ay be recogn ized before it is cut or stretch ed. The n erve m ay also be trapped betw een com pon en ts of a posterior m ediastin al goiter. Th e posterior m ediastin al goiter m ay rest in a space boun ded by th e azygous vein in feriorly, vertebral colum n posteriorly, trach ea an d esoph agus m edially, an d subclavian an d in n om in ate vessels an teriorly.17,18 Posterior

m ediastin al goiters are m ore com m on ly foun d on th e righ t side th an th e left , explain ed by th e presen ce of th e aortic arch an d descen din g aorta, w h ich obstructs th e posterior descen t on th e left side.19 Even rarer, approxim ately 1% of substern al goiters are isolated to th e m ediastin um w ith out any con n ection to th e n orm al cervical thyroid. Several in terestin g th eories h ave been put forw ard to explain th e path ogen esis of such goiters. Som e isolated m ediastin al goiters m ay form from em br yological fragm en tation w ith hyperdescen t of thyroid an lagen associated w ith cardiac an d great vessel descen t. An oth er th eor y proposes th at such goiters form as exophytic n odules from th e thyroid in ferior pole, an d over tim e th ere is atten uation of th e n odule-thyroid stalk.11 Fin ally, th ere is th e “forgot ten goiter,” w h ich is a n odule representin g a thyroid tissue fragm en t in th e upper m ediastin um from past goiter surgery. Recogn ition of th e isolated m ediastin al goiter is crit ical for presurgical plann in g because th ese goiters ten d to derive th eir blood supply from th e in tern al m am m ary an d in n om in ate arteries or directly from th e in trath oracic aorta. Fig. 16.1 dem on strates a forgot ten goiter recogn ized after h em ithyroidectom y over 20 years prior.

Fig. 16.1 (a) A posteroanterior chest radiograph and (b) a computed tom ographic film of a large m ediastinal goiter that developed after a hem ithyroidectomy over 20 years ago. (c) An additional m edian sternotomy was required for the com plete rem oval of (d, e) the m ediastinal com ponent.

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Surgical Managem ent of Thyroid Diseases

16.4 Incidence and Prevalence Multin odular goiter is com m on , a ect in g 4% of th e US population an d 10% of th e British population . Iodin e deficien cy con tributes to goiter form ation , especially in n on coastal m oun tain ous an d low lan d region s w h ich are especially at risk for en dem ic goiter. Th e prevalen ce of substern al goiters is di cult to determ in e based on th e various defin ition s an d sin ce th e n um ber of n on -operative substern al goiters rem ain s largely un kn ow n . It is estim ated to be present in 0.02% of th e gen eral population an d 0.05% of fem ales older th an 40, based on screen in g radiography in Australia an d th e Un ited States.20,21 Th e in ciden ce of substern al goiter sign ifican tly in creases w ith age; 60% of substern al goiters occur in patien ts older th an 60.20 In surgical series, th e rates of substern al goiters in patien ts un dergoing thyroidectom y h ave been estim ated to be betw een 2.6 an d 21%.22,23,24

16.5 Clinical Present at ion and Physical Exam Most substern al goiters arise in th e settin g of a preexistin g cervical goiter, grow slow ly, an d are in frequen tly m align an t. Most patien ts presen t in th e fifth decade or later, an d th ere is a fem ale prepon deran ce, w ith a fem ale to m ale ratio of 3:1.25 A positive fam ily h istory can be presen t in up to 30% of pat ien ts.26 Alth ough som e patien ts are asym ptom at ic, presen tin g after an in ciden tal fin din g on radiograph ic studies, oth ers presen t w ith a palpable n eck m ass or w ith respirator y sym ptom s varyin g from a sim ple irritative cough to h oarsen ess, in spiratory stridor, or fran k sh ort n ess of breath .2,13,27 Acute air w ay obstruct ion is an un com m on but life-th reaten in g em ergen cy for ben ign goiters an d occurs alm ost exclusively in patien ts w ith substern al exten sion .28 Fig. 16.2 dem on st rates a patien t w ith acute airw ay obst ruction . Th e exact reason for th e sudden on set of airw ay obst ruction is un clear, but th is h as been th ough t to be related to sudden en largem en t of th e goiter due to h em orrh age, cystic degen eration , or m align an t ch ange w ith in th e substern al com pon en t.29 In addition to respirator y dist ress, dysph agia an d

globus sen sation are sym ptom s suggestive of local com pression . Every pat ien t sh ould be question ed about sign s of dyspn ea, dysph agia, an d dysph on ia. Wh en th e n eck vasculature is com pressed, superior ven a cava (SVC) syn drom e or even cerebral edem a m ay occur.30 True SVC syn drom e is alm ost exclusively associated w ith substern al m align an cy an d sh ould be carefully radiograph ically assessed preoperatively. Hem atem esis secon dar y to esoph ageal varices, chyloth orax secondar y to th oracic obstru ct ion , an d transien t isch em ic attack th rough “thyroid steal syn drom e” h ave all been reported as in itial presentation s of substern al goiters.28,31

16.6 Physical Exam inat ion Th e physical exam of a patien t presen tin g w ith a substern al goiter sh ould focus on th e airw ay. Th e lar yn x an d trach ea sh ould be assessed for deviation from th e m idlin e, t ypically to th e con tralateral side of an asym m etrically en larged cervical goiter. It is im perative to en doscopically exam in e th e vocal cords in all patien ts w ith a substern al goiter. Vocal cord palsy w ith out previous surgery is suggestive of th e presen ce of invasive thyroid m align an cy un til proven oth erw ise. Occasion ally, vocal cord paralysis m ay occur as a result of th e m ass e ect of th e large goiters, an d bilateral vocal cord paralysis in a n on m align an t substern al goiter h as been reported.32 Patien ts sh ould be asked to raise both arm s above th e n eck to elicit th e Pem berton ’s sign (flush in g of th e face, dilation of the extern al jugular vein s, an d/or sym ptom atic airw ay com pression ).4,30 Oth er clin ical features, such as Horn er’s syn drom e, can occur occasion ally.27 Th e size an d con sisten cy of th e thyroid en largem en t sh ould be n oted, alth ough up to 30% of patien ts w ith substern al goiters m ay h ave n o palpable cervical com pon en t.6,13 Th e physical exam can un derestim ate th e goiter, especially in patien ts w ith a sh ort n eck or m orbid obesity. Th e World Health Organ ization gradin g system for goiters can be docum en ted ( Table 16.2). Fin ally, th e cer vical lym ph n odes sh ould be adequately assessed.

16.7 Preoperat ive Assessm ent 16.7.1 Thyroid Funct ion Test ing After a com plete h istory an d physical exam in at ion , th e preoperative assessm en t in substern al goiter focuses on adequate surgical preparation . All patien ts sh ould un dergo thyroid fun ction testin g. Hyperth yroidism is n ot un com m on in substern al goiters.4,13,33,34,35 Screen in g for hyperthyroidism is especially im portan t because iatrogen ic iodin e exposure sh ould be

Table 16.2 The World Health Organization grading system for goiters

Fig. 16.2 Com puted tom ographic scan of a patient intubated emergently for respiratory com prom ise from a substernal goiter. The patient and fam ily decided against surgery, and the patient died from airway com prom ise after elective extubation.

Grade 0

Impalpable/invisible

Grade 1a

Palpable but invisible even in full extension

Grade 1b

Palpable in neutral position/visible in extension

Grade 2

Visible but no palpation required to make diagnosis

Grade 3

Visible at a distance

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Subst ernal Goiter avoided due to th e risk of developm en t of overt hyperthyroidism .36,37 In particular, elderly patien ts w ith hyperthyroidism m ay be m ore pron e to cardiac com plication s, such as atrial fibrillation . Addition ally, hypothyroidism h as been reported in up to 16% of cases.13 A m assive, firm goiter can result from a fibrotic varian t of Hash im oto’s disease.

16.7.2 Im aging A CT scan is essen tial in th e assessm en t of patien ts w ith substern al goiters. Th e CT scan provides im portan t in form ation for su rgical p lan n in g, in clu d in g t h e in t u bat ion an d air w ay m an agem en t , great vessel m an agem en t , an d t h e an t icip at ion of invasive m align an cy. It p rovid es im p or t an t in for m at ion , su ch as t rach eal d eviat ion , t rach eal com p ression , ret rotrach eal ext en sion , as w ell as esop h ageal an d m ajor vessel d isp lacem en t an d /or com p ression .3 8 Th e d em on st r at ion of t h ese relat ion sh ip s by p reop erat ive CT assist s n ot on ly in su rgical p lan n in g bu t also in t h e an est h esia p rovid er’s in t u bat ion ap p roach . In ad d it ion , CT fin d in gs, su ch as m ed iast in al lym p h n od es an d loss of t issu e p lan es, p rovid e in form at ion for d iagn osin g invasive m align an cy. Determ in in g t h e relat ion sh ip s of m ed iast in al st r u ct u res by CT allow s for safe op erative m an agem en t for large p ost erior m ed iast in al goiters. CT scan is also essen t ial in p lan n in g for t h e p oten t ial n eed for st ern otom y.

16.7.3 Fine-Needle Aspirat ion Th e routin e use of fin e-n eedle aspiration (FNA) is con troversial in substern al goiters. Th e risk of m align an cy ran ges from 3 to 16% in selected series.30 Because th ere is already an in dication for surgery on th e basis of a substern al goiter, FNA can be om itted if it w ould n ot alter th e plan of m an agem en t.6,14,39,40 Furth erm ore, th ere is a sm all poten tial risk of bleedin g in to a substern al n odule, w h ich m ay convert a com prom ised airw ay to an acute obst ruction . How ever, if th ere is any suspicion of m align an cy durin g h istory takin g, physical exam in ation , or radiograph ic evaluation , FNA evaluation m ay en h an ce an accurate preoperative diagn osis an d facilitate perioperative plan n in g.

16.7.4 Ot her St udies Plain ch est radiography provides lim ited in form ation on th e size or exten t of th e substern al goiter, th ough in som e patien ts th e first sign of a substern al goiter m ay be a m ass associated w ith trach eal n arrow in g, trach eal deviation , or superior m ediastin al w iden in g on th e ch est radiograph .41 Up to 41% of patien ts w ith substern al goiters h ave a n orm al ch est radiograph preoperatively.13,35,42,43,44 In terestin gly, trach eal diam eter estim ated on plain ch est radiography film s is sign ifican tly larger th an th at m easured on axial CT scan an d in cadaveric studies.38,45 Th erefore, th e CT scan is a better preoperative tool for airw ay m easurem en t an d plan n in g. Fun ct ion al tests, such as pulm on ary studies an d flow volum e loops, h ave n ot been con sidered as a routin e part of preoperative w orkup. Alth ough th e presen ce of airw ay obst ruction can be accurately determ ined w ith th ese studies, th ey do n ot sign ifican tly a ect th e m an agem en t of patien ts.

16.7.5 Ext ent of Thyroidect om y Total thyroidectom y sh ould be carried out in patien ts w ith bilateral goiters. If th e substern al goiter involves on ly on e lobe, an d t h e con tralateral lobe is essen t ially n orm al, lobect om y can be carr ied ou t to relieve trach eal com p ression w ith a low er risk of com p licat ion s.46 In exp er ien ced cen ters, t h e rates of p erm an en t recu rren t lar yn geal n er ve p aralysis an d hyp op arathyroid ism for t ot al thyroid ect om y d id n ot ap p ear to be sign ifican t ly greater t h an th ose u n d ergoin g less ext en sive t hyroid resection s.47 Th erefore, a tot al thyroid ect om y is recom m en d ed as th e p roced u re of ch oice for th e m ajorit y of p atien ts w ith bilateral substern al goiters treated in exp erien ced cen ters.

16.8 Surgical Technique in Subst ernal Goit er 16.8.1 Int ubat ion Th e in tubation of a patien t w ith a substern al goiter sh ould be carried out carefully to avoid laryn geal traum a an d edem a or loss of airw ay con trol. Trach eal deviation does n ot result in a di cult in t ubat ion , an d th ere is n o ben efit to routin e fiberoptic in tubation .48 On e series reported di cult in tu bation w as presen t in 11.9% of goiter surgeries, w ith patien t age bein g th e on ly sign ificant factor.49 In tubation sh ould be carried out carefully by an experien ced an esth esiologist because an em ergen cy trach eotom y is n ot an easy option for airw ay m an agem en t in th e patien t w ith substern al goiter.

16.8.2 Early Surgical St eps Most of th e surgical prin ciples in thyroid surgery origin ally defin ed by Th eodore Koch er rem ain relevan t to goiter surgery an d sh ould be sim ilarly applied in substern al goiter procedures.50 Up on in d u ct ion of gen eral an est h esia an d en d ot rach eal in t u bation , t h e p atien t is p laced in a su p in e p osit ion w it h t h e n eck ext en d ed . Th e p at ien t is t h en p laced in a sem isit t in g p osit ion in ord er to red u ce th e n eck ven ou s con gest ion becau se su bstern al goiters m ay ext en d in t o t h e t h ora x, cau sin g com p ressive ven ou s en gorgem en t . If a st er n otom y is con sid ered , t h e ch est sh ou ld be p rep p ed an d d rap ed , w it h t h e t h oracic su rgeon on st an d by. A collar skin in cision sh ould be m ade. A sligh tly h igh er skin in cision (1–2 cm m ore ceph alad th an n orm al) is useful in a low lying goiter because it allow s better access to th e lobe in feriorly by facilitatin g upw ard traction on th e glan d after ligation an d division of th e upper pole vessels. Upper an d low er subplatysm al flaps are developed an d sutured or retracted. Th e strap m uscles can be m obilized from th e stern ocleidom astoid m uscles to facilitate subsequen t m obilization of th e thyroid lobes. Th e strap m uscles are separated in th e m idlin e. Som e surgeon s routin ely tran sect th e strap m uscle to im prove access of th e glan d, but th is is frequen tly n ot n ecessary in substern al goiter surgery.14,15 In case of strap tran section , th e m uscles sh ould be divided as cran ially as possible so as to lessen th e e ect of n er ve den ervation .

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Surgical Managem ent of Thyroid Diseases

16.8.3 Thyroid Mobilizat ion, Parat hyroid Glands, and Recurrent Laryngeal Nerve An im portan t first step in goiter surgery is to iden tify th e carotid sh eath because th is is th e lan dm ark for th e lateral boun dar y of th e goiter. Locatin g th e carotid sh eath con ten ts also allow s a surgeon to “follow th e n eck in to th e ch est” an d becom e orien ted as to th e best approach for th e specific goiter on e is facin g. It is n ot n ecessary to deliberately look for an d ligate th e m iddle thyroid vein as th e first step because th e vein is often push ed an d com pressed by th e en larged thyroid lobe. Dissection sh ould be kept close to th e thyroid capsule an d m ove cran ially tow ard th e upper pole. On ce th e lateral aspect of th e upper pole h as been m obilized, th e m edial space betw een th e cricothyroid m uscle an d thyroid lobe is open ed. Th is step is best facilitated by gen tle lateral retract ion of th e upper pole. Th e usual precaution of iden tifyin g an d preservin g th e extern al bran ch of th e superior lar yngeal n er ve sh ould be m ade. On ce th e upper pole h as been m obilized an d delin eated, th e upper pole vessels are doubly ligated close to th e thyroid capsule. Th e superior parathyroid glan d sh ould be iden tified n ext an d sh ould be con sidered for reim plan tat ion if its viabilit y is doubtful. Th e parathyroid glan ds m ay be adh eren t to th e thyroid cap sule or con siderably displaced; th erefore special atten tion sh ould be m ade to th e superior parathyroid because th e in ferior parathyroid m ay n ot be readily iden tifiable. After rem oval, th e thyroid sh ould be carefully exam in ed for capsular parathyroid glan ds, w h ich sh ould be reim plan ted as n ecessary. Th e substern al goiter can sign ifican tly alter th e position of th e RLN, w h ich sh ould be iden tified before goiter delivery. In on e series, th e RLN w as en t rapped in fascial ban ds or splayed on th e goiter in 16% of cases.51 Th is puts th e n er ve at h igh risk for traction or avulsion injur y if n ot properly iden tified. Th e RLN can be iden tified w h ere it crosses th e in ferior thyroid artery an d can be traced superiorly in som e cases. In m any large goiters, th e RLN m ust be iden tified th rough a superior approach an d dissected aw ay from th e goiter in a retrograde fash ion o th e posterior surface of th e glan d. Th e superior approach involves iden tifyin g th e RLN en terin g th e lar yn x on ce th e upper pole h as been fully reflected. As in all thyroidectom ies, w h en con tem platin g bilateral surgery, th e ipsilateral vagus an d RLNs sh ould h ave adequate electrom yograph ic (EMG) activit y prior to proceeding w ith dissect ion on th e oth er thyroid lobe. Th e substern al com pon en t can th en be retracted in to th e n eck base. Upw ard traction allow s rotation of th e cervical portion of th e glan d from lateral to m edial an d also facilitates gen tle, blun t fin ger dissection on th e surface of th e capsule th rough areolar plan es aroun d all borders of th e goiter. Attach m en ts to th e great vessels are gen erally loose areolar t issue, w h ich can be easily separated, th ough attach m en ts to th e carin a can be m ore di cult to dissect.52 Th e surgeon’s fin ger sh ould be used to confirm th at all palpable adh esion s h ave been divided, an d th e substern al com pon en t could n ow be delivered in to th e n eck. Apart from usin g th e surgeon’s fin ger, in strum en ts, such as a sterile tablespoon , deliver y forceps, an d Foley cath eters, h ave been em ployed in th e past to facilitate th e deliver y of th e substern al portion out to th e cervical w oun d.53,54 On ce th e in trath oracic com pon en t h as been delivered in to th e w oun d,

th e glan d is retracted m edially, an d th e rem ain der of th e operation proceeds in th e t ypical fash ion .55 A drain can be con sidered for patien ts w ith obesit y, sign ificant dead space, or physical lim itation s, w h ich w ould m ake detect ion of a h em atom a m ore di cult. How ever, drain placem en t sh ould n ot be expected to reduce th e rate of postoperative h em orrh age.

16.8.4 St ernot om y in Subst ernal Goit er Most auth ors h ave dem on strated convin cin gly th e feasibilit y an d safety of operatin g an d deliverin g a substern al goiter th rough a stan dard cervical approach in th e vast m ajorit y of cases.2,3,6,15,30,39,56,57 In fact, th e routin e or liberal use of a stern otom y or th oracotom y sh ould be avoided un less it is absolutely n ecessary. Th e adoption of m ore routin e stern otom y appears to be associated w ith an in creased operative m orbidit y an d th e len gth of h ospital stay.39 Auth ors h ave sh ow n th at th e n eed for stern otom y is related to th e position of th e goiter, rath er th an size.58 Several surgical series h ave reported stern otom y use w ith a goiter th at exten ds beyon d th e aort ic arch .19,58 Oth ers h ave reported exten sion below th e carin a or a “con ical sh ape” of th e goiter to be associated w ith stern otom y use.52 Fig. 16.3 dem on st rates a pat ien t w ith a subcarin al goiter th at required a partial stern otom y for adequate exposure. Oth er factors associated w ith stern otom y in clude loss of fat plan es on CT an d recurren t or m align an t disease.19,59 Prim ar y substern al goiters or th ose w ith posterior m ediastinal exten sion h ave an in trath oracic blood supply, w h ich m ay n ecessitate stern otom y. Wh en required, a part ial stern otom y is t ypically used, reservin g a full stern otom y for exception al cases. An oth er poten t ial, but rare, situation requirin g a stern otom y or a th oracotom y is th e so-called crossed substern al or posterior m ediastin al goiter (t ype IIB). Th is is a rare varian t of substern al goiter in w h ich th ere is exten sion from on e side to th e opposite side of th e posterior m ediastin um . A righ t an terolateral th oracotom y th rough

Fig. 16.3 Com puted tom ographic scan of a substernal goiter extending below the carina. The patient required a partial sternotomy for successful rem oval.

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Subst ernal Goiter Table 16.3 Com parison of the proportion of substernal goiters, need for sternotomies/thoracotom ies/tracheostom ies and the num ber of in-hospital deaths in substernal goiters in surgical series reported over 2 decades First author, year

No. of thyroid resections

No. (%) of substernal goiters

No. (%) of sternot om ies/ thoracotom ies

No. of postoperative tracheostom ies

No. of hospital deaths

Sand 1983 73

n/a

31

6 (19.4)

0

0

Allo 1983 30

872

50 (5.7)

1 (2.0)

0

0

Katlic 1985 2

n/a

80

2 (2.5)

0

0

Melliere 1988 74

2,908

58 (2.0)

5 (8)

0

0

Michel 1988 35

170

34 (20.0)

4 (11.8)

1

0

Shaha 1989 46

370

72 (19.5)

1 (13.9)

2

0

Madjar 1995 4

222

44 (19.8)

6 (13.6)

0

0

Torre 1995 65

3,338

237 (7.1)

8 (3.4)

5

2

Hsu 1996 47

1,585

234 (14.8)a

4 (1.7)

3

0

Moron 1998 75

234

16 (6.8)

3 (1.9)

0

0

Nervi 1998 76

5,263

621 (11.8)

44 (7.1)

1

0

Netterville 1998 57

150

23 (15.3)

0 (0.0)

0

0

Pulli 1998 39

n/a

21

3 (14.3)

0

0

Vadasz 1998 60

1,458

175 (12.0)

42 (24.0)

2

2

Rodriguez 1999 27

780

72 (9.2)

7 (9.7)

0

0

Abdel Rahim 1999 62

n/a

103

0 (0.0)

13

0

Dedivitis 1999 77

204

32 (15.7)

2 (6.3)

0

1

Ozdem ir 2000 78

1,320

30 (2.3)

2 (6.7)

0

0

Mussi 2000 16

7,480

374 (5.0)

43 (11.5)

0

0

Hedayati 2002 12

381

116 (30.4)

2 (1.7)

2

1

Erbil 2004 13

2,650

170 (6.4)

12 (7.1)

0

0

Shen 2004 3

n/a

60

1 (1.7)

0

1

Chow 2005 24

287

24 (8.4)

2 (8.3)

1

0

Sancho 2006 79

n/a

35

13 (37.1)

3

2

Chauhan 2006 14

755

199 (26.4)

0 (0.0)

0

0

Ahm ed 2006 15

267

40 (15.0)

9 (22.5)

5

0

Abbreviation: n/a, not available. a Recurrent substernal goiters.

th e fourth in terspace is recom m en ded for th is t ype of substern al goiter.60

16.8.5 Tracheom alacia and Tracheost om y At th e en d of th e thyroidectom y, prior to th e closure of th e w oun d, th e surgeon sh ould ch eck th e in tegrit y of th e trach ea by obser vation durin g th e respirator y cycle an d by gen tle pressure betw een th e th um b an d in dex fin ger. Th is can be don e m ore e ect ively by askin g th e an esth esiologist to pull out th e en dotrach eal t ube sligh tly w h ile th e surgeon applies gen tle pressure to th e t rach ea. An obvious collapse or soften ing of th e

trach eal rin gs in dicates trach eom alacia, a con dition th at is poorly un derstood, extrem ely rare, an d reversible.3,61,62,63 Trach eom alacia w ill m an ifest as postoperat ive airw ay obstru ction w ith paradoxical collapse of th e airw ay durin g in spiration because th e t rach eal rin g soften s an d loses stren gth secon dary to ch ron ic extrin sic com pression . Th e reported in ciden ce of trach eom alacia secondar y to large goiters ran ged from 0.001 to 1.5% in surgical series.33,42,63 With th e advan ces in an esth esia tech n iques an d th e early treatm en t of large substern al goiters, th e true in ciden ce of trach eom alacia from goiter com pression is likely low er. In sit uation s w h en th e presen ce of trach eom alacia is certain , som e auth ors w ould recom m en d keepin g th e en dotrach eal tube in place for 24 to 48 h ours before attem pting a con trolled extubation .64 Oth er option s, in cludin g cont in uous

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Surgical Managem ent of Thyroid Diseases positive pressure ven tilation , trach eal graft in g, trach eopexy, an d postoperat ive t rach eostom y, h ave been described.65 Alth ough trach eostom y is rarely in dicated in th e postoperative period after thyroidectom y, th e in ciden ce ran ged from 0 to 12.6% in reported thyroidectom y series for substern al goiters ( Table 16.3). Apart from trach eom alacia, oth er in dication s for trach eostom y w ould in clude bilateral vocal cord palsies, lar yn geal edem a, postoperative bleedin g, an d traum atic en dotracheal in t ubat ion .47,62

16.8.6 Out com es Th e com plication s of substern al goiter resection are prim arily h em orrh age, RLN paralysis an d hypoparathyroidism . Substern al goiter surgery can be associated w ith h igh er com plication rates, w h ich are reported to be as h igh as 30 to 44% in som e series.19,66 Pat ien ts w ith recurren t goiter an d m align an cy lead to th is in creased com plication rate.19 Oth ers h ave dem on strated n o in creased com plication rate but did report lon ger operative tim es an d h ospital stay.59 Th e rates of postoperat ive RLN paralysis var y in th e literat ure from 2 to 27%.67,68,69 Sim ilarly, rates of perm an en t hypoparathyroidism var y in th e literature from 1 to 8% of pat ien ts un dergoing goiter resection .67,70 It is en couraging to n ote th at th e com plication rate in expert h an ds is expected to be low.27,70,71 Also en couragin g, after goiter resection , position al dyspn ea im proves in 82.4% of patien ts.72 Th erefore, alth ough th e stan dard risks apply to substern al goiter surgery, in expert h an ds th e rate of risk is low an d th e patien t ben efit is h igh .

16.9 Conclusion Surgical m an agem en t of substern al goiters poses a ch allenge to t hyroid su rgeon s bu t reflect s t h e u lt im at e t r iu m p h of t h e su rgeon’s ar t in thyroid su rger y. Th e m ajorit y of th e p roced u res can be accom p lish ed th rough a cer vical in cision , an d an ad d it ion al st ern otom y, t h oracot om y, or t rach eostom y is reser ved for a sm all su bset of p at ien t s on ly. Becau se t h e con d ition w as first d escribed m ore th an a cen tu r y ago, im p rovem en t in p reop erat ive d iagn osis an d evalu at ion an d refin em en ts in su rgical tech n iqu e h ave en su red safe an d excellen t ou tcom es in p atien ts u n d ergoing thyroid ectom ies for su bstern al goiters.

References [1] Crile GC. In trath oracic goiter. Cleve Clin Quaterly 1939; 6; 313–322 [2] Katlic MR, Grillo HC, Wan g CA. Substern al goiter. An alysis of 80 patien ts from Massach usetts Gen eral Hospital. Am J Surg 1985; 149(2); 283–287 [3] Sh en W T, Kebebew E, Duh QY, Clark OH. Predictors of airw ay com plication s after thyroidectom y for substern al goiter. Arch Surg 2004; 139(6); 656–659, discussion 659–660 [4] Madjar S, Weissberg D. Retrostern al goiter. Ch est 1995; 108(1); 78–82 [5] Golden berg IS, Lin dskog GE. Di eren tial diagn osis, path ology, an d treatm en t of substern al goiter. J Am Med Assoc 1957; 163(7); 527–529 [6] San ders LE, Rossi RL, Sh ah ian DM, W illiam son WA. Mediastin al goiters. Th e n eed for an aggressive approach . Arch Surg 1992; 127(5); 609–613 [7] Ríos A, Rodríguez JM, Balsalobre MD, Tebar FJ, Parrilla P. Th e value of various defin ition s of in trath oracic goiter for predictin g in tra-operative an d postoperative com plication s. Surgery 2010; 147(2); 233–238 [8] Lah ey FH, Sw in ton NW . In trath oracic goiter. Surg Gyn ecol Obstet 1934;59 [9] Higgin s CC. In trath oracic goitre. Arch Surg 1927; 15; 895–901

[10] Coh en JP, Ch o HT. Surger y for substern al goiter. In : Friedm an M, ed. Operative Tech niques in Otolaryn gology an d Head an d Neck Surgery. Ph iladelph ia;WB Saun ders, 1994:118–125 [11] Ran dolph GW . Surgery of Cer vical an d Substern al Goiter. In : Ran dolph GW , ed. Surgery of th e thyroid an d parathyroid. Philadelph ia, PA: W.B. Saun ders; 2003:70–99 [12] Hedayati N, McHen ry CR. Th e clin ical presen tation an d operative m an agem en t of n odular an d di use substern al thyroid disease. Am Surg 2002;68(3); 245–251, discussion 251–252 [13] Erbil Y, Bozbora A, Barbaros U, Ozarm ağan S, Azezli A, Molvalilar S. Surgical m an agem en t of substern al goiters: clin ical experien ce of 170 cases. Surg Today 2004; 34(9); 732–736 [14] Ch auh an A, Serpell JW . Thyroidectom y is safe an d e ect ive for retrostern al goitre. ANZ J Surg 2006; 76(4); 238–242 [15] Ah m ed ME, Ah m ed EO, Mah adi SI. Retrostern al goiter: th e n eed for m edian stern otom y. World J Surg 2006; 30(11); 1945–1948, discussion 1949 [16] Mussi A, Am brogi MC, Iaccon i P, Spin elli C, Miccoli P, An geletti CA. Mediastin al goitres: w h en th e tran sth oracic approach ? Acta Ch ir Belg 2000; 100(6); 259–263 [17] Sh ah ian DM, Rossi RL. Posterior m ediastin al goiter. Ch est 1988; 94(3); 599– 602 [18] Sh ah ian DM. Surgical treatm en t of in trath oracic goiter. In : Cady B RR, ed. Surgery of th e thyroid an d parathyroid glan ds. Ph iladelph ia: W B Saun ders; 1991 [19] Sakkar y MA, Abdelrah m an AM, Mostafa AM, Abbas AA, Zedan MH. Retrostern al goiter: th e n eed for th oracic approach based on CT fin din gs: surgeon ’s view. J Egypt Natl Can c In st 2012; 24(2); 85–90 [20] Reeve TS, Rubinstein C, Rundle FF. In trath oracic goitre: its prevalen ce in Sydn ey m etropolitan m ass radiography sur veys. Med J Aust 1957; 44(5); 149– 156 [21] Run dle FF, De Lam bert RM, Epps RG. Cer vicoth oracic tum ors: a techn ical aid to th eir roen tgen ologic localization . Am J Roen tgen ol Radium Th er Nucl Med 1959; 81(2); 316–321 [22] Pem berton J. Surgery of substern al an d in trath oracic goiter. Arch Surg 1921; 2 [23] Wax MK, Brian t TD. Man agem en t of substern al goitre. J Otolaryn gol 1992; 21 (3); 165–170 [24] Ch ow TL, Ch an TT, Suen DT, Ch u DW, Lam SH. Surgical m an agem en t of substern al goitre: local experien ce. Hon g Kon g Med J 2005; 11(5); 360–365 [25] Joh n ston JH, Jr, Tw en te GE. Surgical approach to in trath oracic (m ediastin al) goiter. An n Surg 1956; 143(5); 572–579 [26] W ych ulis AR, Payn e W S, Clagett OT, Wooln er LB. Surgical treatm en t of m ediastin al tum ors: a 40 year experien ce. J Th orac Cardiovasc Surg 1971; 62(3); 379–392 [27] Rodriguez JM, Hern an dez Q, Piñ ero A, et al. Substern al goiter: clin ical experien ce of 72 cases. An n Otol Rh in ol Lar yn gol 1999; 108(5); 501–504 [28] Abrah am D, Sin gh N, Lan g B, Ch an W F, Lo CY. Ben ign n odular goitre presen tin g as acute airw ay obstruct ion . ANZ J Surg 2007; 77(5); 364–367 [29] Torres A, Arroyo J, Kastan os N, Estopá R, Rabaseda J, Agustí-Vidal A. Acute respirator y failure an d trach eal obstruct ion in patien ts w ith in trath oracic goiter. Crit Care Med 1983; 11(4); 265–266 [30] Allo MD, Th om pson NW. Ration ale for th e operative m an agem en t of substern al goiters. Surgery 1983; 94(6); 969–977 [31] Bédard EL, Deslauriers J. Bleedin g “dow n h ill” varices: a rare com plication of in trath oracic goiter. An n Th orac Surg 2006; 81(1); 358–360 [32] Souza JW, W illiam s JT, Ayoub MM, Jerles ML, Dalton ML. Bilateral recurren t n erve paralysis associated w ith m ultin odular substern al goiter: a case report . Am Surg 1999; 65(5); 456–459 [33] Mackle T, Mean ey J, Tim on C. Trach eoesoph ageal com pression associated w ith substern al goitre. Correlation of sym ptom s w ith cross-section al im aging fin din gs. J Lar yn gol Otol 2007; 121(4); 358–361 [34] DeAn drade MA. A review of 128 cases of posterior m ediastin al goiter. J Surg 1997; ; 1 [35] Mich el LA, Bradpiece HA. Surgical m an agem en t of substern al goitre. Br J Surg 1988; 75(6); 565–569 [36] Saw in CT, Geller A, Wolf PA, et al. Low serum thyrotropin con cen tration s as a risk factor for atrial fibrillation in older person s. N Engl J Med 1994; 331(19); 1249–1252 [37] Földes J, Tarján G, Szath m ari M, Varga F, Kraszn ai I, Hor vath C. Bon e m in eral den sit y in patien ts w ith en dogen ous subclinical hyperth yroidism : is th is thyroid status a risk factor for osteoporosis? Clin En docrin ol (Oxf) 1993; 39(5); 521–527 [38] Dekker E, Ledeboer RC. Com pression of th e trach eobron chial tree by th e act ion of th e volun tar y respirator y m usculature in n orm al in dividuals an d in

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Subst ernal Goiter

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patien ts w ith asth m a an d em physem a. Am J Roen tgen ol Radium Th er Nucl Med 1961; 85; 217–228 Pulli RS, Con iglio JU. Surgical m an agem en t of th e substern al thyroid glan d. Lar yn goscope 1998; 108(3); 358–361 Hash m i SM, Prem achan dra DJ, Ben n ett AM, Parr y W . Man agem en t of retrostern al goitres: results of early surgical in terven tion to preven t airw ay m orbidity, an d a review of th e English literature. J Lar yn gol Otol 2006; 120(8); 644–649 Ch en AY, Bern et VJ, Carty SE, et al. Surgical A airs Com m ittee of th e Am erican Th yroid Association . Am erican Thyroid Association statem en t on optim al surgical m an agem en t of goiter. Th yroid 2014; 24(2); 181–189 Makeie M, Marlier F, Kh udjadze M, Garrel R, Cram pette L, Guerrier B. [Substern al goiter. Report of 212 cases] An n Ch ir 2000; 125(1); 18–25 Arm our RH. Retrostern al goitre. Br J Surg 2000; 87(4); 519 Wrigh t CD, Math isen DJ. Mediastin al tum ors: diagn osis an d treatm en t. World J Surg 2001; 25(2); 204–209 Barker P, Mason RA, Th orpe MH. Com puterised axial tom ography of th e trach ea. A useful investigation w h en a retrostern al goitre causes sym ptom atic trach eal com pression . An aesthesia 1991; 46(3); 195–198 Sh ah a AR, Alfon so AE, Ja e BM. Operative treatm en t of substern al goiters. Head Neck 1989; 11(4); 325–330 Hsu B, Reeve TS, Guin ea AI, Robin son B, Delbridge L. Recurren t substern al n odular goiter: in ciden ce an d m an agem en t. Surgery 1996; 120(6); 1072– 1075 Hon g BW , Mazeh H, Ch en H, Sippel RS. Routin e ch est X-ray prior to thyroid surgery: is it alw ays n ecessary? World J Surg 2012; 36(11); 2584–2589 Loft us PA, Ow TJ, Siegel B, Tassler AB, Sm ith RV, Sch i BA. Risk factors for perioperative airw ay di cult y an d evaluation of in tubation approach es am on g patien ts w ith ben ign goiter. An n Otol Rh in ol Lar yn gol 2014; 123(4); 279–285 Koch er T. textbook of Operative Surgery. In : Styles TbHJ, ed. 4th ed ed. Lon don 1903:133–151 Ran dolph GW, Sh in JJ, Grillo HC, et al. Th e surgical m an agem en t of goiter: Part II. Surgical treatm en t an d results. Lar yn goscope 2011; 121(1); 68–76 Ri at F, Del Pero MM, Fish B, Jan i P. Radiologically predictin g w h en a stern otom y m ay be required in th e m an agem en t of retrostern al goiters. An n Otol Rh in ol Lar yn gol 2013; 122(1); 15–19 Lan dren eau RJ, Naw araw on g W , Boley TM, Joh n son JA, Curt is JJ. In trath oracic goiter: approach ing th e posterior m ediastin al m ass. An n Th orac Surg 1991; 52(1); 134–135, discussion 135–136 Pan dya S, San ders LE. Use of a Foley cath eter in th e rem oval of a substern al goiter. Am J Surg 1998; 175(2); 155–157 Delbridge L. Total thyroidectom y: th e evolution of surgical tech n ique. ANZ J Surg 2003; 73(9); 761–768 Grain ger J, Saravan appa N, D’Souza A, Wilcock D, Wilson PS. Th e surgical approach to retrostern al goiters: th e role of com puterized tom ography. Otolar yn gol Head Neck Surg 2005; 132(6); 849–851 Netter ville JL, Colem an SC, Sm ith JC, Sm ith MM, Day TA, Burkey BB. Man agem en t of substern al goiter. Lar yn goscope 1998; 108(11 Pt 1); 1611–1617 Casella C, Pata G, Cappelli C, Salern i B. Preoperative predictors of stern otom y n eed in m ediastin al goiter m an agem en t. Head Neck 2010; 32(9); 1131–1135

[59] Ra aelli M, De Crea C, Ron ti S, Bellan ton e R, Lom bardi CP. Substern al goiters: in ciden ce, surgical approach , an d com plication s in a tert iar y care referral cen ter. Head Neck 2011; 33(10); 1420–1425 [60] Vadasz P, Kotsis L. Surgical aspects of 175 m ediastin al goiters. Eur J Cardioth orac Surg 1998; 14(4); 393–397 [61] Geelh oed GW. Trach eom alacia from com pressin g goiter: m an agem en t after thyroidectom y. Surgery 1988; 104(6); 1100–1108 [62] Abdel Rah im AA, Ah m ed ME, Hassan MA. Respirator y com plication s after thyroidectom y an d th e n eed for trach eostom y in patien ts w ith a large goitre. Br J Surg 1999; 86(1); 88–90 [63] Ben n ett AM, Hash m i SM, Prem achan dra DJ, Wrigh t MM. Th e m yth of trach eom alacia an d di cult in tubation in cases of retrostern al goitre. J Lar yn gol Otol 2004; 118(10); 778–780 [64] Sh ah a AR. Surgery for ben ign thyroid disease causing trach eoesoph ageal com pression . Otolaryn gol Clin Nor th Am 1990; 23(3); 391–401 [65] Torre G, Borgon ovo G, Am ato A, et al. Surgical m an agem en t of substern al goiter: an alysis of 237 patien ts. Am Surg 1995; 61(9); 826–831 [66] Arici C, Dertsiz L, Altun bas H, Dem ircan A, Em ek K. Operative m an agem en t of substern al goiter: an alysis of 52 patien ts. In t Surg 2001; 86(4); 220–224 [67] Sh in JJ, Grillo HC, Mathisen D, et al. Th e surgical m an agem en t of goiter: Part II. Surgical treatm en t an d results. Lar yn goscope 2010 [68] Sin clair IS. Th e risk to th e recurren t lar yn geal n erves in thyroid an d parathyroid surgery. J R Coll Surg Edin b 1994; 39(4); 253–257 [69] Hockauf H, Sailer R. Postoperative recurren t n er ve palsy. Head Neck Surg 1982; 4(5); 380–384 [70] Th om usch O, Mach ens A, Sekulla C, et al. Multivariate an alysis of risk factors for postoperative com plication s in ben ign goiter surgery: prospect ive m ulticen ter study in Germ an y. World J Surg 2000; 24(11); 1335–1341 [71] Reeve TS, Delbridge L, Coh en A, Crum m er P. Total thyroidectom y. Th e preferred option for m ultin odular goiter. An n Surg 1987; 206(6); 782–786 [72] Stan g MT, Arm stron g MJ, Ogilvie JB, et al. Position al dyspn ea an d trach eal com pression as in dication s for goiter resection . Arch Surg 2012; 147(7); 621– 626 [73] San d ME. Law s HL, McElvein RB. Substern al an d in trath oracic goiter. Recon sideration of surgical approach . Am Surg 1983; 49; 196–202 [74] Mellière D, Saada F, Etien n e G, Becquem in JP, Bon n et F. Goiter w ith severe respirator y com prom ise: evaluation an d treatm en t. Surgery 1988; 103(3); 367–373 [75] Moron JC, Sin ger JA, Sardi A. Retrostern al goiter: a six-year in stit ution al review. Am Surg 1998; 64(9); 889–893 [76] Nervi M, Iaccon i P, Spin elli C, Jan n i A, Miccoli P. Thyroid carcin om a in in trath oracic goiter. Lan gen becks Arch Surg 1998; 383(5); 337–339 [77] Dedivitis RA, Guim arães AV, Mach ado PC, Sueh ara AN, Noda E. Surgical treatm en t of th e substern al goitre. In t Surg 1999; 84(3); 190–192 [78] Ozdem ir A. Hasbah ceci M, Ham aloglu E, Ozen c A. Surgical treatm en t of substern al goiter. In t Surg 2000; 85; 194–197 [79] San ch o JJ, Kraim ps JL, San ch ez-Blan co JM, et al. In creased m ortalit y an d m orbidity associated w ith thyroidectom y for in trath oracic goiters reach ing th e carin a trach eae. Arch Surg 2006; 141(1); 82–85

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Surgical Managem ent of Thyroid Diseases

17 Surgical Managem ent of Medullary Thyroid Cancer Jennifer Yu and Je rey F. Moley

17.1 Int roduct ion Medullar y thyroid carcin om a (MTC) is an un com m on m align an cy w ith un ique clin ical an d path ological features th at in fluen ce pat ien t evaluation an d surgical approach . MTC accoun ts for 5 to 10% of all thyroid can cers. MTCs arise from th e parafollicular or thyroid C cells an d do n ot take up iodin e, w h ereas differen tiated thyroid can cers (papillar y an d follicular) arise from th e thyroid follicular paren chym a an d do con cen t rate iodin e. MTC is h ereditar y in 25% of cases (m ult iple en docrin e n eoplasia t ype 2 syn drom es).1 Early surgical in ter ven t ion is th e corn erston e of treatm en t w ith com plete excision of th e prim ary tum or an d n odal m etastases. Residual an d/or recurren t disease in th e n eck is also gen erally m an aged by surgical resection because adjuvan t th erapies h ave yet to dem on st rate a durable ben efit. New system ic treatm en t s w ith targeted m olecular th erapies h ave sh ow n prom ise in clin ical t rials.

17.2 Pat hology C cells con stitu te approxim ately 1% of thyroid cells, con tributin g 0.1% of th e n orm al thyroid m ass, an d are derived em br yologically from th e ultim obran ch ial body an d th e fourth bran ch ial pouch . Th ey are foun d th rough out th e thyroid but are con cen t rated in th e posterior upper th ird of th e glan d, gen erally arran ged in groups of six to eigh t cells at th e edge of thyroid follicles. C cells are respon sible for th e production of several peptides an d h orm on es, th e m ost n otable of w h ich is calciton in , a polypeptide h orm on e w h ose physiological e ect is to decrease serum calcium . Calciton in h as m in im al, if any, e ect on n orm al calcium h om eostasis in h um an s, an d n o appreciable fun ction al deficit h as been iden tified w ith loss of C cells follow in g total thyroidectom y. How ever, as a product of C cells, an d th erefore of MTC cells, calciton in h as been sh ow n to be a h igh ly sen sitive an d specific tum or m arker. It can be m easured in th e blood, both in th e basal state an d after stim ulation , by adm in istration of a secretagogue, such as calcium or pen tagastrin (n ot available in th e Un ited States). Calciton in is useful in prethyroidectom y screen in g of patien ts w ith h ereditar y MTC an d in postt reatm en t sur veillan ce of all MTC patien ts. Tum ors of MTC are usually slow -grow in g an d in dolen t, grossly n oted to be gray an d firm w ith w ell-dem arcated m argin s, an d th ey are com m on ly foun d in th e upper portion of th e thyroid lobes. On h istology, cells are un iform an d gen erally polygon al or spin dle sh aped, w ith cen tral n uclei an d fin ely gran ular eosin oph ilic cytoplasm ( Fig. 17.1). Most MTC cells also stain positive for carcin oem bryon ic an tigen (CEA) an d n egative for thyroglobulin .2 A feature of MTC t um ors foun d in on e-th ird of cases is th e presence of strom al am yloid, w h ich is com posed of calciton in or procalciton in m olecules. Sporadic tum ors var y con siderably in size, but m ost are solitar y, w h ereas th e m ajorit y of t um ors in fam ilial form s are m ultifocal an d bilateral.3 C-cell hyperplasia, believed to be a precursor to m align an t transform ation in MTC, is m ost com m on ly presen t in fam ilial form s an d can often be foun d distan t to th e prim ar y carcin om a w ith in th e glan d.4,5,6,7

17.3 Clinical Course Patients w ith sporadic MTC or index cases of fam ilial MTC often present w ith a palpable m ass w ithin the thyroid or neck. Sporadic MTC m ay arise clinically at any age, but the incidence t ypically peaks bet w een the fourth and sixth decade of life, considerably later than in patients w ith know n fam ilial syndrom es. Sporadic MTC also dem onstrates a slight fem ale predom inance.8,9 Approxim ately 15% of patients w ho present w ith clinically apparent disease m ay be sym ptom atic w ith dysphagia, dyspnea, or hoarseness; nodal m etastases are present in regional lym ph nodes in m ore than 50% of patients w ho present w ith palpable prim ary tum ors.10 The m ost frequently involved lym ph nodes reside in the central com partm ent (level VI), follow ed by levels II through V in the ipsilateral jugular chain of nodes, then the contralateral lateral nodes.11 Metastatic spread to the upper and anterior m ediastinum m ay be observed, and hem atogenous dissem ination to distant sites, including the liver, lungs, bone, brain, and soft tissues, m ay occur throughout the course of MTC.1,11 Diagnosis of distant m etastases m ay be m ade m ore difficult due to the fine m iliary pattern of m etastatic disease, w hich is poorly visualized by standard im aging; however, diagnostic laparoscopy w ith direct visualization of the liver m ay help to identify sm all m etastatic deposits in 25% of patients w ith elevated calcitonin levels follow ing therapeutic surgery.12 Per th e Am erican Join t Com m ittee on Can cer (AJCC) TNM classification system , th e 10-year survival rates for patien ts w ith stages I th rough IV disease are 100%, 93%, 71%, an d 21%.13 Adjusted 10-year sur vival rates ran ge from 70% to > 85%; h ow ever, h igh er lon g-term sur vival rates up to 98% h ave been reported for pat ien ts w h ose seru m calciton in levels return to n orm al after surgery.11,13,14,15,16,17 In a series of 1,252 patien ts diagn osed w ith MTC betw een 1973 an d 2002 w h o w ere m on itored by th e Sur veillan ce, Epidem iology, an d En d Results (SEER)

Fig. 17.1 Micrograph of m edullary thyroid carcinom a (hematoxylineosin staining).

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Surgical Managem ent of Medullary Thyroid Cancer registr y, 48% w ere diagn osed w ith localized disease, 35% w ith exten sion beyon d th e thyroid an d region al disease, an d 13% w ith distan t m etastases. A sim ilar tren d w as revealed in 10year sur vival rates at 95.6%, 75.5%, an d 40%, respect ively. Th e average size of prim ar y tum or at th e tim e of diagn osis w as 2.8 cm . Mult ivariate an alysis in dicated th at older age, h igh er tum or stage at diagn osis, lesser exten t of thyroidectom y, an d extern al beam radiation th erapy (EBRT) w ere sign ifican t n egative predictors of overall sur vival.18 In several oth er studies, age at diagnosis an d tum or stage w ere th e m ost sen sitive progn ostic factors; oth er predictors in cluded postoperative basal calciton in levels, exten t of surgical in terven tion , an d presen ce of distan t m etastases.16,19

17.4 Fam ilial MTC Classificat ion Th ough th e m ajorit y of MTC is sporadic in origin , a fam ilial syn drom e m ust be considered in any pat ien t presen tin g w ith a n ew diagn osis of MTC. Multiple en docrin e n eoplasia types 2A an d 2B (MEN 2A an d MEN 2B) are th e h ereditar y syn drom es th at in clude MTC as a h allm ark, th ough th ese vary in aggressiven ess of m align an cy an d associated con dition s. Fam ilial n on MEN MTC (FMTC) is ch aracterized by th e presen ce of MTC on ly an d h as been design ated a varian t of MEN 2A by th e n ew Am erican Thyroid Association (ATA) guidelin es (Wells, et al).82 All are autosom al-dom in an t condition s an d h ave a h igh pen etran ce for MTC (> 90% of a ected pat ien ts w ill develop MTC durin g th eir lifetim e). MEN 2A is th e m ore com m on syn drom e, accoun tin g for m ore th an 90% of h ereditar y cases. Oth er features of MEN 2A are un ilateral or bilateral ph eoch rom ocytom a (40–50% pen etran ce), an d hyperparathyroidism (10–30% pen etran ce); less com m on fin din gs in clude a cutan eous condition (lich en plan us am yloidosis) or Hirsch prun g’s disease.20,21,22 MEN 2B patients develop MTC in 100% of cases, and pheochrom ocytom a in 40%, but this group of patients is distinguished by di erent com orbid conditions, w hich include m ultiple m ucosal neurom as, “m arfanoid” habitus, intestinal ganglioneurom atosis, m edullated corneal nerve fibers, and m egacolon.23 MEN 2B accounts for approxim ately 5% of patients w ith fam ilial disease, and these MTC tum ors are often present at birth. MTC in MEN 2B is a m ore aggressive variant, w ith early m etastasis, m aking early diagnosis and treatm ent critical for successful m anagem ent. Thyroidectom y is recom m ended in infancy, w hen possible ( Fig. 17.2).21 Lastly, FMTC is a variant of MEN 2A characterized by predisposition to MTC only, though caution is w arranted because som e kindreds designated as FMTC have subsequently developed pheochrom ocytom a and parathyroid abnorm alities.

17.5 Genet ic Analysis Th e RET (rearran ged durin g tran sfect ion ) proto-on cogen e on ch rom osom e 10q11.2 plays a critical role in th e un derstan din g of MTC, both in diagn osis an d in fam ilial screen in g. RET en codes a t yrosin e kin ase receptor protein th at is com posed of an extracellular dom ain contain in g a ligan d-bin din g site w ith a cystein e-rich region , a tran sm em bran e dom ain , an d t w o in tracellular t yrosin e kin ase dom ain s.3,24 All of th e h ereditar y MTC syn drom es are caused by m issen se germ lin e m utation s in RET. In terestin gly, th ese m utation s are “gain of fu n ction ” m utation s

Fig. 17.2 Total thyroidectom y specim en with m ultiple enlarged central lym ph nodes from multiple endocrine neoplasia 2B patient. Photo courtesy of Dr. Jeffrey F. Moley.

as opposed to “loss of fun ction ” germ lin e m utation s seen in all oth er h ereditar y can cer syn drom e gen es. Som atic (n on -germ lin e) m utation s of RET h ave also been iden tified in 40 to 50% of sporadic MTC cases.25 In sporadic MTC, patien ts w ith som atic codon 918 RET m utation s h ave been foun d to h ave m ore aggressive disease progression an d w orse progn osis.25 There are strong genotype–phenotype correlations in the MEN 2 syndrom es. Disease severit y and expression of associated pathologies (pheochrom ocytom a, hyperparathyroidism , Hirschprung’s disease, lichen planus am yloidosis, and MEN2B phenot ype) correlate w ith the codon and functional dom ain of m utation w ithin the RET protein. For virtually all MEN 2A patients, the m utation occurs w ithin the cysteine-rich extracellular dom ain, w hich results in ligand-independent receptor dim erization and constitut ive activity.26 In the FMTC variant, m utations are usually sim ilar to those in MEN 2A, but som e fam ilies have m utations in the intracellular dom ain. Unlike MEN 2A and FMTC, MEN 2B nearly always involves the sam e codon 918 m utation, in the intracellular tyrosine kinase dom ain.27 Th e in creasin g availabilit y of gen etic an alysis over th e last 20 years h as revolut ion ized treatm en t of patien ts w ith h ereditar y syndrom es. Now, based on iden tification of a m utated RET allele, tu m or aggressiven ess an d disease course can be m uch m ore clearly predicted, an d th is greater kn ow ledge of

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Surgical Managem ent of Thyroid Diseases gen ot ype–ph en ot ype correlation s t ran slates in to tim ely an d appropriate pat ien t coun selin g. Th e ATA recom m en ds RET testin g as early as possible to patien ts w ith fam ily h istory con sisten t w ith MEN 2 or FMTC; for MEN 2B, th is sh ould occur sh ortly after birth , an d for MEN 2A an d FMTC, testin g sh ould be perform ed before 5 years of age.28 In fam ilies w ith a kn ow n specific RET m utation , a targeted approach can be em ployed to detect its presen ce. For patien ts w ith n ew ly diagn osed MTC or in fam ilies w ith un characterized RET m utation s, th e usual strategy curren tly em ployed is to sequen ce exon s 10 an d 11 (codon s 609, 611, 618, 620, 634) an d exon s 13, 14, 15, an d 16 w h ere th e m ajorit y of m utation s are foun d.

17.6 Diagnost ic Evaluat ion In th e in itial con sultation of a patien t presen tin g w ith MTC, a full patien t an d fam ily h istor y sh ould be obtain ed, an d part icular atten tion sh ould be placed on th e h istory of any thyroid or parathyroid disease, un con trolled hyperten sion , sudden death , or adren al tu m ors. Ever y pat ien t sh ould be con sidered to h ave possible fam ilial MTC un til proven oth erw ise, an d gen etic screen in g sh ould be o ered to pat ien ts w ith MTC or w ith oth er associated features, in cludin g lich en plan us am yloidosis or Hirschprung’s disease.3,22 On physical exam , any palpable m ass should be assessed for size or fixation to surrounding structures, and the presence of m ultiple nodules, lymphadenopathy, or evidence of distant m etastases should be noted. Com puted tom ography of the neck and chest is especially helpful. Particularly in MEN 2B patients, several overt clinical features, such as tongue nodules or a prom inent m id-upper lip, m ay be present. In patients presenting w ith sym ptom s of respiratory di culty or hoarseness, direct laryngoscopy for exam ination of the vocal cords should be done as this could indicate extensive local disease and possible involvem ent of the recurrent laryngeal nerve. Patients w ith high levels of calcitonin or m etastatic disease m ay also present w ith sym ptom s of flushing, diarrhea, and weight loss. Diagnostic workup should proceed w ith fine-needle aspiration (FNA) biopsy of the dom inant nodule and include im m unohistological staining for calcitonin. This has been show n to be successful in diagnosing MTC in approxim ately 50 to 80% of patients.9,29,30 Preoperative laborator y testin g sh ould in clude m easurem en t of serum calciton in , CEA, m etan eph rin es, n orm etan eph rin es, and calcium levels. RET proto-on cogen e an alysis sh ould be perform ed for any n ew ly diagnosed MTC patien t. Serum calciton in h as proven to be a sen sitive an d cost-e cien t m arker in detectin g MTC; h ow ever, routin e m easurem en t in patien ts w ith n odular thyroid disease h as rem ain ed controversial. Several studies h ave dem on strated an in ciden ce of MTC in 0.5 to 2% of patien ts w ith out suspected m align an cy, an d th e ben efit in reach ing an earlier diagn osis an d subsequen t treatm en t suggests th at im plem en tation of routin e calciton in m easurem en t m ay be an e ect ive sur veillan ce option .30,31,32 Th ough calciton in levels m ay be m ildly elevated in oth er clinical con dition s (e.g., ren al in su cien cy, n euroen docrin e tum ors), a basal or stim ulated calciton in level > 100 pg/m L stron gly suggests th e presen ce of MTC, an d th e extrem ely elevated level alon e is an in dication for surgery. Sim ilarly, a basal level > 10 to 20 pg/m L n ecessitates furth er w orkup of possible MTC.23,30,31,32,33,34 Serum CEA levels are also h elpful in th e risk stratification of patien ts w ith MTC. Preoperative levels > 30 n g/m L h ave been

sh ow n to porten d a poor progn osis for surgical curabilit y an d are associated w ith involvem en t of local lym ph n odes in approxim ately 70% of patien ts; at levels > 100 n g/m L, 90% of patien ts h ad cont ralateral n eck lym ph n ode involvem en t, an d 75% w ere foun d to h ave distan t m etastases.35 All MTC patien ts > 8 years of age sh ould un dergo bioch em ical testin g for ph eoch rom ocytom a w ith plasm a m etan eph rin es an d catech olam in es or 24-h our urin e collection for m etan eph rin es or catecholam in es. If positive, th e pat ien t sh ould un dergo treatm en t for th e ph eoch rom ocytom a prior to defin itive thyroidectom y for MTC. Fin ally, hyperparathyroidism foun d by elevated calcium an d parathyroid h orm on e levels is m an aged w ith con curren t parathyroidectom y at th e t im e of surgery for MTC. Im aging plays a vital role in th e assessm en t of MTC an d first involves a n eck ultrasoun d w ith lym ph n ode m appin g of th e cervical com partm en ts. Th is is critical in th e preoperative settin g because th e sen sitivit y of in traoperative palpation to detect n odal m etastases is on ly 64%, even w h en perform ed by experien ced surgeon s.10 Son ograph ic fin din gs of MTC com m on ly in clude hypoech ogen icit y, in tern al vascularit y, an d calcification s sim ilar to oth er thyroid m align an cies.36 In MTC patien ts presen tin g w ith a palpable thyroid n odule, m ore th an 75% w ill h ave associated n odal m etastases, an d 10 to 15% w ill also dem on strate eviden ce of distan t disease.10,37 MTC does n ot concen trate iodin e an d w ill appear as a cold n odule on thyroid scin tigraphy. Com puted tom ograph ic (CT) im aging of th e n eck, ch est, an d abdom en m ay reveal distan t sites of involvem en t, particularly in th e lun gs, liver, an d m ediastin al lym ph n odes, an d local m ass e ects ( Fig. 17.3). Prim ar y tum ors h ave relatively n on specific CT features but gen erally appear as n odules w ith calcification s. As m en tion ed earlier, lun g an d liver m etastases can be quite sm all, n um erous, an d have a m iliar y appearan ce. Magn etic reson an ce im aging (MRI) w ith con trast adm in istration can also be used in evaluation of m etastatic disease an d is con sidered th e m ost sen sitive im agin g tech n ique for detect in g liver m etastases. Bon e lesion s are t ypically best seen eith er on axial MRI or on bon e scin tigraphy.38 Use of fludeoxyglucose positron em ission tom ography (FDG-PET) rem ain s con troversial because som e studies h ave sh ow n FDG-PET to h ave low sen sitivit y.38,39,40 Serum calciton in levels h ave been sh ow n

Fig. 17.3 Com puted tom ographic scan of advanced m edullary thyroid carcinoma with tracheal com pression.

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Surgical Managem ent of Medullary Thyroid Cancer to correlate w ell w ith tu m or volum e, an d distan t m etastases are gen erally associated w ith elevated calciton in levels; im agin g is th erefore recom m en ded for th ese patien ts an d for th ose w ith local lym ph n ode m etastases.41

17.7 Init ial Surgical Approach Surgery for MTC is th e m ost im portan t in itial pat ien t treatm en t , an d early in terven t ion is of param oun t im portan ce due to th e m ore aggressive n ature of MTC an d th e h igh er rates of recurren ce an d m ortalit y w h en com pared to di eren tiated thyroid can cer. Surgery also o ers th e on ly possible defin itive cure for MTC an d is a ver y e ect ive option for palliation . System ic th erapies, w h ile sh ow in g prom ise, are n ot curative.42 Outcom es are im proved in patien ts w ith com plete rem ission follow in g surgical resection w h en com pared to pat ien ts w ith bioch em ically persisten t disease (i.e., persisten t elevation of calciton in levels) or to th ose w ith distan t m etastatic disease. For pat ien ts w ith fam ilial syn drom es, th e best curative option is com plete surgical resection before m align an t tran sform ation or before spread beyon d th e thyroid glan d.3,43 Per th e ATA, prophylactic thyroidectom y sh ould be recom m en ded to all patien ts w ith positive gen etic testin g for h ereditar y MTC w h o h ave n ot yet developed clin ically apparen t disease.28 Tim in g of surgery di ers based on th e gen ot ype–ph en ot ype correlation s, an d risk levels developed by th e ATA regarding aggressiven ess of disease are used as guidelin es for pat ien ts w ith hereditar y syn drom es. For in stan ce, patien ts w ith m utation s involving codon 918, associated w ith MEN 2B an d th e youn gest age of on set of MTC, h igh est risk of m etastases, an d disease-specific m ortalit y, are given an ATA level D an d are recom m en ded to un dergo prophylactic total thyroidectom y in in fancy. Th is is in con trast to patien ts w ith ATA level A m utation s, considered at low est risk, w h o are advised to un dergo thyroidectom y prior to 5 years of age but w h o m ay con sider th e option to delay surgery beyon d age 5 years if certain screen in g criteria are m et (i.e., n orm al an n ual basal serum calciton in , n orm al an n ual n eck ultrasoun d, less aggressive MTC fam ily h istory).28 In our 2005 study of children w ith MEN 2A RET m utations, no evidence of persistent or recurrent MTC (as indicated by elevated serum calcitonin levels) w as found in 44 of the 50 children w ho underw ent total thyroidectom y and central lym ph node dissection before age eight years.43 A European series of 207 patients w ith MEN 2A reported that none of the children younger than 14 years of age developed lym ph node m etastases.44 We have treated bulky nodal m etastatic disease in a 9-year-old index MEN 2A patient, and cervical lym ph node m etastases developed in a teen 10 years after a preventive thyroidectom y. The perform ance of a central neck lym ph node dissection should be based on the calcitonin level and the preoperative physical exam and ultrasound. Current recom m endations for MEN 2A patients advise total thyroidectom y alone prior to age 5 years if preoperative ultrasound dem onstrates thyroid nodules < 5 m m and the basal serum calcitonin level is < 40 pg/m L. Current ATA guidelines suggest that central neck dissection should be done in patients w ith a basal serum calcitonin > 40 pg/m L, and/or clinical evidence of cervical lym ph node involvem ent.28,43,44,45,46 All pat ien ts w ith MTC, both sporadic an d h ereditar y, w h o presen t w ith palpable disease sh ould un dergo total thyroidectom y w ith var yin g exten ts of concurren t system atic lym ph

n ode dissection an d parathyroid autotran splan tation . Given th at lym ph n ode m etastases m ay be di cult or im possible to detect eith er by im aging or by palpation , select ive n ode dissection (“berr y pickin g”) is discouraged because th is h as been sh ow n to h ave h igh er rates of recurren ce, low er rates of bioch em ical cure, an d w orse sur vival w h en com pared to m eticulous com partm en t-orien ted dissect ion ( Fig. 17.4).10,47 In a series of 73 patien ts treated at th e auth ors’ in stit ut ion w h o h ad presen ted w ith an in itial palpable m ass, 80%w ere foun d to have cen tral n ode (level VI) involvem en t, 75% h ad ipsilateral jugular n ode (levels II–IV) involvem en t, an d 47%h ad con tralateral jugular n ode involvem en t.10 Th erefore, at a m in im um , cen tral an d ipsilateral lateral com partm en t n ode dissection sh ould be perform ed at th e tim e of thyroidectom y in pat ien ts w ith a palpable prim ary tum or. Furth er com part m en t-orien ted dissection m ay be w arran ted based on preoperative im agin g, calciton in an d CEA levels, an d in traoperative fin din gs.3,10 Of n ote, in patien ts w ith sporadic MTC, th e in ciden ce of bilateral tu m or is relat ively low, an d a 2002 study exam in ed th e utilit y of total versus un ilateral thyroidectom y in patien ts w ith sporadic MTC an d n o iden tified RET germ lin e m utation .48 With 22 patien ts in retrospective review an d 15 patien ts treated prospect ively, un ilateral thyroidectom y w ith isth m usectom y, system atic bilateral cent ral lym ph n ode dissect ion , an d ipsilateral m odified radical n eck dissection w as perform ed. Th e prospective populat ion w as foun d to h ave a bioch em ical cure rate of 80%, w ith n o recurren ces in th e rem ain in g thyroid lobe.48 Alth ough un ilateral thyroidectom y o ers th e advan tages of low er risks of hypoparathyroidism an d recurren t n erve injur y an d n o n eed for thyroid supplem en tation , furth er investigation w ill be n eeded to elucidate th e risks an d ben efits of un ilateral thyroidectom y in com parison to rem oval of all thyroid tissue. Curren t recom m en dation s rem ain th at th e operat ive procedure sh ould rem ove all thyroid an d n odal tissue from th e level of the hyoid bon e superiorly to th e in n om in ate vessels in feriorly an d to th e carotid ar teries laterally.49 Ultrasou n d m appin g of region al lym ph n odes prior to surgery is particularly useful, an d suspicious n odes can be m arked on th e skin preoperatively, w h ich is h elpful to th e surgeon in plan n in g exten t of surgery, an d w h eth er con tralateral level II through V node dissection w ill be necessary. In a study of 195 patients w ith MTC, it w as found that as the num ber of central node m etastases increased, the frequency of ipsilateral and contralateral lateral com partm ent lym ph node m etastases also increased in direct relation. When 10 or m ore central com partm ent lym ph nodes w ere involved, nearly all patients had ipsilateral node involvem ent, and 77% had contralateral m etastases, w hich supports undertaking bilateral lateral com partm ent dissection during thyroidectom y w hen num erous central node m etastases are identified.50 Discontinuous lym phatic spread (“skip m etastases”) have also been described in the literature and underscores the im portance of a thorough preoperative evaluation to determ ine lym ph node involvem ent sites.10,51 Preoperative basal serum calciton in levels are also useful in estim atin g th e exten t of possible n odal involvem en t an d n eed for dissection . A report of 300 pat ien ts w ith MTC treated by com partm en t-orien ted surgery iden tified di eren t th resh olds at w h ich lym ph n ode m etastases w ere foun d in di eren t com partm en ts; n on e of th e patien ts w ith calciton in levels < 20 pg/ m L h ad eviden ce of lym ph n ode involvem en t, w h ich cont rasted

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Surgical Managem ent of Thyroid Diseases

Fig. 17.4 Lym ph node levels of the neck with com partm ent group designations. Adapted with permission (Musholt et al, J Surg Oncol. 2006 Dec 15;94(8):737-47)

sh arply w ith patien ts w ith calciton in levels > 10,000 pg/m L, w h o dem on strated > 80% w ith lym ph n ode involvem en t in th e n eck, > 50% in th e upper m ediastin um , an d > 70% prevalen ce of distan t m etastases.52 Th is can assist decision m akin g in operative plan n in g for th e in dex procedure, an d, in pat ien ts w ith elevated basal calciton in levels > 200 pg/m L, con tralateral lateral n eck dissection is recom m en ded as w ell. Careful m an agem ent of th e parathyroids is crit ical to preser ve fun ct ion durin g total thyroidectom y an d n eck dissection . Th e exten t of surgical m an ipulation h as been con troversial because th e adequacy of cent ral com part m en t dissection is arguably com prom ised by leavin g th e parathyroids in place w ith su cien t blood supply. Th e previous approach at th e auth ors’ in stit ut ion in cluded routin e four-glan d parathyroidectom y w ith autotran splan tation durin g cen tral n eck dissection ; h ow ever, our curren t pract ice en tails resection an d autotran splan tation of on e or t w o parathyroids on th e side of th e prim ary tum or an d th e con tralateral low er parathyroid, if it is n ot able to be preser ved on a viable vascular pedicle. Th e cont ralateral upper parathyroid is left in place on its n ative vascular supply. Preservation of parathyroid fun ct ion can th en be accom plish ed by transplan tin g m in ced 1 m m fragm en ts of th e rem oved parathyroid tissue in to in dividual m uscle pockets created in th e stern ocleidom astoid m uscle or a forearm m uscle.1,53 Due to th e risk of subsequen t graft-depen den t hyperparathyroidism , a n on dom in an t forearm m uscle m ay be used for MEN 2A patien ts, w h ereas th e stern ocleidom astoid is usually used for patien ts w ith sporadic disease, MEN 2B, or FMTC. All

parathyroid t issue sh ould be left in th e patien t if possible, an d tran splan tation of w h ole glan ds is n ot advised. If a patien t h as already developed prim ar y hyperparathyroidism before thyroidectom y, appropriate parathyroidectom y sh ould be perform ed. Su rgical op t ion s in clu d e in t raop erat ive p arat hyroid h orm on e m on it orin g w it h rem oval of on ly visibly en larged glan d s, su bt ot al p arathyroid ect om y leavin g on e glan d or a p iece of on e glan d in situ , or total p arathyroid ectom y w ith forearm au t ot ran sp lan t at ion .

17.8 Post operat ive Managem ent Total thyroidectom y h as relatively low m orbidit y an d m ortalit y, but im portan t com plication s of hypoparathyroidism an d recurren t laryn geal n er ve injur y m ust be carefully avoided. Accordin g to th e Am erican College of Surgeon s Com m ission on Can cer Patien t Care Evaluation St udy, th e overall risk of recurren t lar yngeal n er ve injury durin g thyroid can cer procedures is approxim ately 1.3%, ran gin g from 0.7% for total thyroidectom y alon e to 2.7% if con curren t lym ph n ode dissection is perform ed.54 Rates of tem porar y hypocalcem ia, a com m on postoperative occurren ce, also var y from 12% w ith out to 14% w ith lym ph n ode dissection . Th e risk of lon g-term hypoparathyroidism rem ains low w ith routin e use of parathyroid autotran splan tation , ran gin g from 1 to 4%.53,55 Patien ts sh ould be started on replacem en t th erapy of levothyroxin e w ith tit ration to a goal serum thyroid-stim ulat in g

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Surgical Managem ent of Medullary Thyroid Cancer h orm on e (TSH) level betw een 0.5 an d 2.5 m IU/L w h en ch ecked 2 to 3 m on th s after surgery. Suppression of TSH is n ot in dicated in MTC patien ts. Appropriate supplem en tation is particularly cru cial in ch ildren follow in g thyroidectom y. Mon itorin g for possible hypocalcem ia sh ould also be im plem en ted, an d sym p tom at ic treatm en t w ith calcium an d vitam in D can be adm in istered tem porarily as sym ptom s resolve or in defin itely if th e patien t is determ in ed to be perm an en tly aparathyroid.28 For patien ts w ith h ereditar y MTC an d n o eviden ce of associated en docrin e lesion s prior to thyroidectom y, routin e sur veillance for ph eoch rom ocytom a in MEN 2A an d MEN 2B patien ts sh ould begin at age 8 years w ith an n ual plasm a m etan eph rin es. Sim ilarly, to m on itor for prim ar y hyperparathyroidism in MEN 2A patien ts, serum calcium levels sh ould be ch ecked an n ually for at least 5 years.22 Calciton in levels usually decrease to a n ew baselin e by 72 h ours after surgery, but, because th ey m ay con tin ue to fall, seru m calciton in sh ould be ch ecked 3 m on th s postoperatively to allow levels to reach a n adir.8,56,57 A postoperative decrease in th e calciton in level to w ith in n orm al lim its is associated w ith decreased lon g-term risk of MTC recurren ce an d im proved survival rates.58 Norm alization of th e calciton in level is m ore com m on ly ach ieved in patien ts w ith disease con fin ed to th e thyroid. Am ong patien ts w ith lym ph n ode m etastases n orm alization occurs in 20 to 30% (< 5% in patien ts w ith 10 or m ore lym ph n ode m etastases).59 Radioactive iodin e ablation is n ot e ect ive in MTC; th erefore, a th orough , com part m en t-orien ted operation is recom m en ded. Calciton in levels m ay be ch ecked ever y 6 m on th s for 1 year, and less frequen tly th ereafter if levels rem ain un ch anged.

17.9 Residual or Recurrent Disease In som e in stan ces, patien ts m ay un dergo h em ithyroidectom y w ith a postoperative diagnosis of MTC based on path ology. For patien ts w ith h ereditar y MTC, com pletion thyroidectom y sh ould be perform ed because th e risk of presen t or subsequen t m align an cy in th e con tralateral lobe n ears 100%. How ever, sin ce th e in ciden ce of bilateral MTC in pat ien ts w ith sporadic disease is gen erally < 20%, com pletion thyroidectom y is n ot n ecessarily in dicated un less a RET germ lin e m utation is discovered, serum calciton in levels are sign ifican tly elevated, radiological eviden ce of residual MTC is presen t postoperat ively, or path ology dem on strates C-cell hyperplasia, m ulticent ric disease, positive surgical m argin , or extrathyroidal exten sion .28,60 Persisten tly elevated calciton in levels in a postoperative patien t suggest residual disease, an d im aging sh ould be perform ed to localize any rem ain in g tum or burden . For patien ts w ith postoperative calciton in levels th at are elevated but < 150 pg/m L, an ultrasoun d of th e n eck an d m ediastin um is adequate. Suspicious lym ph n odes or soft t issue lesion s m ay be biopsied or rem oved. If n oth ing is foun d on im aging, patien ts sh ould un dergo calciton in - an d CEA-level testin g ever y 3 m on th s an d physical exam in ation w ith ultrasoun d ever y 6 m on th s. For patien ts w ith serum calciton in levels > 150 pg/m L, a full m etastatic w orkup sh ould be in itiated w ith addition al im aging, in cluding n eck an d ch est ultrasoun d an d CT scan , contrasten h an ced CT or MRI of th e liver, bon e scin tigraphy, MRI of th e spin e an d pelvis, an d FDG-PET scan .28 Calciton in an d CEA doublin g t im es h ave also been foun d to be an e cien t m easure of

disease progression in th e m ajorit y of pat ien ts an d h ave been related to overall sur vival rate, tim e to recurren ce, an d tim e betw een recurren ce an d death .61,62 Sign ifican tly im proved lon g-term progn osis h as been dem on strated in pat ien ts w h ose calciton in -doubling t im e w as > 2 years w h en com pared to th ose < 6 m on th s; in on e series of 65 patien ts, 100% of patien ts in th e form er categor y w ere alive at 10 years com pared to on ly 8%in th e latter.62 Even w ith a successful in dex procedure, som e pat ien ts w h o achieve bioch em ical rem ission m ay later develop elevated calcitonin levels, in dicative of persisten t or recurren t disease.63 Th ese patien ts sh ould un dergo im aging, as already described, to look for recurren t or m etastatic disease. If im aging dem on strates isolated locoregion al disease w ith in th e n eck, patien ts m ay un dergo addition al surgical resection w ith curative in ten t.11,46 Com plete clearan ce of th e tu m or burden at reoperation for patien ts w ith out distan t m etastases or w ith m in im al distan t m etastases h as been sh ow n to im prove lon g-term survival an d preven t fur th er recurren ce in th e n eck ( Fig. 17.5).11 Durable bioch em ical cure w ith disease-free sur vival > 10 years m ay be ach ieved in m ore th an 25% of th ese patien ts follow in g reoperation .64,65,66 Th erefore, reoperation sh ould be con sidered in patien ts w h ose postoperative calciton in levels rem ain elevated follow in g an in adequate in itial operation , if im aging dem on strates residual or recurren t disease, or in w h om th e tum or burden poses a risk of invasion or com pression of th e trach ea, esoph agus, or great vessels. In spite of th e presence of occult disease, m any patien ts w ith elevated calciton in levels do ver y w ell clin ically w ith out any radiograph ic or sym ptom atic eviden ce of disease recurren ce. Th is is attributed to th e often in dolen t disease course an d variable t um or biology of MTC. Con sequen tly, m an agem en t of th ese patien ts rem ain s con troversial because sur vival rates of patien ts w ith persisten t hypercalciton em ia h ave been foun d to be as h igh as 86% at 10 years in th e absen ce of distan t m etastases.67 If n o an atom ical eviden ce of disease is apparen t on physical exam or im aging, con servative m an agem en t w ith close sur veillan ce is recom m en ded. Altern atively, a th orough extirpation of cent ral an d lateral n odal groups n ot previously rem oved m ay be pursued an d m ay result in rem oval of subclin ical n odal m etastatic disease, w ith n orm alization of calciton in (th ough th is h as n ot been proven to result in im proved sur vival).10,11,28 Th e surgeon m ust approach reexploration of th e n eck w ith caut ion given th e presen ce of scarrin g an d altered an atom y. There is an in creased risk of com plication s, such as th oracic duct leak, hypoparathyroidism , an d injury to a recurren t lar yngeal n er ve. Risk of injur y to th e recurren t laryn geal n er ve in creases to 8% in th e reoperative sett in g, an d frequen cy of hypoparathyroidism m ay be up to four t im es h igh er th an after th e in itial operation .66 Th e surgical procedure is perform ed th rough th e prior low collar in cision w ith exten sion laterally an d superiorly alon g th e stern ocleidom astoid. In reoperative cen tral com part m en t dissect ion , a “backdoor” or lateral approach m ay facilitate appropriate identification of struct ures because the central neck is thus accessed via a tissue plane that has not undergone prior dissection.68 Di ering from the anterior approach, the strap m uscles are now m obilized m edially o of the carotid sheath, exposing the deep central com partm ent and allow ing for clear identification of the recurrent laryngeal nerve and the parathyroids.69 At the authors’ institution, in a series of

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Surgical Managem ent of Thyroid Diseases

Fig. 17.5 Mediastinal dissection for m edullary thyroid carcinom a.

100 central neck reoperations, no recurrent laryngeal nerve injuries were sustained w ith this technique.68 All residual thyroid and nodal tissue is rem oved from the central com partm ent (level VI and VII), extending from the hyoid bone at the superior m argin along the larynx to an inferior m argin of the innom inate artery on the right and a sim ilar level approaching the aortic arch on the left w ith the carotid arteries as the lateral m argins. Any tissue rem aining anterior to the trachea and superior thym ic tissue is also resected. Com partm ental dissection of im ageor biopsy-proven disease in the central or lateral neck com partm ents w ith guidelines sim ilar to those at initial operation should then be perform ed. For patients w ho have not undergone parathyroid autotransplantation, it is critical to identify any parathyroids prior to rem oval of lym ph nodes. Resection of norm al parathyroid tissue w ith autotransplantation m ay be perform ed at this point, or the surgeon m ay leave viable glands in situ if oncologic resection is not com prom ised.70 Due to the increased di culty of identifying the parathyroids in children, reoperative neck exploration is not recom m ended unless previous autotransplantation has been confirm ed, if lim ited exploration avoiding the rem aining parathyroids can be perform ed, or if bulky tum or burden is com prom ising surrounding structures.

17.10 Treat m ent of Advanced Disease In patien ts w ith sign ifican t local involvem en t or distan t m etastases in dicative of advan ced disease, treatm en t option s are un fortu n ately lim ited by poor respon se, even to m ultim odal therapy. Because MTC does not con centrate radioactive iodin e, postoperative treatm en t w ith th is therapy is not recom m en ded in the absence of concurren t di erentiated thyroid can cer.28,42 The goals of surgical in tervention in these patients becom e m ore palliative w ith an aim of reducing sym ptom atic progression or associated com plications. Mainten ance of function in sw allow ing and speech an d decreasing bulky tum or burden

w ithin the neck m ay allow the patien t an im proved quality of life, and addition al adjuvan t therapies, including EBRT or h epatic em bolization of liver m etastases, can be considered. For patien ts w ith lim ited extracervical m etastatic disease, a m ore radical locoregion al approach, including resection of a un ilateral recurrent laryn geal ner ve, m ay be of ben efit to prevent tum or recurrence. In the setting of m ore significan t locally invasive disease involving the trachea, esophagus, or other surrounding struct ures, th e exten t of surgical in tervention w ith in th e neck should be carefully con sidered in th e con text of life expectancy and other m edical com orbidit ies. Sim ilarly, for distan t m etastases, the risks an d ben efits of surgery or system ic th erapies m ust be w eighed against the often slow rate of progressive disease and relatively sustainable patien t qualit y of life, particularly if the patient is asym ptom atic w ith m inim al distant disease. Palliative t um or debulkin g m ay ben efit pat ien ts w h o develop system ic sym ptom s, such as pain , flush in g, or diarrh ea.28,65 System ic m etastases are m ost com m on ly reported in th e liver, lun gs, bon e, an d brain . Liver m etastases h ave been reported in up to 45% of patien ts w ith advan ced MTC, an d defin itive treatm en t sh ould be con sidered in patien ts w h ose h epatic lesion s are large, progressive, or sym ptom atic.28,67 For isolated, large m etastases, surgical resection m ay be possible, an d som e studies h ave foun d variable success w ith radiofrequen cy ablation an d percutan eous eth an ol ablation .71,72 How ever, because h epatic lesion s are com m on ly sm all (1–5 m m ) an d m ultiple, oth er th erapies, such as ch em oem bolizat ion or system ic th erapy, m ay be of greater poten t ial value.12,73,74 Lun g an d m ediastin al m etastases are also sim ilarly m ultiple and m ay require surgical resection to alleviate airw ay com pression or bleedin g. Radiofrequen cy ablation is also recom m en ded in patien ts w h ose lun g lesion s are periph eral an d < 40 m m in diam eter.75 How ever, for sign ifican t airw ay com prom ise an d invasion , airw ay sten t in g can be con sidered an d h as been successful in provision of sym ptom at ic relief an d im provem en t of respirator y an d perform an ce status.76 For bon e an d brain m etastases, surgical excision m ay be n ecessary to preven t fracture in w eigh t-bearin g

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Surgical Managem ent of Medullary Thyroid Cancer bon es, to relieve spin al cord com pression , or if a patien t dem on strates con cern in g n eurological sym ptom s w ith radiological eviden ce of brain m etastasis. EBRT rem ain s lim ited in its utilit y as adjuvan t th erapy for patien ts w ith MTC, an d curren t usage varies w ith in stit ution al preferen ce. Ben efit from EBRT occurs m ain ly w ith palliation of bon e m etastases, but it h as largely rem ain ed in e ective in treatm en t of disease w ith in th e n eck. In on e series, 46 patien ts at di erin g stages of disease un derw en t EBRT w ith n o sign ifican t di eren ce in recurren ce rates; h ow ever, upon subgroup an alysis of 40 pat ien ts w ith “h igh -risk features,” in cluding m icroscopic residual disease, extraglan dular invasion , or lym ph n ode involvem en t, 86% of th e patien ts w h o h ad received EBRT h ad n ot experien ced local/region al recurren ce, w h ereas on ly 52% of th e patien ts w h o h ad n ot received EBRT w ere diseasefree.77 Th is supports th e argum en t th at EBRT m ay im prove sym ptom s an d qualit y of life in patien ts w h o h ave un resectable local disease or com prom ise of crit ical local struct ures. Stan dard system ic ch em oth erapy sh ow ed little clinical e ect an d only part ial respon ses at best in sm all population s of patien ts treated w ith di eren t regim en s, in cludin g dacarbazin e, fluorouracil, an d doxorubicin .78,79,80 Con sequen tly, curren t recom m endations advise against standard chem otherapy in first-line treatm ent of patients w ith persistent or recurrent MTC.28 New m olecular therapies are very prom ising, and the increasing understanding of MTC oncogenesis has led to identification of m ultiple m olecular targets. Because all of the hereditary syndrom es and up to 50% of sporadic MTC can be related to m utations of the RET receptor protein, kinase inhibitors have been under considerable investigation, and agents such as vandetanib, cabozantinib, sorafenib, and sunitinib have show n prom ise in im proving progressionfree survival. However, only vandetanib and cabozantinib are currently approved by the Food and Drug Adm inistration, and significant short-term toxicity w ith little long-term data should be considered before using these agents.75,81

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J Clin En docrin ol Metab 1983; 57(1); 124–128 [43] Skin n er MA, Moley JA, Dilley W G, Ow zar K, Deben edetti MK, Wells SA, Jr. Prophylactic thyroidectom y in m ultiple en docrin e n eoplasia typ e 2A. N Engl J Med 2005; 353(11); 1105–1113 [44] Mach ens A, Niccoli-Sire P, Hoegel J, et al. European Multiple En docrin e Neoplasia (EUROMEN) Study Group. Early m align an t progression of h ereditary m edullary thyroid can cer. N En gl J Med 2003; 349(16); 1517–1525 [45] Dralle H, Gim m O, Sim on D, et al. Prophylactic thyroidectom y in 75 ch ildren an d adolescen ts w ith h ereditary m edullary thyroid carcinom a: Germ an an d Austrian experien ce. World J Surg 1998; 22(7); 744–750, discussion 750–751 [46] Tuttle RM, Ball DW, Byrd D, et al. Nation al Com preh en sive Can cer Netw ork. Medullar y carcin om a. J Natl Com pr Can c Netw 2010; 8(5); 512–530 [47] Dralle H, Dam m I, Scheum an n GF, et al. Com partm en t-orien ted m icrodissection of region al lym ph n odes in m edullary thyroid carcinom a. Surg Today 1994; 24(2); 112–121 [48] Miyauchi A, Matsuzuka F, Hirai K, et al. Prospective trial of un ilateral surgery for n on h ereditary m edullary thyroid carcin om a in patien ts w ith out germ lin e RET m utation s. World J Surg 2002; 26(8); 1023–1028 [49] Stam atakos M, Paraskeva P, Katsaron is P, Tasiopoulou G, Kontzoglou K. Surgical approach to th e m an agem en t of m edullary thyroid can cer: w h en is lym ph n ode dissect ion n eeded? On cology 2013; 84(6); 350–355 [50] Mach ens A, Hauptm an n S, Dralle H. Prediction of lateral lym ph n ode m etastases in m edullary thyroid can cer. Br J Surg 2008; 95(5); 586–591 [51] Mach ens A, Holzh ausen HJ, Dralle H. Skip m etastases in thyroid can cer leapin g th e central lym ph n ode com partm en t. Arch Surg 2004; 139(1); 43–45 [52] Mach ens A, Dralle H. Biom arker-based risk stratification for previously un treated m edullar y thyroid can cer. J Clin En docrin ol Metab 2010; 95(6); 2655–2663 [53] Olson JA, Jr, DeBen edetti MK, Baum an n DS, Wells SA, Jr. Parathyroid autotran splan tation durin g thyroidectom y. Results of lon g-term follow -up. An n Surg 1996; 223(5); 472–478, discussion 478–480 [54] Hun dah l SA, Cady B, Cun n in gh am MP, et al. In itial results from a prospect ive coh ort study of 5583 cases of thyroid carcin om a treated in th e un ited states durin g 1996. U.S. an d Germ an Th yroid Can cer Study Group. An Am erican College of Surgeon s Com m ission on Can cer Patien t Care Evaluation study. Can cer 2000; 89(1); 202–217 [55] Rosato L, Avenia N, Bern an te P, et al. Com plication s of thyroid surgery: an alysis of a m ulticen tric study on 14,934 patien ts operated on in Italy over 5 years. World J Surg 2004; 28(3); 271–276 [56] Ism ailov SI, Piulatova NR. Postoperative calciton in study in m edullar y thyroid carcinom a. En docr Relat Can cer 2004; 11(2); 357–363 [57] Fugazzola L, Pin ch era A, Luch etti F, et al. Disappearan ce rate of serum calciton in after total thyroidectom y for m edullary thyroid carcinom a. In t J Biol Markers 1994; 9(1); 21–24 [58] Ren dl G, Man zl M, Hitzl W, Sun gler P, Pirich C. Lon g-term progn osis of m edullary thyroid carcin om a. Clin En docrin ol (Oxf) 2008; 69(3); 497–505

[59] Scollo C, Baudin E, Travagli JP, et al. Ration ale for cen tral an d bilateral lym ph n ode dissection in sporadic an d h ereditary m edullar y thyroid can cer. J Clin En docrin ol Metab 2003; 88(5); 2070–2075 [60] Moley JF, Fialkow ski EA. Eviden ce-based approach to th e m an agem en t of sporadic m edullary thyroid carcin om a. World J Surg 2007; 31(5); 946–956 [61] Laure Giraudet A, Al Gh ulzan A, Aupérin A, et al. Progression of m edullary thyroid carcin om a: assessm en t w ith calciton in an d carcin oem br yon ic an tigen doublin g tim es. Eur J En docrin ol 2008; 158(2); 239–246 [62] Barbet J, Cam pion L, Kraeber-Bodéré F, Ch atal JF GTE Study Group. Progn ostic im pact of serum calciton in an d carcin oem br yon ic an tigen doubling-tim es in patien ts w ith m edullar y thyroid carcinom a. J Clin En docrin ol Metab 2005; 90 (11); 6077–6084 [63] Fran c S, Niccoli-Sire P, Coh en R, et al. Fren ch Medullar y Study Group (GETC). Com plete surgical lym ph n ode resect ion does n ot preven t auth en tic recurren ces of m edullar y thyroid carcinom a. Clin En docrin ol (Oxf) 2001; 55(3); 403–409 [64] Fialkow ski E, DeBen edetti M, Moley J. Lon g-term outcom e of reoperation s for m edullar y thyroid carcin om a. World J Surg 2008; 32(5); 754–765 [65] Moley JF, Dilley W G, DeBen edetti MK. Im proved results of cer vical reoperation for m edullary thyroid carcin om a. An n Surg 1997; 225(6); 734–740, discussion 740–743 [66] Gim m O, Ukkat J, Dralle H. Determ in ative factors of bioch em ical cure after prim ar y an d reoperative surgery for sporadic m edullary thyroid carcinom a. World J Surg 1998; 22(6); 562–567, discussion 567–568 [67] van Heerden JA, Gran t CS, Gh arib H, Hay ID, Ilstrup DM. Lon g-term course of patien ts w ith persisten t hypercalciton inem ia after apparen t curative prim ar y surgery for m edullary thyroid carcin om a. An n Surg 1990; 212(4); 395–400, discussion 400–401 [68] Moley JF, Lairm ore TC, Doh erty GM, Brun t LM, DeBen edetti MK. Preservation of th e recurren t lar yn geal n er ves in thyroid an d parathyroid reoperation s. Surgery 1999; 126(4); 673–677, discussion 677–679 [69] Tisell LE, Han sson G, Jan sson S, Salan der H. Reoperation in th e treatm en t of asym ptom atic m etastasizing m edullar y thyroid carcin om a. Surgery 1986; 99 (1); 60–66 [70] Coh en MS, Moley JF. Surgical treatm en t of m edullary thyroid carcinom a. J In tern Med 2003; 253(6); 616–626 [71] Werten broek MW , Lin ks TP, Prin s TR, Plukker JT, van der Jagt EJ, de Jon g KP. Radiofrequen cy ablation of h epatic m etastases from thyroid carcinom a. Thyroid 2008; 18(10); 1105–1110 [72] Isozaki T, Kiba T, Num ata K, et al. Medullar y thyroid carcin om a w ith m ultiple h epatic m etastases: treatm en t w ith tran scath eter arterial em bolization an d percutaneous eth an ol inject ion . In tern Med 1999; 38(1); 17–21 [73] From igué J, De Baere T, Baudin E, Drom ain C, Leboulleux S, Sch lum berger M. Ch em oem bolization for liver m etastases from m edullary thyroid carcinom a. J Clin En docrin ol Metab 2006; 91(7); 2496–2499 [74] Loren z K, Brauckh o M, Beh rm an n C, et al. Select ive arterial ch em oem bolization for h epatic m etastases from m edullar y thyroid carcin om a. Surgery 2005; 138(6); 986–993, discussion 993 [75] Sm it J. Treatm en t of advan ced m edullar y thyroid can cer. Thyroid Res 2013; 6 (1) Suppl 1; S7 [76] Tsutsui H, Kubota M, Yam ada M, et al. Airw ay sten ting for th e treatm en t of lar yn gotracheal sten osis secon dary to thyroid can cer. Respirology 2008; 13 (5); 632–638 [77] Brierley J, Tsan g R, Sim pson W J, Gospodarow icz M, Sutcli e S, Pan zarella T. Medullar y thyroid can cer: an alyses of sur vival an d progn ostic factors an d th e role of radiation th erapy in local con trol. Th yroid 1996; 6(4); 305–310 [78] Orlan di F, Caraci P, Berrut i A, et al. Ch em oth erapy w ith dacarbazin e an d 5-fluorouracil in advan ced m edullar y thyroid can cer. An n On col 1994; 5(8); 763– 765 [79] Sch erü bl H, Raue F, Ziegler R. Com bin ation ch em oth erapy of advan ced m edullar y an d di eren tiated thyroid can cer. Ph ase II study. J Can cer Res Clin On col 1990; 116(1); 21–23 [80] Wu LT, Averbuch SD, Ball DW, de Bustros A, Baylin SB, McGuire WP, III. Treatm en t of advan ced m edullary thyroid carcin om a w ith a com bination of cycloph osph am ide, vin cristin e, an d dacarbazin e. Can cer 1994; 73(2); 432–436 [81] Wells SA, Jr, Gosn ell JE, Gagel RF, et al. Van detanib for th e treatm en t of patien ts w ith locally advan ced or m etastatic h ereditary m edullary thyroid can cer. J Clin On col 2010; 28(5); 767–772 [82] Wells SA, Jr, et al. Revised Am erican Thyroid Association guidelin es for th e m an agem en t of m edullar y thyroid carcinom a. Thyroid 2015; 25(6); 567–610

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Surgical Managem ent of Anaplastic Thyroid Cancer

18 Surgical Managem ent of Anaplast ic Thyroid Cancer Brian R. Untch and Luc G. T. Morris

18.1 Int roduct ion An aplastic thyroid can cer (ATC) is a rare thyroid can cer ch aracterized by an aggressive disease course an d a h igh m ortalit y rate.1,2 Com m on ly, patien ts w ill present w ith a rapidly grow in g n eck m ass an d sym ptom s related to invasion or com pression of struct ures w ith in th e n eck. At diagnosis, m any patien ts w ill already h ave w idespread m etastat ic disease.3 Clin ical decision m akin g in a m ajority of cases is directed tow ard palliation . Th is ch apter discusses treatm en t approaches for patien ts w ith ATC an d review s th e lim ited role for surgical in terven t ion .

18.2 The Spect rum of Thyroid Cancers Well-di eren t iated thyroid can cers arisin g from follicular thyroid cells are associated w ith excellen t disease-specific sur vival outcom es. Localized tum ors are m an aged w ith thyroidectom y an d, in select cases, lym ph n ode dissection an d/or adjuvan t radioact ive iodin e th erapy.4 Even pat ien ts w ith m etastatic differen tiated thyroid can cer can experien ce prolon ged survival.5 Th is is in stark con trast to pat ien ts w ith ATC, th e course of w h ich is as aggressive as any oth er h um an can cer. ATCs are com posed of un di eren tiated cells th at do n ot h ave th e abilit y to take up radioactive iodin e. Th ese tum ors are h igh ly fludeoxyglucose (FDG)-avid on positron em ission tom ography (PET).6 Ch aracteristic h istological fin din gs in clude n ecrosis, local invasiven ess, large n uclei, an d frequen t m itotic figures ( Fig. 18.1).7 Th e spin dle cells foun d in ATC can easily be m istaken for oth er spin dle cell n eoplasm s, in cludin g sarcom a. A path ologist experien ced w ith ATC is critical in cases of diagn ostic un certain t y. Th is is because h istopath ologic diagn oses (particularly in th e sett in g of a m etastatic biopsy) can be com plicated by a loss of t ypical di eren tiated thyroid-specific im m un oh istoch em istr y (IHC) m arkers th at iden tify a thyroid origin . Accordin gly, given th e h igh ly un di eren tiated n ature of th ese tum ors, path ological diagn osis of ATC often requires kn ow ledge of th e location of th e tum or biopsy site an d carefu l con sideration of th e patien t’s clin ical h istory. Histological eviden ce suggests th at som e an aplastic can cers m ay origin ate from an teceden t thyroid disease. Both goiter an d w ell-di eren t iated thyroid can cers can be seen adjacen t to

an aplastic cells in resected specim en s. Molecular an alyses dem on strate th at m ut ually exclusive gen om ic ch anges in m itogen activated protein kin ase (MAPK) path w ay gen es (RAS, BRAF, RET/PTC fusion s) con tribute to thyroid can cer path ogen esis. Addition al gen etic ch anges in DNA repair gen es (p53) an d th e telom erase prom oter m ay trigger gen om ic in stabilit y an d cell im m ortalization th at is required for tran sform ation to an un differen tiated tum or.8,9 Given th e h igh in ciden ce of clinical an d subclin ical thyroid can cers in th e gen eral population , clearly th is tran sform ation occurs at a ver y low rate. Th e in ciden ce of ATC in th e Un ited States h as been stable over tim e, ran ging betw een 0.1 an d 0.2 per 100,000 person s, accoun tin g for few er th an 1% of thyroid cancer diagn oses.10 ATCs are respon sible for a large percen tage of deaths related to thyroid can cer in th e Un ited States. Alth ough few large series of patien ts exist, ATC is th ough t to h ave on e of th e sh ortest m edian sur vival rates of all can cers, ran gin g from 3 to 5 m on th s.11 A m ajorit y of pat ien ts w ill h ave m etastatic disease at presen tation ( Fig. 18.2). In addition , m any pat ien ts w ill h ave large, rapidly grow in g n eck tum ors th at can com press th e airw ay. Surgical series frequen tly report patien ts w h o un derw en t thyroidectom y an d received an in ciden tal diagnosis of ATC at th e tim e of path ological an alysis. Th ese are un com m on en t ities an d are n ot represen tative of th e vast m ajorit y of patien ts presen tin g w ith clin ically eviden t ATC. Th us th e outcom es of th ese sin gle-in stit ution al experien ces sh ould be in terpreted cautiously. In th e m ajorit y of cases, ATC is un fortun ately a disease rarely able to be e ect ively treated w ith surgical resection .

18.3 Init ial Evaluat ion of a Rapidly Expanding Neck Mass Patien ts presen tin g w ith an en largin g n eck m ass require a h istological diagn osis an d im aging of th e h ead an d n eck ( Fig. 18.3). Percutan eous core or fin e-n eedle biopsy un der ultrasoun d guidan ce provides excellen t visualization an d can con firm tum or sam pling w h ile avoidin g vital struct ures. Open biopsy is rarely perform ed given th e success of percutan eous tech n iques, but it is occasion ally n eeded. On ce th e diagn osis h as been establish ed, staging w orkup sh ould in clude laborator y testin g an d cont rast-en h an ced im agin g of th e h ead an d n eck, in cluding brain m agn etic reson an ce im agin g (MRI) w ith fullbody FDG-PET ( Fig. 18.4 an d Fig. 18.5).12

Fig. 18.1 Histology of anaplastic thyroid cancer (ATC). (a) Low-power view dem onstrating abnormally shaped cells without papillary or follicular architecture. (b) High-power view demonstrating irregularly shaped cells and heterogeneit y of nuclei, features t ypical of ATC.

