-Catenin alterations in testicular Leydig cell tumour: a immunohistochemical and molecular analysis

Background: Testicular Leydig cell tumours (LCTs) are the most common type of sex cord-stromal tumour in men, representing 1%-3% of all testicular neoplasms. Among testicular sex cord-stromal tumours, CTNNB1 mutations and nuclear expression of beta-catenin have been typically associated with Sertoli cell tumour. Recent genomic analyses have shown that CTNNB1 variants are also identified in a subset of LCTs; however, the frequency and clinicopathologic associations of beta-catenin alterations remain incompletely understood in this tumour type. Methods: In this study, we evaluated 32 LCTs (five malignant/metastasizing, 27 nonmetastasizing) using beta-catenin immunohistochemistry and DNA sequencing. Results: Immunohistochemistry revealed focal or multifocal nuclear beta-catenin expression in 47% of the tumours. Diffuse nuclear beta-catenin expression (in >50% of the tumour cells) was not detected in any of the cases analysed herein. Comparison of beta-catenin-positive and beta-catenin-negative cases did not show significant differences in the frequency of adverse histopathologic findings or malignant clinical behaviour. DNA sequencing performed de novo on a subset of seven cases revealed the presence of exon 3 CTNNB1 variants in four of them (4/7, 57%), with variant allele frequencies (VAF) ranging from 7 to 33%. Two additional beta-catenin-positive cases that had been sequenced as part of a previous study harboured exon 3 CTNNB1 variants at VAF of 28% and 7%, respectively. Conclusion: These results demonstrate that beta-catenin alterations are relatively common in LCT, most likely occurring as subclonal events that are not enriched in cases with aggressive features. Further studies are needed to clarify the oncogenic role of beta-catenin in this tumour type.