**4. HPV and head and neck sites**

Twenty-five percent of HNSCC are associated with HPV [30]. There is increasing evidences that sexual practices are the means by which HPV-Positive HNSCC patients are exposed to virus. Therefore, changes in sexual practices (young people with their first sexual experience at an earlier age, numbers of sexual partners and higher probability of engaging in oral sex compared to individuals from earlier decades) may be associated with HPV-infection preva‐ lence [31].

frequent in epidermodysplasia verruciforme. HPV-5 and -8 are associated with skin carcinoma [20-21]. HPV with mucous tropism infects the anogenital tract, upper aero digestive tract, other head and neck mucosa and are generally subdivided into high-risk and low-risk type based on their oncogenical potential. The most relevant low-risk type are HPV-6 and 11, however the types 40, 42, 43, 44, 54, 61, 70, 72 can be observed in genital benign lesions. Among the highrisk types, the HPV 16 and 18 are most common; especially type 16, which can be found in various cancers such as cervical, oropharyngeal and penile carcinomas. Types 31, 33, 35, 52,

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

HPV life cycle is closely linked to the differentiation program of infected epithelial cells, more specifically the keratinocytes. Infection is initiated through microlesions in the epithelium, which allow virions come in contact with the basal cell layer by direct HPV receptor connection to surface host cell ligands. The receptors involved are not fully identified, but some data revealed a role for α6 integrin and heparin sulfate. Following infection, the virus probably maintains its genome as a low copy number episome in the basal cells of the epithelium, providing a reservoir of viral DNA for further use in cell divisions. When infected basal cells begin to divide, viral DNA is distributed among the daughter cells with a massive upregulation of expression of all early genes mainly the E6 and E7. After mitosis some daughter cells may persist in the basal layers, whereas other move toward the upper layers of the epithelium and begin to differentiate. During this differentiation process there is viral DNA replication that amplifies the amount of virus at least 1000 copies per cell, and finally expression of the coat

The mechanism of viral-induced cell growth is analogous to other tumors viruses that deregulate the cell cycle. Cancer appearance in lesions with persistent HPV is related to the overexpression of E6 and E7 proteins. E6 interfere with the function of p53 whereas E7 with the function of Rb protein, leading to abnormal cells growth by promoting inhibition of apoptosis and dysregulation of cell cycle, respectively. [28]. Basically, HPV infection occurs through sexual contact, non-sexual contact and maternal contact. In healthy individuals most (around 80%) HPV infections clear spontaneously but in some cases, HPV infection persist, leading to cancer development [26,29]. A series of events allows the viral persistence: differ‐ entiation-specific organization of the virus life cycle, mechanisms to maintain genome copynumber in undifferentiated cells, angiogenesis promotion, and strategies to evade both innate

Twenty-five percent of HNSCC are associated with HPV [30]. There is increasing evidences that sexual practices are the means by which HPV-Positive HNSCC patients are exposed to virus. Therefore, changes in sexual practices (young people with their first sexual experience at an earlier age, numbers of sexual partners and higher probability of engaging in oral sex compared to individuals from earlier decades) may be associated with HPV-infection preva‐

58 and 67 belong to a category of moderate to high-risk [20,22-24].

proteins L1 and L2 followed by assembly of infectious virus [25-28].

and adaptive immune surveillance [28].

**4. HPV and head and neck sites**

lence [31].

**Figure 1.** Human Papillomavirus Life Cycle: A: Early gene expression E1, E2, E6 and E7; B: Viral genome amplification; C: Virion assembly and release (Adapted from Moody & Laimins 2010).

Recently, a specific correlation between HPV-positive patients and sexual behavior has been established in HNSCC [32]. This study shown, in patients with HNSCC, that high-risk HPV-16 was correlated with vaginal/oral sex partners, casual sex habits and infrequent users of barriers during vaginal/oral sex. Heck et al. [31] presents association between HNSCC subtypes and sexual behavior. In Oropharynx Cancer the prevalence of HPV infection is close to 36% [30] and this entity was associated with the number of sexual partners and lifetime oral sex partners [31]. A similar result was described by D'Souza et al. [33], which presented an association between HPV-16 measurements and presence of oral HPV-infection. The authors has also found HPV-16–positive oropharyngeal cancer correlated with oral-sex or vaginal-sex partners, engagement in casual sex, early age at first intercourse, and infrequent use of condoms. In tonsillar cancers, Hemminki et al. [34] demonstrated that women with cervical lesions present an increased risk of tonsillar cancer. In addition, increased risk was also found among husbands of women with invasive cervical malignancies. Heck et al., [31] has also found correlation among tonsillar cancers, number of oral sex partners, and earlier age at sexual debut. At the same study, another subtype of HNSCC (Cancer of the Base of the Tongue) was associated with sexual behavior; it was related with oral sex among women, number of sexual partners, and among men presenting history of same-sex sexual contact.

