www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
ORIGINAL
ARTICLE
Hashimoto’s
thyroiditis
---
an
independent
risk
factor
for
papillary
carcinoma
夽
Barbora
Uhliarova
a,∗,
Andrej
Hajtman
baFDRooseveltFacultyHospital,DepartmentofOtorhinolaryngology,BanskaBystrica,Slovakia
bComeniusUniversity,JesseniusFacultyofMedicine,DepartmentofOtorhinolaryngology,HeadandNeckSurgery,Martin, Slovakia
Received13March2017;accepted20August2017 Availableonline14September2017
KEYWORDS Thyroidcancer; Microcarcinoma; Hashimoto’s thyroiditis Abstract
Introduction:ThelinkbetweenHashimoto’sthyroiditisandthyroidcarcinomahaslongbeena
topicofcontroversy.
Objective: Theaimofourstudywas todeterminetheprevalenceofthyroidcarcinomaand
Hashimoto’sthyroiditiscoexistenceinhistopathologicmaterialofthyroidectomizedpatients.
Methods:In a retrospective study, the clinicohistopathologic data of 2117 patients (1738
females/379 males), who underwenttotal orpartial thyroidectomyfor thyroidgland disor-deratasingleinstitutionfromthe1stofJanuary2005tothe31stofDecember2014were analyzed.
Results:Thyroidcarcinomawasdetectedin318cases(15%)andmicrocarcinoma(thyroid
can-cer ≤10mm in diameter) was found inpermanent sections in169 cases (8%). Hashimoto’s thyroiditiswasdetectedin318(15%)patients.Hashimoto’sthyroiditiswassignificantlymore often associated with thyroid carcinoma andmicrocarcinoma compare tobenign condition (p=0.048,p=0.00014,respectively).CoexistenceofHashimoto’sthyroiditisandthyroid carci-noma/thyroidmicrocarcinomadidnotaffecttumorsize(p=0.251,p=0.098,respectively),or tumormultifocality(p=0.831,p=0.957,respectively). Bilateralthyroidmicrocarcinomawas significantlymoreoftendetectedwhenHashimoto’sthyroiditiswasalsodiagnosed(p=0.041), butpresenceofHashimoto’sthyroiditisdidnotaffectbilateraloccurrenceofthyroidcarcinoma (p=0.731).
Conclusion: Hashimoto’sthyroiditisisassociatedwithsignificantlyincreasedriskofdeveloping
thyroidcarcinoma,especiallythyroidmicrocarcinoma.
© 2017 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Published by Elsevier Editora Ltda. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).
夽 Pleasecitethisarticleas:UhliarovaB,HajtmanA.Hashimoto’sthyroiditis---anindependentriskfactorforpapillarycarcinoma.BrazJ
Otorhinolaryngol.2018;84:729---35.
∗Correspondingauthor.
E-mail:[email protected](B.Uhliarova).
PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial. https://doi.org/10.1016/j.bjorl.2017.08.012
1808-8694/©2017Associac¸˜aoBrasileiradeOtorrinolaringologiaeCirurgiaC´ervico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
PALAVRAS-CHAVE
Câncerdetireoide; Microcarcinoma; Tireoiditede Hashimoto
TireoiditedeHashimoto−umfatorderiscoindependenteparaocarcinomapapilar
Resumo
Introduc¸ão:Arelac¸ãoentreatireoiditedeHashimotoeocarcinomadetireoidetemsidoum
temadecontrovérsiaporumlongotempo.
Objetivo:Determinaraprevalênciadacoexistênciadecarcinomadetireoideetireoiditede
Hashimotonoexamehistopatológicodeamostrasdepacientestireoidectomizados.
Método: Emum estudoretrospectivo, foramanalisados osdadosclinico-histopatológicosde
2.117pacientes(1.738mulheres/379homens),submetidosàtireoidectomiatotalouparcial pordistúrbiodaglândulatireoideemumaúnicainstituic¸ão,de1◦dejaneirode2005a31de dezembrode2014.
