Molecular insights into the classification of high-grade endometrial carcinoma

Endometrial carcinoma, which is associated with a mortality rate of approximately 20%, is the most common gynecological malignancy in the Western world. It is a heterogeneous disease, with multiple histotypes, each constituting a different disease entity. However, interobserver diagnostic agreement is suboptimal, particularly among the most lethal histotypes. Most recent data also indicate that histotype assignment is not independently associated with survival, while in contrast, clinicopathological risk stratification and genomic classification are significantly prognostic. Recent work has shown that there are four molecular subgroups of endometrioid carcinomas instead of the two types proposed by Bokhman in the 1970s. Carcinomas with polymerase E (POLE) exonuclease domain hotspot mutations are highly prognostically favourable; those with copy-number alterations and TP53 mutations are highly aggressive; and microsatellite unstable and 'copy-number low' endometrioid carcinomas are associated with intermediate prognoses. This review summarises the genetic foundations of the various histotypes of endometrial carcinoma and synthesises this information in the form of algorithms, or classifiers, that recapitulate genomic classification that is not only prognostic, but also potentially diagnostic and therapeutically predictive. A review of Lynch syndrome and Lynch-like syndrome is also provided.