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M Bongiovanni and others NIFTP impact on ROM: a 181:4 389–396 Clinical Study meta-analysis

Impact of non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) on risk of malignancy in patients undergoing lobectomy/thyroidectomy for suspected malignancy or malignant fine-needle aspiration cytology findings: a systematic review and meta-analysis

Massimo Bongiovanni1, William C Faquin2, Luca Giovanella3, Cosimo Durante4, Peter Kopp5 and Pierpaolo Trimboli3

1Service of Clinical Pathology, Lausanne University Hospital, Institute of Pathology, Lausanne, Switzerland, 2Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA, 3Department of Nuclear Medicine and Thyroid Centre, Ente Ospedaliero Cantonale, Bellinzona, Switzerland, 4Dipartimento di Medicina Traslazionale e di Precisione, Azienda Ospedaliera Universitaria Policlinico Umberto I, Sapienza Università di Roma, Rome, Italy, and 5Service of Endocrinology, Diabetology and Metabolism, CHUV, Lausanne University Hospital, Lausanne, Switzerland Correspondence should be addressed to M Bongiovanni Email massimo.bongiovanni@ chuv.ch

Abstract European Journal of Endocrinology Objective: The second version of The Bethesda System for Reporting Thyroid Cytopathology endorsed the introduction of non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) as a distinct entity with low malignant potential into clinical practice. Consequently, the risk of malignancy (ROM) of cytological diagnoses has changed, but the magnitude of the change remains uncertain. The present systematic review was undertaken to obtain more robust information about the true impact of NIFTP on the ROM among patients undergoing surgery following a fine-needle aspiration cytology (FNAC) diagnosis of suspicious for malignancy (Bethesda V) or malignant (Bethesda VI). As they are managed surgically, these two diagnostic categories are the primary entities that are clinically impacted by the advent of NIFTP. Design: Systematic review and meta-analysis. Methods: A comprehensive literature search of online databases was performed in November 2018. The search was conducted looking for data of histologically proven NIFTP with preoperative FNAC. Results: One-hundred fifty-seven articles were identified and nine were included in the study. Overall, there were 13,752 thyroidectomies with a cancer prevalence of 45.7%. When NIFTP was considered non-malignant, the pooled risk difference for ROM was 5.5%. Applying meta-analysis, the pooled prevalence of NIFTP among nodules with FNAC of Bethesda V or Bethesda VI was 14 and 3%, respectively. Conclusion: This meta-analysis shows that the inclusion of NIFTP leads to a reduction in the ROM for the Bethesda V and Bethesda VI FNAC diagnostic categories by 14 and 3%, respectively. Clinicians should be aware of these data to avoid overtreatment. European Journal of Endocrinology (2019) 181, 389–396

