www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
ORIGINAL
ARTICLE
Influence
of
chronic
lymphocytic
thyroiditis
on
the
risk
of
persistent
and
recurrent
disease
in
patients
with
papillary
thyroid
carcinoma
and
elevated
antithyroglobulin
antibodies
after
initial
therapy
夽
Marina
Carvalho
S.
Côrtes,
Pedro
Weslley
Rosario
∗,
Gabriela
Franco
Mourão,
Maria
Regina
Calsolari
SantaCasadeBeloHorizonte,Servic¸odeEndocrinologia,BeloHorizonte,MG,Brazil
Received5January2017;accepted3May2017 Availableonline2June2017
KEYWORDS Thyroidcancer; Chroniclymphocytic thyroiditis; Elevated antithyroglobulin; Persistentand recurrentdisease Abstract
Introduction:Inpatientswithpapillarythyroidcarcinomawhohavenegativeserum thyroglob-ulinafter initialtherapy, theriskofstructuraldisease ishigheramongthosewithelevated antithyroglobulinantibodiescomparedtopatientswithoutantithyroglobulinantibodies.Other studiessuggestthatthepresenceofchroniclymphocyticthyroiditisisassociatedwithalower riskofpersistence/recurrenceofpapillarythyroidcarcinoma.
Objective:Thisprospectivestudyevaluatedtheinfluenceofchroniclymphocyticthyroiditison theriskofpersistenceandrecurrenceofpapillarythyroidcarcinomainpatientswithnegative thyroglobulinbutelevatedantithyroglobulinantibodiesafterinitialtherapy.
Methods:Thiswasaprospectivestudy.Patientswithclinicalexaminationshowingno anoma-lies,basalTg<1ng/mL,andelevatedantithyroglobulinantibodies8---12monthsafterablation wereselected.Thepatientsweredividedintotwogroups:GroupA,withchroniclymphocytic thyroiditisonhistology;GroupB,withouthistologicalchroniclymphocyticthyroiditis. Results:Thetimeoffollow-uprangedfrom60to140months.Persistentdiseasewasdetected in3patientsofGroupA(6.6%)andin6ofGroupB(8.8%)(p=1.0).Duringfollow-up,recurrences werediagnosedin2patientsofGroupA(4.7%)andin5ofGroupB(8%)(p=0.7).Considering bothpersistentandrecurrentdisease,structuraldiseasewasdetectedin5patientsofGroup A(11.1%)andin11ofGroupB(16.1%)(p=0.58).Therewasnocaseofdeathrelatedtothe disease.
夽 Pleasecitethisarticleas:CôrtesMC,RosarioPW,MourãoGF,CalsolariMR.Influenceofchroniclymphocyticthyroiditisontheriskof
persistentandrecurrentdiseaseinpatientswithpapillarythyroidcarcinomaandelevatedantithyroglobulinantibodiesafterinitialtherapy. BrazJOtorhinolaryngol.2018;84:448---52.
PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial.
∗Correspondingauthor.
E-mail:[email protected](P.W.Rosario).
https://doi.org/10.1016/j.bjorl.2017.05.005
1808-8694/©2017Associac¸˜aoBrasileiradeOtorrinolaringologiaeCirurgiaC´ervico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
Conclusion: Our results do not support the hypothesis that chronic lymphocytic thyroiditis is associated with alowerrisk ofpersistent orrecurrent disease,at leastinpatients with persistently elevatedantithyroglobulin antibodies after initial therapy for papillary thyroid carcinoma.
© 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/). PALAVRAS-CHAVE Câncerdetireoide; Tireoiditelinfocítica crônica; Antitiroglobulina elevada;
Doenc¸apersistentee recorrente
Influênciadatireoiditelinfocíticacrônicasobreoriscodedoenc¸apersistentee recorrenteempacientescomcarcinomapapilíferodetireoideeanticorpos antitireoglobulinaelevadosapósaterapiainicial
Resumo
Introduc¸ão: Empacientescomcarcinomapapilíferodetireoideecomtireoglobulinasérica neg-ativaapósaterapiainicial,oriscodedoenc¸aestruturalémaiorentreaquelescomanticorpos antitireoglobulinaelevadosemcomparac¸ãocompacientessemanticorposantitireoglobulina. Outros estudossugeremqueapresenc¸adetireoiditelinfocíticacrônicaestáassociadaaum menorriscodepersistência/recorrênciadocarcinomapapilíferodeteireoide.
