PDF(Pubmed)
Abstract：
Cribriform morular thyroid carcinoma (CMTC) has been included within the group of thyroid tumors of uncertain histogenesis in the recent World Health Organization classification of endocrine tumors. Most CMTCs occur in young euthyroid women with multiple (and bilateral) thyroid nodules in cases associated with familial adenomatous polyposis (FAP) or as single nodules in sporadic cases. CMTC generally behaves indolently, while aggressiveness and mortality are associated with high‑grade CMTC. This tumor histologically displays a distinctive combination of growth patterns with morular structures. Strong diffuse nuclear and cytoplasmic immunostaining for β‑catenin is the hallmark of CMTC. Tumor cells are also positive for thyroid transcription factor‑1 and for estrogen and progesterone receptors, but negative for thyroglobulin and calcitonin. It is possible that the CMTC phenotype could result from blockage in the terminal/follicular differentiation of follicular cells (or their precursor cells) secondary to the permanent activation of the Wnt/β‑catenin pathway. In CMTC, the activation of the Wnt/β‑catenin pathway is the central pathogenetic event, which in FAP‑associated cases results from germline mutations of the APC regulator of WNT signaling pathway (APC) gene, and in sporadic cases from somatic inactivating mutations in the APC, AXIN1 and CTNNB1 genes. Estrogens appear to play a tumor‑promoting role by stimulating both the PI3K/AKT/mTOR and the RAS/RAF/MAPK signaling pathways. Additional somatic mutations (i.e. RET rearrangements, or KRAS, phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit α, telomerase reverse transcriptase or tumor protein 53 mutations) may further potentiate the development and progression of CMTC. While hemithyroidectomy would be the treatment of choice for sporadic cases without high‑risk data, total thyroidectomy would be indicated in FAP‑associated cases. There is insufficient clinical data to propose therapies targeting the Wnt/β‑catenin pathway, but multikinase or selective inhibitors could be used in a manner analogous to that of conventional thyroid tumors. It is also unknown whether adjuvant antiestrogenic therapy could be useful in the subgroup of women undergoing surgery with high‑risk CMTC, as well as when there is tumor recurrence and/or metastasis.
摘要：
在最近的世界卫生组织对内分泌肿瘤的分类中，组织起源不确定的甲状腺肿瘤已包括在CMTC中。大多数CMTC发生在年轻的甲状腺功能正常的女性中，在与家族性腺瘤性息肉病（FAP）相关的病例中有多个（和双侧）甲状腺结节，或者在散发性病例中有单个结节。CMTC通常表现迟缓，而侵略性和死亡率与高等级CMTC有关。该肿瘤在组织学上显示出生长模式与形态结构的独特组合。β-catenin的强弥漫性核和细胞质免疫染色是CMTC的标志。肿瘤细胞对甲状腺转录因子-1和雌激素和孕激素受体也呈阳性，但甲状腺球蛋白和降钙素阴性.CMTC表型可能是由于Wnt/β‑catenin途径永久激活后滤泡细胞（或其前体细胞）的终末/滤泡分化受阻所致。在CMTC，Wnt/β‑catenin通路的激活是中心致病事件，在FAP相关病例中，WNT信号通路（APC）基因的APC调节因子的种系突变导致，在APC体细胞失活突变的散发性病例中，AXIN1和CTNNB1基因。雌激素似乎通过刺激PI3K/AKT/mTOR和RAS/RAF/MAPK信号通路发挥肿瘤促进作用。额外的体细胞突变（即RET重排，或者KRAS,磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α，端粒酶逆转录酶或肿瘤蛋白53突变）可能进一步增强CMTC的发育和进展。虽然对于没有高风险数据的散发性病例，半甲状腺切除术将是首选治疗方法，全甲状腺切除术将适用于FAP相关病例。没有足够的临床数据来提出针对Wnt/β‑catenin通路的治疗方法，但是多激酶或选择性抑制剂可以类似于常规甲状腺肿瘤的方式使用。还不清楚辅助抗雌激素治疗是否对接受高风险CMTC手术的女性亚组有用，以及当有肿瘤复发和/或转移时。