Resultados: Ocarcinomadetireoidefoi detectadoem 318casos (15%)e omicrocarcinoma
(câncerdetireoide≤10mmdediâmetro) foiencontrado emsecc¸ões permanentesem 169 casos(8%). A tireoiditede Hashimotofoidetectadaem 318(15%)pacientese foiassociada ao carcinoma datireoide eao microcarcinomacom maiorfrequência em comparac¸ãocom condic¸õesbenignas(p=0,048,p=0,00014,respectivamente).Acoexistênciadetireoiditede Hashimotoecarcinoma/microcarcinomanãoinfluenciouotamanhodotumor(p=0,251,p= 0,098,respectivamente)ouamultifocalidadetumoral(p=0,831,p=0,957,respectivamente). Omicrocarcinomadetireoidebilateralfoidetectadocommaiorfrequênciaquandoatireoidite deHashimototambémfoidiagnosticada(p=0,041),masapresenc¸adetireoiditenãoinfluenciou naocorrênciabilateraldecarcinoma(p=0,731).
Conclusão:A tireoiditede Hashimotoestáassociadaaumaumentosignificativodoriscodo
desenvolvimentodecarcinomadetireoide,especialmentemicrocarcinomadatireoide. © 2017 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Publicado por Elsevier Editora Ltda. Este ´e um artigo Open Access sob uma licenc¸a CC BY (http:// creativecommons.org/licenses/by/4.0/).
Introduction
Thyroidcanceristhemostcommonmalignancyofendocrine system and accounts for approximately 1% of all can-cers.The worldwide incidence of thyroid carcinoma (TC) has increased,however, the cause of this increase is not clear. It is questionable, whether this increase is abso-lute or the result of improved diagnostic capabilities.1,2 Moreover,theincidentalfindingofthyroidmicrocarcinoma (TMC)(thyroid cancer≤10mm indiameter)during patho-logicalexaminationoftheresectionspecimensinpatients operated for benign thyroid condition remains a common scenario,inspiteofadvancesinpreoperativeinvestigation, mainlyUltrasound(US)andFineNeedleAspirationCytology (FNAC).3---5
TMCsarefoundatratesof0.5---35.6%atautopsyorin sur-gicalspecimenswherecarcinomahadbeenunsuspected.6,7 Hashimoto’sthyroiditis(HT)isachroniclymphocytic thy-roiditis,andthemostcommoncauseofhypothyroidismin areaswithproperamountsofiodine.8HTwasfirstdescribed in 1912 by Hakaru Hashimoto,9 a Japanese surgeon and pathologist, as an autoimmune disease, affecting 5% of thegeneralpopulation. Thepathologyis characterizedby diffuse lymphocyte infiltration, fibrosis, and parenchymal atrophy. Although the link between chronic inflammation andcanceriswellestablished,theassociationbetweenHT and Papillary Thyroid Carcinoma (PTC) has been contro-versial in literature since its initial description by Dailey et al. in 1955.10 The aim of our study was to determine
theprevalenceofTCandHTcoexistenceinhistopathologic materialofthyroidectomizedpatients.
Methods
Theretrospectivestudywasconductedwithpatients surgi-callytreatedatasingleinstitutionfromthe1stofJanuary 2005tothe31stofDecember2014forthyroidgland disor-der.ThestudywasapprovedbytheEthicsCommittees.All patientssignedtheirinformedconsents.
Thyroidultrasound wasperformed in all patients. The extensionofthethyroidectomywasdecidedbythe endocri-nologistandoperatingsurgeon,dependingontheextension oflesions,patient’sapprovalandintraoperativefindings.
Type of thyroid gland disease was determined by histopathological examination. We studied the following parameters: histopathologic findings, presence of Hashimoto’s thyroiditis, size of the tumor, multifocality, bilateralpresentation.
Pathological classification was performed for all thy-roid specimens according to World Health Organization guidelines.11 Thehistologicalcriteriausedtomakea diag-nosisofHTincludeddiffuselymphoplasmacyticinfiltration, germinal centers,and enlargedepithelial cells withlarge nuclei and eosinophilic cytoplasm (Askanazy or Hürthle cells).Non-specificlymphocyticthyroiditisoccurring imme-diatelyadjacenttoatumorcouldnotbedifferentiatedfrom perineoplasticinflammationandwasnotincludedinnumber
Table1 Generalcharacteristicsofstudypopulation.