Objetivo: Esteestudoprospectivoavaliouainfluênciadatireoiditelinfocítica crônicasobre oriscode persistênciaerecorrência docarcinomapapilíferodetireoideem pacientescom tireoglobulinanegativa,mascomanticorposantitireoglobulinaselevadosapósaterapiainicial. Método: Essefoi um estudo prospectivo,noqual foramselecionados pacientescomexame clínicosemanomalias;tireoglobulinabasal<1ng/mLeanticorposantitireoglobulinaelevados 8-12mesesapósablac¸ão.Ospacientesforamdivididosemdoisgrupos:GrupoA,comtireoidite linfocíticacrônicanoexamehistológico;GrupoB,histologicamentesemtireoiditelinfocítica crônica.
Resultados: Otempodeseguimentovarioude60a140meses.Doenc¸apersistentefoidetectada em3pacientesdoGrupoA(6,6%)eem6doGrupoB(8,8%)(p=1,0).Duranteoseguimento, asrecidivasforamdiagnosticadasem2pacientesdoGrupo A(4,7%)eem5doGrupoB(8%) (p=0,7).Considerandotantoadoenc¸apersistentequantoarecorrente,doenc¸aestruturalfoi detectadaem5pacientesdoGrupoA(11,1%)eem11doGrupoB(16,1%)(p=0,58).Nãohouve nenhumcasodeóbitorelacionadoàdoenc¸a.
Conclusão:Nossos resultados não apoiam a hipótese de que atireoidite linfocítica crônica esteja associada a um menor risco de doenc¸a persistente ou recorrente, pelo menos em pacientescomanticorposantitireoglobulinapersistentementeelevadosapósaterapiainicial docarcinomapapilíferodetireoide.
© 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
Inpatientswithpapillarythyroidcarcinoma(PTC)whohave negativeserumthyroglobulin(Tg)afterinitialtherapy,the riskofstructuraldiseaseissignificantlyhigheramongthose withelevatedantithyroglobulinantibodies(TgAb)compared topatientswithoutTgAb.1---3Otherstudiessuggestthatthe
presenceofchroniclymphocyticthyroiditis(CLT)is associ-ated witha lowerrisk ofpersistence/recurrenceof PTC.4
Although the association of these findings(elevated TgAb andCLT)iscommon,manypatientswithelevatedTgAbdo
nothaveCLT.1,2,5---7Thus,itispossiblethatinpatientswith
elevated TgAb, the risk of tumor persistence/recurrence differs between those with and without associated CLT, withalower riskbeing expectedfor theformer.4 In fact,
some studies have demonstratedthis protective effectof
CLTspecificallyinpatientswithelevatedTgAb.5,7However,
otherseriesfoundnoinfluenceof CLTontheevolutionof these patients.1,2 In contrast, one study demonstrated a
higherriskofpersistent/recurrentdiseaseinpatientswith PTCandelevatedTgAbwhenthelatterwereassociatedwith CLT(comparedtononspecificTgAbandnotrelatedtoCLT).6
Thisdivergenceintheresults,togetherwiththe limita-tionsofthestudiesthatwereretrospectiveandincludeda limitednumberofpatientswithelevatedTgAb,1,2,5---7shows
thattheinfluenceofCLTontumorpersistence/recurrence inpatientswithTgAbremainsundefined.Inaddition,tumor persistenceandrecurrencearedistinctoutcomesandtheir separateanalysisisdesirable.3
In view of the need for further, ideally prospective, studies that include a largernumber of patients and are specificallydesigned,6,7weconductedthisprospectivestudy
toevaluatetheinfluenceofCLTontheriskofpersistence andrecurrenceofPTCinpatientswithnegativeTgbut ele-vatedTgAbafterinitialtherapy.
Methods
Thiswasaprospectivestudy.Thestudywasapprovedbythe EthicsCommitteeonResearchofourInstitution(n◦411.326) andinformedconsentwasobtainedfromeachpatient.
