Clinicopathologic and molecular characterization of uterine and ovarian mixed yolk sac tumor and carcinoma/carcinosarcoma: implications for somatic derivation and therapeutics.

Mixed yolk sac tumors (YST) with carcinoma or carcinosarcoma (Ca/CS) of the uterus and ovary represent exceptionally rare and aggressive malignancies with poorly characterized genetic drivers. Through an integrated clinicopathologic and molecular analysis of nine cases using immunohistochemistry, fluorescence in situ hybridization, and targeted next-generation sequencing, we identified recurrent somatic driver mutations in TP53 (8/9), PIK3CA (3/9), and PTEN (2/9), and absence of i(12p), confirming their somatic origin. Multi-region sequencing revealed that YST and Ca/CS components share truncal mutations yet harbor divergent genetic alterations, supporting a model of clonal origin and lineage-specific evolution. Therapeutically, we identified a high frequency of actionable alterations, including homologous recombination repair (HRR) gene mutations (4/9), HER2 amplification or low expression (7/9), and biomarkers for immunotherapy (positive PD-L1 in 3/9, TMB > 10 mutations > 10 /Mb in 2/9). Consistent with these findings, two patients derived profound clinical benefit from matched PARP inhibitors or anti-HER2 antibody-drug conjugate. Our findings definitively establish the somatic and clonal nature of these mixed tumors and provide a compelling rationale for molecularly guided treatment.