www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
ORIGINAL
ARTICLE
Papillary
thyroid
carcinoma:
does
the
association
with
Hashimoto’s
thyroiditis
affect
the
clinicopathological
characteristics
of
the
disease?
夽
,
夽夽
Fábio
Muradás
Girardi
a,∗,
Marinez
Bizarro
Barra
b,
Cláudio
Galleano
Zettler
baHeadandNeckSurgeryDepartment,HospitalSantaRita,ComplexoHospitalarSantaCasadePortoAlegre,PortoAlegre,RS,Brazil bPathologyDepartment,HospitalSantaRita,ComplexoHospitalarSantaCasadePortoAlegre,PortoAlegre,RS,Brazil
Received20January2014;accepted12April2014 Availableonline22October2014
KEYWORDS Thyroidneoplasms; Prognosis;
Papillarycarcinoma
Abstract
Introduction:Papillarycarcinomaisthemostcommonmalignantthyroidneoplasm.Theeffect oftheconcurrentpresenceofHashimoto’sthyroiditisandpapillarythyroidcarcinomaremains controversial.
Objective: ToevaluatetheassociationbetweenHashimoto’sthyroiditisandclinicopathological parameters inthyroidpapillarycarcinomacases,based onanhistoricalinstitutional cohort analysis.
Methods:Cross-sectionalstudyobtainedfromahistoricalcohort,includingallcasessubmitted tothyroidectomyforpapillarythyroidcarcinomainasingleinstitutionduringan11-yearperiod study.
Results:Atotalof417patientswithpapillarythyroidcarcinomawereenrolled;148(35.4%)also hadHashimoto’sthyroiditis.Afemalepredominanceamongcasesassociated toHashimoto’s thyroiditis was observed.The thyroidtumor, incases associatedwith Hashimoto’s thyroidi-tis, hada smaller mean diameter,lower frequency ofextra-thyroid extension, and earlier clinicopathologicalstaging.
Conclusions: A high proportion of papillary thyroid carcinoma cases are associated with Hashimoto’sthyroiditis.Thereareassociationsamongthesecaseswithseveral histopatholog-icalfactorsalreadyrecognizedfortheirprognosticvalue,whichbythemselvescouldimpact outcomes.
© 2014Associac¸ãoBrasileira de Otorrinolaringologiae CirurgiaCérvico-Facial. Publishedby ElsevierEditoraLtda.Allrightsreserved.
夽 Pleasecitethisarticleas:GirardiFM,BarraMB,ZettlerCG.Papillarythyroidcarcinoma:doestheassociationwithHashimoto’sthyroiditis
affecttheclinicopathologicalcharacteristicsofthedisease?BrazJOtorhinolaryngol.2015;81:283---7.
夽夽Institution:ComplexoHospitalarSantaCasadePortoAlegre,PortoAlegre,RioGrandedoSul,RS,Brazil.
∗Correspondingauthor.
E-mail:[email protected](F.M.Girardi). http://dx.doi.org/10.1016/j.bjorl.2014.04.006
PALAVRAS-CHAVE Neoplasiasda glândulatireoide; Prognóstico; Carcinomapapilar
Carcinomapapilíferodatireoide:aassociac¸ãocomtireoiditedeHashimotoinfluencia nascaracterísticasclínico-patológicasdadoenc¸a?
Resumo
Introduc¸ão:Ocarcinomapapilíferoéaneoplasiamalignamaiscomumdatireóide.Oefeitoda coexistênciadatireoiditedeHashimoto(TH)noprognósticodocarcinomapapilíferodatireóide (CPT)permanececontroverso.
Objetivo:Avaliaraassociac¸ãoentreTHeparâmetrosclínico-patológicosentrepacientescom diagnósticodecarcinomapapilíferodatireóideobtidosatravésdaanálisedeumasériehistórica institucional.
Método: Coorte transversal com baseem uma coorte histórica, envolvendotodos os casos submetidosàtireoidectomiatotalpormotivodecarcinomapapilífero,realizadas namesma Instituic¸ãoaolongode11anos.
Resultados: Umtotalde417pacientesforamincluídosnoestudo,estando148(35,4%) associa-dosàTH.ObservamospreponderânciademulheresentreoscasosassociadosàTH.Essescasosse apresentaramcommenormédiadediâmetrotumoral,menorfrequênciadecomprometimento extra-tireoidianoeestadiamentoclínico-patológicomaisprecoce.
