**Human Papillomavirus Infection and Penile Cancer: Past, Present and Future**

João Paulo Oliveira-Costa, Giórgia Gobbi da Silveira, Danilo Figueiredo Soave, Andrielle de Castilho Fernandes, Lucinei Roberto Oliveira, Alfredo Ribeiro-Silva and Fernando Augusto Soares

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55811

**1. Introduction**

Penile squamous cell carcinoma (PSSC) is an uncommon malignant tumor, which accounts for less than 1% of adult male cancers in North America and Europe, but is markedly higher in developing locations, such as Asia, Africa and South America, representing up to 10% of tumors in men. Human papillomavirus (HPV) infection has shown an important role in penile cancer pathogenesis. In 2009, a systematic review of published literature found that 40% of penile tumors were HPV-related, and that type 16 HPV was the most common subtype in this group (Backes et al., 2009). Another interesting relation between HPV infection and penile cancer is the finding that specific histological subtypes are associated with HPV infection. Penile carcinomas with basaloid differentiation and warty features have shown a strong association with HPV infection, with recent studies showing that HPV infection is present in 76% of basaloid tumors, while the presence in verrucous cancer was 24.5% (Backes et al., 2009).

The recent literature suggests that the oncogenic potential of HPV integration into host DNA genome and their ability to manipulate cell cycle regulators is responsible for the establishment and maintenance of HPV genomes in the squamous epithelium and HPV-related PSCC cancer, which will result in deregulated expression of oncoproteins such as E6 and E7. The oncoprotein E6 is known to induce degradation of the tumor suppressor protein p53 and the oncoprotein E7 binds to retinoblastoma protein (pRb). Thus, the oncoproteins E6/E7 allow cells to evade

© 2013 Oliveira-Costa et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

cell cycle checkpoints and to entrance in S1 phase of cell cycle, leading to disruption of normal cell cycle controls.

of origin and progression of penile squamous cell carcinoma depends on an intricate relation

Human Papillomavirus Infection and Penile Cancer: Past, Present and Future

http://dx.doi.org/10.5772/55811

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The anatomy of the penis is complex and has important implications to define predictive risk model and delineate the prognostic factors (Chaux & Cubilla, 2012). The same authors described 3 anatomical compartments in the penis (Glans, Foreskin and Coronal Sulcus) where the malignant neoplasms may be originated (Fig 1). However, the penile malignant neoplasms have a predilection to originate first on the Gland followed by Foreskin inner mucosa and lastly

**Figure 1.** Paraurethral longitudinal section presenting anatomical levels of the Penis. **CC:** Corpus Cavernosum; **CS:** Cor‐ pus Spongiosum; **LP:** Lamina Propria; **SF:** Skim of the Foreskim and **TA:** Tunica Albuginea. (Adapted from Chaux & Cu‐

Recently, Hernandez et al. (2008) performed an epidemiological study with 4967 United States men with the diagnosis of penile squamous cell carcinoma. Thirty four percent of patients (1712) presented neoplasms arising in gland, 13.2% in prepuce, 5.3% in penis shaft, 4.5%, in overlapping of penis, and 42,5% in unspecified site. Lesions generally initiate on the glans and slowly extend to involve completely the glans and shaft of the penis. During the neoplasm progress Buck's fascia act as a natural barrier to local tumor invasion defending the corporal bodies from tumoral expansion (Pow-Sang et al. 2010). This assessment is schematically

The anatomy of the penis presents a pivotal role in tumor invasion and prognosis of cancer. Moreover, the TNM staging system is based, at least partially, on the commitment of these anatomical levels (Velazquez et al. 2010). The glans can be divided in 4 levels: squamous epithelium, lamina propria, corpus spongiosum, and corpus cavernosum (corpus spongio‐ sum, and corpus cavernosum are subdivided by the tunica albugínea). Anatomical levels in the foreskin, like in glans, are divided in squamous epithelium, lamina propria, dartos muscle,

between anatomy and histopathology.

billa 2012).

illustrated in figure 2.

and outer skin (Chaux & Cubilla, 2012).

the Coronal Sulcus is rarely affected by neoplastic entity.

Following cell division, infected cells leave the basal layer, migrate towards the suprabasal regions and begin to differentiate. Increased understanding of cervical pathogenesis has led to confirmation of HPV as an etiological agent for several cancers and consequently to the development of preventive vaccines targeting HPV antigens for the control of HPV-related cancers. HPVvaccinewasdevelopedas a result ofthe achievement of core technologies,that are able to produce virus-like particles (VLPs), which, in turn, are able to mimic the natural virus andelicithigh-titersofvirusneutralizingantibodies.Withtheprogressthroughadvancedstages of clinical trials and further exploration of combinatorial strategies, there is a great promise for significantadvancesalsointhefieldoftherapeuticHPVvaccinedevelopment,notonlytocervical cancer, but other several malignancies related to HPV infection. Moreover, in this chapter we discuss the current status of HPV vaccines as well as the most common associated factors that might interfere on establishment of strategies that could control the HPV infections and the development of penile carcinoma associated to this infection.