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Fig. 18.2 Com puted tomographic scans of a patient presenting with anaplastic thyroid cancer. (a) The neck m ass results in tracheal and superior m ediastinal shift. (b) Extensive lung metastases in the sam e patient.

Fig. 18.3 (a-c) Three patients presenting with rapidly enlarging neck m asses.

Fig. 18.4 (a) Magnetic resonance im aging (MRI) of the neck in a patient with anaplastic thyroid cancer. The mass is infiltrative and involves m ultiple structures within the neck. The trachea is displaced laterally. (b) Fludeoxyglucose (FDG) positron em ission tom ography of the sam e patient. Locally advanced disease with lym ph node metastases can be seen within the neck. Metastatic disease to the lungs is also observed (circled in red).

Thyroid fun ct ion tests, blood coun ts, an d fu ll ch em ist r y p an els sh ou ld be ch ecked in an t icip at ion of m u lt im od alit y t h erapy (su rger y, ch em ot h erapy, an d rad iat ion ). Lar yn goscopy to assess vocal cord m obilit y sh ou ld be p erform ed in all p at ien t s. Locally u n resect able t u m ors in vad e an d su r rou n d t h e carot id ar t er y, p rever t ebral fascia, m ed iast in al st r u ct u res, t rach ea, lar yn x, or esop h agu s.13 For localized t u m ors t hyroid ect om y w it h lym p h n od e d issect ion is reason able, bu t t h is is an ext rem ely u n com m on p resen t at ion of ATC.1 2 Tu m ors th at exten sively in vad e local st r u ct u res are n ot ap p rop r iate for su rgical resect ion . En bloc resect ion w ou ld

oft en requ ire exten sive su rger y w it h lar yn gect om y, p h ar yn gectom y, an d esop h agectom y, an d is u n likely t o be of valu e, given t h e h igh likelih ood of resid u al gross d isease even aft er exten sive resect ion t ogeth er w it h t h e h igh likelih ood of t h e d evelop m en t of d istan t m etastases w it h in a sh or t tim e in terval. For p at ien ts w it h m etast atic d isease id en t ified on crosssect ion al im aging/PET it sh ou ld be n ot ed t h at t h is m ay rep resen t a m ore w ell-d i eren t iated com p on en t of t h e tu m or. High FDG avid it y suggest s ATC, bu t if t h ere is su sp icion of low -grad e m et ast at ic d isease, seru m t h yroglobu lin levels can be h elp fu l.

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Fig. 18.5 Coronal (a) and axial (b) com puted tom ographic im ages of a patient with metastatic anaplastic thyroid cancer. Multiple m etastases can be seen within the bones of the skull and the brain.

Patien ts w ith distan t m etastatic disease sh ould be referred for system ic th erapy or m ultim odalit y treatm en t s th at in clude radiation .14 Data to suggest on e part icular treatm en t approach over an oth er are lackin g, an d th e auth ors suggest referral to a m ultidisciplin ar y group w ith experien ce in treatin g ATC. En rollm en t in a clin ical trial is optim al. Tim ely coordination of care across experien ced specialists is crit ical to providin g optim al palliative care.

18.4 Resect ion of Anaplast ic Thyroid Cancer Patien ts present in g w ith resectable an aplastic thyroid t um ors are rare. Alth ough prolon ged sur vival after com plete resection is reported in som e series, th ese patien ts t ypically h ave an in ciden tal diagn osis of ATC after thyroidectom y or h ave disease biology th at por ten ds a better progn osis.15 After resection of sm all in ciden tal lesion s, patien ts can be follow ed closely w ith cross-section al im aging. Con sideration sh ould be given to adjuvan t treatm en t . For patien ts w ith large tu m ors an d/or lym ph n ode m etastasis, resectabilit y sh ould be based on im agin g ch aracteristics. In gen eral, rem oval of gross disease sh ould be th e goal, in cluding lym ph n ode dissection s as n eeded. In patien ts w ith exten sive bilateral lym ph n ode m etastasis or upper m ediastin al disease, resection sh ould be part of m ultim odalit y treatm en t . Num erous retrospective series associate com plete resection (R0, n o residual m icroscopic t um or rem ain ing) w ith sur vival.16,17 Un fort un ately, th ese an alyses are com plicated by sign ifican t select ion bias. Th us surgical resection sh ould be considered only after appropriate m etastatic w orkup, pat ien t counselin g, and m ultidisciplin ar y discussion . Adjuvan t t reatm en ts in th e form of radiation an d system ic treatm en t s are acceptable in th is settin g. In som e cases it m ay be reason able to resect a sym ptom atic prim ar y tum or in a patien t w ith distan t m etastatic disease. Patien ts m ay h ave progressive upper aerodigestive sym ptom s th at require palliation . If a tum or is sm all, resectable, an d does n ot involve vital struct ures (i.e., an R0 resection is an ticipated) th en resection can be attem pted. It sh ould be n oted th at th is

situation is ver y un usual. Because recurren t lar yn geal n er ve involvem en t is com m on in ATC, th e contralateral n er ve sh ou ld be carefu lly con sid ered an d sh ou ld be con firm ed t o be fu n ction in g p reop eratively. If a tot al t hyroid ect om y is p erform ed , th e con t ralateral n er ve sh ou ld be fu lly d issect ed an d con firm ed to be in tact an d fu n ction in g before p lacin g th e ip silateral n er ve at risk. If sym pt om at ic im p rovem en t is likely from a lobectom y th en th e con tralateral lobe sh ou ld rem ain in sit u . “Debu lkin g” su rger y h as n o role in t reat m en t of ATC p atien ts. R2 resect ion s (m acroscop ic resid u al d isease p resen t) are u n likely t o ben efit p at ien t s, as obser ved in n u m erou s ot h er aggressive m align an cies.

18.5 Neoadjuvant Mult im odalit y Therapy Alth ough m ost patien ts un dergo palliative m ultim odalit y th erapy in th e form of radiation an d system ic treatm en t , in th eor y patien ts w ith locally advan ced un resectable ATCs could respon d to t reatm en ts, th ereby dow n staging th e t um or an d m akin g it resectable. Th is w as illustrated in a dram atic t reatm ent e ect seen w ith th e targeted agen t vem urafen ib in a pat ien t w ith ATC.18 Akin to th e t reatm en t of patien ts w ith borderlin e resectable pan creat ic aden ocarcin om a, system ic t reatm en t before operation dow n stages t um ors, but, perh aps m ore im portan tly, it selects patien ts w ith favorable disease biology w h o m ay ben efit from resection . Th is th erapeutic strategy could be feasible for ATC patien ts. Un fortun ately, at th e curren t tim e, system ic agen ts in frequen tly “dow n stage” ATC, an d few patien ts presen t w ith localized disease in th e absen ce of distan t m etastases. Accordin gly, th ere is curren tly n o defin ed role for n eoadjuvan t th erapy in ATC.

18.6 Chem oradiat ion Therapy Because of th e ver y lim ited role for surgery in patien ts presentin g w ith ATC, th e m ajorit y of patien ts are treated w ith cytotoxic ch em oth erapy an d radiation th erapy. Th ere are n o level I data to suggest th e stan dard of care. A stan dard approach is con curren t radiation th erapy w ith low -dose doxorubicin .

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Surgical Managem ent of Thyroid Diseases Un for tun ately, early repor ts of e ect ive local cont rol w ith th is regim en w ere probably overstated, perh aps due to m isdiagn osis of som e m ore favorable thyroid h istologies as ATC. Con tem porary data reveal a 1-year sur vival rate of on ly 28% in patien ts treated w ith th is regim en , alth ough toxicit y is quite m an ageable in m ost patien ts.19 In th e h igh est-risk patien ts, th e added value to in ten sive ch em oradiation th erapy is often m argin al, un derlin ing th e im portance of early an d in form ed patien t in put in to th e decision -m akin g plan .20

18.7 Tracheost om y Most pat ien ts w ith ATC w ill n ot be can didates for surgical resection . In fact th e Am erican Thyroid Association guidelin es for ATC suggest th at palliative an d en d-of-life discussions sh ould be in itiated at th e first o ce visit.12 For patien ts w h o are n ot surgical can didates, treatm en t s sh ould be focused on relief of sym ptom s. In ATC, th ese sym ptom s are m ost com m on ly airw ay related an d in clude dyspn ea, stridor, aspiration , an d h oarsen ess (from vocal cord paralysis). In som e cases, t rach eostom y o ers th e option of preven t in g death from airw ay obst ruction . How ever, “prophylactic” t rach eostom y sh ould n ot be un iform ly perform ed in pat ien ts w h o do n ot h ave sym ptom s of airw ay obstruct ion because of th e sign ifican t sym ptom s an d sequelae th at result from h avin g a trach eostom y t ube in th e presen ce of an un con trolled ATC in th e n eck. Un fortun ately, even w ith a trach eostom y tube tum or grow th can still result in asphyxiation . Tum or can also grow th rough th e stom a, resultin g in bleedin g, aspiration , an d con tin ued airw ay sym ptom s. For th is reason , trach eostom y often w orsen s, rath er th an palliates, sym ptom s, and sh ould n ot be un iform ly recom m en ded for patien ts w ith ATC. For patien ts w h o presen t w ith ATC an d do n ot h ave sym ptom atic airw ay obstru ct ion , th e possibility of trach eostom y sh ould be discussed w ith pat ien ts an d fam ilies in th e con text of th e overall progn osis an d goals of care. Given th ese poten tial sequelae of trach eostom y, th is sh ould be o ered to pat ients on a case-bycase basis, rath er th an bein g un iversally perform ed. In recen t years, trach eal an d esophageal sten ts h ave becom e available for th e m an agem en t of obstru ct ive airw ays. How ever, given th e rapidit y of ATC progression , th ese in ter ven tion s sh ould h ave con siderat ion s sim ilar to th ose associated w ith trach eostom y. Sten tin g of th e upper airw ay can be ch allengin g in th e m ost experien ced h an ds, an d com plication s of t um or overgrow th an d t rach eoesoph ageal fistula can be an ticipated. In addition to airw ay disease, ATC patien ts can h ave di cult y sw allow in g. Man aging th ese sym ptom s w ith surgically placed feedin g tubes m ay be a reason able approach for som e patien ts. Th e decision to pursue th is palliative in terven tion sh ould be based on th e goals of care, in a sim ilar m an n er as for trach eostom y.

18.7.1 Met ast asect om y Metastasectom y h as a very lim ited role in pat ien ts w ith ATC. In th e auth ors’ experien ce patien ts w ith dram atic respon ses to system ic th erapy or w ith a lon g in terval betw een resection of th e prim ar y t um or an d recurren ce (> 1 y) could be can didates for m etastasectom y. Th is h igh ly select patien t population likely

in cludes rare varian ts of ATC th at h ave m uch slow er progression th an w h at is t ypically obser ved. Even so, a decision to pursue m etastasectom y in th is settin g sh ould be m ade by a m ultidisciplin ary team of physician s experien ced in th e care of ATC patien ts. An un tim ely operat ion (or com plication s th ereof) could delay th e system ic t reatm en ts th at w ill ultim ately determ in e th e patien t’s sur vival. It is im por tan t to n ote th at, even in m ore com m on diseases, such as colorectal can cer an d n on – sm all cell lun g can cer, m etastasectom y h as n ot been proven to exten d sur vival but is th ough t to be a reason able treatm en t approach in certain in stan ces.

18.8 Clinical Trial Enrollm ent For a rare, aggressive disease w ith lim ited th erapeutic option s th ere is an obvious n eed for clin ical trials. Multi-in st itut ion al collaborative clin ical trials represen t a w ay to stan dardize an d optim ize th erapy. Any patien t w ith ATC sh ould be con sidered for a clin ical trial. Patien ts w ith m etastatic disease w ith good perform an ce status sh ould be en rolled in a trial th at in cludes ch em oth erapeutic an d targeted th erapy regim en s. Given th e pace of disease progression an d th e m ortalit y rate, ATC patien ts sh ould in itiate treatm en t s as soon as possible after diagn osis (days rath er th an w eeks). At Mem orial Sloan Ketterin g, for exam ple, clinical trials to target specific driver m utation s, iden tified by targeted sequen ce strategies, are un der w ay.

18.9 Conclusion ATC is a h igh ly leth al can cer associated w ith distan t m etastatic disease at presentation an d com pressive sym ptom s of n eck struct ures by th e prim ar y t um or. Surgical in terven t ion in th e form of curative resection is rare an d m ore com m on ly aids in palliation in select pat ien ts. For pat ien ts w ith a n ew diagnosis of ATC, palliative an d en d-of-life discussion s sh ould be in itiated at th e first pat ien t visit. Because surgeon s are often th e first specialists to see a patien t w ith n ew ly diagn osed or suspected ATC, th ey ser ve a crit ical role, even if surgery is rarely perform ed. It is obligator y th at surgeon s be prepared to take th e tim e n ecessar y to h ave fran k an d em path etic conversation s w ith pat ien ts about th e n atural h istory of ATC. Furth erm ore, th e surgeon can be invaluable in coordin atin g expedien t referral to m edical an d radiation on cology colleagues so th at treatm en t, if desired, can be in itiated as soon as is pract icable. Clin ical t rial en rollm en t is crit ical to m akin g progress in treatm en t of such a rare disease.

References [1] McIver B, Hay ID, Giu rida DF, et al. An aplastic thyroid carcin om a: a 50-year experien ce at a sin gle in stitut ion . Surgery 2001; 130(6); 1028–1034 [2] Aldin ger KA, Sam aan NA, Iban ez M, Hill CS, Jr. An aplastic carcin om a of th e thyroid: a review of 84 cases of spin dle an d gian t cell carcin om a of th e thyroid. Can cer 1978; 41(6); 2267–2275 [3] Ven katesh YS, Ordon ez NG, Schultz PN, Hickey RC, Goepfert H, Sam aan NA. An aplastic carcinom a of th e thyroid. A clin icopath ologic study of 121 cases. Can cer 1990; 66(2); 321–330 [4] Cooper DS, Doh erty GM, Haugen BR, et al. Am erican Thyroid Association (ATA) Guidelin es Taskforce on Thyroid Nodules an d Di eren tiated Thyroid Can cer. Revised Am erican Thyroid Association m an agem en t guidelin es for

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[5]

[6] [7] [8]

[9]

[10] [11] [12]

patien ts w ith thyroid n odules an d di eren tiated thyroid can cer. Thyroid 2009; 19(11); 1167–1214 Mazzaferri EL, Jh ian g SM. Lon g-term im pact of in itial surgical an d m edical th erapy on papillary an d follicular thyroid can cer. Am J Med 1994; 97(5); 418–428 Bogsrud TV, Karan tan is D, Nath an MA, et al. 18F-FDG PET in th e m an agem en t of patien ts w ith an aplastic thyroid carcin om a. Thyroid 2008; 18(7); 713–719 Carcangiu ML, Steeper T, Zam pi G, Rosai J. An aplastic thyroid carcinom a. A study of 70 cases. Am J Clin Path ol 1985; 83(2); 135–158 Ito T, Seyam a T, Mizun o T, et al. Un ique association of p53 m utation s w ith un di eren tiated but n ot w ith di eren tiated carcinom as of th e thyroid glan d. Can cer Res 1992; 52(5); 1369–1371 Lan da I, Ganly I, Ch an TA, et al. Frequen t som atic TERT prom oter m utation s in thyroid can cer: h igh er prevalen ce in advan ced form s of th e disease. J Clin En docrin ol Metab 2013; 98(9); E1562–E1566 Davies L, Welch HG. In creasing in ciden ce of thyroid can cer in th e United States, 1973–2002. JAMA 2006; 295(18); 2164–2167 Sm allridge RC, Coplan d JA. An aplastic thyroid carcin om a: path ogen esis an d em ergin g th erapies. Clin On col (R Coll Radiol) 2010; 22(6); 486–497 Sm allridge RC, Ain KB, Asa SL, et al. Am erican Thyroid Association An aplastic Thyroid Can cer Guidelin es Taskforce. Am erican Thyroid Association guidelin es for m an agem en t of patien ts w ith an aplastic thyroid can cer. Thyroid 2012; 22(11); 1104–1139

[13] Nel CJ, van Heerden JA, Goelln er JR, et al. An aplastic carcin om a of th e thyroid: a clin icopath ologic study of 82 cases. Mayo Clin Proc 1985; 60(1); 51–58 [14] Foote RL, Molin a JR, Kasperbauer JL, et al. En h an ced sur vival in locoregion ally con fin ed an aplastic thyroid carcinom a: a sin gle-institu tion experien ce usin g aggressive m ultim odal th erapy. Thyroid 2011; 21(1); 25–30 [15] Moh ebat i A, Diloren zo M, Palm er F, et al. An ap last ic t h yroid carcin om a: a 25-year sin gle-in st it u t ion exp erien ce. An n Su rg On col 2014; 21(5); 1665– 1670 [16] Pierie JP, Muzikan sky A, Gaz RD, Faquin W C, Ott MJ. Th e e ect of surgery an d radiotherapy on outcom e of an aplastic thyroid carcin om a. An n Surg On col 2002; 9(1); 57–64 [17] Haigh PI, Ituar te PH, Wu HS, et al. Com pletely resected an aplastic thyroid carcin om a com bined w ith adjuvant ch em oth erapy an d irradiation is associated w ith prolon ged sur vival. Can cer 2001; 91(12); 2335–2342 [18] Rosove MH, Peddi PF, Glaspy JA. BRAF V600E in h ibition in an aplastic thyroid can cer. N Engl J Med 2013; 368(7); 684–685 [19] Sh erm an EJ, Lim SH, Ho AL, et al. Con curren t doxorubicin an d radiotherapy for an aplastic thyroid can cer: a critical re-evaluation in cludin g un iform path ologic review. Radioth er On col 2011; 101(3); 425–430 [20] Haym art MR, Ban erjee M, Yin H, Worden F, Griggs JJ. Margin al treatm en t ben efit in an aplastic thyroid can cer. Can cer 2013; 119(17); 3133–3139

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19 Surgical Managem ent of t he Cent ral Neck Com part m ent for Di erent iat ed Thyroid Cancer Salem I. Noureldine and Ralph P. Tufano

19.1 Int roduct ion Cer vical lym ph n ode m etastases are kn ow n to sign ifican tly correlate w ith both th e persisten ce an d th e recurren ce of thyroid can cer, an d th ey m ay im pact sur vival.1 Cen tral n eck dissection (CND) plays an im portan t role in th e m an agem en t of thyroid m align an cy. Th e prim ar y treatm en t for locally advan ced di eren t iated thyroid can cer (DTC) sh ould con sist of a total thyroidectom y, w ith both a th erapeut ic n eck dissection an d thyroid rem n an t ablation as in dicated.2 Yet, because occult lym ph n ode m etastases are com m on in DTC, som e h ave advocated elective CND (in th e absen ce of any clin ically or radiologically detectable n odal m etastases) as part of routin e surgery for DTC. Neverth eless, th e pertin en t m edical literat ure in dicates th at th ere is n o stan dardizat ion of th is operation am on g surgeon s. Boun daries an d com partm en ts are n ot w ell defin ed, an d th e operative reports often fail to m en tion w h eth er th ese procedures w ere bein g perform ed in th e presence or absen ce of gross lym ph n ode m etastases (clin ically or radiograph ically apparen t). Th ese sh or tcom in gs prom pted th e convergen ce of a subgroup of thyroid can cer specialists un der th e auspices of th e Am erican Thyroid Association (ATA) to form ulate a consen sus statem en t on th e an atom y an d term in ology pert in en t to CND.3 Th e group con cluded th at CND sh ould consist of levels VI an d VII of th e n eck an d m ust contain th e prelar yn geal, pretrach eal, an d at least on e paratrach eal n odal basin . Th e surger y sh ould be design ated as elect ive or th erapeut ic. Clin ically or radiograph ically apparen t cervical lym ph n ode m etastases in th e central n eck sh ould be treated w ith a th erapeutic in ten t accom plish ed by a com partm en tal dissection . Alth ough elective CND is advocated for m edullar y thyroid can cer (MTC) an d oth er aggressive h istologies, con troversy still exists for its application to DTC.4 Th is ch apter discusses th e tech n ique for perform in g a CND an d th e con sideration s for w h en it sh ould be perform ed.

19.2 Incidence and Prevalence DTC, specifically papillar y thyroid can cer (PTC), h as a ten den cy for cervical lym ph atic spread. Cer vical m etastases are foun d in 20 to 50% of patien ts, w ith th e use of stan dard path ological tech n iques, an d h ave been reported by som e auth ors to occur in up to 90% of th ose exam in ed for m icrom etastases.5,6 Thyroid tum or cells spread th rough th e lym ph atic system in a sequen tial fash ion , startin g in th e perithyroidal, pretrach eal, paratrach eal, an d prelar yngeal lym ph n odes of th e cent ral n eck com partm en t , an d th en progress to th e lym ph n odes of th e lateral cervical com part m en ts an d th e superior m ediastin um .7 Alth ough occult m icrom etastases in th e lym ph n odes of th e cen tral n eck h ave been reported to occur in 31 to 62% of patien ts w ith PTC, th e available eviden ce suggests th at m ost rem ain dorm an t , rarely becom e clin ically apparen t, an d are of little clin ical sign ifican ce.8,9 Th e in ciden ce of lym ph n ode

m etastases in follicular thyroid can cer is 20 to 25% in th e Am erican population . In patien ts w ith MTC, clin ically detectable cervical lym ph n ode m etastases are foun d in at least 50% of patien ts.

19.3 Hist ory, Physical Exam inat ion, and Preoperat ive Planning Patien ts w ill usually present w ith a m ass in th e thyroid th at h as been d etected by p alp at ion or d iscovered in cid en tally on rad iograp h ic im aging for evalu ation of oth er d isease p rocesses (e.g., carotid u ltrasou n d , im aging of th e cervical spin e). A d iagn osis is u su ally est ablish ed by u lt rasou n d -gu id ed fin en eed le asp irat ion (FNA) biop sy. Most p atien t s w it h a thyroid m align an cy, w ith or w ith ou t cen tral n eck lym p h ad en op athy, are u su ally asym pt om at ic. Pat ien t s w it h larger or m ore aggressive t u m ors can p resen t w it h h oarsen ess, d ysp h agia, an d d ysp n ea. A patien t w ith suspected thyroid can cer sh ould un dergo a detailed exam in at ion of th e thyroid glan d an d th e cervical lym ph n ode com partm en ts. Cervical ultrasoun d is often th e in itial im agin g m odalit y em ployed in th e assessm en t because it is readily accessible, in expen sive, an d n on invasive. It is also an im portan t tool for postoperative sur veillan ce of patien ts w ith PTC.10,11 High -resolution ultrason ograph y can detect cervical n odal m etastasis in up to 20% of patien ts w ith PTC. Th ese ultrasoun d fin din gs m ay alter th e plan n ed surgical procedure in up to 39% of thyroid can cer pat ien ts.2 Path ological lym ph n odes usually h ave concern in g son ograph ic features th at in clude a roun d sh ape, absen t h ilum , calcification , in tran odal n ecrosis, reticulation , m attin g, an d periph eral vascularit y.12 A detailed cervical ultrasoun d to in clude n odal levels II th rough VI sh ould be perform ed, ideally by a dedicated clin ician , such as th e thyroid en docrin ologist , th e operat in g surgeon , or a radiologist w ith a vested in terest, to detect n on palpable lym ph n ode m etastases in patien ts un dergoing surgical evaluation for any thyroid can cer.11 How ever, ultrasoun d can m iss as m any as 50% of th e involved lym ph n odes in th e cen tral n eck because th e overlyin g thyroid glan d m ay h in der adequate visualization .13 In patien ts w ith suspected m ediastin al disease or w ith bulky (clin ically palpable, > 3 cm in size) cervical lym ph aden opathy, cross-section al im aging w ith com puted tom ography (CT), m agn etic reson an ce im agin g (MRI), an d/or positron em ission tom ography (PET) sh ould be con sidered. Th ough th e sen sitivities of th ese m odalities for th e screen in g an d detect ion of cervical lym ph n ode m etastases can be relatively low (30–40%),14 th ey can aid in th e plan n in g of a n eck dissection an d often iden tify path ological level VII lym ph n odes w ith in th e superior m ediastin um an d paraph ar yn geal, retroph ar yn geal n odes th at are n ot detected on cervical ultrasoun d or physical exam in ation .11

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Surgical Managem ent for Di erentiat ed Thyroid Cancer A CT scan w ith iodin ated con trast m ay be extrem ely h elpful in evaluatin g th e exten t of cervical lym ph aden opathy w h en th ere is gross n odal disease presen t, an d can h elp defin e th e exten t of surgery n ecessary to plan clearan ce of all gross disease in th e n eck.11 CT w ith con trast m ay delay postoperat ive thyroid scan n in g an d radioactive iodin e (RAI) adm in istration for 4 to 8 w eeks, but in th e scen ario of bulky lym ph aden opathy or con cern for locally invasive disease, it appears justified because com plete surgical resection of gross disease is of param oun t im portan ce for disease control.15

19.4 Indicat ions for Cent ral Neck Dissect ion Th ere are several in dication s for th erapeutic or elect ive CND. Patien ts w ith thyroid can cer an d eviden ce of cent ral n eck lym ph aden opathy confirm ed by physical exam in ation , radiologic im agin g, or in traoperative in spection sh ould un dergo th erapeutic CND. CND is also in dicated in pat ien ts w ith recurren t lar yn geal n er ve (RLN) invasion or m edullar y thyroid can cer. Elect ive CND m ay be considered in select patien ts w ith T3 an d T4 di eren tiated thyroid can cer cases or w h en th ere is suspicion of a m ore aggressive varian t of thyroid can cer (in cluding m edullar y thyroid can cer).

19.5 Cont raindicat ions Just as th ere are tim es th at CND m ay be in dicated, th ere are also tim es w h ere th e poten t ial m orbidit y of th e procedure m ay outw eigh th e ben efit. Surgeon s sh ould be ver y caut ious w h en con siderin g elect ive CND of th e paratrach eal n odal basin on th e side of th e on ly fun ct ion in g RLN (i.e., w h en th ere is a preexistin g vocal fold paralysis contralateral to th e paratrach eal n odal basin w h ere th e positive lym ph n ode is located). Patien ts w ith stable recurren t or persisten t disease th at is aw ay from vital struct ures, such as th e t rach ea, m ay be considered for observation rath er th an surgery. Fin ally, CND m ay n ot be appropriate in patien ts w ith kn ow n system ic m etastases th at are progressive an d outpacin g th e recurren t or persisten t cen tral n odal m etastasis.

19.6 Elect ive versus Therapeut ic Cent ral Neck Dissect ion A th erapeutic CND sh ould be perform ed for patien ts w ith DTC an d path ological lym ph n ode involvem en t n oted on preoperative clin ical exam or im aging, or durin g in t raoperative in spection .2 Th e goal of rem ovin g th ese lym ph n odes is to aid in local con trol, preven t recurren ce, an d perhaps im prove sur vival. Th e role of elective CND rem ain s a conten tious issue regardin g its ben efits an d risks. An essen tial com pon en t of any discussion about th e n eed for lym ph aden ectom y is w h eth er patien ts derive any addition al ben efit from h avin g a CND w ith total thyroidectom y an d w h eth er th is can be don e w ith out sign ifican tly in creasin g th e m orbidit y of th e operation . Because m icroscopic n odal disease is rarely of clin ical im portan ce, m any auth ors argue th at elect ive CND of m icroscopic lym ph n ode m etastases th at are n ot clin ically iden tifiable at th e t im e of surgery m ay

n ot im prove lon g-term outcom e an d could subject patien ts to m ore risk th an ben efit.2 Also, if rem oval of subclin ical m etastases alon e w ere an in dicat ion for surgery w ith out an appreciation for th e clinical sign ifican ce of th is disease (w h ich certain ly is debatable), th en th e sam e sh ould th eoretically apply to th e lateral n eck. Oppon en ts also fear th at, if elect ive CND w ere un iversally adopted by all surgeon s perform in g thyroidectom y, th e risk of parathyroid an d n er ve injur y m ay in crease in th e absen ce of sign ifican t on cological ben efit to th e patien ts.4,5,6 Non eth eless, n o con sen sus yet exists regarding th e addition of CND for clin ically n ode-n egative patien ts w ith DTC. To date, n o study h as dem on st rated sign ifican tly reduced recurren ce or m ortalit y rates w ith elect ive CND. A recen t m eta-an alysis foun d n o di eren ce in th e recurren ce rates betw een th ose treated w ith or w ith out elective CND at th e tim e of thyroidectom y.4 A di eren t study suggested th at w h en elective CND is perform ed by experien ced surgeon s it m ay be associated w ith a low er risk of disease recurren ce, an d th at th e n um ber of patien ts th at w ould n eed to be treated to preven t a single recurren ce is 31.16 In ligh t of th ese discordan t fin din gs, th e ration ale for routin e elect ive CND to preven t eith er recurren ce or death is quest ion able in DTC. Conversely, th ere are strategic uses for elect ive CND th at m ay h ave justification . Th ese in clude patien ts w ith h igh er-risk tum ors, such as T3 or T4 lesion s, or th ose exh ibitin g extrathyroidal exten sion , or m ore aggressive h istologies, such as di use sclerosin g, in sular, or poorly di eren tiated t um ors. Elect ive cen tral n eck dissect ion is also recom m en ded for m edullar y thyroid can cer. Th e pros an d con s of th erapeutic an d elect ive CND are outlin ed in Table 19.1.

19.7 Surgical Technique A com plete cen tral n eck dissect ion requires rem oval of all lym ph n odes in th e prelar yn geal, pretrach eal, an d paratrach eal region s. Th e surgical borders of th e cent ral com partm en t are outlin ed in Fig. 19.1 an d Table 19.2 an d sh ould in clude levels VI an d VII.

19.7.1 Prim ary Cent ral Neck Dissect ion Prim ar y CND is usually perform ed at th e tim e of total thyroidectom y an d m ay be perform ed en bloc w ith th e thyroid or sep arately. If n ot already dissected durin g th e thyroidectom y, th e prelaryn geal an d pretrach eal n odes are excised. Th e stan dard thyroidectom y in cision is used. A vertical in cision open s th e m idlin e betw een th e strap m uscles, from th e thyroid n otch to th e stern al n otch . Adequate exposure of th e cen tral n eck m ust be obtain ed to perm it a com preh en sive com partm en tal dissection . Th e strap m uscles m ust be elevated over th e carotid sh eath laterally an d to th e stern um in feriorly. Th e prelar yn geal n odes are easily visualized durin g th e resection of th e pyram idal lobe. Th ey can be dissected at th e tim e of thyroidectom y or after. Th e prelaryn geal dissection starts in feriorly at th e upper m argin of th e thyroid isth m us an d exten ds superiorly to th e hyoid bon e. Th e fibroadipose tissue overlyin g th e cricothyroid an d thyrohyoid m em bran es is in cised an d dissected o of th ese struct ures. It is im portan t to avoid injur y to th e cricothyroid m uscle or th e m em bran es w h en perform in g th is m an euver.

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Surgical Managem ent of Thyroid Diseases Table 19.1 Pros and cons of central neck dissection Therapeutic CND Pros

● ● ●

Decreases risk of disease recurrence Im proves survival May reduce the need for reoperation

Elective CND ● ● ● ●

Cons

● ●

Postoperative hypocalcem ia Postoperative RLN paralysis

● ● ●

May decrease risk of recurrence May im prove survival Reoperative surgery becom es com plicated Provides accurate staging, thus elim inating need for postoperative RAI therapy in select cases Increases postoperative tem porary hypocalcemia May increase rate of RLN paralysis Survival and recurrence benefit yet to be proven

Abbreviations: CND, central neck dissection; RAI, radioactive iodine; RLN, recurrent laryngeal nerve.

Table 19.2 Surgical anatom ical landm arks for levels VI and VII of the central compartm ent for central neck dissection Border

Surgical anatom ical landm ark

Superior

Hyoid bone

Inferior

Axial plane of the innom inate artery

Posterior

Prevertebral fascia

Anterior

Sternothyroid m uscle

Lateral

Com m on carotid artery

Mediala

Medial edge of contralateral strap m uscles

a In

Fig. 19.1 The borders of the central neck dissection are outlined and should include both levels VI and VII lym ph node basins.

Th e pretrach eal dissection starts at th e low er m argin of th e isth m us an d strips th e fibrofatt y tissue an d n odes from th e fron t face of th e trach ea dow n to th e level of th e in n om in ate artery crossin g th e trach ea. Care is taken to avoid injur y to th e in nom in ate artery an d th e brach ioceph alic vein . It is im portan t w h en perform in g a pretrach eal dissect ion n ot to exten d th e dissection dow n in to th e paratrach eal region . Th is can jeopardize th e RLN, especially on th e left side. Iden tification an d excision of th e righ t paratrach eal lym ph n odes, w h ich m ay be foun d both an teriorly an d posteriorly relative to th e ipsilateral RLN an d in ferior thyroid artery m ain trun k, require careful exploration in th e vicin it y of th ese delicate struct ures. Due to th e relatively m edial an d ven t ral course of th e righ t com m on carotid artery, paratrach eal lym ph n odes m ay exist posterior to th is artery on th e righ t side. Th us adequate cen tral n eck dissect ion m ay require lim ited m obilization of th e righ t com m on carotid artery. Th e righ t paratrach eal dissect ion begin s w ith skeleton ization of th e com m on carotid artery from th e thyroid cart ilage superiorly to th e in n om in ate artery in feriorly. Th e dissect ion sh ould n ot proceed deep to th e com m on carotid arter y to avoid injury to th e RLN. On ce th e

cases of unilateral central com partm ent neck dissection.

carotid sh eath is fully dissected, th e vagus n er ve can be stim ulated at 1 m A to determ in e th e n europhysiological in tegrit y of th e RLN. Th e RLN is th en iden tified again in th e area of w h ere it w as exposed for th e thyroidectom y. Th e RLN m ust be dissected from its lar yn geal poin t of in sertion to its m ost in ferior exten t in th e n eck to be able to safely rem ove all of th e lym ph n odes in th e righ t paratrach eal com partm en t. On th e righ t side, it travels m ore ven trally an d obliquely th an th e left RLN ( Fig. 19.2 an d Fig. 19.3). It is follow ed in feriorly un til it can n o lon ger be traced un der th e com m on carotid artery. Min im izing ten sion is im portan t in preservin g RLN fun ct ion an d avoidin g n europraxia. Pruden t use of fin e-tip bipolar cautery aw ay from th e RLN to cauterize sm all vessels is recom m en ded. On ce th e n er ve is com pletely t ran sposed, th e lym ph n ode–bearin g t issue posterior an d m edial to th e carotid artery an d posterior an d lateral to th e RLN can be delivered an teriorly. Th e RLN lar yn geal en t ry poin t is usually used as th e superior border of th e dissect ion . It is essen tial to preserve th e m ain t run k of th e in ferior thyroid artery an d all of its superior bran ch es to m ain tain a blood supply to th e superior parathyroid glan d. Th e in ferior parathyroid glan d m ay n eed to be dissected aw ay from th e adjacen t lym ph n odes to save its blood supply. If th e viabilit y of th e parathyroid glan d appears com prom ised, it sh ould be h ar vested an d kept in cooled salin e for later reim plan tat ion . Approxim ately 10% of it sh ould be sen t for frozen sect ion to confirm parathyroid tissue an d avoid in adverten t autotran splan tation of a path ological lym ph n ode. Th e dissection th en proceeds over th e esophageal m uscularis w ith gen tle an terior retract ion . Th e tissue is dissected over th e trach ea, an d th e pretrach eal lym ph n odes are elevated an d ligated approxim ately at th e m edial edge of th e left strap m uscles. Th e

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Surgical Managem ent for Di erentiat ed Thyroid Cancer

Fig. 19.2 (a) The right recurrent laryngeal nerve (RLN) has greater depth due to it entering more ventrally underneath the bifurcating innominate artery, which lies ventral to the trachea. The right RLN then extends m edially and descends to its laryngeal entry point at the right lateral inferior edge of the cricoid cartilage. The right paratracheal region therefore can be divided into t wo triangles: an upper lateral triangle and a lower m edial triangle. The RLN divides the compartm ent into an anterior and posterior com partm ent. (b) The left paratracheal region is much flatter and m ore t wo-dim ensional because of the tracheoesophageal groove location t ypical of the left RLN as it traverses the region.

Fig. 19.3 A completed reoperative bilateral central neck dissection with rem oval of the prelaryngeal, pretracheal, and bilateral paratracheal nodal basins. Notice on the right side, the recurrent laryngeal nerve (RLN) travels more ventrally and obliquely than the left RLN, which runs in a m ore craniocaudal course and in the tracheoesophageal groove.

in ferior dissection is com pleted by carefu l ligation of all tissue an terior an d superior to th e in n om in ate artery. Level VI does exten d to th e hyoid bon e, but it is un com m on to see lym ph n ode m etastasis superior to th e level of th e RLN laryn geal in sertion site. Any lym ph aden opathy th at does exist in th is area sh ould easily be seen w ith ultrasoun d, an d th e dissection sh ould be exten ded to in clude th is area accordingly. Th e left paratrach eal dissection starts w ith iden tifyin g th e com m on carotid artery. Un like th e righ t , th e left com m on carotid artery h as its ow n takeo from th e aor ta an d is dissected in feriorly to th e level of th e clavicle an d superiorly to th e

thyroid cartilage. Th e RLN is th en t raced in feriorly from w h ere it w as iden tified durin g th e thyroidectom y. Un like th e righ t RLN, th e left RLN run s in a m ore cran iocaudal course an d in th e trach eoesoph ageal groove ( Fig. 19.2 an d Fig. 19.3). It does n ot n eed to be circum feren tially dissected an d tran sposed because th ere are seldom lym ph n odes deep an d m edial to th e left RLN. It is follow ed in feriorly to th e level of th e clavicle. Th e lym ph n ode tissue m edial to th e carotid artery is brough t over th e esophageal m uscularis an d th e RLN. Th e an terior border of th e RLN m ust be freed from th e specim en . On e m ust be careful w h en dissectin g th e RLN in feriorly. Th e RLN is usually ten ted up w ith th e lym ph n ode–bearin g tissue from th e superior m ediastin al paratrach eal region an d thym us. An arbitrar y term in ation of th e dissect ion is th en m ade at th e level of th e superior border of th e in n om in ate artery, takin g care to m eticulously ligate all t issue in th is area an d avoid injur y to th e RLN. Dissection con tin ues superiorly to th e RLN in sertion poin t. Th e parathyroid glan ds are m an aged in th e sam e w ay as described for th e righ t parathyroid glan ds. Sim ilarly, th e rem ain in g pretrach eal lym ph n odes are elevated an d ligated at th e m edial border of th e righ t strap m uscles. Th e operative bed is th en in spected, an d th e parathyroid glan d viabilit y is visually assessed. Liberal use of autot ran splan tation is advocated if th e status of th e parathyroid glan d is quest ion able. Th e physical con tin uit y of th e RLNs is evaluated. Nerve m on itorin g, if used, m ay provide valuable in form ation on th e n europhysiological in tegrit y of th e RLN. Th is m ay in fluen ce th e decision on w h eth er to proceed w ith an elective cont ralateral CND. A Valsalva m an euver is perform ed, an d h em ostasis is ach ieved w ith th e judicious use of bipolar cauter y or sutures. Hem ostatic agen ts m ay also be used. Th e strap m uscles are closed w ith an absorbable suture. Th e use of a drain is left to th e discretion of th e surgeon . Th e closure proceeds sim ilar to

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Surgical Managem ent of Thyroid Diseases th at used for thyroidectom y, an d m edical-grade skin adh esive glue m ay be used to seal th e skin edges.

19.7.2 Reoperat ive Cent ral Neck Dissect ion

artery in ferior in th e n eck an d in th e trach eoesoph ageal groove. Th e rem ain der of th e operat ion proceeds in th e sam e fash ion as described for prim ar y CND ( Fig. 19.1).

19.8 Post operat ive Managem ent

Reoperative CND m ay be con sidered w h en th ere is FNA-con firm ed eviden ce of disease or grow th of a m ass n ot am en able to biopsy. It is gen erally accepted th at reoperative CND im parts a h igh er com plication rate th an prim ary surgery. We believe th at reoperative CND for n odal m etastases alon e m ay be as safe as prim ary CND.17 Non eth eless, th e recom m en dation for surgery versus obser vation sh ould be m ade in a m ultidisciplin ar y fash ion an d tailored to th e pat ien t’s n eeds. All patien ts undergoin g reoperative CND sh ould un dergo a fiberoptic lar yngoscopy to assess vocal fold m obilit y. Often , th e localization an d con firm ation of m etastatic can cer are m ade w ith ultrasoun d an d FNA biopsy. It is im portan t to h ave a clear un derstan din g of th e location of th e can cer an d its relation sh ip to surroun din g struct ures. Th e can cer m ay be in lym ph n odes or at th e prim ar y site. Th is is im portan t to dist in guish because reoperation for m etastat ic can cer versus recurren ce at th e prim ary site h as a strikin gly di eren t risk profile. In our experien ce, w h en th e recurren t disease is at th e prim ar y site, th ere is a m uch h igh er risk of vocal fold paralysis (33%) versus m etastases to th e lym ph n odes (< 1%).17 If ultrasoun d can n ot resolve th is issue, th en axial im aging w ith cont rast m ay be h elpful, especially if th ere is also con cern for local invasion . Ultrasoun d is also ver y h elpful in defin in g w heth er a un ilateral or bilateral paratrach eal lym ph n ode dissection w ill be required. Th is m ay be due to th e im proved sen sitivit y of ultrasoun d to detect subcen tim eter lym ph n ode m etastasis in th e cen tral n eck w h en th e thyroid is n ot presen t. Reoperative CND can be perform ed th rough th e existin g thyroidectom y in cision . Excision of th e origin al in cision m ay be perform ed if n ecessary an d is gen erally recom m en ded to ach ieve th e best cosm et ic result. Th e approach m ay be eith er th rough th e m idlin e raph e of th e strap m uscles w ith elevation of th e strap m uscles over th e thyroid bed or from a lateral approach . Th e lateral approach m ay be w arran ted w h en exten sive scarrin g is presen t. In th is circum stan ce, th e carotid sh eath is iden tified, an d th e strap m uscles are elevated over th e thyroid bed from lateral to m edial. It m ay be advan tageous to divide th e stern othyroid m uscle to ach ieve better access to th e paratrach eal n odal com part m en t. Th e strap m uscles are th en elevated over th e thyroid bed superiorly an d in feriorly, takin g great care to avoid excessive cautery as dissect ion proceeds superiorly to avoid injur y to th e RLN. Th e m ain di eren ce in th e tech n ique for reoperative CND com pared to prim ar y CND is in th e m eth od used to iden tify th e RLNs. Th e region w h ere th e RLN is t ypically foun d durin g thyroidectom y m ay be scarred , an d fam iliar lan dm arks for iden tification of th e RLN are n ot present . RLN m on itorin g m ay be usefu l durin g reoperative CND. Th e vagus n erve can be stim ulated at 1 m A prior to begin n in g the dissect ion to get th e baselin e am plitude on th e electrom yograph ic w aveform . On ce th e carotid artery is iden tified in th e sam e fash ion as in prim ary CND, th e righ t RLN m ay be search ed for, m edial an d deep to th e com m on carotid artery above th e in n om in ate an d subclavian artery jun ct ion , an d th e left RLN m edial to th e com m on carotid

Patien ts un dergoing CND m ay be adm itted overn igh t for observation . Postoperative con sideration s are sim ilar to th ose of total thyroidectom y. Patien ts w h o h ave un dergon e a CND are at in creased risk for tem porar y an d perm an en t hypoparathyroidism .18 Th erefore, patien ts sh ould be follow ed per in dividualized in stit ution al protocols for m an agin g hypocalcem ia. Altern atively, routin e adm in istration of oral calcium an d vitam in D supplem en tation h as been sh ow n to be feasible. Fiberoptic laryn goscopy sh ould be perform ed to con firm true vocal fold m obilit y as an im portan t m easurem en t of surgical qualit y. Observation for bleedin g an d h em atom a form ation is also im portan t . On cological lon g-term results w ill be determ in ed by serial follow -up w ith ultrasoun d an d serum thyroglobulin (Tg) exam in ation . Ultrasoun d is t ypically used for sur veillan ce of th e cen tral n eck after thyroid surgery w ith or w ith out CND. Any suspicious lym ph aden opathy in th e previously operated cent ral n eck sh ould be m on itored if it is ≤ 0.8 cm an d biopsied if it is > 0.8 cm .19 Recurren ce is defin ed as bioch em ical or struct ural iden tification of disease in a pat ien t previously th ough t to h ave n o eviden ce of disease (un detectable baselin e or stim ulated Tg, an d n egative ultrasoun d an d cross-section al im aging). Bioch em ically detectable disease is defin ed as an elevation in th e serum Tg level. Pat ien ts w h o present w ith a detectable seru m Tg level after RAI or an in creasin g seru m Tg level if n o RAI h as been adm in istrated are m ost likely to h ave disease in th e n odal groups, w h ich m ay be in th e central com partm en t (level VI), th e lateral n eck (com m on ly at levels II, III, IV, an d V), or level VII (upper m ediastin al n odes).20 All struct ural an d bioch em ical disease iden tified before a patien t is classified as h avin g n o eviden ce of disease is considered persisten t disease.21,22

19.9 Com plicat ions Th e com plication profile of CND is sim ilar to th at of total thyroidectom y. Th e m ost com m on com plication associated w ith CND is hypoparathyroidism . Tem porar y hypoparathyroidism follow in g CND occurs in 14 to 40% of cases.23,24 Th is w ide ran ge of in ciden ce can be partially attributed to the di eren t n orm al referen ce levels an d th e defin ition of hypoparathyroidism . Th e h igh in ciden ce of tem porar y hypoparathyroidism is likely due to in adverten t in clusion of parathyroid glan ds in th e n odal dissect ion . Th ough repor ts are m ixed regarding th e in ciden ce of perm an en t hypoparathyroidism , a m eta-an alysis perform ed by Ch ish olm et al25 reported a 1.2% in ciden ce as defin ed by th e requirem en t for calcium supplem en tation surpassin g th e 6- to 12-m on th period postoperatively. Th is low in ciden ce of perm an en t hypoparathyroidism m ay be due to th e in creasin g pract ice of parathyroid autotran splan tation at th e t im e of surgery. Injur y to th e RLN or th e extern al bran ch of th e superior laryn geal n er ve occurs in 1 to 2% of pat ien ts.26 In experien ced h an ds th e addition of CND to total thyroidectom y for th e

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Surgical Managem ent for Di erentiat ed Thyroid Cancer treatm en t of thyroid can cer h as n ot in creased th e n erve injur y rates.25 How ever, th e recen t ATA recom m en dation s regarding th erapeutic or elect ive CND sh ould be in terpreted in th e ligh t of available surgical expert ise. Alth ough observation m ay in crease th e ch ance of future locoregion al recurren ce, overall th is approach m ay be safer in less experien ced surgical h an ds. Sosa et al an d oth ers foun d th at h igh -volum e surgeon s (> 100 cases/ 5 y) h ad 75% few er com plication s related to thyroid surgery th an low -volum e surgeon s (4.3% vs. 16.1%).27,28 How ever, th ere are n o sim ilar com parative studies don e for outcom es related to CND. In cases of reoperative CND after eith er previous thyroidectom y or CND, reports h ave n oted in creased n erve injury rates up to 12%,2 w h ereas oth ers h ave sh ow n n o in crease.17

19.10 Pearls and Pit falls ●

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Th e RLN divides th e righ t paratrach eal space in to an an terior an d posterior com partm en t as w ell as a lateral an d m edial com par tm en t . It is n ecessary to skeleton ize th e RLN alon g its en tire cervical course to ach ieve a com plete com partm en tal dissect ion . Avoid excessive or un in ten tion al tract ion on th e n er ve. Attem pts to preserve th e in terior parathyroid glan ds an d th eir blood supply m ay result in in com plete lym ph n ode clearan ce. Preservin g th e m ain trun k of th e in ferior thyroid artery an d superior term in al bran ch es h elps to m in im ize hypoparathyroidism by preservin g th e viabilit y of th e superior parathyroid glan ds. Liberal autotran splan tation of com prom ised parathyroid glan ds (after frozen sect ion con firm at ion ) w ill h elp to m in im ize lon g-term hypocalcem ia. Com part m en tal dissection m ust be perform ed. “Berr y pickin g” m ay n ecessitate fut ure addition al surgery an d is discouraged. Reoperative CND poses un ique ch allenges for RLN an d parathyroid glan d preservation , an d its risk–ben efit profile m ust be carefully w eigh ed in a m ultidisciplin ar y fash ion .

References [1] Mach ens A, Hin ze R, Th om usch O, Dralle H. Pattern of n odal m etastasis for prim ar y an d reoperative thyroid can cer. World J Surg 2002; 26(1); 22–28 [2] Cooper DS, Doh ert y GM, Haugen BRm , et al. Am erican Thyroid Association (ATA) Guidelin es Taskforce on Thyroid Nodules an d Di eren tiated Thyroid Can cer. Revised Am erican Thyroid Association m an agem en t guidelin es for patien ts w ith thyroid n odules an d di eren tiated thyroid can cer. Thyroid 2009; 19(11); 1167–1214 [3] Carty SE, Cooper DS, Doh ert y GM, et al. Am erican Thyroid Association Surgery Workin g Group. Am erican Association of En docrin e Surgeon s. Am erican Academ y of Otolaryn gology-Head an d Neck Surgery. Am erican Head an d Neck Society. Con sen sus statem en t on th e term in ology an d classification of cen tral n eck dissection for thyroid can cer. Th yroid 2009; 19(11); 1153–1158 [4] Zetoun e T, Keutgen X, Buitrago D, et al. Prophylactic cen tral n eck dissection an d local recurren ce in papillar y thyroid can cer: a m eta-analysis. An n Surg On col 2010; 17(12); 3287–3293 [5] Tuttle RM, Fagin JA. Can risk-adapted treatm en t recom m en dation s replace th e 'on e size fits all' approach for early-stage thyroid can cer patien ts? On cology (Williston Park). 2009;23(7):592, 600, 3 [6] Sch eum an n GF, Gim m O, Wegener G, Hun desh agen H, Dralle H. Progn ostic sign ifican ce an d surgical m an agem en t of locoregion al lym ph n ode m etastases in papillar y thyroid can cer. World J Surg 1994; 18(4); 559–567, discussion 567–568

[7] Arturi F, Russo D, Giu rida D, et al. Early diagn osis by genetic an alysis of differen tiated thyroid can cer m etastases in sm all lym ph n odes. J Clin En docrin ol Metab 1997; 82(5); 1638–1641 [8] Hugh es DT, W h ite ML, Miller BS, Gauger PG, Burn ey RE, Doh erty GM. In fluen ce of prophylactic cen tral lym ph n ode dissect ion on postoperative thyroglobulin levels an d radioiodin e treatm en t in papillar y thyroid can cer. Surgery. 148. United States: In c; 2010. p. 1100–6; discussion 006–7 [9] Pereira JA, Jim en o J, Miquel J, et al. Nodal yield, m orbidity, an d recurren ce after cen tral n eck dissection for papillar y thyroid carcinom a. Surgery. 138. Un ited States2005. p. 1095–100, discussion 100–1 [10] Hugh es DT, Doh ert y GM. Cen tral n eck dissection for papillary thyroid can cer. Can cer Con tr 2011; 18(2); 83–88 [11] Yeh MW, Bauer AJ, Bern et V, et al. Am erican Thyroid Association Statem en t on Preoperative Im aging for Thyroid Can cer Surgery. Th yroid 2014 [12] Stulak JM, Gran t CS, Farley DR, et al. Value of preoperative ultrason ography in th e surgical m an agem en t of in itial an d reoperative papillary thyroid can cer. Arch Surg. 141. Un ited States2006. p. 489–94; discussion 94–6 [13] Ah uja AT, Yin g M. Son ograph ic evaluation of cervical lym ph n odes. AJR Am J Roen tgen ol 2005; 184(5); 1691–1699 [14] Sn ozek CL, Ch am bers EP, Readin g CC, et al. Serum thyroglobulin , h igh -resolution ultrasoun d, an d lym ph n ode thyroglobulin in diagn osis of di eren tiated thyroid carcinom a n odal m etastases. J Clin En docrin ol Metab 2007; 92(11); 4278–4281 [15] Kresnik E, Gallow itsch HJ, Mikosch P, et al. Fluorin e-18-fluorodeoxyglucose positron em ission tom ography in th e preoperative assessm en t of thyroid n odules in an en dem ic goiter area. Surgery. 133. Un ited States2003. p. 294–9 [16] Wan g TS, Ch eun g K, Farrokh yar F, Rom an SA, Sosa JA. A m eta-analysis of th e e ect of prophylactic cen tral com part m en t n eck dissection on locoregion al recurren ce rates in patien ts w ith papillar y thyroid can cer. An n Surg On col 2013; 20(11); 3477–3483 [17] Tufan o RP, Bish op J, Wu G. Reoperative central com partm en t dissection for patien ts w ith recurren t/persisten t papillar y thyroid can cer: e cacy, safet y, an d th e association of th e BRAF m utation . Lar yn goscope 2012; 122(7); 1634– 1640 [18] W h ite ML, Gauger PG, Doh ert y GM. Cen tral lym ph n ode dissection in di eren tiated thyroid can cer. World J Surg 2007; 31(5); 895–904 [19] Tufan o RP, Claym an G, Heller KS, et al. Man agem en t of Recurren t/Persisten t Nodal Disease in Patien ts w ith Di eren tiated Thyroid Can cer: a Crit ical Review of th e Risks an d Ben efits of Surgical In terven tion versus Active Surveillan ce. Th yroid 2014 [20] Wu G, Fraser S, Pai SI, Farrag TY, Laden son PW , Tufan o RP. Determ in in g th e exten t of lateral n eck dissection n ecessar y to establish region al disease con trol an d avoid reoperation after previous total thyroidectom y an d radioactive iodin e for papillary thyroid can cer. Head Neck 2012; 34(10); 1418–1421 [21] Tuttle RM, Tala H, Sh ah J, et al. Estim atin g risk of recurren ce in di eren tiated thyroid can cer after total thyroidectom y an d radioactive iodin e rem n an t ablation : usin g respon se to th erapy variables to m odify th e in itial risk estim ates predicted by th e n ew Am erican Th yroid Association staging system . Thyroid 2010; 20(12); 1341–1349 [22] Hugo J, Roben sh tok E, Grew al R, Larson SM, Tuttle RMM. Recom bin an t Hum an TSH-Assisted Radioactive Iodin e Rem n an t Ablation in Thyroid Can cer Patien ts at In term ediate to High Risk of Recurren ce. Thyroid 2012 [23] Roh JL, Park JY, Park CI. Total thyroidectom y plus n eck dissection in di eren tiated papillary thyroid carcin om a patien ts: pattern of n odal m etastasis, m orbidity, recurren ce, an d postoperative levels of serum parathyroid h orm on e. An n Surg. 245. Un ited States2007. p. 604–10 [24] Palestin i N, Borasi A, Cestin o L, Freddi M, Odasso C, Robecch i A. Is cen tral n eck dissection a safe procedure in th e treatm en t of papillary thyroid can cer? Our experien ce. Lan gen becks Arch Surg 2008; 393(5); 693–698 [25] Ch ish olm EJ, Kulin skaya E, Tolley NS. System atic review an d m eta-analysis of th e adverse e ects of thyroidectom y com bin ed w ith cen tral n eck dissect ion as com pared w ith thyroidectom y alon e. Lar yn goscope 2009; 119(6); 1135– 1139 [26] Kan dil E, Abdel Kh alek M, Aslam R, Friedlan der P, Bellow s CF, Slakey D. Recurren t laryn geal n er ve: sign ifican ce of th e an terior extralar yn geal bran ch . Surgery 2011; 149(6); 820–824 [27] Sosa JA, Bow m an HM, Tielsch JM, Pow e NR, Gordon TA, Udelsm an R. Th e im portan ce of surgeon experien ce for clin ical an d econ om ic outcom es from thyroidectom y. An n Surg 1998; 228(3); 320–330 [28] Kan dil E, Noureldin e SI, Abbas A, Tufano RP. Th e im pact of surgical volum e on patien t outcom es follow in g thyroid surgery. Surgery 2013; 154(6); 1346– 1352, discussion 1352–1353

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Surgical Managem ent of Thyroid Diseases

20 Surgical Managem ent of t he Lat eral Neck in Thyroid Cancer Daniel Kwon and Alfred Simental, Jr.

c

20.1 Int roduct ion Th e propen sit y of di eren tiated thyroid can cer (DTC), especially papillar y thyroid can cer (PTC), w ith its predilect ion for lym ph atic m etastases, to dem on strate early spread to cervical lym ph n odes h as been w ell described in th e literature over th e past several decades.1 Th e first echelon of thyroid can cer m etastases are foun d in the paratrach eal an d cen tral n eck lym ph n ode com partm en ts, w ith th e lateral cervical lym ph atic ch ain alon g th e jugular vein com prisin g th e second ech elon of lym ph n odes. Th e rate of m etastases, in cluding m icrom etastases, for PTC ran ges from 50 to 90%.2,3,4,5 Th e cen tral com partm en t is a frequen t site of lym ph n ode recurren ce in thyroid can cer. Th is h as prom pted con siderable debate regarding th e n eed for prophylactic cen tral n eck dissection in an attem pt to avoid th e in creased risk of com plication associated w ith reoperative surgery. Th e debate on th e in itial surgical m an agem en t of region al lym ph n odes also in cludes th e lateral n eck, because recurren ce is possible th ere in up to 30%of cases.6 It is un den iable th at clin ically eviden t or progressive cervical m etastases require treatm en t to im prove outcom e, but th e treatm en t of subclin ical disease is less clear w ith regard to cost, risks, an d ben efit of treatm en t . Addition ally, alth ough cervical m etastatic disease h as been im plicated in som e studies as an in depen den t risk factor for locoregion al recurren ce, its e ect on overall m ortalit y is in con clusive.7,8 Th ere is poten tially sign ifican t addition al m orbidit y an d surgical risk associated w ith lateral cervical lym ph n ode dissection com pared w ith thyroidectom y an d cent ral n eck dissection alon e. As m eth ods of thyroid can cer detect ion h ave im proved sign ifican tly over th e past several decades, an in creasin g n um ber of patien ts face th e possibilit y of n eck surgery. Th is ch apter addresses th e evaluation , t reatm en t, an d im plication s of lateral n eck lym ph n ode m etastases in thyroid can cer.

20.2 Risk Fact ors A n um ber of risk factors are associated w ith th e presen ce of lateral n eck m etastases in thyroid can cer. Papillar y carcin om a often dem on st rates early lym ph atic spread, an d th erefore h as a h igh in ciden ce of lateral cervical lym ph n ode m etastasis. Follicular an d Hü rth le cell carcin om as h ave low er rates of lateral cervical n odal m etastases, th ough th ese do in frequen tly occur.9 In addition to prim ar y tum or h istology an d th e presen ce of central com partm en t disease, lateral n eck m etastases are m ore likely in th e presence of th e follow in g factors: younger patien ts, m ale sex, in creased size of prim ary tum or, lym ph ovascular invasion , extrathyroidal exten sion , m ultifocal disease, an d BRAF m utation s.5,10,11,12,13

The following are factors a ecting lateral neck nodal metastases in well-di erentiated thyroid cancer: ● Prim ary tumor histology. ● Prim ary tumor size. ● Age. ● Extrathyroidal extension. ● Gender.

Molecular m arkers h ave recen tly been investigated regarding th eir ut ilit y to predict aggressive disease an d lym ph n ode m etastasis, as w ell as th eir bein g a basis for targeted th erapy. BRAF is a gen e th at codes for B-raf, a protein in th e m itogen -act ivated protein kin ase cell sign alin g path w ay. Mutation s in th e BRAF gen e h ave been im plicated in a variety of h um an can cers, in cluding m elan om a an d lun g an d thyroid can cers. In papillar y thyroid can cer, m utation s h ave been dem on st rated in som e studies to be th e m ost im portan t in depen den t clin icopath ologic feature of aggressive disease, in cluding lym ph n ode m etastasis, recurren ce, an d d eath .14 How ever, som e of t h e m ore recen t stu d ies are d em on st rat in g a m u ch h igh er p revalen ce of BRAF m u tation s th an p reviou sly d escribed an d fail to fin d an association w ith lateral cer vical lym p h n od e m etastases.15,16,17,18 Ot h er m olecu lar m arkers, su ch as t h e exp ression of t u m orsu p p ression p rotein p 53, h ave also been invest igat ed as r isk fact ors for d isease aggressiven ess an d n od al m et ast asis.19 Th ese m arkers h ave n ot been est ablish ed t o be in d ep en d en t in d icat ion s for elect ive n eck d issect ion in t hyroid can cer bu t m ay ser ve to stratify risk an d gu id e fu r th er p reop erative evalu at ion . Patien t s w it h ad d it ion al risk fact ors w ill be th e m ost likely to ben efit from eith er u ltrasou n d or ad van ced im aging, su ch as com p u ted t om ograp hy (CT) an d m agn et ic reson an ce im agin g (MRI), to evalu ate th e cen tral an d lateral lym p h at ic com p ar t m en t s for t h e p resen ce of m et ast atic d isease.

20.3 Preoperat ive Evaluat ion Th e lateral n eck sh ould be assessed in all pat ien ts un dergoing surgery for thyroid can cer. A com plete h istory sh ould in quire about th e presen ce of any n ew n eck m asses or any first-degree relatives w ith a h istor y of m etastatic thyroid carcin om a. Physical exam in at ion sh ould in clude lar yngoscopy to determ in e vocal fold m obilit y an d careful bim an ual exam in ation of th e n eck for abn orm al lym ph n odes. In postoperative patien ts, elevated levels of thyroglobulin (Tg) an d Tg an tibody can ser ve as a h arbin ger of recurren t prim ary or m etastat ic disease.

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Surgical Managem ent of the Lateral Neck in Thyroid Cancer

20.3.1 Im aging Radiograph ic detect ion of m acroscopic cervical lym ph n ode m etastases is crucial because rem oval of m acroscopic disease at th e in itial surgery w ill decrease th e n eed for revision surgery as w ell as repeated radioact ive iodin e (RAI) treatm en ts. High -resolution ultrasoun d of th e thyroid an d lateral n eck h as been foun d to be reliable an d low cost for th e evaluation of thyroid can cer w h en em ployed by experien ced clin ician s. Un fort un ately, routin e diagn ostic thyroid ultrasoun d frequen tly does n ot address th e lateral n eck. How ever, a protocol em ployin g dedicated, com preh en sive, con sisten t preoperative ultrasoun d assessm en t of th e lateral n eck results in th e detect ion of suspicious lym ph aden opathy in up to 20 to 30% of pat ien ts w ith kn ow n thyroid can cers, an d ultim ately alters surgical t reatm en t in approxim ately 20% of th ese patien ts.20,21 Th e sen sitivit y of ultrasoun d in detect in g cervical lym ph aden opathy in th e cen tral com partm en t h as been reported as 30 to 50%, largely due to th e sh adow in g e ect of th e thyroid glan d. Th e low sen sitivit y of ultrasoun d (US) in th e cent ral n eck is one reason w hy CT im aging is preferred by m any surgeon s in the in itial im agin g evaluation of h igh -risk patien ts. How ever, in th e lateral n eck, ultrasoun d h as up to 90% sen sitivit y in detect in g suspicious lym ph n odes. Specificities approach 90% in both cent ral an d lateral com partm en ts usin g US.15,22 Con cern in g features of lym ph n odes on US in clude size > 1 cm , hypoech oic con sisten cy, roun d sh ape, irregular borders, absen ce of h ilum , periph eral vasculature, calcification s, an d cystic ch anges.23,24,25

c Below are US features of lym ph nodes suggestive of metastases in thyroid cancer: ● > 1 cm in size. ● Hypoechoic lym ph node/cystic changes. ● Irregular border. ● Absence of norm al hilum architecture. ● Peripheral vasculature. ● Calcification.

US has m any advan tages over oth er im aging m odalit ies, such as CT an d MRI. Th ere is n o radiation exposure w ith US, it can be perform ed in th e outpatien t o ce durin g th e in itial visit, an d it is rapid, easily repeatable, an d relatively in expen sive. Fin e-n eedle aspirat ion (FNA) biopsy h as been sh ow n to be m ore accurate w h en coupled w ith US guidan ce an d h as becom e th e stan dard for thyroid an d cervical biopsies.26 Despite th ese advan tages, lim itation s in evaluat in g substern al region s an d invasion of surroun din g organ s, as w ell as in teroperator reliabilit y, presen t som e ch allenges for th e un iversal acceptance of US as th e sole im agin g m odalit y for in itial or recurren t h igh -risk thyroid can cers. Advan ced im aging m odalities, such as CT, MRI, or positron em ission tom ography (PET-CT) h ave sim ilarly h igh sen sitivit y an d specificit y in assessin g cen tral com part m en t an d lateral n eck lym ph n odes.27,28 Th ey o er th e advan tages of better visualization of adjacen t n eck tissues an d periclavicular n eck levels an d less operator depen den ce. Addition ally, com bin in g im aging m odalit ies, such as US an d CT, h as been sh ow n to o er h igh er sen sitivit y th an th e in dividual m odalit ies.29 At

th is tim e, m ost surgeon s are m ore com fortable review ing CT or MRI scan s, rath er th an US im ages, to determ in e th e location s of m etastases. Th us th ese m odalities are w idely preferred for preoperative plan n in g an d locatin g m etastases in un com m on location s. How ever, th e routin e use of CT results in con siderable expen se an d addition al radiation exposure. Th e Food an d Drug Adm in istration (FDA) h as begun to con sider th e e ects of CT radiation on lon g-term h ealth an d h as issued several statem en ts requestin g th e decrease of exposure to m edical radiation .30 Also, th e use of CT con trast dye m ay delay th e adm in istration of postoperat ive RAI for at least 3 m on th s after adm in istration w h ile th e stun n in g e ect of th e con trast on th e thyroid w ears o . Despite th ese lim itation s, CT im agin g w ill provide th e m ost reliable clin ical stagin g an d surgical plan n in g of any curren t im aging m odalit y. Th e use of MRI h as sim ilar advan tages to CT, but th e presence of vascular flow voids, m ovem en t artifacts, an d in ferior osseocart ilagin ous delin eation lim it its utilit y in im aging advan ced thyroid m align an cy.

20.3.2 Pat hological St aging Cer vical lym ph aden ectom y is associated w ith in creased m orbidit y, an d ever y e ort sh ould be m ade preoperatively to establish a cytological diagn osis of suspicious lateral cervical n odes. FNA h as rem arkably im proved th e abilit y to path ologically detect m align an cy in cen tral com partm en t an d lateral cervical lym ph n odes.31 How ever, th e accuracy of cytopath ologic diagn osis is h igh ly depen den t on adequate sam pling of th e lesion an d th e proficien cy of th e path ologist. Palpat ion -guided FNA results in a false-n egative rate of ~ 6%, w ith an addition al 10% of sam ples foun d to be in adequate.32 How ever, w h en US-guided FNA (US-FNA) is perform ed, th e diagn ostic yield im proves, an d in adequate sam pling rates decrease to approxim ately 3 to 7%.26,33 Th is is possible due to real-tim e visualization of n eedle passes th rough th e targeted lym ph n ode.34 Th e diagn ostic yield of US-FNA can also be in creased by select in g n odes w ith m ore suspicious features (as listed in th e previous sect ion ), w ith sen sitivities an d specificities approach ing 100% w h en m ultiple features are presen t.35 Sen sitivit y an d specificit y of US-FNA can be furth er in creased w hen Tg assay of th e aspirated fluid is perform ed in addition to routin e cytopath ologic an alysis.36 Th is is especially h elpful for sam pling sm all-volum e lym ph n odes or n odes w ith sign ifican t cystic com pon en ts, w h ich m igh t yield an in adequate n um ber of cells.37,38 Th e utilit y of Tg serology in FNA is lim ited for sam plin g un di eren tiated, an aplastic, or m edullar y thyroid can cers, w h ich do n ot t ypically produce Tg. In addition , th e presence of Tg an tibody m ay th eoretically a ect th e m easurem en t of Tg, alth ough studies h ave sh ow n th at FNA-Tg m easurem en t is useful, even in th e presen ce of circulat in g seru m Tg an tibody.36 In clusion of any thyroid t issue w ould obviously create a falsepositive; h ow ever, th is is t ypically m ore relevan t to central com partm en t n odes w h ere th e n eedle could m istaken ly pass th rough th e thyroid glan d an d w h ere sm all foci of rem n an t thyroid m ay m im ic lym ph n odes.39 Th us Tg assessm en t w ith FNA is m ost useful w h en sam pling lateral n eck n odes in athyrotic, Tg an tibody–n egative patien ts after RAI adm in istration .40 With or w ith out Tg, US-FNA sh ould be perform ed in all clin ical

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Surgical Managem ent of Thyroid Diseases tract an d also for defin in g lym ph n ode basin s m ost appropriate for evaluation w h en treatin g patien ts w ith th ese m align an cies. Th is h as resulted in stan dardized n om en clat ure for com m un ication of lym ph n ode basin s m ost likely to be a ected by w ell-differen tiated can cer as w ell. For practical purposes, th ere are six lym ph n ode com partm en ts or “levels” in th e n eck th at are described follow in g h ere ( Fig. 20.1). Th ese com partm en ts en com pass th e lym ph n odes in th e fibro-fat t y soft tissue located betw een th e superficial investin g fascia superiorly, an d th e visceral an d prevertebral fascia layers deep. Level I is kn ow n as th e subm an dibular space, an d levels II th rough IV, th e jugular n odes.

20.4.1 Level I Level I is boun d by th e m an dible superiorly an d th e body of th e hyoid in feriorly. Th e an terior border is th e an terior belly of th e con tralateral digast ric m uscle, an d th e posterior border is th e st ylohyoid m uscle. Level I is divided in to IA an d IB by th e an terior belly of th e ipsilateral digast ric m uscle.

20.4.2 Level II Level II is boun d superiorly by th e skull base an d in feriorly by th e h orizon tal plan e of th e in ferior border of th e hyoid bon e. Th e an terior border is th e st ylohyoid m uscle, w h ereas th e posterior border is th e lateral border of th e stern ocleidom astoid (SCM) m uscle. Level II is also divided in to t w o sublevels, IIA an d IIB, by th e vert ical plan e of th e spin al accessor y n er ve.

Fig. 20.1 Prevalence of lateral lym ph node metastasis by com partment. (Adapted from Robbins et al. 49 )

20.4.3 Level III scen arios w ith suspected lym ph n ode m etastasis, w h eth er prim ary or recurren t.

20.3.3 Laborat ory Evaluat ion Serum Tg an d Tg an tibodies are useful tools in sur veillan ce an d are th ough t of as surrogate m easures of fun ct ion al thyroid tissue, ben ign or m align an t .41,42 Th e presen ce of a progressively risin g Tg or Tg an t ibody after surgery an d prim ar y ablat ion of thyroid tissues m ay be a sign of persisten t or recurren t thyroid m align an cy. In addition , testin g for th e presen ce of certain biom arkers, such as BRAF m utation s, w h ich h as been associated w ith lym ph n ode m etastases, m ay aid in risk stratification .17,43,44,45 Studies h ave explored th e utilit y of gen e assays for BRAF in FNA sam ples to predict disease beh avior, in cluding lym ph n ode m etastases.46 How ever, th e sign ifican ce of m any of th ese biom arkers are still un der investigation an d th e assays are n ot w idely available.

20.4 Cervical Lym ph Node Com part m ent s Th e n eck com partm en ts h ave been stan dardized for several decades based on w ell-studied lym ph n ode drain age path w ays an d on cological pattern s of spread.47,48,49 Defin in g key boun daries an d lan dm arks h as been in strum en tal in relatin g m etastat ic can cerous deposits w ith likely sites of un kn ow n prim ar y tum ors in squam ous cell carcin om a of th e upper aerodigestive

Level III is boun d superiorly by th e h orizon tal plan e of th e in ferior border of th e hyoid bon e an d in feriorly by th e h orizon tal plan e created by th e in ferior aspect of th e cricoid cartilage. Th e lateral stern ohyoid m uscle is th e an terior border, an d th e lateral border of th e SCM an d/or cervical rootlets ser ve as th e posterior border.

20.4.4 Level IV Level IV is boun d superiorly by th e h orizon tal plan e of th e in ferior cricoid cartilage an d in feriorly by th e clavicle. Sim ilarly to level III, th e an terom edial border is th e lateral stern ohyoid m uscle, an d th e lateral border is th e lateral SCM an d cervical rootlets posteriorly.

20.4.5 Level V Level V is boun d superiorly by th e convergen ce of th e SCM an d trapezius m uscles an d in feriorly by th e clavicle. Th e lateral edge of th e SCM an d/or cervical rootlets is th e an terior border, w h ereas th e an terior border of th e trap ezius m uscle serves as th e posterior border. Th is level is divided in to VA an d VB by th e h orizon tal plan e of th e in ferior cricoid cart ilage.

20.4.6 Level VI Level VI is boun d by th e hyoid bon e superiorly an d laterally by th e com m on carotid arteries. Th e in ferior lim it is som etim es

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Surgical Managem ent of the Lateral Neck in Thyroid Cancer defin ed as th e stern al n otch , w h ereas oth ers use th e in n om in ate artery as th e in ferior border. Th ese lym ph n odes in ferior to th e stern al n otch in th e an terior m ediastin um are often in cluded in th e defin ition of th e cen tral com partm ent due to th e cont iguous lym ph atic drain age of th e perithyroidal an d paratrach eal lym ph n odes in to th e m ediastin um . Superior m ediastin al lym ph n odes accessible th rough th e n eck are often referred to as level VII lym ph n odes, th ough th is is n ot sup ported by th e con sen sus statem en t of th e Am erican Head an d Neck Society as w ell as th e Am erican Academ y of Otolaryn gology–Head an d Neck Surgery.50

20.5 Lat eral Neck Dissect ion Definit ions Sim ilar to th e defin ition of th e cer vical lym ph n ode com partm en ts, n om en clature an d defin ition s of n eck dissect ion s are im portan t for consisten cy in th e m edical literature and research an d for com m un icat ion am ong clin ician s. Lateral n eck dissection s h ave been relatively w ell defin ed in th e literature, based on th e previously described lym ph n ode levels. Th e radical n eck dissect ion (RND), popularly described by Crile in 1906, is defin ed by rem oval of all ipsilateral cervical lym ph n ode struct ures in com partm en t levels I th rough V alon g w ith th e spin al accessor y n er ve, SCM, an d in tern al jugular vein . Th e boun daries of th is dissection are th e m an dible superiorly, th e clavicle in feriorly, th e lateral hyoid bon e, th e stern ohyoid m uscle, an d th e con tralateral an terior digastric m uscle m edially, an d th e an terior border of th e t rapezius laterally. Th e m odified radical n eck dissection (MRND), in troduced several decades later, refers to th e rem oval of all lym ph atic struct ures in cluded in th e radial n eck dissection (levels I–V), but w ith th e preser vation of at least on e of th e n on lym ph atic struct ures (spin al accessor y n er ve, SCM, in tern al jugular vein ). Despite th e preferen ce for th e term s ra dica l neck dissect ion an d modified ra dica l neck dissect ion, th ere is som e variety in th e n om en clature foun d in th e literature in referen ce to th e rem oval of lym ph n ode levels I th rough V, in cluding complete neck dissect ion or comprehensive neck dissect ion.51 Most recen tly, selective neck dissect ion (SND) h as em erged as a gen eral term th at refers to th e rem oval of som e but n ot all of th e lym ph atic com part m en ts of th e lateral n eck. Th e use of SND represen ts on e of th e m ajor ch anges in h ead an d n eck on cological surgery, w h ere targeted lym ph aden ectom y is guided by know ledge of lym ph atic drain age pattern s specific to th e prim ar y m align an cy site an d h istology.52 Due to th is m ore selective approach to th e n eck, th e literat ure refers to several classification s, such as supraom ohyoid neck dissection , an terolateral n eck dissection , lateral n eck dissection , an d exten ded n eck dissection . How ever, th e exten t of excision described by th ese term s varies am on g in stit ut ion s. Th erefore th e exten t of n eck dissection , according to th e in dividual levels excised, sh ould be specifically described w h en departin g from th e m ore stan dardized term in ology of RND an d MRND. Th is in cludes com m en ts on in clusion or exclusion of lym ph n ode sublevels as w ell as lym ph n odes n ot in cluded in th e com part m en t classification s, such as perifacial, periparotid, paraph ar yngeal, superior m ediastin al, an d suboccipital lym ph n odes. Addition ally, any sacrificed n on lym ph atic struct ure sh ould be n oted as w ell. Th is

is especially im portan t w h en on e is dealin g w ith th e lateral n eck in thyroid can cer because cervical m etastases m ay vary, especially in th e settin g of recurren t disease. Traditionally, the extent of lateral neck dissection for thyroid cancer had been largely left to the discretion of the individual surgeon, leading to disparate procedures and operative descrip tions. To codify these di erences, the 2009 Am erican Thyroid Association (ATA) guidelines recom m ended “therapeutic lateral neck com partm ental lym ph node dissection” for lateral cervical m etastases.53 With the exception of RND and MRND, lateral neck dissections for thyroid cancer should now specifically describe the nodal com partm ents, w hich are dissected, and excision of individual nodes (“berr y picking”) is no longer recom m ended.

20.6 Cervical Lym ph Node Met ast asis in Di erent iat ed Thyroid Cancer Papillary thyroid can cer is th e predom in an t thyroid can cer resultin g in cervical lym ph n ode m etastasis due to its prevalen ce an d h igh propen sit y for lym ph atic spread.

20.6.1 Drainage Pat t erns Cer vical m etastasis in di eren tiated thyroid can cer t ypically occurs in th e cen tral com partm en t , th e first n odal basin , w ith subsequen t stepw ise spread to th e lateral n eck in levels II th rough V. Th ere is also eviden ce of spread to th e lateral n eck directly from th e thyroid glan d.54 Th ese “skip m etastases” h ave been sh ow n to occur in up to 38% of cases, m ost com m on ly from upper pole lesion s.55 Level I is n ot com m on ly a ected by thyroid can cer m etastasis. Levels III an d IV are th e m ost com m on sites of lateral cervical m etastases, but th e in ciden ce of m ultilevel disease a ect in g all levels II th rough V is h igh on ce th e disease h as progressed to th e lateral n eck.56,57 Spread to level IIB is less com m on (~ 15%), w ith rates of involvem en t ran ging from 5 to 62%. Sim ilarly, level VA is on ly involved in approxim ately 8% of cases ( Fig. 20.1).56 Fin ally, it is im portan t to recogn ize th at con tralateral n eck m etastasis m ay occur, especially in m ultifocal tum ors an d tum ors involving th e isth m us. Even in cases of un ilateral thyroid can cer, con tralateral or bilateral lateral n eck m etastases h ave been seen in up to 24% of cases in on e study.58 Th ese cases correlated h igh ly w ith th e presen ce of clin ically eviden t ipsilateral lateral an d con tralateral paratrach eal n odal m etastases, leadin g th e auth ors to suggest bilateral n eck dissection in th ose cases.

20.6.2 Prognost ic Significance of Nodal Met ast asis W h en stratified by low - an d h igh -risk di eren tiated thyroid carcin om a, large, single-in stitut ion studies h ave dem on st rated n o ch anges in survival am ong pat ien ts w ith or w ith out n odal disease.59 Oth er in stit ut ion s h ave suggested decreased sur vival in patien ts w ith n odal m etastasis in certain population s, such as older pat ien ts an d patien ts w ith follicular carcin om a.8,60 Large-populat ion stud ies also h ave conflict in g repor ts regardin g th e sur vival im plication s of n odal m etastases.61,62,63 It is

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Surgical Managem ent of Thyroid Diseases im portan t to recognize th at m ost of th e retrospective sur vival outcom e data in thyroid can cer are plagued by select ion bias, w ith di eren t subjects receivin g di eren t t reatm en ts. Th e lon g sur vival in di eren tiated thyroid can cer m akes it di cult to design a prospective study w ith en ough patien ts an d follow -up len gth to reach sign fican ce.64 How ever, in term s of locoregion al con trol after prim ar y treatm en t , th e presen ce of n odal disease in th e lateral n eck at in itial presen tation h as been sh ow n to be a positive predictive factor for recurren ce, even after n eck dissect ion an d adjuvan t treatm en t .65 Th ere is n o conclusive eviden ce th at RAI treatm en t is e ective in eradicatin g occult lateral n eck m etastasis, an d it h as been sh ow n to be relatively in e ect ive in t reating clin ically apparen t disease.66 Th erefore, alth ough its e ect in overall sur vival is cont roversial, lateral n eck disease in thyroid can cer sh ould be addressed w ith surgery in an attem pt to control region al disease progression an d im prove qualit y of life.

w h ere RAI is n ot routin ely used, prophylactic n eck dissection in low -risk (m icropapillar y) thyroid can cer discovered m etastatic disease in approxim ately h alf of th e cases. How ever, clin ically apparen t lym ph n ode disease developed in on ly 1.2%of patien ts w h o opted for observation alon e after 8 years of follow -up.74 Th ese studies suggest th at m icroscopic cervical m etastases m ay n ot n ecessarily progress to clin ical disease in th e m ajorit y of patien ts. A m eta-an alysis exam in ing th e role of lateral n eck dissect ion in w ell-di eren t iated thyroid can cer concluded th at, w h en considerin g th e risks an d ben efits, th ere w as n o defin itive role for elect ive lateral n eck dissection .75 Alth ough th ere are practical reason s for perform in g con current prophylactic cen tral n eck dissection durin g thyroidectom y, th e cost an d m orbidit y of lateral n eck surgery, com bin ed w ith the sm all decrease in clin ical recurren ce, greatly lim its th e ben efit of routin e lateral n eck dissection in a clin ical N0 patien t.

20.6.4 Therapeut ic Neck Dissect ion

20.6.3 Elect ive/Prophylact ic Neck Dissect ion Th ough m uch m ore com m on in oth er count ries, a m in orit y of cen ters in th e Un ited States advocate prophylactic lateral n eck dissection to preven t th e n eed for future treatm en t-related qualit y-of-life issues. Each tim e a patien t un dergoes an oth er surgical in terven tion , th ere is a “tim e packet” related to preparation an d recovery from th e given procedure. Th us, even th ough sur vival is n ot ch anged, repeated in terven t ion s at tem porally distin ct tim es decrease th e patien t’s n on treatm en trelated sur vival. A pat ien t m ay be subjected to t w o separate 6-w eek recover y periods in stead of on e, th us doublin g th e treatm en t -related recovery. Studies reportin g on prophylact ic lateral n eck dissection h ave dem on strated occult disease rates of up to 50% an d h ave advocated prophylactic lateral n eck dissection , eith er routin ely or in th e presen ce of cen tral com part m en t lym ph aden opathy.67,68 In order to im prove th e detect ion an d rem oval of occult m etastasis, w h ile m in im izing th e m orbidit y of surgical th erapy, th e use of sen tin el lym ph n ode m appin g an d biopsy h as been em ployed. How ever, th e sen tin el lym ph n ode is alm ost alw ays located in th e cen tral com part m en t; th erefore sen tin el lym ph n ode m appin g seldom provides guidan ce in addressin g th e lateral n eck.69 Propon en ts for prophylactic n eck dissection in cludin g th e lateral n eck cite th e ben efits of m ore accurate stagin g an d subsequen t ch anges in th e m an agem en t algorith m .70 But, despite good eviden ce dem on stratin g th e prevalen ce of occult lateral n eck disease, th ere are n o data in dicatin g a lon g-term sur vival ben efit of lateral n eck dissection in th ese pat ien ts.71,72 It is possible th at m icroscopic n odal disease an d clin ically apparen t n odal disease are separate en tit ies in term s of th eir biological beh avior. A m eta-an alysis by th e ATA repor ted th at th e data in dicated th at sm all-volum e m icrom etastases h ad a sign ifican tly m ore ben ign beh avior w h en com pared to clin ical apparen t disease.73 Microscopic m etastases discovered on ly by prophylact ic n eck dissect ion h ad recurren ce rates of approxim ately 6%, w h ich w ere sim ilar to th e 4% recurren ce rates in clin ically N0 patien ts th at did n ot un dergo n eck dissect ion . Th is rate of clin ical recurren ce cont rasted greatly w h en com parin g overall recurren ce rates betw een cN0 an d cN1, w h ich w ere 2% versus 22%, respect ively. In a double-arm ed study from Japan ,

A w ide ran ge of n eck dissection tech n iques h ave been described in th e literature an d used in practice. Lim ited n eck dissection s in clude “berr y pickin g,” th e selective rem oval of m acroscopically involved lym ph n odes, as w ell as “superselect ive” n eck dissection , w h ich is th e rem oval of on ly th e com part m en ts th at h ave involved lym ph n odes. Th ese m eth ods w ere popular in th e past because th e disease course of di eren tiated thyroid can cer is so in dolen t. Th ese lim ited approach es also require less surgical proficien cy an d t ypically result in less m orbidit y. How ever, routin e use of n on com preh en sive cer vical lym ph aden ectom y for th e prim ar y t reatm en t of th e lateral n eck results in a h igh er risk of recurren ce an d subsequen tly in creases treatm en t-related recover y an d m orbidit y. Th e presen ce of lateral n eck disease suggests th at th e biology of th e can cer is m ore aggressive th an m ost clin ically occult varian ts. Th us th e m icrom etastases th at accom pany th e clin ical disease are likely to recur if it is n ot addressed surgically. Preoperative im aging h as been reported to be h igh ly specific involved com part m en ts or th e n um ber of involved n odes.76 Th e use of lim ited n eck dissection m akes reoperation m ore di cult an d in creases th e ch an ce of treatm en t-related m orbidit y in th e previously violated surgical field. Th ese m in im al m eth ods m ay be of som e ut ilit y w h en dealin g w ith recurren t n eck disease follow in g a previous com preh en sive n eck dissection for local con trol. Based on th e foregoing data describin g pattern s of lateral n eck spread in thyroid can cer, th e 2009 ATA guidelin es have advocated for a “com preh en sive lateral n eck dissection .” Th is w as later clarified as rem oval of levels IIA, III, IV, an d VB in th e presen ce of lateral n eck disease.13 Th e Triological Society sim ilarly recom m en ded eith er selective n eck dissect ion , in cluding levels II th rough V w ith or w ith out th e in clusion of IIB an d VA, or MRND for th erapeutic treatm ent of clinically positive lateral n eck m etastasis in Fig. 20.3).77 di eren tiated thyroid can cer ( Fig. 20.2 an d Because level I involvem en t is rare, it t ypically does n ot n eed to be involved in th e dissect ion .

20.6.5 Recurrent Neck Disease In th e case of reoperation for recurren t lateral n eck disease, a com partm en t-based n eck dissect ion sh ould gen erally be con sidered because exten sive scarrin g in creases th e risk of

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Surgical Managem ent of the Lateral Neck in Thyroid Cancer

Fig. 20.3 Surgical specim en showing total thyroidectom y and central and lateral neck contents.

Fig. 20.2 Left neck after dissection. A, internal jugular vein; B, carotid artery; C, spinal accessory nerve; D, cervical rootlet; E, sternocleidom astoid m uscle; F, om ohyoid m uscle; G, digastric m uscle.

n eurovascular injury. Careful evaluation w ith preoperative im aging should evaluate possible involvem ent of the carotid sheath or deep cervical m usculature. Recurrent cancers w ill t ypically occur outside of the field of dissection and m ay be relatively sim ple to rem ove. How ever, in field recurrences treatm ent m ay require resection of im portant neurovascular structures, such as the phrenic nerve, spinal accessory nerve, and brachial plexus, w hich m ay result in significant m orbidities. When the recurrence is in a surgically tenuous location and is sm all, close observation w ith m axim al thyroid-stim ulating horm one (TSH) suppression m ay be a reasonable option. In a series of 166 patients w ith lym ph node recurrence detected on surveillance US that w ere follow ed for 3.5 years, the m ajority of the lym ph nodes rem ained stable, w ith 29% eventually grow ing and 14% resolving on their ow n.78 This study suggests that im m ediate surgical treatm ent of nodal recurrence m ay not be necessary and that active surveillance m ay be a reasonable alternative, reserving treatm ent for progression. In these progressive cases, if patient preference, high risk of m orbidit y, or m edical com orbidit y precludes reoperation, external beam radiation or system ic therapy m ay be em ployed w ith reasonable results.

20.7 Medullary and Poorly Di erent iat ed Thyroid Cancer Medullar y thyroid can cer (MTC) sh ould be con sidered a dist in ct en t it y w h en com pared to DTC an d porten ds a w orse progn osis.

Clin ically apparen t cervical m etastases are com m on on presen tation due to early lym ph atic spread, an d distan t m etastases m ay be present in up to 50%of cases.79 Th e pattern of lym ph atic spread ten ds to be stepw ise, an d th e presence of cen tral com partm en t lym ph aden opathy h as been sh ow n to be in dicative of ipsilateral an d con tralateral lateral n eck spread in m ore th an 70% an d 38% of cases, respect ively. Th ese n um bers in crease dram atically w h en th ere are m ultiple (> 10) cen tral com partm en t n odes.80 Th is h as led som e to advocate for elect ive lateral n eck dissection w h en th ere is central com partm en t involvem en t.81 Un for t u n ately, it h as been d em on strat ed t h at it is d i cu lt to ach ieve bioch em ical rem ission of MTC in cases of cer vical lym p h n od e sp read , w it h rep or t s as low as 10% d esp it e n eck d issect ion .82 How ever, resection of n eck d isease h as been sh ow n t o d ecrease local com p licat ion s, su ch as invasion in t o adjacen t n eck st ru ct u res (e.g., t h e aerod igest ive tract ).83 Th erefore, t h e 2009 ATA MTC gu id elin es recom m en d ed a lat eral n eck d issect ion of levels IIA, III, IV, an d V w h en th ere are clin ically ap p aren t lym p h n od e m etastases, w ith ou t th e n eed for biop sy. In t h e set t in g of d ist an t m et astasis, lateral n eck d issect ion sh ou ld be em p loyed on ly in th e p resen ce of clin ically p osit ive n od es in ord er to con trol region al d isease th at m ay even t u ally resu lt in airw ay, p h on ator y, or sw allow in g d ysfu n ct ion . An aplastic thyroid can cer is extrem ely aggressive an d t ypically presen ts w ith distan t m etastases an d exten sive local invasivion .84 Locoregion al invasion in to th e carotid artery, in tern al jugular vein (IJV), cran ial n er ves, an d aerodigestive tract is com m on . Th erefore, usual con sideration s assessing lym ph n ode involvem en t an d cervical spread t ypically do n ot apply. Isolated in trathyroidal tum ors represen t 10% of cases of an aplastic thyroid can cer an d are usually an in ciden tal fin din g. In th ese cases, th e ATA recom m en ds th erapeutic rem oval of cen tral an d lateral lym ph n ode com partm en ts alon g w ith thyroidectom y.85 Th e role of surger y is oth erw ise based on w h eth er com plete resection w ith gross n egative m argin s is possible w ith reason able m orbidit y.85 Even in th e presence of distan t m etastasis, palliative locoregion al surgery m ay be con sidered to preserve airw ay obstru ct ion .

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An im portan t aspect of lateral n eck dissect ion in thyroid can cer is th e surgical in cision an d scar. Con siderin g th e in dolen t n ature of th e disease an d th e relatively h igh prevalen ce in younger patien ts, optim izing th e cosm etic appearan ce of th e n eck sh ould be am ong th e goals of treatm en t . Wh en treatin g th e lateral n eck concurren tly w ith thyroidectom y, exten ding th e an terior n eck in cision alon g a n atural skin crease laterally m ay h elp m in im ize n oticeable scarrin g. A purely lateral n eck in cision m ay be em ployed, but often th is in cision m ust be exten ded superiorly beh in d th e SCM m uscle for adequate exposure of th e level II basin . Trifurcat in g scars or m ultiple skin in cision s (MacFee) sh ould n ot be n ecessary, an d th ey in crease th e risk of w oun d deh iscen ce, scar cont ract ure, an d flap n ecrosis.86 Basic w oun d-h ealin g prin ciples sh ould be follow ed w ith ten sion -free closure, optim izing n utrition an d m in im izing risk factors for w oun d com plication s. Risk factors for w oun d h ealin g frequen tly in clude previous radiation , diabetes m ellit us, m aln utrition , an d tobacco use. W h en lateral n eck dissection is perform ed after previous thyroidectom y, an e ort to use th e sam e n eck in cision is pruden t. Alth ough cosm esis is taken in to accoun t, successful extirpat ion of disease an d safety sh ould be of ultim ate im portan ce.

return to th e operatin g room for evacuat ion an d con trol of any con tin ued bleedin g. Meticulous in traoperative h em ostasis an d avoidan ce of an ticoagulan t an d an tiplatelet m edication sh ould be used to preven t h em atom a. Surgical drain s do n ot preven t h em atom a (as th ey do in serom a) but m ay aid in recogn izin g an d localizing bleedin g. Chyle leaks m ay occur after left n eck dissect ion in level IV n ear th e site of th e th oracic duct , but up to 25% m ay result from injury of th e righ t lym ph atic duct .89 Because th e th oracic duct an d righ t lym ph atic duct often present as a plexus of vessels, in traoperative ligation w ith clips or suture ties of th e in ferior aspect of n eck dissect ion is prudent . In traoperative Valsalva m ay be don e w h en th ere is suspicion of a chyle leak durin g n eck dissection . Addition ally, application of h em ostatic m aterials, sclerosing agen ts, an d fibrin products h as been described as adjun ct ive treatm en t .90 Chyle leaks m ay occur in up to 2% of cases an d are usually discovered after postoperative resum p tion of en teral feedin g w h en drain fluid ch anges from a serosan guin ous to a m ilky color. Sen din g drain fluid for triglycerides or chylom icron s h elps confirm th e presen ce of chyle. Rarely, chyle leaks m ay progress in to th e ch est th rough th e m ediastin um an d cause chyloth orax. Treatm en t for chyle leaks t ypically starts w ith conser vative m an agem en t consist in g of a m edium ch ain fatt y acid diet an d con tin uin g suct ion drain s.91 Un fort un ately, pressure dressin gs seldom w ork. If th e patien t is able to tolerate oral in take, strict adh eren ce to a diet of fruit an d n on fried vegetables, excluding avocado, for several w eeks, is usually e ect ive in reducin g chyle flow. Som atostatin m ay also be adm in istered to reduce splan ch n ic blood flow an d chyle product ion from th e gastroin testin al tract.92 Chyle leaks are usually con sidered h igh -flow w h en daily drainage exceeds 500 to 1,000 m L. Needle drain age m ay be h elpful, but h igh -flow chyle leaks an d th ose th at fail to stop after con servative treatm en t t ypically require reoperation to avoid m aln utr ition an d im m un ologic dysfun ct ion .

20.8.2 Drains and Fluid Collect ions

20.8.3 Vascular Injury

Th e dissection an d disru pt ion of vascular, lym ph atic, an d adip ose t issu es d u rin g n eck d issect ion p red isp ose to th e collect ion of flu id in th e p oten t ial space form ed u n d er n eat h t h e skin flap an d u n d er th e SCM m u scle. Postop erative serom as, form ed by t h e collect ion of serou s flu id , are relatively com m on , w it h rates as h igh as 20%. Fort u n ately, h em at om a form ation occu rs in on ly ~ 1% of cases.87,88 Flu id collect ion s are u su ally d etected on p h ysical exam an d can gen erally be evalu ated w ith US, red u cin g th e n eed for rad iation an d con trast from CT im agin g. Typ ical p resen t at ion s in clu d e loss of t h e n orm al n eck con tou r, exp an d in g n eck m ass, firm n ess t o p alp ation , an d skin ecch ym osis. Serom as are largely p reven ted by u sin g closed su ct ion d rain s aft er n eck d issect ion , bu t t h ey m ay occu r w it h in correct d rain p lacem en t, d rain clot t in g, or p rem atu re rem oval. Most sm all serom as m ay be obser ved an d allow ed t o reabsorb, bu t becau se t h ese collect ion s m ay p red isp ose th e p atien t to w ou n d in fection or d eh iscen ce, rem oval of flu id m ay som etim es be n ecessar y w ith n eed le asp irat ion or d rain rep lacem en t . Hem atom as sim ilarly in crease th e risk of w oun d com plication s an d sh ould be rem oved w ith eith er bedside evacuation or

Com plicat ion s involving th e com m on carotid artery are th e m ost life-th reaten in g en coun tered durin g n eck dissect ion . In traoperative injury sh ould be repaired prim arily w ith vascular surgery tech n iques an d specialt y con sultation , if possible. Postoperative carotid artery blow out occurs in up to 4% of radical n eck dissection s an d is t ypically associated w ith oth er w oun d com plication s, such as in fect ion , w oun d breakdow n , an d salivar y fistulas.93 Carotid blow out is associated w ith a 50% m ortalit y risk an d carries an addition al m orbidit y risk, such as n eurologic stroke from acute blood loss or in terven tion attem pts, in cludin g surgical ligation , en dovascular an giography, an d em bolization . IJV injur y is also poten tially life th reaten in g but can usually be cont rolled in traoperatively w ith relative ease. Durin g m odified or select ive n eck dissect ion , ever y attem pt sh ould be m ade to preserve th e IJV, especially in cases of bilateral n eck dissect ion . Loss of bilateral IJV flow is associated w ith h ead an d n eck edem a, elevated in tracran ial pressure, stroke, an d blindn ess.94 In addition to surgical ligation of IJV, th rom bosis of th e IJV m ay occur in up to 10 to 30% of MRND due to exten sive h an dlin g an d cath eterization leadin g to adven tit ial dam age an d in t im al dissect ion .95,96

20.8 Surgical Considerat ions, Risks, and Post operat ive Care in Lat eral Neck Dissect ion All proven or poten t ial ben efits of lateral n eck dissection in thyroid can cer m ust be w eigh ed again st th e risks an d m orbidit y of lateral n eck dissection .

