AbstractBackgroundUterine clear cell carcinoma (CCC) consists of either pure clear cell histology but can also display other histological components (mixed uterine CCCs). In this study, the molecular and immunohistochemical background of pure and mixed uterine CCC was compared. Secondly, it was evaluated whether histological classification and molecular background affected clinical outcome.MethodsA retrospective multicenter study was performed comparing pure uterine CCCs (n= 22) and mixed uterine CCCs (n= 21). Targeted next‐generation sequencing using a 12‐gene targeted panel classified cases as polymerase‐ε (POLE) mutated, microsatellite instable (MSI),TP53wildtype orTP53mutated. Immunohistochemistry was performed for estrogen receptor, progesterone receptor, L1 cell adhesion molecule, MSH6, and PMS2.ResultsThe following molecular subgroups were identified for pure and mixed uterine CCCs, respectively:POLEmutated 0% (0/18) and 6% (1/18); MSI in 6% (1/18) and 50% (9/18);TP53wildtype in 56% (10/18) and 22% (4/18);TP53mutated in 39% (7/18) and 22% (4/18) (p= 0.013). Patients with mixed CCCs had improved outcome compared to patients with pure CCCs. FrequentTP53mutations were found in pure CCCs and frequent MSI in mixed CCCs, associated with clinical outcome.ConclusionPure and mixed uterine CCCs are two entities with different clinical outcomes, which could be explained by different molecular backgrounds. These results underline the relevance of both morphological and molecular evaluation, and may assist in tailoring treatment.