Redefining endometrial cancer phenotypes in the era of molecular classification and sentinel lymph node mapping:...

To describe the clinicopathologic phenotypes of endometrial cancer across molecular sub-types and to identify independent predictors of nodal metastasis and sentinel lymph node (SLN) mapping failure.

This multicenter retrospective study included 2592 endometrial cancer patients with defined molecular classification and SLN mapping. Continuous variables are reported as medians. Tumors were classified as POLE-mutated, mismatch repair-deficient, p53-abnormal, or no specific molecular profile. When hormone receptor status was available, no specific molecular profile tumors were further sub-classified according to European Society of Gynaecological Oncology/European Society for Therapeutic Radiology and Oncology/European Society of Pathology 2025 criteria.

Molecular sub-types exhibited distinct phenotypes: POLE-mutated tumors occurred in younger patients (median 56 years), with the lowest body mass index (27.0 kg/m²), smallest tumor size (26 mm), and the lowest nodal metastasis rate (8.0%); p53-abnormal tumors affected older patients (67 years), with the largest tumors (35 mm), frequent non-endometrioid histology (78.4%), and the highest nodal metastasis rate (26.1%); mismatch repair-deficient tumors showed intermediate age (63 years), body mass index (28.5), predominantly endometrioid histology (90.4%), substantial lymphovascular space invasion (28.3%), and a 19.4% nodal metastasis rate; no specific molecular profile tumors, the most common group (55.6%), had the highest body mass index (29.0 kg/m²), were low-grade in 84.2% of cases and endometrioid in 92.5%, and exhibited a low metastasis rate (11.0%). Among no specific molecular profile tumors with available hormone receptor status, a high-risk-like sub-group (22%), characterized by hormone receptor negativity and/or high-grade histology, displayed aggressive features macro-metastases (18.2%), SLN mapping failure (24.3%), substantial lymphovascular space invasion (33.2%), deep myometrial invasion (54.3%), and cervical stromal involvement (23.1%) (resembling a "p53-abnormal-like" phenotype despite their molecular profile). At multivariate analysis, molecular sub-type was not an independent predictor of nodal involvement (p=.20) or SLN mapping failure (p=.75).

Molecular sub-types in endometrial cancer reflect distinct and reproducible phenotypes. However, classic histopathologic features remain the strongest predictors of nodal spread and SLN detection failure.