Cribriform morular thyroid carcinoma: Clinicopathological and molecular basis for both a preventive and therapeutic approach for a rare tumor (Review)

Abstract

Cribriform morular thyroid carcinoma (CMTC) has been included within the group of thyroid tumors of uncer‑ tain 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 transcrip‑ tion 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 activa‑ tion 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