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-19-0223 European Journal of Endocrinology https://eje.bioscientifica.com be avoided.Infact,inbothFNAC DC,surgicalexcisionof management forthesepatients, asovertreatmentshould changes couldhaveasignificant impactonthesurgical on alimitednumberofretrospectivestudies( and 97–99%to45–60%94–96%,respectively, based TBSRTC DC Bethesda V and VI has decreased from 50–75% ( to avariablereductionoftheROMamongcategories with itssixdiagnosticcategorieshasbeenrevisedleading a consequence,theriskofmalignancy(ROM)associated TBSRTC considered NIFTP as a non-malignant tumor; as diagnosis. be consideredonlyasapossibilityinthedifferential of NIFTPandthatitspresencepreoperativelymay highlight thatFNACwillnotprovideadefinitediagnosis between thestudieswasidentified( malignant (M)( SFN), 24%assuspiciousformalignancy(SM)and8% neoplasm orsuspiciousforafollicular(FN/ undetermined significance (AUS/FLUS), 21%as follicular of undeterminedsignificanceorfollicularlesion (ND/U),10%asbenign(B),30%atypia unsatisfactory (TBSRTC): 3% were diagnosed as nondiagnostic/ Bethesda SystemforReportingThyroidCytopathology may beclassifiedinalldiagnosticcategories(DCs)ofThe analysis of15studiesincluding915NIFTP, thesecases reliable way( aspiration cytology (FNAC) is currently not feasible in a refined continuously, NIFTPidentificationbyfine-needle if itshistologicalandcytologicaldiagnosticcriteriaare can onlybediagnosedonsurgicalspecimens,andeven thyroidectomy andradioiodinetherapy( be treated by lobectomy without a need for completion a lowriskofrelapse( behavior, NIFTPshouldbeconsideredasaneoplasmwith diagnostic discrepancies( features characteristicoftheselesions,aresources of and, mostimportantly, borderline-atypicalnuclear expert thyroidpathologists.Microfollicularstructures EFVPTC counterpart,isexpectedtobehigh,evenamong variability inthediagnosisofNIFTP, analogoustoits controversial entity and a popular topic ( thyroid carcinoma (non-invasiveEFVPTC),representsa non-invasive encapsulated follicular variant of papillary like nuclearfeatures(NIFTP),formerlyknownasthe Non-invasive follicularthyroidneoplasmwithpapillary- Introduction 11 Clinical Study ). Particularly, theexpected ROM associated with Since theintroductionofNIFTP, thesecondeditionof 9 ). Infact,asdemonstratedinarecentmeta- 10 ). Importantly, onlymildheterogeneity 6 ). Accordingly, thesepatientscan 3 , 4 , 5 M Bongiovanniandothers ). Duetoitsindolent 10 1 ). Thesefindings , 2 6 ). Interobserver ). Interobserver , 7 , 11 8 ). NIFTP ). These supplementary data supplementary Fig.1,seesectionon to Prismaguidelines(Supplementary This presentsystematicreviewwasconductedaccording Conduct ofreview Methods FNAC reportofBethesdaVorVI. followinga among patientsundergoingthyroidsurgery non-malignant entityand( patients whenconsideringNIFTPasamalignantversus estimate ( V orVIlesions.Accordingly, ourmeta-analysisaimedto due to Bethesda on ROM of patients undergoing surgery more robust information about the true impact of NIFTP lobectomy orathyroidectomy. the lesionsisrecommendedwithoptionsofeithera addition, articleswithoverlapping patientornoduledata according toTBSRTCwas not usedwereexcluded.In studies inwhichpreoperative FNACclassification over aspecificstudyperiodwereincluded.Subsequently, consecutive series of patients undergoing thyroid surgery reporting NIFTPcasesdiagnosedhistologicallyin a As themaininclusioncriterion,onlyoriginalarticles Study selection were alsoscreenedtoidentifyadditionalstudies. to expandthesearch, referencesoftheretrievedarticles and no languagerestrictions were used. With an attempt used. Thesearch wasupdated untilNovember15,2018, cytological assessment.Abeginningdatelimitwasnot and whichcontainedinformationonthepresurgical of studiesthatreportedhistologicallyprovenNIFTP approach