1、概况概况o Histologic subtypes of thyroid cancer Papillary:approximately 80%of all thyroid malignancies;Follicular and Hrthle:approximately 11%;Medullary:less than 5%-8%;Anaplastic:less than 2%.Introduction o Medullary thyroid cancer(MTC)Sporadic MTC:approximately 75%;50%somatic RET mutations(p.M918T)-pr
2、edict a poor prognosis Hereditary MTC:approximately 25%;98%Germline RET mutations,MEN 2A(95%)and MEN 2B(5%)Arises from the neural crest-derived,calcitonin-secreting,parafollicular C cells of the thyroid gland Introduction Sporadic MTC:a solitary and unilateral or a palpable cervical lymph node Hered
3、itary MTC:multicentric and bilateral the upper to middle parts of the thyroid lobes Introduction oInvolvement of cervical lymph nodes is an early and common manifestation in the clinical course of the disease,with 35%to 50%or more,another 10%to 15%may have distant metastases at the time of initial p
4、resentation;oDistant metastatic spread of MTC frequently involves the mediastinal nodes,lung,liver(90%),and bones.p.C611YMEN2AMolecular Aberrations(overexpression)RET mutations VEGFR-2 MET EGFR FGFR RAS (sMTC-56%KRAS+;12%HRAS)(Mutations in RAS appear to be mutually exclusive of RET abnormalities)Som
5、atic RET mutationsMolecular pathways PI3K/Akt/mTOR MAPK JNK RAS/ERKPlay critical roles in regulating cell proliferation,differentiation,motility,apoptosis,and survival Diagnosis and Monitoring FNA,US and CT,MRI or ECT(Ct 500 pg/mL);DNA analysis for the RET germline mutation ATA-2015,ETA-2013,NCCN-20
6、17 Guidelines recommend The MTC specimen is positively stained for Ct,chromogranin A,and CEA or Congo Red.Diagnosis and Monitoring Serum-based biomarkers:calcitonin and CEA(50%)Preoperative:CEA(),Ct(-)-poorly differentiated tumors,Rare;Ct 100 pg/mL-predictive MTC;Ct 150 pg/mL,CEA 30 ng/L-regional sp
7、read;Ct 3000 pg/mL,CEA 100 ng/L-distant spread.Predictors of MTC progress,including recurrence and survival Diagnosis and MonitoringSerum-based biomarkers:calcitonin and CEAPostoperative:Ct()-the first sign of tumor recurrence;Ct(-)and sCt(-)-10-year survival rates(SR)of 100%;yearly Ct measurements;
8、Ct doubling times(DT)1 yr(2yr)-5-and 10-yr SR of 98%and 95%;CEA DT 1 yr-5-and 10-yr SR of 100%；Ct DT 1 yr(6mon)-5-and 10-yr SR of 36%and 18%（25%and 8%）;CEA 3000 pg/mL,CEA 100 ng/L-distant spread.SR for patients with distant metastases MTC is 51%at 1 yr,26%at 5 yr,and 10%at 10 yr,respectively.Predict
9、ors of MTC progress,including recurrence and survivalin limited patients with rapidly progressive disease minimal benefitapproximately 50%-80%,postoperationPreoperative:Prevention-PD/PGDPrevention-PD/PGDATA-2015 Guidelines recommended Reduced Ct levels in many patients;Surgical Management of MTC The
10、 minimum extent of surgery is a total thyroidectomy(TT)with bilateral central neck dissection(Bi)(TT+BiLND);TT with ipsilateral lateral compartment neck dissection;(Unilateral lateral LN+,MTC size 1 cm)(TT+Bi+UniLND)TT with bilateral lateral compartment neck dissection.(Bilateral tumors or extensive
11、 LN+on the contralateral side)(TT+Bi+BiLND)Surgical Management of MTC*Current recommendations for the timing of prophylactic thyroidectomy depends on the risk level of the RET mutation in hereditary MTC(MEN 2).ATA-2015 Guidelines recommendedSurgical Management of MTC ATA-D(HST)-MEN 2B 1yr,TT+Bi LND;
12、ATA-AC(MODH)-MEN 2A basal Ct 40 pg/mL,TT without Bi LND is adequate.(Ct 60 ng/L,Elisei R,et al;Ct 70 ng/L,Qi XP,et al)Female,5.5yr;p.C634Y;bilateral MTC;DFS 6yrResidual and Recurrent Disease Residual and Recurrent:approximately 50%-80%,postoperationCt 150 pg/ml,higher probability of distant metastat
13、ic disease;US,CT/MRI;Residual and Recurrent DiseaseCytoreductive(Salvage)surgery Reduced Ct levels in many patients;Normalization of the Ct levels in up to about 1/3 of patients;The risk of surgical complications Predictors of MTC progress,including recurrence and survivalATA-2015,ETA-2013,NCCN-2017
14、 Guidelines recommendTwo small-molecule TKIs,vandetanib(Apr 2011)and cabozantinib(Nov 2012),are currently available as approved agents for the treatment of advanced or progressive MTC and provide significant increases in progression-free survival(PFS).other small-molecule kinase inhibitors sunitinib
15、,sorafenib,and pazopanibDiagnosis and MonitoringThe minimum extent of surgery is a total thyroidectomy(TT)with bilateral central neck dissection(Bi)(TT+BiLND);Medullary thyroid cancer(MTC)IntroductionThe minimum extent of surgery is a total thyroidectomy(TT)with bilateral central neck dissection(Bi)
16、(TT+BiLND);Residual and Recurrent DiseaseFollicular and Hrthle:approximately 11%;Acknowledgement1yr,TT+Bi LND;Diagnosis and MonitoringCt 150 pg/ml,higher probability of distant metastaticTyrosine kinase receptors and downstream effectorsTwo small-molecule TKIs,vandetanib(Apr 2011)and cabozantinib(No