Conclusões:Um percentual expressivo de casos de CPT apresenta-se associado à TH. A associac¸ãoentreessescasos,comváriosfatoreshistopatológicosjáreconhecidosporseuvalor prognóstico,podeporsísóinfluenciarnodesfechodessespacientes.
©2014Associac¸ãoBrasileira deOtorrinolaringologiaeCirurgiaCérvico-Facial.Publicadopor ElsevierEditoraLtda.Todososdireitosreservados.
Introduction
Papillarythyroidcarcinoma(PTC)andHashimoto’s thyroidi-tis(HT)arecommondiseasesinclinicalpractice.Papillary carcinomaisthemostcommonmalignantneoplasmofthe thyroid.HTisthemostprevalentautoimmunediseaseand oneofthe mostcommon endocrinediseases.1 This
condi-tionisthemostcommoncauseofhypothyroidism,excluding
cases secondary to thyroidectomy, that are predominant
amongfemales.2TheassociationbetweenPTCandHTwas
firstdescribedin1955byDaileyetal.,3andbecameevident
because of an increase in new cases of thyroiditis
diag-nosedbyanatomopathologicalexamsoverthepastdecades.
The concept of chronic inflammation as a risk factor for
thedevelopmentofmalignancieshasbeenwellestablished
forothertumors.However,withrespecttothesetwo
enti-ties, the association of cause and effect between them
remains uncertain.4 Both diseases may have a subclinical
course and may be merely an incidental diagnosis. Most
publicationsonthesubjectarebasedonhistoricalreviews
ofseriesofpatientsundergoingthyroidectomy,oronlarge
exploratorystudiesamongpatientswhounderwentfine
nee-dleaspiration(FNA).4Theresultsnowavailabledonotallow
definitiveconclusions, althoughtheevidencethat
nonspe-cific focal or multifocal lymphocytic infiltrates may also
occur more frequently in cases of PTC suggests that the
tumor can exert some degree of influence on the rest of
thegland.1
SomeauthorshavereportedthatthepresenceofHTin
patientswithPTCisassociatedwithalessaggressive
clini-calpresentationandcourse.5---7However,otherstudieshave
not found similar effects.8---10 The objective of this study
wasto investigate a large institutional series of patients
with PTC noting the prevalence of an association of HT
and, comparing clinicopathological characteristics of PTC
patientswithorwithoutanassociatedHT.
Methods
Patients
The histopathological records of all patients who
under-went total thyroidectomy at this institution with a final
histopathological diagnosis of PTC from June of 2000 to
Decemberof2010werereviewed.Of623casesof
thyroidec-tomy due tothyroid cancer conducted in theperiod, 417
(66.97%)mettheinclusioncriteria.Allpatientsunderwent
clinicalandultrasonographicevaluationinthepreoperative
period. Relevant cases underwent cytologic evaluation of
thyroidnodulesbyFNA.Neckdissectionproceduresinthe
centralorlateralcompartmentarenotperformedelectively
at this institution, but ratherare reservedfor caseswith
clinicalorultrasonographicevidenceoflymphnode
metas-tases.Patientswithnonspecificfocal(16cases)ormultifocal
(40cases)thyroiditis,casesofthyroiddiseaseduetoGraves’
disease (two cases) or xanthogranulomatousinflammation
(fourcases),casessubmittedtopartialthyroidectomy (60
cases), cases with more than one tumor histology in the
samegland(twosynchronouscasesofpapillaryand
follicu-lar carcinoma, andone synchronous case of papillaryand
medullary carcinoma), and cases with no information on
tumoraldiameter(19cases)wereexcludedfromthe
analy-sis.
The following parameters were entered into a
dedi-cated database (Microsoft Excel® 2003 version; Microsoft
Corporation ---Redmond, WA, UnitedStates): age,gender,
detailed histopathological description, predominant
nod-ule diameter, multifocality, multicentricity, extra-thyroid
extension,T,N,andMstaging,andclinicopathological
stag-ing.