Patientsconsecutively seen at ourinstitution whomet thefollowing criteriawere selected:(i)diagnosis of PTC; (ii) submitted to total thyroidectomy followed by abla-tionwith131I(1.1---5.5GBq);(iii)apparentlycompletetumor Resectionand post-therapyWhole-Body Scanning(RxWBS) showing no ectopic uptake; and (iv) clinical examination showing no anomalies, basal Tg<1ng/mL, and elevated TgAb8---12monthsafterablation.8Patientswith
microcar-cinoma restricted to the thyroid or with the noninvasive encapsulatedfollicular variant of PTC werenot included. Ablation wasalso recommendedfor patients with1---4cm PTC confined to the thyroid (n=36) but who had other features(age≤18years or >45years,multicentric tumor, elevatedTgorTgAbafterthethyroidectomy).Thepatients weredividedintotwogroups:GroupA,withCLTon histol-ogy;GroupB,withoutCLTonhistology.
Neck ultrasonography (US), stimulated Tg, and diag-nostic WBS (DxWBS) were obtained from all patients during initial assessment.8 Patients with a stimulated
Tg>1ng/mL without disease on DxWBS and US were evaluatedbychestcomputedtomography(CT), technetium-99m-methoxyisobutylisonitrile(99mTc-MIBI)scintigraphy,and fluorodeoxyglucose positron emission tomography (FDG-PET)/CT.8Inthecaseofpatientswithoutdiseaseinthisfirst
assessment,Tg,TgAbandUSwereobtainedatintervalsof 6months.Inaddition,chestCTwasperformedannuallyin patientswithtumors>4cm,extrathyroidextensionorlymph nodemetastases,andevery2yearsinpatientswithtumors ≤4cmrestrictedtothethyroid,whileTgremainednegative andTgAbcontinuedtobepositive.IfTgAbelevationor pos-itiveTgwasobserved atany timeduringfollow-up,chest CT,99mTc-MIBIscansandFDG-PET/CTwereperformed.TSH wasmaintained≤0.5mIU/L.
Eightto12monthsafterablationwith131I,serumTgwas measuredbyaradioimmunometricassay(ELSAhTG,CISBio International),withafunctionalsensitivityof1ng/mL.TgAb weredeterminedby achemiluminescent assay (Immulite, DiagnosticProductsCorp.),withareferencevalueofupto 40IU/mL.
CLTwasdefinedwhendiffuselymphocyteinfiltrationwas presentintheareaofnormalthyroidtissue.2
MeanswerecomparedbetweengroupsbyStudentt-test
orthenonparametricMann---WhitneyUtest.Fisher’sexact testor2testwasusedtodetectdifferencesinthe propor-tionofcases.Ap-value<0.05wasconsideredsignificant.
Results
GroupsA and Bwere similarin terms of sex, age, lymph nodemetastases, TNMstageand risk category,9 andTgAb
concentrationsafterablation(Table1).Thetimeof follow-uprangedfrom60to140months(median96months).
Table1 CharacteristicsofthepatientsofGroupsAandB. GroupA (n=45) GroupB (n=68) Sex Women 42(93.3%) 61(89.7%) Men 3(6.6%) 7(10.2%) Age[range (median),years] 13---72(46) 18---74(48) Riskclassification9 Lowrisk 18(40%) 26(38.2%) Intermediate risk 27(60%) 42(61.7%) Lymphnode metastases 20(44.4%) 28(41.2%) Stage9 I 24(53.3%) 40(58.8%) II 4(8.9%) 6(8.8%) III 9(20%) 14(20.6%) IVA 8(17.7%) 8(11.7%) TgAb[range (median), IU/mL]a 65---2845(556) 76---2567(568) Timeoffollow-up [range (median), months] 60---140(96) 62---140(96)
GroupA,withchroniclymphocyticthyroiditis(CLT)onhistology; GroupB,withoutCLTonhistology.
TgAb,antithyroglobulinantibodies.
a 8---12monthsafterinitialtherapy.
8---12 months after ablation, persistent disease was detectedin3patientsofGroupA(6.6%)andin6ofGroup B (8.8%) (p=1.0), including lymph node metastases in 2 patientsofGroupA(4.4%)andin4ofGroupB(5.9%)(p=1.0) anddistantmetastasesin1patientofGroupA(2.2%)andin 2ofGroup B(2.9%)(p=1.0).Neck USshowedlymphnode metastasesinfourpatients.DxWBSrevealedectopicuptake intwopatientsandCTshowedlymphnodesinthe topogra-phy ofectopicuptake. Inanotherpatient,DxWBSshowed pulmonarymetastases,butachestCTwasnormal.DxWBS was negative in two patients, but pulmonary metastases weredetectedbychestCTinoneandbonemetastaseswere detectedbyFDG-PET/CTintheother.
