RESPONSE: Re: Sex-Related Differences in Bronchial Epithelial Changes Associated With Tobacco Smoking

There is a sex difference in the distribution of histologic subtypes of lung cancer worldwide (1). In the United States and Canada, squamous cell carcinoma accounts for approximately 37% of the lung cancers in men but only 20% of the lung cancers in women. In Europe, a similar sex difference was observed (approximately 47% in men versus 27% in women). We discussed in our previous report that “in women, the major histologic lung cancer cell type found is adenocarcinoma, whereas, until recently, in men the predominant cell type was squamous cell carcinoma… . Most adenocarcinomas arise from epithelial cells in the peripherally located bronchi, bronchioles, and alveoli that are beyond the range of an adult-size fiberoptic bronchoscope” (2). The lower prevalence of preinvasive bronchial lesions in the central airways of women (14% versus 31% in men), most of which are precursors of squamous cell carcinoma, closely reflects reality. In our updated, larger cohort of 721 smokers older than 45 years, a similar, statistically significant sex difference in the prevalence of preinvasive lesions was observed, whether we use our previous definition of preinvasive lesion or the more restrictive definition suggested by Paris et al. (Table 1). With our definition, a lower prevalence in women (odds ratio = 0.7) was also observed by Paris et al. Their results confirm our observations, although the differences that they observed did not reach statistical significance, probably because of their skewed study population and comparatively smaller sample size. Although our previous study included only healthy volunteer smokers, Paris et al. included patients with cured invasive lung cancer, patients with synchronous invasive lung cancer, and smokers who were exposed to occupational carcinogens and who had a statistically significantly higher prevalence of preinvasive lesions. By including women who had or were more prone to develop these lesions, it should not be surprising that different results are observed. Furthermore, the sex difference in the prevalence of preinvasive lesions in the central airways is not equivalent to overall cancer risk differences between men and women. In former smokers, although the cumulative lifetime risk of lung cancer does not continue to increase as it does in current smokers, a substantial risk persists in those who stop smoking after the age of 50 years (3,4). Approximately 50% of the patients with newly diagnosed lung cancer are now former smokers, many of whom had given up smoking for at least 5 years (5). Our previous observation that the prevalence of preinvasive lesions did not change substantially for more than 10 years after cessation of smoking is in keeping with this observed persistent risk. However, our data should not be interpreted as showing an equal risk between former and current smokers. With continual exposure to tobacco smoke carcinogens, the risk of lung cancer is higher for current smokers because more preinvasive lesions will form and the lesions are more likely to progress to invasive cancer. Data from a cross-sectional study such as ours are not at odds with longitudinal studies that show a lower lifetime risk of lung cancer in former smokers. In summary, we believe the relatively modest disagreements between the study by Paris et al. and ours were caused by differences in study populations and the different interpretation by Paris et al. of published reports. Sex differences in the prevalence of preinvasive bronchial lesions

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