Microsatellite Instability as a Risk Factor for Occult Lymph Node Metastasis in Early-Stage Endometrial Cancer: A Retrospective Multicenter Study

Objectives: This study investigates the association between microsatellite instability (MSI) and the risk of occult lymph node metastases (LNMs) in patients with early-stage endometrial cancer (EC) who showed no evidence of nodal involvement on preoperative imaging. Methods: A retrospective multicenter cohort study was conducted, including 237 patients with EC who underwent primary staging surgery between January 2022 and October 2024. The patients were stratified into two groups based on MSI status. The primary outcome was the prevalence of occult LNMs. Statistical analyses included univariate and multivariate logistic regression models, adjusting for potential confounders such as tumor grading and lymphovascular space invasion (LVSI). The significance of the models was assessed using the maximum likelihood method and Bayesian Information Criterion (BIC). Measures to reduce bias included blinding the data analyst, standardization of histopathological evaluation, and exclusion of patients with genetic conditions predisposing to MSI. Results: The MSI group had a significantly higher incidence of occult LNMs compared to the MSS group (19% vs. 6.7%, p = 0.005). The multivariate analysis confirmed MSI as an independent risk factor for LNMs (OR = 1.105, 95% CI 1.016–1.202, p = 0.020). The sub-analysis showed that loss of MLH1/PMS2 or both MLH1/PMS2 and MSH2/MSH6 heterodimers further increased LNMs risk, independently from other risk factors. Conclusions: MSI is independently associated with a higher risk of occult LNMs in early-stage EC, suggesting a potential role for MSI profiling in refining lymph node staging strategies. Future prospective studies should assess the prognostic impact of this association and its implications for surgical decision-making.