Definitionsandpathology
Inthisstudy,tumorswereconsideredmultifocalwhentwoor
morefociwerefoundinthesamelobeofthegland.Tumors
were considered multicentricwhen the presence of more
than one tumor focusin different lobes of the glandwas
found.Thediagnosis ofHTwasbasedonhistopathological
findings.Accordingtothestudy ofMizukamietal.,11 only
caseswithanassociationoflymphoplasmacyticinfiltration
with germinative center formation, oxyphilic cell
meta-plasia (Hürtle), atrophy, and fibrosis of thyroid follicles12
(also called signs of chronic oxyphilic lymphocytic
thy-roiditis) wereclassified asHT. Papillary microcarcinomata
weredefinedastumorswithdiameter≤1.0cmat
histologi-calexamination.Theclinicopathologicalstagingprocedures
wereperformed accordingtotheAmericanJoint
Commit-teeonCancerTNMstagingsystem(7thEdition).13Thelymph
nodestatuswasdefinedbypathologicalevidenceof
metas-tasisinthelymphnodesthatwereremoved.Extra-glandular
involvement wasdetermined basedon evidenceof tumor
infiltratesbeyondtheglandcapsule,atmicroscopic
exam-ination. All data were collected by the same researcher
(GirardiFM)andallpathologicreviewswereperformedby
thesamepathologist(BarraMB).
Statisticalanalysisandethicalaspects
Descriptive analysis was used to summarize data. The
Kolmogorov---Smirnovtestwasperformedtoassessthe
nor-mality of continuous variables. Continuous variables with
normaldistributionwereexpressedasmeansandstandard
deviations. Those with non-normal distribution were also
expressedasmedianandminimum---maximum values.
Cat-egoricalvariableswereexpressedasabsoluteandrelative
frequency.Student’st-test wasusedtocomparemeansof
age,theMann---WhitneyUtesttocomparetumorsize,and
thenon-parametricchi-squaredtestforthecomparisonof
categoricalvariables.Thisstatisticalanalysiswasperformed
usingSPSS softwareversion15.0 (SPSSInc.--- Chicago,IL,
UnitedStates). Alltestsconsidered asignificance levelof
5%.
Theauthorsguaranteethepreservationofdataandthe
confidentialityofthematerialobtained.Asnointerventions
were performed, an informedconsentdid not apply.This
projectwasapprovedbytheresearchethicscommitteeof
thisinstitution(ProjectNo.3483/11).
Results
Atotal of417 caseswere included inthis study,
compris-ing 66.97% of the cases submitted to thyroidectomy for
cancerat theinstitutionfrom2000to2010.Of thistotal,
339(81.2%)werewomen.Themale:femaleratiowas1:4.3.
Themeanagewas46.73(12.14)years,rangingfrom13to
87 years. In 148 (35.4%) cases,the patient harbored PTC
together with HT. A statistically significant association of
PTCwithHTwasobserved,whencomparedtoother
histo-logicalsubtypes(p<0.001).PatientswithcoexistingPTCand
HTpresentedatanearlierclinicopathologicalstageandwith
alowerrateofextra-glandularinvolvement(Table1).There
wasapredominanceoffemalesamongcasesassociatedwith
thyroiditis. This study did notobserve statistically
signifi-cantdifferencesinthevariable‘‘age’’betweengroups,nor
withrespecttomultifocality,multicentricity,neurovascular
invasion,andMstaging.Similarly,nosignificantdifference
was found with respect to N staging, despite the higher
frequencyof cervicallymphadenectomy inthegroup with
chroniclymphocyticdisease.
Discussion
ThecoexistenceofHTandthyroidcancerhasbeenreported
severaltimesinliterature.Lohetal.foundastrong
associ-ationbetweenPTCandlymphocyticthyroiditis6---afinding
consistentwithother studies.2,5,14---16 Inthe present study,
the prevalence of HT associated with PTC was 35.4%, a
ratesimilar tothat found in the study conducted by Kim
et al.17 However, its influence on the behavior of
thy-roid carcinoma is still a matter of debate. Some studies
reported a worse prognosis among cases associated with
thyroiditis.18,19Otherinvestigationsfoundasimilarbehavior
amongcaseswithorwithoutassociatedthyroiditis.20
How-ever,themajorityofstudiesshowedaprotectiveeffectof
lymphocyticdisease.5,6,14,21---25Kashimaetal.reported
mor-talityanddisease-freeintervalaftertenyearsof5%and85%
amongpatientswithoutassociatedthyroiditis,comparedto
0.7%and95%amongcaseswithassociation,respectively.5
Thefavorableoutcomeofthesepatientssuggeststhatthe
association with thyroiditis may represent an anti-tumor
response,26 although it is not clear whether the
coexis-tenceof both diseases is not simplya greater chance for
asynchronousoccurrenceoftwohigh-prevalencediseases.