20.8.1 Skin Incision and Wound Com plicat ions

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20.8.4 Nerve Injury Th e low er division s of th e facial n er ve are at risk for injur y durin g dissection of levels I an d II an d w h en raisin g skin flaps. Wh en operatin g in level I, past series h ave reported perm an en t paralysis of th e m argin al m an dibular n er ve in approxim ately 1% of cases, but rates m ay in crease to 6% in cases of m align an cy.97,98 Vagal n er ve injur y, alth ough un com m on , is particularly un desirable because it t ypically results in dysphon ia an d dysphagia due to loss of both m otor an d sen sor y fu n ct ion to th e lar yn x an d ph ar yn x, an d it h as greater m orbidit y w h en com pared w ith isolated recurren t laryn geal n er ve injur y from thyroid an d cen tral com part m en t surgery. Th e spin al accessor y n er ve in th e n eck is com posed en t irely of m otor fibers to th e SCM an d trapezius m uscles. Injur y or sacrifice to th e spin al accessor y n erve causes sh oulder droop an d w eakn ess, ran ge of m otion lim itation , “w in ged scapula,” an d pain due to adh esive capsulit is of th e sh oulder join t. With th e in creased e orts to preserve th is n er ve, in cluding departu re from routine radical n eck dissection an d select ive dissection of IIB an d VA, rates of sh oulder dysfun ct ion h ave decreased over th e past several decades. Now SND involving levels II th rough IV are associated w ith a 5% in ciden ce of postoperat ive sh oulder dysfun ct ion, th ough th is in creases to 30% w h en level V is in cluded.99 Th is dysfun ction m ay be perm an en t, alth ough patien ts can h ave at least som e return of fun ction over tim e w h en th e n er ve is n ot com pletely tran sected. Even w ith com plete tran saction , m any sym ptom s of spin al accessor y n er ve injur y m ay be am eliorated by physical th erapy an d sh oulder reh abilitation . Preven tion of injur y is best em ployed by early iden tification an d careful h an dlin g of th e n er ve. It is im portan t to recogn ize th e variable course of th e n er ve in respect to th e IJV as w ell as variable in sertion in to th e SCM m uscle.100 Addition ally, avoidan ce of m uscle relaxan ts in traoperatively an d use of a n er ve stim ulator m ay be h elpful in locatin g an d preservin g th e spin al accessor y. Wh eth er t ran sected un in ten tion ally or sacrificed, prim ar y n eurorrh aphy or cable n er ve graft in g should be attem pted. Injur y to oth er m otor n er ves in th e n eck, in cludin g th e hypoglossal n erve an d ph ren ic n erve, are relatively rare, but sim ilarly sh ould be iden tified an d repaired prim arily or w ith a graft w h en tran sected. Sym path etic ch ain injur y t ypically occurs due to com pression durin g retract ion of th e carotid sh eath in n eck dissect ion . Deficits are rare an d t ypically tem porar y but m ay result in Horn er’s syn drom e, w h ich m an ifests as ipsilateral ptosis, m iosis, an d an h idrosis.101 Morbidit y from injur y to sen sory n erves of th e n eck, in cludin g cervical rootlets, th e great auricular n er ve, an d th e lin gual n er ve, can be ver y both ersom e to patien ts an d adversely a ect satisfact ion an d qualit y of life. Sen sor y deficits t ypically h ave a greater likelih ood for recover y due to regen eration over tim e from adjacen t sen sor y n et w orks. Am putat ion n eurom as m ay develop from t ran sected sen sor y n er ves causin g firm , ten der n eck m asses an d m ay be treated w ith excision an d reim plan tation of th e n erve stum p. Th e addition of lateral n eck dissection in th e surgical treatm en t of thyroid can cer con fers sign ifican t addition al risk of com plication s an d m orbidit y w h en com pared to thyroid surgery or central com partm en t surgery alon e. Th is is especially im portan t in th e treatm en t of thyroid can cer, w h ich is

com m on ly t reated by low -volum e surgeon s in low -volum e cen ters. Sim ilar to studies dem on st ratin g im proved outcom es in h igh -volum e thyroid surgical cen ters, n eck dissection at h igh volum e cen ters h as been associated w ith im proved survival outcom es.102 Proper preoperative plan n in g, m eticulous surgical tech n ique, and early recognizan ce an d treatm en t of com plication s are m ost e ect ive in th e preven tion of com plication s in lateral n eck dissection .

20.9 Conclusion Thyroid can cer h as a h igh propen sit y for cervical lym ph n ode m etastasis, an d th e treatm en t of ch oice is largely surgical. Due to th e beh avior an d n atural course of di eren tiated thyroid can cer, th e t reatm en t of th e lateral n eck m ust be properly selected an d system atic. Th e goal is to m axim ize th e on cological an d sur vival ben efit to th e pat ien t w h ile m in im izing risks an d com plication s.

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Th e im pact of assessin g specim en adequacy an d n um ber of n eedle passes for fin e-n eedle aspiration biopsy of thyroid n odules. Th yroid 2006; 16(1); 55–60 [35] Ch ung J, Kim EK, Lim H et al. Optim al in dication of thyroglobulin m easurem en t in fin e-n eedle aspiration for detect in g lateral m etastatic lym ph n odes in patien ts w ith papillar y thyroid carcin om a. Head Neck 2014; 36(6); 795– 801 [36] Cun h a N, Rodrigues F, Curado F et al. Th yroglobulin detect ion in fin e-n eedle aspirates of cer vical lym ph n odes: a tech n ique for th e diagn osis of m etastatic di eren tiated thyroid can cer. Eur J En docrin ol 2007; 157(1); 101–107 [37] Li QK, Nugent SL, Straseski J et al. Th yroglobulin m easurem en ts in fin e-n eedle aspiration cytology of lym ph n odes for th e detection of m etastatic papillary thyroid carcinom a. Can cer Cytopath ol 2013; 121(8); 440–448 [38] Holm es BJ, Sokoll LJ, Li QK. Measurem en t of fin e-n eedle aspiration thyroglobulin levels in creases th e detect ion of m etastatic papillary thyroid carcin om a in cystic n eck lesion s. Can cer Cytopath ol 2014; 122(7); 521–526 [39] Borel AL, Boizel R, Faure P et al. Sign ifican ce of low levels of thyroglobulin in fin e n eedle aspirates from cervical lym ph n odes of patien ts w ith a h istory of di eren tiated thyroid can cer. Eur J En docrin ol 2008; 158(5); 691–698 [40] Gran i G, Fum arola A. Thyroglobulin in lym ph n ode fin e-n eedle aspiration w ash out: a system atic review an d m eta-an alysis of diagn ostic accuracy. J Clin En docrin ol Metab 2014; 99(6); 1970–1982

[41] Spen cer CA, LoPresti JS, Fatem i S, Nicolo JT. Detect ion of residual an d recurren t di eren tiated thyroid carcin om a by serum thyroglobulin m easurem en t. Thyroid 1999; 9(5); 435–441 [42] Ch iovato L, Latrofa F, Braverm an LE et al. Disappearan ce of h um oral thyroid autoim m un it y after com plete rem oval of thyroid an tigen s. An n In tern Med 2003; 139(5 Pt 1); 346–351 [43] Sapio MR, Guerra A, Posca D et al. Com bin ed an alysis of galectin -3 an d BRAFV600E im proves th e accuracy of fin e-n eedle aspiration biopsy w ith cytological fin din gs suspicious for papillar y thyroid carcinom a. En docr Relat Can cer 2007; 14(4); 1089–1097 [44] Kum agai A, Nam ba H, Akan ov Z et al. Clin ical im plication s of pre-operative rapid BRAF an alysis for papillary thyroid can cer. En docr J 2007; 54(3); 399– 405 [45] Bart olazzi A, Orlan d i F, Saggiorato E et al. It alian Th yroid Can cer St u d y Grou p (ITCSG). Galect in -3-exp ression an alysis in t h e su rgical select ion of follicu lar t hyroid n od u les w it h in d eterm in at e fin e-n eed le asp irat ion cyt ology: a p rosp ect ive m u lt ice n t re st u d y. Lan cet On col 2008; 9(6); 543– 549 [46] Xin g M, Clark D, Guan H et al. BRAF m utation testin g of thyroid fin e-n eedle aspiration biopsy specim ens for preoperative risk stratification in papillary thyroid can cer. J Clin On col 2009; 27(18); 2977–2982 [47] Fisch UP, Sigel ME. Cer vical Lym ph atic System as Visualized by Lym ph ography. An n Otol Rh in ol Lar yn gol 1964; 73; 870–882 [48] Sh ah JP, Stron g E, Spiro RH, Vikram B. Surgical gran d roun ds. Neck dissection : curren t status an d fut ure possibilities. Clin Bull 1981; 11(1); 25–33 [49] Robbin s KT, Sh ah a AR, Medin a JE et al. Com m ittee for Neck Dissect ion Classification , Am erican Head an d Neck Society. Con sen sus statem en t on th e classification an d term in ology of n eck dissection . Arch Otolaryn gol Head Neck Surg 2008; 134(5); 536–538 [50] Robbin s KT, Claym an G, Levin e PA et al. Am erican Head an d Neck Society. Am erican Academ y of Otolaryn gology–Head an d Neck Surgery. Neck dissection classification update: revision s proposed by th e Am erican Head an d Neck Society an d th e Am erican Academ y of Otolaryn gology-Head an d Neck Surgery. Arch Otolaryn gol Head Neck Surg 2002; 128(7); 751–758 [51] Hasegaw a Y, Saikaw a M. Update on th e classification an d n om en clature system for n eck dissection : revision s proposed by th e Japan Neck Dissect ion Study Group. In t J Clin On col 2010; 15(1); 5–12 [52] Robbin s KT. In dication s for select ive n eck dissection : w h en , h ow, an d w hy. On cology (W illiston Park) 2000; 14(10); 1455–1464, discussion 1467–1469 [53] Cooper DS, Doh erty GM, Haugen BR et al. Am erican Thyroid Association (ATA) Guidelin es Taskforce on Thyroid Nodules an d Di eren tiated Th yroid Can cer. Revised Am erican Th yroid Association m an agem en t guidelin es for patien ts w ith thyroid n odules an d di eren tiated thyroid can cer. Thyroid 2009; 19 (11); 1167–1214 [54] Ito Y, Jikuzon o T, Higash iyam a T et al. Clin ical sign ifican ce of lym ph n ode m etastasis of thyroid papillar y carcin om a located in on e lobe. World J Surg 2006; 30(10); 1821–1828 [55] Mach ens A, Holzh ausen HJ, Dralle H. Skip m etastases in thyroid can cer leapin g th e central lym ph n ode com partm en t. Arch Surg 2004; 139(1); 43–45 [56] Eskan der A, Merdad M, Freem an JL, W itterick IJ. Pattern of spread to th e lateral n eck in m etastatic w ell-di eren tiated thyroid can cer: a system atic review an d m eta-analysis. Thyroid 2013; 23(5); 583–592 [57] Merdad M, Eskan der A, Kroeker T, Freem an JL. Predictors of level II an d Vb n eck disease in m etastatic papillar y thyroid can cer. Arch Otolaryn gol Head Neck Surg 2012; 138(11); 1030–1033 [58] Noguch i M, Kin am i S, Kin osh ita K et al. Risk of bilateral cervical lym ph n ode m etastases in papillary thyroid can cer. J Surg On col 1993; 52(3); 155–159 [59] Sh ah a AR. Im plication s of progn ostic factors an d risk groups in th e m an agem en t of di eren tiated thyroid can cer. Lar yn goscope 2004; 114(3); 393–402 [60] Mazzaferri EL, Jh ian g SM. Lon g-term im pact of in itial surgical an d m edical th erapy on papillary an d follicular thyroid can cer. Am J Med 1994; 97(5); 418–428 [61] Bh attach ar yya N. A population -based an alysis of sur vival factors in di eren tiated an d m edullary thyroid carcinom a. Otolaryn gol Head Neck Surg 2003; 128(1); 115–123 [62] Podn os YD, Sm ith D, Wagm an LD, Ellen h orn JD. Th e im plication of lym ph n ode m etastasis on sur vival in patien ts w ith w ell-di eren tiated thyroid can cer. Am Surg 2005; 71(9); 731–734 [63] Zaydfudim V, Feurer ID, Gri n MR, Phay JE. Th e im pact of lym ph n ode involvem en t on sur vival in patien ts w ith papillar y an d follicular thyroid carcin om a. Surgery 2008; 144(6); 1070–1077, discussion 1077–1078 [64] Carling T, Carty SE, Ciarleglio MM et al. Am erican Thyroid Association (ATA) Design an d Feasibility of a Prospective Ran dom ized Con trolled Trial of

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Surgical Managem ent of the Lateral Neck in Thyroid Cancer

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Prophylactic Cen tral Lym ph Node Dissect ion for Papillary Th yroid Carcin om a. Thyroid 2011 Leboulleux S, Rubino C, Baudin E et al. Progn ostic factors for persisten t or recurren t disease of papillar y thyroid carcinom a w ith n eck lym ph n ode m etastases an d/or tum or exten sion beyon d th e thyroid capsule at in itial diagn osis. J Clin En docrin ol Metab 2005; 90(10); 5723–5729 Hay ID, Th om pson GB, Gran t CS et al. Papillary thyroid carcin om a m an aged at th e Mayo Clin ic durin g six decades (1940–1999): tem poral tren ds in in itial th erapy an d long-term outcom e in 2444 con secutively treated patien ts. World J Surg 2002; 26(8); 879–885 Du cou dray R, Trésallet C, God iris-Pet it G, Tissier F, Leen h ard t L, Men egau x F. Prop hylact ic lym p h n od e d issect ion in p ap illar y t hyroid carcin om a: is t h ere a p lace for lateral n eck d issect ion ? World J Su rg 2013; 37(7); 1584– 1591 Lim YS, Lee JC, Lee YS et al. Lateral cervical lym ph n ode m etastases from papillar y thyroid carcin om a: predict ive factors of n odal m etastasis. Surgery 2011; 150(1); 116–121 Fukui Y, Yam akaw a T, Tan iki T, Num oto S, Miki H, Mon den Y. Sen tin el lym ph n ode biopsy in patien ts w ith papillar y thyroid carcin om a. Can cer 2001; 92 (11); 2868–2874 Bon n et S, Hartl D, Leboulleux S et al. Prophylactic lym ph n ode dissection for papillar y thyroid can cer less th an 2 cm : im plication s for radioiodin e treatm en t. J Clin En docrin ol Metab 2009; 94(4); 1162–1167 Sippel RS, Ch en H. Con troversies in th e surgical m an agem en t of n ew ly diagn osed an d recurren t/residual thyroid can cer. Th yroid 2009; 19(12); 1373– 1380 Grebe SK, Hay ID. Thyroid can cer n odal m etastases: biologic sign ifican ce an d th erapeutic con sideration s. Surg On col Clin N Am 1996; 5(1); 43–63 Ran dolph GW, Duh QY, Heller KS et al. Am erican Thyroid Association Surgical A airs Com m ittee’s Taskforce on Th yroid Can cer Nodal Surgery. Th e progn ostic sign ifican ce of n odal m etastases from papillar y thyroid carcin om a can be stratified based on th e size an d n um ber of m etastatic lym ph n odes, as w ell as th e presen ce of extran odal exten sion . Th yroid 2012; 22(11); 1144–1152 Ito Y, Urun o T, Nakan o K et al. An observation trial w ith out surgical treatm en t in patien ts w ith papillary m icrocarcin om a of th e thyroid. Th yroid 2003; 13 (4); 381–387 Maden ci AL, Caragacian u D, Boeckm an n JO, Stack BC, Jr, Sh in JJ. Lateral n eck dissection for w ell-di eren tiated thyroid carcinom a: a system atic review. Lar yn goscope 2014; 124(7); 1724–1734 Wu G, Fraser S, Pai SI, Farrag TY, Laden son PW , Tufan o RP. Determ in in g th e exten t of lateral n eck dissection n ecessar y to establish region al disease con trol an d avoid reoperation after previous total thyroidectom y an d radioactive iodin e for papillar y thyroid can cer. Head Neck 2012; 34(10); 1418–1421 Hasn ey CP, Am edee RG. W h at is th e appropriate exten t of lateral n eck dissection in th e treatm en t of m etastatic w ell-di eren tiated thyroid carcinom a? Lar yn goscope 2010; 120(9); 1716–1717 Roben sh tok E, Fish S, Bach A, Dom ín guez JM, Sh ah a A, Tuttle RM. Suspicious cervical lym ph n odes detected after thyroidectom y for papillar y thyroid can cer usually rem ain stable over years in properly selected patien ts. J Clin En docrin ol Metab 2012; 97(8); 2706–2713 Ellen h orn JD, Sh ah JP, Bren n an MF. Im pact of th erapeutic region al lym ph n ode dissection for m edullary carcin om a of th e thyroid glan d. Surgery 1993; 114(6); 1078–1081, discussion 1081–1082 Mach ens A, Hauptm an n S, Dralle H. Prediction of lateral lym ph n ode m etastases in m edullary thyroid can cer. Br J Surg 2008; 95(5); 586–591

[81] Kloos RT, En g C, Evan s DB et al. Am erican Th yroid Association Guidelin es Task Force. Medullar y thyroid can cer: m an agem en t guidelin es of th e Am erican Thyroid Association . Thyroid 2009; 19(6); 565–612 [82] Mach ens A, Schn eyer U, Holzh ausen HJ, Dralle H. Prospects of rem ission in m edullar y thyroid carcinom a accordin g to basal calcitonin level. J Clin En docrin ol Metab 2005; 90(4); 2029–2034 [83] Pelizzo MR, Bosch in IM, Bern an te P et al. Natural h istory, diagn osis, treatm en t an d outcom e of m edullary thyroid can cer: 37 years experien ce on 157 patien ts. Eur J Surg On col 2007; 33(4); 493–497 [84] Dem eter JG, De Jon g SA, Law ren ce AM, Paloyan E. An aplastic thyroid carcin om a: risk factors an d outcom e. Surgery 1991; 110(6); 956–961, discussion 961–963 [85] Sm allridge RC, Ain KB, Asa SL et al. Am erican Th yroid Association An aplastic Thyroid Can cer Guidelin es Taskforce. Am erican Thyroid Association guidelin es for m an agem en t of patien ts w ith an aplastic thyroid can cer. Thyroid 2012; 22(11); 1104–1139 [86] Yii NW , Patel SG, William son P, Breach NM. Use of apron flap in cision for n eck dissection . Plast Recon str Surg 1999; 103(6); 1655–1660 [87] Joh n son JT, Cum m ings CW . Hem atom a after h ead an d n eck surgery —a m ajor com plication ? Otolaryn gology 1978; 86(2); ORL171–ORL175 [88] Cabra J, Herran z J, Mon ux A et al. Postoperative com plication s in fun ction al n eck dissection . Oper Tech Otolaryn gol–Head Neck Surg 1993; 4(8); 318–321 [89] Crum ley RL, Sm ith JD. Postoperative chylous fistula preven tion an d m an agem en t. Lar yn goscope 1976; 86(6); 804–813 [90] Th aw ley SE. “How I do it”—h ead an d n eck. A targeted problem an d its solution . Chylous fistula preven tion an d m an agem en t. Lar yn goscope 1980; 90(3); 522–525 [91] Spiro JD, Spiro RH, Stron g EW . Th e m an agem en t of chyle fistula. Lar yn goscope 1990; 100(7); 771–774 [92] Valen tin e CN, Barresi R, Prin z RA. Som atostatin an alog treatm en t of a cervical th oracic duct fistula. Head Neck 2002; 24(8); 810–813 [93] Sh um rick DA. Carotid artery rupture. Lar yn goscope 1973; 83(7); 1051–1061 [94] Weiss KL, Wax MK, Haydon RC, III, Kaufm an HH, Hurst MK. In tracran ial pressure ch anges durin g bilateral radical n eck dissect ion s. Head Neck 1993; 15 (6); 546–552 [95] Cotter CS, Strin ger SP, Lan dau S, Man cuso AA, Cassisi NJ. Paten cy of th e in tern al jugular vein follow ing m odified radical n eck dissection . Lar yn goscope 1994; 104(7); 841–845 [96] Leon tsin is TG, Currie AR, Man n ell A. In tern al jugular vein th rom bosis follow in g fun ct ion al n eck dissection . Lar yn goscope 1995; 105(2); 169–174 [97] Preuss SF, Klussm an n JP, Wittekin dt C, Drebber U, Beutn er D, Gun tin asLich ius O. Subm an dibular glan d excision : 15 years of experien ce. J Oral Maxillofac Surg 2007; 65(5); 953–957 [98] Mun ir N, Bradley PJ. Diagn osis an d m an agem en t of n eoplastic lesion s of th e subm an dibular triangle. Oral On col 2007 [99] Cappiello J, Piazza C, Giudice M, De Maria G, Nicolai P. Sh oulder disability after di eren t selective n eck dissect ion s (levels II-IV versus levels II-V): a com parative study. Laryn goscope 2005; 115(2); 259–263 [100] Hollin gsh ead W H. An atom y for Surgeon s: Th e Head an d Neck. 3rd ed 1982 Lippin cott William s & W ilkin s Ph iladelph ia [101] Prim MP, De Diego JI, Verdaguer JM, Sastre N, Raban al I. Neurological com plication s follow in g fun ct ion al n eck dissection . Eur Arch Otorh in olar yn gol 2006; 263(5); 473–476 [102] Eskan der A, Merdad M, Irish JC et al. Volum e-outcom e association s in h ead an d n eck can cer treatm en t: A system atic review an d m eta-an alysis. Head Neck 2013

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Part 4 Parat hyroid Diseases

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21 Pathophysiology of the Parathyroid Glands

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22 Parat hyroid Carcinom a

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23 Parat hyroid Im aging

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24 Renal Hyperparathyroidism

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Parathyroid Diseases

21 Pat hophysiology of t he Parat hyroid Glands Brendan C. Stack, Jr. and Galimat Khaidakova

21.1 Int roduct ion

21.2.1 Prim ary Hyperparat hyroidism

Th e parathyroid glan ds are four glan ds located on th e posterior aspect of th e thyroid. Th e parathyroids are sm all (< 50 m g each ) an d produce on ly on e h orm on e, w h ich is kn ow n as parathyroid h orm on e (PTH) or parath orm on e. PTH fun ction s to m ain tain calcium h om eostasis by act in g on th e ren al t ubules an d th e calcium stores in th e skeletal system , an d in directly on th e gast roin testin al tract th rough 1,25-dih dyroxyvitam in D. Th ese glan ds an d th eir fun ct ion appear to be sim ple at first glan ce; h ow ever, clin ician s involved in th e treatm en t of patien ts w ith parathyroid disorders quickly realize th at th e path ophysiology involved can be quite com plex. To accurately diagn ose an d adequately m an age patien ts w ith parathyroid diseases, on e m ust h ave a th orough un derstan din g of th e path ophysiology involved. Th is ch apter review s th e path ological processes th at occur w ith th e parathyroids.

Pat hology

21.2 Hyperparat hyroidism Th e m ost com m on deran gem en t in parathyroid fun ction is th e excess production of parathyroid h orm on e, w h ich is called hyperparathyroidism (HPT). Hyperparathyroidism w as described sim ultan eously in Europe an d th e Un ited States in th e 1920s.1 Patien ts in itially presen ted w ith sign ifican t ren al an d skeletal m an ifestation s, in cluding n eph rolith iasis, ren al failure, osteoporosis, an d path ological fract ures. With our in creased understan din g of th is disease process, an d w ith th e addition of calcium to routin e m etabolic pan els, th e clin ical presen tation h as ch anged drastically. Most pat ien ts curren tly diagn osed w ith hyperparathyroidism are asym ptom atic.2 Alth ough th is early detect ion is an accom plish m en t of screen in g in m odern m edicin e, th e t reatm en t of asym ptom atic patien ts presen ts a th erapeutic dilem m a. Hyperparathyroidism is defin ed as prim ar y, secon dary, or tert iar y based on th e etiology. Prim ar y hyperparathyroidism im plies in appropriately elevated levels of PTH w h en com pared w it h t h e seru m calciu m . In t h e p hysiological st ate, hyp ercalcem ia red u ces th e PTH level by n egative feed back, act in g t h rough calciu m -sen sing recept ors (CaSRs) on t h e p arat hyroid glan d s. Secon d ar y h yp erp arathyroid ism is an elevated PTH level d u e to a lack of n egative feed back. Th e m ost com m on d isease p rocess lead in g to ch ron ic secon d ar y hyp erp arat hyroid ism is vitam in D d eficien cy or ch ron ic ren al failu re. Ter tiar y hyp erp arathyroid ism occu rs w h en glan d s a ected by secon d ar y hyp erp arat hyroid ism h ave been st im u lated t o t h e exten t th at th e glan d s becom e au ton om ou s an d are n o lon ger govern ed by t h e n orm al feed back m ech an ism s from CaSRs. Even if th e u n d erlyin g p ath op hysiology is corrected , th e excess p rod u ct ion of PTH p ersists. Th e classic exam p le of tert iar y h yp erp arat hyroid ism occu rs in a p at ien t w h o, h avin g secon d ar y hyp erp arat hyroid ism d u e t o ch ron ic ren al failu re u n d ergoes a ren al t ran sp lan t, an d th e hyp erp arathyroid state rem ain s.

Prim ar y hyperparathyroidism (PHPT) is hypercalcem ia secon dar y to excess PTH product ion from a dysfu n ct ion al glan d or glan ds, an d is th e m ost com m on cause of hypercalcem ia in th e am bulator y sett in g.3 Prim ar y hyperparathyroidism a ects rough ly 1% of th e adult populat ion , an d th e in ciden ce in creases w ith age. Wom en are a ected at least t w ice as often as m en .3,4,5,6 PHPT can be attributable to a sin gle aden om a (80– 90% of cases), four-glan d hyperplasia (5–10%), double aden om as (4–6%), an d rarely parathyroid carcin om a (< 1%) ( Fig. 21.1 an d Fig. 21.2).7,8,9,10,11,12,13 Gen etic alteration s h ave been sh ow n to cont ribute to th e developm en t of prim ar y hyperparathyroidism . Tw o specific gen et ic m utation s h ave been dem on strated in n on fam ilial parathyroid aden om as.1,12,14,15,16 Decreased expression of th e m ultiple en docrin e n eoplasia t ype 1 (MEN1) tum or suppressor gen e h as been foun d in up to 20% of th ese aden om as. Activation of th e cyclin D1 (CCND1)/PRAD1 on cogen e results in overproduction of cyclin D1 an d is found in up to 40% of aden om as. Parathyroid aden om as w ith th ese gen et ic alteration s are hypercellular an d h ave calcium -sen sing receptors th at do n ot fun ction properly. Th e CaSR plays an im portan t role in calcium h om eostasis. Th is receptor is foun d in abun dan ce on th e surface of th e n orm al parathyroid glan d in addition to m any oth er location s in th e body, in cludin g th e ren al tubules, bon e m arrow, osteoclasts, breast tissue, parafollicular cells of th e thyroid, an d G cells in th e gastric m ucosa. Aden om atous cells h ave a decreased con cen tration of calcium -sen sing receptors com pared w ith n orm al cells, an d h ave altered set poin ts, w h ich allow for in appropriate product ion of PTH despite n orm al or h igh serum calcium levels.2,3,17,18,19

Clinical Manifest at ions Th e clin ical spectrum of PHPT involves m ultip le organ system s. Ren al m an ifestat ion s are th e secon d m ost com m on an d occur in 20 to 30% of th ese patien ts.7 Neph rolith iasis accoun ts for virtually all of th e kidn ey-related com plication s. PTH in creases ren al calcium absorption , ren al ph osph orus excretion , an d activit y of 1α -Hydroxylase. 1 α -Hydroxylase converts vitam in D to its active form , w h ich in creases in testin al absorpt ion of calcium . Th e excess of filtered calcium com pared w ith th at absorbed leads to hypercalciuria an d th e predisposition to calcium ston es. Hyperparathyroidism also leads to a decrease in th e glom erular filtration rate an d a m ild m etabolic acidosis. Neph rocalcin osis is a rare com plication of hyperparathyroidism an d is di use calcification of th e ren al t ubular system an d paren chym a, w h ich can be seen on a plain radiograph .1 Skeletal m an ifestat ion s of PHPT are th e m ost com m on w h en th e sym ptom of bon e pain is in cluded. Osteitis fibrosis cystica, Brow n’s t um ors, an d fractures w ere com m on present in g en t ities w ith hyperparathyroidism in th e past. With earlier

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Pathophysiology of t he Parathyroid Glands detect ion , th ese h ave often been replaced by osteopenia or gen eralized bon e dem in eralization an d bon e pain . Th e osteopen ia associated w ith PHPT cont in ues to carr y a fract ure rate th at is greater th an th at in con trols. In th e curren t form of th e disease, th is gen eralized bon e loss can n ot be visualized w ell on plain radiograph s, but it can be iden tified early w ith bon e den sitom etr y. A dual en ergy X-ray absorptiom etr y (DEXA) scan is used to assess bon e den sit y an d is t ypically reported for th e lum bar spin e, fem oral n eck, an d distal radius. Hyperparathyroidism decreases bon e den sit y in cort ical bon e m ore th an trabecular bon e, an d th erefore th e distal radius is often th e m ost a ected. Th e bon e den sit y is reported as a T-score, w h ich gives th e den sit y as a stan dard deviation from n orm al, an d a T-score of – 2.5 (th e defin in g score for th e start of osteoporosis) is often used as an in dication for surgical in terven t ion on th e parathyroids.2,4,20 Gastroin testin al sym ptom s are less specific but are part of th e clin ical pict ure of HPT. Pan creatit is, peptic ulcer disease, constipation , n ausea, an d em esis h ave all been described. Gastroesoph ageal reflux is m ost com m on ly reported, alth ough n o clear m ech an ism h as been dem on strated. Th ere are several “som atic” sym ptom s associated w ith HPT; th ey are n on specific an d in clude depression , im paired cogn ition , fatigue, m alaise, sleep disorders, an d irritabilit y. Alth ough th ese sym ptom s are di cult to ch aracterize, th ey stress th e im portan ce of obtain in g a th orough n europsych iatric h istor y since th ese sym ptom s h ave been sh ow n to im prove after correct ion of th e un derlying hyperparathyroidism .4,7,21,22,23,24

Evaluat ion

Fig. 21.1 (a) Parathyroid adenoma in vivo. A superior Babcock retracts the thyroid gland anteriorly, and an inferior Babcock retracts the parathyroid adenom a. (b) Histology of parathyroid adenom a surrounding a rem nant of norm al parathyroid tissue.

Prim ar y hyperparathyroidism can be diagnosed w ith precision w ith a serum calcium level, serum PTH level, 24-h our urin ary calcium an d creatin in e, an d an adequate patien t h istory. If th e seru m album in levels are n orm al, total serum calcium is preferred an d m ore reliable th an ion ized calcium .25 Assays th at m easure in tact, biologically active PTH are preferred w h en com pared w ith older m eth ods of m easurin g fragm en ts of th e PTH m olecule. An elevated serum calcium level in the presen ce of elevated levels of parathyroid h orm on e is virtu ally diagnost ic for prim ar y hyperparathyroidism . Th ere are a few exception s th at n eed to be con sidered. Th iazide diuretics an d lith ium

Fig. 21.2 (a) Gross specim en of four-gland hyperplasia. (b) Histology of a hyperplastic parathyroid gland.

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Parathyroid Diseases Table 21.1 Indications for parathyroidectom y in asym ptomatic patients according to 2008 National Institutes of Health guidelines Param eter

Indication

Serum calcium

> 1 m g/dL above norm al range

Age

< 50 years old

Creatinine clearance

< 60

Osteoporosis

T-score < –2.5 standard deviation (forearm )

Neuropsychiatric

Severe psychoneurological disorder

Com pliance

Poor compliance

Renal com plications

Nephrocalcinosis

excess can produce laborator y fin din gs sim ilar to prim ar y hyperparathyroidism an d sh ould be investigated in th e pat ien t h istory.3,26 Tw en t y-four-h our urin ar y calcium an d creatin in e excret ion is im portan t in th e evaluation of hyperparathyroidism . Th ese laborator y results can rule out th e possibilit y of a rare condition kn ow n as fam ilial hypocalciuric hypercalcem ia (FHH) (see discussion later in th e ch apter).20 Urin ar y calcium an d creatin in e excretion can also h elp w ith determ in in g progn osis because total 24-h our calcium excretion > 400 m g/24 h is associated w ith an in crease in ren al com plication s.4 St udies h ave also suggested a role for vitam in D testin g, w h ich can h elp w ith th e evaluation of persisten t elevation of PTH levels postoperatively an d m ay h elp iden tify patien ts th at are at risk for secon dar y HPT an d postoperat ive hypocalcem ia.27,28,29 All pat ien ts w h o are diagn osed w ith prim ary hyperparathyroidism by laborator y data w arran t a DEXA scan to assess bon e m in eral den sit y. Th is w ill determ in e th e degree of secon dary osteopen ia an d risk of im pen din g fract ure. Any pat ien ts w h o h ave n eph rolith iasis w ith calcium ston es, path ological fractures, or sign ifican t osteoporosis sh ould be w orked up for hyperparathyroidism w ith a serum calcium an d PTH level to ru le out hyperparathyroidism as a cause.3

Managem ent Th e t ypical clin ical presen tation of PHPT h as ch anged dram atically sin ce its description in th e 1920s. Wh en th is con dition w as first described, patien ts presen ted w ith th e classic “ren al ston es, pain ful bon es, abdom in al groan s, psych ic overton es, m oan s, an d fatigue.”27 With in creased un derstan din g of PHPT an d th e addition of calcium to routin e m etabolic pan els, patien ts are n ow bein g iden tified m uch earlier in th eir clin ical course. It is estim ated th at on ly 20 to 30% of con tem porary patien ts w ith PHPT presen t w ith sign ifican t sym ptom s.2,3,4,30 Many argue th at a larger n um ber of patien ts are act ually sym p tom at ic but presen t w ith n on specific sym ptom s, in cluding depression , fatigue, bon e pain , or an orexia. Th is debate aside, 60 to 80% of pat ien ts w h o presen t w ith prim ar y hyperparathyroidism presen tly are asym ptom atic or h ave n on specific sym p tom s.2,7,30 Th is can leave practit ion ers w ith th e th erapeut ic dilem m a of w h ich patien ts w arran t treatm en t . Th is dilem m a h as been th e topic of m eetin gs an d recom m en dation s from th e Nation al In stitutes of Health (NIH) as w ell as th e Am erican Association of Clin ical En docrin ologists an d Am erican Association of En docrin e Surgeon s. It h as been

com m on ly accepted th at pat ien ts present in g w ith classic sym p tom s of hyperparathyroidism , in cluding fracture, n eph rolith iasis, an d n eurom uscular com plain ts, w arran t treatm en t . More recen t reports h ave in dicated th at asym ptom at ic hyperparathyroid patien ts h ave a lon g-term in crease in cardiovascular disease an d m align an cy.4,29,30 Furth erm ore, 23 to 62% of patien ts w h o presen t w ith out sym ptom s becom e sym ptom atic w ith in 10 years of presen tation .4 For th ese reason s, in 2008 an NIH con sen sus pan el m et an d m odified its th ird con sen sus guidelin es an d recom m en ded treatm en t for asym ptom atic pat ien ts if any of th e follow in g apply: serum calcium is > 1 m g/dL above th e n orm al ran ge, age is < 50, creatin in e is < 60 m L/m in , th e patien t can n ot participate in follow -up, severe psych on eurological disorder, or oth er com plication s of PHPT, in cluding n eph rocalcin osis or osteoporosis (T-score < – 2.5 stan dard deviation [SD] at th e lum bar spin e, h ip, or w rist) ( Table 21.1).30 An in -depth discussion of all th e surgical an d m edical treatm en t option s can be foun d in oth er ch apters, so curren t treatm en t option s an d recom m en dation s are on ly briefly addressed h ere. Th ere are n o lon g-term studies dem on st ratin g th e e cacy of m edical m an agem en t or observation in th ese patien ts. Several m edication s target th e e ects of hyperparathyroidism w ith out treatin g th e un derlyin g problem . Bisph osph on ates h ave been sh ow n to in crease bon e m in eral den sit y in patien ts w ith hyperparathyroidism , w ith n o sign ifican t e ect on PTH levels.31 Sim ilarly, estrogen replacem en t can stabilize bon e loss in postm en opausal w om en w ith PHPT.32 Furosem ide can h elp to reduce serum calcium levels acutely. Calcim im etic m edication s are an in triguin g class of m edication s th at target th e problem in hyperparathyroidism . With th eir m im etic act ivit y th ese m edication s give n egative feedback on th e calcium -sen sing receptors of th e parathyroids an d can reduce PTH production . On e of th ese m edication s, cin acalcet, h as been sh ow n to reduce PTH levels an d n orm alize serum calcium .33,34 Calcim im etics h ave sh ow n prom ising results, an d, alth ough studies h ave foun d th em to be less e ect ive th an th e gold standard of parathyroidectom y at decreasin g PTH levels, th ere are n o statist ically sign ifican t di eren ces in calcium an d ph osph ate levels betw een th e t w o groups 1 m on th after treatm en t .4,33 If patien ts w ith PHPT are m an aged m edically, th ey require clin ical follow -up, bian n ual serum calcium levels, an n ual serum creatin in e levels, an d an n ual bon e den sitom et r y.1 Associated “som atic” sym ptom s m ay n ot abate w ith drug th erapy, an d patien ts in cur th e cost of ch ron ic ph arm acoth erapy.1 Th e cost of follow -up after several years of m edical m an agem en t for prim ar y hyperparathyroidism h as been sh ow n to exceed th e costs of successful surgical m an agem en t.35 Surgical m an agem en t h as been reported to be 95 to 98% curative, w ith com plication rates of 1 to 2% in experien ced h an ds. It is for th ese reason s th at th e recen t position statem en t from en docrin ologists an d en docrin e surgeon s recom m en ded surgical in terven tion in pat ien ts w h o m eet th e preceding criteria for treatm en t .

Parat hyroid Carcinom a An oth er cause of prim ary hyperparathyroidism th at w arran ts discussion is parathyroid carcin om a (PTC) ( Fig. 21.3). Th is is a rare condition th at accoun ts for < 1% of hyperparathyroidism . It a ect s m en an d w om en equally, an d th e average age of presen tation is 55 years.

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Pathophysiology of t he Parathyroid Glands calcium , parathyroid h orm on e, an d carcin oem bryon ic an tigen (CEA), w ith an in crease bein g an om in ous sign of recurren ce.

21.3 Secondary Hyperparat hyroidism

Fig. 21.3 Histology of parathyroid carcinoma with invasion of the capsule.

On e ch allenge is th at th e diagnosis is rarely apparen t on in itial presen tat ion because th e sym ptom s are th e sam e as ben ign causes of hyperparathyroidism . Con sisten t fin din gs in parathyroid carcin om a are preoperative calcium an d PTH levels m uch h igh er th an th ose t ypically foun d w ith ben ign disease.36 Th e calcium levels for PTC are often > 14.0 m g/dL, an d PTH levels are com m on ly > 300 n g/dL. Th e tu m or itself is usually larger th an th e t ypical aden om a, on average m easurin g 2 to 3 cm in diam eter. A palpable n eck m ass is presen t in up to 70% of patien ts foun d to h ave PTC, w h ich is n ot ch aracteristic of benign disease.37 Cer vical lym ph aden opathy, w h ich sh ould raise suspicion for a m align an t process, is foun d in on e-th ird of patien ts presen tin g w ith PTC. Pat ien ts w ith parathyroid carcin om a are also m ore com m on ly sym ptom atic. In con trast to repor ts of 20 to 30% of pat ien ts w ith prim ar y hyperparathyroidism w h o presen t w ith sym ptom s, in on e series eigh t of n in e patien ts w h o w ere foun d to h ave parathyroid carcin om a in traoperatively h ad “som atic” sym ptom s at presen tation .16,36,37 In traoperative fin din gs th at are con sisten t w ith parathyroid carcin om a in clude adh eren ce to or invasion of surroun din g struct ures (thyroid lobe or strap m uscles), fibrosis, n odularit y, in duration , an d gray color in stead of th e t ypical tan aden om a. Careful atten tion to th ese ch aracteristics is im portan t durin g surgery because th e treatm en t of ch oice for parathyroid carcin om a is w ide surgical excision . Adjuvan t treatm en ts, such as extern al beam radiation an d ch em oth erapy, h ave n ot been show n to im prove sur vival. In traoperative frozen path ology is n ot reliable, m akin g careful in t raoperative exam in ation param oun t . Surgical excision sh ould in clude en bloc excision of th e tum or, in cludin g th e ipsilateral thyroid lobe an d straps if involved.37,38,39 Con sideration sh ould be given to prim ar y level VI dissect ion if th ere is a con cern for lym ph aden opathy discovered at th e t im e of surgery. Parathyroid carcin om a carries a poor progn osis, w ith th e 5year sur vival repor ted as low as 49%. In terestin gly, th ese patien ts usually die as a result of th eir un con trolled hypercalcem ia as opposed to local or m etastatic disease. Harari et al 38 reported a recurren ce rate of 49 to 60% after surgical resection . Th is recurren ce can be determ in ed by m on itorin g serum

Any disorder th at results in hypocalcem ia or vitam in D deficien cy w ill elevate PTH levels an d can ser ve as a secon dary cause of hyperparathyroidism . Classically th is condition is caused by ch ron ic ren al failure, an d th e resultin g alteration s in vitam in D, ph osph orus, an d calcium . Ch ron ic ren al failure results in decreased levels of 1,25-dihydroxyvitam in D, hyperph osph atem ia, an d hypocalcem ia. As ren al fun ction declin es, th ere is loss of available 1 α -Hydroxylase, resultin g in a decrease in active vitam in D (1,25-dihydroxyvitam in D) levels. Th is occurs w h en th e glom erular filtration rate (GFR) drops below 60 m L/m in . Sign ifican t in creases in th e PTH level develop later in th e progression , w h en th e GFR drops to 30 m L/m in , an d sign ifican t hyperph osph atem ia occurs w ith a GFR of 20 m L/m in or low er.1,40,41,42 Th e elevation in ph osph orus levels an d th e hypocalcem ia th at develops from decreased vitam in D act to furth er in crease PTH secretion . Early in th e disease process, th e elevated PTH is appropriate an d ser ves to in crease ph osph ate excret ion an d calcium absorption in th e kidn ey an d coun terbalan ces th e m etabolic deran gem en t. How ever, as ren al disease progresses an d th e filtered fraction of ph osph ate decreases, th e abilit y of PTH to in crease ph osph ate excret ion is saturated, an d th e ph osph ate released from bon e as a result of elevated PTH exacerbates th e hyperph osph atem ia.43 Over tim e, ch ron ic stim ulation leads to hyperplasia of th e parathyroid glan ds. Histological studies from resected glan ds of patien ts w ith secon dary hyperparathyroidism sh ow n odular an d di use hyperplasia.40,41 Decreased expression of th e CaSR h as been dem on strated in both t ypes of hyperplasia but is m ore eviden t in areas of n odular hyperplasia.44,45,46 Th is decreased expression of th e CaSR results in decreased n egative feedback an d explain s w hy PTH levels rem ain elevated w h en calcium levels are n orm al or elevated. Historical sym ptom s of secondar y hyperparathyroidism in clude ren al osteodystrophy, w ith spon tan eous fract ures, bon e pain , radiograph ic bon e lesion s, an d extraskeletal calcificat ion s. How ever, as w ith prim ary hyperparathyroidism , pat ien ts n ow often presen t prior to th e on set of any sign ificant sym ptom s.47 Calciphylaxis, coron ary artery calcification , an d psych on eurological disorders are m ore serious m an ifestation s seen in secon dar y hyperparathyroidism . Calciphylaxis an d coron ary artery calcification h ave been sh ow n to be associated w ith elevated calcium –ph osph orus product . A product over 70 h as been correlated w ith an in creased risk of developin g cerebrovascular acciden t or death .48,49 Secondary hyperparathyroidism is a diagnosis based on the clinical picture and m etabolic derangem ents. The presence of hypocalcem ia and elevated PTH is diagnostic of secondary hyperparathyroidism . When phosphorus levels are also elevated, this points to chronic renal failure as the etiology. If phosphorus levels are low, other anom alies, such as vitam in D deficiency, should be considered. Vitam in D deficiency is an increasingly prevalent cause for secondar y hyperparathyroidism w ith decreasing sun exposure and an aging population.28,29,50

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Parathyroid Diseases Preven t ion is t ruly th e best treatm en t of hyperparathyroidism in ch ron ic ren al failure. Th is is accom plish ed by aggressive phosph orus m an agem en t early in th e progression of ren al failure an d adequate replacem en t of vitam in D. Low ph osph orus diets and the use of phosphorus-binding drugs that prevent enteral absorption can decrease the hyperphosphatem ia. Phosphorus binders containing alum inum are currently avoided because they can be toxic to bones. The current recom m endation is the use of calcium containing phosphorus binders as long as the calcium -phosphorus product is less than 55 m g 2 /m L2 . If the product exceeds 55, or if serum calcium is elevated over 10.2 m g/dL, alternatives such as sevelam er are recom m ended because they have no calcium or alum inum .51 This recom m endation is an attem pt to keep the calcium –phosphorus product < 70 m g 2 /m L2 , at all costs, because coronary artery calcification and calciphylaxis have been show n to occur at these levels.49 Vitam in D or its an alogues can be given to reduce PTH levels. Vitam in D can act on th e parathyroid to reduce PTH, but it can h ave th e un desired e ect of elevatin g serum calcium an d ph osphate. Th erefore, vitam in D form ulation s (e.g., calcitriol) are on ly recom m en ded w h en ph osph orus is < 6 m g/m L. New er vitam in D an alogues are available th at can reduce PTH w ith out undesired e ects. Pat ien ts takin g on e such an alogue, paricalcitol, experien ced few er episodes of hypercalcem ia an d a m ore rapid reduct ion in PTH as com pared w ith pat ien ts takin g calcitriol.51,52,53 Calcim im etic m edication s, such as cin acalcet, h ave prom ise because th ey can suppress th e parathyroid glan ds. Th e in dication s for surgical in terven tion in secondar y hyperparathyroidism are n ot as clear as th ose for prim ar y disease. Th ere are n o Nation al In stit utes of Health guidelin es addressin g surgical in terven tion . Curren tly accepted in dication s for surgery in clude failure of m edical m an agem en t, calcium –ph osph orus products persisten tly > 70 despite m edical in terven tion , serum calcium > 11 m g/dL, serum PTH > 800 pg/m L, severe bon e disease, an ticipated ren al tran splan t, or severe pruritus.47 Som e relative surgical in dication s for secon dary hyperparathyroidism in clude th e follow in g: ● Failure of m edical m an agem en t ● Hypercalcem ia ● Hypercalciuria ● PTH > 800 ● Hyperph osph atem ia w ith calcium –ph osph orus product > 70 ● Severe bon e disease ● Severe sym ptom s ● An ticipated ren al t ran splan t Surger y for correction of secon dary hyperparathyroidism involves subtotal parathyroidectom y w ith excision of th ree or three-an d-on e-h alf glan ds, or total parathyroidectom y w h ere all four glan ds are excised an d on e of th e glan ds is autot ran splan ted in th e stern ocleidom astoid m uscle in th e n eck or in th e brach ioradialis m uscle in th e n on dom in an t or sh un tless forearm . Cr yopreser vation m ay be con sidered w h en perform in g eith er procedure as an option for hypoparathyroidism .

21.4 Tert iary Hyperparat hyroidism Th e defin ition of tert iar y hyperparathyroidism is n ot straigh tforw ard. Tert iary HPT results from progression of secon dary

HPT an d is th e least prevalen t. In tertiar y HPT, PTH, calcium , an d ph osph orus levels are elevated. It is rare for th is con dition to occur outside of ch ron ic ren al failure. Th e distin ct ion betw een secondar y HPT an d tert iar y HPT is th at, in tert iar y HPT, th e glan ds h ave becom e auton om ous. Th is m an ifests by con tin uation of th e elect rolyte derangem en ts despite correction of th e un derlyin g ren al con dition . For exam ple, if a pat ien t w ith ch ron ic ren al failure an d hyperparathyroidism un dergoes a ren al t ran splan t an d con tin ues to h ave hyperparathyroidism , th is w ould be classified as tert iary HPT. Th e in dication s for preven tion an d treatm en t are sim ilar to th ose already listed for secon dary HPT.

21.5 Fam ilial Hypocalciuric Hypercalcem ia Th ere are m any causes of hypercalcem ia th at m ust be di eren tiated from prim ar y hyperparathyroidism . Th is task is usually n ot di cult because oth er causes of hypercalcem ia cause a com pen sator y suppression of PTH by n egative feedback. Th is is in con trast to th e elevated PTH seen despite hypercalcem ia in prim ar y hyperparathyroidism . On e clin ical condition w h ere PTH can also be elevated in th e presen ce of hypercalcem ia, leadin g to a diagnost ic dilem m a, is fam ilial hypocalciuric hypercalcem ia (FHH). FHH is an autosom al dom in an t con dition caused by a defect in th e CaSR located on both th e parathyroid glan ds an d th e ren al t ubule. Th e CaSR h as been m apped to ch rom osom e 3q21q24, an d m ultiple in act ivatin g m utation s h ave been described.26,52 Th is in act ivation of th e CaSR requires a h igh er seru m calcium to act on th e parathyroids to suppress PTH, w h ich in creases th e set poin t allow in g hypercalcem ia in th e presen ce of n orm al to sligh tly elevated PTH levels. In th e ren al tubule, th e defect in th e CaSR leads to in creased calcium an d m agn esium reabsorption .19,30,53,54 Th e n et result is hypercalcem ia, hypocalciuria, an d, frequen tly, hyperm agnesem ia. Patien ts are rarely sym ptom atic, w h ich is in cont rast to prim ar y hyperparathyroidism , in w hich 20 to 30% of patien ts presen t w ith sym ptom s.3,7 Th e distin ct ion betw een th ese tw o disorders is m ade w ith fam ily h istory an d laboratory fin din gs. A fam ily h istory of hypercalcem ia sh ould raise th e suspicion of th is autosom al dom in an t con dition , especially if th ere is a fam ily h istory of hypercalcem ia th at did n ot im prove after parathyroidectom y for presum ed hyperparathyroidism . PTH levels are t ypically n orm al to m ildly elevated in FHH as opposed to prim ar y hyperparathyroidism , in w h ich th ey are m ore sign ifican tly elevated, but th e true laborator y dist in ct ion betw een th ese t w o disease processes is m ade w ith urin ar y electrolyte studies. Tw en t y-four-h our urin e collection for creatin in e an d calcium can confirm th e diagn osis of FHH. In FHH 75% of patien ts h ave 24-h our calcium excretion levels of < 100 m g, w h ereas patien ts w ith prim ar y hyperparathyroidism usually h ave excretion s in excess of 200 m g in 24 h ours. Th e calcium / creatin in e clearan ce ratio is < 0.01 in a m ajorit y of patien ts w ith FHH an d > 0.02 in m ost patien ts w ith prim ary hyperparathyroidism .18,30,55,56 Th e distin ction betw een th ese condition s is n ot di cult if urin e studies are perform ed. How ever, m any patien ts h ave un dergon e surgical in terven tion w ith n o ben efit because th ey w ere in correctly iden tified as h avin g prim ar y

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Pathophysiology of t he Parathyroid Glands Table 21.2 Clinical presentation of m ultiple endocrine neoplasia t ype 1 (MEN1) Clinical m anifestation

Prevalence (MEN1)

Prim ary hyperparathyroidism

90–100%

Pancreatic islet cell tum ors

33%

Pituitary adenom as

20%

Thymic carcinoids

5%

Less com m on findings: angiofibromas, collagenom as, lipom as, spinal ependym om as, thyroid adenom as, adrenocortical adenom as

hyperparathyroidism . Th is un derscores th e im por tan ce of routin e use of th e 24-h our urin e collect ion for calcium an d creatin in e to exclude FHH patien ts from parathyroid surgery. Com m ercially available gen etic testin g can also be useful but is on ly 70%sen sitive for diagnosis.

21.6 Mult iple Endocrine Neoplasia Syndrom es Multiple en docrin e n eoplasia (MEN) syn drom es are ch aracterized by th e presence of fun ct ion al tum ors of en docrin e organ s th at produce h orm on es th at lead to th e ch aracteristic sym p tom s. Th e curren t classification divides th e syn drom es in to MEN1 (Werm er’s syn drom e), MEN2A (Sipple’s syn drom e), an d MEN2B (also kn ow n as MEN3). Th ese syn drom es are in h erited in an autosom al-dom in an t m an n er. Hyperparathyroidism plays a sign ifican t role in MEN1 an d MEN2A but is n ot part of th e spectrum of disease w ith MEN2B.

21.6.1 Mult iple Endocrine Neoplasia Type 1 MEN1 is a disease w ith a gen etic predisposition for tum ors of th e parathyroids, pan creatic islet cells, an d an terior pituitary. Th is syn drom e is also kn ow n to in clude duoden al tum ors, adren al aden om as, thyroid aden om as, carcin oid tum ors, an d lipom as ( Table 21.2). Parathyroid tum or developm en t in MEN1 occurs decades earlier th an in th e sporadic form s, an d th e gastroin testin al tum ors h ave an in creased m align an t poten tial.57 Prim ary hyperparathyroidism is the m ost consistent feature of MEN1 and has been reported to a ect 90 to 100% of these patients by the age of 40, m aking it also the earliest feature of the disease. It is estim ated that up to 2% of prim ary hyperparathyroidism is attributable to MEN1.57 As is the case w ith sporadic prim ary hyperparathyroidism , m ost patients are asym ptom atic. Sym ptom s com m on to MEN1-associated prim ary hyperparathyroidism are the sam e as seen in the sporadic form s.58 The diagnosis of PHPT in MEN1 is the sam e as nonsyndrom ic cases. Alth ough th e presen tin g sym ptom s an d diagnost ic criteria are th e sam e for PHPT in MEN1 as th ey are for sporadic cases of PHPT, th ere are sign ifican t di eren ces in th e patien t population s. For exam ple, hyperparathyroidism develops m uch earlier in patien ts w ith MEN1 th an it does in th e gen eral population . PHPT is alm ost un iversal in pat ien ts w ith MEN1 by th e age of 40, an d an n ual screen in g w ith serum calcium an d PTH is

recom m en ded, begin n in g at 8 years of age.59,60 Th is is 20 years soon er th an th e average presentation of PHPT in oth er patien ts. Th e fem ale predom in an ce seen in n on fam ilial hyperparathyroidism is n ot seen in MEN1-associated hyperparathyroidism , w h ich h as an even m ale-to-fem ale ratio. Perh aps th e m ost im portan t distin ct ion betw een th e PHPT foun d in MEN1 patien ts an d th e sporadic variet y is th at m ultiple glan d involvem en t is ch aracteristic of PHPT in MEN1 patien ts, w h ere 80 to 90% of n on syn drom ic PHPT is caused by a sin gle parathyroid aden om a.12,26,59,61 Th e m ultiple glan d involvem en t foun d in th ese patien ts n ecessitates a th erapeutic approach th at di ers from th e approach taken to oth er patien ts w ith PHPT. Patien ts w ith sporadic prim ary hyperparathyroidism w h o m eet th e NIH criteria for surgery can un dergo surgery directed on ly at th e a ected glan d or glan ds assum in g adequate preoperative localization . How ever, th e m ultiple glan d hyperplasia seen in th e parathyroids of MEN1 patien ts n ecessitates a m ore aggressive approach . Alth ough som e parathyroid glan ds m ay appear grossly n orm al durin g n eck exploration of th ese patien ts, it is felt th at th ese glan ds are n ot h istologically n orm al but represent asym m etric hyperplasia.56,59 Th is explain s th e in creased failure rate foun d in MEN1 pat ien ts w h o un dergo surgical in terven tion for hyperparathyroidism . It is reported th at rough ly 50% of th ese patien ts w ill h ave recurren t hyperparathyroidism 10 to 12 years after surgical correct ion .62,63 Th ere are tw o surgical option s com m on ly em ployed in th ese patien ts. Th e first con sists of a bilateral n eck exploration w ith subtotal parathyroidectom y an d thym ectom y leavin g a 20 to 50 m g rem n an t of vascularized parathyroid tissue in situ . Th e thym ectom y is added due to th e in creased in ciden ce of supern um erar y parathyroid glan ds foun d in MEN1, an d if th e subtotal approach is used, it is advisable to leave a surgical clip at th e site of th e rem n an t parathyroid for referen ce if fu ture n eck exploration s for recurren t hyperparathyroidism are required. The second option em ployed is a total parathyroidectom y com bin ed w ith thym ectom y an d autot ran splan tation of a portion of th e resected parathyroid t issue in to eith er th e stern ocleidom astoid m uscle in th e n eck or th e brach ioradialis m uscle in th e forearm . Th ere is n o con sen sus regarding w h ich of th ese t w o im plan tation sites is m ore appropriate.15,64,65,66,67,68 Due to th e h igh failure rate of surgical in terven tion an d th e kn ow n path ogen esis involving m ultiple-glan d hyperplasia, select ive parathyroidectom y resectin g on ly grossly involved glan ds is gen erally n ot recom m en ded. Due to th e surgical in ten t of bilateral explorat ion w ith exposure of all parathyroid tissue, preoperative localization studies are n ot n ecessar y for in itial surgical in terven t ion , alth ough th ey m ay be usefu l for excluding ectopic glan ds. Studies h ave sh ow n tech n etium -99 m sestam ibi, sin gle-ph oton em ission com puted tom ography (SPECT), an d positron em ission tom ography (PET) w ith 11C-m eth ion in e to be of ben efit in selected pat ien ts un dergoing reoperation for recurren t hyperparathyroidism .58,69,70 In traoperative PTH m easurem en ts h ave becom e popular an d usefu l in determ in in g adequate resection in sporadic cases of HPT, especially w h en caused by a sin gle aden om a. Recen t reports advocate th e use of th e in traoperative PTH assay for reexplorat ion an d for total parathyroidectom y.13,71,72 Th e declin e in PTH is n ot as abrupt as th at seen after th e resection of an o en din g aden om a, an d m ore experien ce w ith th is assay in MEN1 patien ts is required.

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Parathyroid Diseases Alth ough th is ch apter focuses on parathyroid diseases, a discussion of MEN1 w ith out m en tion of its oth er m an ifestation s w ould be in com plete. Pit uitary aden om as are an oth er com m on fin din g in th ese pat ien ts. Most studies repor t a 20% in ciden ce of clin ically eviden t pituitar y aden om as in MEN1 pat ien ts, but on e study dem on st rated th at up to 60% of MEN1 patien ts w ill h ave path ological eviden ce of a pituitar y aden om a if an autopsy is perform ed.60,73,74 Th e m ost com m on pituitar y tu m or foun d is prolact in om a. As com pared w ith n on syn drom ic patien ts, pituitary aden om as in MEN1 ten d to be larger, m ore sym ptom atic, an d h ave a h igh er recurren ce rate after resection .75 Pan creat ic an d gastroin testin al islet cell t um ors are an oth er sign ifican t com pon en t of MEN1. Parathyroid an d pituitar y involvem en t w ith MEN1 can be e ect ively treated, w h ich leaves th e m align an t poten t ial of th e gastroin testin al an d pan creatic islet cell tum ors as th e m ajor cause of m ortalit y.76,77,78,79 As w ith pituitary disease, th ere is a discrepan cy betw een clin ically apparen t islet cell tu m ors (33% of MEN1 patien ts) an d bioch em ical involvem en t (80%). Gastrin om as w ith Zollin ger–Ellison’s syn drom e are th e m ost com m on clin ical m an ifestation in th is group. In sulin om a is th e n ext m ost com m on clinically sign ifican t islet cell t um or, follow ed by rare tu m ors, in cluding vasoactive in testin al polypeptideom a (VIPom a), som atostatin om a, an d pan creatic polypept idom a. Aside from th e classic parathyroid, pituitar y, an d pan creatic involvem en t, patien ts w ith MEN1 are at an in creased risk of developin g m ultiple oth er m an ifest at ion s. For exam p le, u p to 5% of p at ien ts w it h MEN1 d evelop thym ic carcin oid s. In terest in gly, th ese thym ic carcin oid s are fou n d alm ost exclu sively in m ale sm okers w ith MEN1.15,80 Cu tan eou s tu m ors su ch as an giofibrom as an d collagen om as are m ore com m on in t h is grou p , as are ad ren ocort ical ad en om as, thyroid ad en om as, an d spin al cord ep en d ym om as.15,81,82 Th e MEN1 gen e (MEN1) h as been clon ed an d m apped to ch rom osom e 11q13.58,60,79,80,81,82,83 MEN1 is a t u m or su p p ressor gen e t h at en cod es for a p rotein n am ed m en in , an d in act ivation of th is p rotein lead s to tu m or igen esis. Now th at th e gen e is clon ed , gen et ic t est in g is feasible. Prop hylact ic su rgery is n ot p erform ed in MEN1, bu t d u e t o t h e in creased risk con ferred by rad iological screen in g, gen etic test in g is n ow o ered t o first -d egree relat ives of p at ien ts w it h MEN1 in ord er t o d ecrease u n n ecessar y rad iat ion exp osu re in u n affect ed in d ivid u als. Gen et ic t est ing is also suggest ed in p atien ts th at h ave m u ltiglan d u lar PHPT or in PHPT p atien ts u n d er 30.15,79,84

21.6.2 Mult iple Endocrine Neoplasia Type 2 Multiple en docrin e n eoplasia t ype 2 (MEN2) is divided in to th ree subgroups: MEN 2A, MEN 2B, an d fam ilial m edullar y thyroid can cer (FMTC), w h ich is a varian t of MEN2A. As in MEN1, th ese syn drom es are in h erited by an autosom al-dom in an t m ode of tran sm ission . Th e th ree h ave m edullar y thyroid carcin om a as a com m on feature but di er in oth er clin ical m an ifestation s. MEN2A is ch aracterized by m edullar y thyroid carcin om a, p h eoch rom ocyt om a, an d h yp erp arat h yroid ism . Hyp erp arat h yroid ism a ect s 20 t o 30%30,60,8 5 of t h ese p at ien t s an d is m ore com m on ly asym pt om at ic an d m ild er t h an t h e

h yp erp arat hyroid ism fou n d in MEN1.8 6,8 7 As in MEN1, h yp erp arat hyroid ism in MEN2A is ch aract erized by m u ltiglan d u lar h yp erp lasia, an d t reat m en t op t ion s for sym ptom at ic p at ien t s are sim ilar. How ever, becau se t h e sym pt om com p lex is m ild er an d t h e recu rren ce rat e aft er su rger y is m u ch less t h an t h at for MEN1, bilateral n eck exp lorat ion w it h rem oval of on ly grossly en larged glan d s w it h ou t cer vical t h ym ect om y is p erform ed for m ost sym pt om at ic p at ien ts.8 8,89 If hyp ercalcem ia is severe, m ore aggressive ap p roach es, su ch as su bt ot al or t ot al p arath yroid ect om y w it h cer vical t h ym ect om y, can be con sid ered . Th e absen ce of h yp erp arat hyroid ism in MEN2B an d FMTC m akes t h e role of C-cell h yp erp lasia an d elevated calcit on in as a cau sat ive fact or of h yp erp arat h yroid ism in MEN2A less p lau sible. It h as been fou n d t h at t h e RET p roto -on cogen e is exp ressed in t h e p arat hyroid t u m ors of MEN2A, an d , fu r t h erm ore, sp ecific RET m u t at ion s (cod on 634) are fou n d p referen t ially in fam ilies w it h MEN2A in volvin g h yp erp arat h yroid ism . Th is lead s t o t h e con clu sion t h at t h e p arat hyroid hyp erp lasia in MEN2A m ay be related t o t h e exp ression of t h e m u t an t RET p ro t ein .90 Med u llar y t h yroid can cer is t h e m ost con sist en t fin d in g of MEN2A an d is fou n d in 90 t o 95% of p at ien t s. W h en MEN2A is con firm ed by t est in g for t h e RET p roto -on cogen e, p rop hylact ic t h yroid ect om y is recom m en d ed . Th e age at w h ich t h is t h yroid ect om y sh ou ld be p erform ed is a con t ro versial top ic. For h igh -risk gen et ic alt erat ion s (e.g., cod on 634), t hyroid ect om y is recom m e n d e d by 5 years of age.9 1,92 For in t erm ed iate-risk alt erat ion s, it is ar gu ed t h at t h yroid ect om y can be p erform ed later. Ph eoch r om ocyt om a occu rs in n early 40% of p at ien t s w it h MEN2A. Bioch em ical screen in g by u rin ar y or seru m catech olam in es is recom m en d ed for all p at ien t s w it h MEN2 or w it h m ed u llar y t h yroid carcin om a. If p at ien t s are fou n d t o h ave p h eoch rom ocyt om a, t h is sh ou ld be su rgically ad d re ssed p rior to con sid erin g t h yroid ectom y or p arat hyroid e ct om y.8 5 ,9 3 ,94 MEN2A is also associat ed w it h cu t an eou s lich en am yloid osis as w ell as Hirsch sp ru n g’s d isease ( Table 21.3).15,9 5 MEN2B also in volves m ed u llar y t h yroid carcin om a an d p h eoch rom ocyt om a bu t d oes n ot h ave an associat ion w it h h yp erp arat h yroid ism . Med u llar y t h yroid can cer is u n iversal in t h ese p at ien t s, is m ore aggressive t h an MTC fou n d in MEN2A, an d occu rs at an earlier age. Tim ely d iagn osis an d early p rop h ylact ic t h yroid ect om y are im p erat ive for t h e p at ien t ’s u lt im ate p rogn osis. W h en MEN2B is d iagn osed by RET t est in g, t h yroid ectom y is re com m en d ed by 6 m on t h s of age.9 1,9 6 Ph eoch rom ocyt om as occu r in 40% of p at ie n t s w it h MEN2B an d sh ou ld be evalu at ed an d t r eat ed in t h e sam e m an n er as d escribed for MEN2A. Marfan oid h abit u s, in t est in al gan glion eu rom as, an d m u cosal

Table 21.3 Clinical presentation of m ultiple endocrine neoplasia t ype 2A (MEN2A) Clinical m anifestation

Prevalence (MEN2A)

Medullary thyroid carcinom a

90–95%

Pheochrom ocytom a

40%

Hyperparathyroidism

10–25%

Note: Less com m on features: cutaneous lichen amyloidosis, Hirschsprung’s disease.

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Pathophysiology of t he Parathyroid Glands

Fig. 21.4 Calciphylaxis lesion.

n eu rom as in volvin g t h e lip an d ton gu e are also com m on in MEN2B.1 5 ,8 5 ,8 6

21.7 Calciphylaxis Calciphylaxis is a vascular an d tissue m an ifestation of system ic disease.97,98 Th is prim arily occurs in patien ts w ith secon dary hyperparathyroidism an d ch ron ic ren al failure, but isolated cases h ave been reported in pat ien ts w ith oth er un derlying path ology, such as alcoh olic cirrh osis, vitam in D in toxication , prim ar y hyperparathyroidism , m ultiple m yelom a, an d hypercalcem ia of m align an cy.49,99,100,101 Th e term ca lciphyla xis is som ew h at m isleadin g because it im plies an im m un ologic process. Oth er m ore specific term s are ca lcific uremic a rter iolopa thy, uremic sma ll vessel disea se, uremic gangrene syndrome, an d uremic sma ll-a rter y disea se w ith media l ca lcifica t ion a nd intima l hyper pla sia .49,102,103,104,105 As th ese oth er m ore descriptive term s im ply, calciphylaxis is ch aracterized by system ic calcification of th e t un ica m edia of sm all vessels. Th is leads to th e clin ical m an ifestat ion of t issue isch em ia an d n ecrosis. A ected areas in itially m an ifest as pain ful purpuric plaques w ith n odularit y ( Fig. 21.4) an d t ypically progress to n ecrotic ulcers w ith esch ar. Th e un derlyin g m uscle can be involved by th e isch em ic an d n ecrotic process. Wh at ultim ately leads to th e poor progn osis associated w ith calciphylaxis is th e superin fect ion th at often en sues. Th e m or talit y rate rem ain s betw een 60 an d 87%, w ith patien ts usually succum bing to overw h elm in g in fect ion an d sepsis.105 Urem ic sm all artery disease h as been foun d to occur in 4% of patien ts on dialysis. Fem ales are a ected m uch m ore com m on ly th an m ales, an d th e m ean age at presen tat ion is betw een 48 and 57 years.106 Th e path ogen esis is n ot w ell un derstood, but certain risk factors h ave been iden tified in an im al m odels as w ell as in pat ien ts. Elevated PTH, hyperph osph atem ia, an d elevated vitam in D levels seem to provide a m ilieu w h ere calciphylaxis is m ore com m on . How ever, a superim posed even t such as local tissue traum a, inject ion of m edication s, or elevation of oth er laboratory values often leads to th e developm en t of w oun ds in th ese sen sitized patien ts.107 As previously discussed, ch ron ic ren al failure leads to low er levels of vitam in D, w h ich in turn decrease in testin al absorption of calcium leadin g to

hypocalcem ia an d elevated PTH levels. Th is secon dary hyperparathyroidism ultim ately leads to elevated calcium levels, an d, w ith th e addition of ph osph ate reten tion com m on in ren al p at ie n t s, ele vated calciu m –p h osp h orou s p rod u ct s le ad t o soft t issu e an d vascu lar calcificat ion .1 0 3 A calciu m –p h osp h o rou s p rod u ct ≥ 70 in cre ases t h e likelih ood of d evelop in g calcip h ylaxis. Oth er factors felt to con tribu te to calcip h ylaxis are t yp e 1 d iabetes m ellit u s, p rotein C or p rotein S d eficien cy, calciu m carbon ate u sage, p red n ison e, an d ad m in istrat ion of w arfarin .49,100,101,103,105 With th e lack of a specific test for calciphylaxis, th e diagnosis rem ain s a clin ical on e requirin g a h igh degree of clinical suspicion . Th e developm en t of a pain fu l purpuric plaque in a dialysis patien t sh ould provoke close m on itorin g. Alth ough laboratory abn orm alities, such as leukocytosis, hypercalcem ia, hyperph osphatem ia, an d elevated PTH, h ave been described, th e confirm ation of th is diagnosis is w ith t issue biopsy sh ow in g m edial calcification of sm all arteries an d in tim al hyperplasia.103 Th ere is n o ut ilit y in im agin g th ese patien ts for diagn ostic purposes. On ce th is diagn osis is suspected or confirm ed, aggressive m an agem en t is crit ical. Th e treatm en t involves attem ptin g to correct th e un derlyin g hypercalcem ia an d hyperph osph atem ia. Th is is accom plish ed by stoppin g vitam in D supplem en tation an d prescribin g a low -calcium dialysate an d ph osph ate bin ders th at are n ot calcium based, such as sevelam er hydroch loride (Ren agel, Gen zym e Corp.).95,107,108,109 Dressing ch anges (w ith conven t ion al or vacuum dressin gs) an d surgical debridem en t of th e n ecrotic w oun ds are im portan t to preven t superin fection an d ultim ate sepsis.101,110 Th e role of parathyroidectom y for calciphylaxis is con troversial. Reports h ave advocated subtotal parathyroidectom y for im provem en t in w oun d h ealin g, in creased sur vival, an d im provem en t of pain w ith th e ulcers.103,111 How ever, oth er reports h ave refuted th ese claim s. Curren tly, th ere is n o clear consen sus on th e role of, or exten t of, parathyroidectom y in th is patien t populat ion . Calciphylaxis carries such a grim progn osis th at preven tion is of th e utm ost im portan ce. Meticulous m an agem en t of th e ph osph ate an d calcium balan ce in ren al patien ts can preven t th e m etabolic backgroun d, w h ich h as been sh ow n to predispose th ese patien ts to calcip h yla xis. Several recen t stu d ies h ave suggested th e u se of in t raven ous sod iu m t h iosu lfat e, w h ich h as p reviou sly been u sed in cyan id e p oison in g, as a treat m en t for calcip hylaxis. Sod iu m th iosu lfat e is a ch elat in g agen t t h at m ay red u ce circu latin g calciu m an d aid in th e resorp tion of calciu m d ep osits.101,107

21.8 Hypoparat hyroidism Hypocalcem ia can result from m ultiple factors, in cluding hypovitam in osis D, sepsis, hypoalbum in em ia, hypom agn esem ia, an d fluoride poison in g. Hypoparathyroidism w ith decreased product ion of PTH or resistan ce to PTH can also cause sign ifican t hypocalcem ia. Hypoparathyroidism is m uch less com m on th an hyperparathyroidism an d is foun d in congen ital as w ell as acquired form s. Th e m ost com m on cause is iatrogen ic follow in g thyroid or parathyroid surgery.112,113,114 Hypoparathyroidism occurrin g in ch ildren is m ost com m on in th e n eon atal period. Th e m ost com m on fin din g in th e n eon atal period is physiological hypoparathyroidism w ith sym ptom s an d bioch em ical eviden ce of hypoparathyroidism th at are

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Parathyroid Diseases tran sien t an d w arran t n o treatm en t . Th e path ogen esis of th is physiological hypoparathyroidism is poorly un derstood, but kn ow n risk factors in clude m atern al diabetes, birth asphyxia, an d preterm deliver y w ith low birth w eigh t.115 Oth er form s of hypoparathyroidism th at occur early, in th e first 24 h ours of life, are caused by hypoplasia or agen esis of th e parathyroid glan ds. DiGeorge’s an om aly is on e exam ple of parathyroid agen esis associated w ith oth er fin din gs. DiGeorge’s an om aly is caused by failure of m igration of n eural crest cells in to th e th ird an d four th ph ar yngeal pouches, w h ich results in failure of appropriate developm en t of th e parathyroids and thym us. Th e clin ical pict ure in cludes im m un e deficits secon dary to th e lack of T-cell fun ct ion , hypoparathyroidism w ith hypocalcem ia, cardiac defects in cluding trun cus arteriosus, an d ch aracteristic facies.116,117,118 Microdeletion s m apped to ch rom osom e 22q11 h ave been described in up to 90% of patien ts w ith DiGeorge’s an om aly.119 Con gen ital hypoparathyroidism can occur in th e face of n orm al-appearin g parathyroid glan ds, an d a collection of gen etic defects h as been described. Th ere is an autosom aldom in an t form caused by a m utation in th e CaSR. Th is m utation is an act ivatin g m utation th at sign als parathyroid cells an d oth er cells in th e body, in dicatin g th at th ere is adequate serum calcium , despite hypocalcem ia. Th e clinical pict ure of hypocalcem ia an d hyperph osph atem ia results in th e presen ce of a n orm al in tact PTH. Th is condition also h as a paradoxical h igh or h igh n orm al urin ary calcium due to act ivation of th e calcium receptor in th e ren al t ubule.53,114 Th ese patien ts are usually asym ptom at ic despite sign ifican t hypocalcem ia, an d attem pts to treat th e hypocalcem ia sh ould be reserved for sym ptom at ic patien ts because treatm en t can result in elevated urin ar y calcium excretion , n eph rolith iasis, n eph rocalcin osis, an d ren al in su cien cy.53,114,120,121 Th ere are t w o oth er form s of in h erited hypoparathyroidism . On e is a defect in th e sign al peptide of th e PTH precursor preven t in g conversion to active PTH, an d th e oth er is in h erited w ith sen sorin eural h earin g loss an d ren al dysplasia, w h ich h as recen tly been attributed to m utation s in tran scription factor GATA3.121,122,123 Autosom al recessive an d X-lin ked recessive form s of hypoparathyroidism h ave been reported, but specific gen etic defects are n ot yet kn ow n .124 Late n eon atal hypoparathyroidism occurs days after deliver y. Tw o m itoch on drial disorders, Ken ny–Ca ey’s syn drom e an d Kearn s–Sayre’s syn drom e, are associated w ith late n eon atal hypoparathyroidism .113 Ch ildh ood hypoparathyroidism can also be seen as a part of an autoim m un e com plex. Th e m ost com m on exam ple is hypoparathyroidism in conjun ct ion w ith a dren al in su cien cy an d mucocutan eous can didiasis (HAM syn drom e). An oth er syn drom e w ith autoim m un e destru ct ion of th e parathyroids is autoim m un e polyglan dular syn drom e t ype I (also kn ow n as autoim m un e polyen docrin opathy–can didiasis–ectoderm al dystroph y [APECED] syn drom e). Im m un ologic destruct ion of th e h orm on e-producing cells in th e parathyroids is a com m on den om in ator in th ese t w o syn drom es. En docrin opath ies in APECED, such as diabetes m ellit us, hypogon adism , an d hypothyroidism , m ust be excluded.125 Pseudohypoparathyroidism is a condition in w h ich hypocalcem ia an d hyperph osph atem ia are accom pan ied by elevated levels of PTH, in dicatin g th at th e path ology is n ot absen ce of parathyroids or PTH but rath er resistan ce of th e en d organ s to th e e ects of PTH. Th ere are t w o distin ct form s of

pseudohypoparathyroidism described. Type 1 is attributable to a blun ted respon se of th e cyclic aden osin e m on oph osph ate (cAMP) cascade to PTH, an d is subdivided in to t ype 1a, t ype 1b, an d pseudopseudohypoparathyroidism , w h ich is a related disorder.114 Th e gen e coding for th e stim ulatory Gs- α 1 protein in th e adenylyl cyclase com plex (GNAS1) h as been sh ow n to be involved in all of th ese disorders. Th e GNAS1 gen e is kn ow n to be im printed w ith th e m atern al allele expressed in th e kidn ey. Th erefore, m atern al an d patern al t ran sm ission di er in clin ical presen tation s. Type 1a pseudohypoparathyroidism h as a described m utation in GNAS1.126 Man ifestation s of th is disease in clude n ot on ly th e aforem en tion ed m etabolic fin din gs but also sh ort stature, roun d facies, an d sh ort m etatarsal an d m etacarp al bon es, w h ich is also kn ow n as Albrigh t h ereditar y osteodystroph y. Th e spectrum of disease in t ype 1a is th e con sequen ce of m atern al t ran sm ission of a defect ive GNAS1, because th e skeletal m an ifestat ion s are seen in conjun ct ion w ith ren al m an ifestation s.114 In t ype 1b pseudohypoparathyroidism th e defect in GNAS1 is felt to be lim ited to th e kidn ey, because th ese patien ts h ave th e characteristic hypocalcem ia, hyperph osph atem ia, an d elevated PTH but do n ot h ave Albrigh t h ereditar y osteodystrophy. Th is suggests th at a m atern al t ran sm ission is respon sible in t ype 1b. There h ave been a few described defects in GNAS1 for type 1b th at are di eren t from th e defect kn ow n to be respon sible for t ype 1a an d pseudopseudohypoparathyroidism . In t ype 2 pseudohypoparathyroidism th e cAMP respon se to PTH is in tact , but th e ph osph ate excretion in th e kidn ey is altered, leadin g to th e characteristic m etabolic fin din gs. It is felt th at th e dow n st ream e ects of cAMP are blun ted due to resistan ce. Th e sign al tran sduct ion defects seen in all of th ese disorders n ot on ly a ect th e respon se to PTH but also can a ect oth er h orm on al respon ses in th e patien t. Th is can m an ifest as hypogon adism due to resistance to gon adotropin s or hypothyroidism due to resistan ce to thyroid-stim ulatin g h orm on e (TSH).114,124,127 Pseudopseudohypoparathyroidism is th e con sequen ce of patern al t ran sm ission of th e GNAS1 m utation described in t ype 1a an d in cludes Albrigh t’s h ereditar y osteodystrophy but does n ot h ave hypocalcem ia because th e n orm al m atern al allele expressed in th e kidn ey preserves n orm al ren al fun ction .124,128,129 Alth ough all of th e aforem en tion ed syn drom es an d disease processes can cause hypoparathyroidism , th e m ost com m on cause of hypoparathyroidism is iatrogen ic follow in g n eck surgery. Th is can occu r follow in g thyroid ectom y, p arathyroid ect om y, or cen t ral com p ar t m en t n eck d issect ion s. It is estim ated t h at 1 t o 2% of p at ien t s u n d ergoing t ot al t hyroid ect om y for t hyroid can cer d evelop hyp op arathyroid ism an d hyp ocalcem ia.130,131

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Spectr um of pituitar y disease in m ultiple en docrin e n eoplasia type 1 (MEN 1): clin ical, bioch em ical, an d radiological features of pituitar y disease in a large MEN 1 kin dred. J Clin En docrin ol Metab 1996; 81(7); 2642–2646 [74] Padberg B, Sch röder S, Capella C, Frillin g A, Klöppel G, Heitz PU. Multiple en docrin e n eoplasia type 1 (MEN 1) revisited. Virch ow s Arch 1995; 426(6); 541–548 [75] Vergès B, Boureille F, Goudet P, et al. Pituitar y disease in MEN t ype 1 (MEN1): data from th e Fran ce-Belgium MEN1 m ulticen ter study. J Clin En docrin ol Metab 2002; 87(2); 457–465 [76] Marx SJ, Vin ik AI, San ten RJ, Floyd JC, Jr, Mills JL, Green J, III. Multiple en docrin e n eoplasia t ype I: assessm en t of laborator y tests to screen for th e gen e in a large kin dred. Medicin e (Baltim ore) 1986; 65(4); 226–241 [77] Skogseid B, Eriksson B, Lun dqvist G, et al. Multiple en docrin e n eoplasia type 1: a 10-year prospect ive screen ing study in four kin dreds. 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[80] Teh BT, McArdle J, Ch an SP, et al. Clin icopath ologic studies of thym ic carcin oids in m ultiple en docrin e n eoplasia type 1. Medicin e (Baltim ore) 1997; 76 (1); 21–29 [81] Gibril F, Schum an n M, Pace A, Jen sen RT. Multiple en docrin e n eoplasia type 1 an d Zollinger-Ellison syn drom e: a prospect ive study of 107 cases an d com parison w ith 1009 cases from th e literature. Medicin e (Baltim ore) 2004; 83 (1); 43–83 [82] Burgess JR, Harle RA, Tucker P, et al. Adren al lesion s in a large kin dred w ith m ultiple en docrin e n eoplasia type 1. Arch Surg 1996; 131(7); 699–702 [83] Larsson C, Skogseid B, Oberg K, Nakam ura Y, Norden skjöld M. Multiple en docrin e n eoplasia type 1 gene m aps to ch rom osom e 11 an d is lost in in sulin om a. Nature 1988; 332(6159); 85–87 [84] Lassen T, Friis-Han sen L, Rasm ussen AK, Kn igge U, Feldt-Rasm ussen U. Prim ar y hyperparathyroidism in youn g people. W h en sh ould w e perform gen etic testin g for m ultiple en docrin e n eoplasia 1 (MEN-1). J Clin En docrin ol Metab 2014; 99(11); 3983–3987 [85] Rich ar d s ML. Th yr oid can cer ge n et ics: m u lt ip le e n d ocr in e n e op la sia t yp e 2 , n on - m e d u llar y fam ilial t h yr oid ca n cer, a n d fa m ilial syn d r om e s associa te d w it h t h yr oid can cer. Su r g On col Clin N Am 2 0 0 9 ; 1 8 (1 ); 3 9 – 5 2 , viii [86] Raue F, Fran k-Raue K, Grauer A. Multiple en docrin e n eoplasia type 2. Clin ical features an d screen ing. En docrin ol Metab Clin North Am 1994; 23(1); 137– 156 [87] Sch u en ecker I, Virally-Mon od M, Broh et R, et al. Risk an d pen etran ce of prim ar y hyperparathyroidism in m ultiple en docrin e n eoplasia type 2A fam ilies w ith m utation s at codon 634 of th e RET protoon cogen e. J Clin En docrin ol Metab 1998; 83; 487–491 [88] Dotzen rath C, Cupisti K, Goretzki PE, et al. Lon g-term bioch em ical results after operative treatm en t of prim ar y hyperparathyroidism associated w ith m ultiple en docrin e n eoplasia types I an d IIa: is a m ore or less exten ded operation essen tial? Eur J Surg 2001; 167(3); 173–178 [89] O’Riordain DS, O’Brien T, Gran t CS, Weaver A, Gh arib H, van Heerden JA. Surgical m an agem en t of prim ar y hyperparathyroidism in m ultiple en docrin e n eoplasia types 1 an d 2. Surgery 1993; 114(6); 1031–1037, discussion 1037– 1039 [90] Heath H, III, Sizem ore GW , Carn ey JA. Preoperative diagn osis of occult parathyroid hyperplasia by calcium in fusion in patien ts w ith m ultiple en docrin e n eoplasia, type 2a. J Clin En docrin ol Metab 1976; 43(2); 428–435 [91] Mach en s A, Niccoli-Sire P, Hoegel J, et al. Eu rop ean Mu lt ip le En d ocrin e Neop lasia (EUROMEN) St u dy Grou p . Early m align an t p rogression of h ered it ar y m ed u llary t hyroid can cer. N En gl J Med 2003; 349(16);1517– 1525 [92] Bü tter A, Gagn é J, Al-Jazaeri A, Em ran MA, Deal C, St-Vil D. Prophylactic thyroidectom y in pediatric carriers of m ultiple en docrin e n eoplasia type 2A or fam ilial m edullary thyroid carcin om a: m utation in C620 is associated w ith Hirsch sprun g’s disease. J Pediatr Surg 2007; 42(1); 203–206 [93] Wells SA, Jr, Dilley W G, Farn don JA, Leigh t GS, Baylin SB. Early diagn osis an d treatm en t of m edullary thyroid carcin om a. Arch In tern Med 1985; 145(7); 1248–1252 [94] Tan g KL, Lin Y, Li LM. Diagn osis an d surgical treatm en t of m ultiple en docrin e n eoplasia type 2A. World J Surg On col 2014; 12; 8 [95] Verdy M, Weber AM, Roy CC, Morin CL, Cadotte M, Broch u P. Hirsch sprun g’s disease in a fam ily w ith m ultiple en docrin e n eoplasia type 2. J Pediatr Gastroen terol Nutr 1982; 1(4); 603–607 [96] Roy M, Ch en H, Sippel RS. Curren t un derstan ding an d m an agem en t of m edullar y thyroid can cer. On cologist 2013; 18(10); 1093–1100 [97] Won g J, Miller A, Cross N, Grun dy K, Keefe M, Jardin e D. Calciphylaxis: fatal arteriosclerosis of un certain m ech anism . In tern Med J 2014; 44(10); 1040– 1041 [98] Fern an des C, Mayn ard B, Han n a D. Successful treatm en t of calciphylaxis w ith in traven ous sodium th iosulfate in a n on urem ic patien t: case report an d review of th erapy side e ects. J Cutan Med Surg 2014; 18(5); 356–360 [99] Beus KS, Stack BC, Jr. Calciphylaxis. Otolaryn gol Clin North Am 2004; 37(4); 941–948, xii [100] Ken t RB, III, Lyerly RT. System ic calciphylaxis. South Med J 1994; 87(2); 278– 281 [101] Sm ith VM, Oliph an t T, Sh areef M, Merch an t W , W ilkin son SM. Calciphylaxis w ith n orm al ren al fun ction : treated w ith in traven ous sodium th iosulfate. Clin Exp Derm atol 2012; 37(8); 874–878 [102] San tos PW , Hartle JE, Quarles LD. 2005 [103] Jan igan DT, Hirsch DJ, Klassen GA, MacDon ald AS. Calcified subcutan eous arterioles w ith in farcts of th e subcutis an d skin (“calciphylaxis”) in ch ron ic ren al failure. Am J Kidn ey Dis 2000; 35(4); 588–597

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Pathophysiology of t he Parathyroid Glands [104] Hafn er J, Keusch G, Wah l C, et al. Urem ic sm all-arter y disease w ith m edial calcification an d in tim al hyperplasia (so-called calciphylaxis): a com plication of ch ron ic ren al failure an d ben efit from parathyroidectom y. J Am Acad Derm atol 1995; 33(6); 954–962 [105] Coates T, Kirklan d GS, Dym ock RB, et al. Cutan eous n ecrosis from calcific urem ic arteriolopathy. Am J Kidn ey Dis 1998; 32(3); 384–391 [106] An gelis M, Wong LL, Myers SA, Wong LM. Calciphylaxis in patien ts on h em odialysis: a prevalen ce study. Surgery 1997; 122(6); 1083–1089, discussion 1089–1090 [107] Hayden MR, Goldsm ith D, Sowers JR, Kh an n a R. Calciphylaxis: calcific urem ic arteriolopathy an d th e em erging role of sodium th iosulfate. In t Urol Neph rol 2008; 40(2); 443–451 [108] Don BR, Ch in AI. A strategy for th e treatm en t of calcific urem ic arteriolopathy (calciphylaxis) em ployin g a com bin ation of th erapies. Clin Neph rol 2003; 59 (6); 463–470 [109] Naguib MT. Kidn ey disease in th e obese patien t. South Med J 2014; 107(8); 481–485 [110] Pliquett RU, Schw ock J, Pasch ke R, Ach en bach H. Calciphylaxis in ch ron ic, n on -dialysis-depen den t ren al disease. BMC Neph rol 2003; 4; 8 [111] Kan g AS, McCarth y JT, Row lan d C, Farley DR, van Heerden JA. Is calciphylaxis best treated surgically or m edically? Surgery 2000; 128(6); 967–971, discussion 971–972 [112] Stack BC, Jr, Bim ston DN, Boden n er DL, et al. AACE En docrin e Surgery Scien tific Com m ittee Disease Review Statem en t: Hypoparathyroidism -Defin ition s an d Man agem en t. Am erican Association of Clin ical En docrin ologists, En docrin e Surgery Scien tific Com m ittee, Hypoparathyroidism Working Group. En docr Pract [113] Sutters M, Gaboury CL, Ben n ett WM. Severe hyperph osph atem ia an d hypocalcem ia: a dilem m a in patien t m an agem en t. J Am Soc Neph rol 1996; 7(10); 2056–2061 [114] Bilezikian JP, Kh an A, Potts JT, Jr, et al. Hypoparathyroidism in th e adult: epidem iology, diagn osis, path ophysiology, target-organ involvem en t, treatm en t, an d ch allen ges for fut ure research . J Bon e Min er Res 2011; 26(10); 2317– 2337 [115] Mim oun i F, Tsan g RC. Neon atal hypocalcem ia: to treat or n ot to treat? (A review ). J Am Coll Nutr 1994; 13(5); 408–415 [116] Mü ller W , Peter HH, W ilken M et al. Th e DiGeorge syn drom e. I. Clin ical evaluation an d course of partial an d com plete form s of th e syn drom e. Eur J Pediatr 1988; 147(5); 496–502 [117] Mü ller W , Peter HH, Kallfelz HC, Fran z A, Rieger CH. Th e DiGeorge sequen ce. II. Im m un ologic fin din gs in partial an d com plete form s of th e disorder. Eur J Pediatr 1989; 149(2); 96–103

[118] Kobr yn ski LJ, Sullivan KE. Velocardiofacial syn drom e, DiGeorge syn drom e: th e ch rom osom e 22q11.2 deletion syn drom es. Lan cet 2007; 370(9596); 1443–1452 [119] Wilson DI, Burn J, Scam bler P, Goodsh ip J. DiGeorge syn drom e: part of CATCH 22. J Med Gen et 1993; 30(10); 852–856 [120] Mitch ell DM, Regan S, Cooley MR, et al. Lon g-term follow -up of patien ts w ith hypoparathyroidism . J Clin En docrin ol Metab 2012; 97(12); 4507–4514 [121] Ali A, Ch ristie PT, Grigorieva IV, et al. Fun ction al ch aracterization of GATA3 m utation s causing th e hypoparathyroidism -deafn ess-ren al (HDR) dysplasia syn drom e: in sigh t in to m ech anism s of DNA bin din g by th e GATA3 tran scrip tion factor. Hum Mol Gen et 2007; 16(3); 265–275 [122] Arn old A, Horst SA, Gardella TJ, Baba H, Levin e MA, Kron en berg HM. Mutation of th e sign al peptide-en codin g region of th e preproparathyroid h orm on e gen e in fam ilial isolated hypoparathyroidism . J Clin Invest 1990; 86(4); 1084–1087 [123] Bilous RW , Murt y G, Parkin son DB, et al. Brief report: autosom al dom in an t fam ilial hypoparathyroidism , sen sorin eural deafn ess, an d ren al dysplasia. N En gl J Med 1992; 327(15); 1069–1074 [124] An drew Nesbit M, Bow l MR, Harding B, Sch lessin ger D, Wh yte MP, Th akker RV. X-lin ked hypoparathyroidism region on Xq27 is evolution arily con ser ved w ith region s on 3q26 an d 13q34 an d con tains a n ovel P-type ATPase. Gen om ics 2004; 84(6); 1060–1070 [125] Fin n ish -Germ an APECED Con sort ium . An autoim m une disease, APECED, caused by m utation s in a n ovel gen e featurin g tw o PHD-t ype zin c-fin ger dom ain s. Nat Gen et 1997; 17(4); 399–403 [126] Sh apira H, Mouallem M, Sh apiro MS, Weism an Y, Farfel Z. Pseudohypoparathyroidism type Ia: tw o n ew h eterozygous fram esh ift m utation s in exon s 5 an d 10 of th e Gs alph a gene. Hum Gen et 1996; 97(1); 73–75 [127] Sh apiro MS, Bern h eim J, Gutm an A, Arber I, Spitz IM. Multiple abn orm alities of an terior pituitar y h orm on e secretion in association w ith pseudohypoparathyroidism . J Clin En docrin ol Metab 1980; 51(3); 483–487 [128] Liu J, Litm an D, Rosen berg MJ, Yu S, Biesecker LG, Wein stein LS. A GNAS1 im prin tin g defect in pseudohypoparathyroidism t ype IB. J Clin Invest 2000; 106(9); 1167–1174 [129] Yu D, Yu S, Schuster V, Kruse K, Clericuzio CL, Wein stein LS. Iden tification of tw o n ovel deletion m utation s w ith in th e Gs alph a gene (GNAS1) in Albrigh t h ereditar y osteodystrophy. J Clin En docrin ol Metab 1999; 84(9); 3254–3259 [130] Fitzpatrick LA, Arn old A. Hypoparathyroidism . In : DeGroot LJ, ed. En docrin ology, 3rd ed. Ph iladelph ia: W B Saun ders, 1995:1123 [131] Scurr y W C, Jr, Beus KS, Hollen beak CS, Stack BC, Jr. Perioperative parathyroid h orm on e assay for diagn osis an d m an agem en t of postth yroidectom y hypocalcem ia. Lar yn goscope 2005; 115(8); 1362–1366

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Parathyroid Diseases

22 Parat hyroid Carcinom a Jason P. Hunt and Richard B. Cannon

22.1 Int roduct ion Hypercalcem ia in th e presence of h igh parathyroid h orm on e (PTH) levels usually sign ifies th e presence of hyperparathyroidism . W h en th ese calcium levels are extrem e in n ature, it m ay raise th e con cern for parathyroid carcin om a. Th is is a rare disease th at can lead to death by hypercalcem ia if n ot t reated. Regardless of th e rarit y of disease, providers treatin g hyperparathyroidism sh ould be aw are of th e un ique features th at are suggestive of a m align an t process of th e parathyroid glan ds. Th is disease m ay be di cult to dist in guish from a parathyroid aden om a, but m align an t parathyroid n eoplasm s can often be predicted by th e pattern of presentation alon g w ith in traoperative fin din gs. Th ese in dolen t t um ors beh ave di eren tly th an m any h ead an d n eck m align an cies, an d th e cause of death is m ost often related to th e degree of hypercalcem ia. Alth ough th e prim ary treatm en t goal sh ould con sist of com plete surgical excision , residual tum or can persist for lon g periods of tim e. Even w h en surgical cure is n o lon ger possible, m an aging th e patien t’s hypercalcem ia is im portan t . Th is m ay require resection of local, region al, or distan t m etastatic disease. Wh en surgical resection is n ot possible, m edical m an agem en t of th e hypercalcem ia is n ecessary. Th is ch apter discusses th e presen tation of parathyroid carcin om a as w ell as curren t con cepts on its m an agem en t.

22.2 Epidem iology Parathyroid carcin om a w as first described by DeQuervain in 1904.1 It is in terestin g th at th is w as a n on fun ct ion in g tu m or, w h ereas th e vast m ajorit y of parathyroid carcin om as are fun ction in g tu m ors producin g sign ifican t levels of parathyroid h orm on e.2,3,4 It w asn’t un til 1933 th at Sain ton an d Millot described th e first fun ct ion in g parathyroid carcin om a.5 Th ough m ost parathyroid carcin om as are fu n ct ion in g t um ors w ith severely elevated calcium levels, w h ich aids th e diagn osis, n on fun ction in g tum ors m ay n ot be diagn osed un til th ey are m ore advan ced. With out th e extrem e elevation of serum calcium assistin g w ith th e detect ion of th e parathyroid m align an cy, th ese m ay n ot be recogn ized un til th ere is a palpable n eck m ass or it h as invaded struct ures of th e n eck th at a ect voice or sw allow in g. Parathyroid carcin om a a ect s approxim ately 0.005% of in dividuals per year according to a review of th e 286 cases in th e Nation al Can cer Database by Hun dah l an d colleagues.6 In a sep arate study, Lee an d colleagues evaluated th e Sur veillan ce, Epidem iology, an d En d Results (SEER) can cer regist ry from 1998 to 2003.7 Th ey n oted th at th e in ciden ce of parathyroid carcin om a h ad in creased by 60% in th e latter h alf of th e study. Th is in crease in in ciden ce m ay be related to im proved rates of diagn osis, but th e exact reason is un kn ow n . Th is in ciden ce also varies geograph ically per count r y. In location s such as Japan an d Italy, th e in ciden ce h as been reported as h igh as 5% of all cases of hyperparathyroidism .8,9 How ever, th e in ciden ce in th e Un ited States is < 1% of all hyperparathyroidism cases.10 Th ere are m any possible explan ation s for th e geograph ic di eren ces,

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in cluding gen etic di eren ces, referral pattern s, an d diagnost ic criteria, am ong oth ers. Alth ough th is is a low percen tage of patien ts, th e diagnosis m ust be kept in m in d w h en evaluatin g a patien t w ith hyperparathyroidism , an d un derstan din g th e presen tin g sign s an d sym ptom s is h elpful in th is process. In con trast to prim ar y hyperparathyroidism , w h ich h as a 3 to 4:1 fem ale to m ale distribution , parathyroid carcin om a a ects m ales an d fem ales equally.6 Most a ected in dividuals are m iddle-aged, th ough cases h ave been reported from 12 to 90 years of age.7,11,12,13 We outlin e epidem iological di eren ces betw een in dividuals w ith prim ar y hyperparathyroidism versus th ose w ith parathyroid carcin om a. Th e follow in g con dition s are associated w ith parathyroid carcin om a: ● Neck irradiation ● Hyperparathyroidism —jaw tum or syn drom e ● Fam ilial isolated hyperparathyroidism ● Multiple en docrin e n eoplasia t ype 1 Alth ough parathyroid carcin om a is rare, it m ust be con sidered in all in dividuals w ith prim ar y hyperparathyroidism . Certain w arn in g sign s on presen tation m ake th e diagn osis m ore likely. Th ese fin din gs w ill be presen ted later in th is ch apter.

