Molecular Classification as a Predictor of Nodal Involvement and Survival Outcomes in Presumed Early-Stage Endometrial Cancer

Background: Molecular classification has transformed risk stratification in endometrial cancer, providing prognostic information beyond traditional clinicopathologic features. However, the relationship between molecular subtype, nodal involvement, and recurrence risk remains incompletely defined. This study aimed to compare lymph node metastasis rates across molecular subgroups and evaluate survival outcomes and prognostic factors for recurrence. Methods: We conducted a retrospective study including 158 patients with a preoperative diagnosis of presumed early-stage endometrial carcinoma treated surgically between 2021 and 2024. Molecular classification was performed according to WHO criteria, including POLE-ultramutated, mismatch repair deficient (MMRd), p53-abnormal (p53-abn), and no specific molecular profile (NSMP). Sentinel lymph node biopsy (SLNB) was the primary method for nodal staging. Survival outcomes were assessed using a Kaplan–Meier analysis, and logistic regression was used to identify prognostic factors for recurrence. Results: NSMP was the most frequent molecular subtype (44.3%), followed by MMRd (29.1%), p53-abn (20.9%), and POLE-mutated tumors (5.7%). Overall, 11.4% of patients had nodal metastases, most commonly in the p53-abn subgroup, which showed significantly higher rates of positive sentinel lymph nodes (p = 0.010). Prognosis differed significantly across molecular subtypes. POLE-mutated and NSMP tumors demonstrated the most favorable outcomes, while p53-abn tumors showed the poorest overall survival and progression-free survival. In a univariate analysis, grade, lymphovascular space invasion (LVSI), myometrial invasion, FIGO stage, and molecular classification were associated with recurrence. Stratified analyses suggested LVSI as the most relevant prognostic factor within the MMRd subgroup. Conclusions: Molecular classification is strongly associated with nodal involvement and survival outcomes in early-stage endometrial cancer. Integrating molecular subtype with clinicopathologic factors may improve recurrence risk stratification and guide individualized surgical and adjuvant treatment strategies.