Kravvas, Georgios; Haider, Aiman; Millar, Michael; Alnajjar, Hussain; Freeman, Alex; Muneer, Asif; Bunker, Christopher; Kravvas, Georgios; Haider, Aiman; Millar, Michael; Alnajjar, Hussain; Freeman, Alex; Muneer, Asif; Bunker, Christopher; Ahmed, Aamir; - view fewer (2024) Transcriptionally active human papillomavirus (HPV) in male genital lichen sclerosus, penile intraepithelial neoplasia, and penile squamous cell carcinoma. JID Innovations (In press).

Text Kravvas et al 2024.pdf - Accepted Version Access restricted to UCL open access staff until 10 April 2025. Download (1MB)

Abstract

Male genital lichen sclerosus (MGLSc) is an inflammatory and fibrosing dermatosis associated with significant morbidity and is an accepted risk factor for the development 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 unclear; 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 via differentiated PeIN (dPeIN); others from high-risk (HR) HPV infection, which can lead to undifferentiated (u) PeIN and PeSCC via a separate oncogenic pathway. However, the exact relationship between MGLSc, PeIN, PeSCC and HPV remains unclear. Tissue arrays were constructed from MGLSc, u- and dPeIN, usual type PeSCC, and disease-adjacent (normal) tissues. Staining for p16, and for high risk (HR) and low risk (LR) HPV subtypes via RNAscope were performed. The expression of HPV ribonucleic acid (RNA) and p16 were quantified, and condign statistical comparisons were undertaken. Transcriptionally active HR HPV was prevalent in uPeIN (77%) and less so in PeSCC (46%). The HR HPV signal was exiguous or absent in the other conditions, and in normal tissues. LR HPV was only observed in two tissue cores, one of dPeIN (constituting 7% of tissue samples), and one of uPeIN (4%); all other tissue sample cores were negative for LR HPV. Furthermore, strong p16 positivity was found to be a reliable surrogate marker for the detection of transcriptionally active HR HPV. These findings confirm that transcriptionally active HPV is 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.

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