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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 β‐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 β‐catenin alterations remain incompletely understood in this tumour type. Methods: In this study, we evaluated 32 LCTs (five malignant/metastasizing, 27 nonmetastasizing) using β‐catenin immunohistochemistry and DNA sequencing. Results: Immunohistochemistry revealed focal or multifocal nuclear β‐catenin expression in 47% of the tumours. Diffuse nuclear β‐catenin expression (in >50% of the tumour cells) was not detected in any of the cases analysed herein. Comparison of β‐catenin‐positive and β‐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 β‐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 β‐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 β‐catenin in this tumour type. [ABSTRACT FROM AUTHOR]

Aims: Yolk sac tumour postpubertal‐type (YSTpt) shows a wide range of histological patterns and is challenging to diagnose. Recently, forkhead box transcription factor A2 (FoxA2) emerged as a driver of YSTpt formation and a promising marker for diagnosing YSTpt. However, FoxA2 has not been tested in the different patterns of YSTpt. This study aimed to assess the staining pattern of FoxA2 in te different patterns of YSTpt and other germ cell tumours of the testis (GCTT), comparing it with glypican‐3 (GPC3) and α‐fetoprotein (AFP). Methods and results: FOXA2, GPC3 and AFP immunohistochemistry was performed on 24 YSTpt (24 microcystic/reticular, 10 myxoid, two macrocystic, five glandular/alveolar, two endodermal sinus/perivascular, four solid, two polyembryoma/embryoid body and two polyvesicular vitelline) and 81 other GCTT. The percentage of positive cells (0, 1+, 2+, 3+) and the intensity (0, 1, 2, 3) were evaluated regardless of and within each YSTpt pattern. FoxA2 was positive in all YSTpt (24 of 24) and all but one (23 of 24) exhibited 2+/3+ stain, with higher intensity [median value (mv): 2.6] than AFP (1.8) and GPC3 (2.5). Both FoxA2 and GPC3 were positive in all microcystic/reticular (24 of 24), myxoid (10 of 10), macrocystic (two of two), endodermal sinus/perivascular (four of four) and polyembryoma/embryoid body (two of two) patterns. Nevertheless, only FoxA2 was positive in all glandular/alveolar (five of five), solid (four of four) and polyvesicular vitelline (two of two) patterns. The intensity of FoxA2 was higher than AFP and GPC3 in almost all YST patterns. In the other GCTT, FoxA2 was positive only in teratoma postpubertal‐type (Tpt) [13 of 20 (65%)], with staining almost exclusively confined to the mature gastrointestinal/respiratory tract epithelium. Conclusions: FoxA2 is a highly sensitive and specific biomarker that supports the diagnosis of YSTpt. FoxA2 is superior to GPC3 and AFP, especially in rare and difficult‐to‐diagnose histological patterns of YSTpt, but mature glands of Tpt could represent a potential diagnostic pitfall. [ABSTRACT FROM AUTHOR]

Aims: To investigate the morphological and molecular characteristics of Leydig cell tumours (LCTs) of the testis for the identification of cases that may metastasise. Methods and results: Six parameters for a predictive model of the metastatic risk were evaluated in 37 benign and 14 malignant LCTs of the testis [LCT Scaled Score (LeSS)]. The tumour size (benign LCTs, mean 13.3 mm; malignant LCTs, mean 44 mm) (P < 0.001) and five other parameters (infiltrative margins, necrosis, vascular invasion, mitotic count, and nuclear atypia) showed significant differences (Wilcoxon's test, P < 0.001). Eight metastatic LCTs and one benign LCT had infiltrative margins. Foci of coagulative necrosis occurred in 10 metastatic LCTs, whereas vascular invasion was identified in nine of 14 metastatic LCTs and none of 37 benign LCTs. Benign LCTs showed <2 mitoses/10 high-power fields (HPFs), whereas a high mitotic count (range, 3-50 mitoses/10 HPFs) was a feature of malignant LCTs. These parameters were selected by use of an inferential analysis based on univariate logistic regression models to develop a score. A LeSS of <4 correctly identified all histologically and clinically benign LCTs. A LeSS of ≥4 correctly identified all malignant LCTs. MDM2 and CDK4 immunostains were applied in all 51 cases: benign LCTs were negative; three of 11 malignant LCTs (27%) showed strong and diffuse immunopositivity and high levels of MDM2 and CDK4 amplification as determined with fluorescence in-situ hybridisation analysis and next-generation sequencing. Conclusion: We provide a new tool, the LeSS, for the prediction of malignant behaviour in LCTs. [ABSTRACT FROM AUTHOR]

This article discusses the immunophenotypical assessment of post-chemotherapy glandular tumors of germ cell origin. These tumors can exhibit a range of morphologies and lack differentiation to specific somatic lineages. Recent studies suggest that adenocarcinomas may arise from postpubertal-type yolk sac tumors (YST). The expression of transcription factors FOXA2 and HNF1b can help elucidate the origin of these tumors, with most post-chemotherapy glandular tumors expressing two or more of these factors and being considered part of the spectrum of glandular YST. However, a small subset of tumors may be considered "somatic-type" adenocarcinomas. Further research is needed to understand the development and progression of these tumors. [Extracted from the article]