Clinical Behavior and Molecular Landscape of Stage I p53-Abnormal Low-Grade Endometrioid Endometrial Carcinomas

Abstract

Purpose: The clinical significance of the p53-abnormal (p53abn) molecular subtype in stage I low-grade endometrioid endometrial carcinoma (EEC) is debated. We aimed to review pathologic and molecular characteristics, and outcomes of stage I low-grade p53abn EEC in a large international cohort.

Experimental design: Previously diagnosed stage I p53abn EC (POLE-wild-type, mismatch repair-proficient) low-grade EEC from Canadian retrospective cohorts and PORTEC-1&2 trials were included. Pathology review was performed by six expert gynecologic pathologists blinded to p53 status. IHC profiling, next-generation sequencing, and shallow whole-genome sequencing was performed. Kaplan-Meier method was used for survival analysis.

Results: We identified 55 stage I p53abn low-grade EEC among 3,387 cases (2.5%). On pathology review, 17 cases (31%) were not diagnosed as low-grade EEC by any pathologists, whereas 26 cases (47%) were diagnosed as low-grade EEC by at least three pathologists. The IHC and molecular profile of the latter cases were consistent with low-grade EEC morphology (ER/PR positivity, patchy p16 expression, PIK3CA and PTEN mutations) but they also showed features of p53abn EC (TP53 mutations, many copy-number alterations). These cases had a clinically relevant risk of disease recurrence (5-year recurrence-free survival 77%), with pelvic and/or distant recurrences observed in 12% of the patients.

Conclusions: A subset of p53abn EC is morphologically low-grade EEC and exhibit genomic instability. Even for stage I disease, p53abn low-grade EEC are at substantial risk of disease recurrence. These findings highlight the clinical relevance of universal p53-testing, even in low-grade EEC, to identify women at increased risk of recurrence.

Figure 1.

Flowchart of patient selection. Low-grade means grade 1–2.

Figure 2.

Molecular landscape of stage I low-grade (grade 1–2) p53abn EECs and controls. Histopathologic and molecular landscape of p53abn ECs previously diagnosed as low-grade endometrioid. Cases are stratified by consensus on a low-grade endometrioid diagnosis after blinded pathology review by six expert gynecologic pathologists. White tiles indicate missing data due to insufficient material or failed analysis. L1CAM, L1 cell adhesion molecule; NSMP, no specific molecular profile.

Figure 3.

Three representative examples of p53abn low-grade (grade 1–2) EEC. H&E slides (A, C, E) and p53 IHC (B, D, F) of three cases diagnosed as low-grade endometrioid by at least three of the expert pathologists upon blinded pathology review. Note the glandular architecture, smooth luminal borders, and presence of only mild to moderate nuclear atypia.

Figure 4.

Kaplan–Meier survival curves for 5-year probability recurrence-free for cases assigned low-grade (grade 1–2) by ≥3 expert pathologists and stage I low-grade NSMP EEC and stage I high-grade p53abn EEC controls. Figure 4A shows the Kaplan–Meier survival curves for stage I p53abn low-grade EEC, NSMP low-grade EEC, and p53abn high-grade EEC. Figure 4B includes only stage IA cases. Differences in survival were assessed with the log-rank test: *, P = 0.003; **, P = 0.09; †, P = 0.14; ‡, P = 0.023.