BrazJOtorhinolaryngol.2019;85(2):237---243
www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
REVIEW
ARTICLE
Prophylactic
central
neck
dissection
and
local
recurrence
in
papillary
thyroid
microcarcinoma:
a
meta-analysis
夽,夽夽
Hui
Su,
Yujie
Li
∗NingboNo.2Hospital,DepartmentofSurgicalOncology,Ningbo,China Received10April2018;accepted19May2018
KEYWORDS Centralneck dissection; Localrecurrence; Papillarythyroid microcarcinoma; Meta-analysis Abstract
Introduction:Forpapillarythyroidmicrocarcinomapatients,thereportedincidenceoflymph nodemetastasisisashighas40%,andtheseoccurmainlyinthecentralcompartmentofthe neck.Becausethesemetastasesaredifficulttodetectusingultrasonographypreoperatively, some authors advocateroutine centralneck dissectioninpapillary thyroidmicrocarcinoma patientsatthetimeofinitialthyroidectomy.
Objective: Toevaluate whetherprophylacticcentralneckdissectioncandecreasethelocal recurrencerateofpapillarythyroidmicrocarcinomaafterthyroidectomy.
Methods:The publiclyavailable literature published from January 1990 toDecember 2017 concerningthyroidectomyplusprophylacticcentralneckdissectionversusthyroidectomyfor papillary thyroidmicrocarcinoma wasretrieved bysearching thenational andinternational onlinedatabases.Ameta-analysiswasperformedafterthedataextractionprocess.
Results:Four studieswere finallyincludedwithatotalof727patients,ofwhom,366cases underwent thyroidectomy plusprophylactic centralneckdissectionand 361 casesreceived thyroidectomyonly.Asshownbythemeta-analysisresults,therecurrenceratesincasesof thyroidectomyplusprophylacticcentralneckdissectionwereapproximately1.91%andwere sig-nificantlylowerthanthosewiththyroidectomyonly(OR=0.24,95%CI[0.10,0.56],p=0.0009).
Conclusion: Forpatientswithpapillarythyroidmicrocarcinoma,thyroidectomyplus prophylac-ticcentralneckdissectionisasafeandefficientprocedureanditresultsinlowerrecurrence rate.Sincetheevidencesareoflowquality(non-randomizedstudies),furtherrandomizedtrials areneeded.
© 2018 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:SuH,LiY.Prophylacticcentralneckdissectionandlocalrecurrenceinpapillarythyroidmicrocarcinoma:a meta-analysis.BrazJOtorhinolaryngol.2019;85:237---43.
夽夽PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial. ∗Correspondingauthor.
E-mail:liyujie24@gmail.com(Y.Li).
https://doi.org/10.1016/j.bjorl.2018.05.004
1808-8694/©2018Associac¸˜aoBrasileiradeOtorrinolaringologiaeCirurgiaC´ervico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
PALAVRAS-CHAVE Esvaziamento cervicalcentral; Recidivalocal; Microcarcinoma papilíferode tireoide; Metanálise
Esvaziamentocervicalcentralprofiláticoerecidivalocaldemicrocarcinoma papilíferodetireoide:umametanálise
Resumo
Introduc¸ão:A incidênciarelatadade metástaseslinfonodaischega a40%em pacientescom microcarcinomapapilíferodetireoideeessasocorremprincipalmentenocompartimento cer-vicalcentral.Comoessasmetástasessãodifíceisdeserdetectadascomousodeultrassonografia no pré-operatório, algunsautores defendem o esvaziamentocervical central de rotina em pacientesportadoresdemicrocarcinomapapilíferodetireoidenomomentodatireoidectomia inicial.
Objetivo:Avaliarseoesvaziamentocervicalcentralprofiláticopodediminuirataxade recor-rêncialocaldemicrocarcinomapapilíferodetireoideapósatireoidectomia.
Método: A literatura disponível,publicada de janeirode 1990 adezembro de 2017, sobre tireoidectomiacomesvaziamentocervicalcentralprofilático versus tireoidectomiasomente para microcarcinomapapilífero de tireoidefoi obtida atravésdebusca nasbases dedados onlinenacionaiseinternacionais.Ametanálisefoifeitaapósoprocessodeextrac¸ãodedados.