22.3 Tum or Pat hogenesis Parathyroid carcin om a m ay develop spon tan eously or occur as part of a fam ilial syn drom e. Several con dition s h ave been associated w ith spon tan eous developm en t of parathyroid carcin om a as already m en tion ed . Neck irradiation a ects parathyroid glan ds an d in creases th e likelih ood of parathyroid disease,14,15 an d it h as been associated w ith m any cases of parathyroid carcin om a.16,17 Koea an d Shaw foun d th at 1.9% of parathyroid carcin om as w ere associated w ith previous radiation .18 Th is path w ay of parathyroid carcin ogen esis h as also been suggested in at least on e an im al study w h ere parathyroid carcin om a w as seen in m ice after exposure to n eck irradiat ion .19 Th is is n ot surprisin g because radiation is kn ow n to h ave carcin ogen ic e ects years after exposure. Parathyroid carcin om a h as also been associated w ith prim ar y hyperparathyroidism ,4,6,20 secon dar y hyperparathyroidism ,21 an d en d-stage ren al disease.22 How ever, th e rarit y of disease m akes stron g correlation s di cult. Fam ilial con dition s associated w ith parathyroid carcin om a in clude fam ilial isolated hyperparathyroidism , m ultiple en docrin e n eoplasia t ype 1 (MEN1), an d hyperparathyroidism –jaw tum or (HPT-JT) syn drom e. Fam ilial isolated hyperparathyroidism is an autosom al-dom in an t disease th at is distin ct from MEN syn drom es.23 It can h ave pron oun ced elevation s of calcium an d parathyroid h orm on e levels, an d it is associated w ith an in creased risk of developin g parathyroid can cer. MEN1 is an oth er h ereditar y syn drom e th at h as an association w ith parathyroid carcin om a.24,25,26 Som e studies h ave suggested th at th e gen et ic m utation s associated w ith MEN1 are respon sible for th e in creased risk, but th e defin itive eviden ce for th is causalit y is lackin g at th e presen t.27

Parathyroid Carcinom a Table 22.1 Clinical features of hyperparathyroidism and hypercalcem ia because of parathyroid carcinomas versus benign disease Organ system

Presenting sym ptom s and com plaints

Percent affected Malignant

Benign

Renal

Polyuria, polydipsia, urolithiasis, and kidney failure

56

20

Bone

Osteopenia, osteoporosis, pathological fractures, and bone pain

63

8

Neurom uscular

Fatigue, muscle aches, proxim al m uscle weakness, decreased memory, irritabilit y, 74 and depression

38

Gastrointestinal

Anorexia, nausea, vom iting, constipation, peptic ulcers, and pancreatitis

18

8

Rheum atologic

Gout, pseudogout, chondrocalcinosis, and calcific tendinitis

12

1

Cardiovascular

Decreased QT interval, arrhythm ias, and hypertension

14

1

Asymptomatic

2

47

Data from Obara and Fujim oto 12, Kvols36 , and Uden P, Chan A, Duh QY, Siperstein A, Clark OH. Prim ary hyperparathyroidism in younger and older patients: Sym ptoms and outcomes of surgery. World J Surg 1992; 16: 791–798.

HPT-JT syn drom e is an oth er autosom al-dom in an t syn drom e th at h as ossifyin g jaw tum ors, ren al n eoplasm s, uterin e t um ors, and hyperparathyroidism . Th e gen et ic defect associated w ith th is disease is a m utation in th e HRPT2 gen e th at codes for parafibrom in .28 Th is protein is con sidered to be a tum or suppressor because it can in duce apoptosis. Th is in ciden ce of parathyroid carcin om a has been reported to be as h igh as 15% in th is con dition .2,29 Sporadic cases of parathyroid carcin om a are also frequen tly associated w ith HRPT2 gen e m utation s. Multiple studies h ave foun d a h igh rate of HRPT2 gen e m utation s in depen den t of HPT-JT syn drom e.30,31 Because parafibrom in in activation is lin ked to a large portion of parathyroid carcin om as, th is m utation is con sidered a m arker for parathyroid carcin om a. Th is gen e m ay be involved in th e m ajorit y of cases of sporadic parathyroid carcin om a.

22.4 Clinical Present at ion 22.4.1 Hist ory Parathyroid carcin om as are rare, t ypically slow -grow in g tum ors w ith a ten den cy to recur locally an d m etastasize late. As previously stated, parathyroid can cer is equally distributed betw een m en an d w om en , w h ereas parathyroid aden om as an d hyperplasia are th ree tim es m ore com m on in w om en .32 Som e studies suggest th ese t um ors m ay presen t earlier in life com pared w ith ben ign hyperparathyroidism . Th e average age at presentation is betw een 40 an d 60, th ough it h as been reported across a w ide age ran ge.7,33 Nearly all tum ors are fun ction al (95%) an d result in severe prim ar y hyperparathyroidism . Typically, serum calcium an d PTH levels are sign ifican tly elevated, w ith 70% h avin g serum calcium con cen t ration s > 14 m g/dL, an d patien ts are ver y often sym ptom at ic from th eir hypercalcem ia.12,34 Frequen tly, patien ts w ill presen t w ith both bon e an d kidn ey disease. In addition , patien ts can present w ith voice com plain ts an d recurren t laryn geal n erve dysfun ction , w h ich, w h en coupled w ith prim ary hyperparathyroidism , sh ould raise con cern for parathyroid can cer. How ever, som e parathyroid can cers m ay n ot be fu n ct ion al

an d presen t on ly w ith sym ptom s related to local tum or invasion . Sym ptom s of hypercalcem ia are n ot un ique to parathyroid carcin om a. In fact , < 1% of pat ien ts w ith hypercalcem ia an d on ly 0.5 to 2% of pat ien ts w ith hyperparathyroidism w ill h ave can cer of th e parathyroid glan d.35 How ever, patien ts w ith can cer t ypically h ave severe sym ptom s. Hypercalcem ia can cause ren al, bon e, n eurom uscular, rh eum atologic, gast roin testin al, an d cardiovascular sym ptom s, as w ell as form calcium deposits in th e skin , corn ea, an d lun gs ( Table 22.1).36 Alth ough th ese sym p tom s m ay raise th e level of suspicion for can cer, th e degree of hypercalcem ia sh ould be th e clin ician ’s best w arn in g sign .

22.4.2 Physical Findings Approxim ately 40% of patien ts w ith parathyroid can cer w ill presen t w ith a n eck m ass.37 Th is occurs in th e t ypical location for parathyroid glan ds: just o m idlin e, on eith er side, an d low in th e n eck. A n eck m ass in th is location can be con fused w ith level IV cervical lym ph aden opathy or a thyroid n odule. Non fun ction al parathyroid carcin om as also m ost com m on ly presen t w ith a n eck m ass. Th ese patien ts rem ain n orm ocalcem ic an d usually h ave m ore advan ced-stage disease at presentation , an d th eir tu m ors are m ore aggressive. In con trast to patien ts w ith fun ct ion al parathyroid can cers, patien ts w ith n on fun ction al tum ors die from m ass e ect an d tum or burden , rath er th an from hypercalcem ia.34 Approxim ately 10% of pat ien t w ill present w ith recurren t laryn geal n er ve dysfun ction .12 Vocal fold paresis an d paralysis sym ptom s in clude dysph on ia, a h oarse or breathy voice, sh ortn ess of breath , an d/or aspiration . Th e diagn osis is m ade by direct or in direct lar yn goscopy dem on st ratin g un ilateral decreased or absen t m ovem ent of th e vocal fold.

22.5 Evaluat ion 22.5.1 Laborat ory St udies Hyperparathyroidism is t ypically diagn osed w ith serum calcium an d PTH levels. Studies h ave sh ow n th at serum calcium

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Parathyroid Diseases (MRI) is less com m on ly used because of th e expen se, an d m any studies h ave sh ow n it is n ot superior to CT for isolatin g parathyroid m asses. Fin ally, a parathyroid scan , or scin tigraphy, is com m on ly used to iden tify parathyroid t um ors. Th is test uses th e radioisotopes th allium -201 an d tech n etium -99 m an d com puter subtraction tech n iques to localize en larged parathyroid glan ds. Th allium 201 con cen trates in both parathyroid an d thyroid tissues, an d th en tech n etium -99 m con cen trates in th e thyroid, so subtraction allow s im aging of parathyroid glan ds an d tum ors. It h as good sen sitivit y, but its specificit y can be a ected by con com itan t thyroid disease, an d it is n on specific for aden om as an d carcin om as.

22.6 Di erent ial Diagnosis

Fig. 22.1 CT im age of a parathyroid carcinom a (arrow). (Courtesy of Richard Wiggins, MD.)

levels are > 14 m g/dL in 65 to 75% of patien ts w ith m align an t hyperparathyroidism com pared to on ly 10% of patien ts w ith ben ign disease.12,34 Also, PTH levels are usually ver y h igh an d at least 5 tim es h igh er th an th e upper lim it of n orm al, w ith th e m ean elevation 10.2 tim es h igh er th an th e upper lim it of n orm al.11 In addition , vitam in D deficien cy, hypoph osph atem ia, an d hypercalciuria are often seen in patien ts w ith parathyroid carcin om as. Ren al dysfun ct ion presen ts w ith elevated blood urea n itrogen (BUN) an d creatin in e, an d elevated am ylase an d lipase are h allm arks of acute pan creatitis. An em ia is com m on in parathyroid carcin om a (~ 80% of patien ts), in con trast to ben ign parathyroid disease (< 10% of patien ts).

22.5.2 Im aging High -resolution ultrason ography is th e m ost com m on ly em ployed tech n ique to visualize parathyroid tum ors. Ultrasoun d gives excellen t soft tissue resolution , is n on invasive, an d is relatively ch eap, but its results are operator depen den t . Also, it is lim ited to im aging th e an terior n eck; retroesoph ageal, retrotrach eal, an d m ediastin al areas are poorly visualized. Parathyroid carcin om as appear as hypoech oic m asses th at ten d to be larger, m ore h eterogen eous, an d m ore lobulated th an ben ign aden om as, w h ich are sm aller, h om ogen eous, an d h ave sm ooth borders.38 In filtrative lesion s an d th ose w ith calcification s are suspicious for can cer.39 In addition , th e depth –w idth (DW) ratios are distin ctly di eren t, w ith a m ean n ear 1.21 for carcin om a versus a m ean of 0.64 for aden om as. Con trast-en h an ced com puted tom ography (CT) is com m on ly used to visualize th e soft tissue of th e n eck an d can be h elpful to fully evaluate n earby struct ures. Th is is a useful im agin g m odalit y in cases of carcinom a because it allow s for full evaluation of th e local disease exten t an d m etastases. It m ay give a superior evaluation of th e cent ral n eck an d superior m ediastin um for lym ph n ode evaluation . Fig. 22.1 sh ow s a t ypical CT im age of a parathyroid carcin om a. Magn et ic reson an ce im agin g

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Th e clin ician m ust also rule out oth er causes of can cer-related hypercalcem ia. Th ese in clude lytic bon e m etastasis an d ectopic product ion of PTH by n on parathyroid tum ors, such as ren al, ovarian , bladder, breast , an d sm all cell lun g carcin om as. Urin ar y cyclic aden osin e m on oph osph ate (cAMP) an d ph osph ate can be used to h elp distin guish th e un derlyin g cause. Tum ors secreting PTH w ill h ave a h igh urin ary cAMP an d low ph osph ate, an d lytic bon e m etastases w ill h ave a low urin ar y cAMP an d n orm al ph osph ate. Also, tum or-excretin g ectopic PTH w ill h ave low levels of in tact PTH, an d PTH m essen ger RNA (m RNA) w ill n ot be expressed. Fin ally, PTH-related protein (PTHrP) is expressed in som e can cers (in cluding squam ous cell carcin om as of th e lun g, esoph agus, an d h ead an d n eck) an d m ay cause hypercalcem ia. PTHrP can be detected by radioim m un oassay. Th e frequen t sim ilarit y to a ben ign parathyroid aden om a presen ts a m ajor diagnost ic ch allenge. In fact, m any parathyroid carcin om as are n ot diagn osed un t il durin g surgery or after excision . As previously described th e h istory, physical exam , labs, an d im aging can be suggestive of a parathyroid carcin om a, but h istological con firm ation is required to secure th e diagn osis. Th is can be a di cult task because th ere is n o sin gle h istopath ological feature th at defin es a parathyroid can cer. Th ese lesion s ten d to be large, den se tum ors as seen in th e gross picture in Fig. 22.2. A m align an t parathyroid n eoplasm can be assured on ly by distin ct invasion of th e surroun din g struct ures, vascular invasion , or m etastases. Th ere are som e features th at are h igh ly suggestive of parathyroid carcin om a. Th ese in clude a th ick fibrous capsule, capsular invasion , m itotic figures, prom in en t n uclear en largem en t, an d pleom orph ism ( Fig. 22.3). How ever, th ese features m ay occasion ally be seen in n on m align an t parathyroid disease. At tim es, th e defin itive diagn osis can n ot be m ade un til th e patien t is n oted to h ave recurren ce or m etastatic disease on follow -up. In dividuals w ith a parathyroid n eoplasm th at is suspicious, but n ot diagnostic, for carcin om a sh ould be follow ed as if th e lesion w ere m align an t.

22.7 Treat m ent 22.7.1 Surgery Surgical excision is th e m ain stay of th erapy an d is th e on ly curative treatm en t . Th e th orough n ess of th e in itial operation is cru cial, an d tum or spillage often results in local t um or recurren ce. A preoperative diagnosis is n ot alw ays secure, an d th e

Parathyroid Carcinom a surgeon m ust recogn ize certain in traoperative fin din gs th at suggest a carcin om a. Th ese gross fin din gs in clude a th ick fibrous capsule, gray-w h ite color, invasion in to adjacen t structures, large size, an d h ard con sisten cy. Th e approach to th e in itial surgery h as evolved from an aggressive procedure involving an ipsilateral thyroidectom y, isth m usectom y, excision of th e adjacen t strap m uscles, an d a low th resh old to rem ove th e recurren t lar yn geal n er ve, to a m ore conser vative parathyroidectom y or en bloc resection of th e t um or w ith any adjacen t invaded struct ures an d a rim of h ealthy tissue. In th e SEER database, 78.6% of parathyroid carcin om as w ere rem oved via surgeon -reported parathyroidectom y, an d 12.5% w ere rem oved by en bloc resection .7 Th e recurren t lar yn geal n erve sh ould be

sacrificed, if involved, due to a h igh rate of local recurren ce w ith attem pts to dissect th e tum or from th e n er ve. Elect ive n eck dissection is con troversial but gen erally n ot recom m en ded due to low rates of region al m etastasis. For residual disease w ith a positive m argin or region al recurren ce, reoperation is recom m en ded to rem ove all tum or tissue. Most recurren ces occur w ith in th e n eck.40 In addition , due to th e lim ited e cacy of n on surgical th erapies, surgical resection of m etastat ic disease can be con sidered, prim arily to debulk th e tum or an d palliate th e e ects of hypercalcem ia. Th ese m easures are n ot likely to be curative but m ay provide lastin g control by reducin g th e tum or volum e. Studies h ave sh ow n th at palliation of hypercalcem ia is frequen tly achieved in reoperation s, an d respon ses m ay last from a few m on th s to several years.8,11,13,17 Postoperative m an agem en t prim arily consists of m on itorin g patien ts closely for hypocalcem ia or h ungr y bon e syn drom e an d repletin g th eir seru m calcium levels w ith oral an d in traven ous calcium an d vitam in D as n eeded. Th ese patien ts m ay h ave low levels of vitam in D preoperatively w ith ver y h igh levels of serum calcium . Th is com bin ation m ay in crease th e risk of h un gry bon e syn drom e over th at of th e routin e parathyroid aden om a resection .

22.7.2 Radiat ion Parathyroid carcin om as ten d to be radioresistan t, an d th e literature is lim ited to sm all obser vation al studies w ith out prolon ged follow -up. In th e prim ar y settin g, th ere is 1 case report of lon g-term sur vival, 11 years, of a patien t w ith invasive parathyroid carcin om a treated w ith defin itive radiation.11 A series out of MD An derson sh ow ed th at adjuvan t radioth erapy h ad a local recurren ce rate of 16.7% (1/6 patien ts), w h ereas th ose w ith out adjuvan t radioth erapy h ad a local recurren ce rate of 50% (10/20 pat ien ts).37 Also, a series out of th e Mayo Clin ic dem on st rated a low er risk of locoregion al disease progression an d im proved cause-specific sur vival w ith adjuvan t radiation based on four pat ien ts w h o received adjuvan t radiation th erapy for locoregion al disease progression after in itial surgery.41 In addition , radioth erapy can be con sidered for palliation of pain from bon e m etastasis an d for sym ptom s of hypercalcem ia.

22.7.3 Chem ot herapy

Fig. 22.2 Gross specim en of a parathyroid carcinom a.

Experien ce w ith ch em oth erapy is lim ited to case reports in th e palliative settin g for severe, refractory hypercalcem ia. Dacarbazin e, 5-fluorouracil, an d cycloph osph am ide resulted in n orm alization of serum calcium for 13 m on th s in on e patien t w ith pulm on ar y m etastases.2 Th is regim en sh ow ed a com plete

Fig. 22.3 Pathological slides of parathyroid carcinoma. (a) Light m icrophotograph of parathyroid carcinom a showing thick fibrous bands intersecting the gland with areas of necrosis (hem atoxylin-eosin stain; original m agnification × 4). (b) Light m icrophotograph of parathyroid carcinom a further showing thick fibrous bands along with encasem ent of surrounding vasculature (hematoxylin-eosin stain; original m agnification × 100). (Courtesy of Benjam in Witt, MD.)

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Parathyroid Diseases sym ptom at ic respon se an d a part ial bioch em ical respon se for 5 m on th s w ith m oderate gastroin testin al side e ects.42 Dacarbazin e alon e sh ow ed a dram atic respon se for 2 m on th s w ith n orm alization of serum calcium in a patien t w ith aggressive locally recurren t disease despite five previous n eck exploration s. 43 In on e patien t w ith a m etastatic n on fun ct ion al parathyroid carcin om a, ch em oth erapy w ith m eth otrexate, adriam ycin , cycloph osph am ide, an d lom ustin e sh ow ed a dram atic an d com plete resolution of th eir m ediastin al m ass an d pleural e usion after 18 m on th s of treatm en t .44

22.7.4 Medical Managem ent Mortalit y from parathyroid carcin om a gen erally results from un con trolled hypercalcem ia. Con trollin g hypercalcem ia is th erefore im portan t an d can be a di cult task. Surgical resection of a fu n ct ion in g tum or is th e best option , even if lim ited m etastatic deposits exist,2 an d th ere m ay be a role for resectin g m etastatic disease. Wh en th ere are n o surgical option s rem ain in g for treatin g th e can cer, th e provider is lim ited to con trollin g th e calcium levels th rough m edical m an agem en t. Th is approach requires aggressive hydration an d th e use of a calcim im etic agen t or in traven ous bisph osph on ate. Calcim im etics suppress th e product ion of parathyroid h orm on e by in creasin g th e sen sitivit y of th e calcium -sen sing receptor. Cin acalcet is th e agen t curren tly available for treatm en t of parathyroid related hypercalcem ia. It is often used w h en surgery is n ot an option an d patien ts h ave sign ifican t hypercalcem ia. On e study by Silverberg sh ow ed th at cin acalcet could reduce calcium levels by at least 1 m g/dL in th e m ajorit y of patien ts. Oth er calcim im etics h ave also been looked at w ith sim ilar results.45,46 Side e ects related to calcim im et ics in clude n ausea, vom itin g, diarrh ea, an d dehydration . Patien ts m ay n eed con tin uous hydration to m an age th ese side e ects. Bisph osph on ates can also be h elpful in reducin g calcium levels. Th ey w ork by suppressin g osteoclast-m ediated bon e resorption an d m ay h elp con trol hypercalcem ia over an exten ded t im e w ith m ultiple doses.2,47 Th ere are m ultiple option s to ch oose from , in cluding den osum ab, w h ich is a fully h um an ized m on oclon al an tibody th at h as been used to treat postm en opausal osteoporosis an d to preven t skeletal even ts from bon e m etastases. It h as also recen tly been advocated for use in con trol of hypercalcem ia of m align an cy, in cluding th at caused by parathyroid carcin om a.48,49 Oth er poten t ial treatm en t s in clude im m un oth erapy an d radiofrequen cy ablation . In som e studies, in fusin g a set of PTH peptide im m un ogen s con trolled hypercalcem ia an d w as even seen to in duce regression of m etastatic t um or.50,51 Oth er studies sh ow ed less e ect iven ess.52 Radiofrequen cy ablation h as been used to con trol focal m etastatic lesion s th at lead to hypercalcem ia. It h as been sh ow n , in case reports, to cont rol serum calcium levels.47,53 Th e e ects h ave been tem porar y, but it can be repeated.

22.8 St aging and Survival Th ere is n o stan dardized staging system for parathyroid can cer. Th is is in part due to th e rare in ciden ce of th is en tit y as w ell as

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th e di cult y in m akin g a path ological diagn osis. Th ere are n ot clear diagn ostic h istological features of parathyroid carcin om a in th e absen ce of fran k tum or invasion or m etastases. Typical factors related to disease progn osis, such as th e T (size of th e prim ar y tum or), N (lym ph n ode status), an d M (distan t m etastases status) status h ave proven to be less reliable predictors of outcom e in parathyroid carcin om a th an in oth er en docrin e tum ors.6,7 Invasion in to adjacen t struct ures is com m on an d often used in th e diagnostic criteria. Th ere is also a ten den cy to invade n er ves in th e area, such as th e recurren t lar yn geal n erve (RLN). Th e im pact of RLN invasion on sur vival is un kn ow n , but it is recom m en ded to sacrifice th is n er ve if it is foun d to be invaded. Th e lym ph n ode status is also n ot ver y useful because < 5% of parathyroid carcin om as present w ith lym ph n ode involvem en t.6 Also, lym ph n ode involvem en t does n ot appear to im pact lon g-term sur vival. Wh en lym ph n ode m etastases occur, th ey are m ore likely to be associated w ith recurren t cases of parathyroid can cer.

22.9 Out com es Parathyroid carcin om a is often a slow -grow in g in dolen t disease. Th e overall sur vival h as been reported from 49 to 95% at 10 years.6,7,40 Lee’s study usin g th e SEER database did sh ow a tren d tow ard im proved sur vival in m ore recen t years alon g w ith a tren d tow ard in creased surgical in terven tion .7 Alth ough patien ts often die of hypercalcem ia, aggressive m edical m an agem en t m ay be able to im prove lon g-term sur vival by con trollin g serum calcium levels, an d th is approach m ay explain som e reports of 10-year sur vival rates as h igh as 77%.54 Local disease con trol m ay be di cult due to th e ten den cy for invasion of surroun din g struct ures, an d recurren ce occurs in approxim ately 50% of patien ts.37,40 Th e tim e to recurren ce averages 3 years, w ith a ran ge up to 20 years.55,56 Alth ough th ere are few, if any, progn ostic factors th at predict outcom e, early detect ion an d en bloc resection h ave been suggested as th e best w ay to control disease. How ever, patien ts n eed lon g-term follow -up to assess for recurren ce as w ell as th e n eed for possible m edical m an agem en t of hypercalcem ia. Follow -up sh ould con sist of a clin ical evaluation , in cluding a periodic physical exam ination , laborator y studies, an d im aging. In tact parathyroid h orm on e an d serum calcium levels provide an e cien t w ay to follow patien ts w ith fun ct ion in g parathyroid carcin om as. For n on fun ct ion in g can cers, im agin g an d physical exam are th e prim ar y m odes of sur veillan ce. Im aging option s m ay var y but w ould often in clude ultrasoun d or CT evaluation of th e n eck. CT of th e abdom en an d pelvis m ay be required to evaluate pat ien ts at risk for distan t disease.

22.10 Conclusion Parathyroid carcin om a is a rare disease. Un derstan din g th e t yp ical presen tat ion can prepare th e clin ician for m akin g th e correct diagnosis. Surgery is th e prim ar y treatm en t in th is in dolen t m align an cy, but con trollin g th e degree of hypercalcem ia is im portan t , even in in curable cases, to provide lon g-term sur vival.

Parathyroid Carcinom a

References [1] DeQuer vain F. Parastrum a m align a aberrata[Malign an t aberran t parathyroid] Deusche Zeitsch r Ch ir 1904; 100(1); 334–352 [2] Sh an e E. Clin ical review 122: Parathyroid carcinom a. J Clin En docrin ol Metab 2001; 86(2); 485–493 [3] Sch aapveld M, Jorn a FH, Aben KK, Haak HR, Plukker JT, Lin ks TP. In ciden ce an d progn osis of parathyroid glan d carcin om a: a population -based study in Th e Neth erlan ds estim atin g th e preoperative diagn osis. Am J Surg 2011; 202 (5); 590–597 [4] W ilkin s BJ, Lew is JS, Jr. Non-fun ct ion al parathyroid carcin om a: a review of th e literature an d report of a case requirin g exten sive surgery. Head Neck Path ol 2009; 3(2); 140–149 [5] Sain ton P, Millot J. Malegn e dun aden om a parathyroidien e eosin oph ile; au cours dun e de Recklin gh ausen . An n An atom ie Patholgique 1933; 10; 813 [6] Hun dah l SA, Flem in g ID, Frem gen AM, Men ck HR Th e Am erican College of Surgeon s Com m ission on Can cer an d th e Am erican Can cer Society. Tw o h un dred eigh t y-six cases of parathyroid carcinom a treated in th e U.S. betw een 1985–1995: a Nation al Can cer Data Base Report . Can cer 1999; 86(3); 538– 544 [7] Lee PK, Jarosek SL, Virn ig BA, Evasovich M, Tuttle TM. Tren ds in th e in ciden ce an d treatm en t of parathyroid can cer in th e United States. Can cer 2007; 109 (9); 1736–1741 [8] Fujim oto Y, Obara T. How to recogn ize an d treat parathyroid carcinom a. Surg Clin North Am 1987; 67(2); 343–357 [9] Favia G, Lum ach i F, Polistin a F, D’Am ico DF. Parathyroid carcin om a: sixteen n ew cases an d suggestion s for correct m an agem en t. World J Surg 1998; 22 (12); 1225–1230 [10] Ruda JM, Hollen beak CS, Stack BC, Jr. A system atic review of th e diagn osis an d treatm en t of prim ar y hyperparathyroidism from 1995 to 2003. Otolaryn gol Head Neck Surg 2005; 132(3); 359–372 [11] W yn n e AG, van Heerden J, Carn ey JA, Fitzpatrick LA. Parathyroid carcinom a: clin ical an d path ologic features in 43 patien ts. Medicin e (Baltim ore) 1992; 71 (4); 197–205 [12] Obara T, Fujim oto Y. Diagn osis an d treatm en t of patien ts w ith parathyroid carcinom a: an update an d review. World J Surg 1991; 15(6); 738–744 [13] Holm es EC, Morton DL, Ketch am AS. Parathyroid carcin om a: a collective review. An n Surg 1969; 169(4); 631–640 [14] Ippolito G, Palazzo FF, Sebag F, Hen r y JF. Lon g-term follow -up after parathyroidectom y for radiation -in duced hyperparathyroidism . Surgery 2007; 142 (6); 819–822, discussion 822.e1 [15] Woll ML, Mazeh H, An derson BM, Ch en H, Sippel RS. Breast radiation correlates w ith side of parathyroid aden om a. World J Surg 2012; 36(3); 607–611 [16] Favia G, Lum ach i F, Polistin a F. DÁm ico DF. Parathyroid carcinom a: sixteen n ew cases an d suggestion s for correct m an agem en t. World J Surg 1998; 22; 1225–1230 [17] Obara T, Okam oto T, Kan be M, Lih ara M. Fun ction in g parathyroid carcinom a: clin icopath ologic features an d ration al treatm en t. Sem in Surg On col 1997; 13; 134–141 [18] Koea JB, Sh aw JH. Parathyroid can cer: biology an d m an agem en t. Surg On col 1999; 8(3); 155–165 [19] Oh m ach i Y, Yosh ida M, Ogiu T. Tw o cases of m etastatic parathyroid carcinom a in m ale C3 H m ice follow ing irradiation . J Toxicol Path ol 2013; 26(4); 413–417 [20] Mash burn MA, Ch on kich GD, Ch ase DR, Petti GH, Jr. Parathyroid carcinom a: tw o n ew cases—diagn osis, th erapy, an d treatm en t. Lar yn goscope 1987; 97 (2); 215–218 [21] Raw at N, Kh etan N, W illiam s DW , Baxter JN. Parathyroid carcin om a. Br J Surg 2005; 92(11); 1345–1353 [22] Wu CW , Huan g CI, Tsai ST, Ch ian g H, Lui W Y, P’en g FK. Parathyroid carcinom a in a patien t w ith n on -secretor y pituitar y tum or: a varian t of m ultiple en docrin e n eoplasia type-I? Eur J Surg On col 1992; 18(5); 517–520 [23] Wassif W S, Mon iz CF, Friedm an E, et al. Fam ilial isolated hyperparathyroidism : a distin ct genetic en tit y w ith an in creased risk of parathyroid can cer. J Clin En docrin ol Metab 1993; 77(6); 1485–1489 [24] Agh a A, Carpen ter R, Bh attach ar ya S, Edm on son SJ, Carlsen E, Mon son JP. Parathyroid carcin om a in m ultiple en docrin e n eoplasia type 1 (MEN1) syn drom e: t w o case reports of an un recogn ised en tit y. J En docrin ol Invest 2007; 30 (2); 145–149 [25] Sh ih RY, Fackler S, Maturo S, True MW, Bren n an J, Wells D. Parathyroid carcin om a in m ultiple en docrin e n eoplasia type 1 w ith a classic germ lin e m utation . En docr Pract 2009; 15(6); 567–572

[26] Sato M, Miyauchi A, Nam ih ira H, et al. A n ew ly recogn ized germ lin e m utation of MEN1 gen e iden tified in a patien t w ith parathyroid aden om a an d carcinom a. En docrin e 2000; 12(3); 223–226 [27] del Pozo C, García-Pascual L, Balsells M, et al. Parathyroid carcin om a in m ultiple en docrin e n eoplasia t ype 1. Case report an d review of th e literature. Horm on es (Ath ens) 2011; 10(4); 326–331 [28] Carpten JD, Robbin s CM, Villablan ca A, et al. HRPT2, en codin g parafibrom in , is m utated in HPT-jaw tum or syn drom e. Nat Gen et 2002; 32; 676–680 [29] Mizusaw a N, Uch ino S, Iw ata T, et al. Gen etic an alyses in patien ts w ith fam ilial isolated hyperparathyroidism -jaw tum or syn drom e. Clin En docrin ol (Oxf) 2006; 65; 9–16 [30] Sh attuck TM, Välim äki S, Obara T, et al. Som atic an d germ -lin e m utation s of th e HRPT2 gen e in sporadic parathyroid carcin om a. N En gl J Med 2003; 349 (18); 1722–1729 [31] How ell VM, Haven CJ, Kah n oski K, et al. HRPT2 m utation s are associated w ith m align an cy in sporadic parathyroid tum ours. J Med Gen et 2003; 40(9); 657– 663 [32] Wan g CA, Gaz RD. Natural h istor y of parathyroid carcin om a. Diagn osis, treatm en t, an d results. Am J Surg 1985; 149(4); 522–527 [33] Robert JH, Trom betti A, Garcia A, et al. Prim ar y hyperparathyroidism : can parathyroid carcin om a be an ticipated on clin ical an d bioch em ical groun ds? Report of n in e cases an d review of th e literature. An n Surg On col 2005; 12 (7); 526–532 [34] Sh an e E, Bilezikian JP. Parathyroid carcin om a: a review of 62 patien ts. En docr Rev 1982; 3(2); 218–226 [35] Wei CH, Harari A. Parathyroid carcin om a: update an d guidelin es for m an agem en t. Curr Treat Option s On col 2012; 13(1); 11–23 [36] Kvols LK. Parathyroid carcin om as, ph eoch rom ocytom as, an d m ultiple en docrin e n eoplasia syn drom es. In : Kufe DW , Pollock RE, Weich selbaum RR, et al., editors. Hollan d-Frei Can cer Medicin e. 6th edition . Ham ilton (ON): BC Decker; 2003 [37] Busaidy NL, Jim en ez C, Habra MA, et al. Parathyroid carcin om a: a 22-year experien ce. Head Neck 2004; 26(8); 716–726 [38] Hara H, Igarash i A, Yan o Y, et al. Ultrason ograph ic features of parathyroid carcin om a. En docr J 2001; 48(2); 213–217 [39] Sidh u PS, Talat N, Patel P, Mulh ollan d NJ, Sch ulte KM. Ultrasoun d features of m align an cy in th e preoperative diagn osis of parathyroid can cer: a retrospective an alysis of parathyroid tum ours larger th an 15 m m . Eur Radiol 2011; 21 (9); 1865–1873 [40] San d elin K, Au er G, Bon d eson L, Grim eliu s L, Farn ebo LO. Progn ost ic fact ors in p arat hyroid can cer: a review of 95 cases. World J Su rg 1992; 16(4); 724–731 [41] Mun son ND, Foote RL, Nor th cutt RC, et al. Parathyroid carcinom a: is th ere a role for adjuvan t radiation th erapy? Can cer 2003; 98(11); 2378–2384 [42] Bukow ski RM, Sh eeler L, Cun n in gh am J, Esselstyn C. Successful com bin ation ch em oth erapy for m etastatic parathyroid carcinom a. Arch In tern Med 1984; 144(2); 399–400 [43] Calan dra DB, Ch ejfec G, Foy BK, Law ren ce AM, Paloyan E. Parathyroid carcinom a: bioch em ical an d path ologic respon se to DTIC. Surgery 1984; 96(6); 1132–1137 [44] Ch ah in ian AP, Hollan d JF, Nieburgs HE, Marin escu A, Geller SA, Kirsch n er PA. Metastatic n on fun ction in g parathyroid carcinom a: ultrastruct ural eviden ce of secretor y gran ules an d respon se to ch em oth erapy. Am J Med Sci 1981; 282 (2); 80–84 [45] Silverberg SJ, Rubin MR, Faim an C, et al. Cin acalcet hydroch loride reduces th e serum calcium con cen tration in in operable parathyroid carcin om a. J Clin En docrin ol Metab 2007; 92(10); 3803–3808 [46] Collin s MT, Skarulis MC, Bilezikian JP, Silverberg SJ, Spiegel AM, Marx SJ. Treatm en t of hypercalcem ia secon dar y to parathyroid carcin om a w ith a n ovel calcim im etic agent. J Clin En docrin ol Metab 1998; 83(4); 1083–1088 [47] W it t eveen JE, Haak HR, Kievit J, Morreau H, Rom ijn JA, Ham d y NA. Ch allen ges an d p it falls in t h e m an agem en t of p arat hyroid carcin om a: 17-year follow -u p of a case an d review of t h e lit erat u re. Horm Can cer 2010; 1(4); 205–214 [48] Karuppiah D, Th an abalasingh am G, Sh in e B, et al. Refractor y hypercalcaem ia secon dar y to parathyroid carcin om a: respon se to h igh -dose den osum ab. Eur J En docrin ol 2014; 171(1); K1–K5 [49] Vellan ki P, Lan ge K, Elaraj D, Kopp PA, El Muayed M. Den osum ab for m an agem en t of parathyroid carcinom a-m ediated hypercalcem ia. J Clin En docrin ol Metab 2014; 99(2); 387–390 [50] Bradwell AR, Har vey TC. Con trol of hypercalcaem ia of parathyroid carcin om a by im m un isation . Lan cet 1999; 353(9150); 370–373

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Parathyroid Diseases [51] Betea D, Bradw ell AR, Harvey TC, et al. Horm on al an d bioch em ical n orm alization an d tum or sh rin kage in duced by an ti-parathyroid h orm on e im m un oth erapy in a patien t w ith m etastatic parathyroid carcin om a. J Clin En docrin ol Metab 2004; 89(7); 3413–3420 [52] Horie I, An do T, In okuch i N, et al. First Japan ese patien t treated w ith parathyroid h orm on e peptide im m un ization for refractor y hypercalcem ia caused by m etastatic parathyroid carcin om a. En docr J 2010; 57(4); 287–292 [53] DasGupta R, Sh ett y S, Kesh ava SN, Gupta M, Paul MJ, Th om as N. Metastatic parathyroid carcin om a treated w ith radiofrequen cy ablation : A n ovel th erapeutic m odalit y. Australas Med J 2014; 7(9); 372–375

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[54] Claym an GL, Gon zalez HE, El-Naggar A, Vassilopoulou-Sellin R. Parathyroid carcinom a: evaluation an d in terdisciplin ar y m an agem en t. Can cer 2004; 100 (5); 900–905 [55] Rao SR, Sh ah a AR, Sin gh B, Rin aldo A, Ferlito A. Man agem en t of can cer of th e parathyroid. Acta Otolaryn gol 2002; 122(4); 448–452 [56] Kebebew E. Parathyroid carcin om a. Curr Treat Option s On col 2001; 2(4); 347–354

Parathyroid Im aging

23 Parat hyroid Im aging Rosemarie Metzger and Mira Milas

23.1 Int roduct ion

23.2 Ult rasound

Much tim e h as passed sin ce th e days w h en palpation an d barium sw allow studies w ere th e preoperative localization m eth ods of ch oice for prim ary hyperparathyroidism . Th erm ography, selen om eth ion in e scin tiscan n in g, an d esoph ageal cin eradiography h ave likew ise join ed th eir ran ks in th e h istory books.1 Today, th e m odalit ies of ch oice for parathyroid im agin g in clude ultrasoun d an d tech n etium -99 m ( 99m Tc)-sestam ibi (sestam ibi) im agin g, an d, m ore recen tly, four-dim en sion alcom puted tom ography (4D- CT) scan n in g. In com bin ation w ith th e developm en t of in traoperative parathyroid h orm on e m easurem en t, advan ces in parathyroid im aging en abled th e adop tion of focal parathyroid explorat ion as a surgical strategy. At presen t, w h eth er surgery is focal or bilateral explorat ion ,2,3,4 th e role of parathyroid im aging rem ain s critically im portan t. Preoperative kn ow ledge of sin gle versus m ultiglan d disease, con com itan t thyroid path ology, an d ectopic glan d location is crit ical to ach ievin g operative success. Parathyroid im aging m ust be perform ed in th e correct con text . It is used for localization , to supplem en t an d aid surgical dissection , but n ever to h elp attain a diagn osis. Th e bioch em ical diagn osis of hyperparathyroidism sh ould be m ade prior to em barkin g on localization , an d im aging sh ould be pursued in th ose patien ts w h o are surgical can didates. Th e n um ber an d t ype of im aging studies to perform are based largely on surgeon preferen ce an d in stit ut ion al availabilit y. Study perform an ce an d sen sitivit y are also im portan t, alth ough on e m ust rem em ber w h en in terpretin g data on im agin g perform an ce an d sen sitivit y th at th e sen sitivit y of all m odalit ies is depen den t on in traoperative fin din gs, w h ich are in fluen ced by w h eth er or n ot bilateral exploration w as pursued. Th e prevalen ce of m ultiglan d disease in fluen ces th e perceived accuracy of localizing studies,5 an d it varies w ith th e th orough n ess of th e surgical explorat ion .6 Im aging m ust also be in terpreted w ith a th orough un derstan din g of parathyroid em br yology an d an atom y. Most patien ts h ave four glan ds, alth ough supern um erary glan ds h ave been reported.7 Th e superior glan ds are derived from th e fourth bran ch ial pouch alon g w ith th e lateral lobes of th e thyroid; th e in ferior glan ds arise from th e th ird pouch alon g w ith th e thym us. Superior glan ds are located in a m ore posterior plan e w h en com pared w ith in ferior glan ds, an d th is plays an im portan t role w h en review in g im agin g, especially cross-sect ion al or sagittal im ages. Alth ough superior glan ds are t ypically located beh in d th e m idportion of th e superior thyroid lobe n ear th e cricothyroid jun ct ion , th ey can also descen d in to a relat ively in ferior cervical location . Recogn izin g th is posterior position in th e n eck can h elp distin guish th em from in ferior parathyroid glan ds, w h ich are t ypically also foun d in th e low n eck in close proxim it y to th e in ferior pole of th e thyroid, alth ough in a m ore an terior plan e. Likew ise, in ferior glan ds th at reside w ith in cervical or m ediastin al thym ic tissue w ill rem ain in a relatively an terior plan e. Th is ch apter focuses on th e m ost com m on parathyroid im agin g m odalities used today an d th eir roles in both prim ar y an d reoperative cases.

Reports from 1975 an d 1978 w ere th e first to detail th e use of ultrason ography to iden tify parathyroid glan ds > 5 m m in size,8,9 an d Barraclough et al provided addition al support in 1981.1 For m any years n ow, it h as often been th e first m odalit y used to detect abn orm al parathyroid glan ds an d can be perform ed in th e outpatien t o ce sett in g. Alth ough radiologists h ave classically perform ed or in terpreted ultrasoun ds, surgeon perform ed ultrasoun d is becom in g in creasin gly com m on . Th e patien t is position ed supin e on th e exam in ation table w ith a pillow position ed at th e level of th e sh oulders to allow for n eck exten sion . A h igh -frequen cy lin ear array tran sducer of 7.5 to 15 MHz is used to system atically scan th e n eck to iden tify both thyroid an d parathyroid abn orm alit ies. Norm al parathyroid glan ds are t ypically too sm all an d struct urally sim ilar to adjacent thyroid tissue for son ograph ic detect ion , suggestin g th at alm ost any glan d iden tified is in h eren tly path ological in n ature. On gray-scale im aging en larged parathyroid glan ds are un iform ly hypoech oic an d classically ovoid or teardrop in sh ape w ith w ell-defin ed m argin s created by a hyperech oic lin e of adven t itia alon g th e an terior an d posterior surfaces ( Fig. 23.1).10 Large aden om as can appear bilobed or irregularly sh aped.11,12 Cyst ic degen eration can be foun d in 1 to 2% of en larged glan ds.13 Color Doppler im aging is used to iden tify th e vascular pedicle, th e en larged, extrathyroidal feedin g artery that typically arises from branches of the inferior thyroidal artery. This feeding artery t ypically supplies the adenom a at the pole of its long axis, in contrast to lym ph nodes, w hich have a central, hilar blood supply.10,11,12,14 Vascular arcs surrounding parathyroid glands from 90 to 270° have also been described in m ore than 50% of adenom as.15 These arcs arise from arborization of the feeding artery around the periph ery before sm aller braches penetrate deeper, and were first described in angiography literature ( Fig. 23.2).12,16 Although these features can be confirm atory in cases of large, m ore obvious parathyroid adenom as, their value is often greatest for lesions that are sm aller and less readily identifiable as an enlarged parathyroid.11,12,14 Gradually applying en ough pressure w ith th e ultrasoun d probe to gen tly deform th e subcutan eous tissue an d strap m uscles can h elp elucidate glan ds th at m igh t be oth erw ise di cult to see, such as th ose deep in th e t rach eoesoph ageal groove or laterally in th e carotid sh eath .12 Th is tech n ique can be valuable even w h en glan ds are obvious; en larged glan ds m ay be com pressible an d can th erefore be seen to “m ove” or ch ange sh ape durin g ultrasoun d w ith gradual com pression by th e son ograph er. Conversely, en larged lym ph n odes do n ot exh ibit th is sam e deform abilit y. Superior parathyroid glan ds are gen erally foun d posterior to th e upper or m iddle th ird of th e thyroid lobe an d can som etim es be m ore readily iden tified w ith th e probe in lon gitudin al orien tation . In ferior glan ds are t ypically foun d im m ediately adjacen t to th e low er border of th e thyroid lobe or in th e fibrofatt y cen tral n eck t issue.12 Lym ph n odes can also be frequen tly iden tified in th e cen tral n eck spaces an d m ay be di cult to distin guish from en larged parathyroid glan ds. On e clue to

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Parathyroid Diseases

Fig. 23.1 Classical oval shape of enlarged parathyroid gland on ultrasound (arrow). (a) Transverse im age. (b) Longitudinal image.

Fig. 23.3 Papillary thyroid cancer within the thyroid lobe adjacent to a large parathyroid gland (dotted line).

Fig. 23.2 Vascular pedicle (a) and arcs of peripheral arborization (b) on a large left superior parathyroid adenom a.

distin guish lym ph n odes from parathyroid glan ds is to exam in e th e ech ogen icit y of th e thyroid glan d. Coarse thyroid ech ogen icit y can sign ify an un derlying thyroidit is, such as Hash im oto’s thyroidit is. In th ese cases it is n ot un com m on to fin d m ultiple

192

en larged lym ph n odes in th e cen tral n eck spaces. In gen eral, lym ph n odes ten d to be m ore roun d in sh ape th an parathyroid glan ds, an d th ose associated w ith subacute thyroiditis m ay dem on st rate cent ral, lin ear vascular flow th at correspon ds to th e h ilum . Lym ph n odes in patien ts w ith Hash im oto’s thyroiditis t ypically lack any blood flow, reflectin g th e ch ron ic n ature of th e in flam m atory process.17 Given its low cost, ease of adm in ist ration , an d lack of ion izing radiation , ultrasoun d is rapidly becom ing th e preferred parathyroid im aging m odalit y; m any view it as a m an dator y localization strategy.18,19 Th is is especially true am on g surgeon s because th e superior an atom ical resolution provided by realtim e ultrasoun d can be invaluable in operat ive plan n in g an d execution . Sen sitivit y of surgeon -perform ed ultrasoun d is h igh , ran ging from 76 to 88%,20,21,22 an d h as been reported by som e to be h igh er th an th at of radiologist-perform ed ultrasoun d.23,24,25 Glan d size, w eigh t , an d volum e can predict th e likelih ood of son ograph ic detect ion , as can son ograph er skill. Patien t obesity; sm all, m ultiple, hyperplastic, or ectopic glan ds; an d thyroid nodular disease are all lim itation s to successful ultrasoun d.26 How ever, visualization of concom itan t thyroid path ology, w h ich occurs in 25 to 84% of prim ar y hyperparathyroidism pat ients an d is m align an t in n early 20% of cases, can also be ben eficial in th e preoperative settin g ( Fig. 23.3). Th is kn ow ledge can alter th e plan n ed operative approach , h elp to

Parathyroid Im aging avoid un n ecessary thyroid surgery for lesion s first en coun tered in traoperatively, an d poten tially avoid future reoperative n eck surgery for m issed path ology.27,28 Milas et al determ in ed th at preoperative detect ion an d biopsy of thyroid n odules decreased con com itan t thyroidectom y to 6%, as opposed to 30% in th ose w h o h ad thyroid n odules discovered in traoperatively at th e tim e of parathyroid surgery.27 Doppler flow can h elp di eren tiate thyroid n odules (w h ich lack a polar vascular pedicle) from parathyroid aden om as, as can iden tificat ion of a w ell-defin ed tissue plan e separatin g a parathyroid glan d from th e thyroid. Thyroid n odules are m ore likely to be h eterogen eous in echotext ure, as opposed to th e un iform hypoech oic n ature of a parathyroid aden om a. Ultrasoun d can also be useful in iden tifyin g in trathyroidal parathyroid glan ds an d facilitatin g fin e-n eedle aspiration biopsy if n ecessar y. Fin ally, ultrasoun d can h elp differen tiate n odular thyroid disease from parathyroid act ivit y, w h ich m ay be di cult to distin guish on n uclear scin tigraphy im aging alon e. Ectopic glan ds, especially those located in ret roesoph ageal, in trathym ic, an d m ediastin al location s, as w ell as m ultiglan d disease, reduce th e overall success of ultrasoun d. Th e upper m ediastin um an d posterior clavicular spaces m ay be better im aged w ith a cur ved probe. Deglutit ion durin g exam in ation can h elp elevate glan ds in these location s in to th e field of view.29 Color flow Doppler im aging is less ben eficial for ectopic glan ds in th e superior m ediastin um because th ese glan ds are frequently supplied by th e thym ic bran ch of th e in tern al m am m ar y artery an d are n ot son ograph ically accessible. Adjun ct ive m easures, in cludin g axial rotation of th e patien t’s h ead, m ay be h elpful w h en search in g for ectopic glan ds. How ever, in terferen ce by osseous struct ures an d th ose poorly pen etrated by ultrasoun d (esoph agus an d t rach ea) can still ultim ately lim it iden tification .30 Care m ust also be taken to evaluate th e h igh cervical region n ear th e carotid bifurcation an d alon g th e thyrothym ic ligam en t in th e cen tral n eck.11 Multiglan d hyperplasia can be di cult to im age because th ese glan ds are t ypically sm aller th an aden om atous glan ds, and all involved glan ds are rarely visualized. In patien ts w ith asym m etric hyperplasia or double aden om as, fin din g of a sin gle en larged glan d on ultrasoun d m ay lead to th e in correct conclusion th at on ly on e diseased glan d is presen t.4,31 Conversely, m ultiglan d disease in th e settin g of secon dary and tert iary hyperparathyroidism can lead to four son ograph ically iden tifiable glan ds.

23.3 Nuclear Scint igraphy Radioisotope im aging of th e parathyroid glan ds requires a source of radioactivit y, kn ow n as th e tracer, as w ell as a cam era w ith w h ich to capture th e em itted radiation . Follow in g m argin al success w ith selen ium -75-m eth ion in e, th allium -201 ( 201 Tl) w as th e first radiotracer to gain w idespread acceptan ce for parathyroid localization . Origin ally used for m yocardial perfusion im agin g, 201 Tl is a potassium an alogue th at is rapidly in tegrated in to th e in tracellular potassium pool.32 Den sely hypercellular t issues, such as en larged parathyroid glan ds, as w ell as thyroid t issue, accum ulate 201 Tl. Today, use of 201 Tl h as been aban don ed in favor of tech n etium -99 m ( 99m Tc)-sestam ibi (sestam ibi) due to superior im age qualit y, im proved accuracy, an d m ore favorable dosim etr y.32 A lipoph ilic com poun d th at

becom es trapped in tracellularly, prim arily by sequest ration in th e m itoch on dria,33 sestam ibi w as origin ally design ed to be a m yocardial perfusion agen t; its uptake by parathyroid tissue w as seren dipitously discovered. Coakley et al reported th e first use of sestam ibi in parathyroid im agin g in 1989.34 Alth ough , like 201 Tl, it is taken up by both parathyroid an d thyroid tissue, sestam ibi w ash out tim e from parathyroid tissue is lon ger due to m itoch on drial-rich oxyph il cells in hypercellular parathyroid glan ds.35 Addition ally, ow in g to th e superior physical ch aracteristics of sestam ibi for gam m a cam era im aging, th e radiation dose to th e patien t per un it adm in istered is approxim ately 20 tim es less th an th at for 201 Tl.34 99m Tc-tetrofosm in (tetrofosm in ), an oth er m yocardial perfusion agen t , h as also been used for parathyroid scin tigraphy. Parathyroid tissue avidly takes up tet rofosm in but dissipates it m ore quickly th an sestam ibi.36,37 Despite th is rapid clearan ce, som e h ave in dicated th at th e isotopes h ave sim ilar sen sitivities.38,39 Most, h ow ever, feel tetrofosm in is sign ifican tly less sen sitive 40 an d less accurate in orien t in g th e surgeon to th e diseased glan d,41 an d th erefore use sestam ibi in stead. Th e tech n iques used in parathyroid scin tigraphy h ave evolved over tim e, an d th ere are m ultiple protocols th at rem ain in use. Th e tw o basic protocols are dual-isotope sin gle-ph ase (subtract ion ) an d single-isotope dual-ph ase (w ash out). Both tech n iques serve to isolate activit y attributable to just th e parathyroid glan ds because 201 Tl, sestam ibi, an d tetrofosm in all h ave a n it y for both thyroid an d parathyroid tissues. Subt ract ion w as popularized by th e in troduct ion of 201 Tl for parathyroid scin tigraphy in 1983, an d relied on con com itan t use of tech n etium -99 m ( 99m Tc)-pertech n etate ch loride (pertech n etate), w h ich accum ulates in th e thyroid but n ot th e parathyroid glan ds. 201 Tl an d pertech n etate are adm in istered in a sin gle session , w ith out m ovin g th e pat ien t. Th e pertech n etate, or thyroid im age, is th en subtracted from th e 201 Tl, or parathyroid im age. Residual act ivit y represen ts abn orm al parathyroid tissue.42 Iodin e-123 ( 123 I) is also used for subtraction , w h ich , alon g w ith pertech n etate, is con cen t rated in thyroid cells via th e thyroid Na + /I- sym porter, alth ough on ly 123 I is organ ified in thyroid follicles.43 Because of its sim ilar h alf-lives in both thyroid an d parathyroid tissue, tetrofosm in requires th at a subtraction protocol be used, as opposed to a w ash out protocol, for w h ich sestam ibi is suitable.44 Subtraction im agin g m ay be m ost useful in patien ts w ith thyroid abn orm alit ies because thyroid n odules are th e m ost frequen t cause of false-positive results in parathyroid scin tigraphy.32,45 Man y thyroid lesion s th at accum ulate sestam ibi or tetrofosm in also accum ulate pertech n etate an d iodin e an d can th erefore be subtracted. Th e subtraction tech n ique, th ough useful, h as certain lim itation s. Patien t m otion durin g data acquisit ion m ay lead to registration errors of th e sestam ibi/tetrofosm in an d pertech n etate/iodin e im ages, resultin g in a false-positive study. An oth er pitfall of th e subtraction tech n ique is decreased or absen t thyroid uptake of pertech n etate or iodin e, w h ich m ay ren der th e subtract ion im age invalid. A detailed thyroid h istory is valuable, in cluding thyroid h orm on e supplem en tation or recen t com puted tom ograph ic (CT) scan w ith iodin ated contrast. Ver y in ten se sestam ibi or tet rofosm in uptake by a parathyroid lesion m ay occasion ally cause “sh in eth rough ” on th e per tech n etate/iodin e im age an d be erron eously in terpreted as a thyroid n odule. Occasion ally, a

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Parathyroid Diseases

Fig. 23.4 Sestam ibi scan with initial (top row) and washout (bottom row) phases. From left to right, im ages represent coronal views starting anteriorly and proceeding posteriorly in the neck. A large single focus of residual radiotracer labels a (presum ably) single enlarged parathyroid gland in the right neck.

Fig. 23.5 Single-photon em ission com puted tomography (SPECT) of a patient. From left to right, the first im age represents the initial sestam ibi im age. Radiotracer is seen ascending a vein in the left arm where it was injected, and a smudge representing the left thyroid gland is visible in the left neck. The subsequent four im ages are after radiotracer washout and show a single abnorm al collection of radiotracer marking an abnormal parathyroid gland in the right neck. Four angles are captured to dem onstrate the utilit y of SPECT imaging.

parathyroid lesion w ill be sit uated im m ediately beh in d a thyroid lesion an d is elim in ated w h en th e thyroid im age is subtracted.32 Taillefer et al in troduced th e sin gle-isotope dual-ph ase im agin g (w ash out) tech n ique in 1992 based on th e observation th at t h e w ash ou t of sest am ibi from abn or m al p arat hyroid tissu e is slow er th an t h at from su rrou n d in g t hyroid t issu e.46 Th is sim p le an d easy-to-p erform st u d y requ ires on ly a sin gle inject ion of sest am ibi follow ed by im aging ap p roxim ately 15 m in u t es an d 1.5 t o 3 h ou rs later. A p ersist en t focu s of act ivit y on d elayed im aging is in d icative of a p arathyroid lesion ( Fig. 23.4). Un for tu n at ely, som e p arathyroid lesion s d o n ot ret ain sest am ibi, w h ereas som e thyroid lesion s, an d even cer vical lym p h n od es, accu m u late an d retain sestam ibi, resu ltin g in both false-n egative an d false-p ositive stu d ies.32,43,47 Th is tech n iqu e also lacks sen sit ivit y for d etect ing m u lt iglan d d isease.48 Th e acquisit ion tech n ique can also a ect sen sitivit y of scin tigraphy. Use of a fixed or m obile gam m a cam era w ill determ in e w h eth er plan ar (t w o-dim en sion al) or th ree-dim en sion al im ages are acquired, respectively, w h ereas th e t ype of collim ator (len s equivalen t of a gam m a cam era) used determ in es th eir resolution . Collim ators filter em itted gam m a rays in to a sin gular direct ion so th at a clear im age is produced an d spat ial orien tation is m ain tain ed, sim ilar to a polarizing len s. Parallel-h ole collim ators filter a stream of parallel rays allow in g for sim ultan eous im agin g of both th e n eck an d th e ch est. Pin h ole collim ators provide th e h igh est resolution , lim it im agin g to th e n eck

194

on ly, m agnify th e struct ures bein g im aged, an d can also be position ed so as to obtain oblique view s.32 Th ey are sign ifican tly m ore sen sitive th an parallel im aging for glan ds of all sizes, in cludin g m ultiglan d disease.49,50 Th e addition of sin gle-ph oton em ission com puted tom ography (SPECT) allow s for th ree-dim en sion al im agin g by usin g a m obile gam m a cam era to collect im ages at m ultiple an gles aroun d th e pat ien t ( Fig. 23.5). Th e m ultiple im ages are com piled by a com puter an d displayed as th ree-dim en sion al im ages, sim ilar to positron em ission tom ography (PET) im agin g. SPECT in creases th e sen sitivit y of scin tigraphy com pared to plan ar im agin g alon e.51,52 Th e addition al detail is useful for n ot on ly detect in g but also localizing ectopic parathyroid glan ds, because tom ography provides m ore detailed an atom ical in form ation about th e glan d, its size, an d its relation sh ip to oth er struct ures, in cluding th e stern um , spin e, an d h eart.53 It is also h elpful in di eren tiatin g thyroid lesion s from parathyroid lesion s. Because th e parathyroid glan ds are t ypically foun d posterior to th e thyroid th ey can subsequen tly lie directly beh in d a thyroid n odule. Plan ar im aging alon e is un likely to distin guish an an terior thyroid lesion from a posterior parathyroid glan d; tom ography is able to di eren tiate th ese spatial relationsh ips.32 Th e latest adjun ct to scin tigraphy is hybrid SPECT/CT im agin g, a m odalit y com bin ing n uclear m edicin e an d CT tech n ology in to a sin gle physically in tegrated in strum en t ( Fig. 23.6). Th e CT portion provides an an atom ical m ap, w h ich , w h en m erged w ith th e radiotracer uptake dem on strated on SPECT im ages, aids in dem on stratin g th e relation sh ip of sestam ibi-avid lesion s

Parathyroid Im aging

Fig. 23.6 The sam e focus of parathyroid disease as in Fig. 23.4 is shown in an axial single-photon em ission com puted tom ography (SPECT) / computed tom ography im age.

to adjacen t struct ures. Because CT an d SPECT acquisit ion can be perform ed in a sin gle im aging session w ith out m ovin g th e patien t , th ere is n ear-perfect coregistration of th e im ages. Atten uation correction a orded by SPECT/CT im proves th e sen sitivit y for th e detect ion of deeper lesion s, an d visualization of correspon ding an atom y im proves th e di eren tiat ion of abn orm al from physiologic sestam ibi accum ulation .47 Th ese advan tages can lead to a sign ifican t reduction in false-positive fin din gs over SPECT im agin g alon e.54 Th e success of scin tigraphy is depen den t on th e particular scan n in g tech n ique used, an d th erefore reported sen sitivities vary w idely. Subtraction scan n in g h as been dem on st rated to be superior to sin gle-agen t dual ph ase w ash out.55,56,57 Many advocate for th e com bin ed use of both plan ar an d SPECT im aging. Nich ols et al58 n oted th at th e use of SPECT im agin g alon e did n ot a ord in creased sen sitivit y from plan ar im aging, 88%versus 83%, respect ively. How ever, th e addition of SPECT to plan ar im aging led to th e greatest sen sitivit y, specificit y, an d accuracy (90%, 89%, an d 89%, respect ively). Mult iglan d disease con tin ues to rem ain a m ajor ch allenge in parathyroid im aging, an d in th is study ever y tech n ique w as sign ifican tly less sen sitive in th e detect ion of m ultiglan d disease (MGD) th an in th e detect ion of sin gle-glan d disease (SGD).58 Specificit y w as also sign ifican tly low er for MGD th an for SGD for in terpretation of all im ages (73% vs. 98%, p < 0.001).58 Lavely an d colleagues also foun d th at SPECT w as n ot m ore sen sitive th an plan ar im aging, but th ey did fin d th at SPECT/CT w as sign ifican tly m ore sen sitive th an both plan ar an d SPECT im aging (dual-ph ase im aging; subtraction protocol n ot used).59 Sh arm a et al, in a study of 833 patien ts, foun d th at, alth ough accuracy for iden tifyin g SGD w as equivalen t betw een plan ar an d SPECT m odalities (SPECT, SPECT/CT, an d SPECT 123 I), all SPECT-based scan s h ad a statistically h igh er rate of disease detect ion (i.e., low er false-n egat ive rate) th an plan ar im aging.60 Regardless of th e t ype of study perform ed th ere w ill alw ays rem ain biological factors beyon d th e con trol of surgeon s an d radiologists th at con tribute to th e sen sitivit y an d specificit y of scin tigraphy. Th ese factors, in cludin g size, w eigh t, an d oxyph il conten t of parathyroid glan ds, in addition to P-glycoprotein expression , h ave all been dem on strated to a ect detect ion by scin tigraphy.41,61,62,63,64,65 Alth ough positive scan s are associated w ith aden om as of sign ifican tly larger volum e an d w eigh t , m any equally large glan ds can be m issed, w h ereas glan ds of m uch sm aller stature are iden tified.26,58,61,63,64 Th ese fin din gs suggest th ere are oth er factors at play. Successful scin tigraphy can be related to an aden om a’s oxyph il cell conten t; oxyph il cells are rich w ith den sely packed m itoch on dria an d rapidly sequester

sestam ibi.61,63,64 Oxyph il conten t in parathyroid aden om as is variable, alth ough pure oxyph il cell aden om as are rare.66 Erbil et al dem on st rated th at oxyp h il cell con ten t > 20% w as n ecessar y to obtain positive sestam ibi scan results in glan ds th at w ere < 600 m g, w h ereas in glan ds > 600 m g, low oxyph il cell con ten t did n ot a ect im agin g results.61 In a sim ilar fash ion , expression of P-glycoprotein (P-gp) or m ultidrug resistan cerelated protein (MRP) can also a ect parathyroid scin tigraphy results in depen den t of parathyroid size. Specifically, th e reten tion of sestam ibi in parathyroid cells depen ds on th e act ivity of th e P-gp coded on th e m ultidrug resistan ce (MDR1) gen e, w h ich fun ction s as an aden osin e triph osph ate (ATP)-depen den t e ux pum p, preven t in g th e accum ulation of lipoph ilic, cationic radioph arm aceut icals, in cludin g tet rofosm in an d sestam ibi.41 Mitch ell an d colleagues elegan tly dem on st rated th at it w as n ot size, but rath er an oth er factor, such as P-gp expression , th at w as th e prim ary determ in an t of parathyroid reten t ion of sestam ibi.67 Sun an d Kao, in t w o separate studies, w en t on to dem on strate th at eith er P-gp expression , MDR expression , or both w ere p resen t in ever y sin gle p arathyroid w ith a corresp on d in g false-n egative sestam ibi scan .62,68 Bioch em istr y is also im p ort an t, alt h ough t h e correlat ion bet w een p reop erat ive p arathyroid h orm on e (PTH) an d calciu m levels an d scin tigrap hy resu lts is variable. Som e h ave fou n d n o statist ically sign ifican t relat ion sh ip .26,61,64,65,69,70 Meh t a et al suggested th at PTH exp ression w as greatest in glan d s con sistin g of p red om in an t ly ch ief cells, an d t h erefore, given t h e corresp on d in g red u ced oxyp h il cell con cen tration , tend ed to lead to n egative st u d ies.63 Conversely, oth ers h ave fou n d h igh er p reop erative calciu m an d PTH valu es are p red ict ive of p osit ive scan s.71 Th ese biological factors are in h eren t ly n on m od ifiable. How ever, u se of levot hyroxin e t o en h an ce t h e sen sit ivit y of sestam ibi im aging in eu thyroid p atien ts, an d d iscon tin u ation of calciu m ch an n el blockers in p atien ts w ith p rim ar y hyp erp arathyroid ism , h ave both been suggested as w ays in w h ich th e sen sitivit y of im aging can be altered at a biological level.72,73

23.4 Com put ed Tom ography Conven tion al axial im agin g h as n ever been a preferred m eth od for parathyroid localization , ow in g to decreased sen sitivit y largely related to low spatial resolution of early scan n ers usin g th ick scan slices. Developm en t of very th in acquisition th ickn esses an d m ultid etector CT, h ow ever, in addition to in corporatin g th e perfusion ch aracteristics of parathyroid aden om as, h as brough t about th e em ergen ce of a n ew im aging m odalit y, 4D- CT. Th e fourth dim en sion relies on tim e an d th e rapid uptake an d w ash out of con trast from parathyroid aden om as. Non con trasted CT of th e n eck is perform ed at th e outset. Iodin ated cont rast is th en rapidly adm in istered, an d im agin g is perform ed at m ultiple subsequen t tim e poin ts. Th e in itial postcon t rast im aging begin s at 25 to 30 secon ds after th e injection an d is con sidered th e “arterial” ph ase. Wash out im ages are obtain ed betw een 30 an d 60 secon ds after th e in itial arterial im age ( Fig. 23.7). Th e h igh ly detailed, m ultiplan ar im ages obtain ed allow for visualization of hyperfun ction in g parathyroid glan ds, w h ich dem on strate rapid uptake an d w ash out com pared to n orm al parathyroid glan ds an d oth er struct ures in th e n eck.74,75

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Parathyroid Diseases

Fig. 23.7 Abnorm al parathyroid gland (arrow) in tracheoesophageal groove is better seen in the delayed arterial phase (a) than in the venous phase (b) of a four-dim ensional com puted tom ographic scan.

Separate studies by Rodgers et al an d Starker et al dem on strated th at th e sen sitivit y of 4D-CT (70% an d 85.7%, respectively) w as statistically superior to both ultrasoun d an d sestam ibi (single-agen t dual-ph ase SPECT/CT an d SPECT, respect ively) for defin in g th e precise location (quadran t of th e n eck) of abn orm al parathyroid glan ds.75,76 It sh ould be n oted th at surgeon -perform ed ultrasoun d w as n ot in cluded in eith er study.75,76 Mult iglan d disease w as variably predicted. In Starker et al’s study m ultiglan d disease w as iden tified in 6 of 7 patien ts (85.7%), as opposed to 5 of 11 pat ien ts (45%) in Rodgers et al’s study, w ith on ly 3 of th ese (27%) h avin g all diseased glan ds suggested on im aging.75,76 Lubitz et al studied a m ore varied population , in cludin g reoperative patien ts, all of w h om h ad n egative, discordan t , or oth erw ise in con clusive stan dard parathyroid im aging (ultrasoun d an d sestam ibi im aging) an d also foun d a h igh rate (60%) of accurate localization .77 Th ere are, h ow ever, disadvan tages to 4D-CT relating to availabilit y, in terpretat ion , an d radiation exposure. Alth ough th e calculated e ect ive radiation doses for 4D- CT an d sestam ibi (sin gle-agen t dual-ph ase SPECT) are relat ively sim ilar (10.4 an d 7.8 m Sv, respect ively), th e calculated thyroid dose (92 m Gy) is sign ifican tly h igh er w ith 4D-CT (about 57-fold). Th is correspon ds to a calculated lifetim e attributable risk of thyroid can cer for a 20-year-old fem ale exposed to 4D- CT of approxim ately 0.1%, or 1,040/m illion .78 Th is n um ber tapers precipitously in th e follow in g decades of life, w h ich is w h en th ose w ith hyperparathyroidism are m ost frequen tly diagn osed.78 To m in im ize radiation exposure, m any in stit ut ion s h ave altered th eir 4D tech n ique an d n ow lim it th e n um ber of ph ases perform ed. Ragh avan et al retrospectively review ed 29 4D-CT scan s in five di eren t com bin at ion s of ph ases (un en h an ced an d arterial ph ase; un en h an ced, arterial, an d early ven ous ph ases; all four ph ases; arterial ph ase alon e; an d arterial an d early ven ous ph ases) an d foun d th at th e accuracy, sen sitivit y, and specificit y for localization of th e arterial ph ase alon e (91%, 83.6%, an d 93.4%, respectively) w ere com parable to all four phases (90.5%, 82.1%, an d 93.2%, respect ively).79 In a sim ilar study, t w o-ph ase (un en h an ced an d arterial) an d t radition al four-ph ase studies w ere com pared. Sen sitivit y (85.3% an d 86%) an d accuracy (60.3% an d 65.5%) did n ot sign ifican tly di er betw een th e 2an d 4-ph ase tech n iques, respect ively.80

23.5 Ot her Modalit ies Magn et ic reson an ce im aging (MRI) an d positron em ission tom ography (PET) h ave been used to a lesser degree for parathyroid im aging. Hyperfun ct ion in g glan ds dem on strate hypoin ten se to in term ediate sign al in ten sity on T1-w eigh ted MRI sequen ces. Most aden om as dem on st rate h igh sign al in ten sity on T2-w eigh ted im ages an d avid en h an cem en t follow in g

196

adm in istration of in traven ous gadolin ium ; n orm al parathyroid glan ds are n ot t ypically visualized.47,74,81 Acute h em orrh agic an d cystic aden om as can h ave equally h igh in ten sity on both T1- an d T2-w eigh ted im ages. Conversely, low sign al in ten sity on both T1- an d T2-w eigh ted im ages is reflective of cellular degen erative ch anges, old h em orrh age w ith h em osiderin -laden m acroph ages, an d fibrosis of th e glan d.82 Con curren t thyroid path ology, in addition to sarcoid n odules, neurofibrom as, n orm al lym ph n odes, follicular lym ph aden itis, an d oth er lym ph n ode path ologies can appear hyperin ten se on T2-w eigh ted im aging, leadin g to false-positive results. MRI is also lim ited by artifact in t roduced by patien t m ovem en t, in cluding physiological m otion , an d in dw ellin g m etal, such as clips from previous surgery. Its use m ay be best suited for cases w ith n egative or discordan t im agin g.83 Both fludeoxyglucose (FDG) an d 11 C-m eth ion in e PET h ave dem on st rated reason ably h igh sen sitivit y an d specificit y for localizing parathyroid glan ds.84,85,11 C-m eth ion in e PET/CT h as been sh ow n to perform w ell, especially in th e settin g of con com itan t thyroid disease.86 As w ith oth er m odalities, h ow ever, m ultiglan d disease is poorly im aged. As w ith MRI, cost an d accessibilit y e ectively lim it th e use of PET to cases of n egative or discordan t prior im aging.

23.6 St udy Select ion Th ere is n o perfect localization study. Wh ich study to use w ill depen d n ot on ly on patien t factors, such as ren al fun ct ion an d body h abitus, but also in stit ut ion al availabilit y, radiation exposure, an d surgeon preferen ce. Success w ill be in h eren tly lim ited by th e presence of m ultiglan d disease as w ell as in stit ution al di eren ces in im aging algorith m s an d practices. A recen t m eta-an alysis suggested ultrasoun d an d sestam ibiSPECT w ere essen tially com parable in term s of accurately localizing abn orm al parathyroid glan ds, w h ereas 4D- CT w as ben eficial in th ose w ith n egative or in con clusive results on oth er im aging.87 Many contin ue to prefer dual localizing studies because on e m ay be h elpful for correlatin g or con firm in g un certain fin din gs in th e oth er. Th e com bin ation of sestam ibi scin tigraphy an d ultrasoun d is th e preferred approach by a m ajorit y of U.S. surgeon s.88 False-positive sestam ibi im aging due to thyroid n odules, in flam m atory thyroiditis, an d cervical lym ph aden op athy can be m in im ized w ith ultrasoun d evaluation to di eren tiate betw een thyroid, parathyroid, an d oth er cervical lesion s. Addition ally, com bin ed ultrasoun d an d sestam ibi scin tigraphy are reported to h ave in creased sen sitivit y for th e preoperative localization of parathyroid aden om as; w h en both are positive an d con cordan t th e accuracy is approxim ately 94 to 99%.89,90 In fact, som e h ave even suggested th at use of in t raoperative PTH m on itorin g is n ot n ecessar y in th ese patien ts.91 How ever,

Parathyroid Im aging con cordan ce rates ran ge betw een 42 an d 59%, th us lim it in g th e applicabilit y of th is approach.31,89,91,92 Addition ally, even in th e settin g of con cordan ce an d an appropriate drop in in t raoperative PTH level follow in g focused exploration , an addition al abn orm al glan d, in dicatin g m ultiglan d disease, can be foun d durin g con tralateral exploration in up to 16% of patien ts.4 Th ere is a m ovem en t tow ard single-m odalit y im agin g. Given th e accuracy an d conven ien ce of surgeon -perform ed ultrasoun d, th e on ce gold stan dard scin tigraphy is m ore often bein g reserved for cases in w h ich th ere is an un clear or n egative surgeon -perform ed ultrasoun d.20,22,93,94 In m ore th an 50% of cases, sin gle-glan d disease m issed on ultrasoun d but subsequen tly detected by scin tigraphy is due to a posteriorly located upper glan d in th e trach eoesoph ageal groove or oth er retroesoph ageal location .95 How ever, th e added ben efit of sestam ibi scin tigraphy in patien ts w ith n on localizin g ultrasoun ds can be lim ited, w ith success rates of < 50% in iden tifyin g any abn orm al glan ds.96 Cost is an oth er con sideration . As our h ealth care system con tin ues to evolve, value w ill be of equal if n ot greater im portan ce in ch oosin g am on g th e im aging m odalit ies. Ultrasoun d is easily the cheapest m odality, and w hen used in isolation, the potential cost advantage is staggering. Of 119 patients undergoing sestam ibi scintigraphy, Arora et al reported 57 had correctly localized glands w ith findings corroborated by surgeon-perform ed ultrasound.20 Tw enty-eight patients had incorrectly localized glands by scintigraphy, but correctly localized ultrasound findings. Therefore, these 85 patients could have theoretically undergone surgeon-perform ed ultrasound only, representing a potential cost savings of at least $90,000.20 Wang and colleagues and Lubitz et al, in separate studies, found the m ost cost-e ective strategies to be ultrasound com bined w ith sestam ibi-SPECT, then 4D-CT if needed, or an algorithm of ultrasoun d follow ed by 4D-CT, w hen ultrasound w as inconclusive. Both, how ever, rely on the assum ption that bilateral neck exploration is a m ore costly procedure than focal exploration.97,98

23.6.1 Reoperat ive Neck Surgery In patien ts w ith previous parathyroid or thyroid surgery, scarrin g an d altered t issue plan es m ake localization param oun t . Four-glan d or m ultiglan d exploration in th is settin g is avoided if possible. Scarrin g of th e operative bed m akes for a tedious dissection th at can be m ore pron e to bleedin g, th us obscurin g th e oth erw ise subtle color di eren ces crit ical to iden tification of parathyroid glan ds an d th e recurren t lar yngeal n er ve. Th e approach to th ese cases sh ould be to fin d an d resect an abn orm al glan d or glan ds w h ose location s are kn ow n preoperatively w ith a h igh degree of an atom ical certain t y. Detailed kn ow ledge of th e pat ien ts’ clin ical h istory is crit ical, so th at th e surgeon can m ore accurately predict w h eth er residual sin gle- or m ultiglan d disease is presen t an d appropriately in terpret localization studies.99 If n o hypercellular parathyroid tissue w as resected durin g th e previous surgery, a sin gle aden om a m ay be expected; previous rem oval of hypercellular t issue sh ould raise suspicion for m ultiglan d disease.99,100 Alth ough th e preferred sequen ce for reoperative localization is subject to surgeon preferen ce an d in stit ution al availabilit y, th e gen eral consen sus is to begin w ith n on invasive m odalities and progress to th ose th at are invasive.99,101,102,103 Wh eth er t w o con cordan t studies are n ecessary is debatable. Udelsm an an d

colleagues h ave outlin ed a sequen ce begin n in g w ith cer vical ultrasoun d an d/or scin tigraphy w ith SPECT. Negative or un con vin cin g studies are follow ed by a 4D-CT scan . Select ive ven ous sam pling or ultrasoun d-guided biopsy of suspicious cervical lesion s (w ith aspirate sen t for PTH m easurem en t as w ell as cytology) is reserved for cases in w h ich th is h ierarch ical approach h as failed to localize an abn orm al glan d.30,104 It is im portan t to rem em ber all im aging studies are less reliable in th e reoperative n eck, an d as is th e case for prim ar y procedures, m ultiglan d disease lim its localization sensitivit y.104 Alth ough ultrasoun d can h elp iden tify a vascular pedicle, an d m ore precisely pin poin t an atom ical location , detect ion of an abn orm al parathyroid glan d can be m ore ch allen ging th an in patien ts w ith out prior surgery, an d false-n egative rates up to 68% h ave been reported.105 For th ose th at h ave un dergon e prior partial or total thyroidectom y, th e usual an atom ical lan dm arks are altered or absen t. Postoperat ive fibrosis, sh ift s in vascular struct ures, an d skin scarrin g all con tribute to di cult y in iden tifyin g an abn orm al glan d.105 Addition ally, th e h igh rate of failure is likely reflect ive of w h ere th ese glan ds are located. Reoperative parathyroid surgery perform ed for persisten t disease, as opposed to recurren t disease, im plies a m issed glan d, w h ich is often paraesoph ageal, m ediastin al, or in trathym ic.106,107 Th ese region s are classically n ot w ell visualized by ultrasoun d due to sh adow in g by th e t rach ea an d esoph agus or in terferen ce from th e clavicle or oth er osseous struct ures. Nuclear scintigraphy should be relatively una ected by scarring. How ever, especially in cases w here the thyroid is surgically absent, it provides little anatom ical detail other than cervical versus thoracic. SPECT/CT, and especially 4D-CT, can th erefore provide critical structural and anatom ical detail to help guide reoperation, although the sen sitivity of 4D-CT is significantly greater than that of SPECT/CT for reoperative parathyroid surgery (93% vs. 55%, p = 0.04).100 Ven ous sam pling, though lacking acute anatom ical precision, can localize to a side w hen all previous stu dies have failed to identify any site of abn orm al parathyroid tissue.108,109 How ever, challenges arise ow ing to the aberrant venous anatom y resulting from a previous operation.

23.7 Conclusion Th e role an d n ature of parathyroid im aging con tin ue to expan d as th e operative approach to parathyroidectom y h as evolved. Alth ough localization is param oun t for focal explorat ion , it is equally im por tan t prior to plan n ed bilateral explorat ion to assess for con com itan t thyroid path ology an d detect any ectopic hyperfun ct ion al parathyroid t issue. Ult rasoun d, especially surgeon -perform ed ultrasoun d, h as becom e a favored approach by m any, an d, in som e cases, th e on ly m odalit y perform ed prior to prim ary parathyroidectom y. Nuclear scin tigraphy h as becom e in creasin gly m ore sen sitive an d accurate w ith th e addition of SPECT/CT. New er m odalit ies, such as 4D-CT, h ave dem on st rated con sisten tly h igh accuracy an d h ave sign ifican t ut ilit y in th e settin g of reoperative parathyroid surgery. Multiglan d disease w ill cont in ue to lim it successful localization regardless of m odalit y. Surgeon s are en couraged to learn th e m odalit ies available to th em an d view th e im ages of th ese studies prior to perform in g an operation . Ultim ately, th e im aging techn ique used is largely based on in stit ution al availability, surgeon preferen ce, an d, in creasin gly, cost.

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[71] Pariksh ak M, Castillo ED, Con rad MF, Talpos GB. Im pact of hypercalcem ia an d parathyroid h orm on e level on th e sen sitivity of preoperative sestam ibi scan n in g for prim ar y hyperparathyroidism . Am Surg 2003; 69(5); 393–398, discussion 399 [72] Friedm an K, Som er vell H, Patel P, et al. E ect of calcium ch an n el blockers on th e sen sitivity of preoperative 99m Tc-MIBI SPECT for hyperparathyroidism . Surgery 2004; 136(6); 1199–1204 [73] Royal RE, Delpassan d ES, Sh apiro SE, et al. Im provin g th e yield of preoperative parathyroid localization : tech n etium Tc 99m -sestam ibi im aging after thyroid suppression . Surgery 2002; 132(6); 968–974, discussion 974–975 [74] Ph illips CD, Sh atzkes DR. Im aging of th e parathyroid glan ds. Sem in Ultrasoun d CT MR 2012; 33(2); 123–129 [75] Rodgers SE, Hun ter GJ, Ham berg LM, et al. Im proved preoperative plan n ing for directed parathyroidectom y w ith 4-dim en sion al com puted tom ography. Surgery 2006; 140(6); 932–940, discussion 940–941 [76] Starker LF, Mah ajan A, Björklun d P, Sze G, Udelsm an R, Carling T. 4D parathyroid CT as th e in itial localization study for patien ts w ith de n ovo prim ar y hyperparathyroidism . An n Surg On col 2011; 18(6); 1723–1728 [77] Lubitz CC, Hun ter GJ, Ham berg LM, et al. Accuracy of 4-dim en sion al com puted tom ography in poorly localized patien ts w ith prim ar y hyperparathyroidism . Surgery 2010; 148(6); 1129–1137, discussion 1137–1138 [78] Mah ajan A, Starker LF, Gh ita M, Udelsm an R, Brin k JA, Carling T. Parathyroid four-dim en sion al com puted tom ography: evaluation of radiation dose exposure durin g preoperative localization of parathyroid tum ors in prim ar y hyperparathyroidism . World J Surg 2012; 36(6); 1335–1339 [79] Ragh avan P, Durst CR, Orn an DA, et al. Dyn am ic CT for parathyroid disease: are m ultiple ph ases n ecessar y? AJNR Am J Neuroradiol 2014; 35(10); 1959– 1964 [80] Noureldin e SI, Aygun N, Walden M, Tufan o R. Four-dim en sion al CT vs 2-ph ase CT in patien ts w ith prim ar y hyperparathyroidism : h ow m any ph ases do w e really n eed? Surgery 2014; 156(6); 1300–1306 [81] Higgin s CB, Au erm an n W . MR im agin g of t hyroid an d p arat hyroid glan d s: a review of cu rren t st at u s. AJR Am J Roen t gen ol 1988; 151(6); 1095–1106 [82] Au erm an n W, Guis M, Tavares NJ, Clark OH, Higgin s CB. MR sign al in ten sit y of parathyroid aden om as: correlation w ith h istopath ology. AJR Am J Roen tgen ol 1989; 153(4); 873–876 [83] Grayev AM, Gen tr y LR, Hart m an MJ, Ch en H, Perlm an SB, Reeder SB. Presurgical localization of parathyroid aden om as w ith m agn etic reson an ce im agin g at 3.0 T: an adjun ct m ethod to supplem en t tradition al im agin g. An n Surg On col 2012; 19(3); 981–989 [84] Hellm an P, Ah lström H, Bergström M, et al. Positron em ission tom ography w ith 11C-m eth ionin e in hyperparathyroidism . Surgery 1994; 116(6); 974– 981 [85] Neum an n DR, Esselstyn CBJ, Jr, MacIn t yre W J, et al. Prim ar y hyperparathyroidism : preoperative parathyroid im aging w ith region al body FDG PET. Radiology 1994; 192(2); 509–512 [86] Weber T, Maier-Fun k C, Oh lh auser D, et al. Accurate preoperative localization of parathyroid aden om as w ith C-11 m ethion in e PET/CT. An n Surg 2013; 257 (6); 1124–1128 [87] Ch eun g K, Wan g TS, Farrokhyar F, Rom an SA, Sosa JA. A m eta-analysis of preoperative localization tech n iques for patien ts w ith prim ar y hyperparathyroidism . An n Surg On col 2012; 19(2); 577–583 [88] Green e AB, Butler RS, McIn tyre S, et al. Nation al tren ds in parathyroid surgery from 1998 to 2008: a decade of ch ange. J Am Coll Surg 2009; 209(3); 332– 343 [89] Arici C, Ch eah W K, Ituar te PH, et al. Can localization studies be used to direct focused parathyroid operation s? Surgery 2001; 129(6); 720–729 [90] Lew JI, Solorzan o CC. Surgical m an agem en t of prim ar y hyperparathyroidism : state of th e art . Surg Clin North Am 2009; 89(5); 1205–1225 [91] Gaw an de AA, Mon ch ik JM, Abbruzzese TA, Ian n uccilli JD, Ibrah im SI, Moore FDJ, Jr. Reassessm ent of parathyroid h orm on e m on itorin g durin g parathyroidectom y for prim ar y hyperparathyroidism after 2 preoperative localization studies. Arch Surg 2006; 141(4); 381–384, discussion 384 [92] Ch o NL, Gaw an de AA, Sh eu EG, Moore FDJ, Jr, Ruan DT. Crit ical role of iden tification of th e secon d glan d durin g un ilateral parathyroid surgery: a prospective review of 119 patien ts w ith con cordant localization . Arch Surg 2011; 146 (5); 512–516 [93] Un t ch BR, Ad am MA, Sch e r i RP, e t al. Su r ge on - p e r for m e d u lt r asou n d is su p e r ior t o 9 9 Tc- sest am ib i scan n in g t o localize p arat hyr oid ad e n om as in p at ie n t s w it h p r im a r y h yp e r p ar a t hyr oid ism : r e su lt s in 51 6 p at ie n t s ove r 1 0 ye a r s. J Am Coll Su r g 2 01 1 ; 2 1 2 (4 ); 5 2 2 – 5 29 , d iscu ssion 5 2 9 – 531

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Parathyroid Diseases [94] Vitetta GM, Neri P, Ch iecch io A, et al. Role of ultrason ography in th e m an agem en t of patien ts w ith prim ar y hyperparathyroidism : retrospect ive com parison w ith tech n etium -99 m sestam ibi scin tigraphy. J Ultrasoun d 2014; 17(1); 1–12 [95] Harari A, Mitm aker E, Grogan RH, et al. Prim ar y hyperparathyroidism patien ts w ith positive preoperative sestam ibi scan an d n egative ultrasoun d are m ore likely to h ave posteriorly located upper glan d aden om as (PLUGs). An n Surg On col 2011; 18(6); 1717–1722 [96] Sm ith RB, Evasovich M, Girod DA, et al. Ultrasoun d for localization in prim ar y hyperparathyroidism . Otolaryn gol Head Neck Surg 2013; 149(3); 366–371 [97] Lubitz CC, Steph en AE, Hodin RA, Pandh aripan de P. Preoperative localization strategies for prim ar y hyperparathyroidism : an econ om ic an alysis. An n Surg On col 2012; 19(13); 4202–4209 [98] Wan g TS, Ch eun g K, Farrokh yar F, Rom an SA, Sosa JA. Would scan , but w h ich scan ? A cost-utility an alysis to optim ize preoperative im aging for prim ar y hyperparathyroidism . Surgery 2011; 150(6); 1286–1294 [99] Sh in JJ, Milas M, Mitch ell J, Berber E, Ross L, Siperstein A. Im pact of localization studies an d clin ical scen ario in patien ts w ith hyperparathyroidism bein g evaluated for reoperative n eck surgery. Arch Surg 2011; 146(12); 1397–1403 [100] Morten son MM, Evan s DB, Lee JE, et al. Parathyroid exploration in th e reoperative n eck: im proved preoperative localization w ith 4D-com puted tom ography. J Am Coll Surg 2008; 206(5); 888–895, discussion 895–896 [101] Hessm an O, Stålberg P, Sun din A, et al. High success rate of parathyroid reoperation m ay be ach ieved w ith im proved localization diagn osis. World J Surg 2008; 32(5); 774–781, discussion 782–783

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[102] Rich ards ML, Th om pson GB, Farley DR, Gran t CS. Reoperative parathyroidectom y in 228 patien ts durin g th e era of m in im al-access surger y an d in traoperative parathyroid h orm on e m on itoring. Am J Surg 2008; 196(6); 937–942, discussion 942–943 [103] Yen TW, Wan g TS, Do ek KM, Krzyw da EA, W ilson SD. Reoperative parathyroidectom y: an algorith m for im agin g an d m on itorin g of in traoperative parathyroid h orm on e levels th at results in a successful focused approach . Surgery 2008; 144(4); 611–619, discussion 619–621 [104] Udelsm an R. Approach to th e patien t w ith persisten t or recurren t prim ar y hyperparathyroidism . J Clin En docrin ol Metab 2011; 96(10); 2950–2958 [105] Krudy AG, Sh aw ker TH, Doppm an JL, et al. Ultrason ic parathyroid localisation in previously operated patien ts. Clin Radiol 1984; 35(2); 113–118 [106] Sh en W, Dü ren M, Morita E, et al. Reoperation for persisten t or recurren t prim ar y hyperparathyroidism . Arch Surg 1996; 131(8); 861–867, discussion 867–869 [107] Silberfein EJ, Bao R, Lopez A, et al. Reoperative parathyroidectom y: location of m issed glan ds based on a con tem porar y n om en clature system . Arch Surg 2010; 145(11); 1065–1068 [108] Gh ah eri BA, Koslin DB, Wood AH, Coh en JI. Preoperative ultrasoun d is w orth w h ile for reoperative parathyroid surgery. Lar yn goscope 2004; 114(12); 2168–2171 [109] Sugg SL, Fraker DL, Alexan der R, et al. Prospect ive evaluation of select ive ven ous sam pling for parathyroid h orm on e con cen tration in patien ts un dergoing reoperation s for prim ar y hyperparathyroidism . Surgery 1993; 114(6); 1004–1009, discussion 1009–1010

Renal Hyperparathyroidism

24 Renal Hyperparat hyroidism Steven R. Bomeli and David J. Terris

24.1 Int roduct ion Secon dary hyperparathyroidism (HPT) occurs w h en parathyroid h orm on e (PTH) levels rise to com pen sate for an oth er disease process, m ost com m on ly vitam in D deficien cy or ren al failure. Th e PTH elevation is con sidered an appropriate physiological respon se in order to m ain tain n orm ocalcem ia. Tertiary HPT is th e con dition in w h ich hypercalcem ia develops in th e settin g of lon g-stan ding secon dar y hyperpah arathyroidism . It occurs due to auton om ously fun ct ion ing parathyroid glan ds th at h ave lost th eir abilit y to respon d to n egative feedback. Th e term tertia r y HPT also refers to HPT th at persists after successful ren al t ran splan tation , w h erein th e PTH an d calcium elevation s persist despite n orm alization of th e m etabolic abn orm alities in h eren t to ren al failure. Both secon dary an d tert iary HPT are far less com m on th an prim ary HPT. Wh ere prim ary HPT is caused by a sin gle aden om a in th e m ajorit y of cases, secon dar y an d tert iary HPT involve hyperplasia of all four parathyroid glan ds, at least at som e poin t th rough out th e progression of th e disease. Because th e physiological m ech an ism s associated w ith secon dar y HPT related to ren al failure are so specific an d un ique, th e auth ors prefer th e term rena l HPT.

24.2 Pat hophysiology Ren al HPT is com m on am ong patien ts in ren al failure, w ith a prevalen ce of 90% at th e tim e of in itiation of h em odialysis.1 Vitam in D deficien cy, lon g-term lith ium th erapy, osteom alacia, rickets, an d m alabsorption are oth er causes of secon dary HPT, an d are exclusively m edically m an aged.2,3 In ch ron ic kidn ey disease (CKD), hyperph osph atem ia occurs as th e glom erular filtration rate decreases, an d th is process, alon g w ith reduced conversion of vitam in D to its act ive m etabolite, is th ough t to be th e drivin g factor in th e on set of secon dar y hyperparathyroidism . Th ere are several separate m ech an ism s by w h ich hyperph osph atem ia results in in creased PTH levels. Hyperph osph atem ia acts directly on ch ief cells in th e parathyroid glan ds to stim ulate PTH production . Mild hypocalcem ia is in duced w h en calcium precipitates w ith ph osph oru s as th e equilibrium is sh ifted by hyperph osph atem ia. Th is hypocalcem ia fur th er stim ulates production of PTH.2 Hyperph osph atem ia also causes product ion of a recen tly discovered protein kn ow n as fibroblast grow th factor 23 (FGF23), w h ich is secreted by osteocytes.4 Th is n ovel protein is n ow th ough t to be th e m ost im portan t regulator of ph osph orus h om eostasis. It acts on th e kidn ey to in crease ph osph orus clearan ce, an d it in h ibits th e 1-α -hydroxylase en zym e w h ose baselin e production is already reduced by th e un derlying ren al failure, th ereby decreasin g th e act ive 1,25-dihydroxyvitam in D (calcitriol) levels.5 Th e resultin g decreased in testin al absorption of calcium fur th er exacerbates hypocalcem ia, w h ich in creases PTH secretion . Loss of n egative feedback of vitam in D on th e vitam in D receptors in th e parathyroid glan ds poten tiates PTH secretion .6 Th e factors leadin g to secon dary hyperparathyroidism from ch ron ic ren al failure are depicted in Fig. 24.1.

Early in ren al failure, ph osph orus an d calcium levels usually rem ain n orm al, but PTH an d FGF23 are elevated. As th e glom erular filtration rate (GFR) drops below 30 m L/m in (stage IV kidn ey disease), PTH is upregulated an d decreases ph osph orus reabsorption in th e kidn ey w h ile its act ion s to release calcium an d ph osph orus from th e bon e cont in ue. Th e result is a situation w h ere hyperph osph atem ia causes PTH secretion , an d elevated PTH levels in crease ph osph ate release from bon e, w orsen in g th e hyperph osph atem ia. Th is path ophysiology a ect s all parathyroid glan ds an d th erefore results in four-glan d hyperplasia, alth ough th e en largem en t is n ot alw ays sym m etric ( Fig. 24.2).

24.3 Sym pt om s Most patien ts w ith ren al hyperparathyroidism are asym ptom atic because patien ts w ith CKD are usually screen ed an d treated prior to th e on set of sym ptom s. How ever, sym ptom s m ay occur w ith advan ced an d lon g-stan ding ren al HPT, even despite appropriate m edical treatm en t. Th e h igh rate of bon e turn over from osteoclast activation by PTH m ay lead to bon e pain , skeletal deform ities from w eak bon e arch itecture, an d even path ological fract ures. Neurological sym ptom s can in clude irritabilit y, in abilit y to focus, gen eralized m uscle w eakn ess, an d prurit is. Calciphylaxis, also kn ow n as calcific urem ic arteriolop athy, occurs w h en arterial w alls becom e calcified an d th e blood supply to t issue is com prom ised. Sym ptom s begin w ith pain ful distal extrem ities, w h ich develop violaceous n odules. Radiograph ic im aging of th e arterial supply m ay reveal arterial calcification ( Fig. 24.3).

Fig. 24.1 The factors that result in secondary hyperparathyroidism as a consequence of chronic kidney disease. FGF, fibroblast growth factor; PTH, parathyroid horm one.

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Parathyroid Diseases Th e progressive isch em ic n ecrosis of skin is a cause of sign ificant m orbidit y an d is associated w ith a m ortalit y rate as h igh as 80% on ce ulceration s develop.7 Its presen ce is, th erefore, an in dication for em ergen t parathyroidectom y. In cont rast, patien ts w ith tert iar y disease after successful ren al t ran splan tation usually experien ce th e classic sym ptom s of prim ar y hyperparathyroidism , con sistin g of bon e pain , n eph rolith iasis, an d m en tal status ch anges (in cluding m em or y loss, irritabilit y, im paired con cen tration , an d poor sleep).

24.4 Diagnosis Laborator y assessm en t is essen tial in confirm in g th e diagn osis of ren al HPT. Pat ien ts usually h ave m ild hypocalcem ia or

n orm ocalcem ia, hyperph osph atem ia, decreased vitam in D levels, an d som etim es dram atic elevation s of PTH. In cont rast, patien ts w ith tert iar y hyperparathyroidism t ypically h ave laboratory fin din gs consisten t w ith th ose of prim ary hyperparathyroidism . Th e calcium is usually m ildly to m oderately elevated, vitam in D an d ph osph ate levels m ay be decreased, an d PTH levels are m ildly elevated. Alkalin e ph osph atase m ay be elevated, sign alin g h igh bon e t urn over. Depen din g on th e duration of un treated disease, bon e m in eral den sit y assessm en t (dual-en ergy X-ray absorptiom etr y [DEXA] scan n in g) m ay in dicate osteopen ia or osteoporosis. Brow n t um ors ch aracteristic of osteitis fibrosa cystica are rarely seen an d are in dicative of severe an d protracted disease.

24.5 Medical Managem ent

Fig. 24.2 Asym m etric four-gland hyperplasia seen in renal hyperparathyroidism .

Th e m ajorit y of patien ts w ith ren al hyperparathyroidism are n ow m an aged m edically. Th e m ain stays of th erapy are ph osph ate bin ders (calcium carbon ate, calcium acetate, sevelam er hydroch lorid e, lan th an um carbon ate), vitam in D an alogues (ergocalciferol, ch olecalciferol, calcitriol, 22-oxacalcitriol, falecalcitriol, alfacalcidol, paricalcitol, an d doxercalciferol), an d th e calcim im etic cin acalcet HCl.8 Ph osph ate bin ders th at do n ot con tain calcium are in creasin g in popularit y because th ere is a low er risk of hypercalcem ia.9 Vitam in D an alogues, such as ch olecalciferol or ergocalciferol, carr y a low er risk of hypercalcem ia in patien ts w ith ch ron ic kidn ey disease th an calcitriol, th e m ost act ive form of vitam in D.10 Cin acalcet (Sen sipar, Am gen ) is a calcim im et ic ph arm aceutical th at in creases th e sen sitivit y of th e calcium -sen sing receptor on th e surface of th e ch ief cells of parathyroid glan ds, w h ich are respon sible for n egative feedback. It h as been sh ow n to reduce PTH, calcium , ph osph orus, an d calcium –ph osph orus product values in ran dom ized, placebo-con trolled t rials.11,12,13 Population studies

Fig. 24.3 Clinical and histological presentation of calciphylaxis. (a) Nonhealing ulceration on the left lower leg with a necrotic border. (b) Radiograph of the left lower leg with diffuse calcifications and stenosis of the arteries (arrows). (c) Histological examination of skin biopsy from the ulceration: calcific sclerosis and m icrothrom bi within a sm all artery (hem atoxylin-eosin stain, magnification × 200). (d) Calcium deposition in an artery (von Kossa stain, m agnification × 200); calcium deposits are highlighted as dark granules (arrow). (From Zhou Q, Neubauer J, Kern JS, Grotz W, Walz G, Huber TB, Calciphylaxis. Lancet 2014;383[9922]:1067. Reproduced with perm ission.)

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Renal Hyperparathyroidism

Fig. 24.4 Increased parathyroid horm one (PTH) levels correlate with increased cardiovascular m ortalit y in hem odialysis patients. iPTH, intact parathyroid horm one. (From Marco et al. 20 Reproduced with perm ission.)

of dialysis pat ien ts h ave in dicated a decrease in th e rate of parathyroidectom y after Jan uar y 2006, w h ich correspon ds to th e availabilit y of cin acalcet.14 Alth ough th e adven t of cin acalcet h as represen ted a m ajor breakth rough in th e m edical m an agem en t of ren al HPT, its use is occasion ally lim ited by gast roin testin al side e ects an d com plian ce, ow in g to its oral route of adm in istration .12,15 Velcalcetide (AMG 416, Am gen ) is a n ovel in traven ous calcim im etic drug th at h as been evaluated for treatm en t of ren al hyperparathyroidism . In a ph ase 1 trial, it decreased seru m PTH an d FGF23 levels for a duration of up to 24 h ours.16 Alth ough it appears safe an d w ell tolerated, m ore studies are necessar y before it can be w idely recom m en ded. Th e n eed for m edical in terven t ion h as been supported by observation al studies of dialysis patien ts, w h ich h ave sh ow n th at elevated ph osph orus, calcium , PTH, alkalin e ph osph atase, an d FGF23 levels are associated w ith in creased m or talit y an d a h igh er frequen cy of cardiovascular even ts.17,18 Furth erm ore, a h igh calcium –ph osph orus product is associated w ith th e poten tial for soft t issue an d vascular calcification s, w ith associated in creases in m orbidit y an d m ortalit y ( Fig. 24.4).19,20 For th ese reason s, laborator y guidelin es for th e treatm en t of HPT in patien ts w ith ren al failure h ave been developed. In 2003, th e Kid n ey Foun dation of th e Un ited States suggested m ain tain in g a calcium level of betw een 8.4 an d 9.5 m g/dL, a ph osph orus level betw een 3.5 an d 5.5 m g/dL, a calcium –ph osph orus product < 55 m g 2 /dL,2 an d a PTH level betw een 150 an d 300 pg/m L.21 Th e m ost recen t Kidn ey Disease Im provin g Global Outcom e (KDIGO) in tern ation al guidelin es of 2009 suggests th at ph osph orus levels sh ould be kept just above th e n orm al laborator y range, w h ereas th e PTH level sh ould be m ain tain ed betw een t w o an d n in e tim es th e upper lim it of n orm al.22 Alth ough parathyroidectom y is th e t reatm en t of ch oice for tert iary HPT, m edical m an agem en t w ith cin acalcet h as been described. In several sm all series, it h as been sh ow n to decrease PTH an d n orm alize calcium w ith out com prom isin g ren al allograft fun ction .23,24 Treatm en t m ust be cont in ued in defin itely, h ow ever, an d there is little justification to w ith h old parathyroidectom y as th e defin itive m an agem en t except in rare circum stan ces.25

Percutan eous eth an ol inject ion un der ultrasoun d guidan ce h as been described as a n on surgical altern ative to parathyroidectom y in patien ts w ith tert iar y hyperparathyroidism .26 Th is approach h as n ot been em braced in th e Un ited States, prin cipally because of th e risk to th e recurren t lar yngeal n er ve an d th e in h eren t scarrin g th at is created, but it h as been used in oth er coun tries for patien ts w h o are n ot surgical can didates.

24.6 Surgical Indicat ions Ren al tran splan tation is th e surgical treatm en t of ch oice for ren al hyperparathyroidism . Calcium , PTH, vitam in D, an d ph osph orus levels gen erally n orm alize w ith in 1 year after ren al tran splan tation ,27 an d patien ts w h ose values do n ot n orm alize in a year by defin ition h ave tert iar y HPT. Parathyroidectom y becom es n ecessary w h en tran splan tation is n ot feasible or w h en m edical m an agem en t fails. Approxim ately 1 to 2% of patien ts w ith ren al hyperparathyroidism w ill require parathyroidectom y each year.28 Historically, sym ptom s such as pruritis an d bon e pain , an d fin din gs such as vascular calcification s an d calciphylaxis, drove th e decision for surgery. Curren tly, m ost patien ts are referred for surgery w h en laborator y values can n ot be m ain tain ed w ith in the recom m en ded lim its w ith m edical m an agem en t alon e. Although precise clin ical in dication s for surgery vary betw een expert s an d am on g patien ts, in th e h an ds of expert surgeon s sign ifican t decreases in th e levels of PTH, calcium , an d ph osph orus m ay be an ticipated w ith parathyroidectom y.22 For surgical can didates, an object ive in crease in qualit y of life th rough sym ptom control h as been dem on strated for patien ts w ith both ren al an d tert iar y HPT.29 Th e severit y of ren al an d tert iary hyperparathyroidism h as been correlated w ith ultrason ograph ic ch aracteristics of parathyroid glan ds. An atom ical features an d vascular supply can be used to predict th erapeutic respon se to m edical m an agem en t for ren al HPT.30,31 En larged an d n odular parathyroid glan ds appear to be resistan t to cin acalcet .32 Despite th e association betw een th ese ultrasoun d fin din gs an d failure of m edical m an agem en t, th ere is n ot su cien t evidence for ultrasoun d fin din gs to be considered a surgical in dication at th e presen t t im e.

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Parathyroid Diseases kn ow n to occur in as m any as 40% of pat ien ts w ith ren al HPT ( Fig. 24.5).41 Alth ough a bilateral n eck exploration w ith iden tification of all four parathyroid glan ds is alw ays perform ed, th e addition al in form ation provided by preoperative im aging studies is part icularly ben eficial for reoperative parathyroidectom y. For persisten t or recurren t hyperparathyroidism after total parathyroidectom y, th e sen sitivit y of Tc-99 m h as been reported to be as h igh as 100%.42

24.8 Surgical Approaches

Fig. 24.5 Sestamibi scan indicating a m ediastinal parathyroid gland in a patient with persistent hyperparathyroidism after total parathyroidectom y (2 hours after sestam ibi injection).

Ectopic vascular calcification s an d calciphylaxis top th e list of surgical in dication s because th e n ecrotic skin is n ot capable of h ealin g due to lack of perfusion , an d it can lead to lim b loss, sepsis, an d death. Fort un ately it is rare, occurrin g in on ly 4% of patien ts h avin g surgery.33 Patien ts w ith calciphylaxis due to ren al HPT w h o un dergo subtotal parathyroidectom y h ave im proved w oun d h ealing an d in creased sur vival com pared w ith th ose m an aged m edically.34 Surger y h as also been sh ow n to im prove fat igue, m usculoskeletal pain , bon e den sit y, an d rates of lim b salvage.35 Parathyroidectom y is th e t reatm en t of ch oice for tert iar y hyperparathyroidism . Th e likelih ood of persisten t auton om ous parathyroid fun ction after ren al tran splan tation is th ough t to be related to th e duration of dialysis prior to surgery.36 Th ough th ere are n o absolute guidelin es for w h en to con sider surgery, hypercalciuria, th e associated ren al t ubular injur y, an d th e in creased risk of n eph rolith iasis are all particularly th reaten in g for a t ran splan ted kidn ey.37 Gen erally pat ien ts w ith persisten t hypercalcem ia 1 year after tran splan t are con sidered can didates for parathyroidectom y. Th e decision for surgery sh ould be m ade cautiously, h ow ever, because som e stud ies suggest th at tran splan t graft fu n ct ion can be com prom ised after parathyroidectom y.38,39 Oth ers h ave foun d th at, alth ough th e glom eru lar filtration rate of t ran splan ted kidn eys w as decreased after parathyroidectom y for tert iary HPT, th e lon g-term graft sur vival w as n ot a ected by th e surgery.40

24.7 Im aging St udies Alth ough ren al HPT a ect s all four parathyroid glan ds, preoperative localization studies h ave proven to be of con siderable value in plan n in g th e in itial surgical approach . Th e sen sitivities of tech n etium -99 m (Tc-99m ) sestam ibi scan n in g for th e localization of parathyroid glan ds in ren al HPT are as h igh as 70%, an d are especially h elpful in th e settin g of ectopic glan ds, w h ich are

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Th ere are th ree prin cipal option s for surgery in patien ts w ith ren al hyperparathyroidism for w h om parathyroidectom y is un dertaken . Th e first option is a subtotal parathyroidectom y, w h ere all four glan ds are iden tified, th ree an d a portion of th e fourth are resected, an d th e rem n an t is preserved w ith its blood supply in tact . Th e location of th e rem n an t parathyroid tissue is m arked w ith a h em oclip or a perm an en t suture in case reoperative surgery is n ecessary. Alth ough th e m ost n orm al-appearin g parathyroid is preferred for selection as th e rem n an t, th is con sideration is t rum ped by location . Reoperative surgery is far easier w h en th e rem n an t is in an in ferior location safely rem oved from th e recurren t lar yn geal n er ve. An oth er im portan t prin ciple is th e sequen ce of th e operation . Because th e vascular in tegrit y of th e rem n an t m ay be lost durin g its subtotal resection , it is best to first iden tify all of th e parathyroid glan ds, an d th en prepare th e rem n an t. On ly w h en it is apparen t th at th e rem n an t is h ealthy an d w ill sur vive sh ould th e rem ain in g th ree glan ds be resected (as th ey can easily ser ve as a rem n an t if th e in itially ch osen glan d appears com prom ised after preparation ). Fin ally, alth ough h istorically th is procedure h as also been called a 3½ glan d parathyroidectom y (or even a 3¾ parathyroidectom y), th e portion of th e glan d th at is retain ed as a rem n an t m ay var y con siderably depen din g on th e size of th e parathyroid glan ds. In stead, th e surgeon sh ould en deavor to preserve approxim ately 30 to 60 m g of parathyroid tissue (approxim atin g th e size of a sin gle n orm al parathyroid glan d). Th e secon d surgical option for patien ts w ith ren al HPT is a total parathyroidectom y w ith reim plan tation of a portion of th e m ost n orm al-appearin g (n on n odular) region of on e of th e four parathyroid glan ds. Th is autotran splan tation involves m in cin g approxim ately 30 to 60 m g of parathyroid t issue (to in crease th e surface area) an d placin g it in to a recept ive pocket. Alth ough classically th e recipien t bed ch osen w as th e n on dom in an t brach ioradialis m uscle, because of th e in conven ien ce of a secon d site of surgery, an d m ore im portan tly th e substan tial poten tial m orbidit y associated w ith its rem oval, th is pract ice h as been largely aban don ed.43 We prefer to reim plan t th e parathyroid tissue in to a soft tissue pocket in th e prestern al region separate from th e cervical dissection , but conven ien t in location ( Fig. 24.6). Th e m orbidit y of resectin g this (sh ould it be n ecessary in th e fut ure) is n early zero.44 Wh en autotran splan tation is required durin g thyroid surgery, w e prefer usin g th e ipsilateral stern ohyoid m uscle, an d m arkin g th e pocket w ith a 3–0 Prolen e suture (Eth icon , In c.). An altern ative to surgical im plan tation is th e subcutan eous inject ion of resected parathyroid. Th e t issue is m in ced, suspen ded in salin e, an d th en injected in to m uscle. Th is approach appears to sh orten th e m edian t im e of

Renal Hyperparathyroidism

24.9 Int raoperat ive Parat hyroid Horm one

Fig. 24.6 Location for presternal autotransplantation of m inced parathyroid gland below the cervical incision after total parathyroidectomy (marked in purple).

parathyroid recovery from 9 m on th s to 2 m on th s.45 Reoperation can gen erally be perform ed un der local an esth esia so lon g as th e recurren ce is n ot due to a glan d in th e n eck th at w as m issed durin g th e in itial operation . Th e ch oice betw een a subtotal parathyroidectom y versus total parathyroidectom y w ith autotran splan tation is largely driven by th e pat ien t’s eligibilit y for a ren al tran splan t. We prefer to leave a rem n an t w hen th ere is a possibilit y for tran splan tation in th e fut ure. Th e fin al surgical option for patien ts w ith ren al HPT is represen ted by total parathyroidectom y w ith out autot ransplan tation . Alth ough th is m ay seem extrem e, th e risk of recurren t disease is close to zero, an d th e an ticipated hypocalcem ia m ay be m an aged by a com bin ation of oral calcium supplem en tation an d a calcium -rich dialysate bath . Wh en th is approach is pursued, com m un ication w ith th e m an aging n eph rologist is part icularly im portan t. A routin e tran scervical thym ectom y to rem ove poten tial ectopic parathyroid tissue an d parathyroid rests is con troversial.37 Th e auth ors in corporate th is if an in ferior glan d is n ot iden tified or if th e in traoperative PTH degradation suggests a supernum erar y glan d. Patien ts w ith postt ran splan t tert iar y HPT are m an aged m uch di erently th an th ose w ith dialysis-depen den t ren al failure an d ren al HPT. Th eir condition is fu n ct ion ally quite sim ilar to prim ar y HPT. Alth ough tradit ion ally a four-glan d explorat ion w as pursued in th ese pat ien ts, it h as been recogn ized th at th e residual parathyroid hyperplasia is som etim es asym m etric. Som e of th e glan ds are clearly n on auton om ous an d dorm an t . For th is reason, m any un its (in cluding th at of th e auth ors) approach th ese pat ien ts w ith th e prospect of doin g less th an a four-glan d exploration , an d guide th e approach w ith both preoperative im aging to localize th e hyperfun ction al glan d(s), an d in traoperative PTH testin g to en sure rem oval of all hyperfun ct ion al tissue.46,47 Th rough th is approach , m any pat ien ts can avoid th e addition al risk of tem porar y an d perm an en t hypoparathyroidism posed by bilateral exploration .

Th e in t raoperative PTH assay h as been used in parathyroidectom y for ren al HPT. How ever, th e in terpretation of th e values is com plicated because th is populat ion h as decreased ren al fun ction , an d, th erefore, delayed ren al clearan ce of PTH. Th e t radition al criteria of a > 50% drop in PTH at 10 m in utes postoperatively h as been foun d by som e to be a useful tool w h en perform in g subtotal parathyroidectom y in patien ts w ith ren al HPT.48 Th e ration ale is th at, alth ough th e PTH n adir m ay n ot be reach ed un til 30 m in utes postexcision in patien ts w ith ren al failure, th e 10-m in ute value is h igh ly predict ive of th e 30m in ute value.49 Oh e et al h ave suggested th at an 80% drop in PTH at 20 m in utes predicts cure w h en perform in g total parathyroidectom y w ith autot ran splan tation , w h ereas a decay of < 70% is in dicative of a m issed or supern um erar y glan d.50 Oth er auth ors h ave foun d th e sam e criteria som ew h at un reliable in th eir predict ive value of cure, an d suggest th at th ese values can be used on ly as a guide w h en perform in g total parathyroidectom y.51 Th e use of th is assay h as n ot been as w ell defin ed as it h as been for prim ar y HPT, an d th e criteria for predictin g a curative operat ion for both ren al HPT an d for tert iar y disease con tin ue to evolve.

24.10 Cryopreservat ion Cr yopreservation w as origin ally described by Wells in 1974 an d involves preservin g resected parathyroid tissue at – 80°C.52 It h as been proposed (in th e prein traoperat ive PTH era) as a strategy to preven t perm an en t hypoparathyroidism . How ever, th e n eed for parathyroid reim plan tation is ver y low at 1% in experien ced h an ds, th e viabilit y of th e tran splan ted t issue is n o better th an 50%, an d it falls to n early zero after 2 years of cryopreservation .53 With cost contain m en t bein g an im portan t con sideration for health care in th e Un ited States, m ost surgeon s h ave aban don ed th e use of cr yopreser vation due to its low cost-e cien cy.54,55 More strin gen t criteria are n eeded to determ in e if th ere are pat ien ts w h o w ould ben efit from h avin g parathyroid tissue cryopreserved at th e t im e of surgery.

24.11 Renal Prot ocol Patien ts un dergoing parathyroidectom y for ren al hyperparathyroidism are treated in a m ultidisciplin ary fash ion because of th eir poten tial for profoun d hypocalcem ia in th e settin g of com plicated m edical m an agem en t, an d occasion al large fluid sh ifts. Neph rology, en docrin ology, en docrin e surgery, t ran splan t surgery, an d social w ork coordin ate th e perioperat ive m an agem en t of th ese patien ts. On e w eek preoperatively, patien ts are started on 2 to 3 g of oral calcium per day an d 2 µg of calcitriol in traven ously durin g each session of dialysis. A subclavian cen tral lin e is placed by a tran splan t surgeon after th e adm in ist ration of gen eral an esth esia but before surgery com m en ces. Th is facilitates ph lebotom y an d allow s adm in istration of in traven ous calcium . Postoperatively, calcium an d elect rolyte abn orm alities are m an aged by th e n eph rology an d en docrin ology ser vices. Th is stan dardized treatm en t protocol an d en h an ced

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Parathyroid Diseases com m un icat ion betw een services allow s th e m an agem en t of th ese com plex patien ts to proceed in a stream lin ed fash ion .

24.12 Conclusion Ren al HPT is a disease of all four parathyroid glan ds th at occurs com m on ly in dialysis-depen den t CKD pat ien ts. It is treated w ith ph osph ate bin ders, vitam in D an alogues, an d calcim im etic agen ts un t il PTH an d elect rolyte abn orm alit ies are w ith in th e recom m en ded ran ges or ren al tran splan tation occurs. Wh en p arathyroid ectom y is in d icated , it sh ou ld be p erform ed in h igh -volu m e cen ters by exp erien ced su rgeon s becau se of t h e com p lex p eriop erative elect rolyte abn orm alit ies, w h ich requ ire a m u ltid iscip lin ar y ap p roach for m an agem en t. A bilateral n eck exp lorat ion is p er for m ed in all in stan ces, an d a su bt otal p arat hyroid ect om y, a t ot al p arat hyroid ectom y w it h au t ot ran sp lan tat ion , or a t ot al p arat hyroid ectom y w ith ou t au t ot ran sp lan tat ion is p erform ed . Tertiar y HPT is diagn osed by elevated calcium an d PTH levels, w h ich persist or develop after successful ren al t ran splan tation . Surgical m an agem en t of tert iar y disease is sim ilar to th at of prim ary hyperparathyroidism in w h ich on ly hyperfun ct ion in g parathyroid tissue is rem oved, an d th e am oun t of tissue rem oved is determ in ed by preoperative localizing studies an d in traoperative PTH levels.

References [1] Mem m os DE, W illiam s GB, East w ood JB, et al. Th e role of parathyroidectom y in th e m an agem en t of hyperparathyroidism in patien ts on m ain ten an ce h aem odialysis an d after ren al tran splan tation . Neph ron 1982; 30(2); 143–148 [2] Pitt SC, Sippel RS, Ch en H. Secondar y an d tert iar y hyperparathyroidism , state of th e art surgical m an agem en t. Surg Clin North Am 2009; 89(5); 1227–1239 [3] Saun ders BD, Saun ders EF, Gauger PG. Lith ium th erapy an d hyperparathyroidism : an eviden ce-based assessm en t. World J Surg 2009; 33(11); 2314– 2323 [4] Nabesh im a Y. [Discover y of alph a-Kloth o an d FGF23 un veiled n ew in sigh t in to calcium an d ph osph ate h om eostasis] Clin Calcium 2008; 18(7); 923–934 [5] Kovesdy CP, Kalan tar-Zadeh K. Bon e an d m in eral disorders in pre-dialysis CKD. In t Urol Neph rol 2008; 40(2); 427–440 [6] Holick MF. Vitam in D an d th e kidn ey. Kidn ey In t 1987; 32(6); 912–929 [7] Fin e A, Zach arias J. Calciphylaxis is usually n on -ulcerating: risk factors, outcom e an d th erapy. Kidn ey In t 2002; 61(6); 2210–2217 [8] Alvarez JA, Law J, Coakley KE, et al. High -dose ch olecalciferol reduces parathyroid h orm on e in patien ts w ith early ch ron ic kidn ey disease: a pilot, ran dom ized, double-blin d, placebo-con trolled trial. Am J Clin Nutr 2012; 96 (3); 672–679 [9] Fukagaw a M, Kom aba H, Kakuta T. Hyperparathyroidism in ch ron ic kidn ey disease patien ts: an update on curren t ph arm acoth erapy. Expert Opin Ph arm acoth er 2013; 14(7); 863–871 [10] Mazzaferro S, Goldsm ith D, Larsson TE, Massy ZA, Cozzolin o M. Vitam in D m etabolites an d/or an alogs: w h ich D for w h ich patien t? Curr Vasc Ph arm acol 2014; 12(2); 339–349 [11] Quarles LD, Sh errard DJ, Adler S, et al. Th e calcim im etic AMG 073 as a poten tial treatm en t for secon dar y hyperparathyroidism of en d-stage ren al disease. J Am Soc Neph rol 2003; 14(3); 575–583 [12] Block GA, Mart in KJ, de Fran cisco AL, et al. Cin acalcet for secon dary hyperparathyroidism in patien ts receivin g h em odialysis. N En gl J Med 2004; 350(15); 1516–1525 [13] Lin dberg JS, Culleton B, Won g G, et al. Cin acalcet HCl, an oral calcim im etic agen t for th e treatm en t of secon dar y hyperparathyroidism in h em odialysis an d periton eal dialysis: a ran dom ized, double-blin d, m ulticen ter study. J Am Soc Neph rol 2005; 16(3); 800–807 [14] Lafran ce JP, Cardin al H, Leblan c M, et al. E ect of cin acalcet availability an d form ular y listin g on parathyroidectom y rate tren ds. BMC Neph rol 2013; 14; 100

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[15] Gin ch erm an Y, Molon ey K, McKee C, Coyn e DW. Assessm en t of adh eren ce to cin acalcet by prescription refill rates in h em odialysis patien ts. Hem odial In t 2010; 14(1); 68–72 [16] Mart in KJ, Bell G, Pickth orn K, et al. Velcalcetide (AMG 416), a n ovel peptide agon ist of th e calcium -sen sing receptor, reduces serum parathyroid h orm on e an d FGF23 levels in h ealthy m ale subjects. Neph rol Dial Tran splan t 2014; 29 (2); 385–392 [17] Floege J, Kim J, Irelan d E, et al. ARO Investigators. Serum iPTH, calcium an d ph osph ate, an d th e risk of m ortalit y in a European h aem odialysis population . Neph rol Dial Tran splan t 2011; 26(6); 1948–1955 [18] Gutiérrez OM, Man n stadt M, Isakova T, et al. Fibroblast grow th factor 23 an d m ortalit y am on g patien ts un dergoin g h em odialysis. N En gl J Med 2008; 359 (6); 584–592 [19] Block GA, Hulbert-Sh earon TE, Levin NW , Por t FK. Association of serum ph osph orus an d calcium x ph osph ate product w ith m ortalit y risk in ch ron ic h em odialysis patien ts: a n ation al study. Am J Kidn ey Dis 1998; 31(4); 607– 617 [20] Marco MP, Craver L, Betriu A, Belart M, Fibla J, Fern án dez E. High er im pact of m in eral m etabolism on cardiovascular m ortalit y in a European h em odialysis population . Kidn ey In t Suppl 2003(85); S111–S114 [21] Nation al Kidn ey Foundation . K/DOQI clin ical pract ice guidelin es for bon e m etabolism an d disease in ch ron ic kidn ey disease. Am J Kidn ey Dis 2003; 42 (4) Suppl 3; S1–S201 [22] Kidn ey Disease: Im provin g Global Outcom es (KDIGO) CKD-MBD Work Group. KDIGO clin ical practice guidelin e for th e diagn osis, evaluation , prevention , an d treatm en t of Ch ron ic Kidn ey Disease-Min eral an d Bon e Disorder (CKDMBD). Kidn ey In t Suppl 2009(113); S1–S130 [23] Serra AL, Sch w arz AA, W ick FH, Mart i HP, Wü th rich RP. Successful treatm en t of hypercalcem ia w ith cin acalcet in ren al tran splan t recipien ts w ith persisten t hyperparathyroidism . Neph rol Dial Tran splan t 2005; 20(7); 1315–1319 [24] Pin h o LR, Ribeiro San tos MJ, Pestan a Vascon celos M. Cin acalcet in th e treatm en t of persisten t hyperparathyroidism after kidn ey tran splan tation . Clin Neph rol 2011; 75(3); 263–268 [25] Yan g RL, Freem an K, Rein ke CE, et al. Tert iar y hyperparathyroidism in kidn ey tran splan t recipien ts: ch aracterist ics of patien ts selected for di eren t treatm en t strategies. Tran splan tation 2012; 94(1); 70–76 [26] Douth at WG, Orozco SE, Main o P, et al. Percutan eous eth an ol inject ion th erapy in post-tran splan t patien ts w ith secon dar y hyperparathyroidism . Tran spl In t 2007; 20(12); 1031–1035 [27] Gh an ekar H, Welch BJ, Moe OW , Sakh aee K. Post-ren al tran splan tation hypoph osph atem ia: a review an d n ovel in sigh ts. Curr Opin Neph rol Hyperten s 2006; 15(2); 97–104 [28] Tripon ez F, Clark OH, Van ren th ergem Y, Even epoel P. Surgical treatm en t of persisten t hyperparathyroidism after ren al tran splan tation . An n Surg 2008; 248(1); 18–30 [29] Ch en g SP, Lee JJ, Liu TP, et al. Parathyroidectom y im proves sym ptom atology an d quality of life in patien ts w ith secon dary hyperparathyroidism . Surger y 2014; 155(2); 320–328 [30] Vulpio C, Bossola M, Magalin i SC, et al. Parathyroid-glan d ultrason ography in clin ical an d th erapeutic evaluation of ren al secon dar y hyperparathyroidism . Radiol Med (Torin o) 2013; 118(5); 707–722 [31] Hirai T, Nakash im a A, Takasugi N, Yorioka N. Association of n odular hyperplasia w ith resistan ce to cin acalcet th erapy for secon dar y hyperparathyroidism in h em odialysis patien ts. Th er Aph er Dial 2010; 14(6); 577–582 [32] Okada M, Tom in aga Y, Izum i K, et al. Tertiar y hyperparathyroidism resistan t to cin acalcet treatm en t. Th er Aph er Dial 2011; 15 Suppl 1; 33–37 [33] An gelis M, Wong LL, Myers SA, Wong LM. Calciphylaxis in patien ts on h em odialysis: a prevalen ce study. Surgery 1997; 122(6); 1083–1089, discussion 1089–1090 [34] Girotto JA, Harm on JW, Ratn er LE, Nicol TL, Won g L, Ch en H. Parathyroidectom y prom otes w oun d h ealin g an d prolon gs sur vival in patien ts w ith calciphylaxis from secon dar y hyperparathyroidism . Surgery 2001; 130(4); 645– 650, discussion 650–651 [35] Milas M, Weber CJ. Near-total parathyroidectom y is ben eficial for patien ts w ith secon dar y an d tertiary hyperparathyroidism . Surgery 2004; 136(6); 1252–1260 [36] Apaydin S, Sariyar M, Erek E, et al. Hypercalcem ia an d hyperparathyroidism after ren al tran splan tation . Neph ron 1999; 81(3); 364–365 [37] Tripon ez F, Dosseh D, Hazzan M, et al. [Results of system atic subtotal parathyroidectom y w ith thym ectom y for tert iar y hyperparathyroidism after ren al tran splan tation - 70 patien ts] An n Ch ir 2006; 131(3); 203–210 [38] Lee PP, Sch i m ann L, O erm an n G, Beige J. E ects of parathyroidectom y on ren al allograft sur vival. Kidn ey Blood Press Res 2004; 27(3); 191–196

Renal Hyperparathyroidism [39] Sch w arz A, Rustien G, Merkel S, Raderm ach er J, Haller H. Decreased ren al tran splan t fun ct ion after parathyroidectom y. Neph rol Dial Tran splan t 2007; 22(2); 584–591 [40] Kan dil E, Florm an S, Alabbas H, et al. Explorin g th e e ect of parathyroidectom y for tert iar y hyperparathyroidism after kidn ey tran splan tation . Am J Med Sci 2010; 339(5); 420–424 [41] Loft us KA, An derson S, Mulloy AL, Terris DJ. Value of sestam ibi scan s in tertiar y hyperparathyroidism . Lar yn goscope 2007; 117(12); 2135–2138 [42] Lai EC, Ch in g AS, Leon g HT. Secondar y an d tert iar y hyperparathyroidism : role of preoperative localization . ANZ J Surg 2007; 77(10); 880–882 [43] Melck AL, Carty SE, Seeth ala RR, et al. Recurren t hyperparathyroidism an d forearm parathyrom atosis after total parathyroidectom y. Surgery 2010; 148 (4); 867–873, discussion 873–875 [44] Ech enique-Elizon do M, Am on darain JA, Vidaur F, et al. Parathyroid subcutan eous pre-stern al tran splan tation after parathyroidectom y for ren al hyperparathyroidism . Lon g-term graft fun ct ion . World J Surg 2007; 31(7); 1403– 1409 [45] Ng JC, Wan g W , Ch ua MJ, et al. Subcutan eous inject ion is a sim ple an d reproducible option to restore parathyroid fun ct ion after total parathyroidectom y in patien ts w ith secon dar y hyperparathyroidism . Surgery 2014; 155(4); 682– 688 [46] Pitt SC, Pann eerselvan R, Ch en H, Sippel RS. Tert iar y hyperparathyroidism : is less th an a subtotal resection ever appropriate? A study of lon g-term outcom es. Surgery 2009; 146(6); 1130–1137 [47] Nich ol PF, Starling JR, Mack E, Klovn ing JJ, Becker BN, Ch en H. Lon g-term follow -up of patien ts w ith tert iar y hyperparathyroidism treated by resect ion of a sin gle or double aden om a. An n Surg 2002; 235(5); 673–678, discussion 678–680

[48] Gioviale MC, Gam bin o G, Maion e C, et al. In traoperative parathyroid h orm on e m on itorin g durin g parathyroidectom y for hyperparathyroidism in w aitin g list an d kidn ey tran splan t patien ts. Tran splan t Proc 2006; 38(4); 1003–1005 [49] Ch ou FF, Lee CH, Ch en JB, Hsu KT, Sh een -Ch en SM. In traoperative parathyroid h orm on e m easurem en t in patien ts w ith secon dar y hyperparathyroidism . Arch Surg 2002; 137(3); 341–344 [50] Oh e MN, San tos RO, Kun ii IS, et al. In traoperative PTH cuto defin ition to predict successful parathyroidectom y in secon dary an d tert iary hyperparathyroidism . Braz J Otorh in olaryn gol 2013; 79(4); 494–499 [51] Con zo G, Pern a A, Aven ia N, et al. Evaluation of th e ‘putative’ role of in traoperative in tact parathyroid h orm on e assay durin g parathyroidectom y for secon dar y hyperparathyroidism . A retrospect ive study on 35 con secutive patien ts: in traoperative iPTH assay durin g parathyroidectom y. En docrin e 2012; 42(3); 606–611 [52] Wells SA, Jr, Ch ristian sen C. Th e tran splan ted parathyroid glan d: evaluation of cr yopreser vation an d oth er environ m en tal factors w h ich a ect its fun ction . Surgery 1974; 75(1); 49–55 [53] Coh en MS, Dilley W G, Wells SA, Jr, et al. Lon g-term fun ction alit y of cryopreser ved parathyroid autografts: a 13-year prospect ive an alysis. Surgery 2005; 138(6); 1033–1040, discussion 1040–1041 [54] Sh epet K, Alh efdh i A, Usedom R, Sippel R, Ch en H. Parathyroid cr yopreser vation after parathyroidectom y: a w orth w h ile practice? An n Surg On col 2013; 20(7); 2256–2260 [55] Sch n eider R, Ram asw am y A, Slater EP, Bartsch DK, Sch losser K. Cr yopreser vation of parathyroid tissue after parathyroid surgery for ren al hyperparathyroidism : does it really m ake sen se? World J Surg 2012; 36(11); 2598–2604

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Part 5 Surgical Managem ent of Parat hyroid Diseases

25 Conventional Parat hyroidect om y

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26 Minim ally Invasive Parat hyroidectomy

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27 Intraoperative Parat hyroid Horm one Assay

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28 Radioguided Parathyroid Surgery

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29 Reoperative Parathyroid Surgery

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Surgical Managem ent of Parathyroid Diseases

25 Convent ional Parat hyroidect om y Jennifer Leonard and Geo rey B. Thompson

25.1 Int roduct ion Sin ce th e first description of th e parathyroid glan ds by Sir Rich ard Ow en in 1852, great strides h ave been m ade in th e un derstan din g of diseases of th e parathyroid glan ds an d th eir surgical treatm en t . Th e first parathyroidectom y w as perform ed in 1925 by th e Vien n ese surgeon Felix Man dl. Th e Nobel Prize– w in n in g w ork of Berson an d Yallow in 1963 fun dam en tally ch anged th e w ay m any h orm on ally active t um ors are diagn osed. With th e subsequen t developm en t of a h igh ly accurate w h ole-m olecule im m un oassay to m easure parathyroid h orm on e (PTH) levels in serum , pat ien ts can n ow be screen ed w ith seru m calcium an d PTH testin g in stead of w aitin g for th e disease to becom e advan ced an d clin ically apparen t. In addition , it sim plifies testin g by elim in atin g th e n eed to rule out all of th e oth er possible causes of hypercalcem ia. Today, m ost patien ts presen tin g for parathyroidectom y are m in im ally sym ptom atic or asym ptom atic w ith out subject ive com plain ts; but few tr uly h ave n o sequelae.

25.2 Epidem iology and Causes Prim ar y hyperparathyroidism (HPT) is a com m on disease a ect in g approxim ately 0.7% of th e population overall an d up to 2% of post m en opausal w om en . Th e average age at diagn osis is 55, an d th e m ajorit y of in dividuals presen t betw een th e ages of 40 an d 70 years.1,2 Prim ary HPT is m ost com m on ly sporadic an d caused by a sin gle aden om a; h ow ever, sporadic m ultiglan d disease (MGD) is routinely en coun tered in up to 15%of patien ts, w ith double aden om as an d carcin om as occurrin g less frequen tly. In a recen t review of 828 pat ien ts w h o un derw en t bilateral n eck explorat ion for parathyroidectom y, 15% w ere foun d to h ave double aden om as an d 13% w ere foun d to h ave MGD. Double aden om as m ost often occur in th e superior glan ds, an d preoperative im aging correctly iden tified th em in on ly 25% of cases.3 Multiglan d hyperplasia is m ost com m on ly sporadic but is associated w ith a gen etic syn drom e in 5% of cases. Th ese syn drom es in clude m ultiple en docrin e n eoplasia t ype 1 (MEN1), m ultiple en docrin e n eoplasia t ype 2A (MEN2A), hyperparathyroid–jaw tum or syn drom e, an d fam ilial isolated HPT.4 Acquired predisposin g factors for prim ar y HPT in clude exposure to low -dose ion izing radiation an d certain drugs, such as lith ium .5 Patien ts w ith fam ilial hypocalciuric hypercalcem ia (FHH) an d those takin g hydroch loroth iazide m ay presen t w ith sim ilar laborator y fin din gs as th ose seen in prim ary HPT w ith out th e system ic e ects.6 Th ese patien ts w ill, h ow ever, h ave low urin ary calcium excretion . Secon dary HPT an d tert iar y HPT com m on ly arise in th e settin g of ren al failure an d vitam in D deficien cy states an d are am on g th e m ost ch allenging com plication s to m an age in th is patien t population . Secon dary HPT arises due to a 1,25-dihydroxyvitam in D deficien cy an d hyperph osph atem ia. Th ese factors result in reduced ion ized calcium , w h ich directly in creases PTH con cen t ration s. Over tim e th is process m ay result in decreased expression of calcium -sen sing receptors in th e

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parathyroid glan ds an d resultan t parathyroid hyperplasia.7 Th ere are a n um ber of m edical m an agem en t option s available to th ese patien ts, an d surgery is usually reserved for severe cases refractor y to oth er treatm en ts.8 Given th at som e of th e m edication s used to t reat th is con dition are poten tially n eph rotoxic an d are also expen sive, th e ideal m an agem en t strategy for th is com plex disorder is n ot w ell establish ed in patien ts w ith ren al failure n ot yet on dialysis. Parathyroidectom y h as been sh ow n to be e cacious an d cost e ect ive after approxim ately 7 to 8 m on th s of m edical treatm en t .9 Tertiar y HPT is th e auton om ous secret ion of PTH th at is n o longer respon sive to plasm a calcium con cen tration an d w h ich persists after th e correct ion of en d-stage ren al failure, usually by ren al tran splan t. Tert iar y HPT is likely th e result of an in crease in parathyroid m ass rath er th an a ch ange in th e set poin t of PTH release, as seen in FHH, or a ch ange in m ass an d set poin t th at is seen in prim ar y HPT.10

25.3 Diagnosis Th e diagn osis of HPT is m ost com m on ly suspected in relat ively asym ptom at ic pat ien ts w ith an elevated serum calcium concen tration . How ever, a m in orit y of pat ien ts w ill presen t w ith sym ptom s of th e disease, in cludin g ren al ston es, bon e pain , fatigue, w eakn ess, pan creatitis, hypercalcem ic crisis, or n eurocogn itive sym ptom s. Th ere m ay be a fam ily h istory of hyperparathyroidism . All pat ien t evaluation s sh ould begin w ith a careful h istory an d physical exam in ation . Th e h istory sh ould elicit both overt an d subtle sym ptom s of HPT as w ell as a review of previous h ead an d n eck procedures an d any h istory of prior radiation exposure. Curren t an d prior m edication s sh ould be review ed for eviden ce of exposure to drugs kn ow n to con trib ute to parathyroid or calcium alteration s. It is also im portan t to take a careful fam ily h istory to elucidate any possibility of an in h erited syn drom e. Any patien ts w h o presen t w ith voice ch anges or th ose un dergoing reoperative surgery sh ould un dergo a form al assessm en t of th eir vocal fold m obilit y. A total calcium level sh ould th en be repeated to con firm th e m easurem en t an d any h istorical laborator y values review ed. Long-stan din g asym ptom at ic hypercalcem ia raises th e possibilit y of fam ilial hypocalciuric hypercalcem ia. To confirm th e diagn osis of HPT, in tact PTH h orm on e levels sh ould be m easured at th e sam e t im e as th e seru m calcium . Eigh t y to 90% of patien ts w ith prim ary HPT w ill h ave elevated serum PTH con cen tration s.11 A m in orit y of patien ts w ill present w ith in appropriately n orm al PTH levels given th eir degree of hypercalcem ia, an d th ese pat ien ts are also con sidered to h ave HPT. A 24-h our urin e calcium an d screen in g for calcium -sen sing receptor m utation s sh ould be obtain ed to rule out FHH. Eucalcem ic hyperparathyroidism can also occur. During th e diagn ostic evaluation , it is also im por tan t to exclude oth er causes of hypercalcem ia, in cluding the use of th iazide diuretics or lith ium . Th iazide diuretics increase calcium reabsorption in th e distal ren al tubules an d can result in m ild hypercalcem ia. Patien ts w ith m ild HPT m ay be prescribed

Conventional Parathyroidectomy th iazide diuretics for hyperten sion , w ith an even fur th er in crease in th eir serum calcium . Som e of th ese patien ts w ill h ave t rue HPT th at h as been un m asked by th e th iazide diuretics but a large proport ion w ill n ot. Th erefore, in asym ptom atic patien ts on th iazide diuretics w ith bioch em ical HPT it is recom m en ded to stop th e m edication for 3 m on th s an d th en repeat testin g before any surgical th erapy is un dertaken . Lith ium is an oth er drug associated w ith HPT. It in terferes w ith calcium m etabolism by decreasin g th e sen sitivit y of th e parathyroid glan ds to calcium an d reducin g urin ar y calcium excret ion . A m in orit y of patien ts on th is drug develop elevated PTH w ith in creased serum calcium an d hypocalciuria. Treatm en t of th is is discon tin uation of lith ium if th e psych iatric con dition of th e pat ien t perm its. After cessation of th e drug, serum calcium w ill likely n orm alize if th e durat ion of th erapy h as been sh ort but m ay persist if th e patien t h as been takin g th e m edication for m ore th an 10 years, n ecessitatin g parathyroidectom y. Oth er condition s th at are associated w ith hypercalcem ia in clude vitam in D excess, sarcoidosis, m align an cy, prolon ged im m obilization , or FHH. In all of th ese con dition s except FHH, th e PTH values w ill be ver y low. FHH is a h ereditar y disorder caused by an in act ivatin g m utation in th e calcium -sen sing receptor in th e parathyroid glan ds an d ren al t ubules.12 Up to 20% of th ese patien ts w ill presen t w ith asym ptom atic hypercalcem ia an d an elevated PTH, m akin g it di cult to distinguish from prim ar y HPT. Patien ts w ith FHH, h ow ever, w ill h ave ver y low levels of urin ary calcium excretion an d a low calcium /creatin in e clearan ce ratio. Th e distin ction betw een th ese t w o diseases is im portan t because FHH is a ben ign in h erited condition , an d parathyroidectom y w ill n ot cure th ese pat ien ts. Th is disorder is n ot associated w ith th e sequelae seen in prim ar y HPT, an d th ere is often a fam ily h istor y of failed n eck explorat ion s an d lifelon g hypercalcem ia.

25.4 Indicat ions for Surgical Managem ent Surgical th erapy o ers th e on ly defin itive treatm en t for patien ts w ith HPT. Em ergin g data suggest th at even patien ts w ith subclin ical HPT an d m ild elevation in PTH an d calcium levels can ben efit from treatm en t .13 Surger y for HPT h as grow n safer an d m ore com m on over t im e. From 1999 to 2008, th e an n ual case volum e h as risen 177%. With th is rise in case volum e, com plication rates h ave declin ed from 5.2 to 3.8%, w ith th e h igh est-volum e cen ters reportin g th e low est com plication rates.14 In dication s for surgical m an agem en t of HPT fall un der th ree categories, sym ptom at ic disease, asym ptom at ic disease, an d HPT associated w ith ren al disease. Patients present in g w ith bon e disease, kidn ey ston es, m uscle w eakn ess, or a serum calcium > 12 m g/dL are con sidered sym p tom at ic an d sh ould un dergo operative m an agem en t. Th e decision to operate on asym ptom atic or m in im ally sym ptom at ic patien ts balan ces th e risk of developin g lon g-term com plication s w ith th e risks of surgery. Rao an d colleagues con ducted a ran dom ized prospective clinical trial evaluatin g surgery versus expectan t m an agem en t for patien ts w ith asym ptom at ic HPT. In th is study, 53 patien ts w ere ran dom ly assign ed to eith er parathyroidectom y or routin e follow -up. Follow in g parathyroidectom y, th ere w as an in crease in bon e m in eral den sit y

as m easured at th e fem oral n eck an d a m odest in crease in qualit y of life scores.15 Th ese results suggested th at even patien ts w ith m ild asym ptom atic HPT could ben efit from surgical th erapy. Th e curren t guidelin es for operative m an agem en t of asym ptom at ic disease w ere elucidated at th e four th in tern ation al w orksh op on th e m an agem en t of prim ar y HPT in 2014 an d are gen erally accepted. Th ese in clude a serum calcium > 1 m g/dL above th e upper lim it of n orm al, creatin in e clearan ce < 60 in th e absen ce of an oth er cause, patien ts < 50 years of age presen tin g w ith prim ar y HPT, or bon e m in eral den sit y th at is reduced by > 2.5 stan dard deviation s (by T-score) m easured at th e at lum bar spine, total h ip, fem oral n eck, or distal 1/ 3 radius.16

25.5 Indicat ions for Bilat eral Neck Explorat ion (Convent ional Parat hyroidect om y) Un til th e last decade, bilateral n eck explorat ion (BNE) w as th e prim ary procedure perform ed for HPT. With im proved in traoperative PTH m on itorin g an d preoperative localization studies, m in im ally invasive parathyroidectom y (MIP) h as recen tly becom e th e m ore com m on procedure.17 Th ere are, h ow ever, m ultiple clin ical circum stan ces for w h ich BNE is th e m ost appropriate procedure because it h as over tim e been proven to be safe an d e ect ive. Th e follow in g are som e in dicat ion s for conven t ion al parathyroidectom y: ● Negative or discordan t preoperative im aging ● MIP w ith failure of decrease in in traoperative PTH ● Con com itan t thyroid path ology ● MEN1 ● MEN2A ● Fam ilial isolated HPT ● History of n eck irradiation , in cluding radioiodin e treatm en t ● History of lith ium use ● Cer tain reoperative settin gs ● Secon dary an d tert iary HPT In our experien ce at Mayo Clin ic, th e cure rate for patien ts un dergoing stan dard BNE for n on fam ilial, n on m align an t prim ary operation s is 99.5%, w ith an operative m ortality of 0.3%. Com plicat ion rates w ere low an d in cluded persisten t vocal cord paralysis (0.8%) an d perm an en t hypocalcem ia (0.3%).18 MIP relies on accurate preoperative localization studies to direct an d lim it surgical exploration ( Fig. 25.1, Fig. 25.2, Fig. 25.3, Fig. 25.4, an d Fig. 25.5). Preoperative localization studies usin g sestam ibi scin tigraphy an d/or ultrasoun d are variably successful in iden tifyin g a sin gle aden om a in 61 to 93% of cases.19 In a recen t prospective an alysis of factors con tributin g to n egative preoperative localization , ultrasoun d w as sh ow n to be superior to sestam ibi for th e detect ion of abn orm al glan ds. On m ultivariate an alysis, body m ass in dex, glan d size, an d glan d volum e w ere statistically sign ifican t in depen den t factors in fluen cin g th e predictive abilit y of both ultrasoun d an d sestam ibi scan n in g.20 Wh en preoperative im aging is n egative or discordan t, BNE is th e preferred procedure. Th ere is also som e argum en t th at, even w ith concordan t preoperative im aging studies, a sign ifican t proportion of patien ts w ith MGD could be m issed. Siperstein et al an alyzed th e success

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Fig. 25.1 (a-e) Sestam ibi subtraction scan dem onstrating a left inferior parathyroid adenom a. LAO, left anterior oblique; RAO, right anterior oblique.

Fig. 25.2 Sestamibi scan (lateral view) dem onstrating an intrathym ic parathyroid adenom a. Fig. 25.3 Sestam ibi scan dem onstrating an undescended (inferior) parathyroid adenom a overlying the carotid bifurcation.

of lim ited explorat ion usin g sestam ibi, ultrasoun d, an d in traoperative PTH m on itorin g.20 Over a 9-year period, 1,158 patien ts un der w en t MIP follow ed by BNE to iden tify addition al parathyroid path ology. Th e auth ors sh ow ed th at, even w ith con cordan t preoperative im aging an d in traoperative PTH m on itorin g, MIP failed to iden tify MGD in up to 20% of cases.20 Oth er data sh ow th at in 50% of patien ts w ith recurren t HPT follow in g in itial surgical treatm en t th e recurren ce is due to th e presen ce of MGD.21 Th ese data dem on st rate th at surgeon s m ust be proficien t in both MIP an d BNE to adequately treat all pat ien ts w ith HPT. Bilateral n eck exploration is accepted as th e procedure of ch oice in cases of suspected or confirm ed fam ilial HPT. Often th ese patien ts w ill require subtotal parathyroidectom y or total parathyroidectom y w ith autotran splan tation alon g w ith tran scervical thym ectom y. Because pat ien ts w ith in h erited HPT are susceptible to recurren t disease an d oth er path ologies, th e goals of parathyroidectom y are to ach ieve an d m ain tain n orm ocalcem ia for th e lon gest t im e possible w h ile avoidin g poten tial com plication s associated w ith surgical th erapy an d facilitatin g fut ure surger y for recurren t disease. MEN1 is an autosom al-dom in an t disorder caused by m utation s in the MEN1 gen e. In dividuals w ith MEN1 are at risk for

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Fig. 25.4 Neck ultrasound demonstrating a classic hypoechoic beanshaped parathyroid adenom a.

Conventional Parathyroidectomy an terior pituitar y t um ors, pan creatic n euroen docrin e tu m ors, foregut carcin oid tum ors, an d a variet y of skin lesion s.22 Vir tually all patien ts w ith th is disorder develop prim ar y HPT by th e th ird to fift h decade. All parathyroid t issue in th ese in dividuals is abn orm al, an d th e risk of recurren t disease w ith any parathyroid t issue left in situ is h igh . How ever, total parathyroidectom y w ith autotran splan tation can be com plicated by graft failure an d perm an en t hypocalcem ia in up to 33% of pat ien ts.23,24,25

Given th e rarit y of th is con dition , w ith approxim ately 1:30,000 in dividuals bein g a ected, th ere are n o large studies to evaluate th e best operat ive approach . We an alyzed our experien ce w ith 106 patien ts w h o un derw en t surgery for MEN1. MGD w as iden tified in 90% of pat ien ts an d prim ary exploration resulted in surgical cure in 94%. After 10-year follow -up, 16% h ad recurren ce of hypercalcem ia after prim ar y exploration an d 30% after reoperative procedures. From th is experien ce w e concluded th at all pat ien ts w ith MEN1 sh ould un dergo four-glan d exploration w ith subtotal resection to en sure in itial cure w h ile facilitatin g possible reoperation . Due to th e h igh likelih ood of supern um erary thym ic parathyroid glan ds in th is population w e also recom m en d t ran scervical thym ectom y at in itial operation .26 MEN2A is an autosom al-dom in ate con dition caused by m utation s in th e RET on cogen e an d is ch aracterized by th e develop m en t of m edullar y thyroid can cer, ph eoch rom ocytom a, an d HPT. Th e in ciden ce of HPT in th is patien t population is sign ificantly low er th an in MEN1, occurrin g in 19 to 34% of pat ien ts.27 Com pared w ith MEN1, HPT associated w ith MEN2A is m ilder an d less sym ptom atic, w ith a m ajorit y of pat ien ts possessin g a sin gle aden om a an d a sm all m in orit y w ith MGD. In our an alysis of parathyroidectom y for patien ts w ith MEN2A w e foun d th at, w h eth er treated by total, subtotal, or m ore lim ited resection s, all patien ts w ere cured an d n on e h ad recurren ce after a m edian of 5.8 years of follow -up. Th us, in th is patien t populat ion , w e do n ot recom m en d routin e subtotal resection because th e HPT is readily cured an d th e recurren ce is rare w h en addressin g visibly en larged glan ds alon e.26

25.6 Operat ive Technique

Fig. 25.5 Four-dim ensional com puted tom ographic scan dem onstrating a left paraesophageal parathyroid adenom a (arrow).

Th e pat ien t is placed in th e supin e position w ith both arm s loosely tucked. Th e n eck is sligh tly hyperexten ded in th e sn i in g position ( Fig. 25.6). We routin ely use an in traoperative n er ve m on itor an d in traoperative PTH m on itorin g. Because iden tification of th e parathyroid glan ds relies on discrim in atin g subtle di eren ces in color an d textu re, m eticulous h em ostasis

Fig. 25.6 Positioning (a) and planned incision (b) for bilateral neck exploration. (c) Dissection is aided with loupe m agnification and appropriate illum ination.

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Surgical Managem ent of Parathyroid Diseases is n ecessar y durin g exploration . It is n early im possible to accurately iden tify th e parathyroid glan ds in a bloody field. We begin w ith a Koch er in cision approxim ately t w o fin gerbreadth s above th e stern al n otch . Th e len gth of th e in cision is determ in ed by th e patien t’s body h abitus. Th e subcutan eous tissues

Fig. 25.7 Strap m uscles divided along m edian raphe.

are dissected w ith electrocauter y th rough th e platysm a m uscle. Subplat ysm al flaps are th en raised carefully, rem ain ing superficial to th e an terior jugular vein s. Th e strap m uscles are divided alon g th e m edian raph e ( Fig. 25.7). Th is is t ypically an avascular plan e, but care m ust be taken to ligate sm all vessels crossing betw een th e an terior jugular vein s. It is usually possible to retract th e strap m uscles laterally at th is poin t, but in di cult cases th ey m ay be divided to im prove access. With retract ion of th e strap m uscles, th e thyroid glan d w ill be exposed. Application of gen tle pressure w ill deliver th e glan d m edially, exposing th e m iddle thyroid vein . Th is vein sh ould be divided to facilitate addition al m obilization of th e thyroid glan d ( Fig. 25.8). After m edial m obilization of th e thyroid th e recurren t lar yn geal n er ve sh ould be iden tified an d carefu lly preserved ( Fig. 25.9).

Fig. 25.8 Exposure of the middle thyroid vein.

Fig. 25.9 Exposure of the recurrent laryngeal nerve with parathyroid glands in their classic anatom ical position. The inferior parathyroid gland is ventral to the plane of the recurrent laryngeal nerve, whereas the superior parathyroid gland is dorsal. ITA, inferior thyroid artery.

214

Conventional Parathyroidectomy

Fig. 25.10 Inferior parathyroid gland anterior to the plane of the recurrent laryngeal nerve.

Th e recurren t lar yngeal n er ve classically is iden tified n ear th e trach eoesoph ageal groove w ith in 3 m m of th e ligam en t of Berr y an d rarely m ay be located w ith in th e ligam en t. Sim ilar exposure is obtain ed on th e contralateral side alon g w ith dem on stration of th e prevertebral fascia, carotid arter y, an d esoph agus. At th is poin t, all four parathyroid glan ds are iden tified. Th e superior thyroid glan ds originate from th e fourth bran ch ial pouch an d m igrate caudally w ith th e thyroid. Th ey are em br yologically an d an atom ically related to th e tubercle of Zuckerkan dl an d usually foun d on th e posterior aspect of th e upper t w o-th irds of th e thyroid glan d, approxim ately 1 cm superior to th e in tersection of th e recurren t lar yngeal n er ve an d th e in ferior thyroid artery. It is often n ecessar y to fu lly m obilize th e thyroid to expose th e superior parathyroid glan ds. If th e thyroid is n ot fully m obilized th e glan ds can be m issed because th eir m igration can take th em in to th e trach eoesoph ageal groove, retroesoph ageal area, or posterior m ediastin um . Th e in ferior glan ds arise from th e th ird bran chial pouch an d m igrate caudally w ith th e thym us. Th ey are usually foun d an terior or posterolaterally to th e low er pole of th e thyroid, although ectopic glan ds m ay be foun d anyw h ere alon g th eir path of descen t from th e proxim al n eck (un descen ded at th e carotid bifurcation ) to th e m ediastin um . Th e in ferior glan ds are located m ore ven trally th an th e superior glan ds in th e plan e an terior to th e recurren t lar yngeal n erve ( Fig. 25.10). All four glan ds sh ould be exposed an d in spected before any resection is com pleted. Multiple studies h ave sh ow n th at th e m ost com m on location for a m issin g parathyroid aden om a foun d on reoperation is in th e n orm al an atom ical location .28,29 Oth er poten tial sites for m issing aden om as in clude in trathym ic, in trathyroidal, retroesoph ageal, carotid sh eath , or m ediastin al location s. If MGD is suspected based on preoperative im aging or th e patien t h as con firm ed h ereditar y HPT, a subtotal parathyroidectom y w ith or w ith out autot ran splan tation m ay be required. Typically th e sm allest glan d is left in situ. If th is glan d is foun d to be m ore th an t w ice th e n orm al size, part ial resection m ay be required. Th e decision to un dertake subtotal resection sh ould be m ade on th e basis of patien t disease ch aracteristics an d visual in spect ion of all glan ds. Alth ough som e stud ies sh ow good sen sitivit y an d specificit y for a > 50% decrease in PTH levels, th e role of in traoperative PTH values in th e settin g of MGD h as

Fig. 25.11 Autotransplantation of parathyroid tissue into the forearm brachioradialis muscle following total parathyroidectomy.

been con troversial.30 Th ese patien ts h ave altered kin etics of PTH release an d degradation as w ell as asym m etric proliferation an d secretor y status.31 Most of th e available studies are lim ited by sm all size, sh ort follow -up, h eterogen eous patien t population s, an d di eren t surgical tech n iques. We routin ely use in t raoperative PTH m onitorin g in pat ien ts w ith MGD to lim it th e exten t of resection an d to preven t operative failure, especially in pat ien ts w ith n on localizing or discordan t preoperative im aging stud ies. In th is circum stan ce, w e look for a return to n orm al PTH values in addition to a 50% decrease from baselin e. Total parathyroidectom y w ith forearm autot ran splan tation is an oth er option for patien ts w ith MGD an d is n ot favored by th e auth ors due to a greater risk of perm an en t hypoparathyroidism ( Fig. 25.11).

25.7 The Missing Gland On e of th e greatest ch allenges in parathyroid surgery is w h at to do w h en th ree n orm al glan ds are foun d an d th e sough t-after fourth glan d rem ain s occult. Biopsy of n orm al glan ds sh ould be con sidered, but great care m ust be taken to avoid iatrogen ic injury of n orm al glan ds. A soun d kn ow ledge of th e em br yon ic developm en t of th e parathyroid glan ds is essen tial in parathyroid surgery ( Fig. 25.12). If a superior glan d is m issin g on e sh ould m obilize th e upper pole of th e thyroid by dividing an d ligating th e superior pole vessels. Th is w ill often brin g th e superior glan d an d th e distal recurren t lar yngeal n er ve in to view. If n ot , th e dissection sh ould exten d alon g th e trach eoesoph ageal groove w h ere th e m issing glan d can often be carefu lly palpated ( Fig. 25.13 an d Fig. 25.14). Furth er explorat ion sh ould con tin ue beh in d th e esoph agus an d dow n in to th e upper posterior m ediastin um . Th ese m an euvers w ill usually result in success; oth erw ise a deep -seated m ediastin al glan d sh ould be suspected. Mediastin al procedures (m edian stern otom y, th oracotom y, or th oracoscopy) sh ould n ever be perform ed w ith out preoperative localization . If an in ferior glan d is m issing, first a t ran scervical thym ectom y sh ould be perform ed ( Fig. 25.15). If n egative, th e carotid

215

Surgical Managem ent of Parathyroid Diseases sh eath sh ould be open ed up to th e carotid bifurcation . Fin ally, a thyroid lobectom y (partial or com plete) w ith ultrasoun d guidan ce sh ould be considered. Approxim ately 10 to 15% of patien ts h ave supern um erar y glan ds, m ost often in th e n eck or thym us. Ectopic glan ds outside th e reach of a collar in cision accoun t for 1 to 2%of cases of HPT. After all four glan ds are visualized an d abn orm al glan ds resected, closure is perform ed in layers w ith an in terrupted absorbable suture an d a run n in g 4–0 absorbable subcuticu lar suture ( Fig. 25.16).

Fig. 25.12 Migration of the superior and inferior parathyroid glands. The superior parathyroid gland may descend into the posterior mediastinum , whereas the inferior gland m ay descend into the chest with the thym ic tissue.

Fig. 25.14 Right superior parathyroid adenom a (held in forceps). Note the norm al inferior parathyroid gland in its usual anatomical location surrounded by a halo of fat (arrow).

Fig. 25.13 Excision of the left superior parathyroid adenom a. (a) The m iddle thyroid vein has been divided between clips and the thyroid gland rotated m edially, exposing the superior parathyroid adenom a, inferior thyroid artery, and recurrent laryngeal nerve. (b) The fat pad attached to the adenom a is gently grasped and used to manipulate the gland. (c) Blunt dissection is used to expose the vascular pedicle of the adenom a. (d) The vascular pedicle is clipped and divided.

216

Conventional Parathyroidectomy

Fig. 25.16 Wound closure. (a) The strap m uscles are reapproximated in the m idline with absorbable sutures, leaving space for egress of fluid from the thyroid com partm ent. (b) A layered skin closure is perform ed with interrupted absorbable sutures and a running 4–0 absorbable subcuticular suture. (c) An adhesive bandage is applied. Fig. 25.15 Partial transcervical exposure of an intrathym ic inferior parathyroid gland.

25.8 Post operat ive Care Postoperatively, all of our patien ts un dergoing bilateral n eck exploration are obser ved overn igh t in th e h ospital, an d repeat seru m calcium an d PTH values are obtain ed th e n ext m orn in g. If patien ts h ave ver y low seru m calcium levels or sym ptom atic hypocalcem ia w e adm in ister supplem en tal oral calcium w ith or w ith out act ivated vitam in D, depen din g on th eir PTH values. Rarely, severe hypocalcem ia w ill require in traven ous calcium adm in istration via a cent ral ven ous cath eter. Most patien ts requirin g an autotran splan t w ill require supplem en tal calcium an d activated vitam in D un til th e autograft begin s to fun ct ion . In our practice, perm an en t recurren t lar yn geal n erve injur y is rare, at 0.8%. If th is occurs on on e side th e patien t w ill experien ce h oarsen ess, if bilateral injur y occurs th is can be devastatin g an d require trach eostom y. Rarely, bleedin g associated w ith th e procedure w ill require a ret urn to th e operatin g room for h em atom a evacuation . Th e sm all space an d close proxim it y to th e airw ay m ake m eticulous h em ostasis durin g th is operation exceedin gly im portan t . Most pat ien ts are dism issed th e n ext m orn in g an d follow -up seru m calcium is obtain ed in 2 w eeks to en sure cure.

25.9 Conclusions Diagn osis an d t reatm en t of prim ary HPT h ave advan ced sign ifican tly over th e last several decades, an d surgery rem ain s th e on ly defin itive curative th erapy. Surgery is recom m en ded for

patien ts w ith sym ptom atic disease, fam ilial disease, an d asym ptom at ic disease associated w ith reduced ren al fun ct ion , osteoporosis, serum calcium > 1 m g/dL above n orm al, or age < 50 years. Parathyroidectom y h as been sh ow n to be cost-e ective com pared w ith m edical th erapy, an d even patien ts w ith m ild disease can ben efit from treatm en t. Alth ough MIP is appropriate in selected pat ien ts w ith good preoperative localization studies, bilateral n eck exploration is recom m en ded for patien ts w ith n egative or discordan t im aging, MGD, fam ilial disease, ren al disease, or lith ium -in duced HPT, an d in som e cases of persisten t or recurren t disease. Th e m ost com m on cause of failed parathyroid operation s is a m issed aden om a, an d th ese are usually foun d in n orm al an atom ical location s on reoperation . A good un derstan din g of th e an atom y an d em br yology of th e parathyroid glan ds an d surrou n din g struct ures is crit ical for safe an d e ect ive surgery. Meticulous dissection is m an dator y to m in im ize th e risk of com plication s, w h ich , alth ough rare, can be severe. Conven tion al parathyroidectom y rem ain s an excellen t treatm en t option in th e h an ds of an experien ced parathyroid surgeon in th e absen ce of good preoperative localization an d th e availabilit y of in traoperative PTH m on itorin g.

References [1] Lun dgren E, Rastad J, Th urfjell E, Akerstrom G, Ljungh all S. Population -based screen ing for prim ar y HPT w ith serum calcium an d parathyroid h orm on e values in m en opausal w om en . Surgery 1997; 121(3); 287–294 [2] Yeh MW , Ituar te PH, Zh ou HC, et al. In ciden ce an d prevalen ce of prim ar y HPT in a racially m ixed population . J Clin En docrin ol Metab 2013; 98(3); 1122– 1129

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Surgical Managem ent of Parathyroid Diseases [3] Milas M, Wagn er K, Easley KA, Siperstein A, Weber CJ. Double aden om as revisited: n on un iform distribution favors en larged superior parathyroids (fourth pouch disease). Surgery 2003; 134(6); 995–1003, discussion 1003– 1004 [4] Stålberg P, Carling T. Fam ilial parathyroid tum ors: diagn osis an d m an agem en t. World J Surg 2009; 33(11); 2234–2243 [5] McKn igh t RF, Adida M, Budge K, Stockton S, Goodw in GM, Geddes JR. Lith ium toxicity profile: a system atic review an d m eta-analysis. Lan cet 2012; 379 (9817); 721–728 [6] Werm ers RA, Kearn s AE, Jen kin s GD, Melton LJ, III. In ciden ce an d clin ical spectrum of th iazide-associated hypercalcem ia. Am J Med 2007; 120(10); 911.e9–911.e15 [7] Cun n in gh am J, Locatelli F, Rodriguez M. Secondar y HPT: path ogen esis, disease progression , an d th erapeutic option s. Clin J Am Soc Neph rol 2011; 6(4); 913–921 [8] Messa P, Regalia A, Alfieri CM, et al. Curren t in dication s to parathyroidectom y in CKD patien ts before an d after ren al tran splan tation . J Neph rol 2013; 26(6); 1025–1032 [9] Narayan R, Perkin s RM, Berban o EP, et al. Parathyroidectom y versus cin acalcet hydroch loride-based m edical th erapy in th e m an agem en t of HPT in ESRD: a cost utilit y an alysis. Am J Kidn ey Dis 2007; 49(6); 801–813 [10] In dridason OS, Heath H, III, Kh osla S, Yoh ay DA, Quarles LD. Non -suppressible parathyroid h orm on e secretion is related to glan d size in urem ic secon dar y HPT. Kidn ey In t 1996; 50(5); 1663–1671 [11] En dres DB, Villan ueva R, Sh arp CF, Jr, Sin ger FR. Im m un och em ilum in om etric an d im m un oradiom etric determ in ation s of in tact an d total im m un oreactive parathyrin : perform an ce in th e di eren tial diagn osis of hypercalcem ia an d hypoparathyroidism . Clin Ch em 1991; 37(2); 162–168 [12] Fuleih an Gel-H. Fam ilial ben ign hypocalciuric hypercalcem ia. J Bon e Min er Res 2002; 17 Suppl 2; N51–N56 [13] Macfarlan e DP, Yu N, Leese GP. Subclinical an d asym ptom atic parathyroid disease: im plication s of em ergin g data. Lan cet Diabetes En docrin ol 2013; 1(4); 329–340 [14] Abdulla AG, Ituar te PH, Harari A, Wu JX, Yeh MW . Tren ds in th e frequen cy an d quality of parathyroid surgery: an alysis of 17,082 cases over 10 years. An n Surg 2014(Jun ); 19 [15] Rao DS, Ph illips ER, Divin e GW , Talpos GB. Ran dom ized con trolled clin ical trial of surgery versus n o surgery in patien ts w ith m ild asym ptom atic prim ar y HPT. J Clin En docrin ol Metab 2004; 89(11); 5415–5422 [16] Bilezikian JP, Bran di ML, Eastell R et al. Guidelin es for th e m an agem en t of asym ptom atic prim ar y hyperth yroidism : sum m ar y statem en t from th e fourth in tern ation al w orksh op. J Clin En docrin ol Metab 2014; 99; 3561–3569 [17] Green e AB, Butler RS, McIn tyre S, et al. Nation al tren ds in parathyroid surgery from 1998 to 2008: a decade of ch ange. J Am Coll Surg 2009; 209(3); 332– 343

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[18] van Heerden JA, Gran t CS. Surgical treatm en t of prim ar y HPT: an in stitut ion al perspective. World J Surg 1991; 15(6); 688–692 [19] Gran t CS, Th om pson G, Farley D, van Heerden J. Prim ar y HPT surgical m an agem en t sin ce th e in troduct ion of m in im ally invasive parathyroidectom y: Mayo Clin ic experien ce. Arch Surg 2005; 140(5); 472–478, discussion 478– 479 [20] Siperstein A, Berber E, Barbosa GF, et al. Predictin g th e success of lim ited exploration for prim ar y HPT usin g ultrasoun d, sestam ibi, an d in traoperative parathyroid h orm on e: an alysis of 1158 cases. An n Surg 2008; 248(3); 420– 428 [21] Bagul A, Patel HP, Ch adw ick D, Harrison BJ, Balasubram an ian SP. Prim ar y HPT: an an alysis of failure of parathyroidectom y. World J Surg 2014; 38(3); 534–541 [22] Bran di ML, Gagel RF, An geli A, et al. Guidelin es for diagn osis an d th erapy of MEN type 1 an d type 2. J Clin En docrin ol Metab 2001; 86(12); 5658–5671 [23] Elaraj DM, Skarulis MC, Libutti SK, et al. Results of in itial operation for hyperparathyroidism in patien ts w ith m ultiple en docrin e n eoplasia type 1. Surgery 2003; 134(6); 858–864, discussion 864–865 [24] Hellm an P, Skogseid B, Oberg K, Juh lin C, Akerström G, Rastad J. Prim ar y an d reoperative parathyroid operation s in hyperparathyroidism of m ultiple en docrin e n eoplasia type 1. Surgery 1998; 124(6); 993–999 [25] Hubbard JG, Sebag F, Maw eja S, Hen ry JF. Subtotal parathyroidectom y as an adequate treatm en t for prim ar y hyperparathyroidism in m ultiple en docrin e n eoplasia type 1. Arch Surg 2006; 141(3); 235–239 [26] O’Riordain DS, O’Brien T, Gran t CS, Weaver A, Gh arib H, van Heerden JA. Surgical m an agem en t of prim ar y hyperparathyroidism in m ultiple en docrin e n eoplasia types 1 an d 2. Surgery 1993; 114(6); 1031–1037, discussion 1037– 1039 [27] Mulligan LM, Pon der BA. Gen etic basis of en docrin e disease: m ultiple en docrin e n eoplasia type 2. J Clin En docrin ol Metab 1995; 80(7); 1989–1995 [28] Silberfein EJ, Bao R, Lopez A, et al. Reoperative parathyroidectom y: location of m issed glan ds based on a con tem porar y n om en clature system . Arch Surg 2010; 145(11); 1065–1068 [29] Th om pson GB, Gran t CS, Perrier ND, et al. Reoperative parathyroid surgery in th e era of sestam ibi scan n in g an d in traoperative parathyroid h orm on e m on itorin g. Arch Surg 1999; 134(7); 699–704, discussion 704–705 [30] Cayo AK, Sippel RS, Sch aefer S, Ch en H. Utilit y of in traoperative PTH for prim ar y hyperparathyroidism due to m ultiglan d disease. An n Surg On col 2009; 16(12); 3450–3454 [31] Clerici T, Bran dle M, Lan ge J, Doh erty GM, Gauger PG. Im pact of in traoperative parathyroid h orm on e m on itorin g on th e predict ion of m ultiglan dular parathyroid disease. World J Surg 2004; 28(2); 187–192

Minim ally Invasive Parathyroidectomy

26 Minim ally Invasive Parat hyroidect om y William S. Duke and David J. Terris

26.1 Int roduct ion Tradition al parathyroid surgery required a large tran sverse cervical in cision , bilateral n eck exploration w ith identification of all four glan ds, an d rem oval of any visibly abn orm al glan ds. Patien ts t ypically w ere m an aged w ith drain s an d w ere adm itted to th e h ospital for postoperative m on itorin g. Alth ough th ere are patien ts w h o still clearly require bilateral exploration , th e m ajorit y of hyperparathyroidism is due to sin gle-glan d disease.1 In recen t years, sign ifican t advan ces in early disease detect ion , im proved preoperative localization m odalit ies, an d in n ovative surgical adjun cts, such as rapid in traoperative parathyroid h orm on e (IOPTH) assays an d h an d-h eld gam m a probes, h ave m ade m in im ally invasive, drain less, outpatien t procedures a feasible an d appropriate altern ative for m ost patien ts requirin g parathyroid surgery. Th ere is n o con sen sus as to w h at defin es m in im ally invasive parathyroid surgery.2 Th ere are n um erous di eren t surgical access option s, recom m en ded in cision len gth s, an d exten ts of exploration th at m ay be perform ed.2,3,4,5 In a broad sen se, m in im ally invasive surgery sign ifican tly reduces th e t issue traum a required com pared w ith tradit ion al surgical exposures.6 Alth ough n o strict defin ition exists, m in im ally invasive parathyroid procedures gen erally lim it th e length of th e skin in cision an d m ore im portan t ly reduce th e exten t of dissect ion to on ly th at w h ich is n ecessary to locate an d safely rem ove th e hyperfun ction al glan d(s). Exposure of all four parathyroid glan ds, regardless of th e size of th e in cision , can n ot be con sidered m in im ally invasive surgery.7 Alth ough com pletely en doscopic parathyroid surgery usin g CO2 in su ation of th e n eck h as been reported,8 m in im ally invasive parathyroidectom y (MIP) is n ow m ost com m on ly perform ed usin g an open gasless tech n ique, eith er w ith or w ith out en doscopic assistan ce.

26.2 Indicat ions for Minim ally Invasive Parat hyroidect om y Prim ar y hyperparathyroidism (PHPT) is on e of th e m ost com m on causes of hypercalcem ia, an d its prevalen ce is in creasin g.9 Appropriate can didates for parathyroid surgery in gen eral sh ould h ave a secure diagn osis of PHPT an d h ave n o cont rain dication s to surgical in terven tion . Most patien ts are eith er sym p tom at ic or m eet con sen sus in dication s for surgery 10 ; h ow ever, surgery is n ot w ith h eld sim ply on th e basis of th ose relatively strict criteria. Th e follow in g are som e in dication s for parathyroidectom y in asym ptom at ic patien ts 10 : 1. Serum calcium > 1 m g/dL above upper lim its of n orm al 2. Creatin in e clearan ce < 60 m L/m in 3. Tw en t y-four-h our urin ar y calcium > 400 m g/d an d in creased risk of n eph rolith iasis 4. Neph rolith iasis or n eph rocalcin osis 5. Bon e m in eral den sit y T-score < – 2.5 at th e lum bar spin e, fem oral n eck, total h ip, or distal radius, or a vertebral fract ure 6. Age < 50 years old

7. Patien t requests surgery or is poor can didate for long-term observation As m any as 85%of pat ien ts w ith PHPT h ave sin gle-glan d disease an d th erefore m ay be can didates for MIP if oth er criteria are m et.4 Patien ts considered for MIP gen erally do n ot h ave a diagn osis associated w ith m ultiglan d disease, such as m ultiple en docrin e n eoplasia (MEN) t ypes 1 or 2A, prior cervical radiation , a h istor y of lith ium use, or ren al hyperparathyroidism .1 Alth ough m in im ally in vasive con cepts, in cision len gth s, an d d issect ion tech n iqu es can be ap p lied to som e p atien ts w ith t h ese con d it ion s, t h ey gen erally requ ire fou r-glan d exp lorat ion an d often rem oval of m u lt ip le glan d s. Alt h ough n ot absolu te con t rain d icat ion s for MIP, su rgeon s sh ou ld also be cau t iou s abou t o erin g t h e p roced u re t o p at ien ts w h o h ave a h ist ory of p rior cen t ral com p ar t m en t su rger y, t hyroid it is, or large goiters. On ce th e diagn osis of hyperparathyroidism is con firm ed an d th e decision is m ade to proceed w ith surgery, pat ien ts bein g con sidered for MIP sh ould un dergo at least on e preoperative im aging study to iden tify th e location of th e abn orm al parathyroid t issue. It sh ould be em ph asized th at localization studies play n o role in th e diagn osis of prim ary hyperparathyroidism , n or are th e results used to determ in e if a patien t requires surgery.11 Im aging studies are used on ly to iden tify th e likely site of th e hyperfun ct ion in g parathyroid tissue an d determ in e th e m ost appropriate operation for th e patien t.11 Alth ough m any preoperative localization studies are available, tech net ium 99 m sestam ibi (sestam ibi) an d a cervical ultrasoun d are th e m ost com m on ly used tech n iques for in itial parathyroid surgery. MIP requires th at fin din gs suggestive of abn orm al parathyroid tissue be presen t on at least on e of th e stud ies; optim ally th e sestam ibi an d ultrasoun d w ill be concordan t an d iden tify a suspected parathyroid aden om a in th e sam e quadran t. Sestam ibi is particularly im portan t in evaluating for th e presen ce of an ectopic aden om a, w h ich m ay n ot be am en able to resection w ith MIP. Th e details of preoperative localization studies are presen ted m ore fu lly in Ch apter 23.

26.3 Techniques for Minim ally Invasive Parat hyroidect om y 26.3.1 General Considerat ions Th ough th ere are m any variation s of m in im ally invasive parathyroid surgery, th e un ifyin g determ in an t th at qualifies a procedure as a MIP is a lim ited explorat ion th at does n ot expose all four parathyroid glan ds to th e risks of surgical traum a; secon dar y elem en ts are a sm all in cision (gen erally < 4 cm ),2 an d reduced exten t of dissection . It is recogn ized th at curren t m in im al-access tech n iques allow all four glan ds to be iden tified w ith m in im al dissection th rough a ver y sm all, centrally placed in cision .12 MIP m ay be perform ed as an open or en doscopically assisted procedure, un der local or gen eral an esth esia.2,12 Th is ch apter presen ts a gen eral description of th ese approach es,

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Fig. 26.1 The inferior parathyroid gland (white arrow) is always ventral to the recurrent laryngeal nerve (black arrow), whereas the superior parathyroid gland is dorsal.

alth ough th ey m ay be tailored to fit th e preferen ces of th e in dividual surgeon an d n eeds of each specific patien t. Kn ow ledge of th e usual an d poten t ial ectopic glan d location s is critical for successful parathyroid surgery. Th e superior glan ds are usually located w ith in a 2 cm region w h ose cen ter is 1 cm cran ial to th e in tersect ion of th e recurren t lar yn geal n er ve an d th e in ferior thyroid artery,13 an d th ey are alw ays dorsal to th e recurren t lar yn geal n er ve. Th e location of th e in ferior parathyroid glan ds is m ore variable. Th ey are t ypically located w ith in 1 cm of th e in ferior aspect of the thyroid glan d, an terior to a coron al plan e draw n th rough th e recurren t lar yngeal n er ve ( Fig. 26.1), but th ey m ay be intim ately associated w ith th e thym us or thyrothym ic t ract in up to 26% of patien ts.13,14 Alth ough m ost parathyroid aden om as are foun d in th ese predictable location s w ith in th e central n eck com partm ent, up to 13% of patien ts h ave supern um erar y glan ds, w h ich m ay be path ological, an d as m any as 11% of patien ts h ave m ore th an on e aden om a.1,14 Min im ally invasive parathyroid surgery relies on in traoperative adjun cts, rath er th an visual in spection of all four parathyroid glan ds, to en sure th e com plete rem oval of all hyperfun ct ion al parathyroid tissue. Th ese adjun cts in clude IOPTH assays, w h ich are discussed h ere an d in Ch apter 27, an d h an dh eld gam m a probes, discussed fur th er in Ch apter 28.

26.3.2 Minim ally Invasive Parat hyroidect om y (Nonendoscopic) Th e n on en doscopic MIP tech n ique uses retractors to m ain tain th e operative space, w h ich is accessed th rough a sm all cervical in cision . To en sure th e fin al scar w ill be predictably con cealed in a n aturally occurrin g n eck crease, th e procedure begin s by m arkin g th e plan n ed in cision site w h ile th e patien t is aw ake an d uprigh t in th e preoperative h oldin g area.1,15 Th e pat ien t is placed supin e on th e operatin g table, an d gen eral an esth esia is in duced. A lar yn geal electrom yograph ic en dotrach eal tube is used to in t ubate th e pat ien t if n erve m on itorin g is desired. Gen erally n o sh oulder roll is required, but gen tle n eck exten sion is obtain ed by sligh tly low erin g th e h ead rest of th e bed. Th e table

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Fig. 26.2 Mobile intraoperative parathyroid hormone assay equipm ent in the operating room.

is rotated 180° so th e patien t’s low er extrem it ies face th e an esth esia station . Th is allow s th e an esth esia team to obtain blood from vein s in th e patien t’s foot for IOPTH assessm en t, an d obviates th e n eed for an arterial lin e. A baselin e IOPTH level is obtain ed before th e in cision is m ade. Th e PTH assay is perform ed by a tech n ician w ith a m obile w orkstat ion in th e operatin g room , elim in atin g th e tran sport tim e associated w ith sen din g th e specim en s to th e m ain laborator y ( Fig. 26.2). On ce th e patien t is in th e fin al operative position, th e surgeon perform s an ultrasoun d to h elp guide th e subsequen t dissection . Th e plan n ed in cision site is th en in filtrated w ith a local an esth etic w ith epin eph rin e. A 2 to 2.5 cm in cision is m ade in th e m idlin e. Th e plat ysm a is divided, an d dissect ion con tin ues deeply un til th e strap m uscles are iden tified.4 A guarded elect rocauter y tip preven ts in adverten t tissue injur y in th e n arrow operative space. Meticulous atten tion m ust be given to h em ostasis because any bleedin g can obscure th e crit ical visualization of deeper struct ures. No subplatysm al flaps are elevated. Th e strap m uscles are separated vertically in th e m idlin e an d th e thyroid isth m us is iden tified. Th e strap m uscles are blun tly elevated o th e an terior an d lateral face of the thyroid lobe on th e side to be explored first an d secured un der retractors ( Fig. 26.3). Atten tion is then directed tow ard th e m ost likely location of th e path ological glan d, as predicted by preoperative localization studies. Exploration of th e superior glan d is facilitated by retract in g th e thyroid lobe ven trally an d m edially, exposing th e posterior aspect of th e thyroid an d th e paratrach eal region . Th is exposure can usually be ach ieved w ith out division of th e m iddle thyroid vein, th ough ligation of th is vessel is occasion ally n ecessary to su cien tly m obilize th e thyroid. Th e in ferior parathyroid glan d m ay be foun d by gen tly dissect in g th e soft t issue ven tral to th e inferior pole of th e thyroid glan d or m ay be iden tified dorsal to th e glan d after gen tle retract ion of th e thyroid lobe. Th e coronal plan e of th e recurren t lar yngeal n er ve, if

Minim ally Invasive Parathyroidectomy

Fig. 26.3 Proper placem ent of retractors for m inimally invasive parathyroid surgery.

iden tified, provides a good referen ce poin t to h elp determ in e th e appropriate depth of dissection . Because th ere are often n o n orm al glan ds exposed for referen ce, th e abilit y to visually distin guish a n orm al from abn orm al parathyroid glan d is crucial to successful m in im ally invasive parathyroid surgery. Norm al parathyroid glan ds are t ypically flat, ligh t brow n to tobacco color an d are 3 to 8 m m lon g w ith an average w eigh t of 40 m g.1,13 Th ey are usually surroun ded by or capped w ith fat ( Fig. 26.4). Parathyroid aden om as are t ypically larger, m ore roun ded or n odular, rubbery, an d a darker red-brow n in color ( Fig. 26.5). Gen tle spreading of th e overlyin g t issue m ay h elp reveal th e en larged glan ds. On ce iden tified, blun t dissection is used to liberate th e glan d from th e surrou n din g soft tissue, un til on ly th e vascular pedicle rem ain s attach ed to th e glan d. Soft tissue adh eren t to th e capsule of th e glan d m ay be grasped to facilitate retract ion an d dissection , but care sh ould be taken to avoid grasping th e glan d itself or applying excessive m an ipulation . Such forceful m an euvers m ay stim ulate th e release of stored parathyroid h orm on e an d alter subsequen t IOPTH levels,16 or violate th e capsule of th e glan d, riskin g parathyrom atosis. Th e recurren t lar yngeal n er ve m ay be iden tified an d is preserved durin g th is dissection . On ce free from th e surroun din g tissue, th e vascular pedicle of th e aden om a m ay be coagulated w ith elect rocautery or ligated w ith vessel clips an d sh arply divided if it is n ear th e recurren t lar yn geal n er ve. Frozen sections are n ot gen erally required. On ce th e suspicious glan d h as been rem oved th e surgical field is irrigated, h em ostasis assured, an d h alf a sh eet of Surgicel (Eth icon , In c.) is placed in to th e w oun d bed. Th e strap m uscles are eith er left open or reapproxim ated in th e m idlin e w ith a sin gle 3–0 Vicr yl (Eth icon , In c.) figure-ofeigh t suture. Th e subcutan eous tissue is closed w ith buried in terrupted 4–0 Vicr yl sutures, an d th e skin edges are closed w ith tissue adh esive an d a sin gle tran sverse Steri-Strip (3 M Corp.) ( Fig. 26.6). No drain s or extern al sutures are used. Postexcision al IOPTH levels are draw n at 5 an d 10 m in utes after rem oval of th e a ected glan d. Th is m ay be exten ded to a 15-m in ute in ter val if n ecessary. Obtain in g levels at th ese tim e poin ts allow s th e surgeon to assess th e PTH declin e an d m ake a

Fig. 26.4 Norm al parathyroid gland (arrow) dem onstrating surrounding fat.

Fig. 26.5 Parathyroid adenom a.

decision about th e likelih ood of a successful operat ion . Th e procedure is usually considered successful an d term in ated if th e postextirpation IOPTH level h as fallen at least 50% below th e baselin e value an d is w ith in th e n orm al ran ge.17,18,19 In our practice, patien ts are disch arged h om e on th e day of surgery w ith a prescription for a sh ort-term taperin g oral calcium regim en .20 Failure of th e IOPTH levels to decrease as an ticipated sh ould raise th e surgeon’s suspicion for m ultiglan d disease. If th ere is any doubt about th e abilit y to adequately iden tify th e glan ds or if an ectopic glan d is suspected, th e procedure sh ould be

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Surgical Managem ent of Parathyroid Diseases converted to a stan dard bilateral exploration an d all poten tial glan d location s explored as in dicated. Th is can com m on ly be don e w ith out exten ding th e in cision . In ch allengin g cases, frozen section confirm ation th at parathyroid tissue h as been correctly iden tified is som etim es pursued, an d bilateral PTH sam pling from th e in tern al jugular vein s m ay prove to be h elpful.

26.3.3 Minim ally Invasive Video -Assist ed Parat hyroidect om y Draw in g on th e success of oth er m in im ally invasive experien ces, a hybrid procedure, th e m in im ally invasive video-assisted parathyroidectom y (MIVAP), w as described by Miccoli et al in 1997.21 In th is approach , th e in cision can be reduced to as little

Fig. 26.6 The skin is closed with tissue adhesive and a quarter inch Steri-Strip, which facilitates rem oval of the adhesive at 3 weeks postoperatively.

as 1.5 cm ,12 an d en doscopic visualization is used to assist th e iden tification an d extirpation of th e abn orm al gland(s). Th e lim ited am oun t of dissection associated w ith th is approach facilitates a rapid recover y w ith less pain th an conven t ion al parathyroid surgery.22 Alth ough th is approach is prim arily used to perform focused surgery on a sin gle abn orm al glan d, by usin g a m idlin e n eck in cision bilateral exploration is still easily accom plish ed if n ecessar y. Th e patien t is m arked, position ed, an d prepared for surgery as described above for th e open MIP procedure. Th e surgeon stan ds to on e side of the pat ien t (gen erally th e righ t). On e assistan t stan ds at th e patien t’s h ead an d uses retractors to m ain tain th e operative space w h ile a secon d assistan t stan ds opposite th e surgeon an d con trols th e en doscope. A video m on itor placed on both sides of th e pat ien t’s h ead allow s all surgeon s to ergon om ically view th e procedure ( Fig. 26.7). Th e in itial steps of the procedure are sim ilar to th e open MIP tech n ique. Retractors are used to m ain tain th e operative space. Th ough m any retractor t ypes m ay be suitable for th is task, th e Terris thyroid retractors (Medtron ic, In c.) are an gled to provide im proved visualization of th e surgical field an d are part icularly ben eficial w h en w orkin g in such n arrow con fin es. Th e strap m uscles are divided vertically in th e m idlin e an d are blun tly elevated o th e thyroid lobe on th e side of th e suspected aden om a. On ce th e lateral aspect of th e thyroid is iden tified, it is secured un der a retractor an d pulled m edially an d ven trally w h ile a second retractor directs th e strap m uscles laterally ( Fig. 26.3). Th is vector of retract ion is critical in exposin g th e proper tissue plan es. Wh ile th e assistan t at th e h ead of th e bed m ain tain s th e operat ive space, th e cam era operator in troduces a 30° 5 or 7 m m en doscope th rough th e in cision w ith th e len s in itially orien ted in feriorly. Un der en doscopic visualization , blun t dissection w ith elevators is used to gen tly separate th e t issue overlyin g th e suspected location of th e aden om a ( Fig. 26.8). On ce iden tified, con tin ued circum ferential blun t dissection is used to free th e aden om a un til on ly the pedicle rem ain s. Th e pedicle is th en cauterized an d divided or clipped an d sh arply divided if th ere is any concern about its proxim it y to th e recurren t lar yn geal n er ve. Th e aden om a an d en doscope are rem oved, an d th e w oun d is closed as already described. IOPTH levels are obtain ed.

Fig. 26.7 The operating table is rotated 180° so the patient’s lower extrem ities are facing the anesthesia team . Using t wo video m onitors gives the entire surgical team an ergonom ic view of the procedure.

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Minim ally Invasive Parathyroidectomy

Fig. 26.8 Endoscopic visualization facilitates blunt dissection of the adenom a (arrow) away from the surrounding tissue.

26.3.4 Minim ally Invasive Parat hyroidect om y Modificat ions As w ith any operation , m in im ally invasive approach es to parathyroid surgery can be m odified to suit th e particular requirem en ts of an in dividual patien t’s disease. Th e procedures can be perform ed un der local an esth esia usin g a cervical block an d m on itored an esth esia care, w h ich m ay be an attractive option for patien ts w ith m edical com orbidities th at preclude th e safe use of gen eral an esth esia.23,24 In cision len gth s can be adjusted relative to th e patien t’s body habit us, alth ough previous w ork in thyroidectom y patien ts h as sh ow n th at m in im ally invasive, video-assisted en docrin e surgery th rough a sm all in cision is safe in patien ts w ith an elevated body m ass in dex.25 If n ecessar y, MIP can often be converted to a bilateral exploration w ith out exten din g th e m idlin e n eck in cision . Th is m ay be useful for iden tifyin g an d obtain in g a biopsy of a secon d, n orm al-appearin g glan d in in stit ution s th at rely on frozen -section an alysis rath er th an IOPTH assays or in cases w h ere th e previously suspected abn orm al glan d on preoperative im aging appears to be n orm al on in traoperative in spection . MIP m ay be perform ed th rough a lateral approach in carefully selected pat ien ts w ith posteriorly based aden om as. A lateral n eck in cision is m ade, an d dissect ion is directed betw een th e lateral aspect of th e strap m uscles an d th e stern ocleidom astoid m uscle to access th e region posterior to th e thyroid glan d. Th is approach m ay o er fast, m ore direct access to deep aden om as an d m ay be m ore com fortable for patien ts un dergoing local an esth esia for th eir procedure. It m ay also be beneficial in reoperative cases w h en sign ifican t m idlin e an d thyroid com partm en t scar tissue after prior cent ral n eck surgery is expected to com plicate th e dissection .3 Min im ally invasive parathyroid surgery m ay also be accom plish ed w ith th e assistan ce of radioguidan ce tech n ology. Min im ally invasive radioguided parathyroidectom y (MIRP) is perform ed usin g a h an dh eld gam m a probe to eith er localize or confirm th e rem oval of hyperfun ction al parathyroid tissue after an inject ion w ith tech n etium -99 m sestam ibi.26 Th is tech n ique is m ore fully described in Ch apter 28.

26.4 Out com es Num erous studies h ave sh ow n th at th e MIP approach es yield cure rates th at are com parable to or exceed th ose of tradit ion al four-glan d exploration ,4,12,27,28,29 an d are associated w ith less

pain , faster operative t im es, an d less cost th an bilateral surgery.12,30,31 Miccoli et al12 reported an in itial success rate of 99% in 652 patien ts un dergoing MIVAP, w ith a m ean operative tim e of 30 m in utes. Sim ilarly, Udelsm an et al4 reported a 99.4% cure rate in 1,037 pat ien ts un dergoing MIP, w ith a sign ifican tly low er com plication rate, len gth of stay, an d cost th an tradit ion al bilateral surgery. Despite th ese advan tages, on ly about 70% of patien ts w ith PHPT m ay be can didates for MIP.1 Pat ien ts m ay h ave un derlyin g con dition s th at predispose to m ultiglan d disease, such as MEN, or m ay h ave im aging studies th at fail to localize th e hyperfun ction al glan d. Surgeon s sh ould always be prepared to perform bilateral surgery if dictated by in traoperative fin din gs, such as failure of th e IOPTH assay to drop as expected.

26.5 Conclusion Min im ally invasive parathyroidectom y tech n iques h ave revolution ized th e m an agem en t of prim ar y hyperparathyroidism . Th e durable cure rates of th ese procedures m atch or exceed th ose of conven t ion al open four-glan d exploration , an d th ey are associated w ith a faster, less m orbid recover y w ith a reduced cosm etic im pact. Min im ally invasive parathyroidectom y is appropriate for m ost pat ien ts requirin g surgery an d sh ould be con sidered for all patien ts w ith sporadic, localizing disease.

References [1] Ritter H, Milas M. Bilateral parathyroid exploration for hyperparathyroidism . Operative Tech niques in Otolaryn gology. 2009; 20; 44–53 [2] Udelsm an R, Pasieka JL, Sturgeon C, Young JE, Clark OH. Surgery for asym ptom atic prim ar y hyperparathyroidism : proceedings of th e th ird in tern ation al w orksh op. J Clin En docrin ol Metab 2009; 94(2); 366–372 [3] Sh in do ML, Rosen th al JM. Min im al access parathyroidectom y usin g th e focused lateral approach : tech n ique, in dication , an d results. Arch Otolaryn gol Head Neck Surg 2007; 133(12); 1227–1234 [4] Udelsm an R, Lin Z, Don ovan P. Th e superiorit y of m in im ally invasive parathyroidectom y based on 1650 con secutive patien ts w ith prim ar y hyperparathyroidism . An n Surg 2011; 253(3); 585–591 [5] Gracie D, Hussain SSM. Use of m in im ally invasive parathyroidectom y tech n iques in sporadic prim ar y hyperparathyroidism : system atic review. J Lar yn gol Otol 2012; 126(3); 221–227 [6] Hun ter JG. Min im ally invasive surgery: th e n ext fron tier. World J Surg 1999; 23(4); 422–424 [7] Norm an J, Lopez J, Politz D. Aban don ing un ilateral parathyroidectom y: w hy w e reversed our position after 15,000 parathyroid operation s. J Am Coll Surg 2012; 214(3); 260–269 [8] Gagn er M. En doscopic subtotal parathyroidectom y in patien ts w ith prim ar y hyperparathyroidism . Br J Surg 1996; 83(6); 875 [9] Yeh MW , Ituar te PHG, Zh ou HC, et al. In ciden ce an d prevalen ce of prim ar y hyperparathyroidism in a racially m ixed population . J Clin En docrin ol Metab 2013; 98(3); 1122–1129 [10] Bilezikian JP, Bran di ML, Eastell R, et al. Guidelin es for th e m an agem en t of asym ptom atic prim ar y hyperparathyroidism : sum m ar y statem en t from th e Fourth In tern ation al Worksh op. J Clin En docrin ol Metab 2014; 99(10); 3561– 3569 [11] Mih ai R, Sim on D, Hellm an P. Im aging for prim ar y hyperparathyroidism —an eviden ce-based an alysis. Lan gen becks Arch Surg 2009; 394(5); 765–784 [12] Miccoli P, Materazzi G, Bon ari G, et al. Min im ally invasive video-assisted parathyroidectom y. Operative Tech niques in Otolaryn gology 2008; 19; 22–25 [13] Fan cy T, Gallagh er D, III, Horn ig JD. Surgical an atom y of th e thyroid an d parathyroid glan ds. Otolaryn gol Clin North Am 2010; 43(2); 221–227, vii [14] Moren o MA, Callen der GG, Woodburn K, et al. Com m on location s of parathyroid aden om as. An n Surg On col 2011; 18(4); 1047–1051 [15] Terris DJ, Seybt MW , Elch oufi M, Ch in E. Cosm etic thyroid surgery: defin in g th e essen tial prin ciples. Lar yn goscope 2007; 117(7); 1168–1172

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Surgical Managem ent of Parathyroid Diseases [16] Pellitteri P. In traoperative assessm en t of parathyroid h orm on e. Operative Tech niques in Otolaryn gology 2009; 20; 60–65 [17] Heller KS, Blum berg SN. Relation of fin al in traoperative parathyroid h orm on e level an d outcom e follow in g parathyroidectom y. Arch Otolaryn gol Head Neck Surg 2009; 135(11); 1103–1107 [18] Rich ards ML, Th om pson GB, Farley DR, Gran t CS. An optim al algorith m for in traoperative parathyroid h orm on e m on itorin g. Arch Surg 2011; 146(3); 280– 285 [19] Kan dil E, Malazai AJ, Alrash eedi S, Tufano RP. Min im ally invasive/focused parathyroidectom y in patien ts w ith n egative sestam ibi scan results. Arch Otolaryn gol Head Neck Surg 2012; 138(3); 223–225 [20] Sin ger MC, Bh akta D, Seybt MW , Terris DJ. Calcium m an agem en t after thyroidectom y: a sim ple an d cost-e ective m ethod. Otolaryn gol Head Neck Surg 2012; 146(3); 362–365 [21] Miccoli P, Pin ch era A, Cecch in i G, et al. Min im ally invasive, video-assisted parathyroid surgery for prim ar y hyperparathyroidism . J En docrin ol Invest 1997; 20(7); 429–430 [22] Miccoli P, Ben din elli C, Bert i P, Vign ali E, Pin chera A, Marcocci C. Video-assisted versus conven tion al parathyroidectom y in prim ar y hyperparathyroidism : a prospective ran dom ized study. Surger y 1999; 126(6); 1117–1121, discussion 1121–1122

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[23] Suliburk JW , Perrier ND. Prim ar y hyperparathyroidism . On cologist 2007; 12 (6); 644–653 [24] Starker LF, Fonseca AL, Carling T, Udelsm an R. Min im ally invasive parathyroidectom y. In t J En docrin ol 2011; 2011; 206502 [25] Duke W S, Wh ite JR, Waller JL, Terris DJ. En doscopic thyroidectom y is safe in patien ts w ith a h igh body m ass in dex. Thyroid 2014; 24(7); 1146–1150 [26] Stack BC, Jr. Min im ally invasive radioguided parathyroidectom y. Operative Tech niques in Otolaryn gology 2009; 20; 54–59 [27] Westerdah l J, Bergenfelz A. Un ilateral versus bilateral n eck exploration for prim ar y hyperparathyroidism : five-year follow -up of a ran dom ized con trolled trial. An n Surg 2007; 246(6); 976–980, discussion 980–981 [28] Bellan ton e R, Ra aelli M, DE Crea C, Train i E, Lom bardi CP. Min im ally-invasive parathyroid surgery. Acta Otorh in olaryn gol Ital 2011; 31(4); 207–215 [29] Vaid S, Pandelidis S. Min im ally invasive parathyroidectom y: a com m unity h ospital experien ce. Arch Surg 2011; 146(7); 876–878 [30] Gracie D, Hussain SSM. Use of m in im ally invasive parathyroidectom y tech n iques in sporadic prim ar y hyperparathyroidism : system atic review. J Lar yn gol Otol 2012; 126(3); 221–227 [31] Sch n eider DF, Mazeh H, Sippel RS, Ch en H. Is m in im ally invasive parathyroidectom y associated w ith greater recurren ce com pared to bilateral exploration ? An alysis of m ore th an 1,000 cases. Surgery 2012; 152(6); 1008–1015

Intraoperative Parathyroid Horm one Assay

27 Int raoperat ive Parat hyroid Horm one Assay Latha V. Pasupuleti and James A. Lee

27.1 Int roduct ion Over th e past few decades th e surgical m an agem en t of prim ary hyperparathyroidism h as evolved dram atically. Historically, all patien ts un derw en t a bilateral n eck explorat ion to assess all four parathyroid glan ds, an d any grossly diseased glan ds w ere resected. Today, w ith th e adven t of im proved localization studies com bin ed w ith in t raoperative parathyroid h orm on e (IOPTH) m on itorin g, m in im ally invasive parathyroidectom y h as gain ed w idespread acceptance, particularly am on g experien ced en docrin e surgeon s. Th is ch apter discusses th e developm en t of th e IOPTH assay as w ell as th e curren t recom m en dation s an d tech n iques for its usage.

