Prognostic Stratification of Multiple-Classifier Endometrial Cancers: Cohort Study and Meta-Analysis

<b>Background/Objectives</b>: The integration of molecular classification has significantly refined prognostic stratification in endometrial carcinoma (EC). However, a tumor subset harboring more than one molecular classifier challenges the current hierarchical classification systems, and their biological and clinical significance remains incompletely defined. <b>Methods</b>: We analyzed an expanded cohort of 150 EC patients using next-generation sequencing and immunohistochemistry, integrating molecular and clinicopathological data. Multiple-classifier ECs were identified and compared with those of single-classifier tumors sharing at least one molecular feature. A systematic review and meta-analysis including our cohort were also performed to estimate the incidence and distribution of multiple-classifier ECs. <b>Results</b>: In our cohort, 6% of ECs harbored molecular multiple-classifiers. POLEmut-MMRd/MSI tumors generally retained POLE-mutated features, including ultrahigh tumor mutational burden (TMB), early-stage disease, and favorable clinicopathological characteristics, consistent with a highly immunogenic phenotype. In contrast, MMRd/MSI-p53abn/TP53mut tumors were more frequently associated with adverse clinicopathological features and showed lower and heterogeneous TMB values, suggesting that the coexistence of TP53 alterations may modify the typical intermediate-risk of MMRd/MSI-only tumors. Triple-classifier tumors were exceedingly rare, precluding definitive conclusions regarding prognosis. The meta-analysis demonstrated an overall prevalence of multiple-classifier ECs of approximately 5.4%, with substantial inter-study heterogeneity largely attributable to differences in molecular testing strategies, analytical sensitivity, and variant interpretation criteria. <b>Conclusions</b>: Multiple-classifier ECs represent a small but clinically relevant subset encompassing biologically heterogeneous entities. Our findings highlight the limitations of current molecular classification hierarchies and underscore the need for harmonized molecular testing and standardized reporting to improve risk stratification and the management of multiple-classifier ECs.