Resultados: Quatroestudosforamfinalmenteincluídosnametanálise,com727pacientes,dos quais366foramsubmetidosàtireoidectomiacomesvaziamentocervicalcentralprofiláticoe 361 sóreceberam tireoidectomia.Comomostrado pelosresultados dametanálise, astaxas de recorrência com tireoidectomiacom esvaziamentocervical centralprofilático foram de 1,91%eforamsignificantementemenoresdoqueaquelasempacientessubmetidossomenteà tiroidectomia(OR=0,24,IC95%[0,10-0,56],p=0,0009).
Conclusão:Parapacientescommicrocarcinomapapilíferodetireoide,oesvaziamentocervical centralprofilático éum procedimentoseguroeeficienteeresulta emmenortaxade recor-rência.Comoasevidênciassãodebaixaqualidade(estudosnãorandomizados),maisestudos randomizadossãonecessários.
© 2018 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
Papillarythyroidmicrocarcinoma(PTMC)isdefinedasa pap-illarythyroidcarcinomathatisequaltoorlessthan1.0cm at the greatest dimension according to the World Health Organization classification system for thyroid tumors.1
The majority of PTMCs are not palpable and clinically inapparent.2ForPTMCpatients,thereportedincidenceof
lymphnode metastasisis ashigh as40%, andtheseoccur mainlyinthecentralcompartmentoftheneck.3---5Because
thesemetastasesaredifficulttodetectusing ultrasonogra-phypreoperatively,someauthorsadvocateroutineCentral NeckDissection(CND)inPTMCpatientsatthetimeofinitial thyroidectomy.6---9 The purposeofthisstudy istoevaluate
the influence of CND on the postoperative complications andrecurrenceofpatientswithPTMC.
Materials
and
methods
Searchstrategy
PubMed,WebofKnowledge,Ovid’sdatabaseweresearched fromJanuary1990toDecember2017withEnglishlanguage. The search terms used were ‘‘thyroidectomy’’, ‘‘central neck dissection’’, ‘‘local recurrence’’ and ‘‘papillary thyroid microcarcinoma’’. The reference lists of relevant studies were checked manually to locate any missing studies.
Studyselection
Identifiedstudieswereassessedforeligibilityforinclusionin thereviewbyscrutinizingthetitles,abstractsandkeywords ofeveryrecordretrieved.Studieswererestrictedtothose publishedinEnglish.Clinicalstudiesconcerningcomparisons ofanyaspectsbetweentheCND+groupandCND−groupfor PTMCwerealsoincluded.
Dataextraction
Twocoauthors(LYandSH)independentlyassessedthe meth-odological quality of each study using the Methodological IndexforNon-RandomizedStudiescriteria(MINORS).10The
followingvariableswererecorded:authors,journalandyear ofpublication,numberofpatients,age,transientRLNpalsy, permanentRLNpalsy,transienthypoparathyroidism, perma-nenthypoparathyroidismandrecurrence.Ifnecessary,the correspondingauthorsofstudieswerecontactedtoobtain supplementaryinformation.
Statisticalanalysis
Aformalmeta-analysiswascarriedoutforallincluded stud-iescomparingtheresultsofCND+andCND−forPTMC.The outcomes in our study were transient RLN palsy, perma-nent RLN palsy, transient hypoparathyroidism, permanent hypoparathyroidismandrecurrence.Afixedeffects model wasusedtocalculateapooledOddsRatio(OR)withits95%
CNDandLRinPTMC 239
142 Potentially relevant articles identified in database searches
67 Irrelevant 107 Excluded
31 Excluded
17 Not papillary thyroid microcarcinoma
14 No appropriate control 4 Articles included in
Meta-analysis
35 Articles retrieved for detailed assessment
12 Meeting abstract 28 No appropriate control
Figure1 Flowchartoftheresultsoftheliteraturesearch.
confidenceinterval(CI).Heterogeneitywasexploredusing I2statistics,ameasureofhowmuchthevariancebetween studies,ratherthanchance,canbeattributedtointer-study differences. I2>50% was regarded toindicate strong het-erogeneity.The Cochrane Collaboration’s Review Manager Software(RevManversion5.0)wasutilizedforthedata anal-ysis.
