Uterine Carcinosarcoma: Mutational Profiling of p53-Abnormal Tumors and Its Association with Histologic Subtypes and...

Uterine carcinosarcoma is a rare and highly aggressive malignancy characterized by biphasic epithelial and mesenchymal components. Although molecular classification has improved risk stratification in endometrial carcinoma, the mutational profile of carcinosarcoma by heterologous versus homologous sarcomatous component is not well characterized. We performed a retrospective review of 27 cases diagnosed between January 2021 and June 2025. Most patients were postmenopausal women (median age, 67 yr), with a predominance of African American patients (20/27, 74.1%), and 16 of 27 (59.3%) presented with FIGO stage I-II disease. Twenty-five tumors (92.6%) were classified as p53-abnormal and 2 (7.4%) as mismatch repair-deficient. TP53 alterations predominated and were accompanied by recurrent mutations involving genes associated with cell cycle regulation, PI3K-RTK-RAS signaling, DNA damage repair, and chromatin remodeling, highlighting molecular heterogeneity within a shared p53-abnormal background. Nineteen tumors exhibited homologous and eight heterologous sarcomatous differentiation; all but one case had a serous epithelial component. Homologous tumors demonstrated a higher disease-specific mortality rate (57.9% vs. 12.5%) and significantly shorter disease-specific survival than heterologous tumors (log-rank P=0.041), whereas progression-free survival showed a similar trend (P=0.057). Despite the predominance of early-stage disease, survival outcomes remained poor.