Multiple-classifier endometrial cancers: the first multicenter clinicopathological study from five Polish institutions

Introduction: Endometrial cancer (EC) exhibits molecular heterogeneity, classified into four subtypes: POLEmut (POLE ultramutated), MMRd (mismatch repair deficient), p53abn (p53 abnormal), and NSMP (no specific molecular profile). Tumors with multiple classifiers (multiple-classifier ECs) challenge risk stratification, particularly MMRd-p53abn and POLEmut-related subtypes. Method: This study aims to assess the prevalence and clinicopathological features of multiple-classifier ECs, focusing on MMRd-p53abn versus classical MMRd and p53abn, and their ESGO/ESTRO/ESP risk group alignment. Results: We analyzed 1205 EC patients from five Polish oncology centers, molecularly profiled post-surgery. Subtypes included MMRd, p53abn, POLEmut, and multiple-classifier groups (MMRd-p53abn, POLEmut-p53abn, POLEmut-MMRd, POLEmut-MMRd-p53abn). Histotype, grade, myometrial invasion, lymphovascular space invasion, and risk groups classification were assessed. Multiple-classifier ECs comprised 7.5% (90/1205), with MMRd-p53abn at 4.2% (51/1205), POLEmut-p53abn 0.3% (4/1205), POLEmut-MMRd 1.9% (23/1205), and POLEmut-MMRd-p53abn 1.0% (12/1205). MMRd-p53abn tumors showed more non-endometrioid histology (9.8% vs 2.86%, p=0.035), high-grade (G3) tumors (27.45% vs 12.14%, p=0.005), and assignment to high-intermediate or high-risk (HIR/HR) groups (62.75% vs 37.50%, p=0.001) than MMRd, but less non-endometrioid histology than p53abn (9.8% vs 35.63%, p=0.001). POLEmut-p53abn tumors had higher G3 (75.00% vs 5.88%, p=0.005) and more FIGO III-IV stages (75.00% vs 5.88%, p=0.005) than POLEmut. Conclusions: MMRd-p53abn tumors are more aggressive than MMRd yet less adverse than p53abn, while POLEmut-p53abn diverge from POLEmut’s favorable prognosis. Their frequent assignment to high-intermediate or high-risk (HIR/HR) groups suggests refined risk stratification is needed. As Poland’s first multi-center EC study, these data may inform future guidelines.