Results
Studyselection
Weidentified142potentiallyrelevantarticles(Fig.1).After exclusionofduplicatereferences,non-relevantliterature, andthosethatdid notsatisfyinclusioncriteria, 35 candi-datearticleswereconsidered forthemeta-analysis.After carefulreview ofthe full textofthese articles,4studies wereincluded.Thestudycharacteristicsweresummarized inTable1.
Patientdemographicsforthe4studiesarepresentedin
Table 1. Allpapers were retrospective clinical trials. The publicationdates ranged fromJanuary 1990 toDecember 2017. Study sizes ranged from 101 to 242 patients. The assessmentsof thenon-randomized studiesareillustrated inTable2.Themedianqualityscorewas12.5.
Outcomemeasures
Atotalof366patientswhounderwentCND+and361patients whounderwentCND− wereanalyzed.The criteriaforthe temporary/permanent hypocalcemia, transient Recurrent LaryngealNerve(RLN)palsyandrecurrenceswere summa-rizedinTable3.
Transientrecurrent laryngealnervepalsywasobserved inthreestudies,CND−grouphadlesstransientRLNpalsy, butnosignificant difference wasfound (OR=1.28, 95%CI [0.42---3.92], p=0.66) (Fig. 2). The prevalence of perma-nentRLN palsywas 0.79%in the CND+group vs.1.36% in theCND− group without significant difference(OR=0.59, 95%CI[0.10---3.57],p=0.56)(Fig.2).Threestudiesassessed patientsfortransienthypocalcemia.Theprevalenceof tran-sienthypocalcemiawas32.23%intheCND+groupvs.19.71% intheCND−group,andthisdifferencewasnotsignificant (OR=2.09,95%CI[0.98---4.45],p=0.06)(Fig.3).The preva-lenceof permanenthypocalcemia was 2.99% inthe CND+ groupvs.1.09%intheCND−group,andnosignificant differ-encewasobserved(OR=2.43,95%CI[0.74---7.91],p=0.14) (Fig.2).
Recurrencewasassessedinallfourstudies. The recur-rence rates in CND+ were approximately 1.91% and were significantly lowerthan those in CND− (OR=0.24, 95% CI [0.10,0.56],p=0.0009)(Fig.4).
Discussion
Higher rates of complications suchastemporary hypocal-cemia,permanenthypocalcemia,and RLNpalsyareoften citedin argumentsagainst prophylacticCND inthe treat-ment of PTMC.15,16 Temporary hypocalcemia has been
reported to be between 20% and 50%.17---19 In our
meta-analysis, the incidence of temporary and permanent hypocalcemiahad nodifferencebetweenthe twogroups, suggestingthatdissectionofthecentralneckcompartment didnot enhance damage tothe parathyroid glands. Simi-larly,theratesoftemporaryandpermanentRLNinjurydid notincreasewithprophylacticCND.
Some studies reported that the role of CND in PTMC remainsuncertain because noevidencehasdemonstrated that CND improves locoregional control or survival in
Table1 Overviewofthereviewedstudies. Author,year Country No.of
patients
Sex
(male/female)
Patientsource Meanage Studydesign Hyunetal., 201211 Korea 152 CND+:9/56 CND−:20/67 UniversityofUlsan CND+:46 CND−:48 Retrospective Choietal., 200812 Korea 101 CND+:6/42 CND−:11/42 UniversityofUlsan CND+:52 CND−:48 Retrospective Zhangetal., 201513 China 242 CND+:26/108 CND−:27/81 PekingUnion MedicalCollege Hospital, CND+:48 CND−:45 Retrospective Soetal., 201214 Korea 232 CND+:98/21 CND−:97/16 Sungkyunkwan UniversitySchool ofMedicine, CND+:49.18 CND−:49.75 Retrospective
Su
H,
Li
Y
Table2 Assessmentofthequalityofthestudiesusingthemethodologicalindexfornon-randomizedstudies(MINORS).
