High-grade endometrial carcinomas: Morphologic spectrum and molecular classification

High-grade endometrial carcinoma (HGEC) is a heterogeneous group of tumors with various morphologic, genetic, and clinical characteristics. Morphologically, HGEC includes high-grade endometrioid carcinoma, serous carcinoma, clear cell carcinoma, undifferentiated/dedifferentiated carcinoma, and carcinosarcoma. The morphologic classification has been used for prognostication and treatment decisions. However, patient management based on morphologic classification is limited by suboptimal interobserver reproducibility, variable clinical outcomes observed within the same histotype, and frequent discordant histotyping/grading between biopsy and hysterectomy specimens. Recent studies from The Cancer Genome Atlas (TCGA) Research Network established four distinct molecular subtypes: POLE-ultramutated, microsatellite unstable, copy number high, and copy number low groups. Compared to histotyping, the TCGA molecular classification appears superior in risk stratification. The best prognosis is seen in the POLE-ultramutated group and the worst in copy number high group, while the prognosis in the microsatellite unstable and copy number low groups is in between. The TCGA subtyping is more reproducible and shows a better concordance between endometrial biopsy and resection specimens. It has now become apparent that the molecular classification can supplement histotyping in patient management. This article provides an overview of the pathologic diagnosis/differential diagnosis of HGEC and the TCGA classification of endometrial cancers, with the clinical significance and applications of TCGA classification briefly discussed when appropriate.