Abstract
OBJECTIVE: The molecular classification system of endometrial carcinoma (EC) in 'The Cancer Genome Atlas' is widely acknowledged for its prognostic utility. Subsequently, more simplified classification system that incorporate DNA polymerase epsilon (POLE) exonuclease domain mutations, mismatch repair deficiencies (MMRd), and abnormal p53 (P53abn) has also demonstrated its clinical utility. These classifications helped identifying a 'POLE ultramutated' (POLEmut) category of patients, most of whom show excellent prognoses despite having high-grade ECs. We aimed to investigate the clinicopathological and molecular characteristics of high-grade ECs with POLEmut. METHODS: We investigated 414 patients with high-grade ECs (including endometrioid carcinomas grade 3, serous carcinomas, clear cell carcinomas, mixed carcinomas, undifferentiated and dedifferentiated carcinomas, and carcinosarcomas) by sequencing and immunohistochemical staining. RESULTS: Forty-three tumors (10.4%) were classified as POLEmut, including 2 with new, possibly pathogenic POLE mutations at P286C and L424V. These patients had very good prognoses except for 1 with stage IV disease and residual tumor. Eleven patients in this group also had P53abn and 4 had MMRd; molecular analysis revealed that patients with synchronous POLE pathogenic mutation and other mutations had a POLEmut or MMRd phenotype; survival analysis found no difference in prognosis between these patient categories. The prognoses of patients in the POLEmut EC group were not significantly influenced by treatment or risk category. CONCLUSIONS: Patients with high-grade EC exhibiting POLEmut have very good clinical outcomes, and should be identified urgently in daily work owing to their conflicting morphology. Our findings also provide guidance on subclassifying ECs with poor histological appearance.