Loh et al. noted that the association with HT was
asso-ciatedwithlower recurrenceand mortalityrates. In that
study,thegroupwiththehigherrecurrencerateshoweda
higherfrequencyoflymphnodemetastases,whichmayhave
contributedgreatly totherisein thisrate. Evenwiththe
maintenanceof statisticalsignificanceafterthe
multivari-ateanalysisofthe associationwithgoodprognosis among
casesaffectedby HT, theresearchersofthat study failed
toelucidatethedifferencesinaspectsrelatedtotreatment
betweenthetwostudy groups.Moreover,thevarious
sub-types of thyroid lymphocytic infiltrate were included. No
oneknowstheexactprognosticinfluencesofthesesubtypes,
althoughitisknownthattheymayrepresentthespectrum
ofmanifestationsofchroniclymphocyticthyroiditis.6These
methodologicalfeatureswerefurtherexploredinthestudy
byJeongetal.,whoalsodemonstratedalowerrecurrence
amongcases associated with HT.27 However,both in that
studyandinothers,theassociation withHTdidnot
func-tionasanindependentpredictorofalowerrecurrencerate
afteramultivariateanalysis.23,27
Itis possible that thebetter prognosisof cases
associ-atedwithHTsimplyarises fromanassociation withother
factorshistoricallyrecognizedforbetterprognoses,ashas
been observed among variantsor tumor histopathological
Table1 Analysisofclinicalandpathologicalcharacteristicsaccordingtothepresence orabsenceofHashimotothyroiditis amongcasesofpapillarythyroidcarcinoma.
Hashimotothyroiditis
Present Absent Total p-Value
Mean(SD) Mean(SD) Mean(SD)
Age(years) 45.97(14.10) 47.15(14.14) 46.73(14.12) 0.418
Tumordiameter(cm) 1.40(1.15) 1.91(1.70) 1.73(1.54)
---Median(Min---Max) Median(Min---Max) Median(Min---Max) p-Value
Tumordiameter 1.2(0.04---6.5) 1.3(0.1---9) 1.2(0.04---9) 0.007
n(148) %(35.4) n(269) %(64.5) n(417) %(100) p-Value
Women/men 136/12 91.8/8.1 203/66 75.4/24.5 339/78 81.2/18.7 <0.001
Neurovascularinvasion 9 6.0 18 6.6 27 6.4 0.972
Multifocality 32 21.6 53 19.7 85 20.3 0.735
Multicentricity 54 36.4 78 28.9 132 31.6 0.143
Extracapsularinvasion 33 22.2 96 35.6 129 30.9 0.006
Lymphadenectomy 79 53.3 102 37.9 181 43.4 0.003
Tstage
1 98 66.2 126 46.8 224 53.7
0.002
2 12 8.1 31 11.5 43 10.3
3 38 25.6 109 40.5 147 35.2
4 0 0 3 1.1 3 0.7
Nstage
0ouX 115 77.7 200 74.3 315 75.5
0.240
1a 23 15.5 37 13.7 60 14.3
1b 10 6.7 32 11.8 42 10.0
Mstage
0 148 100 267 99.2 415 99.5
0.755
1 0 0 2 0.7 2 0.4
Clinicopathologicalstaging
I 119 80.4 181 67.2 300 71.9
0.019
II 5 3.3 10 3.7 15 3.5
III 22 14.8 63 23.4 85 20.3
IV 2 1.3 15 5.5 17 4.0
n,absolutefrequency;%,relativefrequency;SD,standarddeviation;Min---Max,variationbetweenminimumandmaximum;p-value, levelofsignificanceused;multifocality,referstomorethanonetumorfocusinthesamelobe;multicentricity,referstothepresence ofbilateraldisease.
