PURE AND MIXED CLEAR CELL CARCINOMA 93 4 deficient DNA repair mechanisms 13. Even though the number of patients was limited, the observation that POLE mutations and MSI were seen almost exclusively in mixed tumors could indicate that these tumors actually have a high burden of secondary acquired (shared and non-shared) mutations that lead to morphological divergence, dedifferentiation and the presence of different histological components. A recent meta-analysis included 136 uterine CCCs (114 pure and 22 mixed) and found similar rates of molecular subgroups: 4% POLE mutated, 11% MSI, 50% TP53 wildtype and 35% TP53 mutated in pure CCCs 29. In mixed CCCs, no POLE mutations were found, whereas 59% was MSI, and only 18% was TP53 mutated. In our study, similar rates of TP53 mutated tumors were found (39% and 22%, respectively), as well as frequent MSI in mixed uterine CCCs (50%). This meta-analysis also showed a favorable outcome in POLE mutated and MSI tumors, which supports recent recommendations by the European Society of Gynaecological Oncology (ESGO), European Society for Radiotherapy and Oncology (ESTRO) and the European Society of Pathology (ESP), encouraging molecular classification in all endometrial carcinomas, especially high-grade tumors 10. In the present study, we have analyzed immunohistochemical patterns within both components. In case of loss of one of the MMR proteins, absence of the protein was always seen in both components. In contrast, loss of ER and/or PR, and L1CAM positivity was discrepant in most cases, and was seen more often in the CCC component. These findings suggest that loss of hormone receptors, as well as L1CAM expression is obtained in a more advanced stage within tumor progression. Compared to literature, showing ER expression in 0 – 16% of uterine CCC cases, we found a somewhat higher prevalence (24%) in pure uterine CCCs, even though ER was only focally positive in 4/5 cases 17, 30, 31. PR expression was found in only 1 patient (5%), which is in line with literature. In mixed uterine CCCs, frequency of ER and PR expression was surprisingly high in the clear cell components of mixed uterine CCCs (52% and 29%). Previous papers have shown that mixed CCCs can display unexpected IHC staining patterns, including (patchy) ER/PR expression, which may be attributed to the fact that these tumors arise from a single clone and subsequently diverge 28, 32. As a potential target for HER2 directed antibody therapy, ERBB2 mutations could be of interested for uterine CCCs. A pathogenic ERBB2 mutation was found in four cases (12%), which is in line with literature showing ERBB2 mutations in 11% of patients 18. In our study, L1CAM expression was frequent and associated with impaired survival. Two previous studies did not find a correlation between L1CAM expression and impaired survival, possibly due to a limited sample size 16, 33. L1CAM is a transmembrane protein that is involved in increasing invasiveness, motility and metastatic potential, and has been found to be a poor prognostic factor in several cancers 34, 35. More recently, L1CAM positivity was found to be
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