27.2 Hist ory of t he Int raoperat ive Parat hyroid Horm one Assay In th e 1970s, physician s at th e Un iversit y of Miam i first began usin g a radioim m un oassay to m easure parathyroid h orm on e (PTH) levels for patien ts un dergoing parathyroidectom y. How ever, th is early assay m easured fragm en ts of th e m olecule, rath er th an th e in tact m olecule, w h ich often led to in con sisten t results. In 1987, Sam uel Nussbaum at th e Massach usetts Gen eral Hospital reported a h igh ly sen sitive t w o-site an tibody im m un oradiom etric assay to m easure in tact PTH. Th e surgeon s at Massach usetts Gen eral Hospital subsequen tly reported th eir results at th e Am erican Association of En docrin e Surgeon s (AAES) an n ual m eetin g an d proposed th at th eir assay could be used as an in traoperative tool, because it h ad a sh ort, 15m in ute turn aroun d tim e. How ever, th eir report w as received w ith skepticism as bein g an un n ecessary test in th e h an ds of an experien ced en docrin e surgeon . Shor tly th ereafter, surgeon s at th e Un iversit y of Miam i started to perform th eir ow n in traoperative assay w ith a sim ilar turn aroun d t im e of 15 m in utes. Th eir “quick” PTH (QPTH) assay h ad sim ilar results to th e stan dard assay. Usin g th eir assay, th ese surgeon s studied sam ples m easured at various operative in tervals. Th ey also learn ed th at m an ipulatin g th e glan d raised in traoperative m easurem en ts. Th rough th eir various lab value com parison s, th ey discovered th at th e h alf-life of PTH w as 3.5 to 4 m in utes.1 Aroun d th is t im e, surgeon s in Fran ce publish ed reports of usin g a n ew, lim ited approach to parathyroidectom y perform ed w ith ultrasoun d localization , local an esth esia, an d con firm ation of excision of an aden om a w ith PTH assays an d cyclic aden osin e m on oph osph ate (cAMP) levels. How ever, th eir assays took m ore th an 45 m in utes to run , an d th ey often did n ot con firm rem oval of disease un til lon g after th e operat ion w as concluded. If th ere w as eviden ce of m ultiglan d disease based on th e IOPTH assay values, th e patien t h ad to un dergo a secon d operation .1,2,3 Nich ols In stit ute Diagn ostics fin ally brough t a m ajor advan cem en t to IOPTH m on itorin g in th e Un ited States w ith an im m un och em ilum in om etric assay (ICMA) in 1993. Th is m eth od did n ot use radioisotopes, th us m akin g it portable. Th e assay w as rapid, stable, an d sh ow ed n o cross-reactivit y w ith PTH fragm en ts like previous assays did.1

In 1992, surgeon s at th e Un iversit y of Miam i began usin g sestam ibi scan s for preoperative localization of parathyroid aden om as. Com bin in g preoperative localization w ith in traoperative PTH assays, th ey sh orten ed th eir operat ive tim es for parathyroidectom y. At aroun d th e sam e tim e, Boggs et al sh ow ed th at ICMA h ad a sen sitivit y of 97%, specificit y of 100%, an d overall accuracy of 97% for predictin g postoperat ive calcium levels.1,4 Th ese results w ere presented at th e AAES in 1996, after w h ich a sudden in terest w as spurred in th e focused parathyroidectom y m eth od n ow w idely perform ed.1 How ever, th e cost of usin g th is n ew in traoperative PTH assay tech n ology w as in itially h igh , slow in g adoption by surgeon s. The Un iversit y of Miam i evaluated th e decreased costs associated n ot on ly w ith sh orter operative t im es, but th eir abilit y to perform th e surgery as an outpat ien t. Th ey sh ow ed th at sam eday parathyroid surgery versus an overn igh t stay cost 39% less.1 Th us cost-e ectiven ess w as an oth er drivin g factor in support of usin g IOPTH m on itorin g to h elp perform m ore focused parathyroidectom ies.

27.3 Di erences in t he Molecular St ruct ure of PTH and It s E ect on t he Assay Th e m olecular path w ay an d struct ure of PTH h ave a sign ifican t e ect on h ow th e assay is m easured. PTH is first tran slated in th e en doplasm ic reticulum of th e parathyroid ch ief cell as a 115-am in o-acid-sequen ce m olecule called preproPTH. Subsequen tly, t w o am in o acid sequen ce cleavages occur, first to create proPTH an d th en to create th e fin al 84-am in o-acid-len gth in tact PTH m olecule term ed (1–84) PTH. Less th an 1% of (1–84) PTH reach es th e PTH receptors in target organ s after bein g released from th e parathyroid glan ds. Wh en PTH is m etabolized, on ly th e in active C-term in al portion s (cPTH) are rereleased in to th e circulation . Th e N-term in al products (n PTH) h ave biological act ivit y but m ake up a m uch sm aller portion of circulatin g h orm on e. In cont rast, cPTH h as a lon ger h alf-life an d is secreted prim arily by th e kidn eys. Th us cPTH fragm en ts are elevated in patien ts w ith ren al dysfun ct ion , w h ich m ay adversely a ect th e results of assays m easured in pat ien ts w ith ren al failure. Fig. 27.1 depicts th e product ion an d degradation path w ay of PTH.5 “In tact PTH” assays are t w o-site san dw ich assays in w h ich th e n PTH an d cPTH en ds are boun d by separate an tibodies. Ideally, a PTH assay w ill select ively bin d an d m easure (1–84) PTH. How ever, (1–84) PTH circulates in m uch sm aller n um bers th an th e various PTH fragm en ts, m akin g its m easurem en t ch allenging. In fact, m ost of th e early assays reacted w ith th e m ore abun dan t, sm aller cleavage products an d fragm en ts of PTH (w h ich are devoid of bioactivit y) m ore th an w ith th e act ive (1– 84) PTH m olecule. Addition ally, th e ratio of (1–84) PTH to its fragm en ts can var y sign ifican tly in patien ts w ith ren al dysfun ction an d varyin g parathyroid glan d activit y. Th ese ch allenges associated w ith th e accuracy of IOPTH assays an d w h ich

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Surgical Managem ent of Parathyroid Diseases

Fig. 27.1 Production and degradation of parathyroid horm one. Molecules highlighted in yellow are biologically active. aa, amino acids; PTH, parathyroid horm one; nPTH, am ino-term inal fragment of PTH; cPTH, carboxy-term inal fragm ent of PTH. (Reproduced from Carter AB, Howanitz PJ. Intraoperative testing for parathyroid hormone: a com prehensive review of the use of the assay and the relevant literature. Arch Pathol Lab Med 2003;127:1425, with permission from Archives of Pathology and Laboratory Medicine. Copyright 2003 College of Am erican Pathologists.)

m olecules w ere act ually bein g m easured h ave been studied an d evaluated exten sively. Fort un ately, n ew er gen eration s of IOPTH assays h ave im proved rates for detect in g th e actual (1–84) PTH m olecules, rath er th an th e in act ive fragm en ts.5,6

27.4 Int raoperat ive PTH Monit oring Im proves t he Success of Minim ally Invasive Parat hyroidect om y With th e in creased accuracy of preoperative localization studies, m any surgeon s h ave sh ifted tow ard m in im ally invasive parathyroidectom y rath er th an routin e four-glan d exploration . Min im ally invasive parathyroidectom y tech n iques use focused, un ilateral, an d often en doscopic m eth ods.7 How ever, durin g m in im ally invasive parathyroidectom y, because all four glan ds are n ot directly visualized, th e surgeon does n ot n ecessarily kn ow w h eth er or n ot all of th e diseased parathyroid tissue h as been rem oved. By in corporatin g IOPTH assessm en t, surgeon s can excise th e im age-localized aden om a an d im m ediately assess for bioch em ical resolution of th e hyperparathyroidism to determ in e if th e operat ion h as been successful. If in traoperative PTH levels fail to declin e appropriately, th e surgeon can im m ediately convert to a bilateral n eck exploration , th us poten tially avoidin g a secon d operation for th e pat ien t. Wh en ultrasoun d iden tifies a single aden om a, th e addition of IOPTH m easurem en ts in creases th e operative success from 71 to 86%.7 Likew ise, w h en sestam ibi scan localizes a single

226

aden om a, use of IOPTH im proves th e operative success from 83 to 92%.7 Wh en both ultrasoun d an d sestam ibi scan are used an d h ave concordan t results, th eir com bin ed accuracy in localization is 95%.7 Wh en IOPTH assessm en t is added to ultrasoun d an d sestam ibi in th is settin g, th e operative success in creases to 97%.7 Som e argue th at th is gain of 2% does n ot justify th e use of IOPTH m on itorin g in th is settin g an d in creases th e len gth of operation an d costs.7 IOPTH assessm en t is especially h elpful in th e settin g of discordan t fin din gs on preoperative im aging studies. About h alf to t w o-th irds of patien ts w ith hyperparathyroidism w ill h ave discordan t im aging fin din gs.7 Th e use of IOPTH m on itorin g in th is settin g h as been sh ow n to guide th e operative m an agem en t in 74% of th ese patien ts, leadin g to an operative success rate of 93%. Sixt y-six percen t of these patien ts w ere able to h ave successful un ilateral explorat ion .7 Cayo et al prospectively studied m ore th an 755 pat ien ts w ith prim ar y hyperparathyroidism an d foun d th at IOPTH m on itorin g accurately predicted success of parathyroidectom y in 97.5% of patien ts w ith m ultiglan d disease.8 How ever, oth er studies report th at IOPTH is n ot as successful w ith m ultiglan d disease.9,10 Siperstein et al reported th at, w h en a bilateral n eck exploration is routin ely perform ed, even w h en preoperative localization studies iden tified a sin gle aden om a, un suspected addition al m orph ologically abn orm al parathyroid glan ds are iden tified in 20 to 22% of patien ts. Adding IOPTH on ly reduced th e rate of iden tifyin g un suspected m ultiglan d disease to 16 to 17%. How ever, on e crit icism of th is study is th at, alth ough th e addition al glan ds w ere m orph ologically abn orm al, th ey m ay n ot h ave been fun ction ally abn orm al. Overall, IOPTH

Intraoperative Parathyroid Horm one Assay assessm en t correctly predicts m ultiglan d disease in on ly 22% of patien ts w h o h ave it.11

27.5 Applicat ion of t he IOPTH Assay Logistical con sideration s in usin g IOPTH m on itorin g in clude location of blood draw s, location of th e lab run n ing th e assay, t ype of IOPTH assay used, an d t im ing an d n um ber of blood draw s required to accurately determ in e bioch em ical cure. Surgeon preferen ce usually dictates w h eth er th e sam ples are draw n from th e in tern al jugular vein or a periph eral in traven ous site. Cen tral ven ous sam plin g is conven ien t because th e in tern al jugular vein is in th e operative field, th ough a periph eral sam ple obtain ed aw ay from th e surgical field m ay be less susceptible to fluct uation s in PTH related to m an ipulation of th e parathyroid glan ds. Cen trally collected sam ples h ave h igh er PTH values on average, but th is does n ot cause a statist ically sign ifican t di eren ce in percen tage drop th at a ect s th e outcom e of th e operat ion .12,13,14 Regardless of site used, all sam ples sh ould be draw n from th e sam e location .12,13,14 High -volum e cen ters are often able to use th e h igh est-qualit y, fastest assays, an d often h ave eith er a dedicated lab facility adjacen t to th e operatin g room or th e capabilit y to perform th e assay in th e operatin g room to en able faster t urn aroun d tim e. One option , th e STAT IO-iPTH assay (Fut ure Diagn ostics) can be perform ed in 8 m in utes an d o ers por table, poin t-of-care results w ith in th e operatin g room . At low -volum e cen ters, th e sam ples m ay h ave to be sen t to th e stan dard h ospital lab for processing, th us takin g m uch lon ger to get results. Th is delay in lab results can prolon g th e operation , th ereby n egatin g som e of th e ben efit of h avin g a sh orter, m ore focused operation . PTH sam ples are m ost com m on ly draw n as a baselin e (prior to th e start of th e operation ), tim e 0 (T0) (just prior to ligating t h e vascu lar p ed icle), an d 5 an d 10 m in u tes aft e r excision of t h e ad e n om a ( Fig. 27.2a). Th e baselin e an d T0 sam p les ar e refe rre d t o as t h e p re excision valu e s, w h ereas t h e 5- an d 10-m in u t e sam p les are calle d t h e p ost excision valu es. Tw o p ree xcision valu es are d raw n becau se t h e T0 is oft e n h igh er t h an t h e baselin e valu e d u e to m an ip u lat ion of t h e d ise ase d p arat h yroid (s). How e ve r, t h e T0 is som et im es low er t h an t h e baselin e if t h e blood su p p ly h ad alr ead y be en ligate d p rior t o d raw in g of t h e T0 sam p le.1 5,16 Of n ote, p reop e rat ive PTH valu es sh ou ld n ot be u se d in t h e in t raop erat ive d e te rm in at ion of bioch em ical su ccess. Because th e h alf-life of PTH is 3.5 to 5 m in utes, th e 10-m in ute value sh ould h ave fallen by m ore th an h alf of th e h igh er of th e t w o preexcision values to be considered a successful operation , a guidelin e often referred to as th e Miam i criterion . Man y surgeon s believe th at, in addition to a 50% drop, IOPTH levels sh ould also n orm alize to avoid m issing persisten t disease. If th e PTH h as fallen by m ore th an 50% but rem ain s elevated above n orm al at 10 m in utes, sam ples at later tim e poin ts m ay be sen t. Frozen -section an alysis can be used if th ere is un certain t y about th e resected specim en .5 Oth er reason s for a prolon ged declin e in PTH values in clude a reduced ren al clearan ce of PTH in cases of overt or subclin ical ren al in su cien cy an d in ciden tal in traoperative PTH spikes from excessive glan d m an ipulation

( Fig. 27.2b).15,16 Obtain in g a delayed value at 30 m in utes postexcision can h elp discern if th ere w as truly persisten t disease. Alth ough th e Miam i criterion is th e m ost com m on ly em ployed stan dard for IOPTH m on itorin g, n um erous oth ers h ave also been advocated as bein g th e m ost e ect ive at determ in in g a successful operation . Table 27.1 sum m arizes th e Miam i, Vien n a, Halle, an d Rom e criteria.17 A n um ber of studies h ave com pared th e e ect iven ess of th e various criteria on th e sam e set of patien ts. In a com parison of various in traoperative PTH criteria, Carn iero et al reported th e best results w ith th e Miam i criterion , w h ich ach ieved th e h igh est accuracy (97%), w ith a false-positive rate of 0.9% an d a false-n egative rate of 2.6%.16,18 Th e Miam i criterion h as been com pared to oth er m ore strin gen t criteria th at focused on detect in g m ultiglan dular disease w ith a h igh er sen sitivit y. How ever, any attem pts to low er th e n um ber of false-positive results an d decrease th e n um ber of operat ive failures traded an in creased specificit y in predictin g com plete resection for a low er sen sitivit y an d low er overall accuracy, leadin g to fur th er un n ecessary n eck exploration s an d a prolon ged operat ive t im e.16,18 Barczyn ski et al perform ed a retrospect ive review of 260 patien ts w ith sporadic prim ar y hyperparathyroidism an d con cordan t sestam ibi scan n in g an d ultrasoun d results to com pare th e predict ive values of th e Halle, Miam i, Rom e, an d Vien n a criteria ( Table 27.2). Th ey concluded th at th e Miam i criterion , follow ed by th e Vien n a criterion , w as th e m ost balan ced, w ith th e h igh est accuracy for predictin g cure. How ever, th e Rom e criterion , follow ed by th e Halle criterion , w as n oted to be th e m ost useful in in traoperative detect ion of m ultiglan dular disease. Despite th is fin din g, th ey believed th at, in pat ien ts w ith concordan t sestam ibi an d ultrasoun d results, usin g th e Rom e or Halle criterion w ould result in a sign ifican tly h igh er n um ber of unn ecessary conversion s to bilateral n eck exploration s an d on ly a m argin al im provem en t in th e success rate of prim ar y operation s.18

27.6 Lim it at ions of t he Parat hyroid Horm one Assay Th ere are m ultiple reason s for in accurate IOPTH results. Th e m etabolism an d clearan ce of PTH vary greatly betw een patien ts an d are in fluen ced by th e rate of th e production of PTH as w ell as by its m etabolism , th e pat ien t’s ren al fun ct ion , an d th e t ype of parathyroid disease th at is presen t.5 Hem olysis of postexcision blood specim en s m ay artificially decrease th e PTH level, resultin g in false-positive IOPTH levels.19 Multiglan d disease can cause m isleadin g IOPTH values ( Fig. 27.2c). For in stan ce, m ore th an h alf of patien ts w ith double adenom as are reported to h ave false-positive IOPTH results.20 Th is error m ay be due to size di eren ces betw een th e aden om as; if th e larger glan d is rem oved first, th ere m ay be a larger drop in PTH in itially th at m ay lead a surgeon to conclude th at th e on ly diseased glan d w as rem oved.20 As discussed earlier, as PTH is processed, th ere are m any degradation products an d fragm en ts produced. Th e ideal IOPTH assay select ively detects th e act ual (1–84) PTH m olecules. How ever, th ere is cross-reactivit y of fragm en ts th at can alter IOPTH results, especially w h en older assays are used for m easurem en ts.5,6

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Fig. 27.2 Patterns of intraoperative parathyroid horm one (IOPTH) decline after parathyroid adenom a excision. The dotted line represents the assay upper lim its of norm al. (a) Decline to cure after rem oval of a single adenom a. (b) Parathyroid hormone spike at T0 from excessive gland m anipulation, followed by decline to cure. (c) Initial failure to decline, followed by appropriate decline to cure after resection of a second adenom a. TB, baseline; T0, tim e of excision.

Table 27.1 Comparison of the m ajor criteria used to guide intraoperative decision m aking with intraoperative parathyroid horm one

228

Criterion

Description

Miam i

> 50% decline from either the highest preincision or preexcision parathyroid horm one (PTH) value within 10 m inutes of gland rem oval

Rom e

> 50% decline from the highest preexcision level, and/or PTH level within the reference range at 20 m inutes after excision, and/or a PTH value < 7.5 ng/ L lower than the value at 10 minutes after excision

Halle

Decline into the low norm al range (PTH < 35 ng/ L) within 15 m inutes of gland rem oval

Vienna

> 50% decline from the preincision value within 10 m inutes of gland resection

Intraoperative Parathyroid Horm one Assay Table 27.2 Com parison of the e ectiveness of the m ajor criteria used for intraoperative parathyroid hormone decision m aking Criterion

Sensitivit y (%)

Specificit y (%)

PPV (%)

NPV (%)

Overall accuracy (%)

Miam i

97.6

93.3

99.6

70

97.3

Rom e

82.9

100

100

26.3

83.8

Halle

62.9

100

100

14.2

65

Vienna

92.2

93.3

99.6

60.9

92.3

Abbreviations: NPV, negative predictive value; PPV, positive predictive value. Source: Data from Barczynski M, Konturek A, Hubalewska-Dydejczyk A, et al. Evaluation of Halle, Miami, Rom e, and Vienna intraoperative iPTH assay criteria in guiding m inim ally invasive parathyroidectom y. Langenbecks Arch Surg 2009;394:846.

27.7 Conclusion Im proved preoperative localization studies com bin ed w ith faster, m ore accurate IOPTH assays h ave spurred th e w ide adoption of m in im ally invasive parathyroidectom y. Various criteria h ave been used to assess IOPTH results for bioch em ical cure. Curren tly, th e Miam i criterion (≥ 50% decrease in th e IOPTH levels at 10 m in utes from th e h igh er of th e preexcision values) is th e m ost w idely used an d h as an accuracy above 97% w ith th e low est false-positive an d -n egative rates. Th e adven t of IOPTH m on itorin g is a prim e exam ple of h ow an im proved un derstan din g of h orm on al path w ays an d kin etics an d evolving tech n ology can drive in n ovation s in m edicin e.

References [1] Ir vin GL III. “Th e ‘Miam i Criterion ’ an d th e Evolution of Min im ally Invasive Parathyroidectom y”. In : Zeiger, MA, Sh en W T, Felger EA, eds. Th e Suprem e Trium ph of th e Surgeon’s Art: A Narrative Histor y of En docrin e Surgery. San Fran cisco, CA: Universit y of Californ ia Medical Hum an ities Con sort ium 2013: 194–203 [2] Ch apuis Y, Fulla Y, Icard P, Non n em ach er L. [Peroperative assay of active parath orm on e 1–84 in surgery of prim ar y hyperparathyroidism ] Presse Med 1990; 19(31); 1461–1462 [3] Ch apuis Y, Icard P, Fulla Y, et al. Parathyroid aden om ectom y un der local an esth esia w ith in tra-operative m on itorin g of UcAMP an d/or 1–84 PTH. World J Surg 1992; 16(4); 570–575 [4] Boggs JE, Ir vin GL, III, Carn eiro DM, Molin ari AS. Th e evolu t ion of p arat hyroid ect om y failu res. Su rgery 1999; 126(6); 998–1002, d iscu ssion 1002–1003 [5] Carter AB, How an itz PJ. In traoperative testin g for parathyroid h orm on e: a com preh en sive review of th e use of th e assay an d th e relevan t literature. Arch Path ol Lab Med 2003; 127(11); 1424–1442 [6] Gao P, D’Am our P. Evolution of th e parathyroid h orm on e (PTH) assay—im portan ce of circulatin g PTH im m un oh eterogen eity an d of its regulation . Clin Lab 2005; 51(1–2); 21–29 [7] Guerrero MA, Clark OH. A Com preh en sive Review of In traoperative Parathyroid Horm on e Mon itorin g. World Journ al of En docrin e Surger y. 2010; 2(1); 21–27

[8] Cayo AK, Sippel RS, Sch aefer S, Ch en H. Utilit y of in traoperative PTH for prim ary hyperparathyroidism due to m ultiglan d disease. An n Surg On col 2009; 16(12); 3450–3454 [9] Clerici T, Bran dle M, Lan ge J, Doh erty GM, Gauger PG. Im pact of in traoperative parathyroid h orm on e m on itorin g on th e predict ion of m ultiglan dular parathyroid disease. World J Surg 2004; 28(2); 187–192 [10] Siperstein A, Berber E, Mackey R, Algh oul M, Wagn er K, Milas M. Prospective evaluation of sestam ibi scan , ultrason ography, an d rapid PTH to predict th e success of lim ited exploration for sporadic prim ar y hyperparathyroidism . Surgery 2004; 136(4); 872–880 [11] Siperstein A, Berber E, Barbosa GF, et al. Predictin g th e success of lim ited exploration for prim ar y hyperparathyroidism usin g ultrasoun d, sestam ibi, an d in traoperative parathyroid h orm on e: an alysis of 1158 cases. An n Surg 2008; 248(3); 420–428 [12] Woodrum DT, Saun ders BD, En glan d BG, Burn ey RE, Doh ert y GM, Gauger PG. Th e in fluen ce of sam ple site on in traoperative PTH m on itorin g durin g parathyroidectom y. Surgery 2004; 136(6); 1169–1175 [13] Broom e JT, Schrager JJ, Bilh eim er D, Ch am bers EP, Jacobs JK, Ph ay J. Cen tral ven ous sam plin g for in traoperative parathyroid h orm on e m on itorin g: are periph eral guidelin es applicable? Am Surg 2007; 73(7); 712–716 [14] Beyer TD, Ch en E, Ata A, DeCresce R, Prin z RA, Solorzan o CC. A prospect ive evaluation of th e e ect of sam ple collection site on in traoperative parathorm on e m on itorin g durin g parathyroidectom y. Surgery 2008; 144(4); 504– 509, discussion 509–510 [15] Riss P, Kaczirek K, Bieglm ayer C, Niederle B. PTH spikes durin g parathyroid exploration —a possible pitfall durin g PTH m on itorin g? Lan gen becks Arch Surg 2007; 392(4); 427–430 [16] Carn eiro DM, Solorzan o CC, Nader MC, Ram irez M, Ir vin GL, III. Com parison of in traoperative iPTH assay (QPTH) criteria in guiding parathyroidectom y: w h ich criterion is th e m ost accurate? Surgery 2003; 134(6); 973–979, discussion 979–981 [17] Riss P, Kaczirek K, Hein z G, Bieglm ayer C, Niederle B. A “defin ed baselin e” in PTH m on itoring in creases surgical success in patien ts w ith m ultiple glan d disease. Surgery 2007; 142(3); 398–404 [18] Barczyn ski M, Kon turek A, Hubalew ska-Dydejczyk A, Cich on S, Now ak W . Evaluation of Halle, Miam i, Rom e, an d Vien n a in traoperative iPTH assay criteria in guidin g m in im ally invasive parathyroidectom y. Lan gen becks Arch Surg 2009; 394(5); 843–849 [19] Moalem J, Ruan DT, Farkas RL, et al. Hem olysis falsely decreases in traoperative parathyroid h orm on e levels. Am J Surg 2009; 197(2); 222–226 [20] Sitges-Serra A, Díaz-Aguirregoitia FJ, de la Quin tan a A, et al. Weigh t di eren ce betw een double parathyroid aden om as is th e cause of false-positive IOPTH test after resect ion of th e first lesion . World J Surg 2004; 28; 1224–1226

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28 Radioguided Parat hyroid Surgery Sarah C. Oltmann and Herbert Chen

28.1 Int roduct ion As th e surgical m an agem en t of prim ar y hyperparathyroidism (PHPT) h as t ran sition ed from routin e, bilateral n eck exploration to a m ore focused, m in im ally invasive approach , parathyroid surgeon s h ave developed m ultiple preoperative an d in traoperative tools to im prove t reatm en t outcom es.1 Th ese tools in clude advan ced im aging tech n iques to iden tify an d localize th e parathyroid aden om a prior to surgery, rapid in traoperative parathyroid h orm on e (IOPTH) m easurem en ts to in dicate w h en all hyperfun ct ion in g parathyroid tissue h as been rem oved, an d detect ion m eth ods of tech n etium -99 m sestam ibi w ith in th e path ological parathyroid glan d(s).2,3 Tech n et ium -99 m sestam ibi w as in itially used in cardiac im aging for its abilit y to con cen trate in m itoch on dria-rich tissues.4 Durin g its in itial years of use, “h ot spots” w ere observed in th e neck of som e patien ts. Th ese patien ts w ere n oted to h ave prim ary hyperparathyroidism , w ith aden om as in location s correspondin g to th e areas of in creased act ivit y. Th e use of tech n etium -99 m sestam ibi in parathyroid surgery w as first described in 1989 by Coakley et al for purposes of preoperative localization im aging.5 Over th e follow in g 10 to 15 years, th e ten den cy of abn orm al parathyroid tissue to con cen t rate th is isotope w as fur th er exploited, leadin g to th e developm en t of radioguided parathyroid surgery. Th is tech n ique uses an inject ion of tech n etium -99 m sestam ibi on th e day of surgery to allow in traoperative detect ion of th e gam m a rays, w h ich guides th e dissection an d con firm s th e iden tit y of th e resected tissue.6,7,8 Th is tech n ique, w h ich is applicable in both four-glan d exploration s an d directed approach es, is still in use today an d is taugh t by som e of th e dedicated en docrin e surgery fellow sh ips.9

28.2 Pat ient Select ion After m akin g th e decision to operate for hyperparathyroidism , th ere are few th in gs to consider before determ in in g if radioguided parathyroid surgery is appropriate. It is im portan t to n ote th at a successful radioguided surgery program requires sign ifican t coordin ation an d cooperation betw een several areas an d team s w ith in th e h ospital. Th e isotope inject ion s are usually perform ed in n uclear m edicin e, an d for optim al use, n eed to be tim ed rough ly 90 m in utes prior surgery.10 To accom plish th is, com m un ication betw een depart m en ts, in cludin g preoperative h oldin g an d n uclear m edicin e, an d th e operat ive team , is cru cial to en sure th e pat ien t h as return ed from nuclear m edicin e in a tim ely fash ion , an d th at th e inject ion does n ot occur too soon prior to th e operation . Th e auth ors h ave foun d th at, th rough th e consisten t use of th is tech n ique, all involved parties develop a routin e, en surin g th e patien t is prepared for surgery w ith th e isotope at optim um stren gth for detect ion durin g th e procedure.

28.2.1 Prim ary Hyperparat hyroidism Patien ts w ith a diagnosis of prim ar y hyperparathyroidism m ake up th e vast m ajorit y of patien ts un dergoing radioguided

230

parathyroidectom y. Regardless of preoperative sestam ibi scan results or suspicion for sin gle-glan d versus m ultiglan d disease, parathyroid uptake of tech n etium -99 m sestam ibi on th e day of surgery can provide h elpful guidan ce in th e operat in g room .6,11 Wh en perform in g a focused, directed parathyroidectom y in a w ell-localized pat ien t, th e gam m a probe provides the surgeon w ith in stan tan eous feedback th at th e excised tissue is parathyroid in origin , an d n ot lym ph n ode, adipose, thym us, or thyroid n odule tissue.8 Durin g a four-glan d exploration , a m in im ally invasive in cision can accom m odate th e probe an d direct th e surgeon to th e glan d(s) of in terest.

28.2.2 Secondary and Tert iary Hyperparat hyroidism Patien ts w ith a diagn osis of secon dary or tert iary hyperparathyroidism gen erally h ave di use parathyroid glan d hyperplasia in respon se to lon g-stan ding ren al disease or oth er disorders of calcium m etabolism . For th is reason , th e operative procedure of ch oice is a subtotal or total parathyroidectom y. Th is results in th e explorat ion of both sides of th e n eck; th us preoperative im aging is n ot often obtain ed. How ever, because th ese patien ts m ay often h ave supern um erary glan ds due to hyperplasia of parathyroid rests, th e gam m a probe is a h elpful tool to en sure th at addition al h ot spots are n ot bein g left beh in d.12 Alth ough th e un derlying etiology of hyperplasia m ay di er from th at in prim ar y hyperparathyroidism , th e concen tration of sestam ibi w ith in th e glan ds is equivalen t.

28.2.3 Ect opic Glands For patien ts n oted to h ave a m ediastin al glan d on preoperative im aging, a laparoscopic gam m a probe provides an excellen t guide to dissection of th e m ediastin um durin g video-assisted th oracoscopic surgery (VATS).13,14 VATS provides a m in im ally invasive altern ative to m edian stern otom y for m ediastin al aden om as. Th e gam m a probe also provides m easurem en ts of ex vivo coun ts, w h ich im m ediately confirm th at a parathyroid aden om a is con tain ed w ith in th e specim en versus th e n eed for addition al resection w h ile aw aiting IOPTH or frozen -section results. Wh en a m issin g glan d is en coun tered durin g th e course of a four-glan d exploration , or a supern um erar y glan d is suspected, in vivo coun ts w ith th e gam m a probe can also detect glan ds in ectopic location s (retro-esophageal, carotid sh eath , etc.).15,16

28.2.4 Ext rem es of Pat ient Age Use of th e gam m a probe durin g parathyroidectom y h as been exten sively studied in patien ts of all ages.17,18 Adjustm en ts in th e dose of tech n etium -99 m sestam ibi adm inistered to ch ildren m ust be m ade. How ever, low -dose protocols for patien ts of all ages also exist .19 In th e ver y youn g an d th e ver y old, decreasin g th e exten t of dissect ion w h en possible is advan tageous. Regardless of th e tech n ique used for resection , surgical

Radioguided Parathyroid Surgery m an agem en t of prim ary hyperparathyroidism sh ould n ot be deterred based on patien t age because excellen t outcom es can be ach ieved at any age w h en th e procedure is perform ed by a h igh -volum e surgeon .20,21,22,23,24,25,26

28.2.5 Obesit y Obese pat ien ts present a ch allenge to th e parathyroid surgeon . Th e am oun t of subcutan eous adipose tissue m ay lim it th e qualit y of preoperative im ages, alth ough several studies h ave dem on strated equivalen t perform an ce of both ultrasoun d an d sestam ibi w h en h igh -qualit y studies are perform ed.27,28,29 Th e addition al soft tissue m ay also in crease th e n eed for larger incision s in order to en sure adequate exposure.29 An d lastly, th e w eigh t of th e soft tissue on th e relaxed airw ay raises concern s for airw ay protect ion , both durin g th e procedure an d im m ediately after.27,29 Given th e abilit y to im prove glan d detect ion w ith in a lim ited field an d discern parathyroid tissue from surroun din g n eck struct ures, radioguided parathyroidectom y can be advan tageous to th e parathyroid surgeon for th is di cult patien t population.

28.2.6 Reoperat ive Surgery In patien ts w ith persisten t or recurren t disease or a h istory of exten sive previous cer vical operation s, th e surgeon m ust deal w ith den se scarrin g, disrupted t issue plan es, an d altered an atom y. Previous exploration s m ay h ave displaced th e parathyroid glan ds from th e t ypical location s.30,31 For th ese reason s, th e parathyroid surgeon n eeds precise in form ation regarding th e target for resection in order to optim ize sucess.32 Th is can be obtain ed via preoperative im aging in som e in stan ces, but in traoperative detect ion w ith th e gam m a probe can isolate th e area of dissection . Th is focus can m in im ize th e am oun t of scar t issue th at n eeds to be disru pted, an d th eoretically keep th e crit ical struct ures of th e n eck safe.

28.2.7 Forearm Graft s Forearm grafts m aybe required for th ose patien ts un dergoing subtotal or total parathyroidectom y. In dication s for th is m ore exten sive parathyroid excision in clude fam ilial causes of prim ar y hyperparathyroidism , secon dary hyperparathyroidism , an d occasion ally tert iar y hyperparathyroidism . Because th ese patien ts often h ave eith er on goin g physiological stim ulus to th e rem n an t or gen et ic alterat ion leadin g to persisten t proliferation , th e forearm graft can becom e hyperplastic w ith tim e. Th e ver y reason in g for placin g th e graft w ith in th e forearm w as to be able to di eren tiate recurren t disease in th e n eck from hyperplasia in th e graft . On ce th e graft is determ in ed to be th e culprit , it m ust be debulked. If th e graft location (s) w ere n ot appropriately m arked w ith clips or perm an en t suture at th e tim e of im plan tation , it can be di cult to fin d th e parathyroid tissue w ith in th e forearm m usculature.12 Several auth ors h ave described th e successful use of radioguidan ce to aid in th e resection an d debulkin g of forearm grafts.33,34,35 Wh en usin g radioguidan ce for th is patien t population , it is crit ical to en sure th e isotope is injected in th e con tralateral upper extrem it y or eith er low er extrem it y. Th is m in im izes issues w ith h igh backgroun d coun ts.

28.2.8 Parat hyroid Carcinom a Parathyroid carcin om a is a rare en t it y.36 Invasion of adjacen t struct ures is com m on , an d en bloc resection w ith out disruption of th e tum or is critical. Th e h igh propen sit y for m ultiple local recurren ces in patien ts w ith parathyroid carcin om a is th ough t to be due to in adequate in itial resection or th e seedin g of tu m or cells durin g prior surger y. Th ese deposits m ay var y in size an d location . With th e h elp of th e gam m a probe, th e surgeon can be directed to residual areas of gam m a em ission , as w ell as lim it th e degree of scar tissue th at m ust be m an ipulated.37

28.2.9 Cont raindicat ions Few con train dication s exist for radioguided parathyroidectom y. Due to concern s of possible fetal exposure, pregn an t patien ts are n ot can didates for th is approach .38 Addition ally, patien ts felt to h ave dose lim itation s for tech n etium -99 m sestam ibi can n ot un dergo th is procedure. An addition al relative con train dication is recen t diagnost ic im aging w ith tech n etium -99 m sestam ibi because it m ay take m ore th an 3 days to com pletely flush th is from th e system before an oth er dose can be adm in istered for surgery. Conversely, prolon ged delay betw een inject ion an d th e procedure w ill dim in ish th e utilit y of th e gam m a probe durin g th e procedure.39

28.3 Day of Surgery 28.3.1 Preparat ion of t he Pat ient Th e m orn in g of surgery th e patien t w ill un dergo an inject ion via a perip h eral in traven ous cath eter of tech n etium -99 m sestam ibi. Dosin g protocols var y greatly, ran gin g from 1 to 25 m Ci bein g adm in istered.6,17,19,40 Low er-dose protocols require m uch sh orter t im e in ter vals betw een inject ion an d operation , w h ereas doses closer to th e 25 m Ci am oun t allow for both diagnost ic im aging as w ell as a lon ger tim e fram e before surgery.19,40 Th e auth ors favor a m idran ge dose of 10 m Ci for adult patien ts injected rough ly 90 m in utes prior to surgery.6 No n uclear im agin g is obtain ed th e day of surgery. Again , it is critical to stress th e im portan ce of coordin ation w ith in th e h ealth system to en sure tim ely inject ion . By routin e use of th is tech n ique, all parties involved are fam iliar w ith th e process, m akin g delays or disruption s less likely.

28.3.2 In t he Operat ing Room Th e pat ien t is placed on th e operatin g room table in a supin e, m odified beach ch air position . Because th e level of radiation em itted from th e patien t is both low an d rapidly deteriorates w ith distan ce, n o particular safety precaution s are n ecessary for th e operatin g room person n el.41,42 Patien t , surgeon , an d an esth esia preferen ce can determ in e the t ype of an esth esia perform ed, alth ough th is procedure can be safely don e w ith local an esth esia, local w ith m on itored anesth esia, or gen eral an esth esia w ith a lar yngeal m ask airw ay or en dotrach eal t ube.40,43 An ultrasoun d for localization con firm at ion an d in cision plan n in g can be perform ed by th e surgeon at th is tim e. Equipm en t n ecessary for radioguided parathyroid surgery is often already on h an d in th e operat in g room because th e sam e

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Surgical Managem ent of Parathyroid Diseases

Fig. 28.2 Measuring background counts over the thyroid isthmus.

Fig. 28.1 Collim ated gam m a probe and base unit (Neoprobe 2000 Gam ma Detection System , by Ethicon Endo-Surgery Breast Care).

Fig. 28.3 In vivo m easurements within the wound.

device used for sen tin el lym ph n ode biopsies for breast an d m elan om a cases can be program m ed for parathyroidectom y. We use an 11 m m collim ated gam m a probe (Neoprobe 2000 Gam m a Detection System , by Eth icon En do-Surger y Breast Care) ( Fig. 28.1). A sterile coverin g for th e gam m a probe perm its its use th rough out th e procedure w ith in th e operative field.

232

Th e p robe is h eld over t h e t hyroid ist h m u s t o obt ain a m easu rem en t of backgrou n d em ission ( Fig. 28.2). Alt ern at ive sit es t o establish backgrou n d cou n t s in clu d e th e sh ou ld er op p osit e t h e in ject ion arm an d t h e ear. In p at ien t s w it h ou t clear localization p rior to su rger y, qu ick m easu rem en ts can be obt ain ed in t h e bilateral u p p er an d low er n eck. Areas of in creased cou n t s con vey t o t h e su rgeon t h e locat ion of en larged glan d s.8 In cision an d dissect ion is carried out to iden tify th e en larged glan d(s). As n eeded, th e probe can be in serted in to th e w oun d to con firm th e direction an d depth n ecessar y for dissection , particularly for ectopic glan ds ( Fig. 28.3) Tissues con sidered suspicious for parathyroid aden om as can be assessed for in vivo radioact ivit y prior to resection .38 On ce a glan d is excised, ex vivo counts are obtain ed, an d a percen tage of backgroun d is calculated ( Fig. 28.4 an d Fig. 28.5). Note th at th e excised t issue is placed directly on th e tip of th e probe an d h eld aw ay from th e patien t to m in im ize any em ission detected from th e patien t. Tissue n oted to em it coun ts th at are at least 20% of th e in itial backgroun d m easurem en t are con sisten t w ith parathyroid tissue, w h ereas adipose t issue, lym ph n odes, scar, an d thyroid w ill be w ith in sin gle digits.8,39 Alth ough surgeon s perform in g routin e bilateral exploration w ith radioguidan ce m ay om it th e use of addition al in traoperative adjun cts (i.e., in traoperative parathyroid h orm on e m on itorin g), th e auth ors feel stron gly th at patien ts un dergoing a directed or focused procedure m ust h ave addition al con firm ation to en sure resection of all hyperfun ct ion in g t issue an d m in im ize th e risk of persisten t disease.38,40,44,45 On ce th e hyperfun ct ion al glan d h as been excised it is th e authors’ practice to obtain 5-, 10-, an d 15-m in ute postexcision al m easurem en ts of IOPTH, in addition to a prein cision baselin e. Our in stit ution al criterion for cure is based on a variation of th e Miam i criterion , a 50% declin e from baselin e at any tim e poin t.38,46 Alth ough aw aitin g return of IOPTH values, th e in cision is injected w ith a lon g-act in g local an esth etic an d is closed. On ce confirm at ion via IOPTH levels th at n o addition al exploration is required, th e pat ien t is w aken ed an d taken to recover y.

Radioguided Parathyroid Surgery

Fig. 28.5 Base unit displaying ratio of target (ex vivo) count over initial background count. In this instance the excised gland measured 117% (220/188), well above the 20% rule diagnostic for parathyroid tissue.

Fig. 28.4 Excised specim en placed on the tip of the gamm a probe to obtain ex vivo counts.

available for all, or th at cases are n ot sch eduled to overlap if lim ited m ach in es are available. Th e dosin g protocols for radioguided parathyroidectom y are safe for th e pat ien t an d operative team alike.41,42 How ever, cen ters perform in g extrem ely h igh volum es of th is procedure m ay elect to cover th e pat ien t w ith a lead blan ket to m in im ize th e cum ulative exposure over t im e to th e operatin g room sta .40

28.4 Pearls and Pit falls Because th e probe sim ply m easures th e em itted gam m a rays from th e direct ion of th e tip, th e surgeon m ust be cogn izan t of th e an gulation of th e t ip w h en it is used w ith in th e surgical w oun d. In creased backgroun d em ission s from th e salivary glan ds, carotid arteries, h eart, an d liver can all lead to false-positive readin gs. Th is is of particular im portan ce w h en on e is takin g in vivo readin gs of th e thym us an d search in g for an upper m ediastin al aden om a from a cervical in cision . Addition ally, th e thyroid tissue can h ave in con sisten t uptake in n odular disease. To optim ize reliabilit y of th e in vivo coun t, th e surgeon m ust m easure coun ts on th e targeted tissue from various di eren t an gles. In addition to th e system -related issues discussed earlier, th e surgeon also m ust h ave fam iliarit y w ith th e tech n ique th at on ly consisten t use can provide in order to en sure depen dable results. Because th e levels of tech n etium -99 m sestam ibi are depen den t on a di eren tial uptake of th e isotope w ith in th e tissues as w ell as clearan ce from th e body as tim e passes, tim in g of th e inject ion an d surgery is crit ical. Based on our dosin g protocol, an operative w in dow of 45 to 90 m in utes is ideal. With larger doses of m Ci given too close to surgery, n ot en ough of a di eren t ial w ith in th e tissues m ay exist to direct dissection . If too m uch tim e h as elapsed betw een inject ion an d surgery, coun ts m ay be too w eak to provide useful in form ation . As m en t ion ed, th e equipm en t required for gam m a detect ion is also used for breast can cer an d m elan om a cases. Th is requires operatin g room coordin ation to en sure en ough equipm en t is

28.5 Post operat ive Care On ce m eetin g criteria, th e pat ien t is gen erally disch arged h om e from th e recover y room . Patien ts are advised to use topical ice packs to th e an terior n eck to m in im ize pain an d any postoperative sw ellin g.47 Pain con trol is ach ieved w ith th e use of oral an algesics. Patien ts are kept on oral calcium w ith or w ith out vitam in D supplem en tation , w ith explicit coun selin g on th e sym ptom s of hypocalcem ia an d in struct ion s to take addition al doses sh ould any of th ose sym ptom s occur. At th e postoperative visit, serum calcium an d PTH levels are draw n to docum en t resolution of hypercalcem ia an d PTH elevation , to in dicate patien ts w ith persisten t disease, an d to predict th e clin ical course for patien ts experiencin g profoun d hypocalcem ic sym ptom s. Addition al calcium an d PTH m easurem en ts are obtain ed at 6 m on th s after surgery to docum en t cure.

28.6 Conclusion Radioguided parathyroidectom y is a h elpful tool for any parathyroid surgeon . It can be applied to n early any an d all patien ts or procedure t ypes. As w ith any operation , it is on ly w ith pract ice an d repetition th at optim al results can be expected. In an era of several in traoperative adjun cts an d variation in th e availabilit y of th ese aids, th e m ore option s surgeon s can em ploy, th e m ore likely th ey can adapt to any operatin g environ m en t.

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References [1] Ir vin GL, III, Carn eiro DM, Solorzan o CC. Progress in th e operative m an agem en t of sporadic prim ar y hyperparathyroidism over 34 years. An n Surg 2004; 239(5); 704–708, discussion 708–711 [2] Ir vin GL, III, Dem brow VD, Prudh om m e DL. Operative m on itorin g of parathyroid glan d hyperfun ction . Am J Surg 1991; 162(4); 299–302 [3] Sfakian akis GN, Ir vin GL, III, Foss J, et al. E cien t parathyroidectom y guided by SPECT-MIBI an d h orm on al m easurem en ts. J Nucl Med 1996; 37(5); 798– 804 [4] Sporn V, Perez Balin o N, Holm an BL, et al. Sim ultan eous m easurem en t of ven tricular fun ct ion an d m yocardial perfusion usin g th e tech n etium -99 m ison itriles. Clin Nucl Med 1988; 13(2); 77–81 [5] Coakley AJ, Kettle AG, Wells CP, O’Doh ert y MJ, Collin s RE. 99Tcm sestam ibi—a n ew agen t for parathyroid im aging. Nucl Med Com m un 1989; 10(11); 791– 794 [6] Ch en H, Mack E, Starling JR. Radioguided parathyroidectom y is equally e ective for both aden om atous an d hyperplastic glan ds. An n Surg 2003; 238(3); 332–337, discussion 337–338 [7] Norm an J, Ch h eda H. Min im ally invasive parathyroidectom y facilitated by in traoperative n uclear m appin g. Surgery 1997; 122(6); 998–1003, discussion 1003–1004 [8] Murphy C, Norm an J. Th e 20% rule: a sim ple, in stan tan eous radioactivit y m easurem en t defin es cure an d allow s elim in ation of frozen sect ion s an d h orm on e assays durin g parathyroidectom y. Surgery 1999; 126(6); 1023–1028, discussion 1028–1029 [9] Wan g TS, Pasieka JL, Carty SE. Tech niques of parathyroid exploration at North Am erican en docrin e surgery fellow sh ip program s: w h at th e n ext gen eration is bein g taugh t. Am J Surg 2014; 207(4); 527–532 [10] Ch en H. Radioguided Parathyroid surgery. Adv Surg 2004; 38; 377–392 [11] Ch en H, Sippel RS, Schaefer S. Th e e ect iven ess of radioguided parathyroidectom y in patien ts w ith n egative tech n etium tc 99m -sestam ibi scan s. Arch Surg 2009; 144(7); 643–648 [12] Nich ol PF, Mack E, Bian co J, Haym an A, Starling JR, Ch en H. Radioguided parathyroidectom y in patien ts w ith secon dar y an d tert iar y hyperparathyroidism . Surgery 2003; 134(4); 713–717, discussion 717–719 [13] Weigel TL, Murph y J, Kabban i L, Ibele A, Ch en H. Radioguided th oracoscopic m ediastin al parathyroidectom y w ith in traoperative parathyroid h orm on e testin g. An n Th orac Surg 2005; 80(4); 1262–1265 [14] O’Herrin JK, Weigel T, W ilson M, Ch en H. Radioguided parathyroidectom y via VATS com bined w ith in traoperative parathyroid h orm on e testin g: th e surgical approach of ch oice for patien ts w ith m ediastin al parathyroid aden om as? J Bon e Min er Res 2002; 17(8); 1368–1371 [15] Rubello D, Casara D, Pagetta C, Piotto A, Pelizzo MR, Sh apiro B. Determ in an t role of Tc-99 m MIBI SPECT in th e localization of a retrotrach eal parathyroid aden om a successfully treated by radioguided surgery. Clin Nucl Med 2002; 27(10); 711–715 [16] Rubello D, Piotto A, Pagetta C, Pelizzo M, Casara D. Ectopic parathyroid aden om as located at th e carotid bifurcation : th e role of preoperative Tc-99 m MIBI scin tigraphy an d th e in traoperative gam m a probe procedure in surgical treatm en t plan n in g. Clin Nucl Med 2001; 26(9); 774–776 [17] Burke JF, Jacobson K, Gosain A, Sippel RS, Ch en H. Radioguided parathyroidectom y e ect ive in pediatric patien ts. J Surg Res 2013; 184(1); 312–317 [18] Rubello D, Casara D, Gian n in i S, et al. Min im ally invasive radioguided parathyroidectom y: an attract ive th erapeutic option for elderly patien ts w ith prim ary hyperparathyroidism . Nucl Med Com m un 2004; 25(9); 901–908 [19] Rubello D, Al-Nah h as A, Marian i G, Gross MD, Ram pin L, Pelizzo MR. Feasibility an d long-term results of focused radioguided parathyroidectom y usin g a “low ” 37 MBq (1 m Ci) 99m Tc-sestam ibi protocol. In tern ation al sem in ars in surgical on cology: ISSO. 2006;3:30 [20] Oltm an n SC, Sch n eider DF, Sippel RS, Ch en H. Presen tation , m an agem en t, an d outcom es of hyperparathyroidism in octogenarians an d n on agen arian s. An n Surg On col 2013; 20(13); 4195–4199 [21] Wan g TS, Rom an SA, Sosa JA. Predictors of outcom es follow ing pediatr ic thyroid an d parathyroid surgery. Curr Opin On col 2009; 21(1); 23–28 [22] Lam bert LA, Sh apiro SE, Lee JE, et al. Surgical treatm en t of hyperparathyroidism in patien ts w ith m ultiple en docrin e n eoplasia type 1. Arch Surg 2005; 140(4); 374–382 [23] Durkin ET, Nich ol PF, Lun d DP, Ch en H, Sippel RS. W h at is th e optim al treatm en t for ch ildren w ith prim ar y hyperparathyroidism ? J Pediatr Surg 2010; 45(6); 1142–1146

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[24] Oltm an n SC, Rajaei MH, Sippel RS, Ch en H, Schn eider DF. Prim ar y hyperparathyroidism across th e ages: presen tation an d outcom es. J Surg Res 2014; 190 (1); 185–190 [25] Kebebew E, Duh QY, Clark OH. Parathyroidectom y for prim ar y hyperparathyroidism in octogenarians an d n on agen arian s: a plea for early surgical referral. Arch Surg 2003; 138(8); 867–871 [26] Kun del A, Th om pson GB, Rich ards ML, et al. Pediatric en docrin e surgery: a 20-year experien ce at th e Mayo Clin ic. J Clin En docrin ol Metab 2014; 99(2); 399–406 [27] Pitt SC, Pann eerselvan R, Sippel RS, Ch en H. In fluen ce of m orbid obesity on parathyroidectom y outcom es in prim ar y hyperparathyroidism . Am J Surg 2010; 199(3); 410–414, discussion 414–415 [28] Adam MA, Untch BR, Dan ko ME, et al. Severe obesity is associated w ith sym ptom atic presen tation , h igh er parathyroid h orm on e levels, an d in creased glan d w eigh t in prim ar y hyperparathyroidism . J Clin En docrin ol Metab 2010; 95(11); 4917–4924 [29] Norm an J, Aron son K. Outpatien t parathyroid surgery an d th e di eren ces seen in th e m orbidly obese. Otolaryn gology–h ead an d n eck surgery: o cial journ al of Am erican Academ y of Otolaryn gology- Head Neck Surg 2007; 136 (2); 282–286 [30] Perrier ND, Edeiken B, Nun ez R, et al. A n ovel n om en clature to classify parathyroid aden om as. World J Surg 2009; 33(3); 412–416 [31] Pitt SC, Pann eerselvan R, Sippel RS, Ch en H. Radioguided parathyroidectom y for hyperparathyroidism in th e reoperative n eck. Surgery 2009; 146(4); 592– 598, discussion 598–599 [32] Pow ell AC, Alexan der HR, Ch an g R, et al. Reoperation for parathyroid aden om a: a con tem porar y experien ce. Surger y 2009; 146(6); 1144–1155 [33] Cutress RI, Manw arin g-W h ite C, Dixon K, Dh ir A, Sken e AI. Gam m a probe radioguided parathyroid forearm surgery in recurren t hyperparathyroidism . An n R Coll Surg En gl 2009; 91(7); W 1–3 [34] Ardito G, Revelli L, Giustozzi E, Giordan o A. Radioguided parathyroidectom y in forearm graft for recurren t hyperparathyroidism . Br J Radiol 2012; 85 (1009); e1–e3 [35] Sippel RS, Bian co J, Ch en H. Radioguided parathyroidectom y for recurren t hyperparathyroidism caused by forearm graft hyperplasia. J Bon e Min er Res 2003; 18(5); 939–942 [36] Sh an e E. Clin ical review 122: Parathyroid carcinom a. J Clin En docrin ol Metab 2001; 86(2); 485–493 [37] Placzkow ski K, Ch ristian R, Ch en H. Radioguided parathyroidectom y for recurren t parathyroid can cer. Clin Nucl Med 2007; 32(5); 358–360 [38] Ch en H, Mack E, Starling JR. A com preh en sive evaluation of perioperative adjun cts durin g m in im ally invasive parathyroidectom y: w h ich is m ost reliable? An n Surg 2005; 242(3); 375–380, discussion 380–383 [39] Olson J, Repplinger D, Bian co J, Ch en H. Ex vivo radioactive coun ts an d decay rates of tissues resected durin g radioguided parathyroidectom y. J Surg Res 2006; 136(2); 187–191 [40] Norm an J, Politz D. 5,000 parathyroid operation s w ith out frozen section or PTH assays: m easurin g in dividual parathyroid glan d h orm on e production in real tim e. An n Surg On col 2009; 16(3); 656–666 [41] Oltm an n SC, Brekke AV, Macatangay JD, Schn eider DF, Ch en H, Sippel RS. Surgeon an d sta radiation exposure durin g radioguided parathyroidectom y at a h igh -volum e in stitut ion . An n Surg On col 2014; 21(12); 3853–3858 [42] Bekiş R, Celik P, Uysal B, et al. Exposure of surgical sta in surgical probe application s in radioguided parathyroidectom y. Eur Arch Otorh in olar yn gol 2008; 265(12); 1545–1548 [43] Udelsm an R, Lin Z, Don ovan P. Th e superiorit y of m in im ally invasive parathyroidectom y based on 1650 con secutive patien ts w ith prim ar y hyperparathyroidism . An n Surg 2011; 253(3); 585–591 [44] Ah m ed K, Alh efdh i A, Schn eider DF, et al. Min im al ben efit to subsequen t in traoperative parathyroid h orm on e testin g after all four glan ds h ave been iden tified. An n Surg On col 2013; 20(13); 4200–4204 [45] Ch en H, Pruh s Z, Starling JR, Mack E. In traoperative parathyroid h orm on e testin g im proves cure rates in patien ts un dergoing m in im ally invasive parathyroidectom y. Surgery 2005; 138(4); 583–587, discussion 587–590 [46] Ir vin GL, III, Deriso GT, III. A n ew, practical in traoperative parathyroid h orm on e assay. Am J Surg 1994; 168(5); 466–468 [47] Watkin s AA, Joh n son TV, Sh rew sberr y AB, et al. Ice packs reduce postoperative m idlin e in cision pain an d n arcotic use: a ran dom ized con trolled trial. J Am Coll Surg 2014; 219(3); 511–517

Reoperative Parat hyroid Surgery

29 Reoperat ive Parat hyroid Surgery David J. Terris and William S. Duke

29.1 Int roduct ion Parathyroid surgery h as evolved dram atically over th e past decade, prin cipally as a result of th e in t roduct ion of key tech n ologies such as th e sestam ibi scan ,1 h igh -resolution ultrasoun d,2 an d th e rapid in traoperative parathyroid h orm on e assay.3 Collect ively, th ese advan ces h ave facilitated a m in im ally invasive targeted approach to rem ovin g diseased parathyroid glands. Th is h as prom pted outpatien t m an agem en t for th ese cases,4 an approach th at w ould h ave been con sidered reckless in th e early 1990s. Com m en surate w ith th is ch ange in surgical approach th ere h as been a proliferation in surgeon s w h o n ow feel capable of pursuin g parathyroid surgery, despite in som e cases lim ited train in g, an d even m ore lim ited volum es. It is speculated th at th e in creasin gly straigh tforw ard approach to th e m an agem en t of th ese pat ien ts h as attracted atten tion from surgeon s w ho oth erw ise w ould probably h ave deferred to m ore expert surgeon s. Th e result h as been a n ew ph en otype of parathyroid surgery failure, in w h ich a ver y lim ited exploration is perform ed, w ith a failure to correct hypercalcem ia. Alth ough sin gle-glan d surgery can be h igh ly successful, failures regularly occur, w ith a variet y of causes. As w ith m any surgical an d n on surgical con dition s, preven tion is often th e best m edicin e. With th is in m in d, w e propose a system atic approach to th e pat ien t w h o h as su ered a failed parathyroid exploration , alon g w ith strategies to m in im ize failure at th e prim ary operation .

29.2 Confirm t he Diagnosis Wh en asked to assess th e patien t w h o h as un dergon e a failed parathyroid exploration , th e first respon sibilit y is to con firm th e diagn osis. In rare cases, th e surgery m ay h ave been in e ective because th e patien t w as su erin g from fam ilial hypocalciuric hypercalcem ia (FHH) or a m ultiple en docrin e n eoplasia syn drom e. Oth er errors in diagn osis m ay be as sim ple as vitam in D deficien cy w ith secon dary hyperparathyroidism con fused for prim ar y disease. Th e evaluation of th e patien t w ith failed prim ary parathyroid surgery of course begin s w ith a th orough h istor y an d a careful physical exam in ation (w ith a lar yngeal exam to con firm n orm al m ovem en t of th e vocal cords). Th e m ost im portan t assessm en t, h ow ever, is a bioch em ical profile, in w h ich sim ultan eous calcium an d parathyroid h orm on e levels are obtain ed. Both th e total calcium an d th e ion ized calcium sh ould be assessed to iden tify m argin al cases of prim ar y hyperparathyroidism . Ren al fun ction sh ould also be evaluated by m ean s of a serum ph osph orous level an d both a creatin in e level an d a glom erular filtration rate. In equivocal cases a th iazide diuretic ch allen ge m ay be revealin g. Mildly dim in ish ed ren al fu n ct ion m ay be respon sible for persisten tly elevated parathyroid h orm on e levels follow in g curative parathyroid surgery.5 A 24-h our urin e collect ion (w ith a su cien t volum e of urin e) can h elp iden tify pat ien ts w h o h ave FHH an d w h o w ill n ot

ben efit from surgical in terven tion . In th ese cases th e fam ily h istory is of particular im portan ce. Th e in clusion of th e 24-h our urin e calcium level as a th resh old for recom m en din g surgery in asym ptom at ic hyperparathyroidism h as been restored in th e m ost recen t version of th e in tern ation al guidelin es.6 Furth erm ore, a reduced fract ion al excretion of calcium (calcium /creatin in e clearan ce < 0.01) is a relatively defin itive determ in an t of patien ts w ith FHH. Alth ough patien ts w ith parathyroid disease are often m an aged prin cipally by th e surgeon or a prim ar y care physician , if th ere is any question about th e diagn osis, especially in patien ts w h o failed previous surgery, con sultation w ith an en docrin ologist (preferably on e w h o specializes in bon e disease) sh ould be sough t .

29.3 Underst and t he Reason for Failure It is h elpful to un derstan d th e reason w hy a previous exploration failed. To m ake th is determ in ation , previous records an d im aging sh ould be obtain ed if possible. Th e origin al im aging, an d in part icular th e sestam ibi scan , as w ell as th e reports from th e im agin g, m ay sh ed ligh t on th e th ough t process of th e prior surgeon . In addition to im aging, th e m ost object ive elem en t of in form ation w ill be represen ted by th e path ology report from th e prior exploration . Th is sh ould be assessed in conjun ct ion w ith th e operative n ote. A carefully dictated operat ive note m ay provide im portan t clues as to both th e reason for failure an d th e location of an un iden tified parathyroid aden om a. Wh en repeat im aging is perform ed (as it virtually alw ays is) th e fin din gs sh ould be com pared to th ose of th e origin al im agin g ( Fig. 29.1). Th ere m ay be m ultiple reason s for a failed exploration . Of course, an ectopically located glan d is com m on ly presum ed, an d th e m ediastin um m ay h arbor such a m issed glan d ( Fig. 29.2). How ever, large-scale studies h ave dem on st rated th at th e m issed glan d is m ost often in a eutopic location ( Fig. 29.3).7,8 Th ese cases m ay reflect in experien ce on th e part of th e surgeon or an atom ical factors th at m ake exploration m ore ch allengin g (obesit y, presence of thyroiditis, scar t issue from a di erent operation , such as an terior cer vical disk surgery, etc.). Wh en th e m issed glan d rem ain s in th e cervical field despite a seem in gly th orough exploration , an d especially w h en plan ar im aging suggests an in ferior aden om a, experien ce h as proven th at an overly descen ded superior glan d in a paraesoph ageal location is often th e cause ( Fig. 29.4).

29.4 Repeat Im aging In th e pat ien t w ith persisten t hyperparathyroidism , repeat im aging is alm ost alw ays n ecessary. Gen erally, th is begin s w ith th e usual first-lin e im aging of h igh -resolution ultrasoun d by an experien ced ultrason ograp h er an d sestam ibi scan n in g at a

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Fig. 29.1 In addition to obtaining the operative note and the pathology report from a failed parathyroidectom y, review of the previous im aging can be revealing. (a) This patient underwent a unilateral right exploration at an outside institution on the basis of the original sestam ibi scan, with rem oval of a single norm al parathyroid. A thyroid lobectomy was done and an oncocytic adenom a was diagnosed on final pathology. No intraoperative PTH testing was done, and the patient suffered from persistent hypercalcem ia. (b) Repeat im aging revealed an obvious left inferior adenom a. (c) The adenom a was rem oved at subsequent surgery.

Fig. 29.2 Glands m issed at primary surgery m ay be ectopic, and when they are the mediastinum is often the location for these adenomas. A patient with renal hyperparathyroidism had a four-gland exploration, but only three glands were identified. (a) The first im aging he had done was subsequent to the failed primary surgery, and the sestam ibi scan revealed a left m ediastinal hyperplastic gland, early phase, and (b) delayed phase. This gland was retrieved using a transcervical approach with reoperative surgery.

h igh -volum e center (th e yield is con siderably better at in stit ution s th at perform > 30 sestam ibi scan s/y 9 ). Som e investigators advocate th at at least t w o co-localizin g studies are n ecessar y before contem plating reoperative surgery.10 If th e ultrasoun d or sestam ibi scan is n egative or equivocal, addition al im aging m ay be con sidered. Historically, m agnetic reson an ce im aging (MRI) or com puted tom ography (CT) w as often pursued. More recen tly, th e group at MD An derson Can cer Cen ter h as described a n ovel an d robust sequen cing of a CT scan , dubbed a four-dim en sion al (4D)-CT (in w h ich tim e is th e fourth dim en sion ).11 Alth ough th is exposes th e patien t to a considerable am oun t of radiation , a n um ber of auth ors h ave foun d th is m odalit y to be reliable, especially in th e reoperative settin g.12 Invasive localization techniques are also available, but not w ithout substantial risks. Selective venous sam pling w as described as early as the 1970s,13 and m ore recently has been com bined w ith the rapid parathyroid horm one (PTH) assay to identify a gradient that m ay reveal the location of an adenom a.14 Angiography has also been described as a m ethod of identifying

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a tum or “blush” suggestive of an adenom a.15 Angiography has the added advantage of providing a m eans for devascularizing the adenom a w ith em bolization. There have been reports of patient stroke and even death w ith these invasive studies, so they should be reserved for only rare circum stances. Fin ally, th ere are n on radiological physiological adjun cts th at m ay h elp to localize or at least lateralize th e location of a m issin g aden om a. Bilateral in tern al jugular ven ous sam pling for th e PTH level can dem on strate th e side of th e adenom a by virtue of a 5 or 10% gradien t . Th is m ay be don e preoperatively 16 or in traoperatively.17 If a lesion is visualized eith er by ultrasoun d or in traoperatively, a w ash out of a n eedle aspirate m ay be sen t for a PTH level. The result of th is assessm en t is essen tially bin ary; a lym ph n ode, thyroid n odule, or oth er n on parathyroid tissue w ill h ave a level of < 20. Parathyroid tissue w ill h ave a level > 2,000 or 3,000. It is im portan t to n ote th at th is t ype of aspirate sh ould n ot be don e in prim ar y or oth erw ise routin e cases because th ere is a risk of disruptin g th e h istology an d creating a clin ical an d path ological appearan ce th at m im ics parathyroid carcin om a.

Reoperative Parat hyroid Surgery rests in th e thym us th at are kn ow n to occur. Th is rate of ectopy, w h ich approach es 40%, is on e reason w hy im agin g, especially a sestam ibi scan , is appropriate in th is pat ien t populat ion despite h istorical dogm a to th e con trar y.19

29.6 Surgical Considerat ions

Fig. 29.3 The location of m issed glands in 104 patients undergoing reoperative parathyroid surgery as seen in a figure from Wang’s classic article on the topic. (Reproduced from Wang CA. Parathyroid reexploration. A clinical and pathological study of 112 cases. Ann Surg 1977; 186: 140–145. Used with perm ission.)

29.5 Em bryology and Com m on Locat ions for Ect opy It is im portan t to be fam iliar w ith em br yology as it relates to th e parathyroid glan ds. Th e superior parathyroid glan ds are associated w ith th e fourth bran ch ial arch , w h ereas th e in ferior parathyroid glan ds are associated w ith th e th ird bran ch ial arch an d th e thym us. Because th e in ferior glan ds travel a greater distan ce th ey are substan tially m ore variable in location th an th e superior glan ds an d are m ore likely to be ectopic. Th ey m ay be un descen ded, an d th erefore located in th e subm an dibular trian gle or just superior to th e superior vascular pedicle of th e thyroid glan ds. Th ey are com m on ly located in th e thyrothym ic ligam en t, or even in th e thym us proper. Th ey m ay be located anyw h ere alon g th e carotid sh eath . Im portan tly th ey rem ain ven tral to th e recurren t lar yngeal n er ve regardless of th e in ferior/superior position in g ( Fig. 29.5). Th e superior glan ds by con trast rem ain dorsal to th e recurren t lar yn geal n er ve, even w h en th ey are ectopic in th eir location . Th ey m ay be overly descen ded an d in a paraesoph ageal or retroesoph ageal location , or even furth er in ferior in th e posterior m ediastin um . Th ey m ay also be relatively un descen ded an d th erefore retroph ar yn geal. Eith er th e superior or in ferior glan ds m ay also be in trathyroidal, w h ich occurs about 1% of th e tim e ( Fig. 29.6).18 Patien ts w ith ren al hyperparathyroidism pose a particular challenge in th at th ey are m uch m ore likely to h arbor ectopic glan ds. In addition , th ey n ot un com m on ly h ave supern um erar y glan ds. It is likely th at th ese represen t activation of parathyroid

A deliberate approach sh ould be taken w h en con tem platin g reoperative parathyroid surgery. Assum in g th e diagn osis h as been con firm ed, th e reason s for previous failure h ave been determ in ed, an d localization h as been obtain ed, th e surgeon sh ould be m oderately to h igh ly con fiden t of th e aden om a’s location before recom m en ding reoperation . Necessarily, th e th resh old for pursuin g surgery is h igh er because reoperative procedures carr y a greater risk of com plication s, an d scar t issue from th e prior exploration w ill substan tially im pact th e abilit y to accom plish a th orough dissection . Th erefore m ild cases in w h ich im aging is un revealin g m ay be obser ved. Th e quadran t an d th e specific location of th e an ticipated aden om a w ill im pact th e surgical plan n in g. In addition , th e exten t of th e prior exploration w ill be an im portan t factor, particularly if a thyroidectom y (un ilateral or bilateral) h as been accom plish ed. A ven t ral approach is certain to require dissection th rough scar tissue. For th is reason , an d particularly for a superior aden om a or a paraesophageal lesion , a lateral approach (even if usin g a cen trally located in cision ) m ay be advisable. Th is im plies approach ing th e thyroid com part m en t from betw een th e stern othyroid an d th e stern ohyoid m uscles, or lateral to th e stern ohyoid just m edial to th e carotid sh eath . Th is is som etim es called a “back door” approach ( Fig. 29.7) an d m ay also be usefu l for papillar y thyroid can cer lym ph n ode recurren ces in th e cent ral com partm en t . Because of th e risk to th e recurren t lar yn geal n er ve, n er ve m on itorin g is advisable in reoperative surgery. As in prim ar y exploration s, iden tificat ion of th e recurren t n er ve is n ot m an dator y; h ow ever, if exten ded dissect ion is required it m ay be h elpful to kn ow th e location of th e n er ve to allow a m ore aggressive dissection . We prefer a hybrid system of n erve m on itorin g ( Fig. 29.8) th at uses th e Nerve In tegrit y Mon itor (Medtron ic. In c.) in terface w ith a n on disposable stim ulatin g device (Nervean a, Neurovision , In c.). Th e use of in traoperative PTH testin g is h elpful in t w o im portan t dim en sion s. Not on ly does it fun ct ion to assure th at n o residual hyperfun ction al tissue rem ain s after rem oval of th e aden om a (as w ith prim ar y surgery; Fig. 29.9) but it ser ves an addition al im portan t role in h elpin g to m itigate again st perm an en t hypoparathyroidism . Decision s regarding reim plan tation of n orm al or even m ildly abn orm al parathyroid tissue m ay be govern ed by th e level to w h ich th e PTH assay drops. Th e auth ors use th e Future Diagn ostics assay, w h ich is perform ed as a poin t-of-care assay in th e operatin g room an d is accom plish ed w ith a turn aroun d of approxim ately 8 m in utes.20 As m en t ion ed un der th e sect ion on im aging, in traoperative physiological adjun cts m ay prove to be useful. Aspiration of tissue an d assay of th e n eedle w ash out can be don e in traoperatively to distin guish parathyroid tissue from n on parathyroid tissue, an d is faster th an frozen sect ion s.21 Th e in tern al jugular vein s can be sam pled bilaterally, an d a di eren tial betw een th e t w o sides m ay in dicate th e likely side of the aden om a. Fin ally, im m ediate preoperative ultrasoun d ( Fig. 29.10) an d

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Fig. 29.4 (a) Two-dimensional planar im aging m ay be m isleading in a patient like this one, where the appearance is suggestive of an inferior adenom a. (b-d) Three-dimensional im aging with com puted tomography sestamibi revealed the posterior orientation, which is very consistent with an overly descended superior gland and (e) was confirm ed at surgery. The black arrow indicates the recurrent laryngeal nerve; the white arrow indicates the parathyroid adenom a in a paraesophageal location.

occasion ally in traoperative ultrasoun d can be used for verification purposes an d to furth er localize an aden om a. If t h e o en d in g glan d or glan d s can n ot be id en tified in t h eir exp ected locat ion (s), t h e su rgeon w ill n eed to d ecid e if it is in t h e p at ien t’s best in t erest t o p roceed w it h a fu ll, syst em at ic exp lorat ion of all p oten t ial ect op ic locat ion s or if it is m ore p ru d en t to t erm in ate t h e p roced u re w it h ou t cau sin g fu r t h er t issu e d isru p t ion an d p oten t ial m orbid it y. An em p irical thyroid lobectom y sh ou ld n ot be p erform ed becau se it h as a ver y low yield an d w ill ren d er fu t u re exp lorat ion s m ore ch allen gin g.

29.7 Post operat ive Managem ent It is w ell kn ow n th at th e risk of com plication s is substan tially h igh er in patien ts un dergoing reoperative parathyroidectom y com pared w ith prim ar y surgery. Both recurren t n erve injur y an d hypocalcem ia occur at a h igh er rate in th e reoperative settin g.22

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Th e prin cipal value of lar yn geal n erve m on itorin g is th e reduced likelih ood of bilateral n er ve dysfun ct ion , w h ich can occasion ally n ecessitate a surgical airw ay. Alth ough iden tification of th e recurren t lar yn geal n er ve can be ch allengin g, th e stim ulation of th e vagus n erve, w h ich is m ore proxim al in th e lar yngeal n er ve path w ay, allow s verification of elect rophysiological n erve in tegrit y on on e side before contem platin g surgery on th e oth er side an d m ay be usefu l. Part icularly w h en on e or m ore parathyroid glan ds are rem oved at th e previous operation , successful reoperative parathyroid surgery m ay in som e circum stan ces ren der a patien t hypoparathyroid, at least tem porarily. Wh en th is circum stan ce is an ticipated, w e recom m en d early in itiation of calcitriol in addition to our usual 3-w eek calcium supplem en tation regim en , w h ich is used even in th e prim ary surgery sett in g an d for bilateral thyroid surgery.23 Alth ough m ost patien ts un dergoing reoperative parathyroid surgery can be m an aged on an outpatien t basis, as w ith patien ts un dergoing prim ar y surgery th is sh ould be pursued caut iously. Any t ype of ren al parathyroid surgery, w h eth er it is

Reoperative Parat hyroid Surgery

Fig. 29.5 The parathyroid glands have a consistent relationship to the recurrent laryngeal nerve. (a) An inferior adenom a will be ventral to the nerve, which is seen after rem oval of (b) the overlying adenoma. (c) Superior adenom as are deep to the nerve, which in this case is som ewhat displaced over the top of the nerve. (d) After rem oval, the nerve is restored to its anatom ical location.

Fig. 29.6 (a) Intrathyroidal parathyroid adenom as m ay be suspected preoperatively on the basis of ultrasound appearance or computed tom ography sestam ibi findings. (b) The adenom a m ay be retrieved by perform ing a thyroidotomy (without the need for rem oving the lobe). The white arrow indicates the parathyroid adenom a.

Fig. 29.7 When pursuing reoperative surgery after a ventral approach, scar tissue may be avoided by approaching the thyroid com partm ent from lateral to the strap m uscles (and m edial to the carotid sheath).

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Fig. 29.8 (a) The authors have evolved to using a hybrid nerve m onitoring system that exploits the superior user interface of the Medtronic Nerve Integrit y Monitoring System , along with nondisposable instruments crafted by Neurovision Medical Products. We prefer an elevator and right-angle clam p (b,c).

Fig. 29.9 The intraoperative parathyroid horm one (IOPTH) assay can be instrum ental in reducing failure due to a missed double adenom a. The degradation pattern often reflects a reduction in PTH level after excision of the first adenom a, but with a failure to reach the norm al range until the second adenom a is excised.

prim ary or reoperative, w ill require overn igh t h ospitalization , often for several days.

29.8 Out com es and Fut ure Direct ions Patien ts un dergoing reoperative parathyroid surgery are n ot on ly at h igh er risk for com plication s, th ey m ay an ticipate a low er ch ance of surgical success. Neverth eless, in expert h an ds an d especially w ith positive localizing studies th e success rate m ay approach 85 or 90%. Alth ough cryopreser vation h as been advocated in th e past, w ith th e adven t of th e rapid in traoperative PTH assay, an d con siderin g th e expen se an d logist ics associated w ith storin g frozen tissue coupled w ith th e poor lon g-term

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Fig. 29.10 It is helpful to repeat cervical ultrasound after the patient is anesthetized and positioned properly on the operating table.

viabilit y of cryopreserved parathyroid tissue, th is approach h as largely been aban don ed. Prom isin g investigation in th e area of recom bin an t parathyroid h orm on e h olds th e possibility of replacem en t th erapy for eith er postth yroidectom y or post parathyroidectom y patien ts in w h om th ere is n o viable parathyroid tissue rem ain in g.24 In traoperative iden tification of parathyroid t issue is also th e subject of in ten se research , an d application of n ovel tech n iques m ay represen t an oth er im portan t advan ce.25 As w ith th e last decade, it is likely th at tech n ology w ill provide the fulcrum for addition al in crem en tal im provem en ts in th e care of th e pat ien t w ith hyperparathyroidism in th e n ear fut ure.

References [1] Sh ah a AR, Sarkar S, Strash un A, Yeh S. Sestam ibi scan for preoperative localization in prim ar y hyperparathyroidism . Head Neck 1997; 19(2); 87–91 [2] Van Husen R, Kim LT. Accuracy of surgeon -perform ed ultrasoun d in parathyroid localization . World J Surg 2004; 28(11); 1122–1126

Reoperative Parat hyroid Surgery [3] Nussbaum SR, Th om pson AR, Hutch eson KA, Gaz RD, Wan g CA. In traoperative m easurem en t of parathyroid h orm on e in th e surgical m an agem en t of hyperparathyroidism . Surgery 1988; 104(6); 1121–1127 [4] Norm an JG, Politz DE. Safety of im m ediate disch arge after parathyroidectom y: a prospective study of 3,000 con secutive patien ts. En docr Pract 2007; 13(2); 105–113 [5] Den izot A, Pucin i M, Ch agn aud C, et al. Norm ocalcem ia w ith elevated parathyroid h orm on e levels after surgical treatm en t of prim ar y hyperparathyroidism . Am J Surg 2001; 182(1); 15–19 [6] Bilezikian JP, Bran di ML, Eastell R, et al. Guidelin es for th e m an agem en t of asym ptom atic prim ar y hyperparathyroidism : sum m ary statem en t from th e Fourth In tern ation al Worksh op. J Clin En docrin ol Metab 2014; 99(10); 3561– 3569 [7] Wan g CA. Parathyroid re-exploration . A clin ical an d path ological study of 112 cases. An n Surg 1977; 186(2); 140–145 [8] Hessm an O, Stålberg P, Sun din A, et al. High success rate of parathyroid reoperation m ay be ach ieved w ith im proved localization diagn osis. World J Surg 2008; 32(5); 774–781, discussion 782–783 [9] Sin ger MC, Pucar D, Mathew M, Terris DJ. Im proved localization of sestam ibi im aging at h igh -volum e centers. Lar yn goscope 2013; 123(1); 298–301 [10] Pow ell AC, Alexan der HR, Ch an g R, et al. Reoperation for parathyroid aden om a: a con tem porar y experien ce. Surger y 2009; 146(6); 1144–1155 [11] Hun ter GJ, Schellin gerh out D, Vu TH, Perrier ND, Ham berg LM. Accuracy of four-dim en sion al CT for th e localization of abn orm al parathyroid glan ds in patien ts w ith prim ar y hyperparathyroidism . Radiology 2012; 264(3); 789– 795 [12] Morten son MM, Evan s DB, Lee JE, et al. Parathyroid exploration in th e reoperative n eck: im proved preoperative localization w ith 4D-com puted tom ography. J Am Coll Surg 2008; 206(5); 888–895, discussion 895–896 [13] Bilezikian JP, Heath DA, Doppm an JL. Select ive thyroid ven ous cath eterisation in th e localisation of parathyroid aden om a. Lan cet 1973; 1(7817); 1441– 1442 [14] Udelsm an R, Arun y JE, Don ovan PI, et al. Rapid parathyroid h orm on e an alysis durin g ven ous localization . An n Surg 2003; 237(5); 714–719, discussion 719–721

[15] Ern st S, Cupisti K, Kem per J, Dotzen rath C, Goretzki PE, Fü rst G. An giograph ic ablation of an ectopic m ediastin al hyperplastic parathyroid glan d usin g a left in tern al m am m ary arter y coron ar y bypass. AJR Am J Roen tgen ol 2003; 181 (1); 95–97 [16] Carn eiro-Pla D. E ectiven ess of “o ce”-based, ultrasoun d-guided di eren tial jugular ven ous sam pling (DJVS) of parath orm on e in patien ts w ith prim ar y hyperparathyroidism . Surgery 2009; 146(6); 1014–1020 [17] Ito F, Sippel R, Lederm an J, Ch en H. Th e utilit y of in traoperative bilateral in tern al jugular ven ous sam pling w ith rapid parathyroid h orm on e testin g. An n Surg 2007; 245(6); 959–963 [18] Goodm an A, Politz D, Lopez J, Norm an J. In trathyroid parathyroid aden om a: in ciden ce an d location —th e case again st thyroid lobectom y. Otolaryn gol Head Neck Surg 2011; 144(6); 867–871 [19] Loft us KA, An derson S, Mulloy AL, Terris DJ. Value of sestam ibi scan s in tertiar y hyperparathyroidism . Lar yn goscope 2007; 117(12); 2135–2138 [20] Terris DJ, Wein berger PM, Farrag T, Seybt M, Oliver JE. Restorin g poin t-of-care testin g durin g parathyroidectom y w ith a n ew er parathyroid h orm on e assay. Otolaryn gol Head Neck Surg 2011; 145(4); 557–560 [21] Farrag T, Wein berger P, Seybt M, Terris DJ. Poin t-of-care rapid in traoperative parathyroid h orm on e assay of n eedle aspirates from parathyroid tissue: a substitute for frozen section s. Am J Otolaryn gol 2011; 32(6); 574–577 [22] Patow CA, Norton JA, Bren n an MF. Vocal cord paralysis an d reoperative parathyroidectom y. A prospect ive study. An n Surg 1986; 203(3); 282–285 [23] Sin ger MC, Bh akta D, Seybt MW , Terris DJ. Calcium m an agem en t after thyroidectom y: a sim ple an d cost-e ective m ethod. Otolaryn gol Head Neck Surg 2012; 146(3); 362–365 [24] Cusan o NE, Rubin MR, McMah on DJ, et al. PTH(1–84) is associated w ith im proved quality of life in hypoparathyroidism th rough 5 years of th erapy. J Clin En docrin ol Metab 2014; 99(10); 3694–3699 [25] McWade MA, Paras C, Wh ite LM, Ph ay JE, Mah adevan -Jan sen A, Broom e JT. A n ovel optical approach to in traoperative detect ion of parathyroid glan ds. Surgery 2013; 154(6); 1371–1377, discussion 1377

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Part 6 Special Topics

30 Com plications of Thyroid and Parathyroid Surgery

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31 Intraoperative Nerve Monitoring

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32 O ce-Based Ultrasonography

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33 Outpat ient Endocrine Surgery

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Special Topics

30 Com plicat ions of Thyroid and Parat hyroid Surgery Michele N. Minuto and Emanuela Varaldo

30.1 Int roduct ion Th e h istory of thyroid surgery is a perfect exam ple of h ow surgery evolved betw een th e 19th an d 20th cen turies. In th e m id19th cent ury, thyroid surgery w as legally ban n ed by th e Fren ch Academ y of Medicin e an d w as also discouraged by m any surgeon s from di eren t coun tries because of its appallin g results. In 1850, perioperative m ortalit y follow in g thyroid surgery w as 40%.1,2 Th e use of eth er, an tiseptics, an d e ect ive in strum en ts for h em ostasis led to a sign ifican t im provem en t in th e results of thyroid surgery an d h eralded its “m odern era.” Th an ks to icon ic surgeons, such as Koch er, Billroth , Halsted, Mayo, Crile, an d Lah ey, th e decrease in m ortalit y steered discussion tow ard issues of specific “m orbidit y” related to th is surgery. By 1909, w hen Kocher w as awarded the Nobel Prize, m ortality from thyroid surgery had decreased to < 1%. As a result, longterm outcom es could be properly evaluated. Further, com parisons could be m ade betw een the results obtained by Kocher and those of other surgeons, such as Billroth. According to Halsted, w ho visited both Bern and Vienna, Kocher’s patients su ered postoperatively from a condition that was described as “cachexia strum ipriva,” w hereas Billroth’s patients developed a condition sim ilar to tetany. Both of these postoperative com plication s were considered serious. Com plications resulting from dam age to the recurrent laryngeal nerve (RLN), w hich had been know n since the 16th century, led Billroth, Kocher, and Joll to describe a technique called “no see, no harm .” The prem ise was that a low incidence of injury to the RLN could be achieved by not exposing the nerve during surgery. How ever, this proved not to be true. Later, in 1938, based on Bier’s descriptions,3 Lahey reported that routine exposure of the RLN resulted in an injury rate of only 0.3%.4 Durin g th e 20th cen tur y, a greater un derstan din g of th e factors th at led to com plication s resulted in “m in or” tech n ical upgrades th at yielded excellen t results. Th ese ben efits are still eviden t today. Neverth eless, despite ever y tech n ical im provem en t an d e ort to use soun d surgical tech n iques, com plication s associated w ith all surgical procedures are in escapable, even if th ey are extrem ely rare. With in th is context, m orbidit y can be divided in to t w o m ain groups: (1) th e gen eric surgical com plication s th at are com m on to ever y surgical procedure an d m ain ly involve postoperat ive bleedin g, in fect ion s, deep ven ous th rom bosis, an d th e cosm et ic issues related th e site in cision ; an d (2) surgical com plication s th at are specific to thyroid an d parathyroid surgery, such as recurren t an d superior lar yngeal n erve injury an d hypoparathyroidism . Th is ch apter prim arily discusses specific causes of m orbidit y follow in g thyroid an d parathyroid surgery, w ith som e atten tion devoted to th e m ore peculiar aspects of th e gen eral com plication s.

30.2 General Com plicat ions 30.2.1 Bleeding Th e m ost dreaded com plication follow in g thyroid an d parathyroid surgery is th e possibilit y of life-th reaten in g bleedin g.

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Postoperative bleedin g h as been w ell described sin ce th e daw n of th is operation , an d, in 1866, Sam uel L. Gross m em orably described its h orrific n ature.5 Alth ough at th e begin n in g of th e 20th cen tur y, postoperat ive bleedin g (alon g w ith in fect ion ) w as th e m ain cause of m ortalit y, today it is a rare com plication .6 Th e actual in ciden ce of postoperative bleedin g, w h ich occurs m ore after thyroidectom y th an parathyroidectom y, is di cult to assess because of th e diversit y of fin din gs reported in th e literature. Th e reported in ciden ce of postoperat ive bleedin g requirin g surgical in terven tion ran ges from 0.3 to 4.2%.7,8,9,10 It is com m on ly accepted th at th e true in ciden ce is < 1%. Apart from m eticulous h em ostasis durin g th e surgery, th ere is n o eviden ce th at th ere is any e ect ive strategy th at can iden tify patien ts w h o h ave a h igh er risk of bleedin g or th at can prevent its occurren ce follow in g surgery.7,11 Th erefore, n eith er th e use of h em ostatic devices,12,13,14 agen ts,15 or drain s 16 h ave been sh ow n to be e ect ive in low erin g th e in ciden ce of bleedin g or th e n ecessit y for reoperation . In con clusion , a certain rate of bleedin g is un avoidable an d th is, in fact, is th e m ain object ion to th e pract ice of outp atien t thyroid an d parathyroid surgery, w h ich sh ould be lim ited to carefully selected patien ts. Even th ough m ost bleedin g occurs w ith in th e first 6 to 8 h ours, a lon ger observation p eriod is w arran ted becau se delayed bleedin g h as been repor ted .7,10,11,17 Clin ically, th e acute on set of n eck sw ellin g or com pressive sym ptom s (dyspn ea an d dysph on ia) w arran ts strict evaluation an d im m ediate treatm en t . From a strategic poin t of view, th e algorith m for th e m an agem en t of bleedin g com plication s is w ell stan dardized. Th e key poin ts en tail secu rin g th e air w ay an d reop eration in clin ically severe or even d oubtfu l cases.

30.2.2 Infect ion In fect ion is an extrem ely rare com plication follow in g thyroid an d parathyroid surgery, w ith m ost series reportin g an in ciden ce w ell un der 1%.8,18 Th erefore, th e adm in istration of prophylactic an tibiotics does n ot appear to be n ecessary for all patien ts un dergoing surgery (even if th is strategy varies considerably am on g di eren t cen ters), an d sh ould be in dicated on ly in selected patien ts w h o are at a h igh er risk of developin g in fect ion s.

30.2.3 Deep Venous Throm bosis Patien ts un dergoing thyroid an d parathyroid surgery are gen erally m obile in th e im m ediate postoperat ive period, w ith m any cen ters perform in g th e surgery on an outp atien t basis. Con sequen tly, th e in ciden ce of deep ven ous th rom bosis results m ain ly from an ecdotal reports. Because th e poten tial con sequen ces of a bleedin g com plication are sign ifican tly greater in thyroid an d parathyroid surgery th an in oth er t ypes of procedures, m edical prophylaxis of deep ven ous th rom bosis is gen erally con sidered un safe an d un n ecessar y. How ever, ch em ical prophylaxis m ay be appropriate in certain carefully selected h igh -risk patien ts.19

Com plications of Thyroid and Parat hyroid Surgery

30.2.4 Poor Cosm et ic Out com es

30.3 Specific Com plicat ions

In a populat ion w ith a sign ifican t percen tage of fem ale patien ts, a good cosm etic outcom e is essen tial w h en surgery is perform ed in such an exposed an atom ical location as th e an terior n eck. Becau se cosm esis is a cen t ral issu e in t h e overall ou t com e of th is su rger y, th e p ossible form ation of a keloid scar sh ou ld be ad equ ately d iscu ssed w it h t h e p atien t before su rger y, t ogeth er w it h t h e ot h er m orbid it y-related issu es. Th ere are gen eral p rin cip les t h at m u st be st rict ly follow ed w h en p erform in g an in cision on th e n eck th at m igh t red u ce th e risk of keloid form at ion . First th e location of th e in cision n eeds to be adequately plan n ed, keepin g in m in d th at, in th e supin e position , th e scar is alw ays low er th an expected after surgery. Th e in cision lin e sh ould th erefore be m arked w ith th e patien t stan din g in th e uprigh t position w h ile sim ultan eously correct in g for th e distortion s caused by a bulky thyroid, w ith th e aim of obtain in g a sym m etrical result. Tradition ally, th e in cision sh ould be placed on a skin crease, at an average distan ce of t w o fin gerbreadth s from th e stern al n otch (depen din g on th e patien t’s an atom y), an d its len gth sh ould be tailored on th e size of th e glan d to be rem oved. It is w orth n otin g th at th e in cision can be sign ifican tly sm aller th an th e size of th e glan d, because th e m an ipulation an d th e devascularization of th e glan d w ill decrease its size, allow in g for safe extract ion . Th is fact h as been taken to th e extrem e in m in im ally invasive tech n iques.20,21 Neverth eless, th e in cision sh ould n ot be so sm all th at th e skin edges are traum atized by excessive stretch in g from retractors or th at th e risk of un desired n ecrosis is in creased from usin g en ergy in strum en ts in a n arrow space. In obvious or suspected cases of traum atized edges, adequate resection of th e m argin s follow ed by recon stru ct ion at th e en d of th e procedure is h ighly suggested, as described by Terris an d colleagues.22 An oth er sign ifican t factor leadin g to a poorer cosm etic outcom e is th e creation of a w ide skin flap w h en en terin g th e thyroid bed. Avoidin g or lim itin g th is dissection elim in ates dead space un der th e skin w h ere fluid m igh t accum ulate, an d m igh t th erefore be h elpful in obtain in g a good cosm etic result. Th e skin closure can be perform ed usin g several di eren t tech n iques an d m aterials. Th ere is n o large, prospective, ran dom ized study th at clearly dem on st rates th e superiorit y of any on e m eth od. Ever y m aterial (m on ofilam en t, staples, or cyan oacr ylate) an d ever y tech n ique (stitch es or in t raderm ic sutures) h as its ow n pros an d con s. Th erefore, th e ch oice of w hich m eth od to adopt depen ds on th e surgeon’s person al preferen ce. A few w ords sh ould also be devoted to th e placem en t of th e drain s, w h ich do n oth in g to preven t postoperative bleedin g (see earlier). Drain s can be respon sible for cosm et ic im pairm en ts if in correctly placed. Th e correct position s are gen erally considered th ose th at are separate from but in lin e h orizon tally w ith th e m ain in cision . Th is tech n ique m akes th e drain in cision less n oticeable an d often leads to h ealing w ith out a visible scar. Placing th e drain ben eath th e in cision lin e or, w orse, in feriorly and m edially, is n ot suggested, because th e risk of a keloid scar is high er in th is location an d th e in cision is less likely to be h idden . Lastly, th e placem en t of a drain in th e m iddle of th e in cision is discouraged because it can create a w iden ed scar at its poin t of en tr y.

30.3.1 Recurrent Laryngeal Nerve Injury Recurren t lar yn geal n er ve injur y is th e m ost un iversally kn ow n com plication follow in g thyroid an d parathyroid surgery an d h as been described sin ce th e first reports of patien ts un dergoing thyroid surgery w h o survived th e operation . It is also th e m ost obvious com plication th at seriously im pacts th e patien t’s qualit y of life due to its im m ediate im pairm en t of vocal cord fun ction in g, ven t ilation , or sw allow in g. Even th ough th e in ciden ce of RLN injur y is frequen tly reported to be approxim ately 1%, th e actual rate is far greater for several reason s: ● Th e low est in ciden ces reported in th e literature are derived from studies w ith a lim ited n um ber of patien ts. Th ese studies do n ot h ave th e statistical pow er to arrive at defin itive conclusion s about th e true in ciden ce of such a rare even t . ● Th ese sam e studies are gen erally perform ed w ith aim s oth er th an evaluatin g m orbidit y. Th erefore, th e in ciden ce of RLN injur y, alth ough correctly reported, can n ot be con sidered sign ifican t. ● Even th ough an in ciden ce of RLN injury of approxim ately 1% m ay be ach ievable w h en dealin g w ith ben ign thyroid or parathyroid disease, th e studies th at focus on ly on th ese disorders are un com m on . Thyroid surgery perform ed for m align an t disease w ill invariably h ave a w orse injury rate. ● Th e results are often reported w ith out th e con tribution of a routin e pre- an d postoperative lar yngoscopic evaluation , an d th us rely on ly on th e pat ien t’s postoperat ive sym ptom s for diagn osis. Because it is w ell described th at dam age to th e RLN can exist in th e presence of a rem arkably n orm al voice, th e real in ciden ce of injuries can n ot be adequately assessed in th e absen ce of postoperat ive lar yngoscopy. In a series th at w as n ot lim ited to patien ts w h o h ad un dergon e previous n eck surgery, it w as sh ow n th at asym ptom atic paralysis of th e vocal cords is presen t in as h igh as 1.8%of patien ts preoperatively.23 Taken togeth er, th ese observation s place th e repor ted in ciden ce of RLN injur y betw een 0.3% as described by Bergam asch i et al 24 an d 6.6% as reported by Ech tern ach et al.23 Alth ough it is reason able to assum e th at th e true in ciden ce lies som ew h ere betw een th ese t w o extrem es, to our kn ow ledge, n o study h as in cluded a large en ough sam ple size (arguably con sistin g on m ore th an 1,000 n er ves-at-risk) to allow a defin itive con clusion . Th e in ciden ce of t ran sien t an d perm anen t RLN injury in studies w ith a sign ifican t am oun t of n erves-at-risk is sum m arized in Table 30.1.8,23,24,25,26,27,28,29,30,31 A detailed an alysis of th ese studies reveals th at, on ce th e extrem e results are elim in ated, th e in ciden ce of RLN injur y is quite sim ilar across all experien ced groups. Furth er, a reason able rate can be placed at less th an 1% durin g thyroidectom ies for ben ign disease, an d approxim ately 2% for patien ts un dergoing surgery for m align an t disease. Regarding th e latter, it is in terestin g th at a h uge m ulticen ter Italian study by Rosato an d colleagues 8 foun d th at th e in ciden ce of paralysis in creased w ith th e m ore aggressive tum ors, reach ing a h igh of 16.5% in patien ts w ith an aplastic thyroid can cer, follow ed by 5.4% in th ose w ith m edullar y thyroid can cer an d fin ally 1.4% in patien ts

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Special Topics Table 30.1 Sum m ary of recurrent laryngeal nerve (RLN) morbidit y rates in thyroidectomy, as found in studies with significant num bers of nerves at risk/patients St udy

Nerves at risk

Surgical indication

Transient

Perm anent

Study/country

Rosato et al, 2004 8

14,934 patients

Benign and malignant disease

3.4

1.4

Multicenter, Italy

Thomusch et al, 2000 25

13,436

Benign disease

2.1

1.1

Multicenter, Germ any

Bergam aschi et al, 1998 24

2,010

Benign disease

2.9

0.3

Single center, France

Echternach et al, 2009 23

1,365

Benign and malignant disease

6.6

Efrem idou et al, 2009 26 1,864

Benign disease

0.2

1.3

Single center, Greece

Lefevre et al, 2007 27

685 patients

Recurrent disease / completion thyroidectomy

2.6

1.5

Single center, France

Steurer et al, 2002 28

1,080

Benign/malignant / hyperparathyroidism

3.4/7.2/2.5

0.3/1.2/0

Single center, Austria

Chiang et al, 2005 29

704

Benign and malignant disease

5.1

0.9

Single center, Taiwan

Toniato et al, 2008 30

1,008

Malignant disease

2.2

Lo et al, 2000 31

787

Benign and malignant disease

3.3

w ith papillar y thyroid can cer. Given th e rarit y of both m edullar y an d an aplastic thyroid can cer, th is result could on ly h ave been obtain ed w ith confiden ce based on th e large sam ple size of approxim ately 15,000 pat ien ts. Furth er, th ese results con firm th at th e m ore aggressive th e surgery th e h igh er th e rate of iatrogen ic injuries. Reoperation for eith er ben ign or m align an t disease represen ts an oth er preoperative factor th at sign ifican tly im pacts th e rate of RLN inju ries. On e m u lticen ter Germ an st u d y also sh ow ed lobectom y as a p oten t ial h igh er risk fact or, t h ough t h is obser vation is d i cu lt to ju stify.25 Oth er factors th at h ave been t rad it ion ally associated w it h h igh er rates of RLN inju ries, su ch as su rger y p erform ed for Graves’ d isease, su b st ern al goiter, or t hyroid it is, h ave n ot been p roven to in crease t h is m orbid it y in w ell-d esign ed st u d ies. Th e risk fact ors associated w ith a h igh er risk of RLN inju r y are su m m arized in Table 30.2.8,27,31,32,33,34 Preoperatively, patien ts sh ould be m ade aw are th at th eir risk of RLN injur y in m ost cases is approxim ately 1% an d th at th e risk of injury in creases w ith m align an t or recurren t thyroid disease. Conversely, th e in ciden ce of RLN injur y is n egligible in th ose patien ts un dergoing parathyroid surgery.28 From a path ophysiological poin t of view, th e precise m ech an ism s th at lead to injury of th e RLN are still un clear, except for th ose extrem ely rare situation s w h ere th e n er ve is purposely or acciden tally sect ion ed. In th ese circum stan ces, sutur in g th e tran sected n er ve is in dicated, a strategy th at h as been described sin ce th e first years of m odern thyroid surgery. Though suturin g th e n erve rarely leads to a full recover y of vocal cord m otilit y, it at least allow s th e a ected cord to m ain tain som e bulk an d better prepares th e patien t for voice th erapy.35

246

Recurrent laryngeal nerve injury

Single center, Germany

Single center, Italy 0.9

Single center, China

Most com m on ly, p aralysis of t h e vocal cord occu rs w it h ou t t r an sect ion of t h e n er ve. In t h ese cases, t h e d am age m ay h ave resu lted from excessive m an ip u lat ion of t h e n er ve, t r au m a from several cau ses (su ch as p rolon ged com p ression or ot h er m ech an ical inju ries), excessive d issect ion cau sin g d evascu larizat ion , th erm al inju ries from elect rocau ter y or ot h er en ergy in st r u m en t s, or local in flam m at ion . W h en a n er ve is n ot t ran sect ed , vocal cord m ot ilit y gen erally recovers aft er an t i-in flam m ator y th erapy w ith steroid s, som e cycles of voice th erapy, or even sp on tan eou sly, th ough th e t im e t o recover y m ay ran ge from a few h ou rs t o 6 m on t h s. Post op erat ive p aralysis of t h e vocal cord s is con sid ered t em p orar y w h en p resen t in th e first 6 m on th s after su rger y an d sh ou ld be labeled as p er m an en t if it p ersist s beyon d t h at t im e fram e. Oth er rare situ ation s th at m igh t be respon sible for un expected vocal cord paralysis from RLN injur y in clude th e lack of recogn ition of th e n er ve durin g th e thyroidectom y (possibly due to an earlier t ran sect ion ), tran section of a lar yn geal m otor bran ch m istaken for an esop h ageal bran ch (lar yn geal m otor bran ch es are n ot n ecessarily t h e largest on es, t h ough t h ey are gen erally t h ose m ost an t erior an d closest t o t h e t hyroid glan d),36 an d t h e p resen ce of a rare an atom ical an om aly, su ch as a n on recu rren t varian t in p at ien t s w it h an ar teria lu soria (aberran t righ t su bclavian ar t ery),37 w h ich is p resen t in 0.5 t o 1% of t h e p op u lat ion . In t h e lat ter case, if th e varian t is n ot p rop erly recogn ized , th e aberran t n er ve can be tran sected in t h e early p h ases of th e op erat ion . Un for t u n ately, even th ough t h ere are n ow cost ly p reop erat ive t ech n iqu es t h at can correctly id en tify ar teria lu soria,38 t h ese are n ot rou t in ely p erform ed for p at ien t s u n d ergoin g thyroid or p arat hyroid su rger y.