Benign Thyroidcarcinoma Microcarcinoma p-value
N 1630(77%) 318(15%) 169(8%) NA Male 277(17%) 60(19%) 42(24%) 0.122 Female 1348(83%) 261(81%) 129(76%) 0.122 Age 47.2±19.9 36.1±14.7 54.5±17.8 0.025 Multifocality NA 38(12%) 49(29%) 0.015 Bilaterality NA 32(10%) 34(20%) 0.047 PTC NA 197(62%) 159(94%) 0.005 FVPTC NA 74(23%) 7(4%) 0.044 FTC NA 25(8%) 3(2%) 0.034 Others NA 22(7%) 0 0.008 HT+ 163(10%) 57(18%) 98(58%) 0.001
N,numberofpatient;NA,notapplicable;PTC,papillarythyroidcarcinoma;FVPTC,follicularvariantofpapillarythyroidcarcinoma; FTC,follicularthyroidcarcinoma;HT+,Hashimoto’sthyroiditispresent.Dataareshownasmedian±SD.
withHTto avoid over-diagnosisin ourstudy. Hashimoto’s thyroiditiswasclassifiedinonesinglegrade.Tosetupthe diagnosis of HT, pathologists from onesingle center were involved.Pathologicalspecimenswerecollectedfrom medi-calcharts.
Thelargesttumorsizewasrecorded.Patientswere cat-egorizedasTMCifthelargesttumordiameterwas≤1cm. Multifocalthyroidcancerwasdefinedastwoormoretumor sites(withinoneorbothlobesofthyroidgland).Multifocal occurrenceofthyroidtumorinbothlobesofthyroidgland wasclassifiedasbilateral.
The accuracy offine needleaspirationcytology (FNAC) in the differential diagnosis of thyroid nodules was also. In patients with multiple nodules, one dominant nodule or nodule with features for malignancy on USG (hypoe-chogenicity, microcalcifications, absence of peripheral halo, irregular borders, intranodular hypervascularity and regionallymphadenopathy)wasinvestigated.ThyroidFNAC resultwasclassifiedusingtheBethesdasystemforreporting thyroid cytopathology12: (I)Non-Diagnostic/Unsatisfactory (ND/UNS); (II) Benign; (III) Atypia of Undetermined Significance/FollicularLesionofUndeterminedSignificance
(AUS/FLUS); (IV) Follicular Neoplasm/Suspicious for FollicularNeoplasm(FN/SFN);(V)SuspiciousForMalignancy (exceptoffollicularcarcinoma)(SFM);(VI)Malignancy.
The statistical analysiswas performed withSTATISTICA Cz 10. Frequencies of categorical data were tabulated and evaluated with Chi-square test using Yates’s correc-tion. For ordinal data, median and interquartile ranges were calculated and tested with the Kruskal---Wallis test, Mann---Whitneytest or two-factorial ANOVA withpost hoc Duncantest.Ap<0.05wasregardedasstatistically signifi-cant.
Results
Atotalof2117patientsunderwentpartialortotal thyroidec-tomy for thyroid disorder. There were 1738 (82%) female (meanage46.5±19.7years)and379(18%)male(meanage 46.4±20.9years)inthestudygroup.
Thyroid carcinoma was detected in 318 cases (15%) and microcarcinoma was found in permanent sections in 169 cases (8%). There were no differences in the gender
50% 45% 40% 35% 10% 5% 0% 20% 30% 25% Number of patients , %
Graves-basedow d. Thyrotoxicosis Hashimoto’s s t. Multinodular goiter Solitary nodule 15%
35 30 25 20 15 Siz e of tumor , mm Thyroid carcinoma HT+ HT-Microcarcinoma 5 10 0
Figure2 TumorsizeaccordingtothepresenceofHashimoto’sthyroiditis(HT+,Hashimoto’sthyroiditispresent;HT−,Hashimoto’s thyroiditisabsent;dataareshownasmedian±SD).
40% 35% 25% 15% Number of patients , % Multifocal
Thyroid carcinoma Microcarcinoma
HT+ HT-Multifocal Bilateral Bilateral 5% 30% 20% 10% 0% ∗
Figure3 Prevalenceofmultifocality andbilateralityaccording tothepresence ofHashimoto’s thyroiditis(HT+,Hashimoto’s thyroiditispresent;HT−,Hashimoto’sthyroiditisabsent;dataareshownasmedian±SD,*p<0.05).
(p=0.122) of patients between groups (benign condition vs. TC vs. TMC). Patients with malignant tumor were significantlyyoungercomparetopatientswithbenign dis-order of thyroid gland (p=0.002) and PTMC (p=0.003) (Table1).
