Changing Face of Small-Cell Lung Cancer: Real and Artifact

Azzopardi first recognized small-cell lung cancer (SCLC) as a pathologically distinct entity nearly five decades ago, and the clinical community recognized it as a distinct clinical entity more that three decades ago. At that time, the incidence of SCLC was usually reported as comprising 20% to 25% of all diagnosed cases of lung cancer. The recognition of SCLC as a distinct clinical entity, and the very high interand intrarater pathology compliance, facilitated the application of chemotherapy as the foundation of therapy and the application of combined modalities in limited stage disease. Nearly two decades later, in 1993, the American Cancer Society estimated that the incidence of SCLC remained stable. Yet, today, as we see in the clinic, and as reported by Govindan et al in this issue of the Journal of Clinical Oncology, there appears to be a decreasing incidence of SCLC. Is it real or apparent? If real, what is the genesis of this decrease? Is it a possible reflection of changes in smoking habits or changes in cigarettes, or is the change of incidence at least partly an artifact due to changes in the pathologic classification of the disease? Govindan et al report on the incidence of SCLC using the Surveillance, Epidemiology and End Results (SEER) database over the past three decades. They report that the incidence of SCLC as a percentage of the number of patients diagnosed with all types of lung cancer decreased from 17.26% in 1986 to 12.95% in 2002. However, among those diagnosed with SCLC, the proportion of women increased from 28% in 1973 to 50% in 2002. The authors postulate that possible explanations for the decreasing incidences of SCLC overall include a decrease in smoking prevalence (especially in white men), and a change to low-tar filter cigarettes. Similar postulates, including the introduction of filters, have previously been offered as a rationale for the decreasing incidence of central squamous carcinoma of the lung in the US compared with countries in Europe and other countries. We agree, in large part, with the conclusions of Govindan et al. There is a definite relationship between cigarette smoking and the development of SCLC. In clinical practice, one rarely sees a patient with SCLC who never smoked cigarettes. Indeed, most SCLC patients have been very heavy smokers. Why does heavy smoking lead to SCLC? While the answer to that question is not completely known, tobacco smoke is known to contain more than 40 recognized carcinogens. Among others, these include polycyclic aromatic hydrocarbons, N-nitrosamines, and aromatic amines, as well as other organic (for example, benzene) and inorganic compounds. Tobacco smoke is separated into two categories: particulate (tar) and gaseous. The various particle sizes of the smoke deposit in the airways and alveoli of the lung where they can exert their carcinogenic effects. The susceptibility to these carcinogens may also be highly dependent on the polymorphisms of the individual’s metabolizing enzymes. The dose of carcinogens delivered to a smoker’s lung is therefore dependent on the individual’s smoking habits as well as the composition of the cigarette. While high tar cigarettes are associated with an increased risk for the development of lung cancer, filtered cigarettes reduce exposure to tars and should hypothetically reduce the risk of lung cancer. The role of nicotine content is, however, controversial, with some accusations of nicotine having been added by the tobacco companies. However, filtered cigarettes not only reduce the tar and nicotine content of each cigarette, but also cool the cigarette so that smokers usually compensate by both increasing the number of cigarettes smoked and by inhaling more deeply. This will ultimately lead to the increased delivery of carcinogens to the periphery of the lung, and a higher incidence of peripheral (adenocarcinoma) lung cancers. This may in part explain the decrease in the incidence of SCLC, which usually occurs centrally in the lung. In contrast, nonfiltered cigarettes deliver a hotter and more irritating smoke, causing more reaction in the more central bronchi and bronchioles and an increase in the more centralized tumors, such as SCLC and squamous carcinomas. However, while the incidence of SCLC appears to have decreased overall, it has increased relatively in women. This may be due to the still increasing prevalence of smoking in women or to the possibility that women are more susceptible to lung cancer than men, but is counterintuitive to the idea of filtered versus nonfilteed cigarettes, because most women smoke filtered cigarettes. Thus, while the falling smoking prevalence by sex and the addition of filter cigarettes may indeed account for some of the reason for the falling incidence of SCLC, it is also likely that other factors are at play. Another possible explanation for the decrease in the incidence of SCLC is a change in the pathologic classification of SCLC, in which some tumors which would have been called SCLC in the past are now identified as non–small-cell lung cancer (NSCLC) with neuroendocrine features. In order to explore this possibility, it would be useful to understand the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 28 OCTOBER 1 2006