甲状腺髓样癌的分子分型及治疗

甲状腺髓样癌的分子分型及治疗解放军第一一七医院戚晓平概况Histologicsubtypesofthyroidcancer①Papillary:approximately80%ofallthyroidmalignancies;②FollicularandHürthle:approximately11%;③Medullary:lessthan5%-8%;④Anaplastic:lessthan2%.IntroductionMedullarythyroidcancer(MTC)①SporadicMTC:approximately75%;50%somaticRETmutations(p.M918T)-predictapoorprognosis②HereditaryMTC:approximately25%;98%GermlineRETmutations,MEN2A(~95%)andMEN2B(~5%)Arisesfromtheneuralcrest-derived,calcitonin-secreting,parafollicularCcellsofthethyroidglandIntroduction①SporadicMTC:asolitaryandunilateralorapalpablecervicallymphnode②HereditaryMTC:multicentricandbilateraltheuppertomiddlepartsofthethyroidlobesIntroductionInvolvementofcervicallymphnodesisanearlyandcommonmanifestationintheclinicalcourseofthedisease,with35%to50%ormore,another10%to15%mayhavedistantmetastasesatthetimeofinitialpresentation;DistantmetastaticspreadofMTCfrequentlyinvolvesthemediastinalnodes,lung,liver(90%),andbones.p.C611YMEN2AMolecularAberrations(overexpression)①RETmutations②VEGFR-2③MET④EGFR⑤FGFR⑥RAS(sMTC---56%KRAS+;12%HRAS)(MutationsinRASappeartobemutuallyexclusiveofRETabnormalities)SomaticRETmutationsMolecularpathways①PI3K/Akt/mTOR②MAPK③JNK④RAS/ERKPlaycriticalrolesinregulatingcellproliferation,differentiation,motility,apoptosis,andsurvivalDiagnosisandMonitoring①FNA,USandCT,MRIorECT(Ct500pg/mL);②DNAanalysisfortheRETgermlinemutationATA-2015,ETA-2013,NCCN-2017Guidelinesrecommend③TheMTCspecimenispositivelystainedforCt,chromograninA,andCEAorCongoRed.DiagnosisandMonitoring④Serum-basedbiomarkers:calcitoninandCEA(50%)Preoperative:ⅰCEA(↑),Ct(-)--poorlydifferentiatedtumors,Rare;ⅱCt100pg/mL--predictive–MTC;ⅲCt150pg/mL,CEA30ng/L--regionalspread;ⅳCt3000pg/mL,CEA100ng/L--distantspread.PredictorsofMTCprogress,includingrecurrenceandsurvivalDiagnosisandMonitoring④Serum-basedbiomarkers:calcitoninandCEAPostoperative:ⅰCt(↑)--thefirstsignoftumorrecurrence;ⅱCt(-)andsCt(-)--10-yearsurvivalrates(SR)of100%;yearlyCtmeasurements;ⅲCtdoublingtimes(DT)1yr(2yr)--5-and10-yrSRof98%and95%;CEADT1yr--5-and10-yrSRof100%；ⅳCtDT1yr(6mon)--5-and10-yrSRof36%and18%（25%and8%）;CEA1year--5-and10-yrSRof43%and21%.PredictorsofMTCprogress,includingrecurrenceandsurvivalDiagnosisandMonitoring●10-yrSRforpatientswithstagesI,II,III,andIVMTCare100%,93%,71%,and21%,respectively;●SRforpatientswithdistantmetastasesMTCis51%at1yr,26%at5yr,and10%at10yr,respectively.●ATA-2015GuidelinesrecommendedMEN2B-denovoRETp.M918TMEN2B-denovoRETp.M918TMEN2A-CLA,RETp.C634R/FSurgicalManagementofMTC①Theminimumextentofsurgeryisatotalthyroidectomy(TT)withbilateralcentralneckdissection(BiⅥ)(TT+BiⅥLND);②TTwithipsilaterallateralcompartmentneckdissection;(UnilaterallateralLN+,MTCsize1cm)(TT+BiⅥ+UniLND)③TTwithbilaterallateralcompartmentneckdissection.(BilateraltumorsorextensiveLN+onthecontralateralside)(TT+BiⅥ+BiLND)SurgicalManagementofMTC***CurrentrecommendationsforthetimingofprophylacticthyroidectomydependsontheriskleveloftheRETmutationinhereditaryMTC(MEN2).ATA-2015GuidelinesrecommendedSurgicalManagementofMTC●ATA-D(HST)-MEN2B1yr,TT+BiⅥLND;●ATA-A~C(MOD~H)-MEN2AbasalCt40pg/mL,TTwithoutBiⅥLNDisadequate.(Ct60ng/L,EliseiR,etal;Ct70ng/L,QiXP,etal)Female,5.5yr;p.C634Y;bilateralMTC;DFS6yrResidualandRecurrentDiseaseResidualandRecurrent:approximately50%-80%,postoperationⅰCt150pg/ml,residualdiseaseinthethyroidbedordraininglymphnodes;ⅱCt150pg/ml,higherprobabilityofdistantmetastaticdisease;ⅲUS,CT/MRI;ResidualandRecurrentDiseaseCytoreductive(Salvage)surgeryⅰReducedCtlevelsinmanypatients;ⅱNormalizationoftheCtlevelsinuptoabout1/3ofpatients;ⅲTheriskofsurgicalcomplications↑MedicalManagementofAdvancedMetastaticDisease①Cytotoxicchemotherapyinlimitedpatientswithrapidlyprogressivediseaseminimalbenefit②RadionuclidetherapyI-131responsesonlyabout30%to35%,③SomatostatinanalogsoctreotideMedicalManagementofAdvancedMetastaticDisease④TargetedtherapyTyrosinekinasereceptorsanddownstreameffectorsMedicalManagementofAdvancedMetastaticDisease④TargetedtherapyTyrosinekinaseinhibitors(TKIs)--RET,EGFR,VEGFR,andFGFR,METTwosmall-moleculeTKIs,vandetanib(Apr2011)andcabozantinib(Nov2012),arecurrentlyavailableasapprovedagentsforthetreatmentofadvancedorprogressiveMTCandprovidesignificantincreasesinprogression-freesurvival(PFS).MedicalManagementofAdvancedMetastaticDisease●Vandetanib--RET,EGFR,VEGFRandEGFRⅰtwophase2(hereditaryonly)dosedaily300mg100mgPR20%16%stabledisease53%53%medianPFS27.9months24weeksⅱphase3in331patients(H-S-MTC)300mg/d;objectiveresponserate(ORR)45%;medianPFS30.5months.QTprolongation(14%),diarrhea(56%),rash(45%),hypertension(32%),headache(26%)….MedicalManagementofAdvancedMetastaticDisease●Cabozantinib--RET,VEGFRandc-METlesssuitableforelderlypatientsforwhomtheprevalenceofcardiovascularriskfactorsTheestimatedmedianPFSwithvandetanibisnumericallylongerthanwithcabozantinibChoice:Thepatient’scomorbidconditionsandthetoxicityprofilethatthepatientiswillingtobearMedicalManagementofAdvancedMetastaticDisease●othersmall-moleculekinaseinhibitorssunitinib,sorafenib,andpazopanib●Othertargetedtreatmentsmammal