Field effects in penile squamous cell carcinoma: Insights from Wnt-related protein expression

Penile squamous cell carcinoma (PeSCC) is thought to arise through two principal pathogenic pathways, via lichen sclerosus and high-risk human papillomavirus. Molecular alterations in morphologically normal peri tumoral environment are known as 'field effect' and are recognised in other epithelial cancers. Whether similar field effects exist around PeSCC is unknown. As Wnt signaling is a key driver of carcinogenesis, including in PeSCC, perturbations in this pathway may represent an early event in penile tumour evolution.

To determine whether a peritumoral molecular field exists around PeSCC by assessing expression and spatial colocalisation of key Wnt-related proteins in cancer-adjacent versus normal penile skin.

A specialist genitourinary histopathologist reviewed haematoxylin and eosin-stained sections and identified tumour-involved regions, demarcating them from adjacent epithelium that appeared morphologically normal. In this study, immunofluorescence-stained formalin fixed paraffin embedded tissue arrays were probed for Wnt4, cyclin D1, MMP7 and c-MYC proteins. The expression intensity and spatial colocalisation metrics were quantified. Comparisons between normal and cancer-adjacent tissues from 41 patients were conducted for the epidermis and dermis.

Cancer-adjacent tissue showed significant downregulation of Wnt4 in both epidermis and dermis (p < 0.001), and marked upregulation of c-MYC (epidermis: Cohen's d = 2.05; dermis: d = 1.37). MMP7 and Cyclin D1 expression was not significantly changed. Colocalisation analysis revealed significantly increased Global Intersection Coefficients for five combinations within the epidermis (Wnt4/cyclin D1, Wnt4/MMP7, Wnt4/c-MYC, cyclin D1/c-MYC, MMP7/c-MYC), and for two within the dermis (Wnt4/MMP7, Wnt4/c-MYC), indicating enhanced signalling convergence in cancer-adjacent tissues.

This study provides the first evidence of molecular changes in peritumour tissue to demonstrate field effect in PeSCC, characterised by downregulation of Wnt4, upregulation of c-MYC, and altered spatial colocalisation of Wnt-related proteins in cancer-adjacent skin. These findings suggest that peritumoral tissues exhibit early molecular alterations that extend beyond the morphologically defined tumour margin. Recognising these changes may have implications for understanding tumour microenvironment conditioning and for the future development of biomarkers relevant to margin assessment in penile carcinogenesis.