wouldallowidentificationofalargenumber ‘histopathology’ and ‘thyroid cancer’ wasused. This invasive’, ‘encapsulated’,‘follicularvariant’,‘NIFTP’, according toTBRSTC.Acombinationoftheterms‘non- patients inwhichtherewasapresurgicalFNACreport the presenceofNIFTPamongthyroidectomized The search aimedtofind originalstudiesdescribing the online databases of Pubmed/MEDLINE and Scopus. A comprehensiveliteraturesearch wasconductedusing Search strategy meta-analysis NIFTP impactonROM:a In thiscontext,thefocusofstudywastoobtain 1 ) thedifferenceinROMamongallsurgical givenattheendofthisarticle). Downloaded fromBioscientifica.com at10/01/202104:01:17AM 2 ) theprevalenceofNIFTP 181 :4 390 via freeaccess European Journal of Endocrinology possible presence of a publication bias. A funnel plot was value and significantheterogeneity wasdefinedasanI-square used toquantifytheheterogeneity amongthestudies, CIs) anddisplayedusinga forest plot.The (95% data arepresentedwith95%confidenceintervals method (random-effectsmodel)wasused( statistical poolingofdata,theDerSimonianandLaird NIFTP asamalignantornon-malignantentity. For to evaluate the difference of ROM when considering study. Ariskdifference(RD)meta-analysiswas conducted proven NIFTPandthetotalnumberofhistologiesforeach entered intwocolumnsthenumberofhistologically based analysiswasconducted.Datainput:theywere of caseswithacancerdiagnosis.Particularly, a lesion- andwithinthesubgroup surgery patients whounderwent pooled rateofhistologicallyprovenNIFTPamongall A proportionmeta-analysiswasperformedtoobtainthe Statistical analysis low, highandunclearrisk. Risk ofbiasandconcernsaboutapplicabilitywereratedas selection; indextest;referencestandard;flowandtiming. (QUADAS-2) toolforthefollowingaspects:patient Quality AssessmentofDiagnosticAccuracyStudies independently bytworeviewers(MB,PT)throughthe The riskofbiasincludedstudieswasassessed Study qualityassessment and anydiscrepancieswerediscussedmutuallysolved. FNA reportsofBethesdaVorVI.Datawerecross-checked, ( number ofpreoperativeFNAreportsBethesdaVorVI; patients; ( ( number ofthyroidsurgery; of origin); ( of publication, country a pilotedform:( extracted independentlybytwoinvestigators(MB,PT)in For eachincludedstudy, thefollowinginformationwas Data extraction inclusion. full-text oftheremainingarticlestodeterminetheirfinal criteria; then, allauthorsindependently reviewed the abstracts oftheretrievedarticles,applyingselection researchers (MB, PT) independently reviewed titlesand were excluded,andcasereportsnotconsidered.Two 7 Clinical Study ) numberofcancersamongnoduleswithpreoperative > 50%. Egger’s testwascarriedouttoevaluate the 5 ) numberofNIFTPdiagnosedbyhistology;( 1 ) studydata(authors,yearandjournal 4 ) numberofcancersamong M Bongiovanniandothers 2 ) study period; ( I 2 12 indexwas ). Pooled 6 3 ) ) used forthesearchisreported inthetext. Flow chartofsearchstudies. Fullexplanationoftheterms Figure 1 included forthepurposesofthisstudy( full-text paperswereevaluated.Finally, ninearticleswere above criteriaafterreviewoftitlesandabstracts,21 articles. Ofthese,136wereexcludedaccordingtothe comprehensive computer literature search retrieved 157 After exclusionofduplicatepublications,the Eligible articles Results software (StatsDirectLtd;Altrincham,UK). analyses were performed using the StatsDirect statistical different resultswithrespecttothelargerones.Statistical