Papillarycarcinomawasthemostcommonhistologictype in TC (62%) and TMC group (94%). Other histopathologic typesof thyroidmalignanttumorsweresignificantlymore oftendetectedinTCcomparetoTMCgroup(Table1).
Multinodulargoiter(37%)andsolitarynoduleofthyroid gland(28%)werethemostfrequentindicationsforsurgery (Fig.1).Hashimoto’sthyroiditiswasdetectedin318(15%) patients. HT wassignificantly more often associatedwith thyroidcarcinoma andmicrocarcinomacomparetobenign condition(p=0.048,p=0.00014,respectively).
The mean tumor diameter was 5.8±2.9mm in TMC group and 19.6±10.5 in TC group. Therewere no signif-icant differences intumor size according tothe presence
of HT in both groups (p=0.098, p=0.251, respectively) (Fig.2).
Multifocal identification of malignancy was not asso-ciated to the accompanying Hashimoto’s thyroiditis (TC: p=0.831, TMC: p=0.957). Bilateral detection of TMC was significantly more often detected when HT was also diagnosed (p=0.041), but presence of HT did not affect bilateral occurrence of TC (p=0.731) (Fig.3).
Fineneedleaspirationcytologywasperformedin55%of patientswithnodulargoiter.Themostfrequent indication forFNACwassolitarythyroidnodule(50%).FNACwas indi-cated in 44% of patients with HTand in 32% without HT (p=0.371). Results of FNAC according to the presence of HTarepresentedin Table2.Highsensitivityandspecifity inthediagnosis ofmalignantthyroidnodulewasobserved byusingaspirationcytology(HTpresent:67%,92%, respec-tively;HTabsent:82%,97%,respectively).Theaccuracyof FNACinthediagnosisofmalignancywassignificantlyhigher inpatients withoutHT(93%)comparetopatientswithHT (82%)(p=0.031).
Allpatientsinthestudygroupweretreatedsurgicallyby hemithyroidectomyortotalthyroidectomy.When hemithy-roidectomy was initial treatment and pathology revealed malignanttumor(TCorTMC),allpatientsunderwent com-pletionthyroidectomy6---32days(median19±8days)after initial surgery. The final pathologyfromthe remnant thy-roidlobeaftercompletionthyroidectomydetectedbilateral malignanttumorin14%(TC4%,TMC33%).
Discussion
Hashimoto’s thyroiditis, also called chronic lymphocytic or autoimmune thyroiditis, is part of the spectrum of autoimmunethyroiddiseasesandisassociatedwithvarious degrees of thyroid hypofunction and circulating antibod-iestothyroid antigens. The causeof HTis thought tobe acombination ofgeneticsusceptibilityand environmental factors.13
Several studies showed the association of Hashimoto’s thyroiditisandthyroidcarcinoma.1,8,10,14---16Ameta-analysis showed that the HT incidence is 2.77 higher in patients withPTC when comparedto patientswith benign thyroid
diseases. In addition,in patients withthyroid carcinoma, theassociationofHTis1.99timeshigheramongthosewith PTCthaninpatientswithotherpathologicaltypesofthyroid cancer.17 Indirectly,thesefindingsmaysuggesta predispo-sition of HT patients to the development of PTC. In the present study,18% of the cases showed both HTand TC, andevenupto58%casesofTMCwereassociatedwithHT. Themechanismby whichHashimoto’sthyroiditisis associ-atedwiththyroidmalignancyis notfullyunderstood.One ofthepossibleexplanationsisbasedonDNAdamagecaused by chronic inflammation. The inflammatory responsemay cause DNA damage throughformation of reactive oxygen species,resultinginmutationsthateventuallyleadtothe development of PTC.18 The relationship between thyroid autoimmunityand cancer remains controversial. In a ret-rospective non-randomized study,19 it wasshown thatthe presenceofthyroglobulinantibodyisanindependentfactor inthedevelopmentofPTC.