Author,year Aclearly
statedaim Inclusionof consecutive patients Prospective collectionof data Endpoints appropriate totheaim ofthestudy Unbiased assessment ofthestudy endpoint Follow-up period appropriate totheaim ofthestudy Lossto followup lessthan5% Prospective calculation ofthestudy size Score Hyunetal.,2012 2 2 2 2 2 1 2 0 13 Choietal.,2008 2 2 2 1 1 1 2 0 11 Zhangetal.,2015 2 2 2 2 1 2 2 0 13 Soetal.,2012 2 2 2 2 2 1 2 0 13
0,representedthattheitemwasnotreportedinthearticle;1,representedthattheitemwasreportedbutdeficiently;2,representedthattheitemwasreportedcompletelyand appropriately.
CNDandLRinPTMC 241 Table3 Thecriteriaforthecomplicationsandrecurrences.
Author,year Thecriteriausedfor temporaryhypocalcemia
Thecriteriaused forpermanent hypocalcemia
Thecriteriaused fortemporaryRLN palsy
Thecriteriaused forpermanentRLN palsy
Thecriteriaused forthe recurrences Hyunetal., 2012 --- --- --- --- ---Choietal., 2008
Theneedforexogenous calciumreplacementin ordertomaintaina normalrangeofserum totalcalcium
(8---10.4mg/dL)orto eliminatetheclinical signsandsymptomsof hypocalcemia Calcium replacementwas necessaryfor longerthan12 months --- --- Confirmedby ultrasonography-guidedfineneedle aspirationcytology
Zhangetal., 2015
Serumcalcium<8mg/dL anytimeduringthe initial6-monthfollow-up
Aneedfor continuedcalcium beyond6months aftersurgerywith persistentserum calcium<8mg/dL Byfiberoptic laryngoscopy between0and6 monthsafter operation Confirmedbyfiber opticlaryngoscopy beyond6months afteroperation Detectedbyserial cervical ultrasonographies orradioactive thyroidscan Soetal.,2012 Atleast1eventof
hypocalcemicsymptoms (perioralnumbness, paresthesiasofthe handsandfeet,Chvostek sign,andTrousseausign) oratleast1eventof biochemical hypocalcemia(ionized Calevel<1.0mmoL/L) Persistent symptomsor persistent biochemical hypocalcemia greaterthan durationof6 months. Checkedwitha fiberopticflexible laryngoscopeora rigidtelescopic laryngoscope. ---
---PTMC.20,21 Wada et al.2 comparedthe recurrence rate of
235patients withPTMC whounderwentprophylactic neck dissection withthatof 155 patients withincidental PTMC who did not undergo neck dissection. After a 60 month follow-up,therecurrenceratewas0.43%forthedissection groupand0.65%forthenon-dissectiongroup.Nostatistical significancewasobserved.Inaddition,Appetecchiaetal.22
donotbelievethatCNDisnecessary,becausethereported mortality rates of PTMC range from 0% to 1%, and CND provides no survival benefit. However, the recurrence ratesinCND+weresignificantlylowerthanthoseinCND− in our meta-analysis. Shen et al. have shown a similar trendtowarddecreasedrecurrenceinpatientsundergoing prophylacticCND.23
On the other hand, the incidence of central lymph node metastases (CLNMs) arerelatively commonin PTMC patients. Lymph node dissection is generally indicated when there is cervical lymphadenopathy detected either preoperatively or intraoperatively. In this case, central lymphnode dissectionshouldbeperformedatthetimeof thyroid surgery sincesubsequent surgery for node metas-tasesintheneckmaybetechnicallydifficult.However,the effect of prophylactic lymph node dissection on patients without preoperative or intraoperative lymphadenopathy hasbeendisputed.24Currently,thediagnosticperformance
of Ultrasonography (US) for determining the presence of CLNM in PTMC patients is not completely reliable. The sensitivityofUSinpredicting CLNMforPTMCpatientshas beenreportedtorangefrom21.6%to38.0%.6,25,26 Several
studies have demonstrated that CLNMs are observed in about 31%---64.1% of patients with PTMC.22,27,28 Simpson
etal.29 reported two cases of PTMC that both measured
less than 1.5mm with regional lymph node metasta-sis and with histological features of regression. In our included studies,the incidenceof CLNMs in patients with PTMC was 29.2%---40%.11---13 We recommend prophylactic
centralcompartment dissection at the timeof thyroidec-tomy. This recommendation is in line with a previous report.30
Insummary,ourmeta-analysisdemonstratedthatthere was no increased morbidity in CND+ group. Compared with thyroidectomy alone, combined prophylactic CND may decrease the local recurrence rate. However, the present study has some limitations. First, selection bias is the domain that could lead to a biased estimate of the procedural effects in this analysis. Second, the present study may have been limited by its retro-spective non-randomized design. Third, the decision to perform a CND may have been skewed by the surgeon’s preference.