Com plications of Thyroid and Parat hyroid Surgery Table 30.2 Risk factors significantly associated with higher rates of recurrent laryngeal nerve injury during thyroidectomy in studies with significant num bers of patients or nerves at risk Study

Nerves at risk/patients at Risk

Risk fact or(s)

Dralle H et al, 2004 32

29,998

Recurrent benign/m alignant disease, thyroidectom y for cancer, lobectom y

Rosato L et al, 2004 8

14,934 patients

Malignant disease: anaplastic > m edullary > papillary/follicular

Erbil Y et al, 2007 33

3,250 patients

“Extended” thyroidectomy

Lefevre et al, 2007 27

685 patients

Recurrent disease and completion thyroidectom y

Loh et al, 2000 31

787

Malignant disease and recurrent substernal goiters

Shindo et al, 2010 34

512

Lymph node dissection

In traoperative n er ve m on itorin g can be used durin g thyroidectom y an d parathyroidectom y an d is par ticularly useful in iden tifyin g th e RLN. Th ough th is tech n ology m igh t h elp to iden tify h ow dam age to th e n er ve occurs, several studies h ave failed to sh ow th at m on itorin g h as a sign ifican t im pact on th e rate of RLN injuries.39 Clin ically, patien ts su erin g from an RLN injur y gen erally display sym ptom s th at are prim arily related to th e position of th e paralyzed vocal cord, w h ich can be eith er m edial or lateral. Overall, th e voice is gen erally h oarse, th ough it m ay soun d n orm al to in experien ced ears. Alon g w ith th e patien ts th em selves, h ow ever, experien ced thyroid surgeon s can gen erally perceive even m in im al voice ch anges. Th e voice ch anges can also be described as “breath in ess,” w h ich is often a m ore appropriate term because it better reflects th e w eakn ess of th e voice. Th is w eakn ess results from th e relative in com peten ce of th e glottis durin g ph on ation caused by th e lateral position of th e cord so th at th e airflow is n ot e ectively m odulated in a sym m et rical fash ion to th e opposite cord. Th e exten t of th e voice im pairm en t is gen erally directly correlated w ith th e degree of lateral displacem en t. Wh en th e cord is in th e m edial position , dysphon ia m ay be less pron oun ced, but patien ts m ay h ave respirator y com prom ise due to a sign ifican t reduct ion in th e caliber of th e airw ay. Th is com prom ise is gen erally m ore apparen t in situation s of h igh respiratory dem an d, such as physical exert ion . In addition to th e voice alteration s, patien ts w ith RLN injuries m ay also h ave im pairm en t of th eir sw allow in g abilit y, reflectin g th e dam age to th e sen sor y bran ch es th at run lateral to th e m otor bran ch es an d in n er vate th e esoph agus. Th e pat ien ts m ay also com plain of dysph agia w h en th e m otor bran ch es are left in tact an d th e th in n er sen sor y bran ch es are n ot recogn ized an d are in adverten tly injured durin g surgery. Im paired glottic closure coupled w ith loss of sen sation can lead to aspiration . In con clusion , pat ien ts w ith RLN injur y gen erally presen t w ith di eren t sym ptom s according to th e severit y an d th e position of th e paralyzed cord. Th ese in clude variable degrees of voice im pairm en t, dysphagia, respirator y distress, an d, in th e long run , a h igh er rate of respirator y in fect ion s. If a postoperative strobolar yn goscopy is n ot routin ely perform ed after surgery, th e presen ce of th ese sym ptom s w arran ts appropriate diagn osis an d treatm en t .

30.3.2 Bilat eral Recurrent Laryngeal Nerve Injury Wh en a total thyroidectom y is plan n ed, th e patien t sh ould be in form ed durin g th e consen tin g process of th e rare possibility

of bilateral RLN paralysis. Alth ough th ese cases are m ostly an ecdotal, th ey are a part of alm ost ever y surgeon ’s experien ce an d represen t em ergen cies th at require urgen t treatm en t . In th ese cases, th e airw ay sh ould be secured by eith er rein tubation or trach eotom y if th e patien t displays acute respirator y obstruction (in cases w h ere both cords are m edialized). If, after extubation , th e patien t is able to tolerate th e degree of airw ay obstru ct ion , con tin uous m on itorin g of oxygen at ion sh ould be perform ed an d in traven ous steroids given . Wh en th e O2 saturation h as n orm alized an d is stable, th e patien t can un dergo furth er evaluation an d treatm en t . In all oth er cases, a tem porar y trach eotom y sh ould be perform ed an d later rem oved after adequate m otilit y of at least on e vocal cord is con firm ed. Curren t Italian guidelin es 40 recom m en d rein tubation for 24 h ours im m ediately follow in g the diagn osis of bilateral paralysis of th e vocal cords. A second attem pt at extubation sh ould be carried out th e day after surgery follow in g treatm en t w ith steroids. If th e acute obstru ct ion is still presen t th en a secon d extubation is attem pted 48 h ours after surgery. If, after in stit utin g th ese steps, th e patien t still fails to m ain tain an adequate respirator y status, trach eotom y is in dicated.

30.3.3 Superior Laryngeal Nerve Injury Postoperative rates of superior lar yn geal n er ve (SLN) injur y durin g thyroidectom y ran ge from 0 to 28% ( Table 30.3).41,42,43 Th is w ide ran ge essen tially results from th e sam e reason s previously described for th e in ciden ce of RLN dam age. Th e SLN origin ates w ith in th e n odose gan glion of th e vagus. Approxim ately 1.5 cm below th e jugular foram en it divides in to t w o bran ch es: th e in tern al bran ch , supplying th e sen sor y in n er vation to vocal folds an d supraglott ic lar yn x, an d th e extern al bran ch (EBSLN), w h ich provides m otor in n er vation to th e cricothyroid m uscle. Th e EBSLN courses alon g th e in ferior ph ar yn geal con strictor m uscle in close proxim it y to th e bran ches of th e superior thyroid artery. It th en cur ves an teriorly an d m edially an d approach es th e lar yn x w ith in th e stern othyroid–laryn geal t riangle after w h ich it divides in tw o bran ches, on e en terin g th e pars recta an d th e second at th e pars obliqua of th e cricothyroid h eads. Th e EBSLN m otor fibers to th e cricothyroid m uscle cause it to tilt th e thyroid cartilage, ten sing th e vocal cords. Th is action a ect s th e ch aracteristic t im bre of on e’s voice. Injury to th e n er ve ch anges th e qualit y, project ion an d product ion of h igh pitch ed soun ds. In th ese cases, patien ts t ypically com plain of voice fat igue, problem s reach ing h igh -pitch ed soun ds, in creased w ork of ph on ation , an d dysph agia.

247

Special Topics Table 30.3 Visualization and m orbidit y rates for the superior laryngeal nerve during thyroid surgery in studies with a significant num ber of patients Author

No. patients

Visualization rate (%)

Morbidit y rate (%)

Bellantone R et al, 2001 41

289

89 (when searched for) vs. 0 0 vs. 0

Prospective, randomized

Jonas et al, 2000 42

108

37.5

Prospective

Hurtado-Lopez et al, 2005 43

100

78 (when searched for) vs. 0 8 vs. 20

0

Study

Prospective, random ized

Table 30.4 Incidence of postoperative hypoparathyroidism after thyroidectomy, as reported in studies with a significant num ber of patients Author

Patients

Surgical indication

Study/country

Transient

Perm anent

Rosato et al, 2004 8

14,934

Benign and malignant disease

8.3

1.7

Thom usch et al, 2000.25

7,266

Benign disease

6.4

1.5

Bergam aschi et al, 1998 24

1,163

Benign disease

20

4

Efrem idou et al, 2009 26

932

Benign disease

7.3

0.3

Lefevre et al, 2007 27

685

Recurrent disease / com pletion thyroidectomy

5

2.5

Single center, France

6.3

Single center, Italy

Toniato et al, 2008.31 504

Malignant disease

Th e close relation sh ip betw een th e EBSLN an d th e superior thyroid vessels puts it at risk of dam age durin g tran sect ion of th e superior pole of th e thyroid, particularly in th e presence of its m ore caudal varian ts. Di eren t classification sch em es h ave been proposed th at aim to describe lan dm arks th at w ould m ake it easier to iden tify th e EBSLN durin g surgery. Th e m ost com m on ly used system s in clude Cern ea’s, w h ich categorizes th e EBSLN variat ion s according to th e distan ce separatin g th e n er ve from th e vessels of th e superior pole of th e thyroid, an d Friedm an’s, w h ich describes th e relation sh ip betw een th e n erve an d th e in ferior con strictor m uscle (see Ch apter 2).44,45,46 Despite all surgical e ort, a sign ifican t percen tage of patien ts h ave ceph alic varian ts of th e EBSLN th at can n ot be iden tified durin g thyroidectom y w ith out un n ecessarily exten din g th e surgical dissection . As a result , som e thyroid surgeon s recom m en d routin e iden tificat ion of th e EBSLN, w h ereas oth ers do n ot . Th ose w h o support routin e iden tification do so based on studies th at h ave reported a low er in ciden ce of injur y w h en th e n er ve is iden tified.41,43 To th is purpose, th e use of in traoperative n erve m on itorin g h as been described to iden tify th e EBSLN, w ith som e series reportin g successful results.47,48 Meth ods h ave been proposed to aid in traoperative iden tification an d avoid injur y of th e EBSLN.42,46,47,48,49 Careful blun t dissect ion an d gen tle t ract ion of th e superior thyroid pole in a lateral an d caudal direct ion is perform ed to obtain good exposure of th e superior vascular pedicle. Select ive ligation of th e vessels of th e upper pole as close to th e thyroid pole as possible is recom m en ded. Later, to preven t iatrogen ic heat injuries, care m ust be taken to avoid in discrim in ate use of m on opolar electrosurgical or en ergy-based devices for sealin g vessels. EBSLN injur y can be con firm ed postoperat ively on ly th rough a videostroboscopy in conjun ct ion w ith electrom yography of

248

Hypoparathyroidism (%)

Multicenter, Italy

Multicenter, Germ any

Single center, France

Single center, Greece

th e cricothyroid m uscle. Both of th ese evaluation s are operator depen den t an d can create a sign ifican t am oun t of discom fort for th e patien t. For th ese reason s, th ese tests are in dicated on ly in suspicious cases an d are n ot routin ely perform ed. Th is m ay in fact provide a partial explan ation as to w hy EBSLN injuries are un derestim ated. In th e presen ce of a docum en ted EBSLN injury, specific speech th erapy an d voice reh abilitation are recom m en ded because th ese in terven tion s m ay lead to successful rem ission .50,51 Because th e superior an d in ferior parathyroids an d th e EBSLN are n ot an atom ically in close proxim it y, th is injury h as n ever been described durin g parathyroid surger y.

30.3.4 Post operat ive Hypoparat hyroidism Hypoparathyroidism an d postoperative hypocalcem ia are th e m ost com m on com plication s after thyroidectom y, w ith a reported in ciden ce betw een 0.3 an d 20%,8,24,25,26,27,30 as sh ow n in Table 30.4. Because postoperat ive evaluation of serum calcium is routin ely perform ed, hypoparathyroidism can be classified in “bioch em ical” (in th e presence of asym ptom atic hypocalcem ia) or “clin ical” (e.g., w h en patien ts display sym p tom s of hypocalcem ia, such as m ild perioral an d/or distal acral paresth esias, m uscle pain , carpopedal spasm , tetany, an d/or laryn gospasm ), w ith sym ptom s usually m an ifestin g 24 to 48 h ours after surgery. Hypoparathyroidism is defin ed as perm an en t w h en th e hypocalcem ia lasts m ore th an 6 to 12 m on th s after surgery an d is considered tran sien t in all oth er cases. Perm an en t hypoparathyroidism presen ts a sign ificant burden for th e patien t because of th e n eed for lifelon g calcium an d vitam in D supplem en tation an d th e associated in creased risk of

Com plications of Thyroid and Parat hyroid Surgery developin g calcification of th e basal gan glia an d cataracts. Perm an en t hypoparathyroidism also in creases h ealth care costs th rough prolon ged h ospitalization s an d lon g-term h ealth care visits an d blood tests. For th ese reason s, sign ifican t e or t h as been m ade to defin e possible risk factors for hypoparathyroidism an d develop surgical strategies to preserve parathyroid fun ction .52 Th e degree of hypoparathyroidism is directly lin ked to tech n ical factors, such as excessive m an ipulation (i.e., tem porar y “stun n in g” of th e glan ds), devascularization , or in adverten t rem oval of th e glan ds. Iden t ifyin g an d preservin g as m uch function al parathyroid tissue in situ as possible is essen tial to reduce th e risk of hypoparathyroidism .53,54,55 For th is reason , a th orough kn ow ledge of parathyroid an atom y (especially th e n orm al an d ectopic location s in addition to th e blood supply) is crit ical in thyroid surgery. Th e superior parathyroid glan ds often lie in th e posterior aspect of th e superior thyroid pole. Th eir blood supply gen erally com es from bran ch es of th e in ferior thyroid artery, from th e superior thyroid artery (less frequen tly), from an an astom otic loop betw een th e superior an d in ferior thyroid artery, or from th e thyroid glan d. Th eir position is gen erally less variable because of th e lim ited em br yological course th ey follow. Con versely, th e position of th e in ferior parathyroid glan ds is m ore variable because of th eir w ider em br yological course. Th ey can be foun d anyw h ere n ear th e lateral, an terolateral, or posterior aspects of th e low er pole of th e thyroid. Less com m on ly, th ey can be foun d w ith in th e thym us rem n an t. Th eir blood supply is derived from bran ch es of th e in ferior thyroid artery or directly from th e thyroid glan d. On ce iden tified, each parathyroid sh ould be m eticulously preserved by avoidin g excessive dissect ion an d preservin g its blood supply by in dividually ligatin g th e m ultiple bran ches of th e in ferior thyroid artery as close as possible to th e thyroid glan d capsule. If a surface parathyroid h em atom a develops, th e parathyroid capsule sh ould be sliced to avoid parathyroid cap sule edem a.54,55 Wh en th e viability of a parathyroid glan d is question able, or in cases of acciden tal avulsion , autotran splan tation in th e stern ocleidom astoid m uscle is suggested. Th is sh ould be perform ed after th e glan d is cut in to th in slices (1–2 m m w ide) an d possibly after in t raoperative h istological con firm ation of parathyroid tissue h as been obtain ed. Follow in g th is strategy, despite a poten tial rise in th e in ciden ce of tem porar y hypoparathyroidism , th e rate of perm an en t hypoparathyroidism can drop to 0%.56,57,58,59 Oth er factors lin ked to th e developm en t of hypoparathyroidism are related to surgical procedures (e.g., th e exten t of thyroid resection , bilateral cent ral n eck lym ph n ode dissection , an d reoperative thyroid surgery),55,58,60 th e in dication s for surgery (e.g., Graves’ disease), or patien t ch aracteristics (e.g., fem ale sex, younger age, an d preoperative parathyroid h orm on e [PTH], calcium , ph osph ate, m agn esium , an d vitam in D levels).52,61,62,63 To m axim ize th e ch ances of a safe an d early disch arge from th e h ospital, di eren t protocols h ave been developed to iden tify patien ts at h igh risk of developin g hypocalcem ia w h o sh ould be treated w ith calcium an d vitam in D. Som e auth ors recom m en d a PTH evaluation 24 h ours after thyroid surgery.64,65,66 Oth ers suggest th at serum calcium levels sh ould be ch ecked 6 h ours after surger y an d 1 day postoperatively.67 St ill oth ers advocate

ch eckin g ion ized calcium on postoperative days 1 an d 2,68 or both PTH an d serum calcium levels on postoperat ive day 1.69 No sin gle protocol h as been sh ow n to be m ore advan tageous for th e early iden tification of hypoparathyroid patien ts. Di eren t m edical cen ters use di eren t regim en s to treat postoperative hypocalcem ia. Alth ough th ere is n o con sen sus, som e basic prin ciples sh ould be follow ed. Hypocalcem ia sh ould alw ays be m edically t reated. Calcium carbon ate (1–2 g/d) sh ould be adm in istered orally w h en th e patien t is asym ptom atic an d in traven ously in th e presence of sym ptom s. Furth erm ore, in selected cases, th e adm in istration of th e biologically active form of vitam in D (calcitr iol) can be added to calcium th erapy at a dose of 0.25 to 1 µg/d to m axim ize calcium absorption . In patien ts at in creased risk for developin g hypocalcem ia, prophylactic treatm en t w ith oral calcium , an d later w ith vitam in D supplem en tation , h as been proposed as a preven tive m easure. Th ough th is regim en h as sh ow n prom isin g results, clear advan tages h ave n ot been dem on strated in large prospective, ran dom ized t rials. Because in h ibit ion of PTH secretion from th e residual parathyroid tissue is a th eoretical side e ect of th is prophylactic regim en , th is protocol is n ot un iversally follow ed.70,71

30.4 Conclusion Th e procedural an d tech n ological advan ces used in thyroid an d parathyroid surgery h ave grow n expon en tially sin ce th e pion eerin g days at th e begin n in g of th e 20th cen tur y. Alth ough t h ese ad van ces are n ow associated w it h a low er in cid en ce of p oor ou tcom es, greater safet y, an d im p roved m orbid it y, com p lication s follow in g th ese p roced u res h ave n ot com p letely d isap p eared . As w ith any su rgical en d eavor, th e m in im al bu t sign ifican t rate of m orbid it y t h at st ill p ersist s is n ot likely t o be elim in ated com p letely. Su rgeon s m u st , t h erefore, h ave a clear u n d erstan d in g of th e risks of th ese p roced u res, m ech an ism s t o m in im ize t h eir occu rren ce, an d th e abilit y t o recogn ize an d rap id ly m an age com p lication s w h en t h ey d o in evit ably arise.

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[59]

[60]

[61]

[62]

[63]

[64]

preven tin g hypocalcem ia? Head Neck 2008; 30(9); 1148–1154, discussion 1154–1155 Barczyń ski M, Cichoń S, Kon turek A, Cich oń W . Applicability of in traoperative parathyroid h orm on e assay durin g total thyroidectom y as a guide for th e surgeon to select ive parathyroid tissue autotran splan tation . World J Surg 2008; 32(5); 822–828 Th om usch O, Mach en s A, Sekulla C, Ukkat J, Brauckh o M, Dralle H. Th e im pact of surgical tech n ique on postoperative hypoparathyroidism in bilateral thyroid surgery: a m ultivariate an alysis of 5846 con secutive patien ts. Surgery 2003; 133(2); 180–185 Ham m erstad SS, Norh eim I, Paulsen T, Am lie LM, Eriksen EF. Excessive decrease in serum m agn esium after total thyroidectom y for Graves’ disease is related to developm en t of perm an en t hypocalcem ia. World J Surg 2013; 37 (2); 369–375 Sam AH, Dh illo W S, Don aldson M, et al. Serum ph osph ate predicts tem porar y hypocalcaem ia follow in g thyroidectom y. Clin En docrin ol (Oxf) 2011; 74(3); 388–393 Paek SH, Lee YM, Min SY, Kim SW , Ch ung KW , Youn YK. Risk factors of hypoparathyroidism follow in g total thyroidectom y for thyroid can cer. World J Surg 2013; 37(1); 94–101 Julián MT, Balibrea JM, Gran ada ML, et al. In tact parathyroid h orm on e m easurem en t at 24 h ours after thyroid surgery as predictor of parathyroid fun ction at long term . Am J Surg 2013; 206(5); 783–789

[65] Youngw irth L, Ben avidez J, Sippel R, Ch en H. Parathyroid h orm on e deficien cy after total thyroidectom y: in ciden ce an d tim e. J Surg Res 2010; 163(1); 69– 71 [66] Yan o Y, Masaki C, Sugin o K, et al. Serum in tact parathyroid h orm on e level after total thyroidectom y or total thyroidectom y plus lym ph n ode dissect ion for thyroid n odules: report from 296 surgical cases. In t J En docrin ol Metab 2012; 10(4); 594–598 [67] Pfleiderer AG, Ah m ad N, Draper MR, Vrotsou K, Sm ith WK. Th e tim in g of calcium m easurem en ts in h elpin g to predict tem porary an d perm an en t hypocalcaem ia in patien ts h avin g com pletion an d total thyroidectom ies. An n R Coll Surg Engl 2009; 91(2); 140–146 [68] de An drade Sousa A, Salles JM, Soares JM, de Moraes GM, Car valh o JR, Roch a PR. Course of ion ized calcium after thyroidectom y. World J Surg 2010; 34(5); 987–992 [69] Lan dry CS, Grubbs EG, Hern an dez M, et al. Predictable criteria for select ive, rath er th an routin e, calcium supplem en tation follow in g thyroidectom y. Arch Surg 2012; 147(4); 338–344 [70] Bellan ton e R, Lom bardi CP, Ra aelli M, et al. Is routin e supplem en tation th erapy (calcium an d vitam in D) useful after total thyroidectom y? Surgery 2002; 132(6); 1109–1112, discussion 1112–1113 [71] Roh JL, Park JY, Park CI. Preven tion of postoperative hypocalcem ia w ith routin e oral calcium an d vitam in D supplem en ts in patien ts w ith di eren tiated papillary thyroid carcin om a un dergoin g total thyroidectom y plus central n eck dissection . Can cer 2009; 115(2); 251–258

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31 Int raoperat ive Nerve Monit oring Dipti Kamani, Rahul Modi, and Gregory W. Randolph

31.1 Int roduct ion Galen , in th e secon d cent ur y, iden tified an d n am ed th e recurren t lar yngeal n erve (RLN). Th e an atom ical draw in gs of th e RLN distribution w ere provided m uch later, in th e 16th cen tur y by Vesalius.1 In 1938, Lah ey in troduced routin e dissect ion an d dem on stration of th e RLN durin g thyroid surgery.2 Prior to th is, som e research ers believed th at th e RLN w as extrem ely sen sitive an d dissect ion for iden tification of th e RLN led to injur y to th e nerve, but it has since been proven that identification and dissection of the RLN is w ell tolerated. Although RLN identification is the gold standard for prevention of RLN injury, intraoperative nerve m onitoring (IONM) is a useful adjunct and extension to visual identification, adding a new functional dynam ic during thyroid, parathyroid, and neck base surgery. This chapter review s the principles and application of RLN m onitoring techniques, the utility of IONM, and new advancem ents in the technique. The fundam ental philosophy of neural m onitoring is that a visually identified, surgically preserved, and structurally intact nerve m ay not necessarily function norm ally. A visually intact nerve m ay not reveal occult stretch or therm al injury. Several recent studies have established that satisfactory electrom yographic (EMG) activity at the com pletion of surgery carries a high negative predictive value (NPV) of > 95% for nerve injury.3,4,5 Curren t studies suggest a m ajorit y of gen eral an d h ead an d n eck surgeon s use n eural m on itorin g in th eir thyroid surgeries in both th e Un ited States an d Germ an y. In terestin gly, IONM is foun d to be m ore com m on ly used by experien ced surgeon s in h igh er-volum e h ead an d n eck en docrin e surgery un its. Th ere is in creasin g organ izat ion al su p p or t for n eu ral m on itorin g; Germ an Pract ice Gu id elin es an d th e In t ern at ion al Neu ral Mon it orin g St u d y Grou p suggest th at IONM sh ou ld be con sid ered for all su rgeries of t h e t hyroid glan d .6,7 Th e Am erican Acad em y of Otolar yn gology–Head an d Neck Su rger y (AAOHNS) p u blish ed th eir Clin ical Pract ice Gu id elin es in 2013, ou tlin in g 12 key act ion evid en ce-based st atem en ts created by a p an el of ot olar yn gologist s, lar yn gologist s, an est h esiologist s, gen eral su rgeon s, m ed ical en d ocrin ologist s, n u rsin g rep resen t atives, p atien t ad vocacy rep resen tat ives, an d clin ical p ractice gu id elin es exp er ts rep resen t in g t h e Am erican Acad em y of Otolaryn gology, t h e Am erican Thyroid Associat ion , th e Am erican Association of En d ocrin e Su rger y, th e Am erican Head an d Neck Societ y, an d t h e Am erican Med ical Associat ion .8 Th ey recom m en d IONM as an option for p atien ts u n d ergoin g thyroid su rger y, ow in g to establish ed ap p lication of IONM in red u cin g in t raop erative RLN id en tification tim e, in red u cin g t em p orar y vocal cord p aralysis (VCP) rates, an d in evad in g bilateral VCP by p rogn ost icat ion of p ost op erat ive vocal cord fu n ction . Th e Am erican Thyroid Association Surgical A airs Com m it tee recen tly publish ed con sen sus statem en ts (on outpatien t thyroid surgery an d on optim al surgical m an agem en t of goiters) th at support n eural m on itorin g as a tool to confirm in tact n eural fun ct ion at th e en d of surgery, w h ich in tu rn m ay im pact on disch arge plan n in g.9,10 Addition ally, Am erican Head an d Neck

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Society (AHNS) guidelin es for th e m an agem en t of invasive thyroid can cer proposes th at IONM delivers im portan t in traoperative an d postoperat ive fun ct ion al in form ation im pact in g th e tim in g of con tralateral surgery, an d recom m en ds IONM for all cases of thyroid can cer.11

31.2 Report ed Incidence of Iat rogenic Recurrent Laryngeal Nerve Injury Th e literat ure reports perm an en t RLN paralysis rates in expert h an ds in th e 1 to 2% ran ge.12 How ever, th e rates of RLN paralysis after thyroidectom y in m any studies are likely un derestim ated because m ost in traoperative RLN injuries are n ot readily recogn ized by th e surgeon s, surgical un its w ith un favorable data are less likely to report th eir fin din gs, an d n ot all patien ts un dergo postoperative lar yn geal exam in at ion .13 Th e Scan din avian Qualit y Register states th at RLN paralysis rate doubles w h en postoperative lar yn geal exam s are perform ed routin ely in all patien ts.14 Preoperative an d postoperative lar yn geal exam in ation s are n ecessar y in all patien ts in order to appreciate th e true rate of RLN injur y. A recen t review of 27 articles th at an alyzed m ore th an 25,000 thyroidectom y patien ts foun d th e average postoperative VCP rate w as 9.8%.15 Un ilateral VCP can lead to voice ch an ges su cien t to alter vocation , especially in profession al voice users, an d m ay be accom pan ied by dysph agia an d aspiration .16 Bilateral VCP m ay result in trach eotom y. Th e factors associated w ith an in creased risk of RLN injur y in clude lack of in traoperative RLN iden tification , an in experien ced surgeon , surgery for can cer, exten sive bilateral surgery, revision surgery, an d surgery associated w ith greater blood loss.

31.3 Preoperat ive and Post operat ive Laryngeal Exam in All Pat ient s Kn ow ledge of preoperative an d postoperat ive glottic fun ction greatly im pacts RLN m on itorin g as w ell as surgical m an agem en t. A preoperative lar yngeal exam can detect vocal cord paralysis in th e absen ce of associated sym ptom s, suggest invasive disease, im pact in traoperative m an agem en t of an invaded n er ve, avoid w ron gful accusation of postoperative paralysis, an d provide a basis to com pare postoperative vocal cord fun ction . A postoperative laryn geal exam is n ecessar y; it represen ts th e on ly precise outcom e m easure for postoperative RLN fun ction , because voice ch anges an d vocal cord paralysis can occur in depen den tly.17 It allow s com preh en sive in terpretation of in traoperative n eural m on itorin g electroph ysiological param eters an d also allow s for postoperative patien t safety an d plan n in g of con tralateral surgery. Th e AAOHNS voice guidelin es provides recom m en dat ion s for preoperative an d postoperative voice

Intraoperative Nerve Monitoring assessm en t.8 Routin e preoperative an d postoperative lar yn geal exam at th e tim e of thyroidectom y is curren tly recom m en ded by th e British Association of En docrin e an d Thyroid Surgeon s, th e Germ an Association of En docrin e Surgery, an d th e In tern ation al Neural Mon itorin g Stu dy Group.6,7,18 Th e Am erican Thyroid Association An aplastic Can cer Guidelin es recom m en d preoperative laryn geal exam in ation , as do th e Am erican Thyroid Association Goiter Surgery Guidelin es.10 Th e Am erican Head an d Neck Society Invasive Thyroid Can cer Guidelin es an d Nation al Com preh en sive Can cer Net w ork (NCCN) both recom m en d a preoperative lar yn geal exam in all thyroid can cer patien ts.19 Preoperative vocal cord exam fin din gs, in t raoperative n erve stim ulabilit y, an d n er ve invasion h ave a ver y fascin atin g relation sh ip.

31.4 Applicat ion of Int raoperat ive Neural Monit oring Alth ough th e utilit y of IONM in reducin g th e in ciden ce of postoperative VCP h as n ot proven to be statistically sign ifican t w h en com parin g results from surgeries w ith an d w ith out IONM, th e use of IONM defin itely sh ow s a tren d tow ard reduction in postoperative VCP. Th ere are m any un derlyin g reason s for th is observation , th e m ost im portan t bein g th e n eed for a large n um ber of surgeries to ach ieve adequate statist ical pow er. Oth er con foun din g factors relate to m on itorin g tech n iques an d equipm en t. Non eth eless, m any in dividual studies h ave establish ed th at IONM decreases tem porary an d perm an en t vocal cord palsy rates in thyroid surgeries, especially in cases of retrostern al goiters, revision surgeries, an d surgeries for thyroid can cer.20 A study by Dralle h as sh ow n th at th ere is a sign ifican t declin e in th e rate of VCP w h en low -volum e surgeon s apply IONM durin g thyroid surgeries.21 Ben efits of IONM can be categorized as follow s: 1. Neural m appin g 2. In sigh t in to path ological states of th e RLN 3. Progn ost icat ion of n eural fun ction as it relates to in traoperative injur y These ben efits are realized w h en th e elect rical an d fun ct ion al dyn am ic in form ation provided by IONM are applied to com plem en t visual n er ve iden tification . Neural m on itorin g requires a com pletely bloodless field, h as a learn in g cur ve, an d also en tails som e added cost. Th e added cost provides valuable addition al in form ation th at h elps a surgeon in n er ve iden tification , in m akin g decision s regarding in traoperative n er ve m an agem en t, and in foretellin g postoperative expectation s.

31.4.1 Neural Mapping In th e paratrach eal region , lin ear stim ulat ion by a n eural m on itor probe w ith 2 m A stim ulation curren t m ay be em ployed to m ap out th e en tire path of th e n erve elect ron ically prior to its visualization . Th is n eural m ap can ser ve as a guide in directin g subsequen t dissect ion an d visualization of th e n erve in th is region . Th is leads to lim ited, w ell-focused dissect ion w ith th e added ben efit of reducin g operat ive t im e by optim izing th e surgical dissect ion n eeded for n er ve visualization . Neural m appin g can be particularly h elpful in revision surgeries w h ere scar tissue can im pose di cult y in n er ve iden tification an d in cases presen tin g w ith distorted an atom y, for exam ple, large goiters an d invasion by m align an cy.

31.4.2 Insight int o Pat hological Stat es of t he Recurrent Laryngeal Nerve Surgical m an agem en t of th e invaded n er ve can be im pacted by in traoperative elect rom yograph ic (EMG) activity ( Fig. 31.1).22 W h en electrophysiological stim ulation of an invaded n er ve reveals sign ifican t residual EMG act ivit y in th e sett in g of preoperative VCP, th e surgeon becom es cogn izan t of th e fun ct ion al con sequen ces of resection of such a n er ve, in cludin g addition al dysphagia an d aspiration to som e exten t . Such fun ction al in form ation is valuable an d can n ot be ach ieved by visual iden tification of th e n erve alon e.

31.4.3 Prognost icat ion of Neural Funct ion as It Relat es t o Int raoperat ive Injury In traoperative n eural m on itorin g of th e RLN is extrem ely h elp ful in n eural m appin g, n eural iden tification , an d un derstan din g path ological states of th e n erve. How ever, its m ost im portan t application arises from its abilit y to in traoperatively predict postoperative n eural fun ction . In th e absen ce of n eural m on itorin g, visual in spection of th e n er ve is th e on ly available m eth od to determ in e fun ct ion alit y of th e n er ve. A n er ve injured by blun t t raum a or stretch in g m ay rem ain visually in tact , but in such cases struct ural in tegrit y does n ot tran slate in to n orm al postoperat ive fun ct ion . Curren t data in th e literat ure reveal th at on ly approxim ately 10% of all injured n er ves are correctly iden tified by visual in spection .14,23,24 Con trar y to th is, IONM data in th e literature suggest th at EMG testin g of th e vagus–RLN system after thyroid surgery is a h ighly precise n eural fun ct ion test an d h as n egative predict ive value of m ore th an 95%.3,4,5,25,26,27,28

Fig. 31.1 Intraoperative managem ent of invaded nerves based on preoperative vocal cord function and electromyographic (EMG) inform ation. EMG + ve, EMG positive; EMG –ve, EMG negative; RLN, recurrent laryngeal nerve; XRT, radiation therapy.

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Special Topics How ever, positive predict ive value is low er an d can be quite variable an d is related to h ow presum ptive loss of sign al is evaluated w ith respect to equipm en t troublesh ootin g. Un iversal an d accurate defin ition of loss of sign al an d a better kn ow ledge of n orm ative n eural m on itorin g param eters w ill greatly augm en t th e progn ostic fun ct ion of IONM.7,19,29 On ce a loss of sign al resultin g from defin ite n eural injur y is establish ed, retrograde testin g of th e a ected RLN, in itiated at th e laryn geal en tr y poin t an d con tin ued proxim ally, can be perform ed to iden tify th e injured n erve segm en t. Th is presen ts m any th erapeutic as w ell as learn in g opportun ities for th e surgeon . Th e concept of postpon in g th e surgery on th e opposite side in th e settin g of n eural sign al loss represen ts th e greatest exten sion of th e n eural progn ostication abilit y of IONM. Th e loss of sign al is fu rth er explored in th e follow in g sect ion .

31.5 Int raoperat ive Nerve Monit oring St andards Di eren ces exist in th e application of IONM across m ultiple cen ters. Th is variation m ay arise secon dary to th e use of di eren t elect rodes, tech n iques, an d output m eth ods leadin g to m ixed an d in com parable results. Th is h eterogen eity m ay subsequen tly lim it th e overall utilit y an d un iform applicabilit y of th e IONM tech n ology in en surin g en h an ced patien t safety. Also, th e m ost com m on in accuracies in IONM occur due to in correct tube placem en t, tube size errors, or setup -related problem s.30 Keepin g th is in m in d, th e In tern ation al Nerve Mon itorin g Study Group h as developed certain guidelin es to stan dardize n er ve m on itorin g. Major dom ain s review ed in th ese guidelin es include placem en t of en dotracheal tu bes (recordin g elect rodes), equipm en t setup, an d problem solving durin g n eural m on itoring.7

31.5.1 Int raoperat ive Nerve Monit oring Technique A basic setup of th e n eural m on itorin g equipm en t is sh ow n in Fig. 31.2. Th e m ost preferred n eural m on itorin g equipm en t is an en dotrach eal tube–based system th at in cludes a visual graph ic docum en tation of th e EMG w aveform elicited from thyroar yten oid m uscle activit y. Eith er n eedle-based elect rodes or surface electrodes m ay be used. Prefabricated en dotrach eal tubes w ith paired stain less steel electrodes exposed at th e level of th e glottis or a stan dard tube w ith th in elect rodes placed over th e tube w ith adh esive pads can be used. Addition al electrodes to record posterior cricoaryten oid (PCA) m uscle t w itch are also available, h ow ever, th ey add ver y little to th e sen sitivit y to th e system .31,32

31.5.2 The Set up Adh eren ce to a stan dard setup algorith m reduces th e occurren ce of in t raoperative problem s related to IONM. It is im portan t to keep th e elect rocautery un it m ore th an 10 feet aw ay from th e n eural m on itorin g un it to avoid electrical in terferen ce. Groun d electrodes are adh ered to th e sh oulder or th e stern um area. Poor groun din g can cause a n oisy baselin e, m akin g it di cult to in terpret th e EMG data. After th e equipm en t is set up,

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Fig. 31.2 Basic monitoring equipm ent setup. EMG, electrom yographic; ET, endotracheal tube; REC, recording electrodes; GND, ground electrodes.

care is taken to en sure th at th e recordin g side an d th e stim ulation side of th e circuitr y are com plete. Sim ilar to any oth er task in th e operatin g room , IONM requires team w ork. Th e m ajor participan ts are th e surgeon , th e an esth esiologist, an d th e m on itorin g tech n ician . As a key m em ber of th e team , th e an esth esiologist sh ould un derstan d th at th ere are som e special con sideration s for adm in isterin g an esth esia durin g IONM. It h as been sh ow n th at use of m uscle relaxan ts durin g an esth esia m ay atten uate EMG respon se an d m ake it di cult to perform quan titative an alysis durin g IONM.7,33 Th us preservation of spon tan eous m uscular activit y is im portan t, an d use of lon g-act in g m uscle relaxan ts or paralytic agen ts sh ould be avoided. Use of sh ort-act in g m uscle relaxan ts is acceptable at th e tim e of in duct ion . Th e en dotrach eal tube sh ould be in serted w ith out th e use of any lubrican t jelly or any oth er coatin g. Excessive salivation m ay also obscure th e EMG sign als; th us it is recom m en ded to use suct ion an d possibly a dr yin g agen t . It is critical th at th e electrodes sh ould abut th e vocal cords, h en ce select ion of th e largest tu be possible for in tubation is im portan t . It is pruden t also to ch eck proper placem en t of th e tube on ce it is secured because th is is th e first an d forem ost step in en surin g optim um m on itorin g setup. Because tube displacem en t of up to 6 cm can occur durin g fin al position in g of th e patien t, especially w ith n eck exten sion , it is im perative th at tube placem en t ch ecks be perform ed on ce th e pat ien t is in th e fin al position .34 Th e m eth od com m on ly used by our group, w h ich h as proven to be con sisten tly reliable, is th e presen ce of respirator y variation s. Respirator y variat ion s are sm all w aveform s w ith am plitudes betw een 30 an d 70 µV, w h ich cause coarsen ing of th e baselin e EMG ( Fig. 31.3), an d are seen durin g a sm all w in dow of tim e w h en th e e ect of th e m uscle relaxan t given at th e t im e of in duct ion w ears o an d th e patien t is in a ligh ter plan e of an esth esia just before th e pat ien t starts to m ove spon tan eously or “buck.” In th e absen ce of respiratory variation , a repeat direct lar yngoscopy, preferably by th e

Intraoperative Nerve Monitoring

Fig. 31.3 Respiratory variation waveform s. (a) Upper line—baseline noise, t ypically between 10 and 20 µV. Lower line—coarsening of the baseline with respiratory variation (occurring in the 30- to 70-µV range when the patient is on the brink of bucking in the early anesthetic period). (b) Left and right baseline tracings in a patient. The left vocal cord dem onstrates norm al respiratory variation. The right vocal cord is electrically silent (patient had known right vocal cord paralysis from past surgery).

surgeon , to con firm tu be placem en t is recom m en ded. A recen tly publish ed study by our un it foun d th at iden tification of respirator y variation w as possible in 91% of patien ts, w h ereas th e rem ain in g 9% required a repeat lar yn goscopy.35 It w as also foun d th at th e presen ce of respirator y variation s in depen den tly predicted a good in t raoperatively evoked vagus an d RLN respon se, obviatin g a n eed for a repeat lar yngoscopy in th ese patien ts. At fin al position in g, th e im pedan ce of th e elect rodes sh ould be less th an 5 Ω, an d th e im balan ce betw een th e t w o sides sh ould be < 1 Ω. A h igh er im pedan ce im balan ce m ay suggest in appropriate tube placem en t requirin g reposition ing, w h ereas if th e overall im pedan ce is h igh th en th e groun d electrodes sh ould be assessed or replaced. On ce th e setup is com plete, it is im portan t to set the m on itor even t th resh old at 100 µV an d th e stim ulator probe to a pulsatile output of 4/s. At th e in itiat ion of surgery, th e stim ulation of strap m uscles resultin g in a gross m uscle t w itch can be perform ed to confirm th e absen ce of paralytic agen ts as w ell as an in tact stim ulatory path w ay. Predissection in traoperative suprath resh old vagal n er ve stim ulation con firm s a fun ct ion al system an d allow s acceptan ce of a n egative stim ulation as true n egative. For each patien t, essen tial data pertain in g to IONM in clude a preoperative laryn geal exam , an in itial in t raoperative suprath reshold vagal n er ve stim ulation , an in itial in traoperative RLN stim ulat ion an d

also a sim ilar set of even ts recorded at th e en d of th e surgery, follow ed by a postoperat ive lar yn geal exam . Th e aforem en tion ed essen tial elem en ts can be sum m arized by n otin g L1, R1, V1, an d R2, V2, an d L2.36,37 A suprath resh old curren t of 2 m A is usefu l for n eural m appin g; on ce th e RLN h as been visualized th e curren t can be reduced to 1 m A for furth er testin g an d en d of surgery progn ost icat ion . Evoked w aveform s for th e h um an RLN or vagus n er ve are com m on ly biph asic or triph asic. Th e am plitude of a m on itorin g w aveform , as defin ed in th e In tern ation al Guidelin es, is th e vertical h eigh t of th e apex of th e positive in itial w aveform deflect ion to th e low est poin t in th e n et subsequen t opposite polarit y ph ase of th e w aveform .7 Caragacian u et al foun d th at n o statist ically sign ifican t di eren ce exists betw een th e am plitude w h en th e n er ve is stim u lated by suprath resh old levels at 1 or 2 m A.38 Norm ative values w ere th us defin ed at 1 m A. An am plitude of > 250 µV w as foun d to be h igh ly predict ive of a fun ction in g RLN. Th e study also revealed th at, regardless of th e variation s, a clinically useful n orm ative ran ge can be establish ed an d used for surgical decision m akin g ( Fig. 31.4).38 Laten cy is n ot defin ed con sisten tly in th e IONM literature. Th e In tern ation al Mon itorin g Group defin es laten cy as th e tim e from th e stim u lat ion spike to th e first evoked w aveform peak.7 Laten cies recorded durin g in traoperative m on itorin g are distin ctive an d can di eren tiate art ifacts from stim ulated neural struct ures an d can also distin guish th e RLN,

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Fig. 31.4 Am plitude m easures dem onstrating normal range associated with norm al glottic function. 38

superior lar yngeal n er ve, an d vagus n er ve, in cluding th e left from th e righ t vagus n erve. Th resh old is defin ed as th e stim ulation curren t th at first starts to trigger m in im al EMG act ivit y. Our un it h as described n orm ative EMG data an d graph ical w aveform s gen erated from th e RLN, SLN, an d left an d righ t vagus n er ves ( Fig. 31.5).39 Repetitive stim ulation of th e RLN at levels of 1 an d 2 m A h as been reported to be extrem ely safe, an d n o un favorable e ects h ave been reported.38 IONM h as been safely em ployed in ch ildren an d adults, assum in g proper patien t isolation an d groun din g.7

31.5.3 Int erpret at ion of Loss of Signal during Int raoperat ive Nerve Monit oring Loss of sign al (LOS) durin g IONM could be en coun tered due to various reason s ( Fig. 31.6). A surgeon sh ould first rule out equipm en t- or setup -related LOS before considerin g tr ue LOS. As soon as LOS is en coun tered, assessm en t of th e lar yn geal t w itch respon se to ipsilateral an d con tralateral vagal stim ulation sh ould be perform ed to evaluate th e in tegrit y of th e IONM setup. Th e presen ce of a lar yn geal t w itch establish es th at th e stim ulatin g side of th e equipm en t is fun ct ion ing adequately. Recordin g side equipm en t issues m ost com m on ly arise from im proper tube position in g, w h ich sh ould be adjusted if foun d.

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Oth er issues related to adequacy of curren t an d use of paralytic agen ts sh ould also be con sidered. An even t m ust satisfy th ree con dition s to be labeled as true LOS: 1. Presen ce of a satisfactor y EMG (am plitude > 100 µV) prior to th e even t 2. No or low respon se (i.e., ≤ 100 µV) w ith stim u lat ion at 1 to 2 m A in a dry field 3. Absen ce of lar yngeal t w itch an d/or glot tis t w itch on ipsilateral vagal stim ulation A true LOS sh ould prom pt th e surgeon to iden tify th e site of injury. It provides th e opportun it y to treat th e n er ve injur y if possible. Th is m ay also im pact th e surgical plan an d m ay lead to post pon em en t of surgery on th e cont ralateral side.

31.5.4 Passive EMG Act ivit y during Int raoperat ive Nerve Monit oring Any passive EMG act ivit y occurrin g frequen tly sign ifies m ech an ical n er ve injur y or cautery stress an d sh ould prom pt urgen t evaluat ion of th e surgical m an euvers bein g perform ed at th e t im e. Several research ers h ave reported th at such bursts of passive activit y correlate w ith som e degree of n er ve injury.40,41,42 How ever, th eir relation sh ip to fran k vocal cord paralysis is n ot yet establish ed.

Intraoperative Nerve Monitoring

Fig. 31.5 Ipsilateral endotracheal electrode recordings of electrom yographic waveforms for the left and right vagus nerve, pooled recurrent laryngeal nerve (RLN), and pooled external branch of the superior laryngeal nerve (EBSLN) illustrating normative waveform m orphology, latency, and am plitude.

31.6 New Horizons in Int raoperat ive Nerve Monit oring 31.6.1 Cont inuous Vagal Monit oring and Neural Injury Prevent ion One of the biggest draw backs of the existing IONM form at is that it perm its only interm ittent stim ulation and evaluation of the functional integrit y of the RLN. Although IONM is im m ensely useful in resolving certain surgical dilem m as, the nerve rem ains at risk for injury in bet w een stim ulations.21,26 This could possibly explain the suggestion that, in its present form at, IONM m ay have a lim ited ability to prevent neural injury.21,24,27,43 An ideal IONM form at w ould be the one that provides real-tim e EMG data that can alert the surgeon before perm anent or irreversible neural dam age sets in. Early studies have show n that continuous IONM (CIONM) w ith a vagal nerve electrode can provide this inform ation and is not associated w ith significant neural, cardiac, pulm onary, or gastrointestinal vagal side e ects.43,44,45,46

It is im portan t, h ow ever, th at th e accepted form at di eren tiates true even ts from elect rical artifacts. Com bin in g reduct ion in am p litu d e w it h in crease in laten cy, ou r grou p h as d efin ed m ild an d severe com bin ed even t s (m CEs an d sCEs) ( Table 31.1). Ou r st u d y d em on st r ated th at m CEs an d isolated am p lit u d e or laten cy ch an ges w ere n ot associated w it h VCP, w h ereas an sCE sign ified a t yp ically reversible elect rop hysiological ch an ge w h en th e related su rgical m an eu ver w as abor ted , oth erw ise it cou ld lead to LOS (w h ich ch aracteristically is m u ch less reversible) an d t o p ost op erative VCP. Th u s CIONM allow s th e su rgeon s to in st igate correct ive act ion t o p reser ve n er ve fu n ct ion by abor tin g m an eu vers t h at lead t o ad verse EMG ch anges.47 Mod ificat ion of a su rgical m an eu ver w h en su ch an even t occu rs can p reven t d evelop m en t of a com p lete LOS an d su bsequ en t VCP. It is evid en t th at IONM overall is m ore u sefu l for p reven t in g im p en d in g n eu ral d am age secon d ar y t o a st retch or com p ression in ju r y th an an in ad ver t en t t ran se ct ion of t h e n er ve by t h e su rgeon .47

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Special Topics

Fig. 31.6 Intraoperative loss of signal (LOS) evaluation standard. EMG, electrom yographic; ETT, endotracheal tube.

31.6.2 Superior Laryngeal Nerve Monit oring Recen tly publish ed guidelin es on SLN m on itorin g by th e In tern ation al Neural Mon itorin g Study Group h ave h igh ligh ted th e fact th at n eural m on itorin g of th e SLN is associated w ith h igh er rates of n er ve iden tification th an are possible w ith visual iden tification alon e.48 Th e lar yngeal h ead of th e stern othyroid serves as a useful lan dm ark for iden tification of th e extern al bran ch of th e superior lar yn geal n er ve (EBSLN). A t w itch in th e cricothyroid m uscle seen on stim ulation is curren tly th e m ost accurate m easure of n er ve localization . A specially design ed elect rode array in corporated on an en dotracheal tu be can also record EMG act ivit y from th e glottis in 100% of patien ts.49 For a detailed discussion on th e tech n ique an d utilit y of SLN m on itorin g th e reader is requested to refer to th e guidelin es publish ed by th e In tern ation al Mon itorin g Group.48

31.6.3 Neural Monit oring and Staged Thyroidect om y in Thyroid Cancer Surgery: an Em erging Concept Bilateral n odal m etastases in thyroid can cers are frequen tly en coun tered an d require exten sive surgery, t ypically carr yin g a

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h igh er risk of com plication s, w ith bilateral RLN paralysis bein g on e of th e m ost feared com plication s. Stagin g of surgery m ay o set som e of th ese com plication s, especially th ose th at are tem porar y in n ature. RLN w ith n europraxia m ay recover betw een th e t w o stages of surgery, elim in atin g th e risk of bilateral VCP. Sim ilarly, parathyroid glan ds m ay recover fun ction ally in th e in terven in g period. Th e ben efits of staging bilateral radical n eck dissection h ave been docum en ted earlier. It w as Frazzell in 1961 w h o proposed a plan n ed staging of surgeries w h ere sacrifice of bilateral in tern al jugular vein s w as an ticipated.50 Dun h ill in 1912 an d Lah ey in 1936 recom m en ded staged surgery for severe toxic goiter an d severe hyperthyroidism , respect ively.51,52 Eviden ce suggestin g th e ut ilit y of LOS as a decision -m akin g tool durin g surgery is slow ly accum ulatin g. In tegration of LOS in surgical decision m akin g w ith regard to proceeding w ith bilateral thyroidectom y or staging th e opposite-side surgery can greatly in fluen ce th e postoperat ive bilateral VCP rate. Goretski et al h ave reported th at th e in ciden ce of bilateral VCP drops to zero from 17% in bilateral surgery w h en LOS is in corporated in th e surgical strategy.53 Our un it routin ely o ers staged surger y to pat ien ts w ith exten sive thyroid m align an cy w ith bilateral n odal disease. In our un publish ed series of patien ts presen tin g w ith advan ced thyroid can cer un dergoing plan n ed staged surgery, th e

Intraoperative Nerve Monitoring Table 31.1 Mild and severe com bined events suggestive of nerve injury Event t ype

Criteria

Mild com bined event (mCE)

Am plitude decrease of > 50 to 70% with a concordant latency increase of 5 to 10%.

Severe combined event (sCE)

Am plitude decrease of > 70% with a concordant latency increase of > 10%

perm an en t RLN paralysis rate w as zero an d th e perm an en t hypoparathyroidism rate w as 3.3%. Postoperatively thyroglobulin w as un detectable in 90% an d averaged 0.8 n g/m L in 3-year follow -up. Dralle et al foun d th at 94% of surgeon s in Germ any w ould stage a total thyroidectom y if th ey en coun tered an LOS durin g th e surgery.54 Th is is especially true for centers w ith a h igh er caseload. How ever, a detailed preoperative consen t process is im perative w h en staged surgery is bein g con tem plated as a possibility.55

31.6.4 Int raoperat ive Ident ificat ion of a Nonrecurrent Laryngeal Nerve Th e n on recurren t lar yn geal n er ve (NRLN) is an an atom ical varian t of th e RLN th at h as n o fun ct ion al im pact but in creases th e susceptibilit y to in traoperative injur y by a surgeon un aw are of its presence. A righ t NRLN is repor ted to accoun t for 0.5 to 1% of all RLNs an d a left NRLN accoun ts for on ly 0.04%.56,57 Our series on NRLN m on itorin g recom m en ds an electroph ysiological algorith m w h ere th e presen ce of a positive EMG respon se to proxim al stim ulation of th e vagus at th e superior border of th e thyroid cartilage an d th e absen ce of an EMG respon se to distal stim ulation of th e vagus below th e in ferior border of th e fourth trach eal rin g reliably iden tify a NRLN.58 Curren tly, because n o depen dable tech n ique of preoperative recogn ition or exclusion of NRLN is available, th e aforem en tion ed elect rophysiological algorith m reliably alerts a surgeon to th e presen ce of an NRLN prior to th e dissect ion in th e related cervical region . Th is vagal stim ulation tech n ique for NRLN iden tification is supported by Brauckh o et al.59 In th ese cases th e righ t NRLN beh aves sim ilarly to a n orm al righ t RLN in term s of am plitude, th resh old, an d laten cy. Som e w orkers h ave suggested th at a laten cy of < 3.5 m s stron gly suggests NRLN.60 How ever, fur th er studies are w arran ted before it is con sidered as a defin itive in dication of a NRLN.

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[45] Sch n eider R, Przybyl J, Pliquett U, et al. A n ew vagal an ch or elect rode for realtim e m on itorin g of th e recurren t laryn geal n er ve. Am J Surg 2010; 199(4); 507–514 [46] Lam adé W , Meyding-Lam adé U, Buch h old C, et al. [First con tin uous n er ve m on itorin g in thyroid glan d surgery] Ch irurg 2000; 71(5); 551–557 [47] Ph elan EDH, Poten za A, Kam an i D, Loren z K, Sch n eider R, Ran dolph GW . EMG Ch an ges of im pen ding RLN injur y can be recogn ized to preven t n eural injur y: a prospective m ulticen ter study of con tin uous in traoperative n er ve m on itorin g usin g a vagal n erve elect rode durin g thyroid surgery Otolaryn gol Head Neck Surg 2013 [48] Barczyń ski M, Ran dolph GW , Cern ea CR, et al. In tern ation al Neural Mon itorin g Study Group. Extern al bran ch of th e superior laryn geal n er ve m on itorin g durin g thyroid an d parathyroid surgery: In tern ation al Neural Mon itorin g Study Group stan dards guidelin e statem en t. Lar yn goscope 2013; 123 Suppl 4; S1–S14 [49] Darr AE, Tufano R, Ozdem ir S, Kam an i D, Hurw it z S, Ran dolph GW. Superior lar yn geal n erve quan titative in traoperative m on itorin g is possible in all thyroid surgeries. Lar yn goscope 2013 [50] Frazell EL, Moore OS. Bilateral radical n eck dissection perform ed in stages. Experien ce w ith 467 patien ts. Am J Surg 1961; 102; 809–814 [51] Dun h ill A. Discussion on partial thyroidectom y un der local an aesthesia, w ith special referen ce to exoph th alm ic goitre: an address in troductor y to a discussion on th e subject . Proc R Soc Med 1912; 5; 61–69 [52] Lah ey FH. In trath oracic goiter. Surg Gyn ecol Obstet 1936;16 [53] Goretzki PE, Schw arz K, Brin km an n J, W irow ski D, Lam m ers BJ. Th e im pact of in traoperative n eurom on itorin g (IONM) on surgical strategy in bilateral thyroid diseases: is it w orth th e e ort? World J Surg 2010; 34(6); 1274–1284 [54] Dralle H, Sekulla C, Loren z K, Nguyen Th an h P, Schn eider R, Mach en s A. Loss of th e n er ve m on itorin g sign al durin g bilateral thyroid surger y. Br J Surg 2012; 99(8); 1089–1095 [55] Dion igi G, Frattin i F. Staged thyroidectom y: tim e to con sider in traoperative n eurom on itorin g as stan dard of care. Thyroid 2013; 23(7); 906–908 [56] Hen r y JF, Audi ret J, Den izot A, Plan M. Th e n on recurren t in ferior lar yn geal n erve: review of 33 cases, in cluding tw o on th e left side. Surgery 1988; 104 (6); 977–984 [57] Fellm er PT, Böh n er H, Wolf A, Röh er HD, Goretzki PE. A left n on recurren t in ferior lar yn geal n er ve in a patien t w ith righ t-sided aorta, trun cus arteriosus com m unis, an d an aberran t left in n om in ate arter y. Thyroid 2008; 18(6); 647–649 [58] Kam an i D, Poten za AS, Cern ea CR, Kam an i YV, Ran dolph GW . Th e n on recurren t lar yn geal n er ve: an atom ic an d electroph ysiologic algorith m for reliable iden tification . Lar yn goscope 2015; 125(2); 503–508 [59] Brauckh o M, Walls G, Brauckh o K, Th an h PN, Th om usch O, Dralle H. Iden tification of th e n on -recurren t in ferior laryn geal n er ve usin g in traoperative n eurostim ulation . Lan gen becks Arch Surg 2002; 386(7); 482–487 [60] Brauckh o M, Mach ens A, Sekulla C, Loren z K, Dralle H. Laten cies sh orter th an 3.5 m s after vagus n er ve stim ulation sign ify a n on recurren t in ferior laryn geal n erve before dissection . An n Surg 2011; 253(6); 1172–1177

O ce-Based Ultrasonography

32 O ce-Based Ult rasonography David L. Steward and Russell B. Smith

32.1 Int roduct ion O ce-based ultrasoun d (US) h as gain ed popularit y over th e last decade. Most w ould agree th at in corporation of th is tech n ology in to a clin ical pract ice provides advan tages to both th e patien t as w ell as th e physician . For th e patien t, it can sign ifican tly stream lin e m edical care. For exam ple, a patien t w ith a thyroid n odule can be seen for a clin ical evaluation by th e physician an d also un dergo th e n ecessar y diagn ostic im aging as w ell as US-guided biopsy for cytological diagn osis in a sin gle o ce en coun ter. For th e physician , perform in g real-tim e US m axim izes th e diagn ostic yield from th e im aging study. Th ere is little doubt th at physician s w h o perform th e US obtain expon en tially m ore in form ation from th e study th an th ose w h o view on ly static im ages obtain ed by an oth er. Beyon d th at, th e physician is able to couple th eir in h eren t kn ow ledge of th e disease w ith th e fin din gs of th e h istor y an d physical exam to perform a com preh en sive diagn ostic US tailored to th e disease process an d ultim ately optim ize patien t care. But th ere are costs th at m ust be con sidered as on e con tem plates adding o ce-based US to a clin ical practice. Th ese costs exten d beyon d th e m on etary con sideration s of purch asing th e equipm en t; th ey also in clude th e investm en t of tim e an d e or t to com plete th e appropriate t rain in g as w ell as determ in in g h ow to in clude addition al procedures in to an already busy clin ic sch edule. In th e en d, m ost w ill fin d th e ben efits of o ce-based US far exceed th e costs an d w ill feel th at it is an invaluable part of providin g care to patien ts.

32.2 Technique of Perform ing O ce-Based Ult rasound Th ere are som e physics prin ciples th at m ust be un derstood as on e starts perform in g o ce-based US. Th e first prin ciple involves th e relation sh ip betw een soun d w ave frequen cy an d th e depth of pen etration of a soun d w ave in to tissues. Th e depth of pen etration is inversely proportion al to th e frequen cy of th e soun d w ave. Hen ce, low er-frequen cy soun d w aves h ave deeper pen etration , w h ereas h igh er-frequen cy soun d w aves h ave m ore superficial pen etration . Given th at th e vast m ajority of n eck path ology is relatively superficial (< 4 cm ), on e can use a h igh -frequen cy tran sdu cer (≥ 10 MHz) for n eck US. Th e abilit y to use h igh er-frequen cy soun d w aves for n eck US leads to a secon d prin ciple, th at th e use of h igh er-frequen cy soun d w aves for im aging results in better axial an d lateral resolution . Th erefore, th e im ages obtain ed durin g n eck US are of extrem ely h igh qualit y an d allow ver y sm all abn orm alities to be clearly defin ed. In gen eral, th e n eck is a readily accessible area to evaluate w ith US. As th e n eck evaluation exten ds in feriorly an d superiorly, som e lim itation s are en coun tered due to th e presen ce of th e stern oclavicular an d m an dibular bony an atom y, respectively. Th e vast m ajorit y of im agin g is com pleted in B m ode (gray scale) scan n in g, but a w orkin g kn ow ledge of color Dop pler an d pow er Doppler is n ecessary to com plete a th orough evaluation . Th e h igh -frequen cy lin ear tran sducers used for n eck

US are t ypically 4 to 6 cm w ide an d approxim ately 1 cm in th ickn ess. Lead zircon ate tit an ate cr ystals are located in th e en d of th e tran sducer. Wh en th ese cr ystals are stim ulated by electricit y, soun d w aves are gen erated an d subsequen tly em itted in to th e tissue. Conversely, w h en th e soun d w aves return from th e t issue, com pression of th e crystals gen erate an elect rical curren t th at ultim ately creates th e US im age. Th is ph en om en on is kn ow n as th e piezoelectric e ect . Th e cr ystals in th e tran sducer altern ate betw een gen eratin g an d receivin g soun d, an d at any given tim e th e m ajorit y of th e crystals in th e tran sducer are receivin g soun d w aves th at h ave been reflected back from th e tissue. Th e w idth of th e US im age th at is gen erated by th is process is essen tially th e sam e w idth as th e tran sducer, but th e th ickn ess of th e area bein g im aged is m uch th in n er th an th e tran sd ucer (~ 1 m m th ick). Hen ce th e im age gen erated durin g n eck US can be th ough t of as bein g rough ly th e sh ape of a credit card. Th is h as obvious im plication s w h en on e is perform in g USguided n eedle biopsies. Th e room con figuration for o ce-based US w ill gen erally position th e m ach in e to th e patien t’s righ t side ( Fig. 32.1). Th is allow s th e physician to use th e righ t h an d (dom in an t h an d) to h old th e tran sducer durin g th e exam w h ile th e left h an d m an ages th e kn obs an d keys on th e US m ach in e. For som eon e w h o is left-h an d dom in an t , th is con figuration m ay be sw itch ed. Th e US tran sd ucer is h eld betw een th e th um b an d first t w o fin gers n ear th e skin in terface, w h ich th en allow s th e rin g an d/or little fin ger to brace on th e patien t for stabilit y ( Fig. 32.2). For th e m ost part, th e probe is m ain tain ed in a perpen d icular orien tation to th e skin , but subtle an gulation s can be used to im age beh in d struct ures, such as th e lar yn x, trach ea, m an dible, stern um , an d clavicle. An adequate am oun t of gel is required to bridge th e in terface betw een th e t ran sducer an d th e skin . If th ere is n ot en ough gel presen t th e soun d w aves w ill n ot be tran sm itted to th e tissue. If a poor im age is bein g obtain ed th e an gulation of th e t ran sducer n eeds to be adjusted so th at th e

Fig. 32.1 Room configuration for office-based ultrasound. The exam chair should allow the patient to be exam ined in a sitting or supine position. The ultrasound unit is on the patient’s right and a Mayo stand is useful to hold the supplies used during a needle biopsy.

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Special Topics

Fig. 32.2 Holding the ultrasound transducer. The transducer is held between the thumb and first fingers to allow the other digits to extend and stabilize the transducer during the exam .

foot plate sits again st th e n eck skin alon g its en tire w idth ( Fig. 32.3). A system atic approach to n eck evaluation sh ould be con sisten tly ut ilized w h en perform in g n eck US. Th is approach sh ould in clude both th e cen tral an d lateral n eck com part m en ts an d be exten ded to oth er areas such as th e parotid or posterior n eck as n ecessary. Given th at th e m ajorit y of n eck US is perform ed for thyroid an d parathyroid disease, th e evaluation usually starts in feriorly an d cen trally an d th en exten ds laterally an d superiorly. Th e m ajorit y of im aging is perform ed in a t ran sverse plan , but lon gitudin al or oblique im aging m ay occasion ally be n ecessar y. Any path ology th at is iden tified requires a th ree-dim en sion al assessm en t to defin e th e size of a lesion . For cen tral n eck im aging, th e en tire com partm en t from carotid artery to carotid arter y sh ould be evaluated. Frequen tly, th is can n ot be accom plish ed w ith a single pass of th e t ran sducer. Typically, on e w ill position th e tran sducer on th e n eck such th at th e carotid sh eath is on on e side of th e im age an d at least h alf th e trach ea occupies th e oth er side of th e im age. Th is is com pleted for both sides of th e cen tral n eck ( Fig. 32.4). As th e exam exten ds to th e lateral n eck to assess for lym ph aden opathy, on e w ill position th e t ran sducer on th e n eck so th at th e carotid sh eath is on on e side of th e im age an d th e rem ain der of th e tran sducer span s th e n ode-con tain ing area of th e n eck ( Fig. 32.5). Th is allow s levels II th rough IV to be evaluated w ith a sin gle pass of th e tran sducer. Addition al tran sverse passes m ore posteriorly allow level V to be exam in ed. For th e vast m ajorit y of thyroid an d parathyroid disease, evaluation of level I adds little addition al in form ation . But for path ology such as a thyroglossal duct cyst, level I im aging is n ecessar y to fully evaluate th e m ass. Docum en tation of th e US exam in ation is an im portan t aspect of o ce-based US an d often in cludes both a text repor t an d im age in th e m edical record. As path ology is en coun tered th ere are t w o m eth ods to record th e fin din gs, an d in som e situation s both m eth ods m ay be used. Th e first m eth od is to capture a static im age of a represen tat ive part of th e path ology. Th is im age can th en be labeled, m easured, an d th en in corporated in to th e m edical record. Th e second m eth od of recordin g is to com plete a cin e loop of th e area of in terest. Th is loop can be from 3 to 10 secon ds in len gth depen din g upon th e size,

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Fig. 32.3 Poor im age qualit y during ultrasound. (a) Appearance of im age when there is inadequate gel on the patient’s neck. (b) Appearance of im age when the transducer is not fully contacting neck skin. The right side of the transducer is off the skin.

location , an d n um ber of fin din gs th at n eed to be docum en ted. Th is approach w ill n ot allow for as detailed labelin g or m easurin g of a m ass, but can be an im portan t adjun ct to th e static im age.

32.3 Thyroid Ult rasound O ce-based US provides a th orough evaluation of a variet y of path ologies th at a ect th e thyroid glan d. Com pared to com puted tom ography (CT) an d m agnetic reson an ce im aging (MRI), US is th e m ost detailed im agin g m odalit y for assessing thyroid disease. Th e appearan ce of a n orm al thyroid glan d is h om ogen eous an d h as an in term ediate gray scale appearan ce an d is con sidered an isoech oic struct ure of th e n eck. A di use h eterogen eous appearan ce of th e thyroid glan d is associated w ith a w ide variety of in flam m ator y con dition s, w ith Graves’ disease an d Hash im oto’s thyroiditis bein g th e t w o m ost com m on en tities ( Fig. 32.6). With Graves’ disease, th e glan d ten ds to be sligh tly en larged, w ith a di use hypoech oic appearan ce an d in ten sely in creased vascularity on Doppler evaluation , especially w h en n ot con trolled m edically. In patien ts w ith suspected Graves’ disease, US n ot on ly assists in excluding oth er etiologies

O ce-Based Ultrasonography of thyrotoxicosis but also assesses for coexist in g n odular disease, w h ich h as a h igh er risk of m align an cy in th is population .1 With Hash im oto’s thyroiditis, th e glan d m ay be en larged, n orm al sized, or even atroph ied after lon g-stan ding disease. Th e glan d h as a splotchy hypoech oic appearan ce w h en com pared to

Graves’ disease. In addition , th e glan d w ill h ave variable vascularit y, w ith a m ore recen t on set of disease h avin g in creased vascularit y an d a m ore lon g-stan ding disease h avin g lim ited to n o vascularit y. Nodular varian ts of Hash im oto’s disease are frequ en t ly en cou n tered an d m ay h ave a sin gle or m u lt ip le

Fig. 32.4 Evaluation of the central neck. (a) Representative ultrasound (US) im age of the right central neck evaluation with the trachea (T) on the right and the carotid artery (C) on the left. (b) Representative US im age of the left central neck evaluation with the trachea (T) on the left and the carotid artery (C) on the right.

Fig. 32.5 Evaluation of the lateral neck. (a) Representative ultrasound (US) im age of the right lateral neck evaluation with the carotid artery (C) on the right side of the im age. (b) Representative US im age of the left lateral neck evaluation with the carotid artery (C) on the left side of the image.

Fig. 32.6 Typical heterogeneous sonographic appearance of autoim mune thyroid disease. (a) Graves’ disease, left-sided longitudinal plane in gray scale/ B m ode. (b) Graves’ disease, transverse plane with power Doppler showing increased vascularit y. (c) Hashim oto’s thyroiditis, left-sided longitudinal plane in gray scale/ B m ode.

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Special Topics Table 32.1 Sonographic characteristics of a thyroid nodule Benign characterist ics

Malignant characteristics

Isoechoic

Hypoechoic

Sim ple cyst

Solid/com plex mass

Spongiform

Irregular border

Sm ooth well-defined border

Extrathyroidal extension of nodule

Presence of a halo around nodule

Diffuse/central vascularit y

Peripheral vascularity

Taller than wide axial size

Wider than tall axial size

Microcalcifications

Macrocalcifications

Associated suspicious lym ph nodes

n od u les t h at d em on st rate a w id e variet y of son ograp h ic ch aracteristics.2 Docum en tation of a thyroid glan d exam sh ould in clude th e th ree-dim en sion al size of both thyroid lobes as w ell as any n odular disease of th e glan d. Nodular disease of th e thyroid glan d can be accurately sized an d defin ed by use of both B m ode scan n ing an d Doppler evaluation . In patien ts w ith goiter th at con tain s n um erous n odules, it is n ot alw ays practical to m easure ever y n odule. In th is situation , th e largest an d m ost w orrisom e n odules sh ould be recorded an d m easured. In addition to th e size of a n odule, th ere are a n um ber of son ograph ic features of a thyroid n odule th at can be described ( Table 32.1). Several of th ese features can be suggestive of m align an cy an d assist th e physician in determ in in g th e n eed for biopsy.3 Son ograph ic pattern is m ore im portan t th an n odule size w h en evaluatin g th e likelih ood of m align an cy, w ith an accuracy of about 80%.4 Sim ple colloid cysts an d spon giform or m ixed cystic/solid colloid n odules are n early alw ays ben ign , w h ereas hypoech oic n odules w ith irregular borders an d m icrocalcification s are alm ost alw ays m align an t. Solid isoech oic or hyperech oic n odules w ith out suspicious features are son ograph ically in determ in ate an d often cytologically in determ in ate, consisten t w ith possible follicular n eoplasm . Th e revised Am erican Thyroid Association Guidelin es for Thyroid Nodules describes w h ich n odules benefit from biopsy based on size an d son ograph ic appearan ce.5

32.4 Parat hyroid Ult rasound Preoperative parathyroid localization is e ectively perform ed w ith o ce-based US but is tech n ically m ore ch allengin g th an thyroid im aging. Th e t ypical son ograph ic appearan ce of a parathyroid aden om a is a sm ooth ellipsoid or crescen t-sh aped hypoechoic m ass, w h ich m ay h ave a w ell-defin ed vascular pedicle on Doppler evaluation . Th e m ass is t ypically located on th e posterior surface of th e thyroid glan d for a superior aden om a an d n ear th e in ferior pole of th e thyroid glan d for an in ferior aden om a ( Fig. 32.7 an d Fig. 32.8). Di eren t iatin g a superior from in ferior parathyroid aden om a son ograph ically can be di cult, especially w h en th e superior glan d is located in feriorly. In gen eral, a superior aden om a is located deep to th e coron al plan e of th e recurren t laryn geal n er ve, w h ereas an in ferior aden om a is superficial to th is plan e. On e can use th e posterior surface of th e carotid artery as a

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Fig. 32.7 Location of the left superior parathyroid adenom a. (a) Axial im age showing a left adenoma posterior to the thyroid lobe. (b) Longitudinal im age showing a left adenom a posterior to the thyroid lobe.

surrogate m arker for th e coron al plan e of th e recurren t lar yn geal n er ve on t ran sverse im aging to h elp defin e th e glan d th at is a ected. Th is in form ation can be ver y h elpful in traoperatively, especially if perform in g a m in im ally invasive surgery. Th is em ph asizes th e ben efits of surgeon s h avin g o ce-based US at th eir disposal. If an aden om a is n ot iden tified in th e t ypical location s w h en perform in g US for localization , on e sh ould evaluate for possible ectopic location s. Th e m ost com m on location s for an ectopic aden om a in clude th e carotid sh eath , th e retroesoph ageal space, th e thym us, th e an terior an d superior m ediastin um , an d th e thyroid. Special position in g of th e patien t an d th e tran sducer m ay be n ecessary to assess for aden om as in th ese location s. To im prove superior m ediastin al im aging, th e patien t sh ould be position ed w ith a hyperexten ded n eck, an d th e probe sh ould be used tran sversely at th e stern oclavicular area w h ile th e probe is an gled to im age in feriorly. Th is allow s im aging dow n to th e in n om in ate an d subclavian vasculature an d iden tification of a superior m ediastin al aden om a. To im prove im agin g beh in d th e upper aerodigestive tract alon g th e prevertebral fascia, lon gitudin al im aging allow s on e to an gulate th e probe tow ard th e space. Addition ally, in creasin g th e far field t im e gain com pen sation an d use of a low er-frequen cy tran sducer can im prove visualization in th is area. If localization is still n ot successful despite th ese tech n iques, on e m ay h ave to con sider cross-section al im aging usin g CT.6

O ce-Based Ultrasonography con sisten t location in th e n eck an d distin ct boun daries w ith th e adjacen t m uscles an d upper aerodigestive t ract , lym ph n odes are sm aller, m ore variable in location , an d frequen tly in terspersed am on g m ultiple blood vessels m akin g th em less distin ct on im agin g. Th ere are a h ost of ch aracteristics th at can be used to distin guish ben ign from path ological cervical lym ph n odes.8 Th e follow in g are som e ch aracteristics of ben ign cervical lym ph n odes: ● Sm all size ○ Less th an 1.5 cm in level I to II ○ Less th an 1 cm in Level III to V ● Oval sh ape ● Sm ooth w ell-defin ed borders ● Hom ogen eous hypoech oic m ass w ith a hyperech oic h ilum ● Blood flow lim ited to h ilum on Doppler evaluation Th e follow in g are som e ch aracteristics of path ological cervical lym ph n odes: ● Larger size ○ Greater th an 1.5 cm in level I to II ○ Greater th an 1 cm in level III to V ● Roun d sh ape ● Irregular borders ● Heterogen eous m ass w ith cen tral areas of an ech oic sign al ● Di use blood flow on Doppler evaluation ● Clusterin g of m ultiple n odes ● Microcalcification s (for papillar y thyroid can cer)

Fig. 32.8 Location of the left inferior parathyroid adenoma. (a) Axial image showing a small left adenom a inferior to the thyroid lobe in a paratracheal location. (b) Longitudinal im age showing a sm all left adenom a inferior and in the sam e plane as the thyroid lobe.

Wh ile perform in g n eck US for preoperative parathyroid localization , in ciden tal thyroid n odularit y w ill frequen tly be detected. Alth ough th e m ajorit y of th ese n odules w ill be ben ign , thyroid can cers w ill be en coun tered. Preoperative iden tification allow s for US-guided biopsy to be perform ed prior to parathyroid explorat ion . Th is h as been sh ow n to reduce un n ecessary thyroid surgery at th e tim e of parathyroidectom y as w ell as allow appropriate thyroidectom y an d n ode dissection to be perform ed in cases of con com itan t thyroid m align an cy.7 On rare occasion s, m edullar y thyroid can cer w ill occur sim ultan eously w ith parathyroid disease. In th is scen ario, it is im portan t to screen for h ereditar y syn drom es such as m ultiple en docrin e n eoplasia t ype 2A (MEN2A) an d com plete bioch em ical screen in g to rule out ph eoch rom ocytom a prior to parathyroidectom y, thyroidectom y, an d n eck dissect ion .

32.5 Lym ph Node Ult rasound For pat ien ts w ith n odular disease of th e thyroid, th e n eck US w ill often in clude an evaluation of th e cervical lym ph n odes. Lym ph n ode evaluation by US is tech n ically m ore ch allengin g th an evaluation of th e thyroid glan d. Head an d n eck surgeon s h ave an advan tage over th eir en docrin e colleagues w ith th eir in tim ate kn ow ledge of lym ph atic drain age pattern s an d com plex an atom y of th e n eck. Un like th e thyroid glan d, w h ich h as a

It sh ould be n oted th at n on e of th ese ch aracteristics are absolute sign s of m align an cy, an d fin din gs such as larger size or absen ce of a hyperech oic h ilum can occur w ith ben ign lym ph nodes.9 A system atic approach is used for lym ph n ode assessm en t so th at m etastatic disease is n ot overlooked an d left un addressed durin g in itial surgery for thyroid can cer. Evaluation of level VI is best com pleted as a part of th e thyroid glan d evaluation . Cen tral com partm en t lym ph n odes involved w ith thyroid can cer t ypically are iden tified posterior or in ferior to th e thyroid glan d. The evaluation of th e cen tral com partm en t sh ould be to a depth th at th e hyperechoic sign al of th e vertebral bodies is seen . It sh ould also exten d laterally to evaluate th e retrocarotid region an d in feriorly to th e in n om in ate ar ter y to assess for superior m ediastin al m etastases. Lym ph n odes posterior to th e com m on carotid arter y likely represen t m etastasis along th e in ferior thyroid arter y. A com preh en sive lateral n eck evaluation sh ould also be com pleted. Th e largest n orm al lateral n odes usually appear on th e posterior aspect of th e subm an dibular glan d (level I) an d are rarely involved in thyroid can cer. In con trast , lym ph n odes iden tified in levels II, III, IV, an d VI sh ould be carefully evaluated for features of m align an cy. Lym ph n odes in den ting th e jugular vein are also h igh ly suspicious. Level V is im aged last an d is th e m ost di cult to exam in e but rarely dem on strates n odal m etastasis w ith out involvem en t in levels II, III, or IV. As a part of sur veillan ce for thyroid can cer, n eck US is often perform ed ever y 6 to 12 m on th s for th e first 3 years after in itial treatm en t for thyroid can cer, especially if th ere is bioch em ical eviden ce of disease.5 Lym ph n ode evaluation durin g sur veillan ce is critical because th e m ajorit y of recurren ces involve th e cervical lym ph n odes. Especially for patien ts w ith a detectable

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Fig. 32.9 Ultrasonographic appearance of a branchial cleft cyst. The mass is a sim ple cystic lesion with posterior enhancem ent. There is a sm all benign lymph node (N) with a well visualized hilum adjacent to the cyst on left.

thyroglobulin (Tg), n eck US can often iden tify subcen tim eter n odal m etastases. How ever, in low -risk cases w ith an in itial un detectable TSH-stim ulated Tg, n egative an tith yroglobulin an tibodies, an d n egative n eck ultrasoun d, basal Tg an d less frequen t US surveillan ce m ay be su cien t.

32.6 Ult rasound for Nonendocrine Neck Pat hology Wh en perform in g o ce-based US to evaluate thyroid an d parathyroid disease, on e sh ould con sider th at coin ciden tal secon dar y path ology m ay be en coun tered. Conversely, prim ary son ograph ic evaluation of n eck m asses an d salivar y glan d disease can often be ver y h elpful in diagnosis. Th ere are a w ide variet y of ben ign an d m align an t diseases th at m ay be detected durin g n eck US. Com m on ly en coun tered ben ign en tit ies in clude subcutan eous lesion s, such as epiderm al an d sebaceous cysts as w ell as adn exal t um ors. More deeply located ben ign lesion s in clude lipom as, thyroglossal duct cysts, bran ch ial cleft cysts, n eural lesion s, an d salivar y glan d tum ors. Based on sh ape an d location , m ost of th ese en tities are easily distin guish ed from on e an oth er. A bran chial cleft cyst can be on e of th e m ost con fusin g lesion s of th e n eck, an d frequen tly m etastatic cervical aden opathy is m isdiagn osed as a bran ch ial cleft cyst ( Fig. 32.9). Bran ch ial cleft cysts are distin guish ed as solitar y cystic struct ures w ith out irregularly th icken ed areas alon g th e cyst w all. Th e m ass can h ave variable in tern al echogen icity, but posterior en h an cem en t is com m on ly seen .10 Most im portan tly, it sh ould be recogn ized th at n ot all path ological aden opathy is related to thyroid can cer. Alth ough th e presence of m icrocalcification s is alm ost exclusively associated w ith papillary thyroid can cer, th ere are sign ifican t sim ilarit ies in th e son ograph ic appearan ce of m etastatic aden opathy from a m ultit ude of prim ary sites.11 Conversely, path ological lym ph aden opathy associated w ith lym ph om a usually h as a distin ctly di eren t appearan ce relative to m etastatic disease. Th e lym ph n odes ten d to be hypoech oic w ith in tran odal reticulation s, but rarely w ill cen tral n ecrosis be seen ( Fig. 32.10).11

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Fig. 32.10 Pathological lym phadenopathy. (a) Papillary thyroid carcinom a with characteristic m icrocalcifications. (b) Squamous cell carcinoma has a similar appearance but does not contain m icrocalcifications. A com bination of isoechoic solid areas as well as necrotic hypoechoic areas are seen. (c) Lym phom a is m uch less likely to have cystic degeneration; and is usually a solid hom ogeneous enlarged node with a round shape, intranodal reticulations, and loss of the fat t y hilum.

32.7 Ult rasound-Guided Procedures Th e m ost com m on ly perform ed o ce-based US procedure is fin e-n eedle aspiration biopsy (FNAB) of a thyroid n odule. Alth ough palpation -guided FNAB of thyroid n odules is possible in som e situation s, th e use of US guidan ce w ill reduce th e n on diagn ostic biopsy rate by en surin g th at th e solid com pon en t of

O ce-Based Ultrasonography

Fig. 32.11 Long-axis technique for fine-needle aspiration biopsy. (a) The needle is being inserted parallel to the long axis of the transducer. (b) The appearance of the needle (arrowheads) during biopsy of a m ass.

Fig. 32.12 Short-axis technique for fine-needle aspiration biopsy. (a) The needle is being inserted perpendicular to the long axis of the transducer. (b) The appearance of the needle during biopsy of a mass (arrow delineates needle tip).

a m ass is sam pled durin g th e procedure.12 Sim ilarly, usin g US guidan ce for FNAB of a n eck m ass suspected of m etastatic disease w ill im prove th e success of th e procedure given th at th ese m asses w ill frequen tly h ave cen tral n ecrosis. In con trast, USguided biopsy for parathyroid disease is rarely n ecessar y (un less th ere is suspicion of an in trathyroidal parathyroid aden om a), does n ot di eren tiate an aden om a from a carcin om a, an d m ay result in fibrosis, w h ich can m ake subsequen t excision m ore ch allengin g. Oth er US-guided procedures th at m ay be n ecessary in a thyroid an d parathyroid practice in clude drain age of fluid collection s follow in g n eck surgery as w ell as eth an ol ablation of recurren t n eck disease. A n um ber of supplies are n ecessary to perform o ce-based US-guided FNAB. Most biopsies are com pleted w ith eith er a 22gauge or 25-gauge 1.5 in n eedle. Tw o to th ree separate n eedle sam ples are obtain ed from each m ass being biopsied. As th e biopsy is bein g perform ed, aspirat ion w ith approxim ately 1 m L of n egative pressure can be applied via a syringe. It is im portan t to apply n egative pressure on ly after th e n eedle t ip is confirm ed to be in th e m ass. Sim ilarly, th e n egative pressure m ust be released prior to rem ovin g th e n eedle from th e m ass. Biopsies can also be com pleted usin g th e capillar y sam pling tech n ique (n o n egative pressure). Th e advan tages to th is approach in clude less pain an d a low er likelih ood of a bloody aspirate. In som e in stan ces, both approach es are used w h en sam plin g a m ass. After each aspirate h as been obtain ed, it m ust be im m ediately placed on th e slide an d sm eared so th at th e specim en does n ot clot in th e n eedle. In addition to th e slide preparation , part of th e aspirate sh ould be placed in a liquid preparatory m edium for cell block. In cases w h ere thyroid cytom olecular or gen e expression classifier testin g is considered, a por tion of th e specim en sh ould be placed in th e appropriate RNAse. If lym ph om a is suspected, on e w ill n eed to subm it th e specim en in

a Rosw ell Park Mem orial In stitute (RPMI) m edium for flow cytom etr y. Th ere are t w o di eren t approach es to perform in g US-guided FNAB, th e lon g-axis tech n ique an d th e sh ort-axis tech n ique. In th e lon g-axis tech n ique, th e n eedle is in serted parallel to th e lon g axis of th e tran sducer. With th is approach, th e en tire course of th e n eedle is seen an d th e t ip clearly visualized as it en ters th e m ass ( Fig. 32.11). In th e sh ort-axis tech n ique, th e n eedle is in serted perpen dicular to th e long axis of th e tran sducer. For th e sh ort-axis tech n ique, on ly th e tip of th e n eedle is seen w ith in th e m ass as th e plan e of th e n eedle in tersects th e plan e of th e tran sdu cer ( Fig. 32.12). Keepin g th e bevel of th e n eedle tow ard th e US tran sducer w ill in crease th e echogen icity of th e n eedle, w h ich can be especially h elpful w h en usin g eith er tech n ique to en sure th e tip is in th e target. Th e approach to n eedle biopsy of thyroid n odules an d lym ph n odes are sim ilar an d th e cytological preparation is th e m ost crit ical aspect of th e procedure. Lym ph n ode biopsies can poten tially be m ore ch allen ging for a m ultit ude of reason s. First , th e lym ph n odes ten d to be m ore in tim ately associated w ith n eck vasculature com pared to thyroid n odules, m akin g direct access to th e m ass m ore di cult. In addition , th e lym ph n odes ten d to be sligh tly sm aller an d m ove m ore readily in th e n eck com pared to a thyroid n odule as on e attem pts to pass th e n eedle in to th e m ass. In som e in stan ces, addition al testin g beyon d cytology m ay be w arran ted w h en perform in g a biopsy on a lym ph n ode suspected to be recurren t w ell-di eren t iated thyroid can cer. Thyroglobulin w ash in gs can be in cluded as part of th e lym ph n ode biopsy an d if th ere is a h igh level of Tg detected in th e w ash in g, m etastatic disease is con firm ed.13 Sim ultan eous serum Tg testin g is recom m en ded to avoid a false-positive result related to blood con tam in at ion of th e lym ph n ode biopsy.

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Special Topics Table 32.2 Exam ple of annual reimbursem ent for o ce-based ultrasound Procedure

Medicare reim bursem ent

Annual procedure volum e (46 weeks)

Revenue

Low-volum e ultrasound (US) practice Assum ing on average t wo diagnostic ultrasound (US) and one US-guided biopsy per week for 46 weeks 76536

$116.70

92

$10,736.40

76942/10022

$61.21 + $142.83= $204.04

46

$9,385.84

=$20,122.24 High-volum e US practice Assum ing on average five diagnostic US and t wo US-guided biopsies per week for 46 weeks 76536

$116.70

230

$26,841.00

76942/10022

$61.21 + $142.83= $204.04

92

$18,771.68

=$45,612.68

Th e in dication s for parathyroid biopsy are few, but in clude con firm at ion of a suspected in t rathyroidal aden om a an d confirm ation of recurren t disease localization in patien ts th at h ave undergon e m ultiple previous operat ion s. Alth ough Tg w ash in gs are on ly occasion ally n ecessar y w h en perform in g lym ph n ode biopsies, on e sh ould alw ays perform w ash in gs for parathyroid h orm on e (PTH) durin g biopsy of a suspected parathyroid m ass.14 With suspected parathyroid disease, cytology sh ould also be perform ed, but th ere are sign ifican t lim itation s in bein g able to distin guish thyroid epith elium from parathyroid epith elium . W hen perform in g a biopsy for Tg or PTH w ash in gs, th e n eedle aspirate sh ould be flush ed w ith 1 m L of salin e. Th ese procedures sh ould be discussed w ith th e path ology departm en t before sen din g th ese specim en s for processing because th is is t ypically n ot w ith in th eir stan dard biopsy protocol.

32.8 Financial Considerat ions in O ce-Based Ult rasound A sign ifican t fin an cial investm en t is required to in corporate o ce-based US in to a clinical pract ice. A variety of US un its are available for perform in g o ce-based US. Th ese can be m ore tradition al con sole un its, but sm aller, h igh -qualit y laptop version s are also available. If on e is con siderin g sh arin g a un it w ith oth er m edical specialties, th e n um ber of tran sducers required to m eet th e clin ical n eeds is in creased. Good-qualit y un its can ran ge from $25,000 to as m uch as $100,000 depen din g on th e n um ber of features an d t ran sducers th at are in cluded. If on e plan s to lim it th e use to th e h ead an d n eck region , a sin gle h igh -frequen cy lin ear-array t ran sducer can m eet th e vast m ajorit y of clin ical scen arios. Som e w ill ch oose to purch ase a second sm aller lin ear t ran sducer th at m ay be used for US-guided biopsy procedures. Th ere are th ree Curren t Procedural Term in ology (CPT) codes th at are used for o ce-based US. Th e CPT code for diagnost ic n eck US is 76536. Wh en US-guided FNA is perform ed, t w o sep arate CPT codes sh ould be used: 76942 an d 10022. Th e first represen ts th e use of US for n eedle placem en t an d th e secon d for perform in g th e FNA w ith US guidan ce. Th is com bin at ion of codes is repeated for each n odule, n ode, or m ass biopsied, but

268

n ot for each n eedle pass in to th e sam e lesion . Th e follow in g is an exam ple of correct coding for a clin ic en coun ter th at in corporates o ce-based US. A pat ien t is seen in th e clin ic for evaluation of palpable thyroid n odule an d a diagnost ic US is perform ed con firm in g bilateral dom in an t n odules. In addition , US-guided FNA is perform ed of a n odule in each lobe w ith four n eedle passes th rough each . For th is en coun ter in addition al to th e Evaluation an d Man agem en t code, on e w ould bill 76536 for th e diagn ostic US as w ell as 76942/10022 × 2 for bilateral USguided FNAs. Th e 2015 Medicare physician reim bursem en t for each of th ese CPTs is as follow s: 76536—$116.70, 76942—$61.21, an d 10022—$142.83.15 As an estim ate of th e procedure volum e required to cover the cost of an o ce-based US m ach in e, 100 diagn ostic US CPT procedure codes billed an n ually w ould cover a $30,000 m ach in e in about 3 years. If on e also perform s USguided biopsy as a part of th e clin ical pract ice, on e can easily gen erate reven ue to cover th e investm en t for an o ce US m ach in e ( Table 32.2).

32.9 Com pet ency in O ce-Based Ult rasound Over th e last decade, th ere h as been a rapid in crease in th e n um ber of thyroid an d parathyroid surgeon s an d en docrin ologists th at perform o ce-based US as a part of th eir pract ice. Th ese physician s w h o in itially em braced th e tech n ology h ad an obligation to en sure th eir com peten cy to perform an adequate US exam of th e h ead an d n eck region . Th is process w as n ot stan dardized but t ypically involved (1) com pletin g a US course th at in cluded h an ds-on train in g, (2) w orkin g w ith a m en tor, poten tially n ot of th e sam e specialt y, to prom ote addition al skills developm en t , an d (3) perform in g US exam s on patien ts w ith out billin g for th e procedure an d th en sen din g th e patien t to a radiology departm en t to h ave a con firm atory US to en sure accuracy of th e exam . Th is process could take anyw h ere from 6 to 12 m on th s depen din g on th e volum e of exam s perform ed. On ce th is process h ad been com pleted, th e physician w ould in depen den tly perform an d bill for h ead an d n eck US exam s. In addition , physician s w ould n eed to w ork w ith th e h ospital to

O ce-Based Ultrasonography obtain privileges to perform US as a part of th eir practice, if h ospital based. Curren tly, th ere are en ough thyroid an d parathyroid surgeon s an d en docrin ologists in m ost academ ic cen ters perform in g o ce-based US to give residen ts an d fellow s a robust US experien ce as a part of th eir train in g. Th is experien ce defin itely facilitates th e process of developin g com peten cy w ith h ead an d n eck US. How ever, th e surgical residen t an d fellow experien ce w ith o ce-based US is n ot recorded in a stan dardized fash ion , as are surgical cases. Train ees are en couraged to in depen den tly record th eir experien ce w ith h ead an d n eck US so th ey h ave support in g docum en tation as th ey seek clin ical privileges in th e fut ure. A lim ited n um ber of option s exists for US courses w ith h an ds-on train in g. Th e Am erican College of Surgeon s o ers a thyroid an d parathyroid h an ds-on course as a part of th e an n ual clin ical congress. Addition ally, an exported course w ith expan ded h ead an d n eck con ten t is h eld an n ually at th e Am erican Academ y of Otolaryn gology–Head an d Neck Surgery m eetin g. Fin ally, exported US courses are h eld as a com pon en t of m ultiple academ ic in stit ution s’ CME program s th rough out th e year in th e Un ited States. Th e Am erican Association of Clin ical En docrin ologists (AACE) o ers an ultrasoun d course as a part of th eir m eetin gs, w h ich is also exported to th e Am erican Thyroid Association an n ual m eetin g. Com pletion of any of th ese ultrasoun d courses results in receivin g a cert ificate to recogn ize a physician’s part icipation in th e education al even t, but th ese courses do n ot en sure on e’s com peten cy in perform in g h ead an d n eck US. Th ere are curren tly t w o accreditat ion processes for thyroid an d parathyroid US. Both of th ese processes are th rough th e Am erican In stit ute of Ult rasoun d in Medicin e (AIUM). Th e first process is th e En docrin e Cert ification in Neck Ultrasoun d th at is associated w ith th e AACE.16 En docrin ologist s, otolar yngologists/h ead an d n eck surgeon s, en docrin e surgeon s, radiologists, an d cytopath ologists are eligible to participate in this accreditation process. A n ew secon d accreditation process w ill be available start in g in 2015 th rough th e AIUM.17 Th is is a broader process en com passing Head an d Neck Ultrasoun d. Otolaryn gologists/h ead an d n eck surgeon s, gen eral surgeon s, an d radiologists are eligible to participate. Both of th ese path w ays require passing a cert ificat ion exam in at ion , subm itt in g cases for cent ral review, on goin g con tin uin g education , an d recert ification after 3 years.

32.10 Conclusion O ce-based US h as gain ed sign ifican t popularit y for physician s th at care for patien ts w ith thyroid an d parathyroid diseases. Alth ough th ere are cost consideration s for in corporatin g th is tech n ology in to a clin ical practice, it is fin an cially feasible an d th ere are sign ifican t advan tages to both th e patien t an d th e physician . Th e tech n ical aspects of perform in g o ce-based US

are relat ively straigh tfor w ard, an d developin g a system atic approach to perform in g an d docum en tin g th e exam is critical for success. Overall, th ose th at decide to pursue o ce-based US w ill fin d it a valuable com pon en t of providin g patien t care.

