Classification of Endometrial Carcinoma: New Perspectives Beyond Morphology

Endometrial carcinoma has been traditionally divided into type 1 or endometrioid type that is usually moderate to well differentiated and type 2 that is usually poorly differentiated with high histologic grade and aggressive clinical behavior. However, interobserver diagnostic agreement is suboptimal, particularly among the high-grade histotypes. Furthermore, recent data indicate that this histotype assignment does not independently correlate with survival. In recent years, there has been remarkable progress in our understanding of the molecular basis of endometrial carcinoma and extensive molecular studies have been performed under The Cancer Genome Atlas Program (TCGA) leading to molecular classification of endometrial carcinoma that has been shown to be significantly prognostic. This classification system divides the tumors into 4 subgroups namely, polymerase ε exonuclease (POLE) ultramutated, hypermutated microsatellite instability, copy number low, and copy number high (serous-like). Carcinomas with POLE domain hotspot mutations are highly prognostically favorable; those with copy number alterations and TP53 mutations are highly aggressive; and microsatellite unstable and "copy number low" endometrioid are associated with intermediate prognoses. The TCGA applied methods that are too costly and cumbersome for widespread implementation into routine clinical practice. Several other groups have attempted to identify these categories by using immunohistochemical biomarkers rather than molecular studies. Immunohistochemical biomarkers have been used successfully to identify all the subgroups except for POLE ultramutated, which requires sequencing for proper categorization. It is hoped that future studies will identify a suitable biomarker for POLE mutation so that this classification can be routinely used in all medical centers.