Microsatellite Instability and Myometrial Infiltration in Low-Grade Endometrial Cancer: A Focus on MMR Heterodimer Dysfunction by a Retrospective Multicentric Italian Study

Background: Recent studies highlight the role of microsatellite instability (MSI) in tumor progression. This study examines the link between MSI, type of loss of function, and disease progression in low-grade endometrial carcinoma clinically confined to the uterus, focusing on myometrial infiltration. Materials and Methods: This retrospective case-control study analyzed data from 144 women treated for clinical stage I low-grade endometrial carcinoma at two university hospitals. Patients were divided into two groups based on microsatellite status: 118 with microsatellite stability (MSS) and 26 with MSI. Immunohistochemical profiling assessed MMR proteins (MLH1, PMS2, MSH2, MSH6). The primary outcome was the presence of myometrial infiltration, and the secondary outcome was the deepness of infiltration. Data were statistically analyzed using Fisher’s exact, Chi-square, and Wilcoxon tests, with logistic regression applied to evaluate the impact of MSI on these outcomes. Results: Myometrial infiltration was present in 96% of MSS and 98% of MSI cases (p = 0.5). However, deep infiltration (≥50%) was more frequent in patients with MSI (38% vs. 19%, p = 0.042). Stratification by heterodimer loss revealed that loss of MLH1/PMS2 was associ- ated with a higher rate of deep infiltration (47%), while loss of MSH2/MSH6 correlated with lower infiltration risk (14%). In multivariate analysis, MSH2/MSH6 loss remained negatively associated with infiltration (OR 0.88; 95% CI 0.80–0.98; p = 0.020), independent of grade and LVSI. Conclusions: In low-grade endometrial carcinomas clinically confined to the uterus, MSI does not increase the overall prevalence of myometrial infiltration but is associated with deeper invasion, especially in cases with MLH1/PMS2 loss. MSI profiling could aid in risk stratification and therapeutic planning, particularly in candidates for fertility-sparing treatment.