Prognostic significance of lymphovascular space invasion extent across molecular classes in early-stage endometrial cancer: A large retrospective analysis

BACKGROUND: The prognostic role of lymphovascular space invasion (LVSI) in endometrial cancer (EC) remains poorly defined across molecular subgroups. We evaluated the impact of LVSI extent in a large cohort of stage I-II EC classified according to molecular profiling. METHODS: Patients with stage I-II EC who underwent complete primary surgical staging were retrospectively included. According to WHO criteria, cases were classified as LVSI-negative, focal LVSI, or substantial LVSI. Molecular classification was performed using next-generation sequencing and immunohistochemistry, identifying the following groups: POLE-mutated (POLEmut), mismatch repair-deficient (MMRd), p53-abnormal (p53abn), low-risk no specific molecular profile (NSMP-LR), and high-risk NSMP (NSMP-HR). RESULTS: Among 2374 patients, LVSI was absent in 73.7% (n = 1750), focal in 11.5% (n = 273), and substantial in 14.8% (n = 351). Any LVSI was associated with larger tumor size, deeper myometrial invasion, and cervical involvement (all p < 0.001). Substantial LVSI was additionally associated with non-endometrioid histology, grade 3 disease, ER < 10%, and higher prevalence of p53abn and NSMP-HR tumors (all p < 0.001). On multivariable Cox analysis, substantial LVSI independently predicted worse disease-free survival in NSMP-LR, MMRd, and p53abn subgroups, whereas focal LVSI did not affect disease-free survival. No significant survival association was found in POLEmut or NSMP-HR tumors. Nevertheless, substantial LVSI was consistently associated with higher recurrence risk across all molecular classes (RR 2.5-2.8). CONCLUSIONS: In stage I-II EC, focal LVSI does not worsen oncologic outcomes across molecular subgroups. In contrast, substantial LVSI associates with aggressive clinicopathologic features and independently predicts poorer disease-free survival in selected molecular groups, increasing recurrence risk by approximately 2.5-2.8-fold.