**8. HPV vaccines (Therapeutic and prophylactic)**

samples. The most prevalent infected anatomical site was the tongue. The main result of the present study was the significant number of positive HPV samples among non-smoking patients and although, a possible influence of HPV infection on carcinogenesis cannot be ruled out, the low frequency of HPV-positive OSCC cases found in our analysis leads us to suggest that this virus has not the same etiological influence on patients, as tobacco consumption does. Although we cannot to exclude a possible transient role for HPV in the OSCC induction, we believe that occasional detection of HPV-infection in OSCC resulting from the incidental colonization of tumoral lesions might reflect the true correlation of HPV in most analysis. [84].

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

In last decades no significant improvement of overall survival has been observed in patients with HNSCCs. It is believed that loco-regional recurrences, distant metastases and a second primary tumor are factors for this phenomenon [91]. Several studies have now established that head and neck HPV-positive tumors have better prognoses [76,88] and treatment-response rates when compared with HPV-negative tumors [88]. In a study comparing tumors in the same stage Leemans et al., [91] observed favorable prognoses after treatment of HPV-infected HNSCCs as compared to HPV-negative tumors. Univariate analyses for 5-year survival rate have pointed that HPV-positive patients surviving longer than HPV-negative patients (p < 0.05); the 5-year survival rate was 54% for HPV-positive versus 33% for HPV-negative tumors [92]. In addition, a study performed by Fakhry et al. [76] evaluating the correlation between HPV infection and survival rate suggested that HPV-positive HNSCC have a significantly better survival (5-year survival of approximately 70%) when compared with HPV-negative patients (5-year survival of approximately 35%). Dayyani et al. [87] published a Meta-analysis, analyzing the impact of human papillomavirus (HPV) on head and neck squamous cell carcinomas, described that patients HPV-positive presented increased risk for HNSCC (adjusted OR = 1.83; 95% CI = 1.04-2.62; p < 0.0001). However, survival rate was improved in HPV-positive patients when compared to HPV-negative patients (HR = 0.42; 95% CI = 0.27-0.56, p < 0.0001). In other example, evaluation of prognosis and response rates to chemotherapy of oropharyngeal or laryngeal carcinomas showed that HPV-positive tumors present a signifi‐ cantly better overall 2-year survival rate than HPV-negative patients (2-year survival rate of HPV-positive tumors 95% (95% CI = 87%-100%), and 2-year survival rate of HPV-negative tumors 62% (95% CI = 49%- 74%)). The same study found that HPV-positive oropharyngeal carcinomas present higher response rates to chemotherapy compared with HPV-negative (82% vs 55%, difference = 27%, 95% CI = 9.3% to 44.7%, P =.01). Additionally, Dayyani et al. [87] described that HPV-positive head and neck squamous cell carcinomas presented an improved response to radiotherapy (non-adjusted OR = 4.07; 95% CI = 1.48-11.18, p = 0.006) and had a better response to chemo-radiation (non- adjusted OR = 2.87; 95% CI = 1.29-6.41, p = 0.01) as

compared to HPV-negative head and neck squamous cell carcinomas.

A meta-analysis performed by Ragin & Taioli [93] aimed to analyze the impact of tumor HPV status on survival outcomes showed that patients diagnosed with head and neck squamous cells carcinoma HPV-positive had a lower risk of dying in comparison with HPV-negative

**7. HPV — Prognosis and treatment**

Several epithelial lesions are originated by infection with human papillomaviruses (HPVs), mainly benign hyperplasia with low malignant potential like warts or papillomas. However, there is a subgroup of HPVs that are associated with precancerous lesions, which could become a cancer in a small fraction of people [99]. As example of those high-risk HPV subtypes, HPV 16 and 18 [100] are responsible for approximately 70% of cervical cancer cases and are present in more than 60% of HPV-infected penile cancer and HPV-16 is the genotype most frequently detected in head and neck carcinomas, found in up to 90% of HPV-positive cases [99]. Other high-risk HPV types account for virtually all of the remaining cases of cervical cancer, although in other primary sites they do not appear to have a similarly important role [101]. Therefore, cancer of the uterine cervix is most widely accepted malignancy as being associated with HPV infection. HPV high-risk subtypes are also associated with some others anogenital carcinomas, including penile, anal and vulvar cancers [102-103] and a subset of head-and-neck squamous cell carcinomas [104].

