甲狀腺髓樣癌的子型及治療

甲狀腺髓樣癌分子分型及治療

解放軍第一一七醫(yī)院

戚曉平甲狀腺髓樣癌的子型及治療第1頁(yè)概況Histologicsubtypesof

thyroidcancer

①Papillary:approximately80%ofallthyroidmalignancies;

②FollicularandHürthle:approximately11%;

③Medullary:lessthan5%-8%;

④Anaplastic:lessthan2%.

甲狀腺髓樣癌的子型及治療第2頁(yè)IntroductionMedullarythyroidcancer(MTC)①SporadicMTC:

approximately75%;>50%

somatic

RET

mutations(p.M918T)

-predictapoorprognosis

②HereditaryMTC:

approximately25%;

98%Germline

RET

mutations,MEN2A(~95%)andMEN2B(~5%)

Arisesfromtheneuralcrest-derived,calcitonin-secreting,parafollicularCcellsofthethyroidgland

甲狀腺髓樣癌的子型及治療第3頁(yè)Introduction①SporadicMTC:

asolitaryandunilateralorapalpablecervicallymphnode

②HereditaryMTC:multicentricandbilateraltheuppertomiddlepartsofthethyroidlobes

甲狀腺髓樣癌的子型及治療第4頁(yè)IntroductionInvolvementofcervicallymphnodesisanearlyandcommonmanifestationintheclinicalcourseofthedisease,with35%to50%ormore,another10%to15%mayhavedistantmetastasesatthetimeofinitialpresentation;

DistantmetastaticspreadofMTCfrequentlyinvolvesthemediastinalnodes,lung,liver(>90%),andbones.

甲狀腺髓樣癌的子型及治療第5頁(yè)p.C611YMEN2A甲狀腺髓樣癌的子型及治療第6頁(yè)MolecularAberrations

(overexpression)

①RET

mutations②VEGFR-2③MET④EGFR⑤

FGFR⑥

RAS

(sMTC---56%KRAS+;12%HRAS)(MutationsinRASappeartobemutuallyexclusiveofRETabnormalities)

SomaticRETmutations甲狀腺髓樣癌的子型及治療第7頁(yè)Molecularpathways①PI3K/Akt/mTOR②MAPK③JNK④RAS/ERKPlaycriticalrolesinregulatingcellproliferation,differentiation,motility,apoptosis,andsurvival

甲狀腺髓樣癌的子型及治療第8頁(yè)DiagnosisandMonitoring①FNA,USandCT,MRIorECT(Ct>500pg/mL);

②DNAanalysisfortheRETgermlinemutation

ATA-2015,ETA-,NCCN-Guidelinesrecommend

③

TheMTCspecimenispositivelystainedforCt,chromograninA,andCEAorCongoRed.

甲狀腺髓樣癌的子型及治療第9頁(yè)DiagnosisandMonitoring

④Serum-basedbiomarkers:

calcitoninandCEA(>50%)Preoperative:ⅰCEA(↑),Ct(-)--poorlydifferentiatedtumors,Rare;

ⅱCt>100pg/mL--predictive–MTC;

ⅲCt>150pg/mL,CEA>30ng/L--regionalspread;

ⅳCt>3000pg/mL,CEA>100ng/L--distantspread.PredictorsofMTCprogress,includingrecurrenceandsurvival

甲狀腺髓樣癌的子型及治療第10頁(yè)DiagnosisandMonitoring④Serum-basedbiomarkers:

calcitoninandCEAPostoperative:ⅰCt(↑)--thefirstsignoftumorrecurrence;ⅱCt(-)andsCt(-)--10-yearsurvivalrates(SR)of100%;yearlyCtmeasurements;

ⅲCtdoublingtimes(DT)>1yr(2yr)--5-and10-yrSR

of98%and95%;CEADT>1yr--5-and10-yrSRof100%；

ⅳCtDT<1yr(6mon)--5-and10-yrSR

of36%and18%（25%and8%

）;CEA<1year--5-and10-yrSRof43%and21%.

PredictorsofMTCprogress,includingrecurrenceandsurvival

甲狀腺髓樣癌的子型及治療第11頁(yè)DiagnosisandMonitoring●10-yrSRforpatientswithstagesI,II,III,andIVMTCare100%,93%,71%,and21%,respectively;●SRforpatientswithdistantmetastasesMTCis51%at1yr,26%at5yr,and10%at10yr,respectively.