References [1] Alzah ran i AS, Ceresin i G, Aldasouqi SA. Role of ultrason ography in th e di eren tial diagn osis of thyrotoxicosis: a n on invasive, cost-e ective, an d w idely available but un derutilized diagn ostic tool. En docr Pract 2012; 18(4); 567– 578 [2] An derson L, Middleton WD, Teefey SA, et al. Hash im oto thyroiditis: Part 1, son ograph ic an alysis of th e n odular form of Hash im oto thyroiditis. AJR Am J Roen tgen ol 2010; 195(1); 208–215 [3] Bastin S, Bollan d MJ, Croxson MS. Role of ultrasoun d in th e assessm en t of n odular thyroid disease. J Med Im agin g Radiat On col 2009; 53(2); 177–187 [4] Moon W J, Jun g SL, Lee JH, et al. Thyroid Study Group, Korean Society of Neuro- an d Head an d Neck Radiology. Ben ign an d m align an t thyroid n odules: US di eren tiation —m ulticen ter retrospective study. Radiology 2008; 247(3); 762–770 [5] Cooper DS, Doh erty GM, Haugen BR, et al. Am erican Thyroid Association (ATA) Guidelin es Taskforce on Thyroid Nodules an d Di eren tiated Thyroid Can cer. Revised Am erican Thyroid Association m an agem en t guidelin es for patien ts w ith thyroid n odules an d di eren tiated thyroid can cer. Thyroid 2009; 19(11); 1167–1214 [6] Harari A, Zarn egar R, Lee J, Kazam E, In abn et W B, III, Fah ey TJ, III. Com puted tom ograph y can guide focused exploration in select patien ts w ith prim ar y hyperparathyroidism an d n egative sestam ibi scan n in g. Surgery 2008; 144 (6); 970–976, discussion 976–979 [7] Milas M, Men sah A, Algh oul M, et al. Th e im pact of o ce n eck ultrason ography on reducing un n ecessar y thyroid surgery in patien ts un dergoin g parathyroidectom y. Th yroid 2005; 15(9); 1055–1059 [8] Dudea SM, Len gh el M, Botar-Jid C, Vasilescu D, Dum a M. Ultrason ography of superficial lym ph n odes: ben ign vs. m align an t. Med Ultrasoun d 2012; 14(4); 294–306 [9] Miah CF, Zam an JA, Sim on M, Davidov T, Trooskin SZ. Th e utilit y of lym ph n ode m apping son ogram an d thyroglobulin sur veillance in post thyroidectom y papillar y thyroid can cer patien ts. Surgery 2014; 156(6); 1491–1496, discussion 1496–1497 [10] Ah uja AT, Kin g AD, Metrew eli C. Second bran ch ial cleft cysts: variability of son ograph ic appearan ces in adult cases. AJNR Am J Neuroradiol 2000; 21(2); 315–319 [11] Ah uja AT, Yin g M, Ho SY, et al. Ultrasoun d of m align an t cervical lym ph n odes. Can cer Im agin g 2008; 8; 48–56 [12] Robitsch ek J, Straub M, W irt z E, Klem C, Sn iezek J. Diagn ostic e cacy of surgeon -perform ed ultrasoun d-guided fin e n eedle aspiration : a ran dom ized con trolled trial. Otolaryn gol Head Neck Surg 2010; 142(3); 306–309 [13] Moon JH, Kim YI, Lim JA, et al. Thyroglobulin in w ash out fluid from lym ph n ode fin e-n eedle aspiration biopsy in papillary thyroid can cer: large-scale validation of th e cuto value to determ in e m align an cy an d evaluation of discrepan t results. J Clin En docrin ol Metab 2013; 98(3); 1061–1068 [14] Abdelgh an i R, Noureldin e S, Abbas A, Moroz K, Kan dil E. Th e diagn ostic value of parathyroid h orm on e w ash out after fin e-n eedle aspiration of suspicious cervical lesion s in patien ts w ith hyperparathyroidism . Lar yn goscope 2013; 123(5); 1310–1313 [15] Am erican College of Radiology. w w w.acr.org/Advocacy/Econ om ics-Health Policy/Medicare-Paym en t-System s/MPFS/2015-Proposed-Rule [16] En docrin e Cert ification in Neck Ultrasoun d. w w w.aace.com /files/ecn u-can didateh an dbook.pdf [17] Am erican In stitute of Ultrasoun d in Medicin e. w w w.aium .org/accreditation / specialties/h eadNeck.aspx

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Special Topics

33 Out pat ient Endocrine Surgery Michael C. Singer and David J. Terris

33.1 Int roduct ion Over th e past 15 years th e practice of thyroid an d parathyroid surgery h as ch anged sign ifican tly. Tech n ological an d surgical in n ovation s h ave fostered advan ces such as th e m in im ally invasive thyroidectom y an d focused parathyroidectom y. Th e postoperative care of th ese pat ien ts h as also been t ran sform ed . Tradition ally, all patien ts un dergoing thyroidectom y or parathyroidectom y w ere adm itted after surgery. Parathyroid surgery is n ow routin ely perform ed on an outpatien t basis. How ever, despite th e n um erous ben efits provided by am bulatory thyroid surgery it is on ly routin ely perform ed at select in stit ut ion s in th e Un ited States. Th is ch apter review s th e ben efits of am bulator y en docrin e surgery, discusses th e optim al approach to its im plem en tation , an d focuses on specific tech n iques to facilitate its perform an ce.

33.2 Am bulat ory Surgery Outpatien t or am bulator y surgery is defin ed as any surgery th at does n ot require postoperative overn igh t obser vation or adm ission . A 23-h our observation period, w h ich h as becom e popular in th e Un ited States, is n ot con sidered am bulator y care. Rath er, am bulator y patien ts are t ypically obser ved for 2 to 4 h ours in th e postan esth esia care un it or sam e-day surgery cen ter an d th en are disch arged h om e. In th e early 1980s, due to in creasin g concern s over expan ding h ealth care costs, several fin an cial in cen tives w ere im plem en ted th rough Medicare, w h ich prom oted th e perform an ce of outpatien t surgery. Th ese en ticem en ts for in stit ut ion s an d physician s, w h ich w ere subsequen tly adopted by private in surers, led to a dram atic sh ift tow ard an am bulator y approach for m any procedures th at previously w ere perform ed on an in patien t basis. In 1983 on ly 380,000 outpatien t procedures w ere perform ed in th e Un ited States. By 1996 th is h ad in creased to 31.5 m illion , an d by 2006 up to 53.3 m illion am bulator y procedures w ere com pleted. Alth ough in itially adopted due to fin an cial con cern s, sam eday disch arge follow in g surgery is n ow w idely view ed by patien ts as an advan tage, allow in g th em to avoid th e poten tial risks of in patien t care an d to recuperate in th e com fort of th eir h om e.

33.3 Thyroid and Parat hyroid Surgery 33.3.1 Parat hyroid Surgery Historically, all patien ts un dergoing parathyroidectom y w ere hospitalized after surgery. How ever, m irroring overall surgical tren ds, m any of th ese patients in th e United States are n ow m anaged on an am bulatory basis.1 This approach h as been show n to be safe in patients w ith prim ar y hyperparathyroidism .2,3 This is in contrast to patien ts w ith renal hyperparathyroidism , w ho can experience severe hypocalcem ia (as w ell as

270

other elect rolyte im balan ces) after surgery and consequently are m ost appropriately m an aged on an inpatient basis.

33.3.2 Thyroid Surgery A recen t Am erican Thyroid Association statem en t on outpatien t thyroidectom y discusses th is pract ice in depth an d docum en ts m any of th e con cern s surroun din g it.4 Un like am bulator y parathyroidectom y, th e practice of outpatien t thyroid surgery is m uch m ore con troversial. Th erefore, the balan ce of th is ch apter focuses on th is practice. Th e first report of outpatien t thyroidectom y w as publish ed in 1986 by Steckler.5 Lo Gerfo an d colleagues furth er explored its safety an d prom oted its adoption in th e early 1990s.6 Th ese in itial series exam in ing th e possibility of outp atien t m anagem en t w ere lim ited to pat ien ts un dergoing h em i- an d subtotal thyroidectom ies. Alth ough am bulator y h em ithyroidectom y is in creasin gly practiced in th e Un ited States, an extensive sh ift tow ard routin e sam e-day disch arge, part icularly after total or com pletion surgery, h as n ot occurred. Th is is despite a n um ber of large series dem on st ratin g both its feasibilit y an d its safety.7,8,9,10

33.4 Benefit s of Am bulat ory Surgery Studies h ave con sisten tly sh ow n th at perform in g thyroid surgery on an am bulatory basis provides cost savin gs. Th e precise reduct ion in cost per patien t is debatable; h ow ever, several studies h ave in dicated th at an am bulator y approach m ay result in savin gs of up to $2,500 per patien t.11,12 Alth ough in itially spurred by fin an cial con sideration s, am bulator y thyroid surgery provides a h ost of poten tial ben efits to patien ts. As a result m any patien ts w ill opt for th is approach if o ered. Alth ough th e presum ption is th at in pat ient care provides a greater degree of safety th an an am bulator y approach , h ospitalization is n ot w ith out its risks. In patien t care raises th e possibilit y of a h ost of n osocom ial in fect ion s th at oth erw ise are un likely. An addition al con cern w ith in patien t care is th e occurren ce of m edical errors. Alth ough th e care of a patien t after thyroid surgery is relatively straigh tforw ard th e poten t ial exists for sign ifican t m edical errors an d injuries to occur. Both of th ese risks are reduced by am bulator y care. An oth er sign ifican t advan tage of am bulator y surgery is th e abilit y for patien ts to recover in a m ore com fortable sett in g. Many patien ts appreciate th e opportun it y to receive care from fam ily an d frien ds at h om e rath er th an in th e n oisy, disruptive atm osph ere of a h ospital.

33.5 General Principles of Am bulat ory Surgery Above all else, am bulator y en docrin e surgery m ust equal or exceed th e safety profile of th e in patien t approach. Alth ough

Out patient Endocrine Surgery Table 33.1 Potential contraindications to outpatient thyroidectom y Clinical

Social

Procedural

Uncom pensated cardiac or respiratory disease

Excessive distance from skilled facilit y

Massive goiter

Dialysis for renal failure

Living alone with no person to accompany

Extensive substernal goiter

Anticoagulant or antiplatelet therapy

Lack of transportation

Locally advanced cancer

Seizure disorder

Patient preference

Challenging hemostasis

Anxiety disorder

Com m unication barriers

Difficult thyroidectomy with Hashim oto’s thyroiditis or Graves’ disease

Obstructive sleep apnea Hearing loss Visual im pairment Mental im pairm ent Pregnancy Source: Terris et al.13

specific tech n iques can be em ployed to m in im ize th e risks of certain com plication s, several gen eral prin ciples sh ould guide th e im plem en tat ion of an am bulator y thyroid program .

33.5.1 Pat ient Select ion With am bulator y en docrin e surgery, as w ith any surgery, careful patien t select ion is critical to ach ievin g successful outcom es. Th e m ost fun dam en tal con sideration s relate to a pat ien t’s overall h ealth an d abilit y to tolerate an esth esia. Major m edical com orbidities m ay preclude th e option of outpatien t surgery. Th e follow in g are som e criteria for th e eligibilit y for outpatien t thyroidectom y 13 : ● No m ajor com orbidities or ASA IV (Am erican Societ y of An esth esiologists Physical Status Classification System , ASA IV: “A patien t w ith severe system ic disease th at is a constan t th reat to life”) ● Provision an d un derstan din g of preoperative education ● Team approach to education an d clin ical care ● Prim ar y caregiver w illin g an d available ● Social settin g con ducive to postoperat ive m an agem en t ● Proxim it y to skilled facility Im portan tly, advan ced age sh ould, n ot on its ow n , be con sidered a cont rain dication for am bulator y care. In stead, th e in dividual patien t’s overall m edical status sh ould guide th e patien t’s eligibilit y. Beyon d m edical con cern s th e t ype of surgery sch eduled can be used to h elp guide decision s about th e suitabilit y of sam eday disch arge. Som e surgeon s w ill n ot o er am bulator y care to patien ts w h o th ey feel are at greater risk of postoperative com plication s, such as th ose w ith substern al goiters or Graves’ disease or th ose requirin g cen tral n eck dissect ion s. How ever, w ith increasin g experien ce w ith am bulator y thyroidectom y a surgeon m ay becom e less restrictive w ith th ese lim itation s. For exam ple, in th e auth ors’ practices, on ly th e perform an ce of a lateral n eck dissection autom atically m an dates adm ission after surgery.

Several social factors sh ould also be con sidered w h en assessin g a patien t for possible outpatien t thyroid surgery. Th ese in clude th e abilit y of th e patien t an d th e care provider to un derstan d an d follow th e postoperative in struct ion s. Logist ically, pat ien ts sh ould h ave relat ively prom pt access to a m edical facility. A fin al elem en t of pat ien t select ion is a pat ien t’s m otivation to proceed w ith outpatien t care. Patien ts voicin g con cern s about th e prospect of bein g disch arged sh ould be con sidered for in patien t m an agem en t ( Table 33.1).13

33.5.2 Est ablished Program Optim izing outcom es w ith am bulator y thyroid surgery is m ost readily ach ieved in th e context of an establish ed program . Th is allow s a team approach to patien t m an agem en t, in cluding th e surgeon , an esth esiologist, an d n ursin g sta . Postan esth esia care un it n urses play a particularly im portan t role in an am bulator y m odel as th ey can poten tially iden tify early sign s of evolving issues prior to a patien t’s disch arge. Addition ally, th ey h elp determ in e th at a patien t’s pain an d n ausea are adequately con trolled for safe release. As part of an am bulator y program , patien ts sh ould be provided w ith th orough an d easily un derstood w ritten (as w ell as oral) in struct ion s. Lastly, providin g reliable con tact in form ation to kn ow ledgeable sta assures th at patien ts can easily h ave th eir quest ion s an sw ered an d com plication s quickly triaged.

33.5.3 Pat ient Educat ion A system atic approach to am bulator y thyroid surger y dovetails w ith th e education al com pon en t n eeded for th ese patien ts. W ith all m em bers of th e care team providin g a con sisten t m essage patien ts are m ore likely to absorb th e in form ation relayed to th em . From th e t im e of th e in itial consultation th e im plication s of an am bulator y approach sh ould be discussed w ith th e patien t an d caregivers. Im portan tly, th ey m ust un derstan d th e risks associated w ith outpatien t thyroid surgery an d be able to iden tify th e sign s an d sym ptom s of poten tial com plication s.

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Special Topics Addition ally, th e in struct ion s for care of th e pat ien t follow in g disch arge sh ould be review ed un til clearly un derstood.

33.6 Specific Risks In addition to th e gen eral risks of any am bulator y surgery, outpatien t thyroid surgery h as several specific com plication s th at can arise. Con cern s about th e airw ay, th e developm en t of an expan ding h em atom a, an d th e possibilit y of hypocalcem ia all are cited by th ose resistan t to am bulator y thyroidectom y. Alth ough th ese risks do exist, specific tech n iques can be used to reduce th eir in ciden ce an d m itigate th e im pact if th ey do occur.

33.6.1 Airw ay Tem porary or perm an en t injur y of th e recurren t lar yn geal n er ve (RLN) can occur in any thyroid surgery. Given th e possible associated risks in regard to airw ay com prom ise it is ideal to be aw are of th e fun ct ion of th e lar yn x prior to disch arge. Bilateral vocal cord paralysis is th e m ost feared airw ay com plication after thyroidectom y because it m ay cause severe distress, stridor, an d obst ruction . Alth ough th e risk of bilateral vocal cord paralysis can be all but elim in ated w ith th e use of lar yngeal n er ve m on itorin g, it does still occur. Th is com plication is usually recognized soon after extubation due to th e severit y of th e sym ptom s. Th ese patien ts are n ot eligible for sam e-day disch arge because th ey n eed close obser vation an d som etim es require rein tubation . Alth ough less dram atic, a un ilateral vocal cord paralysis can cause m ild airw ay distress, di cult y sw allow in g, an d pat ien t discom fort. Alth ough n ot an absolute contrain dication to sam eday disch arge, patien ts w ith a un ilateral vocal cord paralysis sh ould be properly assessed prior to disch arge. Im portan tly, th e RLN m ay n ot exh ibit im m ediate postoperative fun ct ion despite n orm al an atom ical in tegrit y at th e en d of a surgery. It is th erefore best to test th e fun ct ion of th e n erve an d n ot just rely on visual judgm en t. Th ere are several approach es to assessing th e fun ction of th e RLN after dissection . On e approach is lar yn geal n er ve m on itorin g. Th is is m ost com m on ly perform ed w ith th e use of an electrom yograph ic en dotracheal tube attach ed to a n er ve m on itor. Loss of sign al after dissection can reliably be used to determ in e th e postoperative fun ction of th e vocal cord. Th e lar yngeal n er ve t w itch respon se is an altern ative test of laryn geal fun ct ion th at can be used an d does n ot require a n er ve m on itor or specialized equipm en t. A secon d approach to assess n er ve fun ct ion , w h ich can be used in addition to or in place of n er ve m on itorin g, is postoperative lar yngoscopy perform ed in th e recover y room . Th is provides th e m ost accurate evaluation of vocal cord fu n ct ion . Of n ote, after rem oval of large goiters con cern h as existed over possible airw ay obstruct ion secon dar y to trach eom alacia. Alth ough large goiters can cause com pression of th e trach ea w h ile in sit u it does n ot appear th at th is ever leads to a flaccid trach eal segm en t after rem oval. Wh en th e glan d is rem oved durin g surgery, a com pressed trach ea often im m ediately regain s its n orm al struct ure. Stridor present after thyroidectom y probably is n ot due to m alacia but rath er to vocal cord paralysis. Rem oval of large goiters is th erefore n ot a cont rain dication to am bulator y thyroid surgery.

272

33.6.2 Hem at om a Th e risk of h em atom a form ation is on e of th e prim ar y objection s to am bulator y thyroid surgery. Alth ough sm all fluid collect ion s occur frequen tly, h em atom as of clin ical sign ifican ce occur in < 1%of pat ien ts un dergoing thyroidectom y. It is on ly th e poten t ial to cause airw ay com prom ise th at m akes h em atom as dan gerous. Th e developm en t of a lim ited h em atom a is of little clin ical con cern . Airw ay obstruct ion does n ot result from direct com pression of th e cartilagin ous structures of th e lar yn x an d t rach ea. Rath er, a progressively expan din g h em atom a locked w ith in th e tigh t con fin es of th e central n eck com part m en t exerts pressure on th e surroun din g soft tissue. Th is pressure even t ually can exceed th at of th e lym ph atic an d ven ous drain age of th e lar yn x. Th is obstru ct ion results in w ater y edem a an d sw ellin g of th e supraglottis an d glottis, even tually causin g airw ay com prom ise. Postoperative adm ission th eoretically allow s th e m ajorit y of th ese cases (m ost h em atom as occur w ith in 24 h ours of surgery) to be recogn ized an d m an aged prom ptly. Beyon d in patien t observation , surgeon s h ave tried to preven t sign ifican t h em atom as by usin g drain s (w h eth er active or passive). Many surgeon s w ould also place a pressure dressin g on or aroun d th e w oun d in an e ort to lim it th e expan sion of any collect ion . How ever, n eith er drain placem en t n or dressings h ave been sh ow n to reduce th e risk of h em atom a form ation .14,15,16 Given th is, th e use of drain s an d specialized dressings is un n ecessary. Alth ough select patien ts, such as th ose w ith a clottin g disorder or en d-stage ren al disease, m ay ben efit from drain placem en t, th e vast m ajorit y of pat ien ts do n ot, w h ich greatly sim plifies th eir out pat ien t m an agem en t. For surgeon s reluctan t to forgo th e use of drain s, am bulatory surgery is still an option because patien ts can be disch arged w ith a drain an d follow -up as an outpatien t for rem oval. Alth ough th e auth ors routin ely use advan ced en ergy devices for vessel sealing an d place a h em ostatic agen t in th e w oun d at th e en d of surgery, th ere are n o data to sh ow th at th ese reduce th e rate of h em atom a form ation . A “deep extubation ” (extubation w h ile th e pat ien t is still deeply an esth etized) m in im izes cough in g an d buckin g after surgery. Th is m ay reduce th e risk of bleedin g by preven tin g large in creases in blood pressure. Most im portan t for preven tin g clinically sign ifican t h em atom as, h ow ever, is careful h em ostasis durin g surgery an d th orough assessm en t of th e field prior to closure to assure it is dr y. As already above, th e developm en t of a h em atom a is con cern in g on ly if it causes airw ay obst ruction . Th erefore, th e focus sh ould be on m itigatin g th e im pact of th e rare, clin ically sign ifican t h em atom a (rath er th an sm all an d in dolen t fluid collection s). Un derstan din g th e m ech an ism of airw ay obstruct ion h as led to a w idely adopted tech n ique ch ange involving reapproxim ation of th e strap m uscles. In order to cause lym ph atic an d ven ous outflow obstruct ion a h em atom a m ust apply pressure in th e deeper areas of th e n eck. A m ore superficial h em atom a m ay cause subcutan eous sw ellin g an d ecchym osis but is less likely to cause airw ay obstruct ion . Strap m uscles are reapproxim ated in th e m idlin e after central n eck com partm en t surgery to preven t th e “cobra deform it y,” as w ell as to avoid th e skin from possibly scarrin g dow n directly on to th e trach ea after surgery. Both of th ese deform it ies are ch allengin g to rem edy if th ey occur. Surgeon s h ave reapproxim ated th e strap m uscles in

Out patient Endocrine Surgery

Fig. 33.1 (a,b) Single-point closure, the safest technique for reapproxim ation of the strap m uscles, is demonstrated. (From Terris. 16 Used with perm ission.)

th e m idlin e usin g m ultip le sim ple stitch es or a run n ing stitch from in ferior to superior. How ever, if th at approach is used an d a h em atom a occurs it m ay be locked in th e deep spaces of th e n eck. Con sequen tly, som e surgeon s advocate sin gle-poin t fixation of th e strap m uscles in th e m idlin e w ith on e figure-of-eigh t stitch ( Fig. 33.1) 16 Th is approach accom plish es th e goals of m uscle reapproxim ation but it also allow s egress of blood to th e m ore superficial aspects of th e w oun d. Con sequen tly, if patien ts do develop a h em atom a th ey presen t w ith a subcutan eous sw ellin g in stead of dysphagia an d dyspn ea ( Fig. 33.2). Alth ough th ese tech n iques can h elp reduce th e in ciden ce of clin ically relevan t h em atom as th ey do still som etim es occur. As a result, education of pat ien ts an d th eir caregivers regarding th e sign s an d sym ptom s of h em atom as is a crit ical com pon en t of safe am bulator y thyroid surgery.

33.6.3 Hypocalcem ia Despite m eticulous m an agem en t of th e parathyroid glan ds durin g surgery a sign ifican t percen tage of patien ts (up to 25%) un dergoing total or com pletion thyroidectom y experien ce t ran sien t postoperative hypoparathyroidism an d consequen t hypocalcem ia. Tradition ally, on e of th e prim ar y purposes of adm ission after thyroidectom y w as m on itorin g for possible hypocalcem ia. Close observation , w ith both frequen t laborator y tests an d physical exam in ation s, w as t ypically m ain tain ed for 48 to 72 h ours after surger y (th e n adir for hypocalcem ia t ypically occurs durin g th is tim e period). If hypocalcem ia developed patien ts w ould th en be supplem en ted as n eeded. Alth ough relatively com m on , hypocalcem ia h as been sh ow n to be readily t reatable w ith oral supplem en tation . Furth erm ore, as hypocalcem ia w orsen s pat ien ts experien ce a predictable pattern of sym ptom s th at sign al th e n eed for th erapy (perioral an d fin gert ip paresth esias follow ed by m uscle cram ping). Th ese factors h ave allow ed t w o altern ative approach es to th e m an agem en t of hypocalcem ia to becom e popularized: routin e prophylact ic supplem en tation an d PTH-based select ive supplem en tation . Both option s allay con cern s over hypocalcem ia an d perm it patien ts to be disch arged after thyroidectom y. With un iversal supplem en tation all patien ts at risk of developin g hypocalcem ia are started on calcium supplem en tation after surgery.17 Di eren t regim en s h ave been described but th ey are all prem ised on th e fact th at th ose pat ien ts w h o do n ot n eed supplem entation are put at little addition al risk because th e excess calcium is excreted in th e urin e. Th is allow s th e patien ts w h o do require supplem en tation to be e ect ively treated w ith out risk to th e rem ain in g patien ts. Studies h ave

Fig. 33.2 Using single-point reapproximation of the strap m uscles allows any potential hematom a to collect in the subcutaneous space. This avoids the potential danger of developing a com pressive hematom a.

sh ow n th at, after surgery, patien ts can be started on 1,000 m g of calcium carbon ate th ree tim es daily. Few becom e sym ptom atic an d far few er still require postoperative adm ission for severe hypocalcem ia. On e concern expressed by som e surgeon s is th e possibilit y of hypercalcem ia w ith supplem en tation . Th is is on ly a risk in patien ts takin g calcitriol in addition to calcium . As a result, m ost surgeon s usin g routin e supplem en tation lim it th eir regim en s to calcium alon e. Th e altern ative approach used for calcium m an agem ent in th e con text of am bulator y thyroid surgery is selective calcium supplem en tation .17 In th ese patien ts, postoperative blood tests determ in e w h ich patien ts are m ost at risk of developin g hypocalcem ia. Som e surgeon s use th ese levels to dictate appropriaten ess for am bulator y care. How ever, m ost com m on ly th ese levels are em ployed to establish w h ich patien ts sh ould be started on supplem en tation (an d w ith w h at regim en ). A n um ber of groups h ave described usin g a PTH-based selective sup plem en tation approach .18,19 A PTH level draw n in th e recover y

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Special Topics room (m ost com m on ly 1 to 2 h after surgery) design ates patien ts to on e of th ree disch arge path w ays: n o supplem en tation , supplem en tation w ith calcium , or supplem en tation w ith calcium an d calcitriol. Regardless of th e precise tim ing or regim en th is selective approach h as been sh ow n to be safe an d e ect ive. With calcium m an agem en t, as w ith all elem en ts of am bulatory thyroid surgery, education of pat ien ts an d th eir caregivers is critical. Patien ts sh ould clearly un derstan d th e supplem en tation regim en prescribed an d be able to reliably follow it. Also, th ey sh ould be in structed in th e sym ptom atic presentation of hypocalcem ia an d w h at steps to take if th ose sym ptom s occur.

33.7 Conclusion Am bulator y thyroid an d parathyroid surgery provides patien ts w ith a w ide array of ben efits. Alth ough outpatien t parathyroidectom y h as been w idely adopted, surgeon s h ave been m ore reluctan t to take th is approach w ith thyroidectom y. How ever, a system atic approach com bin ed w ith carefu l pat ien t select ion an d am ple education perm its th e vast m ajorit y of thyroid surgery pat ien ts to be m an aged safely on an outpatien t basis.

References [1] Stack BC, Jr, Spen cer H, Moore E, Medvedev S, Boden n er D. Outpatien t parathyroid surgery data from th e Universit y Health System Con sort ium . Otolaryn gol Head Neck Surg 2012; 147(3); 438–443 [2] Ir vin GL, III, Sfakian akis G, Yeun g L, et al. Am bulatory parathyroidectom y for prim ar y hyperparathyroidism . Arch Surg 1996; 131(10); 1074–1078 [3] Mow sch en son PM, Hodin RA. Outpatien t thyroid an d parathyroid surgery: a prospect ive study of feasibility, safety, an d costs. Surgery 1995; 118(6); 1051–1053, discussion 1053–1054

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[4] Terris DJ, Snyder S, Carn eiro-Pla D, et al. Am erican Thyroid Association Surgical A airs Com m ittee Writ in g Task Force. Am erican Th yroid Association statem en t on outpatien t thyroidectom y. Th yroid 2013; 23(10); 1193–1202 [5] Steckler RM. Outpatien t thyroidectom y: a feasibility study. Am J Surg 1986; 152(4); 417–419 [6] Lo Gerfo P, Gates R, Gazetas P. Outpatien t an d sh ort-stay thyroid surgery. Head Neck 1991; 13(2); 97–101 [7] Seybt MW , Terris DJ. Outpatien t thyroidectom y: experien ce in over 200 patien ts. Lar yn goscope 2010; 120(5); 959–963 [8] Snyder SK, Ham id KS, Roberson CR, et al. Outpatien t thyroidectom y is safe an d reason able: experien ce w ith m ore th an 1,000 plan n ed outpatien t procedures. J Am Coll Surg 2010; 210(5); 575–582, 582–584 [9] Span kn ebel K, Ch abot JA, DiGiorgi M, et al. Thyroidectom y usin g m on itored local or conven tion al general an esth esia: an an alysis of outpatien t surgery, outcom e an d cost in 1,194 con secutive cases. World J Surg 2006; 30(5); 813– 824 [10] Tuggle CT, Rom an S, Udelsm an R, Sosa JA. Sam e-day thyroidectom y: a review of practice pattern s an d outcom es for 1,168 procedures in New York State. An n Surg On col 2011; 18(4); 1035–1040 [11] McHen ry CR. “Sam e-day” thyroid surgery: an an alysis of safety, cost savin gs, an d outcom e. Am Surg 1997; 63(7); 586–589, discussion 589–590 [12] Marin o M, Spen cer H, Hoh m an n S, Boden n er D, Stack BC, Jr. Costs of outpatien t thyroid surgery from th e Un iversit y Health System Con sortium (UHC) database. Otolaryn gol Head Neck Surg 2014; 150(5); 762–769 [13] Terris DJ, Snyder S, Carn eiro-Pla D, et al. Am erican Thyroid Association Surgical A airs Com m ittee Writ in g Task Force. Am erican Th yroid Association statem en t on outpatien t thyroidectom y. Th yroid 2013; 23(10); 1193–1202 [14] Lee SW , Ch oi EC, Lee YM, Lee JY, Kim SC, Koh YW. Is lack of placem en t of drain s after thyroidectom y w ith cen tral n eck dissection safe? A prospect ive, ran dom ized study. Lar yn goscope 2006; 116(9); 1632–1635 [15] Sch oretsan itis G, Melissas J, San idas E, Ch ristodoulakis M, Vlach on ikolis JG, Tsiftsis DD. Does drain in g th e n eck a ect m orbidity follow in g thyroid surgery? Am Surg 1998; 64(8); 778–780 [16] Terris DJ. Novel surgical m an euvers in m odern thyroid surgery. Op Tech n Otolaryn gol Head Neck Surg 2009; 20; 23–28 [17] Sin ger MC, Bh akta D, Seybt MW , Terris DJ. Calcium m an agem en t after thyroidectom y: a sim ple an d cost-e ective m ethod. Otolaryn gol Head Neck Surg 2012; 146(3); 362–365 [18] Houlton JJ, Pech ter W, Stew ard DL. PACU PTH facilitates safe outpatien t total thyroidectom y. Otolaryn gol Head Neck Surg 2011; 144(1); 43–47 [19] W isem an JE, Mossanen M, Ituar te PH, Bath JM, Yeh MW . An algorith m in form ed by th e parathyroid h orm on e level reduces hypocalcem ic com plication s of thyroidectom y. World J Surg 2010; 34(3); 532–537

Index Note: Page n um bers set bold or ita lic in dicate h eadings or figures, respect ively.

A Aden om as, toxic 72, 73 – defin ition of 72 – diagn osis of 73 – m an agem en t of 73 Aden osine m on oph osph ate, cyclic (cAMP) 26 Adenylyl cyclase sign alin g path w ays 70, 180 Advan ced m edullar y thyroid can cers (MTCs) 146 – See a lso Medullary thyroid can cers (MTCs) Aggressive di eren tiated thyroid can cers (DTCs) 97 – See a lso Di eren tiated thyroid can cers (DTCs) – fut ure tren ds in 100 – in troduct ion to 97 – localized th erapies in 97 – referen ces for 100 – system ic th erapies in 98 Agran ulocytosis 71 Airw ay injuries 272 Albrigh t, Fuller 25 Allan -Hern don -Dudley syn drom e 18 Alum in um hydroxide 21 Am bulator y surgery 270 – ben efits of 270 – description of 270 – fut ure tren ds in 274 – in troduct ion to 270 – parathyroid 270 – prin ciples of 270 –– con train dication s 271, 271 –– establish ed program s 271 –– patien t education 271 –– patien t select ion criteria 271 – referen ces for 274 – risks factors for 272 –– airw ay injuries 272 –– h em atom as 272, 273 –– hypocalcem ia 273 –– recurren t lar yn geal n erve (RLN) in juries 272 –– vocal cord paralysis (VCP) 272 – thyroid 270 Am erican Thyroid Association (ATA) guidelin es 163 Am iodaron e 21 An alges, lateral vs. m edial 8 An aplastic thyroid can cers (ATCs) 81, 149 – See a lso Can cers – carcinom as 56, 56 –– See a lso Carcin om as – clin ical trial en rollm en ts an d 152 – defin ition of 81 – diagn osis of 102, 149 –– bioch em ical an alyses 103 –– cytology 102 –– h istology 102 –– in itial evaluation s 149, 150–151 –– m utation al testin g 103, 104 – epidem iology of 102, 149

– fut ure tren ds in 152 – gen e alteration advan ces in 88 – gen etics of 82 –– gen e alteration advan ces 88 –– p53 m utation s 82 –– PAX8/PPARG m utation s 82 –– RAS m utation s 82 –– RET/PTC m utation s 82 – h istology of 149, 149 – m edical m an agem en t of 102 –– ch em oradiation 151 –– in troduct ion to 102 –– n eoadjuvan t m ultim odal th erapies 151 –– radiation th erapy 105 –– referen ces for 109 –– system ic th erapy 106, 107 – m etastases 106 – preexisting can cers an d 81 – preoperative evaluation s 82, 104 – surgical m an agem en t of 149 –– ch em oradiation 151 –– fut ure tren ds in 152 –– in troduct ion to 149 –– m etastasectom y 152 –– n eoadjuvan t m ultim odal th erapies 151 –– referen ces for 152 –– resection s 151 –– trach eostom y 152 – sur veillan ce testin g 108, 108 – TNM stagin g of 82, 104 An atom y 8 – of parathyroid glan ds 13 –– an om alous developm en t of 14 –– em br yology of 13 –– n orm al an atom y of 14 – of thym us 14 – of thyroid glan d, con gen ital an om alies 9 –– lin gual thyroid 9 –– thyroglossal duct (TGD) rem n an ts 10 – over view s of 8 – referen ces for 15 – thyroid glan d, em br yology of 8, 8 – thyroid glan d, lar yn geal n er ves 11 –– extern al bran ch superior laryn geal n er ve (EBSLN) 12, 13 –– in tern al bran ch superior lar yn geal n er ve (IBSLN) 12, 13 –– recurren t lar yn geal n er ve (RLN) 11 –– superior lar yn geal n er ve (SLN) 12 – thyroid glan d, vascular supply 10 –– in ferior thyroid artery (ITA) 10 –– superior thyroid arter y (STA) 10 –– thyroid glan d vasculature 10, 10 An octam in -1 17 An om alies, congenital 45 An tacids 21 An tiarrhyth m ics 21 An tibiotics, prophylatic 244 An tith yroid th ion am ide drugs 18 APECED, see Autoim m un e polyen docrin opathy-candidiasis-ectoderm al dystrophy (APECED) Arom aic am in o acids 26 Arteria lusoria 246 ATCs, see An aplastic thyroid can cers (ATCs)

Autoan tibodies 62 Autoim m un e polyen docrin opathy-can didiasis-ectoderm al dystroph y (APECED) 180 Autoim m un e thyroiditis 31 – See a lso Thyroiditis Autosom al dom in an t genetic syn drom es 80 Axillary approach es 125 Axillo-bilateral-breast approach (ABBA) 126

B BABA, see Bilateral axillo-breast ap proach (BABA) Barbiturates 21 Barth olom aeus Eustach ius 2 Ben ign thyroid diseases 58 – aden om as, pituitar y 72 –– diagn osis of 72 –– m an agem en t of 72 –– thyroid-stim ulatin g h orm on e (TSH)-secretin g 72 – aden om as, toxic 72 –– defin ition of 72 –– diagn osis of 73 –– m an agem en t of 73 – diagn ostic im agin g of 47 – goiters, see Goiters –– com pressive 61 –– di use 74 –– euth roid 74 –– evaluation of 61 –– grow th pattern s of 60 –– m an agem en t of 61 –– m ultin odular (MNGs) 74 –– m ultin odular (MNGs), toxic 73 –– n odular 60 –– n on com pressive 61 –– n on toxic 61 –– path ogen esis of 60 –– substern al 61, 62 – Graves' disease 69 –– defin ition of 69 –– diagn osis of 69, 70 –– hyperth yroidism an d 69 –– m an agem en t of 70, 70 – hyperth yroidism 69 –– defin tion of 69 –– goiter, di use 69, 69 –– Nation al Health an d Nutrition Exam in ation Sur vey III (NHANES III) prevalen ce data for 69 –– overt 70 –– thyrotoxicosis 69 – hypothyroidism 67 –– See a lso Hypothyroidism –– defin ition of 67 –– organ system s a ected by 67, 67 –– prim ar y 67 –– secon dar y 69 – in flam m ator y con dition s 62 –– classification of 60 –– Riedel's stru m a 64 –– thyroiditis 62 ––– See a lso Thyroiditis – in troduct ion to 58 – m edical m an agem en t of 67 – referen ces for 64, 75

– solitar y n odules 58 – toxic n odular disease 72, 73 Berr y, Jam es 4 Beta-blockers 72 Bilateral axillo-breast approach (BABA) 126 Bilateral n eck exploration 211 – See a lso Conven tion al parathyroidectom y Bilateral recurren t lar yn geal n er ve (RLN) injuries 247 Bile acid sequestran ts 21 Billroth, Albert Th eodor 3, 3 Bioch em ical an alyses 103 Bleeding com plication s 244 Breath in ess 247 Brist ish Journ al of Surgery 4 Brush borders 16

C C cells 8 Calciphylaxis 179, 179, 201 Calciton in 16 Calcium 21 Calcium -regulatin g h orm on es 16 cAMP, see Cyclic aden osin e m on oph osph ate (cAMP) Can cers, see Neoplasia – an aplastic thyroid (ATCs) 81, 149 –– ch em oradiation 151 –– clin ical trial en rollm en ts an d 152 –– defin ition of 81 –– diagn osis of 149 –– epidem iology of 149 –– fut ure tren ds in 152 –– gen etics of 82 –– h istology of 149 –– p53 m utation s 82 –– PAX8/PPARG m utation s 82 –– preexisting can cers an d 81 –– preoperative evaluation s 82 –– RAS m utation s 82 –– RET/PTC m utation s 82 –– surgical m an agem en t of 149 –– TNM stagin g of 82 – di eren tiated thyroid (DTCs) 77 –– defin ition of 77 –– gen etics of 78 –– postoperative m an agem en t of 79 –– preoperative evaluation s of 79 –– progn ostic in dicators of 78, 78 –– TNM stagin g of 79 –– w ell-di eren tiated 78 – m edullar y thyroid (MTCs) 80 –– advan ced 146 –– clin ical course of 140 –– defin ition of 80 –– diagn osis of 142 –– fam ilial classification of 141, 141 –– gen etics of 80, 81, 141 –– m ultiple en docrin e n eoplasia (MEN) 2A/2B 80, 81 –– preoperative evaluation s for 81 –– recurren t 145, 146 –– surgical m an agem en t of 140 –– TNM stagin g of 81, 140 – m olecular advan ces in 87 –– fut ure tren ds in 97 –– gen e alteration s 87

275

Index –– in troduct ion to 87 –– m olecular diagn ostics 90 –– referen ces for 97 – preexisting 81 Carbam azepin e 21 Carbim azole (CBZ) 18 Carboxy-term ion al fragm en ts 26 Carcin om as, see Can cers – an aplastic 56, 56 – diagn ostic im agin g of 52 – di eren tiated 52, 53–55 – gen e alteration s in 89 – Hü rth le cell (HCCs) 55 – m edullar y 54, 55 – papillary thyroid 36 –– See a lso See Papillary thyroid can cers (PTCs) –– clear cell 36 –– colum n ar cell 36 –– cribr iform -m orular 36 –– di use sclerosing 36 –– follicular variant (FVPTCs) 36 – parathyroid 184 –– clin ical presen tation of 185, 185 –– diagn osis of 185, 186 –– di eren tial diagn osis of 186, 187 –– epidem iology of 184 –– fut ure tren ds in 188 –– in troduct ion to 184 –– m an agem en t of 186 –– outcom es 188 –– path ogen esis of 184 –– referen ces for 189 –– staging of 188 – poorly di eren tiated 56, 88 Cardiac an tiarrhyth m ics 21 CBZ, see Carbim azole (CBZ) Celsus 2 Cen tral n eck com part m en t 154 Cen tral n eck dissection s (CNDs) 154 – com plication s of 158 – con train dication s for 155 – elect ive vs. th erapeutic 155, 248 – epidem iology of 154 – in dication s for 155 – in troduct ion to 154 – postoperative m an agem en t of 158 – preoperative plan n in g 154 – prim ar y 155, 157 – referen ces for 159 – reoperative 158 – tech n iques 156 Cer vical lym ph n odes 162, 162 – See a lso Lym ph n odes – drain age pattern s 163 – level I 162 – level II 162 – level III 162 – level IV 162 – level V 162 – level VI 162 – m etastases 163 Ch em oradiation 151 Ch ron ic lym ph ocytic thyroiditis (CLT) 31, 31 – See a lso Thyroiditis Ch urch ill, Edw ard 25 CIONM, see Con tin uous in traoperative n er ve m on itorin g (CIONM) Clear cell papillary thyroid carcin om as (PTCs) 36 – See a lso Carcin om as Clin ical trial en rollm en ts 152

276

CLT thyroiditis, see Ch ron ic lym ph ocytic thyroiditis (CLT) CNDs, see Cen tral n eck dissection s (CNDs) Co-localization 18 Colum n ar cell papillar y thyroid carcin om as (PTCs) 36 – See a lso Carcin om as Com plication s 244 – fut ure tren ds in 249 – gen eral 244 –– bleedin g 244 –– deep ven ous th rom bosis (DVT) 244 –– in fect ion s 244 –– poor cosm etic outcom es 245 – h istorical review s of 244 – in troduct ion to 244 – referen ces for 249 – specific 245 –– extern al bran ch superior laryn geal n er ve (EBSLN) injuries 247 –– hypocalcem ia 248 –– postoperative hypoparathyroidism 26, 248 –– recurren t lar yn geal n er ve (RLN) in juries 245, 246–247 –– recurren t lar yn geal n er ve (RLN) in juries, bilateral 247 –– superior lar yn geal n er ve (SLN) injuries 247, 248 –– sw allow in g im pairm en t 247 –– vocal cord paralysis (VCP) 246 Com pressive goiters 61 – See a lso Goiters Com pressive sym ptom s 244 Com puted tom ography (CT) 44 Con gen ital an om alies 45 Con tin uous in traoperative n er ve m on itorin g (CIONM) 257 Conven tion al parathyroidectom y 210 – See a lso Parathyroidectom y – for hyperparathyroidism (HPT) 210 –– See a lso Hyperparathyroidism (HPT) –– diagn osis of 210 –– epidem iology of 210 –– etiology of 210 –– prim ar y 210 –– secon dar y 210 –– surgical m an agem en t in dication s 211 –– tert iary 210 – fut ure tren ds in 217 – h istorical review s of 210 – in dication s for 211, 212–213 – in troduct ion to 210 – m issing glan d 215, 216–217 – operative tech n iques 213, 213, 214– 215 – posoperative care 217 – referen ces for 217 Conven tion al thyroidectom y 114 – See a lso Thyroidectom y – com plication s of 116, 117 –– hypoparathyroidism 117 –– n eck h em atom as 117 –– n er ve injuries 117 – in troduct ion to 114 – operative steps, sequen tial 114, 114, 115–116 – prin ciples of 116, 116 – referen ces for 118 Cope, Oliver 25 Cosm etic outcom es, poor 245

Cribriform -m orular papillary thyroid carcinom as (PTCs) 36 – See a lso Carcin om as Crile, George 4 Cr yopreser vation 205 CT, see Com puted tom ography (CT) Cyclic aden osin e m on oph osph ate (cAMP) 26 Cysts, thyroglossal duct (TGD) 31, 47, 47 Cytoch rom e P450 system 21 Cytokin es 22

D Da Vin ci surgical robot 5 De Quer vain 's thyroiditis 32 – See a lso Thyroiditis Deep ven ous th rom bosis (DVT) 244 DEHAL1 en zym e 18 Deh alogen ation 18 Desault, Pierre-Joseph 2 Developm en tal lesion s 31 DEXA scan n in g, see Dusal-en ergy X-ray absorptiom etr y (DEXA) scan n in g Diagn ostic im aging 44 – in troduct ion to 44 – m odalities 44 –– com puted tom ography (CT) 44 –– m agn etic resonan ce im aging (MRI) 44 –– n uclear scin tigraphy 44 –– ultrasoun d (US) 44, 45 –– ultrasoun d (US), o ce-based 261 ––– See a lso O ce-based ultrasoun d (US) – of ben ign diseases 47 –– Graves' disease 47, 48 –– Hash im oto's disease 48, 49 –– Hash im oto's thyroiditis (HT) 48, 49 – of congen ital an om alies 45 –– ectopic thyroid tissue 46, 46 –– thyroglossal duct (TGD) cysts 47, 47 – of m align an t diseases 52 –– an aplastic carcinom as 56, 56 –– di eren tiated carcinom as 52, 53– 55 –– Hü rth le cell carcin om as (HCCs) 55 –– m edullar y carcinom as 54, 55 –– poorly di eren tiated carcin om as 56 – of parathyroid glan d 191 – referen ces for 56 Di eren tiated thyroid can cers (DTCs) 77 – See a lso Can cers – aggressive 97 –– fut ure tren ds in 100 –– in troduct ion to 97 –– localized th erapies in 97 –– referen ces for 100 –– system ic th erapies in 98 – carcinom as 52, 53–55 –– See a lso Carcin om as – cen tral n eck dissection s (CNDs) 154 –– com plication s of 158 –– con train dication s for 155 –– elect ive vs. th erapeutic 155, 156 –– epidem iology of 154 –– in dication s for 155 –– in troduct ion to 154 –– postoperative m an agem en t of 158

–– preoperative plan n in g 154 –– prim ar y 155, 157 –– referen ces for 159 –– reoperative 158 –– tech n iques 155, 156 – defin ition of 77 – gen etics of 78 – lateral n eck m etastases 160 –– cervical lym ph n odes 162, 162 –– in troduct ion to 160 –– path ology of 161 –– preoperative evaluation s 160 –– progn osis 163 –– recurren t 164 –– referen ces for 167 –– risk factors of 160 –– staging of 161 –– surgical m an agem en t 166 – postoperative m an agem en t of 79 – preoperative evaluation s of 79 – progn ostic in dicators of 78, 78 – TNM stagin g of 79 – w ell-di eren tiated 78 Di use goiters 74 – See a lso Goiters Di use sclerosin g papillar y thyroid carcin om as (PTCs) 36 – See a lso Carcin om as Di use toxic hyperplasia (DTH) 33 DiGeorge's an om aly 179 Dim eric glycoprotein h orm on es 20 Diseases, thyroid 44 – ben ign diseases, thyroid glan d 58 – diagn ostic im agin g for 44 – m align an t diseases, thyroid glan d 77 – m edical m an agem en t 44 –– ben ign thyroid diseases 67 –– of can cer, aggressive di eren tiated 97 –– of can cer, an aplastic thyroid 102 –– of can cer, m edullary 102 – m olecular advan ces, diagn osis an d treatm en t 87 – surgical m an agem en t of 113 –– can cer, an aplastic 149 –– can cer, di eren tiated 154 –– can cer, lateral n eck 160 –– can cer, m edullar y 140 –– cen tral n eck com partm en t 154 –– com plication s of 244 –– h istory an d evolution of 2 –– lateral n eck 160 –– m in im ally-invasive 119 –– rem ote access 125 –– thyoidectom y, conven tion al 114 Dissection s, lateral n eck 163, 165 – Am erican Thyroid Association (ATA) guidelin es 163 – elect ive 164 – m odified radical n eck (MRNDs) 163 – prophylactic 164 – radical n eck (RNDs) 163 – selective n eck SNDs) 163 – th erapeutic 164 Diuretics, th iazide 210 DNA m ethylation 89 Dopam in e 72 Dopam in e agon ists 21 Double aden om as 210 – See a lso Aden om as Dow n regulation 18 Drain age pattern s 163 Drain s 166

Index DTCs, see Di eren tiated thyroid can cers (DTCs) DTH, see Di use toxic hyperplasia (DTH) Dual-isotope sin gle-ph ase (subtract ion ) tech n ique 193 Dun h ill procedure 4 Dun h ill, Th om as Peel 4 DUOX1/DOUX2 18 Dupuytren , Guillaum e 2 Dusal-en ergy X-ray absorptiom etr y (DEXA) scan n in g 221 DVT, see Deep ven ous th rom bosis (DVT) Dysh orm on ogen etic goiter 33 – See a lso Goiter Dysph on ia 244 Dyspn ea 244 Dyston ia 18

Fluid collect ion s 166 FNABs, see Fin e-n eedle aspiration biop sies (FNABs) Follicle-stim ulatin g h orm on e (FSH) 20 Follicular cells 16, 16, 18 Follicular tum ors, gen e alteration s in 88 Follicular varian t papillar y thyroid carcin om as (FVPTCs) 36 – See a lso Carcin om as Forearm grafts 231 Four-glan d hyperplasia 202 Fren ch Nation al Academ y of Medicin e 2 Frugardi, Roger 2 FSH, see Follicle-stim ulating h orm on e (FSH) FVPTCs, see Follicular varian t papillary thyroid carcinom as (FVPTCs)

E

G

Early period h istorical perspect ives 2 EBSLN injuries, see Extern al bran ch superior lar yn geal n er ve (EBSLN) in juries Ectopic glan ds 230 Ectopic thyroid tissue 9, 46, 46 Elective central n eck dissection s (CNDs) 155, 248 – See a lso Cen tral n eck dissection s (CNDs) Elective lateral n eck dissection s 164 – See a lso Lateral n eck dissection s Electrom yograph ic (EMG) activit y 256 EMG act ivity, see Electrom yograph ic (EMG) act ivity En dem ic goiter 33 – See a lso Goiter En dem ic m ultin odular goiter (MNG) 32 – See a lso Goiter En docytosis 18 En doscopic procedures 125, 127 – advan tages vs. disadvan tages of 127 – axillar y approach es 125 – axillo-bilateral-breast approach (ABBA) 126 – bilateral axillo-breast approach (BABA) 126 – ch est/breast approach es 125 En rollm en ts, clin ical trial 152 Eth an ol ablation 73 Eustach ius, Barth olom aeus 2 Euth roid goiters 74 – See a lso Goiters Euthyroid 63 Extern al bran ch superior lar yn geal n er ve (EBSLN) injuries 247 Extracervical thyroidectom y 5

G protein 26 Galen 2 Gastrin 26 GATA3 180 Gcm -2 25 Gen e alteration s, see Mutation s – advan ces in 87–88 – DNA m ethylation 89 – in carcin om as 89 – in follicular tum ors 88 – in m edullary thyroid can cers (MTCs) 89 – in n odules, hyperfun ction in g 89 – in papillary thyroid can cers (PTCs) 87 – in poorly di eren tiated can cers 88 – m iRNA expression 89 Gen e expression m arkers 91 Gen eral com plication s 244 – See a lso Com plication s – bleedin g 244 – deep ven ous th rom bosis (DVT) 244 – in fect ion s 244 – poor cosm etic outcom es 245 Glucocort icoids, h igh -dose 21 GNAS1 gen e 180 Goiters 32 – com pressive 61 – defin ition of 32 – dysh orm on ogen etic 33 – en dem ic 33 – evaluation of 61 – Graves' disease 33, 34, 69 –– See a lso Graves' disease –– defin ition of 69 –– diagn osis of 69, 70 –– hyperth yroidism an d 69 –– m an agem en t of 69, 70 – grow th pattern s of 60 – hyperfun ction in g 33 – hyperplasia 32 –– di use toxic hyperplasia (DTH) 33 –– n odular 33 – m an agem en t of 61 – m ultin odular (MNG) 32, 33 –– en dem ic 32 –– sporadic 32 –– toxic 33 – m ultin odular (MNGs) 74 –– toxic 73 – n odular 60

F Fam ilial classification s 141, 141 Fam ilial hypocalciuric hypercalcem ia (FHH) 176, 210 Fasciitis-like strom as 36 FHH, see Fam ilial hypocalciuric hypercalcem ia (FHH) Fin an cial con sideration s 268 Fin e-n eedle aspiration biopsies (FNABs) 135, 266, 267

– n on com pressive 61 – n on toxic 61 – path ogen esis of 60 – path ology of 32 – substern al 61, 62, 132 –– classification of 132, 132, 134 –– clin ical presen tation of 133–134, 134 –– defin ition of 132 –– diagn osis of 134, 134 –– epidem iology of 134 –– fut ure tren ds in 138 –– in troduct ion to 132 –– outcom es 137, 138 –– path ogen esis of 132 –– preoperative evaluation s 134 –– referen ces for 138 –– tech n iques 135, 136 – toxic m ultin odular (MNG) 33 Graves' disease 33, 34, 69 – See a lso Goiter – defin ition of 69 – derm opathy 69 – diagn osis of 69, 70 – hyperth yroidism an d 69 – m an agem en t of 69, 70 – oph th alm opathy 69 – orbitopathy 69 Gross, Sam uel 2, 244

H H2 receptor an tagon ists 21 HAART, see High ly act ive an tiretroviral th erapy (HAART) Halsted, W illiam 2, 4 Harm on ic Scalpel (Eth icon En doSurgery) 4 Hash im oto's thyroiditis (HT) 62 – See a lso Thyroiditis Hash im oto’s thyroiditis (HT) 31 HCCs, see Hü rth le cell carcinom as (HCCs) h CG, see Hum an ch orion ic gon adotropic (h CG) Hem atom as 117, 272, 273 Hem osiderin -laden m acroph ages 31 Hepatic cytoch rom e P450 system 21 High -dose glucocort icoids 21 High ly active an tiretroviral th erapy (HAART) 21 Historical perspect ives 2 – 19th cen tur y 2 –– Billroth, Albert Th eodor 3, 3 –– Koch er, Th eodor 2, 4 –– Massach usettes Gen eral Hospital 2 –– Morton , W illiam 2 –– Pirogo , Nikolai 2, 3 – 20th cen tur y 4 –– Berr y, Jam es 4 –– Brist ish Journ al of Surgery 4 –– Crile, George 4 –– Dun h ill procedure 4 –– Dun h ill, Th om as Peel 4 –– Halsted, W illiam 4 –– Lah ey, Fran k 4 –– Mayo broth ers 4 –– Royal Society of Medicin e 4 – 21st centur y 4 – early period 2 –– Abis, Abdul Kasan Kelebis 2 –– Barth olom aeus Eustach ius 2 –– Celsus 2

–– Desault, Pierre-Joseph 2 –– Dupuytren , Guillaum e 2 –– Fren ch Nation al Academ y of Medicin e 2 –– Frugardi, Roger 2 –– Galen 2 –– Gross, Sam uel 2 –– Halsted, William 2 –– Operative Stor y of Goitre (Halsted) 2 –– Seton s, iodin e-con tainin g m arin e products 2 –– Vesalius, An dreaus 2 –– Wh ar ton , Th om as 2 – in troduct ion to 2 – m in im ally-invasive approach es 5 –– da Vin ci surgical robot 5 –– en doscopic thyroid surgery 5 –– extracer vical thyroidectom y 5 –– m in im al-access thyroidectom y (MAT) 5 –– m in im ally-invasive open surger y 5 –– m in im ally-invasive video-assisted thyroidectom y (MIVAT) 5 –– over view s of 5 –– robotic facelift thyroidectom y 6 –– scarless surgery 5 –– video-assisted thyroidectom y (VAT) 5 – m odern day tech n ology 4 –– extern al bran ch of superior lar yn geal n er ve (EBSLN) preservation 5 –– Harm on ic Scalpel 4 –– in traoperative n er ve m on itors 4 –– Ligasyre system 4 – outcom es 4 – referen ces for 6 – thyroid glan d, n orm al vs. en larged 2 Hom eostatic m ech an ism s 28 Hot n odules 49 HPT, see Hyperparathyroidism (HPT) HPT-JT, see Hyperparathyroid-jaw tum or (HPT-JT) syn drom e HSA, see Hum an serum album in (HSA) HT, see Hash im oto's thyroiditis (HT) Hum an ch orion ic gon adotropic (h CG) 20 Hum an serum album in (HSA) 20 Hü rth le cell carcin om as (HCCs) 55 – See a lso Carcin om as Hydroch loroth iazide 210 Hypercalcem ia 210 Hypercalcem ia, fam ilial hypocalciuric (FHH) 176, 210 Hyperfun ction in g goiter 33 – See a lso Goiter Hyperfun ction in g n odules 89 Hyperparathyroid-jaw tum or (HPT-JT) syn drom e 210 Hyperparathyroidism (HPT) 172, 210 – diagn osis of 210 – epidem iology of 210 – etiology of 210 – path ophysiology of 172 – prim ar y 172, 210 – ren al 201 –– clin ical presen tation of 201 –– cr yopreservation 205 –– defin ition of 201 –– diagn osis of 202 –– fut ure tren ds in 206 –– im aging of 204, 204

277

Index –– in traoperative parathyroid h orm on e (IOPTH) assays 205 –– in troduct ion to 201 –– m edical m an agem en t of 202, 203 –– path ophysiology of 201, 201, 202 –– protocals for 205 –– referen ces for 206 –– surgical approach es 204, 205 –– surgical in dication s of 203 – secon dar y 175, 201, 210 – surgical m an agem en t in dication s 211 – tert iary 176, 210 Hyperplasia, see Goiter – di use toxic (DTH) 33 – m ultiglan d 210 – n odular 32, 33 – parathyroid 40 Hyperthyroidism 69 – goiter, di use 69, 69 –– See a lso Goiter – Nation al Health an d Nutrition Exam in ation Sur vey III (NHANES III) prevalen ce data for 69 – overt 70 – thyrotoxicosis 69 Hypertroph ic scarrin g 125 Hypocalcem ia 179, 248, 273 Hyponia 18 Hypoparathyroidism 26, 117, 179, 248 Hypoth alam us 19 Hypothyroid 63 Hypothyroidism 67 – defin ition of 67 – organ system s a ected by 67, 67 – prim ar y 67 –– diagn osis of 67 –– m an agem en t of 67, 68 – secon dar y 69 –– diagn osis of 69 –– m an agem en t of 69

I I-, see Iodide (I-) I-123, see Iodin e 123 (I-123) Iatrogen ic recurren t lar yn geal n er ve (RLN) injuries 252 – See a lso Recurren t lar yn geal n er ve (RLN) ILK-2, see In terleukin (ILK)-2 Im aging 44 – of ben ign diseases 47 –– Graves' disease 47, 48 –– Hash im oto's thyroiditis (HT) 48, 49 – of parathyroid glan d 191 – o ce-based ultrasoun d (US) 261 –– com peten cy in 268 –– fin an cial con sideration s of 268 –– fin e-n eedle aspiration biopsies (FNABs) 266, 267 –– fut ure tren ds in 269 –– in dication s for 268 –– in troduct ion to 261 –– of lym ph n odes 265 –– of n on en docrin e n eck path ology 266, 266 –– of parathyroid glan ds 264–265 –– of thyroid glan d 262, 263–264 –– referen ces for 269 –– tech n iques 261, 262–263 –– ultrasoun d (US)-guided procedures 266

278

In cision s 166 In determ in ate cytology thyroid n odules 90 In fect ion com plication s 244 In ferior thyroid ar tery (ITA) 10 In flam m ator y con dition s 62 – classification of 60 – Riedel's stru m a 64 – thyroiditis, see Th yroiditis In tercurren t n on thyroidal illn esses 20 In terferon -alph a (?) 22 In terfollicular zon es 16, 16 In terleukin (ILK)-2 22 In traoperative n er ve m on itorin g (IONM) 4, 252 – Am erican Academ y of Otolaryn gology-Head an d Neck Surgery (AAOHNS) guidelin es 252 – clin ical application s of 253 –– n eural fun ction progn ostication 253 –– n eural m appin g 253 –– path ological states 253, 253 –– vocal cord paralysis (VCP) reduction s 253 – fut ure tren ds in 257 –– con tin uous in traoperative n er ve m on itorin g (CIONM) 257 –– extern al bran ch superior laryn geal n er ve (EBSNL) m on itoring 258 –– m ild com bined even ts (m CEs) 257, 259 –– n eural injur y preven tion 257 –– n on recurren t lar yn geal n er ve (NRLN) iden tification , in traoperative 259 –– severe com bin ed even ts (sCEs) 257, 259 –– staged thyroidectom y 258 –– superior lar yn geal n er ve (SNL) m on itorin g 258 – h istorical review s of 252 – iatrogen ic recurren t lar yn geal n er ve (RLN) injuries 252 – in troduct ion to 252 – postoperative lar yn geal exam s 252 – preoperative lar yn geal exam s 252 – referen ces for 259 – stan dards 254 – tech n iques 254 –– equipm en t setup 254, 254, 255– 257 –– loss of sign al (LOS) evaluation s 256, 258 –– n egative predict ive values (NPVs) 252 –– passive elect rom yograph ic (EMG) act ivit y 252, 256 In traoperative parathyroid h orm on e (IOPTH) assays 225 – clin ical application s of 227, 228 – fut ure tren ds in 229 – h istorical review s of 225 – in m in im ally-invasive parathyroidectom y (MIP) 226 – in troduct ion to 225 – lim itation s of 227 – m olecular path ways 225, 226 – quick (QPTH) 225 – referen ces for 229 Invasive fibrous thyroiditis 32, 64 – See a lso Thyroiditis Iodide (I-) 16

Iodin e 123 (I-123) 44, 193 IOPTH assays, see In traoperative parathyroid h orm on e (IOPTH) assays Iron 21 ITA, see In ferior thyroid arter y (ITA)

J Jod-Basedow e ect 21

K kDa glycoprotein dual oxidases 18 Kearn s-Sayer's syn drom e 180 Ken ny-Ca ey's syn drom e 180 Koch er, E. Th eodor 2, 4, 125

L L-ph enylalanin e 26 L-tr yptoph an 26 Lah ey, Fran k 4 Lar yn geal n er ves 11 – an atom y of 11 – injuries 167, 257 –– preven tion of 257 Lateral n eck m etastases 160 – cervical lym ph n odes 162, 162 –– drain age pattern s 163 –– level I 162 –– level II 162 –– level III 162 –– level IV 162 –– level V 162 –– level VI 162 –– m etastases 163 – fut ure tren ds in 167 – in troduct ion to 160 – lateral n eck dissection s 163, 165 –– Am erican Thyroid Association (ATA) guidelin es 163 –– elect ive 164 –– m odified radical n eck dissection s (MRNDs) 163 –– prophylactic 164 –– radical n eck dissect ion s (RNDs) 163 –– selective n eck dissection s (SNDs) 163 –– th erapeutic 164 – m edullar y thyroid can cers (MTCs) 165 – path ology of 161 – poorly di eren tiated thyroid can cers (DTCs) 165 – preoperative evaluation s 160 – progn osis 163 – recurren t 164 – referen ces for 167 – risk factors of 160 – staging of 161 – surgical m an agem en t 166 –– drain s 166 –– fluid collection s 166 –– in cision s 166 –– n er ve injuries 167 –– vascular injuries 166 –– w oun d com plication s 166 Lateral thyroid an alges 8 Lesion s, developm en tal 31 Leutein izing h orm on e (LH) 20 LH, see Leutein izing h orm on e (LH) Life-th reaten ing bleedin g 244

Ligasyre system 4 Lin gual thyroid 9 Lipoph ilic agents 21 Lith ium 210 Localized th erapies 97 LOS evaluation s, see Loss of sign al (LOS) evaluation s Loss of sign al (LOS) evaluation s 256, 258 Lym ph n odes – cervical 162, 162 –– drain age pattern s 163 –– level I 162 –– level II 162 –– level III 162 –– level IV 162 –– level V 162 –– level VI 162 –– m etastases 163 – o ce-based ultrasoun d (US) of 265

M Macroph ages, h em osiderin -laden 31 Magn esium 26 Magn etic resonan ce im aging (MRI) 44 Malign an t diseases 77 – See a lso Can cers – an aplastic thyroid can cers (ATCs) 81 –– defin ition of 81 –– gen etics of 82 –– p53 m utation s 82 –– PAX8/PPARG m utation s 82 –– preexisting can cers an d 81 –– preoperative evaluation s 82, 82 –– RAS m utation s 82 –– RET/PTC m utation s 82 –– TNM stagin g of 82 – diagn ostic im agin g of 52 – di eren tiated thyroid can cers (DTCs) 77 –– defin ition of 77 –– gen etics of 78 –– postoperative m an agem en t of 79 –– preoperative evaluation s of 79 –– progn ostic in dicators of 78, 78 –– TNM stagin g of 79 –– w ell-di eren tiated 78 – in troduct ion to 77 – m edullar y thyroid can cers (MTCs) 80 –– defin ition of 80 –– gen etics of 80, 81 –– m ultiple en docrin e n eoplasia (MEN) 2A/2B 80, 81 –– preoperative evaluation s for 81 –– RET proto-on cogen e m utation s 80 –– TNM stagin g of 81 – n odules 77 –– defin ition of 77 –– evaluation s of 77, 77 – referen ces for 82 Man dl, Felix 25 MAPK, see Mitogen -activated protein kin ase (MAPK) Mappin g, n eural 253 Markers, gen e expression 91 Martell, Ch arles 25 Massach usettes Gen eral Hospital 2, 25 MAT, see Min im al-access thyroidectom y (MAT) Mayo broth ers 4

Index m CEs, see Mild com bined even ts (m CEs) MCT8, see Mon ocarboxylate tran sporter 8 (MCT8) Medullar y thyroid can cers (MTCs) 80, 140 – advan ced 146 – carcinom as 54, 55 –– See a lso Carcin om as – clin ical course of 140 – defin ition of 80 – diagn osis of 102, 142 –– bioch em ical testin g 103 –– cytology 102 –– h istology 102 –– m utation al testin g 103, 104 – epidem iology of 102 – fam ilial classification of 141, 141 – gen e alteration s in 89 – gen etics of 80, 81, 141 –– an alyses 141 –– RET proto-on cogen e m utation s 80 – m edical m an agem en t of 102 –– in troduct ion to 102 –– radiation th erapy 105 –– referen ces for 109 –– system ic th erapy 106, 107 – m etastases 106 – m ultiple en docrin e n eoplasia (MEN) 2A/2B 80, 81 – path ology of 27, 140 – preoperative evaluation s for 81, 104 – recurren t 145, 146 – referen ces for 109 – surgical m an agem en t of 140 –– advan ced disease 146 –– in itial surgical approach 143, 144 –– in troduct ion to 140 –– postoperative m an agem en t 144 –– referen ces for 147 –– residual disease 145 – sur veillan ce testin g 108, 108 – TNM stagin g of 81, 104, 140 MEN, see Multiple en docrin e n eoplasia (MEN) Metastasectom y 152 Metastases – an aplastic thyroid can cers (ATCs) 106 – m etastasectom y 152 Meth im azole (MMI) 18, 70, 70 Methylation 89 MGD, see Multigland disease (MGD) Microvilli 16 Mild com bin ed even ts (m CEs) 257 MINET, see Min im ally-invasive n on en doscopic thyroidectom y (MINET) Min im al-access thyroidectom y (MAT) 5 Min im ally-invasive approach es 119 – h istorical perspectives of 5 – m in im ally-invasive parathyroidectom y (MIP) 226 –– fut ure tren ds in 223 –– in dication s for 219 –– in troduct ion to 219 –– outcom es 223 –– referen ces for 223 –– tech n iques 219 – thyroidectom y 119 –– com plication s of 123, 123 –– in troduct ion to 119

–– m in im ally-invasive n on en doscopic thyroidectom y (MINET) 125 –– m in im ally-invasive video-assisted thyroidectom y (MIVAT) 5 –– operative steps of 119, 119, 120– 123 –– outcom es 122 –– patien t select ion criteria for 119, 119 –– postoperative care 123 –– referen ces for 123 Min im ally-invasive n on en doscopic thyroidectom y (MINET) 125 Min im ally-invasive parathyroidectom y (MIP) 226 – in traoperative parathyroid h orm on e (IOPTH) assays in 226 Min im ally-invasive video-assisted thyroidectom y (MIVAT) 5, 125 MIP, see See Min im ally-invasive parathyroidectom y (MIP) m iRNA expression 89 Missing glan d 215, 216–217 Mitogen -act ivated protein kin ase (MAPK) 26, 149 MIVAT, see Min im ally-invasive videoassisted thyroidectom y (MIVAT) MMI, see Meth im azole (MMI) MNGs, see Multin odular goiter (MNGs) Modalities, im agin g 44 – See a lso Diagn ostic im aging – com puted tom ography (CT) 44 – m agn etic resonan ce im aging (MRI) 44 – n uclear scin tigraphy 44 – ultrasoun d (US) 44, 45 – ultrasoun d (US), o ce-based 261 Modern day techn ology 4 – extern al bran ch of superior lar yn geal n er ve (EBSLN) preser vation 5 – Harm m on ic Scalpel 4 – in traoperative n erve m on itors 4 – Ligasyre system 4 – m olecular advan ces 87 –– fut ure tren ds in 93 –– gen e alteration s 87 –– in troduct ion to 87 –– m olecular testin g 90 –– referen ces for 93 Modified radical n eck dissection s (MRNDs) 163 Molecular advan ces 87 – fut ure tren ds in 93 – gen e alteration s 87 –– DNA m ethylation 89 –– in an aplastic thyroid can cers (ATCs) 88 –– in carcin om as 89 –– in follicular tum ors 88 –– in m edullary thyroid can cers (MTCs) 89 –– in papillary thyroid can cers (PTCs) 87, 87 –– in poorly di eren tiated can cers 88 –– m iRNA expression 89 –– n odules, hyperfun ction in g 89 – in troduct ion to 87 – m olecular testin g 90 –– approach es to 90, 91–92 –– diagn ostic application s of 91 –– gen e expression m arkers 91 –– of in determ in ate cytology thyroid n odules 90

–– targeted th erapies an d 92, 93 – referen ces for 93 Molecular path w ays 225, 226 Mon ocarboxylate tran sporter 8 (MCT8) 18 Morton , W illiam 2 MRI, see Magn etic resonan ce im aging (MRI) MRNDs, see Modified radical n eck dissect ion s (MRNDs) MTCs, see Medullary thyroid can cers (MTCs) Multiglan d disease (MGD) 210 Multiglan d hyperplasia 210 Multim odal th erapies 151 Multin odular goiters (MNGs) 32, 33, 74 – See a lso Goiter – en dem ic 32 – m an agem en t of 74 – sporadic 32 – toxic 33, 73 –– defin ition of 73 –– diagn osis of 73 –– m an agem en t of 74 –– thyrotoxicosis an d 73 Multiple en docrin e n eoplasia (MEN) 177 – See a lso Neoplasia – MEN1 177, 177 – MEN2 178, 178 – MEN2A/2B 80, 81 Mutation al testin g 103 Mutation s, see Gen e alteration s – p53 82 – PAX8/PPARG 82 – RAS 82 – RET/PTC 82 Myxedem a 68–69

N Na/iodide sym porter (NIS) 17 Nation al Health an d Nutrition Exam in ation Sur vey III (NHANES III) 69 Neck h em atom as 117 Neck sw ellin g, acute on set of 244 Negative predictive values (NPVs) 252 Neoadjuvan t m ultim odal th erapies 151 Neoplasia, see Can cers – m ultiple en docrin e n eoplasia (MEN) 177 –– MEN1 177, 177 –– MEN2 178, 178 –– MEN2A/2B 80, 80, 81 – parathyroid 41 –– aden om as 41, 41 –– carcinom as 41 – thyroid 33 –– classification of 33 –– epith elial 33 –– papillary thyroid can cers (PTCs) 34, 35–36 –– prim ar y 33 –– prim ar y, rare 40 –– secon dar y (m etastatic) 40 Nerve injuries 117, 167 – extern al bran ch superior laryn geal n er ve (EBSLN) injuries 247 – recurren t lar yn geal n er ve (RLN) injuries 117, 245, 246–247 – recurren t lar yn geal n er ve (RLN) injuries, bilateral 247

– superior lar yn geal n er ve (SLN) injuries 247, 248 Nerve m on itorin g, in traoperative (IONM) 4, 252 – Am erican Academ y of Otolaryn gology-Head an d Neck Surgery (AAOHNS) guidelin es 252 – clin ical application s of 253 –– n eural fun ction progn ostication 253 –– n eural m appin g 253 –– path ological states 253, 253 –– vocal cord paralysis (VCP) reduction s 253 – fut ure tren ds in 257 –– con tin uous in traoperative n er ve m on itorin g (CIONM) 257 –– extern al bran ch superior laryn geal n erve (EBSNL) m on itoring 258 –– m ild com bined even ts (m CEs) 257, 259 –– n eural injur y preven tion 257 –– n on recurren t lar yn geal n er ve (NRLN) iden tification , in traoperative 259 –– severe com bin ed even ts (sCEs) 257, 259 –– staged thyroidectom y 258 –– superior lar yn geal n er ve (SNL) m on itorin g 258 – h istorical review s of 252 – iatrogen ic recurren t lar yn geal n er ve (RLN) injuries 252 – in troduct ion to 252 – postoperative lar yn geal exam s 252 – preoperative lar yn geal exam s 252 – referen ces for 259 – stan dards 254 – tech n iques 254 –– equipm en t setup 254, 254, 255– 257 –– loss of sign al (LOS) evaluation s 256, 258 –– n egative predict ive values (NPVs) 252 –– passive elect rom yograph ic (EMG) act ivit y 252, 256 Nerves, lar yn geal, see Lar yn geal n er ves Neural m appin g 253 NHANES III, see Nation al Health an d Nutrition Exam in ation Sur vey III (NHANES III) Nin eteen th cen tur y h istorical perspectives 2 NIS, see Na/iodide sym porter (NIS) Nodular goiters 60 – See a lso Goiters Nodular hyperplasia 32, 33 Nodules – gen e alteration s in 89 – hyperfun ction in g 89 – in determ in ate cytology thyroid 90 – m align an t 77 –– defin ition of 77 –– evaluation s of 77, 77 – solitar y 58 Non classical organ s 28 Non com pressive goiters 61 – See a lso Goiters Non en docrin e n eck path ology 266, 266 Non recurren t lar yn geal n er ve (NRLN) iden tification 259

279

Index Non toxic goiters 61 – See a lso Goiters NPVs, see Negative predictive values (NPVs) NRLN in den tification , see Non recurren t lar yn geal n er ve (NRLN) iden tification Nuclear pseudoin clusion s 35, 35 Nuclear scin tigraphy 44, 193, 194–195

O Obesit y 231 O ce-based ultrasoun d (US) 261 – com peten cy in 268 – fin an cial con sideration s of 268 – fut ure tren ds in 269 – in troduct ion to 261 – of lym ph n odes 265 – of n on en docrin e n eck path ology 266, 266 – of parathyroid glan ds 264–265 – of thyroid glan d 262, 263–264 – referen ces for 269 – tech n iques 261, 261, 262–263 – ultrasoun d (US)-guided procedures 266 –– fin e-n eedle aspiration biopsies (FNABs) 266, 267 –– in dication s for 268 Operative Stor y of Goitre (Halsted) 2 Osteitis fibrosa cystica 202 Outpatien t en docrin e surgery 270 – am bulator y surgery, description of 270 – ben efits of 270 – fut ure tren ds in 274 – in troduct ion to 270 – parathyroid 270 – prin ciples of 270 –– con train dication s 271, 271 –– establish ed program s 271 –– patien t education 271 –– patien t select ion criteria 271 – referen ces for 274 – risks factors for 272 –– airw ay injuries 272 –– h em atom as 272, 273 –– hypocalcem ia 273 –– recurren t lar yn geal n er ve (RLN) in juries 272 –– vocal cord paralysis (VCP) 272 – thyroid 270 Overt hyperth yroidism 70 – See a lso Hyperthyroidism Ow en , Rich ard 210

P p53 m utation s 82 Papillar y thyroid can cers (PTCs) 34, 35–37 – classification of 36 – gen e alteration s in 87 – h istological varian ts of 36, 37 –– clear cell 36 –– colum n ar cell 36 –– cribriform -m orular 36 –– di use sclerosing 36 –– fasciitis-like strom as 36 –– follicular variant (FVPTCs) 36, 37 –– on cocytic 36

280

–– prom in en t h obn ail cell 36 –– psam m om a bodies 35, 35 –– pseudoin clusion s 34, 35 –– solid 36 –– tall cell variant 36 –– Warth rin -like 36 Parafollicular cells 8 Parathyroid diseases 171 – carcinom as 184 –– clin ical presen tation of 185, 185 –– diagn osis of 186 –– di eren tial diagn osis of 186, 187 –– epidem iology of 184 –– fut ure tren ds in 188 –– in troduct ion to 184 –– m an agem en t of 186 –– outcom es 188 –– path ogen esis of 184 –– referen ces for 189 –– staging of 188 – diagn ostic im agin g of 191 – hyperparathyroidism , ren al 201 – path ophysiology of 172 – surgical m an agem en t of 209 –– com plication s of 244 –– parathyroid h orm on e assay, in traoperative 225 –– parathyroidectom y, convention al 209 –– parathyroidectom y, m in im ally-in vasive (MIP) 219 –– radioguided 230 –– reoperative 235 Parathyroid glan ds 13 – an om alous developm en t of 14 – em bryology of 13 – im aging of 191 –– com puted tom ography (CT) 195, 196 –– fut ure tren ds in 197 –– in troduct ion to 191 –– m agn etic resonan ce im aging (MRI) 196 –– n uclear scin tigraphy 193, 194–195 –– positron em ission tom ography (PET) 196 –– referen ces for 198 –– reoperative n eck surgery 197 –– study selection criteria 196 –– ultrasoun d (US) 191, 192 Parathyroid h orm on e (PTH) 25 – calcium receptors an d 25, 25 – parathyrin 25 – purified 25 – receptors 26 – secretion 26 – structu re 26 – target organ s 27, 27 –– bon e 28 –– kidn ey 27, 27 –– n on classical organ s 28 –– vitam in D generation 17, 27 Parathyroidectom y, see Surgical m an agem en t – conven tion al 210 –– See a lso Conven tion al parathyroidectom y –– for hyperparathyroidism (HPT) 210 ––– See a lso Hyperparathyroidism (HPT) –– fut ure tren ds in 217 –– h istorical review s of 210 –– in dication s for 211, 212–213

–– in troduct ion to 210 –– m issing glan d 215, 216–217 –– operative tech n iques 213, 213, 214–215 –– posoperative care 217 –– referen ces for 217 – m in im ally-invasive (MIP) 219 –– fut ure tren ds in 223 –– in dication s for 219 –– in troduct ion to 219 –– outcom es 223 –– referen ces for 223 –– tech n iques 219 Parr y, Caleb Hillier 2 Passive elect rom yograph ic (EMG) activity 256 Path ology 31 – in troduct ion to 31 – parathyroid 40 –– hyperplasia 40 ––– See a lso hyperplasia –– n eoplasia 41 ––– See a lso Neoplasia – referen ces for 41 – thyroid 31 –– cysts, thyroglossal duct (TGD) 31 –– developm en tal lesion s 31 –– goiters 32 ––– See a lso Goiters –– n eoplasia 33 ––– See a lso Neoplasia –– thyroiditis 31 ––– See a lso Thyroiditis Path ophysiology, see Path ology – of parathyroid glan d 172 –– calciphylaxis 179, 179 –– fam ilial hypocalciuric hypercalcem ia (FHH) 176 –– hyperparathyroidism (HPT) 172 ––– See a lso Hyperparathyroidism (HPT) –– hypoparathyroidism 179 –– in troduct ion of 172 –– m ultiple en docrin e n eoplasia (MEN) syn drom es 177 ––– See a lso Multiple en docin e n eoplasia (MEN) syn drom es – of thyroid glan d 31 Patien t education 271 PAX8/PPARG m utation s 82 Pen dred syn drom e 18 Perch lorate (CLO4-) 17 PET, see Positron em ission tom ography (PET) Ph enyl rin gs 18 Ph enytoin 21 Ph osph oin ositide ph osph olipase C (PIPLC) 26 Ph osph olipase A2 (PLA2) 26 Physiology 16, 24 – of parathyroid glan ds 24 –– calcium receptors 25, 25, 28 –– h istorical review s of 24, 24 –– h om eostatic m ech anism s 28 –– in troduct ion to 24 –– parathyroid h orm on e (PTH) 25 ––– See a lso Parathyroid h orm on e (PTH) – of thyroid glan d 16 –– aden osin e triph osph ate (ATP) 17 –– cellular structu re an d arch itecture 16, 16, 17 –– follicular cells 16, 17

–– hypoth alam ic-pituitar y-thyroid (HPT) axis 21 –– hypoth alam ic-pituitar y-thyroid (HPT) n egative feedback loop 20, 20 –– in troduct ion to 16 –– iodam in es 17, 119 –– m itogen -act ivated protein (MAP)kin ase/extracellular sign al regulated kin ase (ERK) path ways 22, 22 –– m on ocarboxylate tran sporter 8 (MCT8) 18 –– perch lorate (CLO4-) 17 –– referen ces for 22 –– RET proto-on cogen e 22 –– sodium (Na)/iodide sym porter (NIS) 17 –– th iocyan ate (SCN-) 17 –– th rocyte grow th , genetic con trol of 22 –– th rocyte grow th , m olecular con trol of 22 –– thyroid fun ct ion al status, drugs affect in g 21 –– thyroid h orm on es, see Th yroid h orm on es –– thyroid states, assessm ents of 20 –– thyrotroph s 20 –– Wol -Ch aiko e ect 17, 22 PI-PLC, see Ph osph oin ositide ph osph olipase C (PI-PLC) Picket fence structure 16 Pirogo , Nikolai 2, 3 Pituitar y aden om as 72 – See a lso Aden om as – diagn osis of 72 – m an agem en t of 72 – thyroid-stim ulatin g h orm on e (TSH)secretin g 72 Pituitar y resistan ce to thyroid h orm on e (PRTH) 72 PKC, see Protein kin ease C (PKC) PLA2, see Ph osph olipase A2 (PLA2) Plum m er's disease 48 Poor cosm etic outcom es 245 Poorly di eren tiated carcinom as 56, 88 Positron em ission tom ography (PET) 196 Postoperative bleedin g 244 Postoperative hypoparathyroidism 26, 248 PPIs, see Proton pum p in h ibitors (PPIs) Preexistin g can cers 81 – See a lso Can cers Pretibial m yxedem a 69 Prim ar y cen tral n eck dissection s (CNDs) 155, 157 – See a lso Cen tral n eck dissection s (CNDs) Prim ar y hyperparathyroidism (HPT) 172, 210 – See a lso Hyperparathyroidism (HPT) Prophylactic lateral n eck dissection s 164 Prophylatic an tibiotics 244 Propylth iouracil (PTU) 18, 70, 70 Protein kin ease C (PKC) 26 Proton pum p in h ibitors (PPIs) 21 PRTH, see Pituitar y resistan ce to thyroid h orm on e (PRTH) Psam m om a bodies 35, 35 Pseudohypoparathyroidism 180

Index Pseudoin clusion s 34, 35 PTCs, see Papillary thyroid can cers (PTCs) PTH, see Parathyroid h orm on e (PTH) PTH1-84, see 84-am in o-acid peptide (PTH1-84) PTU, see Propylth iouracil (PTU)

Q QPTH assays, see Quick parathyroid h orm on e (QPTH) assays Quick parathyroid h orm on e (QPTH) assays 225

R Radical n eck dissection s (RNDs) 163 Radioactive iodin e uptake (RAIU) 70 Radioguided parathyroid surger y 230 – fut ure tren ds in 233 – in troduct ion to 230 – patien t select ion criteria for 230 –– age extrem es 230 –– con train dication s 231 –– ectopic glan ds 230 –– forearm grafts 231 –– hyperparathyroidism , prim ar y 230 –– hyperparathyroidism , secon dar y 230 –– hyperparathyroidism , tert iar y 230 –– obesity 231 –– parathyroid carcin om as 231 –– reoperative surgery 231 – postoperative care 233 – referen ces for 234 – tech qn iues for 231, 232–233 Radioisotope im agin g 193 RAIU, see Radioactive iodin e uptake (RAIU) RAS m utation s 82 RAT, see Robotic procedures Rearran ged durin g tran scription (RET) proto con cogen e 22 Recurren t laryn geal n er ve (RLN) 11 – com plication s of 245 – injuries 245, 246–247 –– am bulator y surgery an d 272 –– bilateral 247 –– iatrogen ic 252 –– in am bulatory surgery 272 Recurren t lateral n eck m etastases 164 – See a lso Lateral n eck m etastases Rem ote access thyroidectom y 125 – See a lso Thyroidectom y – en doscopic procedures 125, 127 –– advan tages vs. disadvan tages of 127 –– axillar y approach es 125 –– axillo-bilateral-breast approach (ABBA) 126 –– bilateral axillo-breast approach (BABA) 126 –– ch est/breast approach es 125 – fut ure tren ds in 130 – h istorical review s of 125 – in troduct ion to 125 – referen ces for 130 – robotic procedures 126, 127 –– advan tages vs. disadvan tages of 127 –– da Vin ci Surgical System 126

–– patien t select ion criteria for 127, 128 –– robotic axillary thyroidectom y (RAT) 126, 128 –– robotic facelift thyroidectom y (RFT) 126–127, 128–130 Ren al hyperparathyroidism (HPT) 201 – See a lso Hyperparathyroidism (HPT) – clin ical presen tation of 201 – cr yopreservation 205 – defin ition of 201 – diagn osis of 202 – fut ure tren ds in 206 – im aging of 204, 204 – path ophysiology of 201, 201 –– ch ron ic kidn ey disease (CKD) 201 –– fibroblast grow th factor 23 (FGF23) 201 –– four-glan d hyperplasia 201, 202 –– glom errular filtration rates (GFRs) 201 –– h em odialysis an d 201 –– hyperph osph atem ia 201 –– secon dar y hyperparathyroidism 201, 201 –– tert iary hyperparathyroidism 201 – protocals for 205 – referen ces for 206 – surgical approach es 205 – surgical in dication s of 203 Reoperative cen tral n eck dissection s (CNDs) 158 Reoperative parathyroid surgery 235 – diagn osis con fir m ation 235 – ectopy location s 237, 239 – em br yology 237 – failure etiology 235, 236–238 – fut ure tren ds in 240 – in troduct ion to 235 – outcom es 240 – postoperative m an agem en t 238 – referen ces for 240 – repeat im aging 235 – surgical approach es 237, 239–240 Resection s 151 Residual disease 145 RET proto-on cogen e m utation s 80 RET/PTC m utation s 82 RFT, see Robotic procedures Rich ardson , Edw ard 25 Riedel's stru m a 32, 64 – See a lso Thyroiditis Rifam pin 21 RLN injuries, see Recurren t lar yn geal n erve (RLN) injuries RNDs, see Radical n eck dissection s (RNDs) Robotic procedures 126, 127 – advan tages vs. disadvan tages of 127 – da Vin ci Surgical System 126 – patien t select ion criteria for 127, 128 – robotic axillar y thyroidectom y (RAT) 126, 128 – robotic facelift thyroidectom y (RFT) 126–127, 128–130 Royal Society of Medicin e 4

S Scarrin g, hypert roph ic 125 sCEs, see Severe com bined even ts (sCEs)

Sch lagen h aufer, Friedr ich 25 Scin tigraphy, n uclear 44, 193, 194–195 Secondar y hyperparathyroidism (HPT) 175, 210 – See a lso Hyperparathyroidism (HPT) Select ive n eck dissection s (SNDs) 163 Selen odeiodin ases 19, 19 – type 1 (D1) 19, 19 – type 2 (D2) 19, 19 – type 3 (D3) 19, 19 Seton s, iodin e-con tainin g m arin e products 2 Severe com bin ed even ts (sCEs) 257 SGT, see Subacute gran ulom atous thyroiditis (SGT) Sin gle-isotope dual-ph ase (w ash out) tech n ique 193 Sistrun k procedure 10 SLN injuries, see Superior lar yn geal n erve (SLN) injuries SNDs, see Select ive n eck dissect ion s (SNDs) Sodium (Na)/iodide sym porter (NIS) 17 Solitar y n odules 58 Special con sidertion s 243 – en docrin e surgery, outpatien t 270 – n erve m on itorin g, in traoperative 252 – surgical m an agem en t, com plication s of 244 – ultrason ography, o ce-based 261 Specific com plication s 245 – See a lso Com plication s – extern al bran ch superior laryn geal n erve (EBSLN) injuries 247 – hypocalcem ia 248 – postoperative hypoparathyroidism 26, 248 – recurren t lar yn geal n erve (RLN) injuries 245, 246–247 – recurren t lar yn geal n erve (RLN) injuries, bilateral 247 – superior lar yn geal n er ve (SLN) injuries 247, 248 – sw allow in g im pairm en t 247 – vocal cord paralysis (VCP) 246 Sporatic m ultin odular goiter (MNG) 32 – See a lso Goiter STA, see Superior thyroid artery (STA) Staged thyroidectom y 258 Stern otom y 140 Strom as, fasciitis-like 36 Subacute gran ulom atous thyroiditis (SGT) 32, 63 – See a lso Thyroiditis Subacute pain less lym ph ocytic thyroiditis 63 Subacute thyroiditis 32 – See a lso Thyroiditis Subfron tal resection s 72 Substern al goiters 61, 62, 132 – See a lso Goiters – classification of 132, 132, 134 – clin ical presen tation of 133–134, 134 – defin ition of 132 – diagn osis of 134, 134 – epidem iology of 134 – fut ure tren ds in 138 – in troduct ion to 132 – outcom es 137, 138 – path ogen esis of 132

– preoperative evaluation s 134 –– fin e-n eedle aspitation biopsies (FNABs) 135 –– im aging 135 –– thyroid fun ct ion testin g 134 –– thyroidectom y, exten t of 135 – referen ces for 138 – tech n iques 135, 136 Subtract ion (dual-isotope sin gle-ph ase) tech n ique 193 Sucralfate 21 Superior laryn geal n erve (SLN) 12 – an atom y of 12 – extern al bran ch (EBSLN) 12, 13 – extern al bran ch (EBSNL) 258 – injuries 247, 248 – in tern al bran ch (IBSLN) 12, 13 – m on itorin g 258 Superior thyroid artery (STA) 10 Suppurative thyroiditis 63 – See a lso Thyroiditis Surgical m an agem en t 244 – en docrin e surgery, outpatien t 270 – fut ure tren ds in 249 – gen eral 244 – h istorical review s of 244 – in troduct ion to 244 – n er ve m on itorin g, in traoperative 252 – of parathyroid diseases 209 –– parathyroid h orm on e assay, in traoperative 225 –– parathyroidectom y, convention al 209 –– parathyroidectom y, m in im ally-in vasive (MIP) 219 –– radioguided 230 –– reoperative 235 – of thyroid diseases 113 –– com plication s of 244 –– for central n eck com part m en t 154 –– h istory an d evolution of 2 –– m in im ally-invasive 119 –– of lateral n eck 160 –– rem ote access 125 –– thyroid can cer, an aplastic 149 –– thyroid can cer, di eren tiated 154 –– thyroid can cer, lateral n eck 160 –– thyroid can cer, m edullary 140 –– thyroidectom y, conven tion al 114 – referen ces for 249 – specific 245 Sur veillan ce testin g 108, 108 Sw allow in g im pairm en t 247 System ic th erapies 98

T Targeted th erapies 93 TBG, see Thyroxin e-bin din g globulin (TBG) Tc-99 m pertech n etate 193 – See a lso Tech n etium -99m (Tc-99m ) pertech n etate Tech netium -99 m (Tc-99m ) pertech n etate 44 Tert iar y hyperparathyroidism (HPT) 176, 210 – See a lso Hyperparathyroidism (HPT) Tetrofosm in 193 Tew nt y-first cen tur y h istorical perspectives 4 Tg, see Thyroglobulin (Tg)

281

Index TGD, see See Thyroglossal duct (TGD) Th erapeutic cen tral n eck dissection s (CNDs) 155, 248 – See a lso Cen tral n eck dissection s (CNDs) Th erapeutic lateral n eck dissection s 164 Th iazide diuretics 210 Th ion am ides 18, 72 Th rocyte grow th 22 – gen etic con trol of 22 – m olecular con trol of 22 Th rom bosis, deep ven ous (DVT) 244 Thym us 14 Thyroglobulin (Tg) 16, 16, 62 Thyroglossal duct (TGD) 10 – rem n an ts 10 Thyroglossal duct cysts (TGDs) 31, 47, 47 Thyroid acropachy 69 Thyroid capsule 16, 16 Thyroid com part m en t 1 – an atom y, developm en tal an d surgical 8 – path ology 31 –– parathyroid glan d 31 –– thyroid glan d 31 – physiology 16, 24 –– parathyroid glan ds 24 –– thyroid glan d 16 – surgical tech n iques, h istor y an d evolution of 2 Thyroid diseases 44 – ben ign diseases, thyroid glan d 58 – diagn ostic im agin g for 44 – m align an t diseases, thyroid glan d 77 – m edical m an agem en t –– ben ign thyroid diseases 67 –– can cer, m edullar y 102 –– of can cer, aggressive di eren tiated 97 –– of can cer, an aplastic thyroid 102 – m olecular advan ces, diagn osis an d treatm en t 87 – surgical m an agem en t of 113 –– can cer, an aplastic 149 –– can cer, di eren tiated 154 –– can cer, lateral n eck 160 –– can cer, m edullary 140 –– cen tral n eck com partm en t 154 –– com plication s of 244

282

–– h istory an d evolution of 2 –– lateral n eck 160 –– m in im ally-invasive 119 –– rem ote access 125 –– thyoidectom y, conven tion al 114 Thyroid h orm on es 16 – am bien t state 19 – deiodin ation of 19, 19 – diiodot yrosin e (DIT) 17, 17 – h om eostasis of 19 – in troduct ion to 16 – iodothyron in es 18 – m on oiodot yrosin e (MIT) 17, 17 – regulation 19, 20 – release 17 – syn th esis 17, 17 – thyrotropin -stim ulatin g h orm on e (TSH) 17 – thyroxin e (T4) 16, 17 – tr iiodothyron in e (3) 16, 17 Thyroid peroxidase (TPO) 62 Thyroid-stim ulating an tibodies (TSAbs) 69 Thyroid-stim ulating h orm on e (TSH)secretin g aden om as 72 – See a lso Aden om as Thyroidectom y, see Surgical m an agem en t – conven tion al 114 –– com plication s of 116, 117 ––– See a lso hypoparathyroidism , n eck h em atom as, n er ve injuries –– in troduct ion to 114 –– operative steps, sequen tial 114, 114, 115–116 –– prin ciples of 116, 116 –– referen ces for 118 – extracer vical 5 – m in im ally-invasive 119 –– com plication s of 123, 123 –– in troduct ion to 119 –– operative steps of 119, 119, 120– 123 –– outcom es 122 –– patien t select ion criteria for 119, 119 –– postoperative care 123 –– referen ces for 123 – rem ote access 125 –– en doscopic procedures 125, 127 –– fut ure tren ds in 130

–– h istorical review s of 125 –– in troduct ion to 125 –– referen ces for 130 –– robotic procedures 126, 127 – robotic facelift 6 – staged 258 Thyroiditis 31 – acute 32 – acute suppurative 63 – autoim m un e 31 – ch ron ic lym ph ocytic (CLT) 31, 31 – de Quervain 's 32 – Hash im oto's (HT) 48, 49, 62 – Hash im oto’s (HT) 31 – invasive fibrous 32, 64 – path ology of 31 – Riedel's stru m a 32 – subacute 32 –– gran ulom atous (SGT) 32, 63 –– pain less lym ph ocytic 63 Thyrotoxicosis 69 Thyrotroph s 20 Thyroxin e-bin ding globulin (TBG) 20 Toxic aden om as 72, 73 – See a lso Aden om as – defin ition of 72 – diagn osis of 73 – m an agem en t of 73 Toxic m ultin odular goiter (MNG) 33 – See a lso Goiter Toxic n odular disease 72, 73 TPO, see Th yroid peroxidase (TPO) Trach eom alacia 137 Trach eostom y 137, 152 Tran ssph en oidal resect ion s 72 TSAbs, see Thyroid-stim ulating an tibodies (TSAbs) TSH receptors (TSHRs) 33 TSHom as 72 TSHRs, see TSH receptors (TSHRs) Tubercules of Zuckerkan dl 9 Tw en tieth centur y h istorical perspectives 4 Tyrosin e kin ase in h ibitors 21

–– –– –– –– –– –– ––

com peten cy in 268 fin an cial con sideration s of 268 fut ure tren ds in 269 in dication s for 268 in troduct ion to 261 of lym ph n odes 265 of n on en docrin e n eck path ology 266, 266 –– of parathyroid glan ds 264–265 –– of thyroid glan d 262, 263–264 –– referen ces for 269 –– tech n iques 261, 261, 262–263 –– ultrasoun d (US)-guided procedures 266 US, see Ultrasoun d (US)

V Vascular en doth elial grow th factor receptors (VEGFRs) 21 Vascular injuries 166 Vascular supply 10 – in ferior thyroid ar tery (ITA) 10 – superior thyroid arter y (STA) 10 – thyroid glan d 10 – vasculature 10, 10 VCP, see Vocal cord paralysis (VCP) VEGFRs, see Vascular en doth elial grow th factor receptors (VEGFRs) Vesalius, An dreaus 2 Vitam in D gen eration 17, 27 Vocal cord paralysis (VCP) 246, 253, 272

W Wash out (sin gle-isotope dual-ph ase) tech n ique 193 Well-di eren tiated thyroid can cers (DTCs) 78 – See a lso Di eren tiated thyroid can cers (DTCs) Wh arton , Th om as 2 Wol -Ch aiko e ect 17, 22 Woun d com plication s 166

U Ultrasoun d (US) 44, 45 – in troduct ion to 261 – o ce-based 261

Z Zon es, in terfollicular 16, 16 Zuckerkan dl, tubercules of 9