Cigarette smoking and the colorectal adenoma-carcinoma sequence: a hypothesis to explain the paradox

As recognized precursor lesions to colorectal cancer, colorectal adenomatous polyps have been studied to enhance knowledge of colorectal cancer etiology. Although most of the known risk factors for colorectal cancer are also associated with the occurrence of colorectal adenomas, cigarette smoking has had a strong, consistent relationship with colorectal adenomas but is generally not associated with colorectal cancer. The explanation for this paradox is unknown. With data collected in 1986-1988 during a large case-control study based on colonoscopy results in New York City, New York, the authors investigated the possibility that the paradox may arise because subjects with colorectal adenomas were included in the control group of cancer case-control studies. The authors found a statistically significant increased risk between heavy cigarette smoking (smokers with > or = 40 pack-years of smoking) and risk of adenoma (odds ratio (OR) = 1.61, 95% confidence interval (CI) 1.06-2.44). They saw no increased colorectal cancer risk from heavy cigarette smoking (OR = 1.02, 95% CI 0.52-1.99) using a "manufactured" control group to simulate a typical unscreened, population-based control group. When the authors compared these colorectal cancer cases with an adenoma-free control group examined by colonoscopy in a polytomous model with several case groups (newly diagnosed adenomas, carcinoma in situ, intramucosal carcinoma, and colorectal cancer), they found that the risk for 20-39 pack-years of smoking was elevated, although not statistically significant, and was similar for all four case groups. The risk for the highest smoking category (> or = 40 pack-years) was more strongly elevated in all four case groups, although it was statistically significant for only the newly diagnosed adenoma and the carcinoma in situ cases (adenomas, OR = 1.59, 95% CI 1.05-2.42; carcinoma in situ, OR = 2.05, 95% CI 1.01-4.15; intramucosal carcinoma, OR = 1.30, 95% CI 0.61-2.77; and colorectal cancer, OR = 1.30, 95% CI 0.64-2.65). While the authors' study is weakened by the lack of statistical significance concerning risk for colorectal cancer, these data offer some support for the hypothesis that the association between cigarette smoking and risk of colorectal cancer may have been masked by inclusion in the control group of subjects with adenomas. They also suggest that the major effect of smoking on the colorectal adenoma-carcinoma sequence occurs in the earlier stages of the formation of adenoma and the development of carcinoma in situ.