17、v 2012),are currently available as approved agents for the treatment of advanced or progressive MTC and provide significant increases in progression-free survival(PFS).Residual and Recurrent DiseaseInvolvement of cervical lymph nodes is an early and common manifestation in the clinical course of the
18、 disease,with 35%to 50%or more,another 10%to 15%may have distant metastases at the time of initial presentation;50%somatic RET mutations(p.Medical Management of Advanced Metastatic Disease Cytotoxic chemotherapy in limited patients with rapidly progressive disease minimal benefit Radionuclide therap
19、y I-131 responses only about 30%to 35%,Somatostatin analogs octreotide Medical Management of Advanced Metastatic DiseaseTargeted therapyTyrosine kinase receptors and downstream effectors Medical Management of Advanced Metastatic DiseaseTargeted therapy Tyrosine kinase inhibitors(TKIs)-RET,EGFR,VEGFR
20、,and FGFR,MET Two small-molecule TKIs,vandetanib(Apr 2011)and cabozantinib(Nov 2012),are currently available as approved agents for the treatment of advanced or progressive MTC and provide significant increases in progression-free survival(PFS).Medical Management of Advanced Metastatic DiseaseVandet
21、anib-RET,EGFR,VEGFR and EGFRtwo phase 2(hereditary only)dose daily 300 mg 100 mgPR 20%16%stable disease 53%53%median PFS 27.9 months 24 weeksphase 3 in 331 patients(H-S-MTC)300mg/d;objective response rate(ORR)45%;median PFS 30.5 months.QT prolongation(14%),diarrhea(56%),rash(45%),hypertension(32%),h
22、eadache(26%).Medical Management of Advanced Metastatic DiseaseCabozantinib-RET,VEGFR and c-MET less suitable for elderly patients for whom the prevalence of cardiovascular risk factors The estimated median PFS with vandetanib is numerically longer than with cabozantinib Choice:The patients comorbid
23、conditions and the toxicity profile that the patient is willing to bear Medical Management of Advanced Metastatic Diseaseother small-molecule kinase inhibitors sunitinib,sorafenib,and pazopanib Other targeted treatments mammalian target of rapamycin(mTOR)inhibitor-everolimus Prevention-PD/PGDPreimpl
24、antation genetic diagnosis of multiple endocrine neoplasia type 2A using informative markers identified by targeted sequencingJ,Thyroid,2017.(UR)Acknowledgement Anaplastic:less than 2%.Anaplastic:less than 2%.CEA(),Ct(-)-poorly differentiated tumors,Rare;Vandetanib-RET,EGFR,VEGFR and EGFRMedical Man
25、agement of Advanced Metastatic DiseaseSurgical Management of MTCThe minimum extent of surgery is a total thyroidectomy(TT)with bilateral central neck dissection(Bi)(TT+BiLND);Hereditary MTC:multicentric and bilateralPreoperative:Ct DT 3000 pg/mL,CEA 100 ng/L-distant spread.Residual and Recurrent Dis
26、easeVandetanib-RET,EGFR,VEGFR and EGFRArises from the neural crest-derived,calcitonin-secreting,parafollicular C cells of the thyroid glandATA-2015,ETA-2013,NCCN-2017 Guidelines recommend Ct 3000 pg/mL,CEA 100 ng/L-distant spread.CEA DT 1 yr-5-and 10-yr SR of 100%；Anaplastic:less than 2%.Arises from
27、 the neural crest-derived,calcitonin-secreting,parafollicular C cells of the thyroid glandCEA 50%)Preoperative:CEA(),Ct(-)-poorly differentiated tumors,Rare;Ct 100 pg/mL-predictive MTC;Ct 150 pg/mL,CEA 30 ng/L-regional spread;Ct 3000 pg/mL,CEA 100 ng/L-distant spread.Predictors of MTC progress,inclu
28、ding recurrence and survival ATA-2015 Guidelines recommendedPredictors of MTC progress,including recurrence and survivalDiagnosis and Monitoring Ct DT 1 yr(6mon)-5-and 10-yr SR of 36%and 18%（25%and 8%）;*Current recommendations for the timing of prophylactic thyroidectomy depends on the risk level of
29、 the RET mutation in hereditary MTC(MEN 2).IntroductionPreoperative:Medullary:less than 5%-8%;Somatostatin analogs Ct DT 24 weeksother small-molecule kinase inhibitors sunitinib,sorafenib,and pazopanibCt 1yr,TT+Bi LND;SR for patients with distant metastases MTC is 51%at 1 yr,26%at 5 yr,and 10%at 10
30、yr,respectively.Preoperative:Hereditary MTC:multicentric and bilateralcalcitonin and CEA(50%)calcitonin and CEA(50%)CEA(),Ct(-)-poorly differentiated tumors,Rare;Tyrosine kinase inhibitors(TKIs)-RET,EGFR,VEGFR,and FGFR,MET Ct(-)and sCt(-)-10-year survival rates(SR)of 100%;yearly Ct measurements;Spor
31、adic MTC:a solitary and unilateralFollicular and Hrthle:approximately 11%;Residual and Recurrent Disease PI3K/Akt/mTORcalcitonin and CEA(50%)calcitonin and CEA(50%)Prevention-PD/PGDVandetanib-RET,EGFR,VEGFR and EGFRoctreotidedose daily 300 mg 100 mgPostoperative:Surgical Management of MTCHereditary MTC:approximately 25%;Hereditary MTC:multicentric and bilateralResidual and Recurrent Disease Ct doubling times(DT)1 yr(2yr)-5-and 10-yr SR of 98%and 95%;The risk of surgical complicationsAcknowledgement
