**5. Prevalence of HPV infection in penile squamous cell carcinoma and histological considerations**

In contrast with the high prevalence of HPV infection in cervix carcinomas, which may be detected in almost 100% of the cases, in penile carcinomas the detection is considerably lower, although it stills an important in penile pathogenesis. According to the current evidences, penile cancer can follow 2 distinct etiologic pathways: one is related to environmental factors, such as phimosis, smoking, poor personal hygiene and chronic inflammation; and other one is the HPV-related penile cancer (Rubin et al., 2001; Cubilla et al., 2010). Several studies have highlighted the prevalence of HPV infection in penile cancer, with an average prevalence of 47% to 48% in more than 60 studies (Backes et al., 2009; Miralles-Guri et al., 2009). Differently from cervix cancer, in penile cancer the prevalence of HPV infection varies according to histological subtypes, being strongly prevalent in basaloid and warty carcinomas, and lesser prevalent in keratinizing variants, such as verrucous, papillary and usual carcinomas (Guimarães et al., 2011). Before understanding the relationship between HPV and specific histological subtypes, a basic knowledge of penile cancer histology is required.

lateral expansion, working to spread infection cells throughout epithelial tissue. While the basal cells and viral DNA divide, some daughter cells may be maintained in the basal layers, whereas other daughter cells move toward the upper layers of the epithelium and begin to differentiate. During this process in which the infected cells enter into the suprabasal layers, the viral genome replicates to a higher copy number; 'late' viral gene (L1 and L2) expression is initiated; and structural proteins, as such capsid proteins, are formed. Subsequently, virions are assembled and released as the upper layer of epithelium is shed (Fehrmann & Laimins,

228 Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective

**Figure 3.** Representation of normal and HPV-infected epithelium according to the cellular differentiation and the dif‐

This provides an important microenvironment for cellular growth aberrations, and is partic‐ ularly important in penile pre-neoplastic lesions. Several authors have reported a higher level of HPV detection in PIN, when compared to penile cancer, open field for a HPV importance in the development of tissue growth abnormalities, leading to a soil field for carcinogenesis. In this model, HPV would be an important co-factor in penile pre-neoplastic development. Due to all of his effects in cell growth and lack of cell cycle control, the formation of lesions such as PIN associated to other important factors in penile carcinogenesis (genera hygiene,

**5. Prevalence of HPV infection in penile squamous cell carcinoma and**

In contrast with the high prevalence of HPV infection in cervix carcinomas, which may be detected in almost 100% of the cases, in penile carcinomas the detection is considerably lower,

ferentiation-dependent viral functions (Adapted from Hebner & Laimins, 2006).

phimosis, chronic inflammation, high number of sexual partners).

**histological considerations**

2003; Scheurer et al., 2005; Vidal & Gillison, 2008).

Squamous cell carcinoma of the penis is currently divided in 12 subtypes. Each one of this subtypes shows distinctive outcomes, and this high number of subtypes makes its difficult to characterize the disease. About half of penile cancers are of the usual squamous histology, while the rest is divided through the special types.

**Basaloid carcinomas:** represent 4-10% of penile tumors. Macroscopically, these tumors show an ulcerative aspect, presenting as a solid, firm invasively neoplasm, with necrosis foci. Microscopically, they present a nesting pattern, with each nest presenting a solid or central necrotic nest (comedonecrosis). Keratinization can be observed, although not pathognomonic. Cells presents as small, basofilic, basaloid, spindle or pleomorphic, with abundance of mitotic and apoptotic figures. Perineural and vascular invasions are often seen.

**Warty carcinomas:** represent 7-10% of all cases. It can be described as verruciform tumors, with an exoendophytical appearance, although a rare non-invasive exophytic tumor may be found. Histologically, a classical condylomatous papilla is observed, with a arborescent pattern, a central fibrovascular core, and keratinized cells, with presence of superficial and deep pleomorphic koilocytosis. Different from giant condillomas, in warty carcinomas these cells are typically malignant. Also, as a differential diagnosis, low-risk HPV or negative p16INK4a status favors a condilloma diagnosis. Prognosis is often good, with no signs of nodal involvment, although it might be present in deep invasive warty carcinoma (Chaux & Cubilla, 2012).

**Verrucous carcinomas:** represent 3-8% of the cases. Macroscopically are classically character‐ ized by exophytic, verrucoid white lesion, with a clear base separating them from the stroma. Microscopically, they are acanthotic, papillomatous neoplasms, with a high degree of difer‐ entiation. As most well differentiated tumors, they have a good prognosis, only presenting metastasis when they present areas with poor differentiation. However, if it presents large areas of undifferentiation, the tumor is classified as a mixed verrucous carcinoma, as the classical verrucous carcinoma is a classicaly well differentiated tumor.

