Sigurd Lax

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.

The new 2023 endometrial cancer FIGO staging system: balancing innovation with complexity

In August 2023, the International Federation of Gynecology and Obstetrics introduced an updated staging system for endometrial cancer that integrates histopathologic and molecular characteristics (optional) of the tumor alongside with anatomic extent of the disease. This innovative approach aims to improve the prognostication of the system and the identification of treatment-relevant patient populations by more accurately stratifying patients based on tumor biology, representing a significant advancement toward personalized medicine. However, its implementation poses challenges, including the heterogeneous availability of molecular testing worldwide, and the need for further standardization and prospective validation of some of the newly introduced histopathological parameters. To address these innovations and related controversies, a meeting of physicians, including gynecologic oncologists and pathologists, was held. This article summarizes the reflections that emerged from this meeting, focusing on key elements such as the integration of histopathologic features (eg, "high-grade, aggressive histologic types," "substantial lymphovascular space invasion"), molecular classification, and the implications for global reproducibility and applicability. It also addresses the basic approach toward staging: should it offer integrated, patient-relevant information to enable accurate prognostication and inform treatment decisions or should a staging system simply provide a common language to communicate disease extent? The meeting provided an opportunity for a group of physicians to share considerations on this evolving topic. Our article highlights focal points of change in the new staging system and identifies key areas for future research, advocating for collaborative efforts to generate more robust evidence on some variables introduced in the staging system through prospective studies. By addressing these challenges, we aim to improve the applicability and effectiveness of the new International Federation of Gynecology and Obstetrics staging system in real-world scenarios and identify elements that may require further refinement, ultimately advancing precision medicine in endometrial cancer care.