Objectives The World Health Organization endorses molecular subclassification of endometrial endometrioid carcinomas. Our objectives were to test the sensitivity of tumor morphology in capturing p53-abnormal (p53abn) cases and to model the impact of p53abn on changes to ESGO/ESTRO/ESP risk stratification.

Methods 292 consecutive endometrial carcinoma resections received at Foothills Medical Centre, Calgary, Canada (2019–2021) were retrieved and assigned to ESGO risk groups without and with p53 status. Three pathologists reviewed representative H&Es, predicted the p53 status, and indicated whether p53 immunohistochemistry would be ordered. Population-based survival for endometrial carcinomas diagnosed 2008–2016 in Alberta was obtained from the Alberta Cancer Registry.

Results The cohort consisted mostly of grade 1/2 endometrioid carcinomas (EEC12; N=218, 74.6%). 152 EEC12 (52.1% overall) were stage IA and 147 (50.3%) were low-risk by ESGO. The overall prevalence of p53abn and subclonal p53 was 14.5% and 8.3%. The average sensitivity of predicting p53abn among observers was 83.6% and observers requested p53 immunohistochemistry on 39.4% with a sensitivity of 98.5% to detect p53abn (99.6% negative predictive value). Cytologic features including tumor giant cells, smudged chromatin, cherry-red/macronucleoli, and atypical mitoses accurately predicted p53abn. In 7/292, p53abn upgraded ESGO risk groups (2 to intermediate-risk, 5 to high-risk). EEC12/stage IA patients had an excellent cause-specific 5-year survival of 98.5%.

Conclusions Pathologists can select cases for p53 testing with high sensitivity and low risk of false negativity. Molecular characterization of endometrial carcinomas has great potential to refine ESGO risk classification for a small subset but offers little value for approximately half of endometrial carcinomas, namely, EEC12/stage IA.