Clinicopathological Features and Risk Stratification of Multiple-Classifier Endometrial Cancers: A Multicenter Study...

Area of Science:

• Oncology
• Molecular Pathology
• Gynecologic Oncology

Background:

• The ProMisE molecular classification aids endometrial cancer (EC) risk stratification.
• A subset of EC cases (3-11%) presents with overlapping molecular features, posing diagnostic challenges.

Purpose of the Study:

• To determine the prevalence and clinicopathological characteristics of multiple-classifier endometrial cancers.
• To evaluate the impact of co-occurring molecular features on EC aggressiveness and risk stratification.

Main Methods:

• Retrospective analysis of 1075 EC cases (2022-2025) from four Polish institutions.
• Molecular classification using MMR and p53 immunohistochemistry, and POLE exon sequencing.
• Definition of multiple-classifier ECs as tumors with ≥2 molecular features (e.g., MMRd-p53abn, POLEmut-p53abn).

Main Results:

• Multiple-classifier ECs accounted for 6.9% of cases, with MMRd-p53abn being the most frequent subtype (3.9%).
• These tumors displayed significantly higher rates of Grade 3, non-endometrioid histology, and high-intermediate/high-risk groups compared to MMRd-only ECs.
• POLEmut-p53abn and POLEmut-MMRd-p53abn subtypes were associated with advanced FIGO stages (III-IV) and increased nodal metastasis rates.

Conclusions:

• The co-occurrence of molecular classifiers in EC, including triple-classifier tumors, is linked to more adverse clinicopathological profiles.
• Current molecular risk stratification paradigms may be insufficient for ECs with overlapping molecular features.
• Further research is needed to refine molecular models for accurate risk assessment in EC, especially in cases with complex molecular profiles.