Molecular classification-driven stage migration and prognostic risk stratification in endometrial cancers: FIGO 2023...

The FIGO 2023 staging system of endometrial cancers (ECs) encourages integration of molecular classification with traditional histopathologic parameters for better prognostication and improved treatment decisions; however, limited availability of molecular profiling hinders its universal adoption. We aimed to assess the impact of adding molecular classification on stage migration, risk-group stratification (ESGO/ESTRO/ESP), and adjuvant treatment protocols using FIGO 2023 vs FIGO 2009 staging. A total of 234 ECs were staged using FIGO 2023 and 2009 staging by either histomorphology alone ("Molecular classification unknown group"; n = 130/234), or by complete morpho-molecular categorization ("Molecular classification known group"; n = 104/203, using Sanger sequencing for POLE mutation, with immunohistochemistry for p53 and Mismatch-repair proteins). Significant stage shifts were noted with FIGO 2023, impacting chiefly low stage (stage I and II) ECs, with stage upshifts predominating over downshifts. Without molecular categorization, tumor stage upshifted in 12.3% and downshifted in 1.5% cases. Complimenting morphology with molecular categorization increased the proportion of stage shifts by 9.3%, with 21.2% upshifts and 1.9% downshifts. Both morphology (aggressive histology, substantial LVSI, tumor location) and molecular profile (p53abn/POLE mutation) contributed to stage shifts. Molecular classification changed prognostic risk-groups in 12.5 (13/104) vs 2.3% (3/130) patients without molecular profiling, potentially impacting adjuvant treatment protocols. Majority of patients with altered risk stratification could potentially benefit from a more aggressive treatment approach, while few patients could benefit from potential treatment de-escalation. Our results indicate that integrated morpho-molecular FIGO 2023 staging significantly impacts both stage and risk group stratification, and will benefit EC patients, particularly in high-grade early stage ECs, with potential treatment implications. Further comprehensive studies are needed to fully establish the implications of molecular classification in the FIGO 2023 staging system.