Reclassifying No Specific Molecular Profile Endometrial Cancer: A Narrative Review of Molecular Heterogeneity,...

Molecular classification has transformed the management of endometrial cancer (EC), yet the no specific molecular profile (NSMP) subtype remains a major challenge for precision oncology due to its substantial biological and clinical heterogeneity. This narrative review summarizes evidence on the molecular features, candidate prognostic biomarkers, procedural implications, and treatment data relevant to NSMP EC and proposes a conceptual framework for further study. Emerging evidence indicates that NSMP represents a heterogeneous disease spectrum rather than a uniform entity. Histological grade and estrogen receptor (ER) expression provide important prognostic refinement, while molecular alterations, including CTNNB1 mutations, ARID1A abnormalities, and L1CAM overexpression, may further discriminate risk. Current trials and guidelines increasingly support biomarker-driven treatment strategies, although prospective validation is needed. In conclusion, NSMP EC requires further refinement beyond conventional risk classification. We propose an evidence-informed three-layer conceptual framework integrating molecular classification (POLE, MMR, and p53 status), clinicopathological factors (grade and ER expression), and emerging biomarkers, including ARID1A and L1CAM. This framework is intended to organize current evidence and generate hypotheses for future validation, which may facilitate individualized prognostic assessment of NSMP EC.