Molecular characterization of undifferentiated carcinoma associated with endometrioid carcinoma

Uterine and ovarian undifferentiated carcinomas (UCs) are often associated with low-grade endometrioid carcinomas (EMCs) and are characterized by a solid growth pattern and a lack of appreciable features of differentiation. As compared with pure EMC, UC is highly malignant, and the molecular pathogenesis that leads to disease aggressiveness remains largely unknown. This study interrogates the molecular pathogenesis of UCs by comparing the molecular alterations between the UC and the EMC components. A total of 20 UCs were studied, 12 of which contained both UC and EMC components. Mutation analysis was performed for the genes commonly mutated in EMC, and immunohistochemistry was used to determine the expression pattern of β-catenin and PTEN. Sequencing analysis revealed that UCs harbored somatic mutations in PIK3CA (50%), CTNNB1 (30%), TP53 (30%), FBXW7 (20%), and PPP2R1A (20%). All somatic mutations detected in EMCs were also present in concurrent UCs. Moreover, additional somatic mutations were detected in the UC component in 5 (42%) cases with concurrent EMC and UC. Concordance of immunostaining pattern for β-catenin and PTEN was recorded in all 12 matched EMCs and UCs, except 4 cases in which nuclear accumulation of β-catenin staining was detected in one of the components but not in the other. Our findings support a clonal relationship between EMCs and their associated UCs. Additional molecular genetics alteration, including mutations of CTNNB1, PPP2R1A, and TP53, may contribute to tumor progression from EMC to UC.