Evaluation of the new European risk classification for endometrial carcinoma: a cohort study

The 2025 endometrial carcinoma risk classification by the European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) integrates new pathologic and molecular features. We evaluated its clinical impact and prognostic performance in comparison with the 2021 system.

This retrospective single-center cohort study included patients categorized according to the 2021 and 2025 risk classifications. Immunohistochemistry and POLE sequencing were conducted for molecular classification and estrogen receptor determination.

We identified 1115 patients with 2021 and 2025 risk classifications (median follow-up: 66 months; range; 0-136). The update re-classified 117 patients (10.5%) into a different risk group: 68 (6.1%) downward, 24 (2.2%) upward, 16 (1.4%) from uncertain to defined, and 9 (0.8%) from defined to uncertain. Both classification systems were prognostic (pooled p < .001 across strata). In pairwise comparisons, the 2025 system did not distinguish high-intermediate-risk from high-risk disease (p = .15 and p = .25 for progression-free survival and disease-specific survival). The 2021 system showed better progression-free survival for high-intermediate-risk compared with high-risk disease (p = .026), but not disease-specific survival (p = .06). Estrogen receptor negativity, which modifies risk in localized low-grade no-specific-molecular-profile carcinomas, was rare in this category (4 [1.3%] negative vs 307 [98.7%] positive). Lymph node involvement (stage IIIC1i-IIIC2ii) differed across molecular tumor categories: 3.0% in POLE-ultra-mutated, 8.7% in mismatch repair-deficient, 5.0% in low-grade and estrogen receptor-positive no-specific-molecular-profile, 13.0% in high-grade or estrogen receptor-negative no-specific-molecular-profile, and 16.5% in p53-abnormal tumors (p < .001).

The ESGO-ESTRO-ESP 2025 classification re-assigns approximately one-tenth of patients, with a meaningful impact on adjuvant therapy. The rarity of estrogen receptor negativity limits its role in no-specific-molecular-profile stratification. Variation in lymph node involvement across molecular tumor categories highlights opportunities for individualized surgical staging.