POLE-mutated endometrial carcinoma with extreme morphological and molecular heterogeneity: spatial clonal divergence...

POLE-mutated endometrial carcinomas are typically associated with favorable prognosis, yet marked spatial heterogeneity may complicate biological and clinical interpretation. We report a unique triphasic carcinoma composed of endometrioid, dedifferentiated-like, and sarcomatoid-like components with distinct morphologic and immunophenotypic profiles. Multiregional sequencing demonstrated a shared pathogenic POLE V411L mutation across all components, confirming a common clonal origin. Progressive molecular divergence was observed, with subclonal MSH6 alteration in the endometrioid region, complete MSH6 loss and dramatic tumor mutational burden escalation in the dedifferentiated-like and sarcomatoid-like components, and acquisition of TP53 and ARID1A truncating mutations restricted to the sarcomatoid-like compartment. Despite high-grade transformation and stage IIC disease, microsatellite stability was maintained, supporting a POLE-driven hypermutator phenotype. This case provides direct morphologic and molecular evidence of spatial clonal evolution in a multiple-classifier endometrial carcinoma. The clinical implications of this spatial heterogeneity remain uncertain and warrant further investigation.