Taken together, these findings supports in several countries, vaccination against some HPV types on girls and young women with the goal of protecting them against HPV-induced cervical cancer [105-106]. Trials with vaccines against cervical cancer shown that crossprotection is possible, because this vaccines also have the potential to prevent other cancers that are caused by the same types of HPV, including some of head and neck cancers [107], and the most of anogenital cancers outside the cervix, including cancer of the vulva, vagina, penis, and anus [108-109]. In theory, these vaccines should target the same viruses at other anatomical sites, as head and neck. This approach could provide important information about the final proof of HPV etiology in these tumors [110].

Prophylactic vaccines work primarily by inactivating HPV before the virus infects the host cells, stimulating humoral immunity [111]. Nowadays, there are two types of prophylactic HPV vaccine available in United States: the quadrivalent vaccine (Gardasil®) and bivalent vaccine (Cervarix®). The quadrivalent vaccine was first licensed for use in females to prevent cervical, vaginal and vulvar cancers and are effective against infection with HPV types 6, 11, 16 and 18 [112]. In 2009 the licensure was expanded to include males demonstrating effective‐ ness to prevent genital warts in both genders [113]. Bivalent vaccine was licensed for use in the U.S. in 2009 providing cervical cancers protection against HPV types 16 and 18 [114]. The impact of HPV prophylactic vaccination will address not only the incidence of cervical and anogenital cancers in women and men but also the incidence of some head and neck tumors. Growing number of head and neck cancers HPV-positive highlights the importance of routine prophylactic vaccination against HPV and, associated with alcohol and tobacco control, may be crucial in head and neck cancer prevention [115].

to personalize the treatment for individual patients. However, for a better understanding about real therapeutic implications of HPV-status of tumors on OSCC clinical outcome, the next generation of clinical trials could be significantly improved and standardized in their design. According to exposed in the present issue, and defended by our research group and other authors [36-37], we believe that diagnosis strategy based in early detection in oral Pre-Cancerous lesions and OSCC reduces the treatment at the advanced stage, thereby increasing the cancer cure chances. Our group also believes that the increasing effects of HPV vaccination in several cancers could help to reduce the number of new HNSCC and OSCC cases. Although knowledge of the accurate effects of HPV vaccination on cancer incidence will probably continue for several years, monitoring the current effects of HPV vaccination is crucial, not

, João Paulo Oliveira-Costa3

, Lucinei Roberto Oliveira4

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

,

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

257

and

only in cervical cancer, but also in HNSCC and OSCC.

Danilo Figueiredo Soave1\*, Mara Rubia Nunes Celes2

\*Address all correspondence to: dsoave@usp.br

diol Endod 2001 91:622–635

20(9):89-91.

, Bruna Riedo Zanetti3

4 Department of Pathology – Vale do Rio Verde University, Brazil

1 Department of Pathology – Ribeirão Preto Medical School – University of Sao Paulo, Brazil

3 Department of Pathology – Ribeirão Preto Medical School – University of Sao Paulo, Brazil

[1] Miller CS, Johnstone BM. Human papillomavirus as a risk factor for oral squamous cell carcinomas: a meta-analysis 1982–1997. Oral Surg Oral Med Oral Pathol Oral Ra‐

[2] Onon TS. History of human papillomavirus, warts and cancer: what do we know to‐ day? Best Pract Res Clin Obstet Gynaecol. 2011 Oct;25(5):565-74. Epub 2011 Jun 25.

[3] McCaffery M. Autopsy of a mummy - warts and all. . Can Fam Physician. 1974 Sep;

[4] zur Hausen H. Papillomaviruses in the causation of human cancers - a brief historical

account. Virology. 2009 Feb 20;384(2):260-5. Epub 2009 Jan 8.

2 Institute of Tropical Pathology and Public Health, Federal University of Goias, Brazil

**Author details**

Giorgia Gobbi da Silveira3

Alfredo Ribeiro-Silva3

**References**

Also, therapeutic vaccines against HPV have to request cell mediated immunity and can also help prevent the progression of low-grade disease and lead existing lesions to regress, avoiding the recurrence of cancer lesions after treatment [116,117]. However, recent studies demon‐ strated the reduced effectiveness of therapeutic HPV-vaccine in established tumors. This could be explained by the fact that they have especially been tested in patients with compromised immune systems due advanced stage cancer [118]. A vaccine that possesses both prophylactic and therapeutic properties could be most effective HPV-vaccine strategy, preventing new and clear established HPV-infections. Additionally, the vaccine could be administered in, sexually inexperienced young individuals or older individuals HPV-infected, beneficiating them [119].
