Original Article Modern Pathology (2009) 22, 1160–1168; doi:10.1038/modpathol.2009.77; published online 22 May 2009 HPV infection and immunochemical detection of cell-cycle markers in verrucous carcinoma of the penis Elzbieta Stankiewicz1, Sakunthala C Kudahetti1, David M Prowse1, Elena Ktori1, Jack Cuzick2, Laurence Ambroisine2, Xiaoxi Zhang1, Nicholas Watkin3, Catherine Corbishley3 and Daniel M Berney1 1Centre for Molecular Oncology and Imaging, Barts and The London School of Medicine and Dentistry, London, UK 2Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK 3The Cellular Pathology Department, St Georges Hospital, Tooting, London, UK Correspondence: Dr DM Berney, MB, BChir, MA FRCPath, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, Centre for Molecular Oncology and Imaging, Institute of Cancer, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK. E-mail: [email protected] Received 25 November 2008; Revised 21 April 2009; Accepted 21 April 2009; Published online 22 May 2009. Top of page Abstract Penile verrucous carcinoma is a rare disease and little is known of its aetiology or pathogenesis. In this study we examined cell-cycle proteins expression and correlation with human papillomavirus infection in a series of 15 pure penile verrucous carcinomas from a single centre. Of 148 penile tumours, 15 (10%) were diagnosed as pure verrucous carcinomas. The expression of the cell-cycle-associated proteins p53, p21, RB, p16INK4A and Ki67 were examined by immunohistochemistry. Human papillomavirus infection was determined by polymerase chain reaction to identify a wide range of virus types. The expression of p16INK4A and Ki67 was significantly lower in verrucous carcinoma than in usual type squamous cell carcinoma, whereas the expression of p53, p21 and RB was not significantly different. p53 showed basal expression in contrast to usual type squamous cell carcinoma. Human papillomavirus infection was present in only 3 out of 13 verrucous carcinomas. Unique low-risk, high-risk and mixed viral infections were observed in each of the three cases. In conclusion, lower levels of p16INK4A and Ki67 expressions differentiate penile verrucous carcinoma from usual type squamous cell carcinoma. The low Ki67 index reflects the slow-growing nature of verrucous tumours. The low level of p16INK4A expression and human papillomavirus detection suggests that penile verrucous carcinoma pathogenesis is unrelated to human papillomavirus infection and the oncogenes and tumour suppressor genes classically altered by virus infection. Keywords: penile verrucous carcinoma, human papillomavirus, p53, p21, p16INK4A, RB Verrucous carcinoma is a rare low-grade squamous cell carcinoma with slow invasive growth and lack of metastasis. It was first described in 1948 by Lauren V Ackerman in the oral cavity.1 Since then it also has been described at other sites, including the anus, female genitalia and penis.2, 3, 4 Grossly, verrucous carcinomas are exophytic white-grey papillomatous neoplasms. Microscopically, hyperkeratosis, papillomatosis and acanthosis are present; koilocytosis is absent. The cells are extremely well differentiated with prominent intercellular bridges. The base of the tumour is broad, with pushing, regular borders composed of broad bulbous projections.5, 6, 7, 8 Squamous cell carcinoma of the penis is itself rare and represents 0.3–0.5% of male malignancies in Europe and the United States of America.9 The most common type of penile squamous cell carcinoma is the usual type (70%), followed by basaloid (10%) and a heterogenous group of ‘verruciform’ tumours (20%).5 However, mixed tumours commonly exist of usual type squamous cell carcinoma and one or more type of verruciform tumour. Verruciform lesions include verrucous carcinoma, warty carcinoma (also known as Buschke–Lowenstein tumour (BLT) or giant condyloma accuminatum) and papillary squamous cell carcinoma, not otherwise specified.8, 10 The reported frequency of penile verrucous carcinoma is low and accounts for 3–20% of all penile cancers.5, 6, 11, 12, 13 However, identification of cases from the literature is sometimes difficult because of the varied nomenclature used in the past, often regarding them as the same lesion as BLT.14, 15 Risk factors for penile verrucous carcinoma seem to be similar as for penile cancer in general, which are poor hygiene, phimosis and chronic inflammation16 but no systematic case series has been studied. The human papillomavirus (HPV) role in pathogenesis of these tumours is not certain because of small number of cases available for studies. One large study on penile cancer has found verrucous carcinoma to be always associated with squamous hyperplasia.17 The treatment of choice for penile verrucous carcinoma is similar to verrucous cases from other sites and involves wide surgical excision, less commonly, radiation or chemotherapy.4, 18 Untreated or inadequately excised verrucous carcinoma can progress locally but distant metastasis are exceptional.5, 16 The rarity of the disease makes it difficult to study, and mostly case reports or studies on small series are available. The aim of this project was to study the HPV status in penile verrucous carcinomas and its potential association with the immunohistochemical detection of key cell-cycle proteins: p53, p21, p16INK4A RB and Ki67 to elucidate their pathogenesis. Top of page
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