lowermean tumor diameter, and lowermean age among cases associated with HT.23 However, in another study, a
higherfrequency of bilateral diseaseamong cases
associ-atedwithHTwasfound,althoughitsauthorsnotedinthe
samepatients,agreater rateoftotal thyroidectomythan
inthe controlgroup.17 Thepresent study observed ahigh
prevalenceofbilateraldisease(31.6%),preponderantinthe
groupassociatedwithHT,althoughwithoutstatistical
signif-icance.SimilartothestudiesofJeongetal.andYoonetal.,
wefoundalowermeantumordiameterandlowerrateof
extracapsularinvasionamongcasesassociatedwithHT.27,29
This set of variables, historically recognized by different
prognosticsteps,distinguishPTCcasesassociatedwithHT
asapeculiarpatternofdiseasepresentation.
Jeongetal.observedagreaternumberoflymphnodes
resected among cases undergoing cervical
lymphadenec-tomyin thegroupassociated withsigns ofHT.27 Similarly,
ourstudyfoundahigherrateofcervicallymphadenectomy
amongcasesassociatedwithHT.Inthisservice,cervical
lym-phadenectomiesareperformedonlyforcaseswithaclinical
suspicion of PTC or withmetastatic disease suggested by
imagingstudies.Sincetheratesofmetastasesdidnot
dif-ferbetweengroups,aswasobservedbyJeongetal.,this
may suggestthat, for some reason,possiblyinflammatory
factors, there are more clinically suspicious lymph nodes
amongpatientswithadiagnosisofHT.27
Conclusions
In this study, we found a high prevalence of association
between HTandPTC. The presenceof HTwasassociated
withdiseasepresentationatanearlierstageandwith
ofsurgery,which couldper seinfluence theprognosisand
recurrence.However,todate,thefindingofanassociation
ofHTwithPTCshouldnotmodifythemedicalmanagement;
rather,thisfindingsimplyshoulddrawthephysician’s
atten-tiontoapeculiarpatternofdiseasepresentation.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
References
1.CaturegliP, DeRemigisA, ChuangK, Dembele M, IwamaA, IwamaS.Hashimoto’s thyroiditis:celebrating thecentennial throughthelensoftheJohnsHopkinshospitalsurgical pathol-ogyrecords.Thyroid.2013;23:142---50.
2.KonturekA,Barczy´nskiM,WierzchowskiW,StopaM,NowakW. Coexistenceofpapillary thyroidcancer withHashimoto thy-roiditis.LangenbecksArchSurg.2013;398:389---94.
3.Dailey ME, Lindsay S, Skahen R. Relation of thyroid neo-plasmstoHashimotodiseaseofthethyroidgland.ArchSurg. 1955;70:291---7.
4.JankovicB,LeKT,HershmanJM.Clinicalreview:Hashimoto’s thyroiditisandpapillarythyroidcarcinoma:istherea correla-tion.JClinEndocrinolMetab.2013;98:474---82.
5.KashimaK,YokoyamaS,NoguchiS,MurakamiN,YamashitaH, WatanabeS,etal.Chronicthyroiditisasafavorableprognostic factorinpapillarythyroidcarcinoma.Thyroid.1998;8:197---202. 6.LohKC,GreenspanFS,DongF,MillerTR,YeoPPB.Influenceof lymphocyticthyroiditisontheprognosticoutcomeofpatients with papillary thyroid carcinoma. J Clin Endocrinol Metab. 1999;84:458---63.
7.SchafflerA,PalitzschKD,SeiffarthC,HöhneHM,Riedhammer FJ,HofstädterF,etal.Coexistentthyroiditisisassociatedwith lowertumour stage in thyroid carcinoma.Eur JClinInvest. 1998;28:838---44.
8.SinghB,ShahaAR,TrivediH,CarewJF,PoluriA,ShahJP. Coex-istentHashimoto’sthyroiditiswithpapillarythyroidcarcinoma: impactonpresentation,management,andoutcome.Surgery. 1999;126:1070---6.
9.Kebebew E, Treseler PA, Ituarte PH, Clark OH. Coexisting chronic lymphocytic thyroiditis and papillary thyroid cancer revisited.WorldJSurg.2001;25:632---7.
10.DelRioP,CataldoS,SommarugaL,ConcioneL,ArcuriMF,Sianesi M.Theassociation betweenpapillary carcinomaand chronic lymphocyticthyroiditis:doesitmodifytheprognosisofcancer. MinervaEndocrinol.2008;33:1---5.
