• 3/12/2008
  • Marua Gillison MD et. al
  • Journal of the National Cancer Institute

Background: High-risk types of human papillomavirus (HPV), including HPV-16, cause a subgroup of head and neck squamous cell carcinomas (HNSCCs). We examined whether the risk factors for HPV-16–positive HNSCCs are similar to those for HPV-16–negative HNSCCs in a hospital-based case–control study.

Methods: Case subjects (n = 240) diagnosed with HNSCC at the Johns Hopkins Hospital from 2000 through 2006 were stratified by tumor HPV-16 status as determined by in situ hybridization. Two control subjects (n = 322) without cancer were individually matched by age and sex to each HPV-16–positive and HPV-16–negative case subject. Data on risk behaviors were obtained by use of audio computer-assisted self-interview technology. Multivariable conditional logistic regression models were used to estimate the odds ratios (ORs) for HPV-16–positive HNSCC and HPV-16–negative HNSCC associated with risk factors. All statistical tests were two-sided.

Results: HPV-16 was detected in 92 of 240 case subjects. HPV-16–positive HNSCC was independently associated with several measures of sexual behavior and exposure to marijuana but not with cumulative measures of tobacco smoking, alcohol drinking, or poor oral hygiene. Associations increased in strength with increasing number of oral sex partners (Ptrend = .01) and with increasing intensity (joints per month, Ptrend = .007), duration (in years, Ptrend = .01), and cumulative joint-years (Ptrend = .003) of marijuana use. By contrast, HPV-16–negative HNSCC was associated with measures of tobacco smoking, alcohol drinking, and poor oral hygiene but not with any measure of sexual behavior or marijuana use. Associations increased in strength with increasing intensity (cigarettes per day), duration, and cumulative pack-years of tobacco smoking (for all, Ptrend < .001), increasing years of heavy alcohol drinking (15 years of 14 drinks per week; Ptrend = .03), and increasing number of lost teeth (Ptrend = .001). Compared with subjects who neither smoked tobacco nor drank alcohol, those with heavy use of tobacco (20 pack-years) and alcohol had an increased risk of HPV-16–negative HNSCC (OR = 4.8, 95% confidence interval [CI] = 1.8 to 12) but not of HPV-16–positive HNSCC (OR = 0.67, 95% CI = 0.29 to 1.9).

Conclusions: HPV-16–positive HNSCCs and HPV-16–negative HNSCCs have different risk factor profiles, indicating that they should be considered to be distinct cancers.

CONTEXT AND CAVEATS

Prior knowledge
High-risk types of human papillomavirus (HPV), including HPV-16, cause a subgroup of head and neck squamous cell carcinomas (HNSCCs), but it is unclear whether the risk factors for HPV-16–positive HNSCCs are similar to those for HPV-16–negative HNSCCs.

Study design
A hospital-based case–control study of HNSCC to compare the risk factor profiles for HPV-16–positive and HPV-16–negative HNSCCs.

Contribution
HPV-16–positive HNSCC was independently associated with several measures of sexual behavior and exposure to marijuana but not with cumulative measures of tobacco smoking, alcohol drinking, or poor oral hygiene. HPV-16–negative HNSCC was associated with measures of tobacco smoking, alcohol drinking, and poor oral hygiene but not with any measures of sexual behavior or marijuana use.

Implications
HNSCCs are a heterogeneous group of malignancies with at least two etiologically distinct pathways for HNSCC pathogenesis, one mediated by tobacco and alcohol and the other by HPV.

Limitations
The use of HPV-16 in situ hybridization alone to stratify cases as HPV-positive or HPV-negative may have misclassified tumor HPV status. The control population may not adequately represent the true prevalence of exposures of interest in the general population. Differential recall bias among case subjects, residual confounding by sexual behavior, or possible confounding by use of other substances could have influenced observed associations between marijuana use and HPV-16–positive HNSCC.

Authors: Maura L. Gillison, Gypsyamber D’Souza, William Westra, Elizabeth Sugar, Weihong Xiao, Shahnaz Begum, Raphael Viscidi
Affiliations of authors: Divisions of Viral Oncology (MLG, WX) and Biometry and Oncology Biostatistics (ES), The Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore, MD; Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (GDS); Departments of Pathology (WW, SB) and Pediatrics (RV), Johns Hopkins Hospital, Baltimore, MD

Correspondence to: Maura L. Gillison, MD, PhD, Johns Hopkins Medical Institutions, CRB I Rm 3M 54A, 1650 Orleans St, Baltimore, MD 21231 (e-mail: [email protected]).