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

Abstract 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 2,374 patients, LVSI was absent in 73.7% (n=1,750), 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.