Molecular Pathology of Uterine Carcinosarcoma

Uterine carcinosarcomas (UCS) account for approximately 2% of all malignancies of the uterine corpus. They are clinically aggressive, high-grade tumours that consist of an epithelial (carcinoma) and a mesenchymal (sarcoma) tumour component. Most UCSs are metaplastic carcinomas, as their malignant behaviour is primarily driven by the carcinomatous component. Recent studies centred on the molecular characterization of UCS have shed light on the genetic alterations shaping UCS pathogenesis. The most common mutational event in UCS is TP53 mutation, frequently accompanied by p16 overexpression. As a result of genomic instability secondary to TP53 mutation, UCS frequently carry a large number of gene copy number alterations, including amplification of important oncogenes, such as CCNE1 and C-MYC. The PI3K pathway is frequently affected in UCS by mutations of different genes or amplification of PIK3CA. While mutations in the frequently mutated genes of endometrial serous carcinomas, such as FBXW7 and PPP2R1A, are also frequent in UCS, genes typically mutated in endometrioid endometrial carcinomas, such as PTEN, ARID1A and CTNNB1, are infrequently mutated. Thus, most UCS belong to copy number high serous-like molecular subtype of endometrial carcinoma. However, a proportion of cases (20%) probably represent the progression of tumours with a copy number low endometrioid-like molecular subtype after the acquisition of TP53 mutations. Finally, only few UCS belong to the microsatellite-unstable hypermutated molecular type and the POLE-mutated ultramutated molecular type. This molecular heterogeneity among UCS may have treatment implications with emerging therapies.