Endometrial cancer is a major gynecologic malignancy, with HGEC comprising aggressive variants such as Grade 3 endometrioid, serous, clear cell, undifferentiated/dedifferentiated carcinomas, carcinosarcoma, and mesonephric-like adenocarcinoma. These tumors are characterized by poor prognosis and resistance to conventional therapies. The limitations of traditional histopathological diagnosis underscore the need for molecular refinement to guide clinical management.
Histopathological Subtypes of HGEC
FIGO Grade 3 Endometrioid Carcinoma (HG-EEC): Characterized by >50% solid architecture, often arising from endometrial hyperplasia. Molecular alterations include loss of ARID1A, PTEN, or mismatch repair (MMR) proteins, with aberrant p53 in about 20% of cases.
Serous Carcinoma: Typically presents in atrophic endometrium with complex papillary architecture, high-grade nuclei, and frequent TP53 mutations. It falls within the TCGA copy-number high (CNH) group and has a poor prognosis.
Undifferentiated and Dedifferentiated Carcinoma (UC/DDC): Highly aggressive tumors with loss of epithelial cohesion and frequent SWI/SNF complex mutations. Often show MMR deficiency or POLE mutations.
Uterine Carcinosarcoma (UCS): Biphasic tumors with carcinomatous and sarcomatous elements. Molecularly similar to serous carcinoma, with frequent TP53 and PPP2R1A mutations.
Clear Cell Carcinoma (ECCC): Exhibits tubulocystic, papillary, or solid patterns with clear or oxyphilic cells. Often shows HNF-1β positivity and falls into both CNH and no specific molecular profile (NSMP) groups.
Mesonephric-like Adenocarcinoma (MLA): A rare, aggressive subtype with Müllerian and mesonephric features, often KRAS-mutated and classified mainly as copy-number low (CNL)/NSMP.
TCGA Molecular Classification
The TCGA initiative reclassified endometrial cancer into four molecular subgroups:
POLE-ultramutated: High mutation burden, excellent prognosis, strong immune infiltration.
MMR-deficient (MSI): Hypermutated, intermediate prognosis, responsive to immunotherapy.
Copy-number high (p53-abnormal): TP53 mutations, poor prognosis, includes serous and many carcinosarcomas.
Copy-number low (NSMP): Intermediate risk, heterogeneous, includes many endometrioid and clear cell carcinomas.
This molecular stratification provides reproducible, prognostically significant categories that complement histology and guide targeted therapy.
Integration into Clinical Practice
While NGS remains the gold standard for molecular subtyping, surrogate immunohistochemical markers (e.g., p53, MMR proteins) enable accessible classification. POLE and MSI tumors may benefit from immunotherapy, while CNH tumors may respond to PARP or HER2-targeted agents. The NSMP group requires further substratification based on additional markers such as L1CAM or CTNNB1.
Challenges and Future Directions
Barriers to implementation include cost, access to sequencing, and the need for prospective trials validating molecular-guided therapies. Further research is needed to refine classification within the NSMP group and improve diagnostic consistency across institutions.
Conclusion
The integration of histopathological evaluation with TCGA-based molecular profiling marks a significant advancement in the management of HGEC. This approach enables precise risk stratification, informs therapeutic decisions, and underscores the importance of precision oncology in improving patient outcomes. Continued efforts to bridge molecular insights with clinical practice are essential to address the heterogeneity and aggressiveness of HGEC.
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https://www.xiahepublishing.com/2771-165X/JCTP-2025-00021
The study was recently published in the Journal of Clinical and Translational Pathology .
Journal of Clinical and Translational Pathology (JCTP) is the official scientific journal of the Chinese American Pathologists Association (CAPA). It publishes high quality peer-reviewed original research, reviews, perspectives, commentaries, and letters that are pertinent to clinical and translational pathology, including but not limited to anatomic pathology and clinical pathology. Basic scientific research on pathogenesis of diseases as well as application of pathology-related diagnostic techniques or methodologies also fit the scope of the JCTP.
