Endometrial carcinoma: molecular subtypes, precursors and the role of pathology in early diagnosis.

Endometrial carcinoma (EC) is classified into a wide range of morphological variants; this list has expanded over the past decade with the inclusion of mesonephric-like and dedifferentiated carcinoma as EC variants in the fifth edition of the WHO Classification of Female Genital Tumours, and recognition that carcinosarcoma is a biphasic carcinoma rather than a sarcoma. Each EC variant has distinct molecular abnormalities, including TCGA-based molecular subtypes, allowing further subclassification and adding complexity. In contrast to this rapid progress in understanding EC, there are only two recognized EC precursor lesions: endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia (EAH/EIN) and serous intraepithelial carcinoma, a situation that has not changed for many years. Diagnosis of EC precursors is a cornerstone of surgical pathology practice, with early diagnosis contributing to the relatively favorable prognosis of EC. In this review we relate the precursor lesions to each of the EC morphological variants and molecular subtypes, discuss how successful early diagnosis is for each variant/molecular subtype and how it might be improved, and identify knowledge gaps where there is insufficient understanding of EC histogenesis.