be consideredwhensmallersizestudieshadonaverage carried outforanyresultsandpublicationbiasmight of Pennsylvania,Philadelphia,PA) wasexcludeddueto institutional experience;oneoftheseries(fromUniversity 15 malignant entity. Inaddition,theprevalenceofNIFTP malignant andtheROMconsideringNIFTPasanon- allowed calculationoftheROMconsideringNIFTPas identified intexts,figuresortablesofthestudies.This Data on the final histological follow-up were clearly thyroidectomies performedoveraspecifictimeperiod. of thyroidhistologicalsamplesfromconsecutiveseries these articles always included a retrospective examination thyroid cancer prevalence of 45.7%. The studydesign of Overall, 13,752thyroidectomiesweredescribedwitha USA, AsiaorEurope( The includedstudieswerepublishedbyauthorsfromthe Qualitative analysis(systematicreview) the riskofoverlappingdatawithotherstudies( meta-analysis NIFTP impactonROM:a , 16 , 17 , 18 , 19 , 20 , 13 21 Downloaded fromBioscientifica.com at10/01/202104:01:17AM , ). Onestudypresentedamulti- 14 , 15 https://eje.bioscientifica.com , 16 , 181 17 :4 , 18 Fig. 1 , 19 ) ( , 20 21 13 391 , ). , 21 14 via freeaccess ). , European Journal of Endocrinology https://eje.bioscientifica.com VI was3%(95%CIfrom1to6)( prevalence of NIFTP among nodules classified as Bethesda was 14%(95%CIfrom6to26)( nodules withacytologicalclassificationofBethesdaV At meta-analysis,thepooledprevalenceofNIFTPamong Bethesda VI.Amongall4329cases,therewere185NIFTP. a FNACdiagnosisofBethesdaVandanother3121with 20 preoperative FNACdatawas557( the overallnumberofhistologicallyprovenNIFTPwith ( reported ineightarticles(asthestudybyLastra was the overallseriesofpatientsundergoingsurgery decreased by5.5%. as anon-malignantentity, theriskofmalignancy from 3.2to7.8)( histology. ThepooledRDofROMwas5.5%(95%CI thyroid surgery, 696(5.1%)NIFTPwereidentifiedat 16 results ofallnineincludedstudies( malignant entity wasestimated pooling thehistological The overallRDofROMwhenconsideringNIFTPasanon- Quantitative analysis(meta-analysis) V 22.5%andBethesdaVI8.3%( 11.2%, BethesdaIII30.9%,IV23.7%, various diagnosticcategories:BethesdaI3.4%,II recent meta-analysiswiththefollowingpercentages inthe in a according to TBRSTC was similar to that observed nine includedstudies.TheoveralldistributionofNIFTP Table 1 the selected studies ( of BethesdaV or VI were clearly reported in eight of among thoselesionswithapreoperativeFNACdiagnosis Total ( ( ( ( ( ( ( ( ( Reference in thestudies.BethesdaVandVIcolumnreport overallcaseswithFNAamongallpatientsoperatedupon. Table 1 21 20 19 18 17 16 15 14 13 19 Clinical Study , , ) ) ) ) ) ) ) ) ) ) didnotreportdataaboutBethesdaVandVI) 17 21 As illustratedin , ). Inthesearticles,therewere1208noduleswith detailsthemaincharacteristicsandfindingsof 18 Main featuresoftheincludedstudies.Casesreviewedrepresent allthyroidhistologicalcasesreviewedretrospectively , 19 Cases reviewed , 20 13,752 2559 2226 1891 2044 1826 1886 353 312 655 Fig. 2 , 21 ). Among 13,752 patients undergoing Table 1 ); then,whenNIFTPwasconsidered 13 , 14 , dataofFNACdiagnosisfor NIFTP found , 696 139 173 15 10 79 26 25 59 16 94 85 M Bongiovanniandothers Fig. 4 Fig. 3

, ). 13 16 Table 1 , , ). 14 ). Also,thepooled 17 , ROM consideringNIFTPasa 15 , ) ( 18 , 13 16 , , , 20 cancer 14 17 45.7 26.4 28.0 45.0 91.2 54.3 32.6 48.0 18.1 52.8 , t al et , , 21 15 18 (%) ). , , .

