Two Major Pathways of Penile Carcinogenesis: HPV-Induced Penile Cancers Overexpress p16ink4a, HPV-Negative Cancers Associated with Dermatoses Express p53, but Lack p16ink4a-Overexpression
Sebastian Mannweiler, Stephan Sygulla, Elke Winter, Sigrid Regauer. Medical University of Graz, Graz, Austria
Background: Penile squamous cell carcinomas (SCC) are rare cancers. They arise either through transforming infections with Human Papilloma Virus (HPV) or independent of HPV, often in the background of lichen sclerosus (LS) and lichen planus (LP). HPV-induced cancers arise through slowly progressing precursor lesions, have a better prognosis than HPV-negative cancers and respond better to radiation therapy. HPV-negative SCC arise through rapidly progressing precursor lesions. In addition to demonstration of HPV-genotypes, immunohistochemical evaluation of overexpression of p16ink4a and p53 allows a stratification of SCC and presursor lesions into these etiologies. Despite the impact of etiology on therapy and prognosis, most diagnoses are still based on histological descriptons only and do not provide information on the etiology of the biopsied lesions.
Design: Archival formalin-fixed material of 112 invasive penile SCC and 43 preinvasive penile lesions were evaluated for the expression of p53 and p16ink4a, and indirect marker for a transforming infection with HPV-HR genotypes, and correlated with the presence of LS and LP and the presence of 28 HPV-genotypes.
Results: 72/112 penile SCC and 33/43 pre-invasive penile lesions were p53 negative, but showed p16ink4a-overexpression, which was independent of the HPV-HR genotype involved. 66/72 SCC and 29/43 precursor lesions revealed a single HPV-HR-genotype (HPV-HR16 in 76%, HPV-HR 33 in 8%, HPV-HR45 and HPV-HR18 in 3% each, and HPV-HR 31, 56, 73 in 1%). 6/72 SCC and 4/43 precursor lesions revealed multiple HPV-HR-genotypes. 40/112 SCC and 10 precursor lesions were p16ink4a-negative, but showed nuclear p53 expression in tumour cells and basal keratinocytes. 10/10 precursor lesions and 38/40 of p16ink4a-negative SCC lacked HPV-DNA. 2/40 SCC contained HPV18 and HPV45 DNA resp., but due to the lack of p16ink4a-overexpression they were classified as non-HPV-induced. In 27/40 SCC peritumoral LS and in 13/40 SCC peritumoral LP could be identified. Histologically, HPV-negative, p53-positive precursors showed various histologies in addition to the differentiated penile intraepithelial neoplasia, such as hyperkeratotic, verrucous, atrophic, flat and basaloid lesions.
Conclusions: p16ink4a-overexpression identifies HPV-HR-induced penile carcinogenesis independent of HPV-HR-genotype. p53-expression along with p16ink4a -negativity identifies HPV-negative cancers. Correct etiologic classification of penile lesions during diagnostic work-up allows optimal therapy decisions.
Category: Genitourinary (including renal tumors)
Tuesday, March 5, 2013 11:00 AM
Proffered Papers: Section A, Tuesday Morning