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 HPVnegative cancers arising in the same tissue.

Key words: human papillomavirus; oral cancer; head and neck carcinoma; risk factorsThe causal link between human papillomavirus (HPV) infection and the development of head and neck carcinomas (HNCs) particularly in the oropharynx are becoming more firmly established. 1-3 A number of unanswered questions remain, however. Unlike cervical cancer, high-risk HPVs in HNC are neither a necessary nor a sufficient cause of cancer and only about 20% of these malignancies are associated with viral infection. 4 As yet limited evidence suggests that HPV can infect the oral cavity and upper respiratory tract through sexual transmission. 1,5 Whether tobacco and alcohol, the major risk factors for HNC, are less frequent exposures among those detected with HPV in HNC also needs clarification as the data are inconsistent. 6,7 Although poorly differentiated grade and nodal involvement have been more frequently reported in HPV-positive cancers, these findings usually are presented without adjustment for other risks and confounders associated with the disease. 8,9 If these findings are accurate, the information could lead to different treatment decisions and follow-up for recurrence in this subset of HNC. Finally, there is a need to determine whether a test based on oral exfoliated cells can be used to provide a sensitive method for predicting oncogenic mucosal HPV types in head and neck tissue. 10

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 HPVnegative 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.

The transcriptional promoter of the candidate E6‐E7 transforming gene region of human papillomavirus (HPV)‐16 (P97) was active in transiently transfected cervical carcinoma cells when linked to the HSV‐1 tk or bacterial cat genes. Sequences 5′ to P97 contain a short enhancer element responding to cellular factor(s) in uninfected human foreskin keratinocytes and in cervical carcinoma cells, but not in human or animal fibroblasts. The E2 trans‐activator products of HPV‐16 or of the related bovine papillomavirus (BPV)‐1 further elevated HPV‐16‐driven transcripts in co‐transfections, and required the presence of E2‐binding ACC(N)6GGT cores in cis. A ‘short E2’ C‐terminal repressor gene product (sE2) of HPV‐16 or the BPV‐1 sE2 repressor not only inhibited viral E2 trans‐activation, but also suppressed enhancer response to keratinocytic factors. Suppression by the sE2 products was abolished by deletion of the E2‐binding cores in cis or by a mutation in the sE2 DNA binding domain. The keratinocyte‐dependent enhancer is likely to contribute to the epithelial cell tropism of HPV‐16, and may direct persistent E6‐E7 gene transcription in response to cellular factors in cervical carcinoma cells in which the viral E2 genes are inactive.