Microsatellite instability and survival outcomes in endometrial cancer: a comprehensive analysis of molecular subtypes and clinical implications

Background: Microsatellite instability (MSI) is a key biomarker in endometrial cancer, present in 20–30% of cases. The prognostic significance of MSI status, particularly MSI-high (MSI-H), remains under investigation, with conflicting reports on survival outcomes. This study aimed to evaluate the impact of MSI on overall and disease-free survival in endometrial carcinoma patients and compare characteristics between MSI-H and microsatellite stable (MSS) tumors. Methods: We retrospectively analyzed 100 patients with surgically treated endometrial carcinoma from March 2018 to March 2024. Patients were grouped as MSI-H or MSS based on immunohistochemical analysis of mismatch repair (MMR) proteins (MLH1 (mutL homolog 1), MSH2 (mutS homolog 2), MSH6 (mutS homolog 6), and PMS2 (postmeiotic segregation increased 2)) in formalin-fixed, paraffin-embedded (FFPE) tissue. We collected and analyzed clinicopathological data, including demographics, tumor features, molecular data, treatments, and survival outcomes. Results: Of the 100 patients, 34 (34%) were MSI-H and 66 (66%) were MSS. No significant differences were found in age, body mass index, or preoperative Cancer Antigen 125 (CA-125) levels. MSI-H tumors were significantly larger (median 65 mm vs. 45 mm, p < 0.001), had higher rates of mucinous differentiation (52.9% vs. 24.2%, p = 0.008), and more frequent poor differentiation (20.6% vs. 3.03%, p = 0.003). MSI-H status was also associated with more advanced-stage disease. The most common MMR protein losses were in PMS2 (79.2%) and MLH1 (67.6%). Over a median follow-up of 48 months, the 5-year overall and disease-free survival rates for the entire cohort were 71.3% and 67.9%, respectively. Conclusions: Although MSI-H endometrial carcinomas have distinct pathological features, MSI status did not significantly affect survival in this cohort. These findings suggest that MSI testing is more valuable as a predictive biomarker for immunotherapy than for prognostic purposes. Comprehensive molecular profiling, including p53 and DNA polymerase epsilon (POLE) analysis, is necessary for a complete understanding of prognosis in endometrial carcinoma.