Kravvas, Georgios; (2024) Dichotomous pathways to penile cancer - human papillomavirus (HPV) and lichen sclerosus. Doctoral thesis (M.D(Res)), UCL (University College London).

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Abstract

Introduction: Male genital lichen sclerosus (MGLSc) is an inflammatory and fibrosing dermatosis associated with significant morbidity and the risks of penile intraepithelial neoplasia (PeIN) and penile squamous cell carcinoma (PeSCC). Chronic, occlusive exposure of susceptible epithelium to urine is central to the aetiopathogenesis of MGLSc, but its relationship to human papillomavirus (HPV) remains incompletely understood. PeIN and PeSCC are also associated with HPV infection. These relationships are thought to be both progressive and dichotomous; ‘usual’ type PeSCC is thought to arise from MGLSc from the differentiated subtype of PeIN (dPeIN); others from high-risk (HR) HPV infection and a separate pathway, from undifferentiated (u) PeIN. Wnt signalling, and its dysregulation, have been implicated in many developmental and pathological processes, including carcinogenesis, and, relevantly, PeSCC, but have not previously been investigated in MGLSc and PeIN, and the dichotomous pathways to PeSCC. Methods To scrutinise the dichotomies and overlap between the differentiated and undifferentiated pathways, tissue arrays were constructed from MGLSc, u- and dPeIN, ‘usual’ type PeSCC, and disease-adjacent tissues; i) RNAscope staining for high risk (HR) and low risk (LR) HPV, and ii) multi-label immunostaining for four Wnt-related proteins (Wnt4, MMP7, cyclin D1, and c-MYC) were performed. The expression of HPV ribonucleic acid (RNA) and Wnt-related proteins was quantified (and for Wnt10 epidermal and dermal colocalisation was determined). and condign statistical comparisons were undertaken. Results Transcriptionally active HR HPV was prevalent in uPeIN (77%) and less so in PeSCC (47%). It was rarely encountered in MGLSc (7%) and PeSCC-adjacent skin (12%), and absent in the other conditions. LR HPV was either rarely encountered (PeSCC 6%, dPeIN 6%) or absent altogether. Statistically significant changes in Wnt-related protein expression and colocalisation were seen in PeSCC and in PeSCC-adjacent tissues. Some statistically significant alterations in expression and colocalisation were seen in MGLSc and dPeIN, e.g., increased expression of Wnt4 in MGLSc; increased epidermal colocalization, in both MGLSc and dPeIN, of the protein pair Wnt4/MMP7. No statistically significant differences could be detected between dPeIN and uPeIN in either protein expression or colocalisation. Conclusions These findings confirm that transcriptionally active HPV is highly unlikely to be implicated in MGLSc and dPeIN, although clearly important in uPeIN. However, the high prevalence of HR HPV in ‘usual’ PeSCC challenges the dichotomous pathway paradigm. Wnt-related protein dysregulation in PeSCC is confirmed, and, for the first time, demonstrated in normal-looking PeSCC-adjacent tissues (field effect); differences between epidermis and dermis are also shown. The pathway to PeSCC from MGLSc via dPeIN can be partially described by dysregulation of Wnt signalling. Avenues for further research are suggested by these findings.

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