Wnt Signaling in Male Genital Lichen Sclerosus, Differentiated Penile Intraepithelial Neoplasia, and Penile Squamous Cell Carcinoma.

INTRODUCTION: Male genital lichen sclerosus (MGLSc) is a chronic inflammatory disease causing scarring and significant morbidity, and predisposing individuals to differentiated penile intraepithelial neoplasia (dPeIN) and penile squamous cell carcinoma (PeSCC). Penile carcinogenesis follows two pathways: HPV-related and non-HPV-related. While HPV drives undifferentiated PeIN and warty/basaloid PeSCC, MGLSc is implicated in non-HPV-related dPeIN and "usual" PeSCC. Wnt signalling, pivotal in carcinogenesis, remains underexplored in MGLSc and PeIN. METHODS: Tissue arrays from 114 archival samples of MGLSc, dPeIN, and PeSCC were analyzed using multi-label fluorescence staining and confocal microscopy for Wnt4, cyclin D1, c-MYC, and MMP7 expression. RESULTS: Wnt signalling proteins were upregulated in PeSCC: cyclin D1 (2.3-fold), Wnt4 (2-fold), c-MYC (2.5-fold), and MMP7 (1.8-fold). Wnt4 expression increased in MGLSc (p=0.02), while dPeIN showed minimal changes. Altered co-localization of Wnt4/MMP7 (p=0.04) was observed in MGLSc and significant co-localization alterations of several protein pairs were also identified in PeSCC. CONCLUSION: Wnt signalling plays a role in progression from MGLSc to PeSCC through protein dysregulation. Overexpression and altered interactions in PeSCC highlight its potential as a diagnostic, prognostic, and therapeutic target.