**5.1. Oral leukoplakia and HPV**

mouthed 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

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

The transformation of normal oral mucosa in OSCC entities can be linked to the emergence of Pre-Cancerous lesion [36]. This association with several oral mucosa disorders such as oral leukoplakia, oral erythroplakia, oral lichen planus, nicotine stomatitis, tobacco pouch keratosis and oral submucous fibrosis (Table1) could be seen. However, that kind of disorders presents a varied spectrum of malignant transformation potential [37]. Reviewing the clinical features of oral Pre-Cancerous lesions and OSCC, the literature emphatically agrees that the early detection is the most important strategy for diagnosis and prevention of OSCC [37]. Applying this diagnosis strategy the OSCC-patients reduces the treatment in advanced stages, thereby increasing the chances of cure [36]. One of the extensive efforts in the clinical management of patients diagnosed with Pre-Cancerous lesions is to delineate clinical outcome, since it is difficult to separate lesions that follow a benign transformation from the entities that are predisposed to malignant course [38]. However, can be observed only a subset of Pre-

**Disease Name Malignant Potential**

Cancerous lesions following the malignant course blowing in OSCC.

Proliferative Verrucous Leukoplakia (PVl) 6 Nicotine Palatinus in Reverse Smokers 5 Erythroplakia 5 Oral Submucous Fibrosis 5 Erythroleukoplakia 4 Granular Leukoplakia 4 Laryngeal Keratosis 3 Actinic Cheilosis 3 Smooth. Thick leukoplakia 2 Smooth. Red Tongue of Plummer-Vinson Syndrome 2 Smokeless Tobacco Keratosis 1 Lichen Planus (erosive forms) 1 Smooth Thin Leukoplakia +/-

**Table 1.** Malignant transformation Potential of *Precancerous Lesions* (adapted from Neville et al. 2009).

HNSCC carcinogenesis [35].

**5. Oral premalignant lesions**

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 5-10 years earlier [41].

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 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 frequent in OSCC.

Information about the role of HPV infection in OE is limited. Reichart & Philipsen (2004) discussed the role of hpv infection in OE together with p53 alterations [56]. Nielsen et al. [57] immunohistochemically detected hpv-infection (by situ hybridisation and PCR) in potentially malignant oral lesions. Fifty percent of OE studied cases were HPV-positive. The authors suggest that HPV may be an etiologic co-factor involved in development of oral cancer. However, we can not assume that HPV is the major etiologic factor involved in malignant

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

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

249

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

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

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

transformation of OE

lesions [59].

observed [42].

**5.3. Oral lichen planus and HPV**

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 induced by influence of survivin on apoptosis process.

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 important role in oral carcinogenesis leading to OL malignant transformation.

### **5.2. Oral erythroplakia and HPV**

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].

Information about the role of HPV infection in OE is limited. Reichart & Philipsen (2004) discussed the role of hpv infection in OE together with p53 alterations [56]. Nielsen et al. [57] immunohistochemically detected hpv-infection (by situ hybridisation and PCR) in potentially malignant oral lesions. Fifty percent of OE studied cases were HPV-positive. The authors suggest that HPV may be an etiologic co-factor involved in development of oral cancer. However, we can not assume that HPV is the major etiologic factor involved in malignant transformation of OE