of thestudies. inpatientselectionandflowtiming risk wasobserved before theintroductionofNIFTPasaseparateentity. Low of cytological specimens of lesions evaluated by FNAC included studiescomprisedaretrospectivere-evaluation for theindextest(i.e.FNAC).Infact,designofall structures ( toexcludethepresenceofanypapillary is necessary to excludeinvasionandanalysisoftheentirelesion the examination of the capsule is an essential prerequisite of thenodulecontentinhistologicalsample,because needs ananalysisoftheentirecapsuleandtotality the introductionofNIFTP. Infact,todiagnoseNIFTP, one the evaluationofhistologicalsampleswasdonebefore reference (i.e. histology). Thisriskofbiasishighbecause a high risk of bias was found regarding the standard The riskofbiasthestudiesisshownin Study qualityassessment that FNACdiagnosesassociatedwithNIFTPmaybefound confirmed whatwasapparentfromtheonset,namely diagnose NIFTPpreoperatively. Yet, arecentmeta-analysis this recommendationassumesthatwemightbeableto ( than 1%onetotwodecadesaftersurgery manage thesepatientssincetherecurrencerateisless to therapy isanadequateandoptimalintervention completion thyroidectomyandwithoutradioiodine that clinical management consisting of lobectomy without Following this reclassification, it has been recommended an entitywithindolentandnon-aggressivebehavior. for lesionsformerlyclassifiedasnon-invasiveEFVPTC, was recentlyintroducedtoreplacethenomenclature NIFTP isthedesignationforathyroidneoplasmthat Discussion meta-analysis NIFTP impactonROM:a ROM consideringNIFTPas non-malignant 22 ). Moreover, ahighriskofbiaswasdetected 40.6 23.3 20.6 38.8 89.9 51.4 27.5 38.5 13.2 39.8 (%) Downloaded fromBioscientifica.com at10/01/202104:01:17AM Bethesda V 1208 210 393 142 238 NA 33 29 69 94 181 :4 Table 2 6 , 22 Bethesda VI ). However, 3121 1038 . Overall, 413 695 587 156 NA 99 39 94 392 via freeaccess European Journal of Endocrinology present studywasundertakenwithadifferentaim,thatis NIFTP is associated with the risk of overtreatment. The categories, andforwhomthehistologicdiagnosisof with lesions classified by FNA in the Bethesda V and VI isunequivocallyrecommended,thatpatients surgery should beaparticularfocusonthosepatientsforwhom on theROMinallTBSRTCDC( et al issue was recently addressed in a meta-analysis by Vuong that thisneoplasmisclassifiedasnon-malignant.This ROM withinthedifferentcytologicalcategories,assuming know towhatextenttheintroductionofNIFTPaffects NIFTP remainsanunrealizedgoal( (Bethesda VI).Thus,thepreoperativeidentificationof in allDCofTBSRTC,i.e.fromND/U(BethesdaI)toM considered. Eggertest: 96.8%). (B)Asshowninfunnel plot, apublicationbiasmightbe 26) ofallcases. The resultsshowthatNIFTPrepresents 14%(95%CIfrom6to 1208 noduleswithapreoperative FNACreportofBethesdaV. (A) Pooledprevalence(95%CI)ofNIFTPcasesamongthose Figure 3 test: in funnelplot,apublicationbiasmightbeconsidered.Egger (inconsistency) was78.6%(95%CI = 54.6–87.2%).(B)Asshown the ROMisreducedby5.5%(95%CIfrom3to7). shows thatifNIFTPisconsideredasanon-malignanttumor, the entity ratherthanmalignant.Theverticallineatpointzeroof thyroidectomies whenconsideringNIFTPasnon-malignant (A) Pooledriskdifference(95%CI)ofROMinall13,752 Figure 2 Clinical Study x . whichshowedforthefirsttimeimpactofNIFTP Important forclinicalpractice,itwouldbeusefulto axisrepresentstheabsenceofdifference.Theresult P = 0.067. I 2 (inconsistency)was95.8%(95% CI = 94.2– P = 0.004. M Bongiovanniandothers 23 10 ). Inaddition,there ). I 2