●甲狀腺髓樣癌的子型及治療第12頁(yè)ATA-2015Guidelinesrecommended甲狀腺髓樣癌的子型及治療第13頁(yè)甲狀腺髓樣癌的子型及治療第14頁(yè)MEN2B-denovo

RET

p.M918T甲狀腺髓樣癌的子型及治療第15頁(yè)MEN2B-denovo

RET

p.M918T甲狀腺髓樣癌的子型及治療第16頁(yè)MEN2A-CLA,RET

p.C634R/F甲狀腺髓樣癌的子型及治療第17頁(yè)甲狀腺髓樣癌的子型及治療第18頁(yè)SurgicalManagementofMTC

①Theminimumextentofsurgeryisatotalthyroidectomy(TT)withbilateralcentralneckdissection(BiⅥ)

(TT+BiⅥLND);②TTwithipsilaterallateralcompartmentneckdissection;

(Unilaterallateral

LN+,MTCsize>1cm)

(TT+BiⅥ+UniLND)③TTwithbilaterallateralcompartmentneckdissection.(BilateraltumorsorextensiveLN+onthecontralateralside)

(TT+BiⅥ+BiLND)甲狀腺髓樣癌的子型及治療第19頁(yè)甲狀腺髓樣癌的子型及治療第20頁(yè)SurgicalManagementofMTC***CurrentrecommendationsforthetimingofprophylacticthyroidectomydependsontheriskleveloftheRETmutationinhereditaryMTC(MEN2).

甲狀腺髓樣癌的子型及治療第21頁(yè)ATA-2015Guidelinesrecommended甲狀腺髓樣癌的子型及治療第22頁(yè)甲狀腺髓樣癌的子型及治療第23頁(yè)SurgicalManagementofMTC●ATA-D(HST)-MEN2B

>1yr,TT+BiⅥLND;

●ATA-A~C(MOD~H)-MEN2A

basalCt<40pg/mL,TTwithoutBiⅥLNDisadequate.(Ct

<

60

ng/L,EliseiR,etal

;Ct

<

70ng/L,QiXP,etal)甲狀腺髓樣癌的子型及治療第24頁(yè)Female,5.5yr;p.C634Y;bilateralMTC;DFS6yr甲狀腺髓樣癌的子型及治療第25頁(yè)ResidualandRecurrentDisease

ResidualandRecurrent:approximately50%-80%,postoperationⅰCt<150pg/ml,residualdiseaseinthethyroidbedordraininglymphnodes;ⅱCt>150pg/ml,higherprobabilityofdistantmetastaticdisease;ⅲUS,CT/MRI;

甲狀腺髓樣癌的子型及治療第26頁(yè)ResidualandRecurrentDiseaseCytoreductive(Salvage)surgery

ⅰReducedCtlevelsinmanypatients;ⅱNormalizationoftheCtlevelsinuptoabout1/3ofpatients;ⅲTheriskofsurgicalcomplications↑

甲狀腺髓樣癌的子型及治療第27頁(yè)MedicalManagementofAdvancedMetastaticDisease

①Cytotoxicchemotherapyinlimitedpatientswithrapidlyprogressivedisease

minimalbenefit

②RadionuclidetherapyI-131responsesonlyabout30%to35%,

③Somatostatinanalogsoctreotide

甲狀腺髓樣癌的子型及治療第28頁(yè)MedicalManagementofAdvancedMetastaticDisease④Targetedtherapy甲狀腺髓樣癌的子型及治療第29頁(yè)

Tyrosinekinasereceptorsanddownstreameffectors甲狀腺髓樣癌的子型及治療第30頁(yè)MedicalManagementofAdvancedMetastaticDisease④Targetedtherapy

Tyrosinekinaseinhibitors(TKIs)--

RET,EGFR,VEGFR,andFGFR,MET

Twosmall-moleculeTKIs,vandetanib(Apr)andcabozantinib(Nov),arecurrentlyavailableasapprovedagentsforthetreatmentofadvancedorprogressiveMTCandprovidesignificantincreasesinprogression-freesurvival(PFS).

甲狀腺髓樣癌的子型及治療第31頁(yè)MedicalManagementofAdvancedMetastaticDisease●Vandetanib--RET,EGFR,VEGFRandEGFRⅰtwophase2(hereditaryonly)

dosedaily300mg100mgPR20%16%stabledisease53%53%medianPFS27.9months>24weeksⅱphase3in331patients

(H-S-MTC)300mg/d;objectiveresponserate(ORR)45%;medianPFS30.5months.

QTprolongation(14%),diarrhea(56%),rash(45%),hypertension(32%),headache(26%)….甲狀腺髓樣癌的子型及治療第32頁(yè)MedicalManagementofAdvancedMetastaticDisease●Cabozantinib--RET,VEGFRandc-MET

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