Beyond the Microscope: Integrating Liquid Biopsies into the Molecular Pathology Era of Endometrial Cancer

Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with a growing incidence and significant molecular heterogeneity that challenges traditional diagnostic and management paradigms. While histopathological assessment remains the gold standard for diagnosis, emerging liquid biopsy technologies provide promising non-invasive alternatives for tumor detection, molecular profiling, and disease monitoring. This review comprehensively explores the current landscape and clinical utility of liquid biopsy analytes-including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), extracellular RNAs, and exosomes-in the context of EC. We discuss the evolving role of pathologists in integrating molecular data with histomorphological features to enhance diagnostic precision, prognostic stratification, and therapeutic decision-making. Novel technologies such as methylation-based assays, tumor-informed ctDNA sequencing, and tumor-educated platelets (TEPs) are highlighted for their diagnostic accuracy and potential for early detection. Furthermore, we summarize key clinical trials and future directions aimed at validating liquid biopsy platforms for routine clinical implementation. As EC care transitions toward a precision oncology model, the integration of liquid biopsy with traditional surgical pathology offers a transformative approach to individualized and personalized patient management.