category ( category manuscript anddidnotincludcasesinthemalignant period ofthesearch of the literatureperformedfor not includedinourmeta-analysisaspublishedafterthe recently bythestudyVentura (14.2%) was also confirmed in the Bethesda V category respectively ( a decrease of ROMinthesetwo DC of16and2.2%, are inlinewiththestudybyVoung ROM decreased by 14 and 3%, respectively. These data considering NIFTPasnon-malignant,wefoundthatthe the FNACcaseswithadiagnosisofBethesdaVandVI, as a non-malignant tumor. Secondly, when we evaluated for all causes decreased by 5% when we considered NIFTP series of consecutive patients undergoing thyroid surgery practice. of thyroidcasesandthepossibleimplicationsforclinical to providemorerobustinformationonthisspecificsubset negative cytologicalNIFTPcasesintheBethesdaVI,one meta-analysis as3%.However, toavoidanypossiblefalse- ROM forthisDC,whichwasestimatedinthepresent VI. Furthermore,itwouldnotsignificantlyalterthehigh the false-positivediagnosisduetoNIFTPinBethesda PTC ( pattern) exclude a NIFTP diagnosis and are diagnostic of of high-gradefeatures(mitosis,necrosis,solid/trabecular pseudo-inclusions, psammomabodiesorthepresence structures withanuclearscoreof3,threeormore features ofmalignancy. Thepresenceofanypapillary limiting thisdiagnosistocaseswithclear-cutcytological criteria usedintheMDCshouldbemorestrictlyapplied, the impactofNIFTP, emphasizesthatthediagnostic considered. Eggertest: (B) Asshowninfunnelplot,apublication biasmightbe all cases. results showthatNIFTPrepresents 3%(95%CIfrom1to6)of nodules withapreoperativeFNAC reportofBethesdaVI.The (A) Pooledprevalence(95%CI)ofNIFTPcasesamong3121 Figure 4 meta-analysis NIFTP impactonROM:a First, ouranalysisdemonstratesthattheROMofa The secondeditionofTBSRTC,takingintoaccount 2 , 25 I 2 24 (inconsistency)was92.7%(95% CI = 88.6–94.9%). , 26 ). 23 , 27 ). The almost similar decrease in the ROM ). Suchanapproachisexpectedtolimit P = 0.004. Downloaded fromBioscientifica.com at10/01/202104:01:17AM https://eje.bioscientifica.com t al et 181 t al et :4 . Thisstudywas . whoshowed 393 via freeaccess European Journal of Endocrinology The riskofbiaswasdefinedaslow(L),high(H)orunclear(U). ( ( ( ( ( ( ( ( ( Reference Table 2 https://eje.bioscientifica.com ultrasound featuresorfavorable molecularsignatures.In cases, forexample,inlesions withanabsenceofworrisome inselectedlow-risk be adaptedandmoreconservative underestimate. For this reason, the management should of 14% in the ROM for the Bethesda V is probably an Endocrine surgeonsshouldbeawarethatthedecrease to maintain a high ROM rate in their Bethesda VI ( NIFTP byhistology( diagnosis – in lesions that were ultimately diagnosed as VI readingsoncytology–hence,avoidingfalse-positive inclusions), ledtoareductioninthenumberofBethesda for PTC(i.e.nucleargroovesand policy andapplyingstrictcriteriatotheirFNACdiagnosis that theintroductionofaninstitutionalqualityassurance are consistentwiththefindingsofOhori no longerbeclassifiedasBethesdaVI.Theseassumptions nuclear features with few nuclear pseudo-inclusions will Purely follicular-patternedlesionsthathavepapillary-like by Vuong FN/SFN) thatiscurrentlyestimatedinthemeta-analysis the ROMalsoin the indeterminateDC (AUS/FLUS and same reasonasabove,wewillexpectafurtherdecreasein identified intheanalysispresentedhere.Moreover, forthe Bethesda Vtoanextentthatisevenhigherthanthe14% Bethesda V, andthisislikelytoreducetheROMin the BethesdaVI(includingNIFTP)willbemovedinto increasing numberofcasesnotfulfillingthecriteriafor diagnosis ofPTC.Forthesereasons,inouropinion,an many are applying stricter criteria for the cytological consequences forthepatient’s management.Therefore, more consciousabouttheNIFTPentityandpotential on retrospectivesstudies.Cytopathologistsarenow 14% inthepresentmeta-analysis,butitisbasedmostly introduction ofNIFTP. TheROMoftheBethesdaVwas V, particularlyaffectedbythe thusmakingthiscategory would expectmorecasestobeclassifiedintheBethesda 21 20 19 18 17 16 15 14 13 Clinical Study ) ) ) ) ) ) ) ) ) Quality assessmentofthestudiesaccordingtoQUADAS-2. t al et Patient selection . tobeat32 and 30%,respectively( L L L L L L L L L 25 ). Consequently, theywereable Index test H H H H H H H H H M Bongiovanniandothers Risk ofbias > Reference standard et al 3 pseudonuclear . whoshowed H H H H H H H H H 25 23 ). ). Flow andtiming improves clinicalmanagement( reduces