Predictive biomarkers in endometrial carcinomas: a review of their relevance in daily anatomic pathology

Abstract

Endometrial carcinoma (EC) is the most common gynecologic malignancy in high-income countries, with its incidence and mortality rising globally, particularly in countries undergoing rapid socioeconomic transitions. Over the past decade, the management of EC has shifted towards molecular classification and biomarker-driven therapies. This shift began in 2013 with the discovery of the 4 prognostic and molecular EC subgroups by The Cancer Genome Atlas (TCGA). Following the TCGA discovery, the Proactive Molecular Risk Classifiers for Endometrial Cancer (ProMisE) and the TransPORTEC initiative have provided 4 pragmatic molecular classifiers by combining next-generation sequencing (NGS) and surrogate immunohistochemical markers to TCGA’s categorization: Mismatch Repair Deficient (MMRd); p53-abnormal (p53abn); No Specific Molecular Profile (NSMP); and POLE-mutant (POLEmut). These subgroups not only provide insights into the biological behavior of EC but also have strong clinical relevance and prognostic implications. In line with these advancements, the World Health Organization (WHO) endorsed molecular classification in 2020, advocating for its integration into EC pathology reports. In 2023, the Federation of International Gynecology and Obstetrics (FIGO) proposed a new staging system that integrates histological parameters and molecular profiles into routine pathology practice. The use of complete molecular classification surrogates in all EC cases, whenever resources permit, is intended to promote prognostic risk-group stratification, data collection, Lynch Syndrome (LS) screening, and potentially influence adjuvant and systemic treatment decisions, as well as predict the efficacy of Immune Checkpoint Inhibitors (ICI). Consequently, the evolving landscape of predictive biomarkers in EC has gained importance in daily oncology practice, profoundly changing the role of pathologists. Pathologists are now crucial in interpreting molecular information and participating as members of multidisciplinary teams in therapeutic decisions. This review article aims to emphasize the importance of molecular classification in EC and encourage pathologists to become familiar with the use of predictive biomarkers in their daily anatomical pathology practice.