Figure2 ForestplotofthecomparisonoftemporaryRLNpalsyandpermanenthypocalcemiaforCND+vs.CND−.
Figure3 ForestplotofthecomparisonoftemporaryhypocalcemiaforCND+vs.CND−.
CNDandLRinPTMC 243
Conclusions
Compared with CND− group, combined prophylactic CND andthyroidectomyisasafeandefficientprocedure.Itnot only excises the occult central lymph node metastases, but also results in lower local recurrence rate of papil-larythyroidmicrocarcinoma.Sincetheevidencesareoflow quality(non-randomizedstudies),furtherrandomizedtrials areneeded.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
References
1.HedingerC,WilliamsED,SobinLH.TheWHOhistological classi-ficationofthyroidtumors:acommentaryonthesecondedition. Cancer.1989;63:908---11.
2.WadaN,Duh QY,SuginoK, IwasakiH, KameyamaK,Mimura T, et al. Lymph node metastasis from 259 papillary thyroid microcarcinomas:frequency,patternofoccurrenceand recur-rence, and optimal strategy for neck dissection. Ann Surg. 2003;237:399---407.
3.HarachHR, FranssilaKO, Wasenius VM.Occultpapillary car-cinoma of the thyroid. A ‘‘normal’’ finding in Finland. A systematicautopsystudy.Cancer.1985;56:531---8.
4.YamamotoY,MaedaT,IzumiK,OtsukaH.Occultpapillary car-cinomaofthethyroid.Astudyof408autopsycases.Cancer. 1990;65:1173---9.
5.RodriguezJM,MorenoA, ParrillaP,SolaJ,SoriaT, TebarFJ, etal.Papillarythyroidmicrocarcinoma:clinicalstudyand prog-nosis.EurJSurg.1997;163:255---9.
6.KimE,ParkJS,SonKR,KimJH,JeonSJ,NaDG.Preoperative diagnosisofcervicalmetastaticlymphnodesinpapillarythyroid carcinoma:comparisonofultrasound,computedtomography, andcombinedultrasoundwithcomputedtomography.Thyroid. 2008;18:411---8.
7.ItoY,TomodaC,UrunoT,TakamuraY,MiyaA,KobayashiK,etal. Clinicalsignificanceofmetastasistothecentralcompartment frompapillary microcarcinomaofthe thyroid.WorldJSurg. 2006;30:91---9.
8.AlvaradoR,SywakMS,Delbridge L, SidhuSB.Central lymph nodedissectionasasecondaryprocedureforpapillarythyroid cancer:isthereaddedmorbidity?Surgery.2009;145:514---8. 9.Chisholm EJ, Kulinskaya E, Tolley NS. Systematic review
and meta-analysis of the adverse effects of thyroidectomy combinedwithcentralneckdissectionascomparedwith thy-roidectomyalone.Laryngoscope.2009;119:1135---9.
10.SlimK,Nini E,ForestierD, Kwiatkowski F,Panis Y, Chipponi J.Methodologicalindexfornon-randomizedstudies(MINORS): developmentandvalidationofanewinstrument.ANZJSurg. 2003;73:712---6.
11.HyunSM,SongHY, KimSY, NamSY, Roh JL, HanMW, etal. Impactofcombinedprophylacticunilateralcentralneck dissec-tionandhemithyroidectomyinpatientswithpapillarythyroid microcarcinoma.AnnSurgOncol.2012;19:591---6.
12.ChoiSJ,KimTY,LeeJC,Shong YK,ChoKJ,RyuJS,etal.Is routinecentralneckdissectionnecessaryforthetreatmentof papillarythyroid microcarcinoma? ClinExp Otorhinolaryngol. 2008;1:41---5.
