1、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,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%;
2、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
3、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
4、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.C611YMEN2A,Molecular Aberrations (overexpression ), RET mutations VEGFR-2 MET EGFR FGFR RAS (sMTC-56% KRAS+;12%HRAS)(Mutati
5、ons in RAS appear to be mutually exclusive of RET abnormalities),Somatic RET mutations,Molecular 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 50
6、0 pg/mL); DNA analysis for the RET germline mutation ATA-2015, 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%)Preoperative: CEA(), Ct (-)-poorly dif
7、ferentiated 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 CEAPostoperative: Ct ()- the fir
8、st 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+Un
9、iLND) 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 (M
10、EN 2).,ATA-2015 Guidelines recommended,Surgical Management of MTC, ATA-D (HST)-MEN 2B 1yr, 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 24 weeksphase 3 in 331 patients (H-S-MTC)300mg/d; objective response rate (ORR) 45%;median
11、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 PF
12、S 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,
