Oncogenic HPV is well established as the main risk factor for cervical cancer and has more recently received attention as an etiological agent for some head and neck cancers (primarily SCCOP). The results of our study suggest that certain sexual behaviors are associated with a subset of head and neck cancers, specifically tumors arising in the oropharynx. The main behaviors associated with SCCOP were having a large number of lifetime sex partners, engaging in oral-genital contact, and having a large number of oral-genital sex partners. These findings remained significant after adjustment for demographic, socioeconomic, and exposure characteristics.
We found that an increasing number of lifetime sex partners was associated with an increasing risk of oropharyngeal cancer site and that having had more than 9 lifetime sex partners increased the risk of oropharyngeal cancer site 34-fold. These findings are consistent with those of others, who have previously found a positive association between lifetime number of sex partners and risk of SCC of the head and neck.6, 10, 17
For example, D’Souza et al found an association between a high lifetime number of vaginal-sex partners (26 or more) and oropharyngeal cancer (OR=3.1; 95% CI=1.5–6.5).6
Smith et al found that in a group of patients with oral cavity and oropharynx SCC, younger patients (≤55 years) who reported 4 or more lifetime sex partners were 4.4 times as likely to have high-risk HPV types detected in their tumor as were older patients (>55 years) with 3 or fewer lifetime sex partners.17
Furthermore, Schwartz et al found that oral cavity and oropharynx SCC patients with 15 or more lifetime sex partners were 2.5 times as likely to have HPV16-positive tumors as were patients with less than 15 partners.10
While HPV16 serologic status is a marker for sexual behavior in general,22, 23
we would assume that the most likely mode of transmission of HPV16 to the upper aerodigestive tract is through oral-genital contact. In this study, we found significant associations between SCCOP and oral-genital sex and lifetime number of oral-genital sex partners. There was a dose-response effect of rising risk of oropharyngeal cancer site with rising number of oral-genital sex partners; SCCOP patients were 16 times as likely as SCCNOP patients to have had more than 4 lifetime partners. Previous studies have also found an association between engaging in oral-genital sex and having an HPV-positive oral cavity or oropharyngeal tumor.6, 17, 24
In a case-control study, cases were more than 3 times as likely as controls to have had 6 or more lifetime oral-genital sex partners; when the analysis was restricted to HPV16-positive patients, cases were almost 9 times as likely to have had 6 or more lifetime oral-genital sex partners.6
Ritchie et al found in a study of patients with SCC of the oral cavity and oropharynx that the prevalence of oral-genital sex was 4.2-fold higher (95% CI=1.5–11.7) among patients with HPV-positive SCC than among patients with HPV-negative SCC.24
Smith et al, found that the odds of having engaged in oral-genital contact were 4.8-times higher among oral cavity and oropharyngeal cancer patients 55 years or younger than among patients older than 55 years (95% CI=1.9–12.1).17
Recently, D’Souza et al evaluated the association between oral sexual behaviors and HPV infection and found that the odds of oral HPV infection increased significantly with the number of oral-genital sex and open-mouth kissing partners among two control groups.14
Taken together, these findings and our own findings support oral-genital sex as a major mode of transmission of oncogenic HPV to the upper aerodigestive tract.
SCCOP patients were more likely to have had a partner with a history of an abnormal Pap test but not with having had a partner with cervical cancer and neither association remained significant in regression analyses. The possible association between SCCOP and having had a partner with a history of an abnormal Pap test is in accordance with a previous report of increased incidence of tonsillar and tongue cancer among husbands of women with cervical cancer.25
We also found that women with SCCOP were more likely than women with SCCNOP to have had an abnormal Pap test themselves prior to their cancer diagnosis. This finding was of only borderline statistical significance and was not significant in regression analyses; however, the small sample size may have contributed to this lack of statistical significance. Large population-based studies using SEER data and other cancer-registry data have confirmed that women with a history of cervical cancer have an increased risk of HPV-associated second primary cancers,26–28
and this association is especially strong for SCCOP.26, 29
The increased risk of HPV-associated second primary cancers after a diagnosis of an HPV-associated primary cancer appears to hold true for men as well.30
Analysis of history of sexually transmitted diseases revealed that both a history of gonorrhea and any sexually transmitted disease were significantly more common among SCCOP patients; however, only a history of gonorrhea remained significantly associated with SCCOP in regression analyses. Several studies have found HPV seropositivity and subsequently the risk of cervical cancer to be increased among women with history of gonorrhea, herpes simplex virus-2 or C. trachomatis
Consequently, it seems plausible that coinfections with bacterial or viral pathogens modulate the risk of HPV-associated SCC, possibly by modulating host immune function, increasing susceptibility to HPV, or delaying viral clearance.