Duringfollow-up ofthe104patientswithout persistent disease,recurrenceswerediagnosedin2patientsofGroup A(4.7%)andin5ofGroupB(8%)(p=0.7),includinglymph node metastases in2 patients of GroupA (4.7%) andin 4 ofGroupB(6.4%)(p=1.0)anddistantmetastasesinanyof thepatientsofGroupAandin1patientofGroupB(1.6%) (p=1.0).USshowedlymphnodemetastasesin 5patients, CTrevealedpulmonarymetastasesinone,andFDG-PET/CT waspositiveinanotherpatient.
Consideringboth persistentandrecurrentdiseaseafter initialtherapy,structuraldiseasewasdetectedin5patients ofGroupA(11.1%)andin11ofGroupB(16.1%)(p=0.58), includinglymphnodemetastases in4patients ofGroup A (8.8%) and in 8 of Group B (11.7%) (p=0.76) and distant
metastasesin1patientofGroupA(2.2%)andin3ofGroup B(4.4%)(p=1.0).
We separately analyzed the outcomes for low-risk and intermediate-risk patients classified according to ATA.9 In
intermediate-riskpatients,persistentdiseasewasdiagnosed in3patientsofGroupA(11.1%)andin6ofGroupB(14.3%) (p=1.0)andrecurrencesoccurredin2patientsofGroupA (8.3%)and3ofGroupB(8.3%)(p=1.0),totaling5patients inGroupA(11.1%)and9inGroupB(13.2%)(p=1.0).Inthe low-riskgroup,9ofthepatientshadpersistentdiseaseand recurrenceswerediagnosedinanyofthepatientsofGroup Aandin2ofGroupB(7.7%)(p=0.51).
Therewasnocaseofdeathrelatedtothedisease.
Discussion
First,itshouldbehighlightedthat,incontrasttoprevious studies,1,2,5---7 this wasa prospective study.To the bestof
ourknowledge,thisisthelargeststudyevaluatingthe influ-enceofCLTspecificallyinpatientswithelevatedTgAb.The minimumtimeoffollow-upwas5yearsanditisknownthat 80% of recurrences occur in thesefirst years.2 Sincethey
aredistinctoutcomes,persistentandrecurrentdiseasewere analyzedseparatelyandcombined.
ItisknownthatmanypatientswithPTCwithpersistently elevatedTgAbafterinitialtherapydonothaveCLT;60%in thepresent series and30%,7 60%2,5 and65%1,6in previous
studies.Itcanbeassumedthatthepersistenceofelevated TgAbaftertreatment ofPTC intheabsenceofunderlying CLTwillindicateresidualdisease.Inaddition,CLThasbeen associatedwithbetterevolutionofPTC.4Thissupportsthe
hypothesisthatCLTisassociatedwithalowerriskof persis-tent/recurrentdiseaseinpatientswithelevatedTgAbafter treatmentofPTC.
EvaluatingspecificallypatientswithelevatedTgAbafter initial therapy, this protective effect of CLT was demon-strated in two series,5,7 but was not confirmed by other
authors.1,2,6OurresultsalsoshowednoinfluenceofCLTon
therateofpersistentor recurrentdiseaseinpatientswith elevated TgAb. Moreover, onestudy showed worse evolu-tionof patientswithelevated TgAbwhen associatedwith CLT.6Inviewofthedivergentresults,1,2,5---7presentstudy,it
ispossiblethatdifferencesinTgAbepitopes6andinthecell
subpopulationofthelymphocyteinfiltrate10explainthe
het-erogeneityoftheinfluenceofCLTontheevolutionofPTC. Asinthepresentstudy,thelackofinfluenceofCLTon recur-rentdiseasehasrecentlybeenreportedforpatientswithout TgAb.11
Finally,althoughpreviousstudiesfoundnodifferencein therateofpersistent/recurrentdisease,theyreportlower tumoraggressivenessoninitialpresentationinpatientswith
CLT.12---14 Although it wasnot theobjective ofthe present
study,wefoundnodifferenceinthepresenceoflymphnode metastases,riskcategoryortumorstagebetweenpatients withversuswithoutCLT.
Conclusion
Inconclusion,ourresultsdonotsupportthehypothesisthat CLTonhistologyisassociatedwithalowerriskofpersistent
orrecurrentdisease,at leastinpatients withpersistently elevatedTgAbafterinitialtherapyofPTC.
Funding
This researchdid notreceive any specific grant fromany fundingagencyinthepublic,commercialor not-for-profit sector.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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