Tumor Grade in Molecularly Defined Endometrial Carcinoma: Prognostic Implications of the ESGO–ESTRO–ESP 2025 Guidelines

As an update to the 2021 guidelines, 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) combines grade 3 endometrioid and nonendometrioid carcinomas into a single “high-grade” category and indicates that, within the mismatch repair-deficient (MMRd) molecular subgroup, tumor grade has limited relevance. We evaluated the prognostic value of tumor grade within the 2025 ESGO–ESTRO–ESP framework in a retrospective, single-center cohort of 1115 patients (median follow-up: 69 mo). Molecular classification and estrogen receptor status were determined by immunohistochemistry and polymerase-ε ( POLE ) sequencing. A 3-category histopathologic classification (grade 1–2 endometrioid, grade 3 endometrioid, and nonendometrioid) was associated with survival within MMRd, no-specific-molecular-profile (NSMP), and p53-abnormal subgroups. Analyses were not feasible in POLE ultramutated carcinomas. Within the MMRd and NSMP groups, disease-specific survival did not differ between grade 3 endometrioid and nonendometrioid carcinomas, supporting their combination into a single high-grade category for adjusted analysis. In localized MMRd tumors, deep myometrial invasion, cervical stromal invasion, and focal or substantial lymphovascular space invasion (LVSI) were associated with poor survival. In localized NSMP tumors, the pooled high-grade category and substantial LVSI predicted poor survival, with similar outcomes observed in stage IIB and IIC tumors. We confirm the lack of independent prognostic impact of grade in MMRd, as reflected in the guidelines. In NSMP, substantial LVSI but not estrogen receptor status has prognostic value beyond grade, supporting refinement of risk stratification in clinical practice.