This is the largest study yet conducted on the association between sexual behaviours and head and neck cancers. Our analyses showed associations, albeit inconsistent, between certain sexual behaviours and cancers of the head and neck. Our results support previous findings of an increased risk of oropharyngeal cancers with HPV.4
In addition, results support an increased risk for cancers of the tonsil and those of the base of the tongue, findings that are concordant with studies of HPV in head and neck tumours.26,28
Associations were seen with a history of ever having oral sex, greater numbers of sexual partners and a history of same-sex contact. Similar to other studies, we found little evidence for any association of sexual behaviours with cancers of the oral cavity or of the larynx.20
The previous studies on this topic took place in the USA, India, Poland, Italy and Cuba, and all were case–control in design, including both hospital10–16
and population based.8,9
In contrast to the present study, most grouped together cancers of any head and neck subsite. Almost all observed elevated risks with some sexual behaviours but not others, with the most consistently elevated risk seen with a larger number of sexual partners,8,9,11,13,16
with the exception of in Cuba, where a majority of cases and controls reported multiple sexual partners, likely limiting the power to find an association.10
In the studies that stratified by gender, differential findings were observed between men and women, although no clear pattern was apparent as to whether men or women may be at greater risk.9,13
In two studies, higher cancer risk was observed with a greater number of marriages, but not simultaneously with a greater number of sexual partners,12,13
suggesting that subjects do modify responses based on social acceptability. Similar to that found here, no consistent elevated cancer risk was seen with STD history,8–10,13,15
although higher effect estimates were observed in US-based studies, possibly due to more widespread STD screening. Studies with the most consistent, elevated effect estimates examined sexual behaviours among HPV-positive patients only.14,16
Variations in results are likely due to small sample sizes (less than 150 cases) and limited numbers of persons who had ever engaged in certain sexual practices,8,12,15
inclusion of HPV-negative cases and differences in the prevalence of HPV in different regions.
There is a possibility that the protective associations seen at some subsites may be due to data collection methods. The timing of interviews for some of the INHANCE studies may have impacted self-reported sexual behaviours because, at some study sites, cases were interviewed at the time of their cancer diagnosis while still in the hospital: at the time of the interview they were more likely to have family members nearby, in comparison with the controls at their time of interview. In order to limit reporting bias, interviewers made efforts to speak to the cases alone. Nonetheless, given this potential reporting bias, we conclude that the results seen may be underestimates.
The tonsil and the base of the tongue form parts of Waldeyer’s tonsillar ring, a group of lymphoid tissues that forms a ring around the opening of the throat. Of the subsites of the head and neck, Waldeyer’s ring tumours exhibit among the highest prevalence of HPV.26,32
Cancers in this area are more likely to have basaloid morphology, express the viral oncogenes E6 and E7 and are more likely to have wild type p53.33–35
The differing morphological characteristics as well as improved survival among HPV-positive head and neck cancer patients have led researchers to suggest that these tumours should be treated as distinct entities.36
A high number of lifetime sexual partners is one of the leading risk factors for HPV acquisition.37
This study found that having four or more lifetime oral sex partners was associated with a 3-fold increase in tonsil cancer risk. With cancer of the base of the tongue, elevated point estimates were seen with two lifetime sexual partners. An increased risk of oropharyngeal and base of the tongue cancers was seen with having two sexual partners, in comparison to having only one. Similar results have been previously reported.38
Nonetheless, no dose–response relationships were seen with an increasing number of sexual partners. Studies of sexual behaviour regularly find that men report more sexual partners than women; a perplexing discrepancy that has been attributed to male exaggeration and female underreporting.39
If non-differential response biases influenced answers in the INHANCE studies, our ability to find a dose–response effect would have been impaired. A lack of a dose–response effect has been seen in other studies.13
In this study, age at sexual debut of ≤18 years was associated with a 2-fold risk of tonsil cancer among men. Studies have previously associated earlier age at sexual debut with risky sexual behaviour, including higher numbers of partners and inconsistent condom use, as well as with greater use of tobacco and alcohol.40
Thus, it is possible that this factor represents a marker for riskier sexual behaviours, rather than a biologically relevant etiologic relationship.
