The role of molecular classification in endometrial cancer: a focus on patients with low-volume metastasis—a retrospective multi-center study and literature review

Objective: The prognosis and optimal management of patients with endometrial cancer with low-volume lymph node metastases remains unclear, particularly, regarding the role of molecular classification. This study investigates the distribution and prognostic role of molecular classes in this cohort of patients, while reviewing existing literature on this topic. Methods: A multi-center, retrospective cohort study involving 8 institutions evaluated 134 patients with endometrial cancer and low-volume metastasis (isolated tumor cells: ≤0.2 mm in diameter or micro-metastasis: >0.2 to ≤2.0 mm). All patients were categorized into 1 of 4 molecular classes: POLE mutated (POLEmut), mismatch repair-deficient (MMRd), p53 abnormal (p53abn), and non-specific molecular profile (NSMP). Recurrence-free survival was estimated using Kaplan-Meier methods and differences between molecular classes were tested using log-rank test. Cox proportional hazards regression models were fit to evaluate the association between molecular class and recurrence after surgery. Results: Of 134 patients, 78 (58.2%) had isolated tumor cells and 56 (41.8%) had micro-metastasis. Molecular classification revealed 78 (58.2%) NSMP, 37 (27.6%) MMRd, 15 (11.2%) p53abn, and 4 (3.0%) POLEmut tumors. No significant differences in recurrence-free survival were observed among molecular classes (log-rank p = .52). At 5 years, recurrence-free survival rates were 84.6% for NSMP, 65.9% for MMRd, and 76.9% for p53abn. No recurrences occurred in POLEmut patients. Predictors of recurrence included micro-metastasis (p = .01) and lympho-vascular space invasion (p = .02), whereas molecular classification was not independently associated with recurrence. The literature review revealed insufficient data on this topic to draw definitive conclusions. Conclusions: Although molecular classification enhances risk stratification in endometrial cancer, its impact should be contextualized in patients with low-volume lymph node metastasis. Pathological factors, such as lymph node metastasis size and lympho-vascular space invasion, continue to represent a key predictor of recurrence. Integrating molecular data with traditional risk factors remains pivotal, especially in intermediate-risk molecular classes, to refine management strategies.