13.ZhangL,LiuZ,LiuY,GaoW,ZhengC.Theclinicalprognosisof patientswithcN0papillarythyroidmicrocarcinomabycentral neckdissection.WorldJSurgOncol.2015;13:138.
14.So YK, Seo MY, Son YI. Prophylactic central lymph node dissectionforclinicallynode-negativepapillarythyroid micro-carcinoma:influenceonserumthyroglobulinlevel,recurrence rate, and postoperative complications. Surgery. 2012;151: 192---8.
15.RosenbaumMA,McHenryCR.Centralneckdissectionfor pap-illary thyroid cancer. Arch Otolaryngology Head Neck Surg. 2009;135:1092---7.
16.Roh JL,Park JY,Park CY. Totalthyroidectomyplusneck dis-sectionindifferentiatedpapillarythyroidcarcinomapatients: patternofnodalmetastases,morbidity,recurrenceand post-operative levels of serum parathyroid hormone. Ann Surg. 2007;245:604---10.
17.MooTA,McGillJ,AllendorfJ,LeeJ,FaheyTIII,ZarnegarR. Impactofprophylacticcentralnecklymphnodedissectionon earlyrecurrenceinpapillarythyroidcarcinoma.WorldJSurg. 2010;34:1187---91.
18.Moo TA, UmunnaB, Kato M, ButriagoD, Kundel A, Lee JA, etal.Ipsilateralversusbilateralcentralnecklymphnode dis-section in papillary thyroid carcinoma. Ann Surg. 2009;250: 403---8.
19.LeeYS,KimSW,KimSK,KangHS,LeeES,ChungKW,etal.Extent ofroutinecentrallymphnodedissectionwithsmallpapillary thyroidcarcinoma.WorldJSurg.2007;31:1954---9.
20.Ito Y, Uruno T, Nakano K, Takamura Y, Miya A, Kobayashi K, et al. An observation trial without surgical treatment in patientswithpapillarymicrocarcinomaofthethyroid.Thyroid. 2003;13:381---7.
21.British Thyroid Association and Royal College of Physicians. Guidelinesforthemanagementofthyroidcancer.2nded;2007. http://www.british-thyroid-association.org/Guidelines/ [cited 28.04.14].
22.Appetecchia M,ScarcelloG, Pucci E,ProcacciniA. Outcome aftertreatmentofpapillarythyroidmicrocarcinoma.JExpClin CancerRes.2002;21:159---64.
23.ShenWT,OgawaL,RuanD,SuhI,DuhQY,ClarkOH.Central necklymphnodedissection forpapillarythyroid cancer:the reliabilityofsurgeon judgementinpredictingwhichpatients willbenefit.Surgery.2010;148:398---403.
24.Ito Y, Higashiyama T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F, et al. Prognosis of patients with benign thy-roid diseasesaccompanied byincidental papillary carcinoma undetectable on preoperative imaging tests. World J Surg. 2007;31:1672---6.
25.ItoY,JikuzonoT,HigashiyamaT,AsahiS,TomodaC,Takamura Y,etal.Clinicalsignificanceoflymphnodemetastasisof thy-roid papillary carcinoma located in one lobe.World J Surg. 2006;30:1821---8.
26.HwangHS,OrloffLA.Efficacyofpreoperativeneckultrasound inthedetectionofcervicallymphnodemetastasisfromthyroid cancer.Laryngoscope.2011;121:487---91.
27.LimYC,ChoiEC,YoonYH,KimEH,KooBS.Centrallymphnode metastasesinunilateralpapillarythyroidmicrocarcinoma.BrJ Surg.2009;96:253---7.
28.Roh JL, Kim JM, Park CI. Central cervical nodal metastasis from papillary thyroid microcarcinoma: pattern and factors predictive of nodal metastasis. Ann Surg Oncol. 2008;15: 2482---6.
29.SimpsonKW,Albores-SaavedraJ.Unusualfindingsinpapillary thyroidmicrocarcinomasuggestingpartialregression:astudy oftwocases.AnnDiagnPathol.2007;11:97---102.
30.So YK, SonYI,Hong SD, SeoMY,Baek CH, JeongHS, et al. Subclinicallymphnodemetastasisinpapillarythyroid micro-carcinoma: a study of 551 resections. Surgery. 2010;148: 526---31.
