Pure and mixed clear cell carcinoma of the endometrium: A molecular and immunohistochemical analysis study

Abstract

Background: Uterine 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.

Methods: A 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), TP53 wildtype or TP53 mutated. Immunohistochemistry was performed for estrogen receptor, progesterone receptor, L1 cell adhesion molecule, MSH6, and PMS2.

Results: The following molecular subgroups were identified for pure and mixed uterine CCCs, respectively: POLE mutated 0% (0/18) and 6% (1/18); MSI in 6% (1/18) and 50% (9/18); TP53 wildtype in 56% (10/18) and 22% (4/18); TP53 mutated in 39% (7/18) and 22% (4/18) (p = 0.013). Patients with mixed CCCs had improved outcome compared to patients with pure CCCs. Frequent TP53 mutations were found in pure CCCs and frequent MSI in mixed CCCs, associated with clinical outcome.

Conclusion: Pure 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.

Keywords: clear cell carcinoma; endometrial cancer; molecular classification.

FIGURE 1

Display of all next‐generation sequencing derived mutated genes in 10 cases with mixed uterine clear cell carcinomas in which both component were sequenced separately. The colors indicate specific genes (see legend). CC, clear cell; E, endometrioid; SE, serous. MSI, microsatellite instable.

FIGURE 2

Kaplan–Meier curves displaying overall survival according to histology (A), molecular subgroup (B), and L1 cell adhesion molecule expression (C).