Cigarettes, sex, and lung adenocarcinoma.

For the past 50 years, the winds of change have been blowing through the epidemiology and demographics of lung cancer. Worldwide changes in the incidences, sex ratios, smoking associations, and pathologic types of lung cancer have been dramatic. Such rapid, extensive, and global changes are unprecedented and have not been observed for any other major form of human cancer. In this issue of the Journal, Thun et al. (1) explore the reasons for one of these changes, the explosive rise in the relative and absolute incidences of lung adenocarcinoma in both sexes. The most common cancer in the world today is lung cancer (2). Although the smoking epidemic has been steadily decreasing in some parts of the world, it continues to spread at an accelerated rate in underdeveloped and developing countries (3– 6). In the United States, lung cancer is the most common cause of cancer deaths in both sexes, and its incidence has been rising for at least 50 years (7). While major geographic differences exist, in all countries the incidence of lung cancer is greater in men than in women (3). However, in Tasmania, for example, the age-standardized lung cancer incidence rates in 25–44-year olds for the 10-year period from 1983 through 1992 were much higher among women than among men (8). This reflects a dismal fact, i.e., although the efficacy of antismoking campaigns is finally beginning to result in lower cancer incidences in some parts of the world, including among white men in this country, increased smoking by young women in many parts of the world (including the United States and Tasmania) has prevented such a decrease in women. Lung cancer consists of four major histologic subtypes. Most centrally located squamous cell and small-cell carcinomas arise from epithelial cells that line the surfaces of the centrally located largeand medium-sized bronchi. In contrast, most adenocarcinomas arise from epithelial cells in the peripherally located bronchioles and alveoli. The large-cell carcinomas probably represent undifferentiated tumors or poorly differentiated examples of the other major types. There are important differences between the molecular changes present in adenocarcinomas and other lung cancers, both in number and in type (9,10), indicating different pathogenetic mechanisms. Although preneoplastic changes in the central airways are well documented for squamous cell carcinoma and are strongly smoking associated (11), preneoplastic changes accompanying adenocarcinomas are rarer and more controversial (12). Of great interest, recent findings (13,14) indicate that clonal genetic alterations of allele loss at sites of known or putative tumor suppressor genes are found in the bronchial epithelium of most current smokers and these alterations persist for many years after smoking cessation. Similar changes have been described in the peripheral airway cells of patients with lung cancer (15). Lung cancer is closely associated with smoking, and tobacco smoke contains many mutagenic and carcinogenic chemicals (16). Results from molecular epidemiology (17) and laboratory (18,19) studies suggest that point mutations in tumor suppressor genes such as TP53 (also known as p53), which are inactivated in all types of lung cancer, and dominant oncogenes such as mutated K-ras genes, which are present in a subset of adenocarcinomas, may be specific both for the type of tumor and for the critical environmental exposure. Thus, the lungs of smokers contain benzo[a]pyrene diol-epoxide-guanine DNA adducts, which are associated with the type of mutations found in the K-ras or p53 genes (G to T transversions). Shifts in histologic type as well as differences in sex and race distribution have accompanied the increased incidence of lung cancers. Several studies (3,4,7,20), including the one in this issue of the Journal (1), indicate that lung cancer incidence increased more rapidly, relative to the other smoking-associated cancers, in women than in men (1). In recent years, lung adenocarcinoma, a rare tumor type at the turn of the century, has replaced squamous cell carcinoma as the most frequent histologic type for all sexes and races combined (7). The adjusted odds ratios for major lung cancer types, especially adenocarcinoma, are consistently higher for women than for men at every level of exposure to cigarette smoke (21). Furthermore, this sex difference cannot be explained by differences in baseline exposure, smoking history, or body size, but it is likely due to the higher susceptibility to tobacco carcinogens in women (21). As discussed by Thun et al. (1), the reasons for the explosive rise in the incidence of adenocarcinoma include diagnostic advances, such as computerized scans and fine-needle aspirations that permit identification of peripherally arising adenocarcinomas, altered criteria and tests for pathologic typing, and changing patterns of cigarette smoking and exposure. Thun et al. (1) examined data from the Connecticut Tumor Registry and two