Clinical and Prognostic Significance of a Squamous Cell Carcinoma Component in Endometrioid Endometrial Carcinoma: A Multicenter Retrospective Cohort Study

Background/Objectives: Contemporary endometrial cancer pathology integrates histological and molecular features for risk classification. Endometrioid endometrial carcinoma (EEC) with a squamous cell carcinoma (SCC) component was historically termed adenosquamous carcinoma but later incorporated into the squamous-differentiation subtype of EEC. This reclassification left an evidence gap, and its prognostic significance remains insufficiently defined. We compared clinicopathological aggressiveness and evaluated associations of an SCC component with overall survival (OS) and lymph node (LN) involvement. Methods: We retrospectively analyzed 7590 surgically staged patients from 24 institutions (2000–2019): 7495 pure EEC and 95 EEC with SCC components. Confounding was addressed using overlap weighting (OW), inverse probability of treatment weighting targeting the average treatment effect on the treated (IPTW-ATT), and 1:4 propensity score matching (PSM), each with doubly robust Cox regression. Survival machine-learning models with SHapley Additive exPlanations (SHAP) assessed histological subtype contribution. LN involvement was assessed by OW/IPTW-ATT-weighted logistic regression. Results: EEC with SCC component had higher grade, deeper myometrial invasion, more advanced stage, and worse unadjusted OS (hazard ratio [HR] 7.04; 95% confidence interval [CI] 3.50–14.16; p < 0.001). After adjustment, the OS disadvantage persisted: OW-adjusted HR 3.05 (95% CI, 1.36–6.85; p = 0.007), IPTW-ATT-adjusted HR 3.26 (95% CI, 1.51–7.01; p = 0.003), and PSM-adjusted HR 3.30 (95% CI, 1.24–8.77; p = 0.017). XGBoost-Survival showed stable discrimination (test C-index 0.797 ± 0.057; 5-year AUC 0.787 ± 0.065), and SHAP supported histological subtype as a prominent risk-associated contributor after class-imbalance correction. In contrast, adjusted LN involvement was not increased (OW odds ratio [OR] 1.000, 95% CI 0.505–1.979; p = 1.000; IPTW-ATT OR 1.035, 95% CI 0.527–2.035; p = 0.920). Conclusions: EEC with SCC component was associated with worse OS after adjustment, without an adjusted increase in LN involvement. These findings support explicit morphologic reporting and future validation incorporating systematically recorded molecular testing when available.