RET/PTC,which isa RETrearrangement,agenewhich codesatyrosine-kinasereceptor,isdescribedasoneofthe mechanismsresponsiblefortheassociationofHTandPTC.20 Thisoncogenewasfoundinthelargemajorityoftissueswith HTandwithoutdetectablePTC,whichmayshowa progres-siontocancer fromchronicthyroiditis.21 The presence of RET/PTCmustnotbesynonymouswithcancer,butrathera molecularmechanismsofcarcinogenesis.22
Anotherdescribedmechanismis theexpressionof p63, atumor-suppressionproteinhomologoustothep53,thatis foundinabout81%oftheHTandPTC,anditisnotfound innormalthyroidtissues,Graves-Basedowdiseaseorother thyroidtumors.23
ItisquestionablewhetherornotunderlyingHTisaworse prognostic factor for PTMC. Some authors suggest a less aggressivecourse ofthediseasewhen thereis association betweenHTandPTC,withtendencytowardasmallertumor size,lesslymphnodeinvolvementandlongersurvival.15,16,24 Ahnetal.18reportedthatpatientswithPTCwerefourtimes morelikelytohave acoexisting HTcomparedtopatients with other thyroid diseases, suggesting a link between chronicinflammationandcancerdevelopmentinthethyroid gland.TherewasalsoatrendinpatientswithPTCandHT forabetterprognosis,includingsmallertumorsizes,alower frequencyoflymphnodemetastasis,higherdisease-freeand
Table2 Resultsoffineneedleaspirationcytologyofthyroidnodules.
HT+ HT−
FNAC Definitivehistology FNAC Definitivehistology
Benign Malignant Benign Malignant
ND/UNS 6% 0% 13% 6% 7% 5% Benign 43% 60% 20% 48% 59% 12% AUS/FLUS 20% 25% 13% 18% 18% 15% FN/SFN 11% 10% 13% 13% 14% 10% SFM 11% 5% 20% 7% 2% 25% Malignant 9% 0% 21% 8% 0% 33%
FNAC,fineneedleaspirationcytology;ND/UNS,nondiagnostic/unsatisfactory;AUS/FLUS,atypiaofundeterminedsignificance/follicular lesionofundeterminedsignificance;FN/SFN,follicularneoplasm/suspectedforafollicularneoplasm;SFM,suspectedformalignancy; HT+,Hashimoto’sthyroiditispresent;HT−,Hashimoto’sthyroiditisabsent.
overallsurvivalrates,thaninpatientswithPTCalone.Ina large retrospective study,19 0.7% cancer-specific mortality anda95%relapse-free10yearsurvivalratewerereported inpatientswithchronicthyroiditiscomparedto5%mortality andan85%relapse-free10yearsurvivalratewithoutchronic thyroiditis.Inourstudy,presenceofHTwasdetectedmore often particularly in patients with TMC. Microcarcinomas are occult carcinoma that are small, ≤10mm in diame-ter,usually papillaryin type andexhibit benign behavior. TMCsrarelymetastasizetodistantsitesandhavean excel-lentprognosiswithareportedmortalitylessthan0.5%.2,25 Furthermore,tumorsizewasnotaffectedbythepresence ofHT.BilateraloccurrenceofmalignancyandHTcorrelated only in TMC group. Based onthese results, the presence ofHashimoto’sthyroiditisisnotaworseprognosticfactor. However,dataintheliteratureontherelationshipbetween PTC and HTwere not primarily focused on tumor size or incidentalomas.
Papillarythyroidcarcinoma(PTC)oftenpresentsas mul-tifocal or bilateral tumors. In our study, the incidence of multifocal tumors was 12% cases in TC and 29% in TMC group. Bilateral occurrence was also higher in TMC group (20%) compare to TC group (10%). Bilateral occur-renceofmalignancyandHTcorrelatedonlyinTMCgroup. On the other hand, Asanuma et al.26 showed that cases of concurrent diseases are more frequently multicentric (93%) when compared to cases without the association (50%).
Fine needle aspiration cytology is the most impor-tant step in the management of thyroid nodules. FNAC has a sensitivity ranging from 65% to 98% and speci-ficity ranging from 72% to 100%.12 In our study, FNAC was performed in 55% of patients with nodular goiter. High sensitivity and specifity of FNACin the diagnosis of malignant thyroid nodule was observed in both groups of patients. Interestingly, the presence of HT negatively affected the accuracy of FNACin the diagnosis of malig-nancy.
Conclusion
Hashimoto’sthyroiditisisassociatedwithanincreasedrisk ofdevelopingthyroidcarcinoma,especiallythyroid micro-carcinoma.
According to the high incidence of thyroid malignancy inpatientswithHashimoto’sthyroiditisandfrequent mul-ticentricity of these tumors, careful follow-up, clinically aswell aswithcytopathological study of the nodules are necessary.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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