thenumberoftotalthyroidectomies,andhence, Bethesda V, thatNIFTPiswithinthedifferentialdiagnosis, Mito inordertoavoidovertreatment.Ofnote, intervention this situation,alobectomymaybetheoptimalfirst-line hand, thisbiasshouldbe absent inBethesdaVorVI typically notbeingmanaged surgically. Ontheother cytological findings in the Bethesda Ior II categories are selection biasintheincluded studiessincepatientswith all cytologicalDC( since asubsetofNIFTPcanbecytologicallyclassified in reviewing theentirecapsuletoexcludeinvasion.Third, parenchymal portionofthetumors,inaddition to have consideredhistologicissuesrelatedtothecentral (i.e. retrospective studies), because pathologists maynot compromised insamplescollectedbeforeitsintroduction analysis. Second,thehistologicdiagnosisofNIFTPcouldbe contributed tohighheterogeneityinthepresentmeta- lower prevalenceofNIFTPinAsiancountriescouldhave V andVIcytologicaldiagnosis),theconsequently still prevalent Western for all Bethesda approach (surgery waiting for indeterminate thyroid cytologies) and the thyroid carcinomasfor low-risk papillary and watchful practice betweensomeAsiancenters(activesurveillance a separate entity. Moreover, the difference in clinical patients managedbeforetheintroductionofNIFTPas the studies included in this analysis presented data of are managedaccordingtotheFNACdiagnosis.However, the pooledresultsofprospectivestudiesinwhichpatients design couldintroduceabias.Ideally, onewouldevaluate NIFTP specificallyfortheirstudy. Ofcourse,thisstudy authors reviewedhistologicalandcytologicalsamplesof included inthisreviewwereretrospectivestudiesandthe study mustbementioned.First,almostallpublications meta-analysis NIFTP impactonROM:a L L L L L L L L L Certain limitationsandstrengthsofthepresent et al . showed that adding an explanatory notetothe . showedthataddinganexplanatory Patient selection 10 L L L L L L L L L ), onecanconcludethattherewasa Downloaded fromBioscientifica.com at10/01/202104:01:17AM Index test Feasibility 27 U U U U U U U U U ). 181 :4 Reference standard L L L L L L L L L 394 via freeaccess European Journal of Endocrinology References to submission. reviewed the manuscript and agreed to their individual contributions prior Bongiovanni: Massimo William C Faquin and Peter Kopp: supervision and editing. All authors have and Trimboli and Cosimo Giovanella Durante: data curation, formal analysis, methodology. Luca conceptualization, investigation, original draft and writing. Pierpaolo Trimboli, Pierpaolo Author contributionstatement the public,commercialornot-for-profitsector. This research did not receive any specific grant from any funding agency in Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisstudy. no is there that declare authors The Declaration ofinterest EJE-19-0223 at paper the of version online the to linked is This Supplementary data overtreatment. individualizing patientmanagementandavoiding which, afterconsideringothercharacteristics,mayhelp clinicians shouldbeawareofthesechangestotheROM, of BethesdaVandVIis143%,respectively. Treating histologically proven NIFTP among lesions with FNAC of theROM.Moreimportantly, theprevalenceof as NIFTPonhistology, resultinginanoverallreduction that 5%ofthesurgicallyremovednodulesareclassified surgical resection. patients withthelatterlesionsaretypicallyundergoing lesions, which are the focus of our present study, since 4 3 2 1 Clinical Study Hirokawa M, Carney JA,Goellner JR, DeLellis RA,Heffess CS, Lloyd RV, Erickson LA,Casey MB,Lam KY, Lohse CM,Asa SL, Rossi ED &Faquin WC.NIFTPrevised:chronicleofachange Baloch ZW, Seethala RR,Faquin WC,Papotti MG,Basolo F, Fadda G, org/10.1097/00000478-200211000-00014) ofSurgicalPathology Journal encapsulated follicularlesionsofthe thyroidgland. 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Accepted 23July2019 Revised versionreceived24June2019 Received 26March2019

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