The sexual behavior has been associated with oral HPV-infection. Univariate analysis showed that oral HPV-infection was significantly increased with the lifetime number of oral/vaginal sex partners. Multivariate analysis demonstrated that oral HPV-infection was significantly elevated among individuals who reported having either 10 oral or 25 vaginal sex partners during their life [35]. In addition, a curious fact was demonstrated: the openmouthed kissing was associated with oral HPV-infections and could contribute to HPVinfection among individuals who might not otherwise be exposed. To summarize, all these findings suggests that HPV- infection sexually transmitted could play an important role in HNSCC carcinogenesis [35].

The role of HPV in cancer has been exhausted discuss during the recent years. However, HPV in Pre-Cancerous lesions malignant transformation remains under study. Currently, some of the most studied Pre-Cancerous lesions in the literature are: Oral leukoplakia, Oral erythro‐ plakia, Oral lichen planus Oral submucous fibrosis and Smokeless tobacco keratosis. Aimed to understand the malignant potential of theses lesions some author have attempted to relate the disorder progression with HPV malignant mechanism. Even so, the complete knowledge of viral infection and malignant transformation still remains obscure and controversial.

The role of Human Papillomavirus in Pre-Cancerous Lesions and Oral Cancers

http://dx.doi.org/10.5772/55943

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Oral leukoplakia (OL) is considered an uncommon potentially malignant lesion of the oral mucosa. In 1978, Kramer and colleagues defined Oral leukoplakia as ''a white patch or plaque that cannot be characterized clinically or histopathologically, as any other disease'' [39]. Observing only oral Pre-Cancerous Lesions, OL is the most frequent potentially malignant lesion of this mucosa, represents 85% of oral Pre-Cancerous Lesions presenting a predilection to male gender [40-42]. However, additional reports found no differences among gender [43]. OL affects 3% of white adults [42] with age distribution in the developed countries between the fourth and seventh decades of life, whilst in the developing countries might occur up to

Clinically, OL can be separated in homogeneous and non-homogeneous leukoplakias entities. The first group (homogeneous) was classified into flat, corrugated, wrinkled and pumice-like, and the latter group of leukoplakias (non-homogeneous) was classified into verrucous, nodular, ulcerated and erythroleukoplakia. The authors has also describes that a non-homo‐ geneous leukoplakias presents an increased malignant potential when compared to homoge‐ neous entities [44]. OL can be microscopically characterized by a hyperkeratosis of squamous epithelium. This hyperkeratosis consists of hyperparakeratosis or hyperorthokeratosis; however, a combination between hyperparakeratosis and hyperorthokeratosis also can be seen. In spite of hyperkeratosis, the underlying epithelium layer can show atrophy or thinning. However, spinous layer can presents acanthosis process and the subjacent connective tissue can present a chronic inflammatory infiltrate, ranging from spread foci of inflammatory cells presented in smooth leukoplakia to the numerous foci observed on speckled leukoplakia [42]. Through the years, OL increases the tendency to malignant transformation [45]. The causes of OL remain unclear, in spite of that tobacco intake is considered the most common risk factor for oral leukoplakia development [41-42]. This relation seems to be universal; it appears both in the developing and developed world [41,46]. HPV-infection was well established as etiologic factor of almost 100% of cervical malignancies [6]. Through this establishment, several studies have addressed to find presence and prevalence of HPV-infection in different tumor sites. In the oral cavity, benign lesions have been associated with 24 types of HPV (1, 2, 3, 4, 6, 7, 10, 11, 13, 16, 18, 30, 31, 32, 33, 35, 45, 52, 55, 57, 59, 69, 72 and 73) and malignant entities have been

associated with HPV types 2, 3, 6, 11, 13, 16, 18, 31, 33, 35, 52 and 57 [47-48].

Presence of HPV-DNA was more frequent in pre-cancerous lesions and OSCC when compared with control samples. However, only pre-cancerous lesions reach a statistical significance (P = 0.0216) [49]. Comparing OSCC and control samples with pre-cancerous lesions pre-cancerous

**5.1. Oral leukoplakia and HPV**

5-10 years earlier [41].
