The relationship between histopathological data and molecular alterations with oncological outcomes in endometrioid-type endometrial cancers and a novel POLE mutation.

Abstract

Objective: To identify molecular subgroups in endometrioid endometrial cancer (EEC), evaluate their association with clinicohistopathological characteristics, and define low-intermediate risk groups by integrating these parameters.

Methods: This retrospective-cohort study included 1,040 patients who underwent surgery between January 2000 and June 2022. Among 900 EEC cases, 72 recurred. Patients with tumor recurrence (n=62) and those without (n=52) were matched. POLE exons 9-14 were examined using Sanger sequencing. p53 and mismatch repair (MMR) protein expression were assessed via immunohistochemistry.

Results: The molecular subgroups were POLE mutation (POLE-mut) 5%, mismatch repair-deficient (MMR-d) 43%, p53 mutation (p53-mut) 5%, and non-specific molecular profile (NSMP) 42%. 5% of cases displayed multiple molecular mutations. POLE-mut were more prevalent in high-grade tumors (p=0.026). MMR-d tumors exhibited higher rates of lymphovascular space invasion and myometrial invasion ≥50% (p=0.032, p=0.020). No recurrences occurred in POLE-mut tumors (p=0.002), while MMR-d was significantly associated with recurrence (p=0.002). Median disease-free survival (DFS) for MMR-d, p53-mut, and NSMP were 34, 49, and 107 months, respectively. Median overall survival (OS) for these groups was 128, 102, and 181 months. Multivariate Cox-regression analysis employing the Backward-Stepwise method identified stage as the strongest predictor of DFS, and grade and stage as predictors of OS.

Conclusion: POLE mutations were linked to the most favorable molecular prognostic factor. NSMP cases showed the longest DFS and OS, while p53-mut had the shortest OS. Except for POLE, molecular features alone were insufficient for establishing risk groups, highlighting the continued importance of histopathology in EEC management.