Association of immunohistochemically defined molecular subtypes with substantial lymphovascular space invasion in early-stage endometrial cancer: a single-center cohort of 575 patients.

OBJECTIVE: To evaluate the association between immunohistochemically (IHC) defined molecular subtypes and substantial lymphovascular space invasion (LVSI) in early-stage endometrial cancer (EC) according to the International Federation of Gynecology and Obstetrics (FIGO) 2023 classification. METHODS: This study included 575 patients who underwent primary surgery for FIGO stage I-II EC between January 2023 and April 2025. LVSI was assessed using World Health Organization criteria and classified as no/focal (Group 1, n=520) or substantial (Group 2, n=55). Molecular subtypes were determined using a surrogate IHC-based approach (no specific molecular profile, mismatch repair-deficient [MMRd], p53-abnormal [p53abn]); POLE mutation analysis was performed in a subset of patients. Clinicopathological variables were compared between groups, and independent predictors of substantial LVSI were identified using multivariable logistic regression. RESULTS: Substantial LVSI was observed in 9.6% of patients (n=55). MMRd (18.5% vs. 34.5%) and p53abn (11% vs. 20%) subtypes were more frequent in the substantial LVSI group (p=0.001). Deep myometrial invasion (≥50%) (21.9% vs. 70.9%, p<0.001), cervical stromal invasion (4.8% vs. 16.4%, p=0.003), and adjuvant therapy (34.6% vs. 92.7%, p<0.001) were also associated with substantial LVSI. Multivariable analysis identified MMRd subtype (adjusted odds ratio [aOR]=2.916; 95% confidence interval [CI]=1.466-5.801; p=0.002) and ≥50% myometrial invasion (aOR=7.935; 95% CI=4.173-15.091; p<0.001) as independent predictors. CONCLUSION: In early-stage EC, substantial LVSI is associated with the MMRd molecular subtype and deep myometrial invasion. Understanding the molecular tumor biology underlying LVSI may facilitate more individualized risk stratification and treatment strategies.