Head and neck cancer in nonsmokers: a distinct clinical and molecular entity.

OBJECTIVES/HYPOTHESIS: Clinical and molecular patterns of head and neck squamous cell carcinoma (HNSCC) in nonsmokers and smokers may be different. Analysis of these patterns may improve understanding and management of this disease. STUDY DESIGN: three hundred five subjects were included (46 nonsmokers, 29 former smokers, and 230 smokers). Subsets were analyzed for p53 mutation, human papillomavirus (HPV), and loss of heterozygosity (LOH) at 10 chromosomal loci. METHODS: Clinical information was analyzed for common patterns of disease among the groups. The p53 gene was sequenced, and polymerase chain reaction was used to detect HPV DNA and LOH at two microsatellite markers for each loci. The chi2 test was used to assess differences in genetic alterations between groups, logistic regression to examine the independence of association of tobacco exposure with each alteration, and Kaplan Meier estimates and the log-rank statistic to assess differences in survival. RESULTS: Nonsmokers included a disproportionate number of women, oral cavity (especially tongue) tumors, and very young or old individuals. Smokers had more tumors of the larynx, hypopharynx, and floor of mouth. The rate of p53 mutation was much greater in smokers; the percentage with HPV was marginally lower. The percentage of LOH at 3p, 4q, and 11q13, and the overall average number of chromosomal losses, was significantly lower in nonsmokers' tumors. Survival did not vary with smoking or age. CONCLUSIONS: The clinical and genetic features of HNSCC are distinct between groups defined by tobacco use. Tumors of nonsmokers contain a lower frequency of common genetic alterations, suggesting that the underlying changes in these tumors may remain undiscovered.