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Title: Aetiological factors in the pathogenesis of male genital lichen sclerosus, penile precancer and penile cancer
Author: Shim, Tang Ngee
ISNI:       0000 0004 6348 4604
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Male genital lichen sclerosus (MGLSc) results in sexual and urological dysfunction and predisposes to penile intraepithelial neoplasia (PeIN) and squamous cell carcinoma of the penis (PSCC). The pathogenesis of MGLSc is controversial. Evidence has accumulated that it is due to chronic, occluded exposure to urine caused by post-micturition microincontinence. Infection with hepatitis C (HCV) or human papillomavirus (HPV), autoimmunity and HLA immunogenotype have been incriminated. PeIN and PSCC are associated with HPV and MGLSc. Down-regulation of the gene Cables 1 (associated with squamous carcinogenesis) has been reported in MGLSc. The role of HLA in PeIN and PSCC is unknown. Urinary microincontinence, HPV, HLA, HCV and Cables 1 have been investigated in MGLSc (n=88), PeIN (n=72) and PSCC (n=37). Clinical charts were reviewed retrospectively for microincontinence. HCV antibody titres were assayed serologically. Cables 1 expression was assessed by immunohistochemistry of biopsies. DNA was extracted from blood and tissue for broad-spectrum HPV and comprehensive HLA typing by specific and sensitive PCR-based methodologies. Nearly 90% of men with GLSc (p = < 0.01) had post-micturition microincontinence. HPV was identified in 37.5% of cases of MGLSc (n=88), 90.2% PeIN and 54.1% PSCC. MGLSc was associated with 34.7% cases of PeIN. No significant HLA associations were found in MGLSc. Significant (p < 0.05) HLA associations were i) susceptibility to a) PeIN (C*15) - specifically HPV16 +ve PeIN (C*15, DQA1*02, DQA1*03) and b) HPV16 +ve PSCC (B*57), and ii) protection against PeIN (DQA1*01). No association between HCV and MGLSc was found. Cables 1 expression was normal. Microincontinence and urinary exposure are implicated in the pathogenesis of MGLSc. HPV is involved in the pathogenesis of PeIN and PSCC but associated with MGLSc only as a passenger phenomenon. Immunogenotype may play a role in the pathogenesis of PeIN and PSCC but not of MGLSc. HCV and Cables 1 are not important in MGLSc.
Supervisor: Bunker, Christopher ; Bell, Derek ; Harwood, Catherine Sponsor: Sir John Fisher Foundation ; Skin Treatment and Research Trust
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral