**5.3. Oral lichen planus and HPV**

lesions the authors also found a significant prevalence of Low- risk HPV in pre-cancerous lesions. Significant prevalence of Low-risk HPV in pre-cancerous lesions has also observed by Miller & Johnstone [1] meta-analysis. They reported that low-risk HPV DNA was more prevalent in OL and; on the contrary, observed that high-risk HPVs was 2.8 times more

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

The presence of HPV has been analyzed in potentially malignant lesions, and HPV DNA has been found in different proportions. Sugiyama et al. [50] detected HPV-16 and -18 in normal, dysplastic, and malignant oral epithelium and found statistical significance between the HPV-16 detection in epithelial dysplasia group and OSCC group. A study comparing normal oral mucosa, OL and OSCC was coordinated by Llamas-Martinez et al. [51], aiming to determinate the HPV genome as an independent clinicopathological factor and detect different HPV-genotypes. The data do not show relationship between HPV-genotypes and clinicopa‐ thological factors. However, the presence of HPV-16 was increased in OL and OSCC (14/35 cases 40%, 11/33 cases 33.3% (p=0,0005); respectively). These results suggest that HPV-16 is related with OL and OSCC pathogenesis. Campisi et al. [52] investigating the relation among High-Risk HPV infection, apoptosis (bcl-2 and survivin) and proliferation biomarkers (PCNA) observed HPV-DNA in 38.1% of samples. HPV infection was associated with survivin and PCNA suggesting the interference of HPV on epithelial maturation. A year before, Lo Muzio et al. [53] showed increased rates of HPV-positive OL related with a survivin expression and suggested an unfavorable clinical outcome to these lesions. This unfavorable behavior was

In conclusion, the correlation between OL malignant transformation and HPV infection were not totally understood. However, these data suggests that HPV-infection could play an

The expression 'erythroplasia' initially was used to describe a reddish precancerous lesion that develops on the glans of penis [55]. Due to clinical and histopathological similarities with genital process, the reddish precancerous oral lesion has also named erythroplakia. The *Oral erythroplakia* (OE) is presented like an unknown-causes lesion. However, it is assumed the same association with OSCC [42]. The authors has also describes that OE presents an increased malignant potential when compared with others pre-cancerous entities [42,55], Older men are predominantly affected by OE with peak prevalence in the sixth decade of life (65 to 74 years). Floor of mouth, tongue, and soft palate are the most common sites of involvement [42].

Clinically, OE may be associated with leukoplakia (erythroleukoplakia) and OSCC [56]. Usually, the lesions do not present symptoms but, is not uncommon some patients reporting a burning sensation and ⁄ or sore. The altered mucosa can present a well-demarcated eryth‐ ematous macule or plaque with a soft, velvety texture [55]. Microscopically, reddish color of erythroplakia can be explained by a combination of features. Red color is presented by underlying microvasculature, and additionally, this color can be due to low keratinization and epithelial thinness [42]. Generally, OE can be associated to severe epithelial dysplasia and, at

the time of biopsy, may presents 'carcinoma in situ' or 'invasive carcinoma' [55].

important role in oral carcinogenesis leading to OL malignant transformation.

frequent in OSCC.

induced by influence of survivin on apoptosis process.

**5.2. Oral erythroplakia and HPV**

In 1869, Dr. Erasmus Wilson provided the first medical report about the chronic derrnatologic disorder *lichen planus*. The British physician appointed the disorder "*lichen planus*" because the skin lesions appear to be quite similar to the symbiotic algae and fungi relationship (*lichen*) [42]. *Oral lichen planus* (OLP) is a chronic mucocutaneous disorder presenting a potentially prema‐ lignant behavior. However, less than 1% of OLP progress to malignancy state [58]. This injury is most common in middle-aged adults within preponderance for female gender (3:2 ratio) [42]. Mattila et al. [58] characterized the OLP in 6 variants: reticular, papular, plaque-type, atrophic, erosive and bullous. Clinically, Neville et al. [42] mentioned reticular and erosive forms as the most common variants presented in the oral mucosa. Although, not common as reticular and erosive, the bullous form was considered a rare oral disorder [59]. Three most common oral mucosa sites involved in OLP are: buccal mucosa, gingivae and lateral borders of the tongue. Additionally, its can be originated in any site of oral mucosa and frequently, is seen as bilateral lesions [59].

Microscopically, the OLP is presented like a non-specific lesion. Moreover, some oral disorders may also demonstrate a similar histopathologic pattern to the OLP-lesions. The injured epithelium may present orthokeratosis and parakeratosis. A spinous cells layer thickness can be observed in different degrees. The rete ridges may be presented as a classically "saw toothed" shape. Due to hydropic degeneration is evident a destruction of the epithelium basal cell layer and, subjacent to epithelium an intense T lymphocytes band-like infiltrate can be observed [42].

Some authors attempt to elucidate the correlation between HPV-infection and malignant transformation of OLP; however, results from pertinent literature are conflicting. The Highrisk HPV-16 was described in 26.3% of OLP*,* with significant statistical difference between High-risk HPV-16 prevalence and OLP when compared to control samples [60]. A study performed by Sand et al. [61] demonstrated the High-Risk HPV-18 in approximately 27% of lichen planus cases but do not found statistical difference between HPV infection and oral lesions suggesting the unclear pathologic correlation between HPV and OLP. On the other hand, Campisi et al. [62] demonstrated the presence of HPV-DNA in 19.7% (n = 14/71) of patients with OLP, with significant statistical difference in comparison with controls cases (5/90; 5.6%) (P = 0.005). In the present study, the High-risk HPV-18 was the most frequent genotype found, it was present in 71.4% (10/14) of samples. In a second analysis, all of cases were pooled in 2 clinical groups: (1) atrophic-erosive (AE) (atrophic, erosive, bullous, and mixed AE variants); and (2) nonatrophic-erosive (non-AE) (reticular, plaque-like, popular, and mixed non-AE variants) to evaluate the association between OLP variants and HPV-infection. However, this analysis failed to find particular correlation between OLP variants and HPVinfection. Analyzing 82 patients diagnosed with atrophic OLP, Mattila et al. [58] found that HPV-infection was present in 15,9% of lesions and was related with High-risk HPV-16. In addition, the HPV-positive cases presented a higher proliferation index and overexpression of Topoisomerase IIa (protein responsible for removal of DNA positive supercoils) in supra‐ basal layers in comparison with HPV-negative cases.

HPV-16 in OSF and OSCC cases, found a 91% prevalence of HPV-DNA in OSF and speculated that epithelium lesions in OSF could be an important factor to integration of HPV in basal cells genome (Jalouli et al. [68]. In conclusion, these studies do not have strength to sustain the idea

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

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

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Several oral manifestations have been associated to use of *Smokeless Tobacco*. Oral manifesta‐ tions occur at the site of Smokeless Tobacco placement including mucosal lesions (Smokeless Tobacco Keratosis "STK") and gingival-periodontal disorders such as gingival recession, gingival inflammation, changes in gingival blood flow and interproximal periodontal attach‐ ment loss [69]. The use of *Smokeless Tobacco* and the STK has been suggested to be involved in

Clinically, the site of Smokeless Tobacco placement presents a leukoplakic lesion referred as "snuff dippers" lesions [71] STK presents a non-specific histopathologic appearance [42]. Squamous epithelium is hyper keratinized [42,70] and acanthotic; in addition, the intra-cellular edema is not uncommon on superficial cells glycogen-rich. In some cases, subjacent connective tissue can present an amorphous eosinophilic material. An increased sub-epithelial vascularity and vessel engorgement also can be seen. [42]. In STK the epithelial dysplasia does not common. In a study conducted by Leopardi et al. [72] they not evidenced cases of epithelial dysplasia. However, when present, epithelial dysplasia is usually mild [42]. Studies on STK

Studies on smokeless tobacco keratosis pointed to three clinical grades: 1) Grade I superficial lesions presenting modest wrinkling and no mucosal thickening. Grade I lesions tends to present similar color to the surrounding mucosa. 2) Grade II superficial whitish lesions with undulating areas displaying moderate wrinkling and no mucosal thickening. 3) Grade III white entities with normal mucosal color areas, STK Grade III shows mucosal thickening and wrinkling [71]. However, this lesion is reversible when the product is discontinued [42]. Related to HPV a work aimed to detect p16 (INK4a) protein expression in smokeless tobacco keratosis as reliable precancerous marker. The author detected HPV-DNA in 15 of 62 (24%) cases and an apparent relation between the three standard grades of STK lesions and HPV-