Cases and controls in this study differed in sexual behaviours, drinking and tobacco use. We observed associations between heavier smoking and alcohol use with risky sexual behaviours, both in the overall sample and when examining only the population-based studies, although the associations were not always consistent. Although there are conflicting findings, other studies suggest persons who drink more heavily are more likely to engage in risky sexual behaviours, such as having multiple sexual partners and less consistent condom use.41
Tobacco use has similarly been associated with certain risky sexual behaviours.42–44
Given these associations the possibility exists for residual confounding in our results. Despite efforts to select controls independent of tobacco use, controls in the Central Europe study had higher smoking rates than expected. Hospitalized patients frequently have higher smoking rates than the general population,45
although the exclusion of persons with tobacco-related diseases, as done in that study, is a common strategy employed to reduce this bias. Nonetheless, given potential associations between alcohol and tobacco use with sexual behaviours, controls may have been overmatched to cases in the Central Europe study.
As there are few reports of cancer rates among men who have sex with men (MSM), the finding of a higher risk of base of the tongue cancers associated with same-sex contact was notable. These results should be taken with caution, because we were not able to adjust for the number of sexual partners in these analyses, as that information was not collected in all studies. Nonetheless, our findings support those of a study that examined cancer incidence among men in registered homosexual partnerships in Denmark, which reported a 5-fold increased risk of cancers of the tonsils and a 4-fold increased risk of cancers of the mouth.46
However, other lifestyle factors may in part explain increased risks of these cancers seen in MSM. Compared with heterosexual men, MSM have greater tobacco use43
and also may have higher passive smoke exposure.47
Differences in HPV prevalence by age have been observed and have been attributed to poorer immune response among older persons.48
In many countries, cervical HPV is highest in adolescence and early adulthood, dropping in mid-life and then rising in older adulthood.49
Variation in risk by age may be also due to cohort effects in risk behaviours. Studies in the USA, Australia, Russia and Brazil point to generational changes in sexual behaviour, with individuals who came of age in recent years having an earlier age at sexual debut, greater numbers of sexual partners and a higher likelihood of engaging in oral sex in comparison with those who came of age in earlier decades.50–53
Birth cohort analyses of cervical cancer incidence find decreasing rates of cervical cancer from cohorts born in 1900 through those born in 1940, followed by increasing rates for later birth cohorts;54
there have additionally been increases in anal and vulvar cancer incidence in the past 40 years.55–57
However, studies in some countries, notably India and Italy, have not found evidence of generational differences in HPV prevalence or sexual behaviour.49,58
The variety of questions asked at the study centres allowed us to examine the potential effects of a number of behaviours. In combination with the stratification by head and neck subsite, this analysis included multiple tests (n = 204) and this limitation must be considered in interpreting results. We a priori hypothesized that elevated risks would be seen for oropharyngeal, tonsil and base of the tongue cancers. For the other analyses, after Bonferroni correction, no findings remained significant, with the exception of oral cavity cancer and age at sexual debut among women (P = 0.02).
A limitation of this study was the pooled design. The studies had different populations, protocols, sources of controls and methods of data collection, which may contribute to different findings across sites. Disparate cohorts may have differing behaviours and reside in areas with a different prevalence of HPV. We tried in part to account for these differences in the analysis by adjustment for study site. In addition, heterogeneity testing yielded little evidence of differences by study in effect estimates. We were unable to stratify by HPV status, as it was not collected in the studies; this may account for null results or the lack of dose–response findings. An additional limitation is that researchers have questioned the validity of self-reported sexual behaviours, with particular concerns for underreporting of stigmatized behaviours.59
All but one of the studies was conducted by face-to-face interview, a method that has the advantage of limiting non-response as well as the possibility of the participant building rapport with the interviewer, but with the disadvantage of limiting privacy. There is also the possibility of recall bias between cases and controls. As all studies on this topic including the present study have been retrospective in nature, we are not able to gauge a possible effect from recall bias. However, one previous study compared risk between HPV-positive and HPV-negative cancer cases, and found strong associations between sexual behaviours among HPV-positive persons only,16
suggesting effects may be observed independent of recall. The types of questions used in these studies are similar to those used on studies of sexual activities and cervical cancer, suggesting they should be sufficient to detect an association. In addition to the above study limitations, we have no information on other factors that may be relevant to HPV transmission, such as frequency of condom use,15
and of other potential risk factors for head and neck cancer, such as diet,60
which was not available from all INHANCE studies.
The associations seen in this study add additional indirect evidence that HPV is a cause of oropharyngeal, tonsillar and base of the tongue cancers, and studies should be undertaken to determine whether HPV vaccines can prevent HPV infection and ultimately head and neck cancers.