医学课件甲状腺髓样癌的子型及治疗.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,概况,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,Medullary thyroid cancer(,MTC,),Sporadic MTC:,approximately 75%;,50%,somatic,RET,mutations,(p.M918T),-predict 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,Hereditary MTC:,multicentric and bilateral,the upper to middle parts of the thyroid lobes,Introduction,Involvement 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 presentation;,Distant metastatic spread of MTC frequently involves the mediastinal nodes,lung,liver(90%),and bones.,p.C611Y,MEN2A,Molecular 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),Somatic,RET,mutations,Molecular,pathways,PI3K/Akt/mTOR,MAPK,JNK,RAS/ERK,Play 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-,20,15,ETA-2013,NCCN-2017 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%),Pre,operative:,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,including recurrence and survival,Diagnosis and Monitoring,Serum-based biomarkers:,calcitonin and CEA,Post,operative:,Ct(,)-the first sign of tumor recurrence;,Ct(-)and sCt(-)-10-year survival rates(SR)of,100%,;yearly Ct measurements;,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 1 cm,),(TT+Bi+UniLND),TT with bilateral lateral compartment neck dissection.,(Bilateral tumors or extensive 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-,20,15 Guidelines recommended,Surgical Management of MTC,ATA-D,(HST)-,MEN 2B,1,yr,TT+Bi LND,;,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,7,0,ng/L,Qi XP,et al,),Female,5.5,yr;p.C634Y;bilateral MTC;DFS 6yr,Residual and Recurrent Disease,Residual and Recurrent:,approximately 50%-80%,postoperation,Ct 150 pg/ml,higher probability of distant metastatic,disease;,US,CT/MRI;,Residual and Recurrent Disease,Cytoreductive(,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,Medical Management of Advanced Metastatic Disease,Cytotoxic chemotherapy,in limited patients with rapidly progressive disease,minimal benefit,Radionuclide therapy,I-131 responses only about 30%to 35%,Somatostatin analogs,octreotide,Medical Management of Advanced Metastatic Disease,Targeted therapy,Tyrosine kinase receptors and downstream effectors,Medical Management of Advanced Metastatic Disease,Targeted therapy,Tyrosine kinase inhibitors(TKIs)-,RET,EGFR,VEGFR,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 Disease,Vandetanib-,RET,EGFR,VEGFR,and EGFR,two phase 2(hereditary only),dose daily 300 mg 100 mg,PR 20%16%,stable disease 53%53%,median PFS 27.9 months 24 weeks,phase 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%),headache(26%).,Medical Management of Advanced Metastatic Disease,Cabozantinib-,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,conditions,and the toxicity profile that the patient is willing to,bear,Medical Management of Advanced Metastatic Disease,other small-molecule kinase inhibitors,sunitinib,sorafenib,and pazopanib,Other targeted treatments,mammalian target of rapamycin(mTOR)inhibitor-everolimus,Prevention-PD/PGD,Preimplantation genetic diagnosis of multiple endocrine neoplasia type 2A using informative markers identified by targeted sequencingJ,Thyroid,2017.(UR),Acknowledgement,