**Papillary carcinoma:** represent 9-10% of all cases. It is also a verruciform tumor, diagnosed after excluding the possibility of a verrucous or warty tumor. Macroscopically is observed as an exophytic large tumor, with a clear jagged interface with stroma. Microscopically, papillo‐ matosis is observed and a low-grade histology is present. Different from verrucous carcinoma, acanthosis is not so prominent, and differently from warty carcinoma, there is no koilocytosis. They have an excellent prognosis with very infrequent metastasis.

represented a more aggressive subtype, with a worst survival when compared to HPVnegative PSCCs. But directly comparing HPV expression and survival curves, the most extensive study on high-risk HPV infection was carried out by Lont and colleagues, whom had demonstrated that penile tumors presenting high-risk HPV infection had a better outcome from those tumors where high-risk HPVs were not detected. Interestingly, HIV infection did

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

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

231

In many countries, vaccines against some HPV types are administered to girls and young women with the goal of protecting them against HPV-induced cervical cancer (Villa et al., 2005; Muñoz et al., 2010). The introduction of HPV vaccines has also drawn more attention to the fact that HPV is associated not only with cervical cancer and genital warts but also with

Although the majority of HPV vaccine research has focused on cervical cancer, some vaccine

Emerging results from vaccine trials have suggested that some cross-protection is possible. Vaccines against cervical cancer also have the potential to prevent other cancers that are caused by the same types of HPV (Herrero et al., 2003, Kreimer et al., 2005), and half or more of anogenital cancers outside the cervix, including cancer of the vulva, vagina, penis, and anus (Daling et al., 2005, Gross & Pfister 2004). Theoretically, these vaccines should also work against the same viruses at other anatomical sites, which would be of great value for the majority of the patients. Since different HPV-related diseases have share the same contamination basis (eg, HPV contamination in sexual act may happen in anogenital, cervical and even in head and neck areas. Also, almost all HPV-related tumors share individual at risk with the same behavior, and it is believed that this prevent potential directed to several organs could reduce the prevalence of several tumors simultaneously. If proven to do so, this approach would represent a major conceptual breakthrough, not only in prevention of these diseases, but equally importantly, by providing the 'missing link' in the chain of evidence for the final proof

The current HPV prophylactic vaccines are based on VLPs, with two prophylactic HPV vaccines being commercially available: the bivalent (HPV 16/18) vaccine Cervarix® (GlaxoS‐ mithKline, Middlesex, UK) and the quadrivalent (HPV 6/11/16/18) Gardasil® (Merck, NJ, USA). Licensed globally, these two vaccines have produced great expectations that they will

The US Food and Drug Administration (FDA) approved Gardasil for females aged 9–26 in 2006. In October 2009, the FDA approved Cervarix for use in females aged 10–25 and approved

prevent infections and tumors induced by different HPV types (Syrjänen, 2010).

other tumors, such as head and neck and anogenital cancers (Zur Hausen, 2006).

developers have targeted other diseases related to different strains of HPV.

of HPV etiology in these tumors (Syrjänen, 2010).

**8. The HPV prophylactic vaccines**

not correlated (Lont et al., 2006).

**7. HPV vaccine**

**Sarcomatoid carcinomas:** correspond to 1-3% of cases. Macroscopically, they are hemorrhagic and necrotic, or polypoid tumors. Microscopically, they can mimic several sarcomas, like leiomyosarcomas, osteosarcomas, or fibrosarcomas. They are observed as tumors with two different cellular presentations, with the presence of epithelial and spindle cells. They are typically located in glans, not in corpora cavernosa, and may present foci of associated penile intraepithelial neoplasia. Immunohistochemical stains with high-molecular-weight cytokera‐ tins and p63.

Other mixed tumors are often rare, which makes very difficult to establish their relationship with HPV infection, and comprises several subtypes, such as Pseudohyperplastic Carcinoma, Carcinoma Cunilatum and Pseudoglandular Carcinoma.

As stated before, distinct pathological variants of PSCC are associated with an indolent behavior (eg, verrucous, warty and Buschke-Lowenstein condyloma) and other with more aggressive forms (eg, usual SCC, basaloid and papillary). For basaloid and warty carcinomas, the HPV-infections are present in 80-100% of all cases. It is important to remember that *in situ* SCC seems to be strongly related with HPV-infection (Kayes et al., 2007). Seems plausible then that HPV-infection is far more important as a co-factor that will prepare the soil for a neoplastic malignant transformation, due to the several pathways in which HPV-infection contributes. This is in accordance with the theory of two major pathways in penile cancer development, being one driven by factors such as poor hygiene, presence of phimosis, chronic inflammation, etc), and another one driven by high-risk HPV-infection (Rubin et al., 2001). As discussed above, this represents an astonishing opportunity for a new approach to prevent this disease, as HPV vaccination researches are under constant evolution. As a health problem, the prevention of HPV infection might be able to avoid the development of these subtypes of HPV in men, if the current knowledge of HPV-driven malignancy is right.

#### **6. HPV-status impact on outcome in penile carcinomas**

Although there are not many studies investigating a prognostic role for HPV-infection in penile carcinomas, some studies maintain HPV as a controversial factor, in terms either of survival, or local metastasis, and lymph node involvement. From the three more important studies, it is still unknown if HPV alone may have an impact in penile cancer`s patients overall survival, as demonstrated in several other solid tumors, such those arising in oral cavity and oropharynx (Lont et al., 2006). In a study conducted by Cubilla et al. (2010), HPV-16 was the most prevalent genotype (72% of all cases), followed by HPV-6 (9%) and HPV-18 (6%). The 16 and 18 genotype (high-risk HPV types) were proposed to be associated with aggressive variants of penile tumors, and to be associated with a poorer outcome in these patients. In several studies, the role of HPV infection in penile cancer could only be observed by indirect means, as the observation that HPV-infected PSCCs were those with more aggressive subtypes, as basaloid and warty tumors. So, it is believed that HPV-infection, specially related to HPV-16 and -18, represented a more aggressive subtype, with a worst survival when compared to HPVnegative PSCCs. But directly comparing HPV expression and survival curves, the most extensive study on high-risk HPV infection was carried out by Lont and colleagues, whom had demonstrated that penile tumors presenting high-risk HPV infection had a better outcome from those tumors where high-risk HPVs were not detected. Interestingly, HIV infection did not correlated (Lont et al., 2006).
