**7. HPV — Prognosis and treatment**

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 tumors (combined HR: 0.85, 95% CI: 0.7–1.0). At the same study, HPV-positive patients had lower risk of disease-failure (recurrence of tumor) as compared to HPV-negative patients (meta HR, 0.62; 95%CI, 0.5–0.8). The evidence for association of OSCC with HPV-infection and its possible role as an oncogenic agent remains controversial. Schwartz et al. (2001) evaluating the HPV-16 influence on survival rate in OSCC demonstrated that patient's HPV-16 positive presented significantly reduced disease-specific mortality in OSCC (HR = 0.17, 95% CI = 0.04, 0.76) when compared with HPV-16 negative patients. This result suggests the HPV-16 infection could be associated with a favorable prognosis in OSCC. However, the mechanism responsible for this improved prognosis conferred by HPV is still unclear [94].

Several hypotheses have been proposed to explain the improved prognosis in tumors HPVpositive. The benefit on survival rate has been attributed to an enhanced radiosensitivity of tumors HPV-positive [95-96], and an improvement of apoptotic secondary response to the presence of unmutated p53 in HPV-associated tumors [95,97]. The improvement of diseasespecific survival rate could be associated with a reduction risk of second primary tumor, since these HPV-positive patients tend to have no prior history of tobacco and/or high alcohol consumption [95]. This finding reduces the field cancerization process (upper respiratory epithelium repeatedly exposed to carcinogens) [98].
