Thomas H. Haugen

There are few well-established patient risk factors associated with human papillomavirus (HPV) infection in cancers of the oral cavity and oropharynx. The purpose of this study was to determine if there were significant different risk factors and tumor characteristics between HPV-positive and HPV-negative cancer cases. HPV was evaluated in cancer tissue and exfoliated oral cells of 193 oral cavity/oropharynx cancer patients using PCR and direct DNA sequencing. A patient questionnaire collected information about risk factors, sexual practices and medical history. The prevalence of HPV high-risk (HR) types was 20% in cancer cases. Three types were identified: HPV-16 (87%), HPV-18 (3%) and HPV-33 (11%). Risk factors for HPV-HR included younger age (< or = 55 years vs. > 55 years; adjusted OR = 3.4; 95% CI = 1.6-7.3) and younger-age cases who had more lifetime sex partners (adjusted OR = 3.8; 95% CI = 1.4-10.1), practiced oral-genital sex (adjusted OR = 4.3; 95% CI = 1.8-10.4) or oral-anal sex (adjusted OR = 19.5; 95% CI = 3.4-113). Compared to HPV-negative cancers, HPV-HR cancers were more likely to have a positive HPV-HR exfoliated oral cytology test (adjusted OR = 7.8; 95% CI = 3.4-18.4), later stage (adjusted OR = 3.0), nodal involvement (adjusted OR = 4.1) and advanced grade (adjusted OR = 3.0). This study shows new evidence that the prevalence of oncogenic mucosal HPV is higher in younger-age oral cavity/oropharynx cancer cases whose sexual practices are typically associated with sexual transmission of the virus. HPV detection also appears to be an indicator of advanced disease characteristics that may require different clinical treatment for this subset of patients. An exfoliated oral cytology test for HPV was a significant predictor of HR types in the cancers, suggesting that an oral rinse may provide an early biomarker of infected tumors.

Human papillomaviruses (HPV) are associated with nearly all cervical cancers, 20% to 30% of head and neck cancers (HNC), and other cancers. Because HNCs also arise in HPV-negative patients, this type of cancer provides unique opportunities to define similarities and differences of HPV-positive versus HPV-negative cancers arising in the same tissue. Here, we describe genome-wide expression profiling of 84 HNCs, cervical cancers, and site-matched normal epithelial samples in which we used laser capture microdissection to enrich samples for tumor-derived versus normal epithelial cells. This analysis revealed that HPV(+) HNCs and cervical cancers differed in their patterns of gene expression yet shared many changes compared with HPV(-) HNCs. Some of these shared changes were predicted, but many others were not. Notably, HPV(+) HNCs and cervical cancers were found to be up-regulated in their expression of a distinct and larger subset of cell cycle genes than that observed in HPV(-) HNC. Moreover, HPV(+) cancers overexpressed testis-specific genes that are normally expressed only in meiotic cells. Many, although not all, of the hallmark differences between HPV(+) HNC and HPV(-) HNC were a direct consequence of HPV and in particular the viral E6 and E7 oncogenes. This included a novel association of HPV oncogenes with testis-specific gene expression. These findings in primary human tumors provide novel biomarkers for early detection of HPV(+) and HPV(-) cancers, and emphasize the potential value of targeting E6 and E7 function, alone or combined with radiation and/or traditional chemotherapy, in the treatment of HPV(+) cancers.

Although studies have established human papillomaviruses (HPVs) as a risk factor for oral and oropharyngeal cancer, it is not clear whether viral infection affects survival in head and neck malignancies. This investigation examined the relationship between HPV and survival in carcinomas of the oral cavity and oropharynx. Formalin-fixed, paraffin-embedded tumor specimens from 139 newly diagnosed cases were tested for HPVs by PCR and DNA sequencing. Patient and tumor characteristics were obtained from questionnaires, pathology reports and cancer registries. Odds ratios (ORs) and relative risks (RRs) were based on logistic and Cox regression models, respectively. HPVs were detected in 21% of the tumors; 83% were HPV-16. Greater risk of HPV infection was associated with males (OR = 2.9, 95% CI = 1.0-8.6), a history of oral-genital sex (OR = 4.2, 95% CI = 1.5-11.7), and oropharyngeal tumors (OR = 10.4, 95% CI = 3.5-31.2). As tobacco usage increased, the odds of HPV detection decreased (OR = 0.97/pack-year, 95% CI = 0.96-0.99). HPV infected patients had better overall survival (RR = 0.3, 95% CI = 0.1-0.8) than those with HPV-negative tumors. There was an interaction between gender and HPV for overall (p = 0.05) and disease-specific (p = 0.03) survival that suggested that HPV infected males had better prognosis than HPV-negative males, but this was not the case among females. HPV status was identified as an independent prognostic factor in oral and oropharyngeal cancers. This result appeared to be gender-specific, suggesting the need for further study of the interaction between HPV and gender on survival.

BACKGROUND: Human papillomavirus (HPV) has been associated with the development of head and neck cancers. In this study, we investigated whether the risk factors for head and neck cancer in relation to HPV infection are different from those in the absence of HPV infection and whether HPV detected in oral exfoliated cells is an independent predictor of head and neck cancer risk. METHODS: We conducted a case-control study in 201 head and neck cancer case patients and 333 control subjects, frequency matched for age and sex. Oral exfoliated cells and tumor tissue were evaluated for HPV using polymerase chain reaction and DNA sequencing to type HPV. Logistic regression was used to calculate odds ratios (ORs) for head and neck cancer with HPV infection and 95% confidence intervals (CIs), adjusted for age, tobacco use, and alcohol consumption. RESULTS: Oncogenic, or high-risk (HR), HPV types were detected in oral cells from 22.9% of case patients and 10.8% of control subjects. HPV16 was the most frequently detected type (19% versus 10% of case patients and control subjects, respectively). After adjusting for age, tobacco use, and alcohol consumption, the risk of head and neck cancer was statistically significantly greater in individuals with HPV-HR types (adjusted OR = 2.6, 95% CI = 1.5 to 4.2) but not in individuals with nononcogenic HPV types (adjusted OR = 0.8, 95% CI = 0.4 to 1.7) compared with HPV-negative individuals. Compared with individuals who were HPV-negative and did not use alcohol or tobacco, there was a statistically significant synergistic effect between detection of HPV-HR and heavy alcohol consumption (OR = 18.8, 95% CI = 5.1 to 69.5) but an additive effect between detection of HPV-HR and tobacco use (OR = 5.5, 95% CI = 2.1 to 14.1). HPV-HR types detected in oral exfoliated cells were predictive of HPV-HR types in tumor tissue. CONCLUSION: Infection of oral exfoliated cells with HPV-HR types is a risk factor for head and neck cancer, independent of alcohol and tobacco use, and acts synergistically with alcohol consumption. HPV testing of an oral rinse may be predictive of an HPV-related head and neck cancer.