Our study had several limitations. First, the low response rate may bias the results if differences exist between the responders and nonresponders with respect to sexual history. The response rate was 40% among the SCCOP patients but only 21% among the SCCNOP patients. Furthermore, SCCOP patients were more likely to have higher education and income than the SCCNOP patients. However, the SCCNOP patients who did respond tended to have higher education and income than those who did not respond. This indicates that the SCCNOP responders were more similar to the SCCOP responders than were the SCCNOP patients overall and therefore may also be more similar with respect to sexual behavior. This being the case, the association between sexual behavior and SCCOP may be underestimated in our study. Furthermore, the low response rate resulted in a small sample size, which limited statistical power and our ability to perform any meaningful subgroup analyses.
Second, the retrospective nature of this study creates a recall bias. While we would expect such recall bias to be nondifferential, several factors might suggest otherwise. For instance, members of the group with SCCOP were younger on average and might have had better memory. Additionally, the age difference could have introduced a cohort effect such that between-group differences in the prevalence of sexual behaviors reflect the years during which patients were born more than differences in tumor site. It would have been convenient to have the two groups be more similar with regard to the demographic, socioeconomic, and exposure characteristics or to have our sample size be large enough to permit rigorous subgroup analyses; however, we did include these variables in our analyses, and our principal findings were relatively stable after adjustment for them.
Third, nondifferential misclassification may have occurred due to the subject matter of the survey and the willingness of the responders to answer sensitive questions. Moreover, differential misclassification could also have occurred owing to the demographic and clinical differences between the SCCOP and SCCNOP patients. A large number of responders failed to completely fill out the questionnaire, resulting in missing data; furthermore, some may have underreported certain behaviors because of associated societal stigmas. Both of these factors would be likely to bias the effect estimate toward the null; however, the anonymous nature of the survey may have mitigated some of the underreporting bias.
Fourth, we used serology to ascertain HPV status. The estimated sensitivity of this technique is 50–75%, indicating a number of possible false-negative results, which would lead to misclassification of HPV16-positive patients as HPV16-negative. This could lead to an underestimation of the association between sexual behavior and HPV16 serologic status. Additionally, serological HPV status may not reflect an infection in the oropharynx, but rather could be due to an infection isolated to the anogenital region.
Fifth, we grouped patients by cancer site because HPV is primarily associated with the oropharynx; however, we can assume that some SCCOP patients were HPV16-negative and some SCCNOP patients were HPV16-positive. For the 42 patients for whom we had HPV16 tumor DNA status available, 19% of SCCOP patients were actually HPV16-negative while 44% of SCCNOP patients were HPV16-positive. Unfortunately, since we only had this data available for a small minority of patients (17%) we were unable to compare by HPV tumor status. Regardless, because our site-specific results may be diluted by HPV negative tumors in the SCCOP group it is likely that there is an underestimation of sexual behaviors associated with HPV-associated cancer. We are currently assessing tumor HPV16 and HPV18 DNA status for all prospectively recruited patients and will include this data in future studies.
While head and neck cancers have traditionally been associated with primarily tobacco and alcohol use it appears that the risk factor profile is changing for these cancers, and an accurate understanding of risk factors is critical to establish effective prevention strategies. We conclude that among patients with SCC of the head and neck, having numerous sex partners (in particular oral-genital sex partners) is a risk factor for oropharyngeal cancer site. We feel that these findings add to the evidence that HPV16 can be sexually transmitted to the upper aerodigestive tract and suggest that oral-genital sex is a risk factor for HPV16-associated SCCOP. A number of models exploring the impact of the HPV16/18 vaccine currently targeted at girls and young women predict a marked decrease in the incidence of cervical cancer over the next several decades.35, 36
Unfortunately, the overwhelming majority of HPV16-associated SCCOP occur in males, and the current vaccination strategy, which targets girls and young women, will benefit men only secondarily as vaccinated women age and the incidence of chronic oncogenic HPV infection in sexually active females declines. Such an effect could take a generation to achieve. We encourage the rapid study of the efficacy, safety, and cost-effectiveness of HPV16/18 vaccines in males and, if results warrant, the vaccination of young adult and adolescent males.