甲状腺髓样癌的分子分型及治疗-38页PPT精选文档

MEN2B-de novo RET p.M918T
MEN2A-CLA, RET p.C634R/F
Surgical Management of MTC
①The minimum extent of surgery is a total thyroidectomy (TT) with bilateral central neck dissection (BiⅥ) (TT+BiⅥLND);
ATA-2019 Guidelines recommended
Surgical Management of MTC
● ATA-D (HST)-MEN 2B
>1yr, TT + BiⅥ LND;
● ATA-A~C (MOD~H)-MEN 2A
basal Ct < 40 pg/mL, TT without BiⅥ LND is adequate. (Ct < 60 ng/L, Elisei R, et al ; Ct < 70 ng/L, Qi XP, et al )
① RET mutations ② VEGFR-2 ③ MET ④ EGFR ⑤ FGFR ⑥ RAS (sMTC---56% KRAS+;12%HRAS)
(Mutations in RAS appear to be mutually exclusive of RET abnormalities)
Somatic RET mutations
●SR for patients with distant metastases MTC is 51% at 1 yr,
26% at 5 yr, and 10% at 10 yr, respectively.
ATA-2019 Guidelines recommended
MEN2B-de novo RET p.M918T
Medical Management of Advanced Metastatic Disease
① Cytotoxic chemotherapy in limited patients with rapidly progressive disease
minimal benefit
② Radionuclide therapy I-131 responses only about 30% to 35%,
Introduction
①Sporadic MTC: a solitary and unilateral or a palpable cervical lymph node
②Hereditary MTC: multicentric and bilateral
the upper to middle parts of the thyroid lobes
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
①Papillary: approximately 80% of all thyroid malignancies; ②Follicular and Hürthle: approximately 11%; ③Medullary: less than 5%-8% ; ④Anaplastic: less than 2%.
draining lymph nodes;
ⅱCt > 150 pg/ml, higher probability of distant metastatic
disease;
ⅲ US, CT/MRI;
Residual and Recurrent Disease
Cytoreductive (Salvage ) surgery ⅰ Reduced Ct levels in many patients; ⅱ Normalization of the Ct levels in up to about 1/3 of patients; ⅲ The risk of surgical complications↑
Distant metastatic spread of MTC frequently involves the mediastinal nodes, lung, liver (>90%), and bones.
p.C611Y MEN2A
Molecular Aberrations (overexpression )
Female, 5.5yr; p.C634Y; bilateral MTC; DFS 6yr
Residual and Recurrent Disease
Residual and Recurrent : approximately 50%-80%, postoperation
ⅰCt < 150 pg/ml, residual disease in the thyroid bed or
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Molecular pathways
① PI3K/Akt/mTOR ② MAPK ③ JNK ④ RAS/ERK
Play critical roles in regulating cell proliferation, differentiation, motility, apoptosis, and survival
③ Somatostatin analogs octreotide
Medical Management of Advanced Metastatic Disease
④Targeted therapy
Tyrosine kinase receptors and downstream effectors
Medical Management of Advanced Metastatic Disease
●Vandetanib--RET, EGFR, VEGFR and EGFR
Diagnosis and Monitoring ① FNA,US and CT, MRI or ECT (Ct >500 pg/mL);
② DNA analysis for the RET germline mutation
ATA-2019, ETA-2019, NCCN-2019 Guidelines recommend
(Bilateral tumors or extensive LN+ on the contralateral side)
(TT+BiⅥ+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).
Medical Management of Advanced Metastatic Disease
④Targeted therapy
Tyrosine kinase inhibitors(TKIs)-- RET, EGFR,
VEGFR, and FGFR, MET
Two small-molecule TKIs, vandetanib (Apr 2019) and cabozantinib(Nov 2019), are currently available as approved agents for the treatment of advanced or progressive MTC and provide significant increases in progression-free survival (PFS).
Preoperative: ⅰ CEA(↑), Ct (-)--poorly differentiated tumors, Rare;
ⅱ Ct >100 pg/mL--predictive –MTC; ⅲ Ct > 150 pg/mL, CEA > 30 ng/L--regional spread; ⅳ Ct > 3000 pg/mL, CEA > 100 ng/L--distant spread.
②TT with ipsilateral lateral compartment neck dissection; (Unilateral lateral LN+, MTC size > 1 cm) (TT+BiⅥ+UniLND)
③ TT with bilateral lateral compartment neck dissection.
Predictors of MTC progress, including recurrence and survival
Diagnosis and Monitoring
④Serum-based biomarkers:
calcitonin and CEA Postoperative:
ⅰ Ct (↑)-- the first sign of tumor recurrence; ⅱ Ct (-) and sCt (-) --10-year survival rates (SR) of 100%; yearly Ct measurements; ⅲ Ct doubling times (DT) > 1 yr (2yr)-- 5- and 10-yr SR of 98% and 95%;
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
Medullary thyroid cancer (MTC)
①Sporadic MTC: approximately 75%;
> 50% somatic RET mutations (p.M918T) -predict a poor prognosis
②Hereditary MTC: approximately 25%;
CEA DT > 1 yr -- 5- and 10-yr SR of 100%；
ⅳ Ct DT < 1 yr (6mon)-- 5- and 10-yr SR of 36% and 18% （25% and 8% ）;
CEA < 1 year -- 5- and 10-yr SR of 43% and 21%.
Predictors of MTC progress, including recurrence and survival
Diagnosis and Monitoring
●●10-yr SR for patients with stages I, II, III, and IV MTC are
100%, 93%, 71%, and 21%, respectively;
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;
③ The MTC specimen is positively stained for Ct, chromogranin A, and CEA or
Congo Red.
Diagnosis and Monitoring ④Serum-based biomarkers:
calcitonin and CEA (>50%)