Clinicopathologic stratification demonstrates survival differences between endometrial carcinomas with mismatch repair deficiency and no specific molecular profile: a cohort study.

Objective: Endometrial carcinomas with mismatch repair deficiency (MMRd) and no specific molecular profile (NSMP) are considered to have intermediate prognoses. However, potential prognostic differences between these molecular subgroups remain unclear due to the lack of standardized control for clinicopathologic factors. This study aims to evaluate outcomes of MMRd and NSMP endometrial carcinomas across guideline-based clinicopathologic risk groups.

Methods: This study analyzed patients treated at a single tertiary center. Immunohistochemistry and polymerase-ϵ sequencing were performed for molecular classification. MLH1-deficient tumors underwent methylation-specific multiplex ligation-dependent probe amplification. Carcinomas were classified into clinicopathologic risk groups according to European guidelines.

Results: The analysis included 420 MMRd and 399 NSMP carcinomas. Among MMRd cases, 224 were subcategorized as MLH1-methylated or MLH1-non-methylated. Median follow-up was 71 months (range; 1-136). Survival differences were most notable in clinicopathologic medium-risk carcinomas, with the MMRd subgroup exhibiting poorer progression-free, disease-specific, and overall survival compared to NSMP. Adjusting for age and adjuvant therapy, MMRd still showed an association with progression-free survival. Both MLH1-methylated (n = 154) and MLH1-non-methylated tumors (n = 70) were associated with more aggressive clinicopathologic risk groups compared to NSMP, but only methylated tumors showed poorer outcomes.

Conclusion: The distinct outcomes for MMRd and NSMP in the clinicopathologic medium-risk group suggest that uterine risk factors may worsen the prognosis for MMRd endometrial carcinomas. Advanced stage may be the primary factor contributing to poor outcomes in high-risk-advanced metastatic carcinomas. Clinicopathologic factors may particularly worsen the prognosis of MLH1-methylated carcinomas.