In the oral cavity, 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) have been associated with benign lesions and 12 types (2, 3, 6, 11, 13, 16, 18, 31, 33, 35, 52 and 57) with malignant lesions [47-48]. Since the first report of the presence of HPV DNA in head and neck cancer, 65 high-risk types have been consistently detected at different sites; however, these types are specifically found in transcriptionally active tumor cells [74]. According to data from a review, 99% of HPV-infections in head and neck cancers are by high-risk types 16, 18, 31 and 33 [75]. Infection with HPV 33 accounts for up to 10% of

that HPV has an important role in the malignant transformation of OSF.

**5.5. Smokeless tobacco keratosis and HPV**

development of oral cancers [70].

pointed to three clinical grades [73].

infection was observed. [71]

**6. Malignant oral lesions and HPV**

Ostwald et al. [63] studying prevalence and influence of Low-risk Hpv 6/11 and high-risk Hpv16/18 in benign oral lesions and OSCC detected the HPV-infection in 15.4% of OLP cases. Low-risk HPV presented the higher prevalence in OLP, whereas the High-Risk HPV presented the higher prevalence in OSCC. These interesting results demonstrated that High-risk HPV infection was successively increased from low-level premalignant lesion to OSCC, suggesting a correlation between High-Risk HPV and malignant potential [64]. The conflicting results of studies involving HPV-infection and malignant transformation of OLP lesions may occur due to differences in sample size of patients, associated comorbidities, and other external factors.

#### **5.4. Oral submucous fibrosis and HPV**

The name "*Oral submucous fibrosis*" (OSF) was firstly presented by Joshi in 1953; however, Schwartz had described this condition in five cases originated from Kenya, a year before, as '*atropica idiopathica mucosae oris*' [65]. OSF is frequently found in South Asian and South-East Asian patients (India, Bangladesh, Sri Lanka, Pakistan, Taiwan, Southern China) aged of 20– 40 years [63]. This potentially malignant disorder has been close related to chronic consump‐ tion of Betel quid and Paan [42].

Microscopically, OSF can be characterized by the submucosal deposition of connective tissue. This deposition is extremely dense and presents a reduced vascular tissue. In early-stage lesion, sub-epithelial vesicles can be observed. On the other hand, the older-stage lesion presents epithelial atrophy with hyperkeratosis. In conjunction with these epithelial changes, 10% to 15% of biopsied tissues present epithelial dysplasia [42].

Although, OSF presents a multifactorial etiology, Betel quid and Paan consumption are considered the major causative agents. In pertinent literature only four studies evaluating the HPV and OSF were found: two studies evaluating an Indian population; one study analyzing differences between HPV-infection prevalence in OCSS and pre-malignant lesion; one study comparing two different HPV detection methods). Study performed by Luo et al. [49] pre‐ sented only two cases of OSF infected by HPV-virion. Although, the lesions had been positive for HPV-infection was not possible to perform other conclusions, because this study used a small number of cases. Chaudhary et al. [66], comparing two HPV-detection methods identi‐ fied around of 27% (total of 208 cases) of OSF patients' positive for HPV-infection. These two reports do not allow us to establish any positive correlation between HPV-infection and malignant transformation. In addition, evaluation of a hundred thirteen cases of OSF, designed by Mehrotra et al. [67], to assess the relationship of human papilloma virus infection and OSF showed no significant correlation between these two entities. Although, the hpv-infection do not show association with OSF an Indian population study, investigating the prevalence of HPV-16 in OSF and OSCC cases, found a 91% prevalence of HPV-DNA in OSF and speculated that epithelium lesions in OSF could be an important factor to integration of HPV in basal cells genome (Jalouli et al. [68]. In conclusion, these studies do not have strength to sustain the idea that HPV has an important role in the malignant transformation of OSF.