11.Mizukami Y, Michigishi T, Kawato M, Sato T, Nonomura A, HashimotoT,etal.Chronicthyroiditis:thyroidfunctionand his-tologiccorrelationsin601cases.HumPathol.1992;23:980---8. 12.LiVolsiVA.Pathologyofthethyroidgland.In:BarnesL,editor.
Surgicalpathologyof theheadandneck. 2nd ed.New York: MarcelDekker;2001.p.1673---718.
13.EdgeSE,ByrdDR,CarducciMA,ComptonCA.AJCCcancer stag-ingmanual.7thed.NewYork:Springer;2010.
14.Matsubayashi S, Kawai K, Matsumoto Y, MukutaT, Morita T, HiraiK,etal.Thecorrelationbetweenpapillarythyroid car-cinomaandlymphocyticinfiltrationinthethyroidgland.JClin EndocrinolMetab.1995;80:3419---24.
15.DeGrootLJ,KaplanEL,McCormickM,StrausFH.Naturalhistory, treatment,and courseofpapillarythyroid carcinoma.JClin EndocrinolMetab.1990;71:414---24.
16.ClarkOH.Predictorsofthyroidtumor aggressiveness.WestJ Med.1996;165:131---8.
17.KimHS,ChoiYJ,YunJS.Featuresofpapillarythyroid microcar-cinomainthepresenceandabsenceoflymphocyticthyroiditis. EndocrPathol.2010;21:149---53.
18.Pellegriti G, Belfiore A, GiuffridaD, LupoL, Vigneri R. Out-comeof differentiatedthyroid cancerin Graves’patients.J ClinEndocrinolMetab.1998;83:2805---9.
19.Ozaki O, Ito K, Kobayashi K, Toshima K, Iwasaki H, Yashiro T. Thyroid carcinoma in Graves’ disease. World J Surg. 1990;14:437---40.
20.MuzzaM,Degl’InnocentiD, ColomboC,Perrino M,RavasiE, RossiS,etal.Thetightrelationshipbetweenpapillarythyroid cancer,autoimmunityandinflammation:clinicalandmolecular studies.ClinEndocrinol(Oxf).2010;72:702---8.
21.OzakiO,ItoK,MimuraT,SuginoK,HosodaY.Papillary carci-nomaofthethyroid:tall-cellvariantwithextensivelymphocyte infiltration.AmJSurgPathol.1996;20:695---8.
22.SegalK,Ben-BassatM,AvrahamA.Hashimoto’sthyroiditisand carcinomaofthethyroidgland.IntSurg.1985;70:205---9. 23.KimEY,KimWG,KimWB,KimTY,KimJM,RyuJS,etal.
Coexis-tenceofchroniclymphocyticthyroiditisisassociatedwithlower recurrenceratesinpatientswithpapillarythyroidcarcinoma. ClinEndocrinol(Oxf).2009;71:581---6.
24.Souza SL, da Assumpc¸ão LVM, Ward LS. Impact of previous thyroidautoimmunediseasesonprognosisofpatientswith well-differentiatedthyroidcancer.Thyroid.2003;13:491---5. 25.HuangBY,HseuhC,ChaoTC,LinKJ,LinJD.Well-differentiated
thyroid carcinoma with concomitant Hashimoto’s thyroiditis presentwithlessaggressiveclinicalstageandlowrecurrence. EndocrPathol.2011;22:144---9.
26.CunhaLL,FerreiraRC,MarcelloMA,VassalloJ,WardLS. Clin-icaland pathologicalimplications ofconcurrentautoimmune thyroiddisordersandpapillarythyroidcancer.JThyroidRes. 2011;2011:387062.
27.JeongJS,KimHK,LeeCR,ParkS,ParkJH,KangSW,etal. Coex-istenceofchroniclymphocyticthyroiditiswithpapillarythyroid carcinoma:clinicalmanifestation and prognosticoutcome.J KoreanMedSci.2012;27:883---9.
28.Girardi FM, Barra MB,Zettler CG.Variants of papillary thy-roidcarcinoma:association withhistopathologicalprognostic factors.BrazJOtorhinolaryngol.2013;79:738---44.
