Abstract
The incidence of endometrial cancer (EC) is rising, increasingly affecting younger women desiring fertility preservation. While the International Federation of Gynecology and Obstetrics staging system guides early-stage EC treatment, its prognostic and predictive accuracies are limited, highlighting the need for more precise tools. Molecular classification, particularly mismatch repair (MMR) status and microsatellite instability (MSI), has emerged as a promising strategy for risk stratification and personalized management. This narrative review synthesizes evidence on the role of MMR and MSI as prognostic and predictive biomarkers in early-stage EC. Using a structured narrative approach, we critically examined studies investigating molecular subtypes, especially MMR deficiency (MMRd), and their association with clinicopathological features, treatment responses, and oncological outcomes. Findings indicate that molecular profiling provides key insights beyond traditional pathology. MMRd is associated with less favorable outcomes, including higher recurrence and reduced response to hormonal or fertility-sparing therapies, potentially increasing treatment failure rates. Distinct responses to adjuvant radiation have been observed in MMRd tumors. Regarding nodal involvement, MSI has been associated with increased occult lymph node metastases, while both p53-abnormal and MMRd groups show higher rates of sentinel lymph node positivity than other subtypes. Overall, the MSI/MMRd status appears to be pivotal for improving prognosis and guiding personalized treatment of early-stage EC. Integrating molecular classification into clinical practice may optimize patient selection for conservative therapies, refine lymph node staging strategies, and inform adjuvant treatment decisions. Large prospective studies are essential to validate these findings and facilitate the adoption of standardized guidelines for individualized care.