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Journal of Clinical Oncology, Vol 24, No 28 (October 1), 2006: pp. 4526-4527 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.3841
Changing Face of Small-Cell Lung Cancer: Real and ArtifactThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
Cancer Institute of New Jersey, New Brunswick, NJ Azzopardi first recognized small-cell lung cancer (SCLC) as a pathologically distinct entity nearly five decades ago,1 and the clinical community recognized it as a distinct clinical entity more that three decades ago.2 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 inter- and 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.3 Yet, today, as we see in the clinic, and as reported by Govindan et al4 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 al4 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.4 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.5 We agree, in large part, with the conclusions of Govindan et al.4 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.6 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.7 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.8 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.9 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,10 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 history of SCLC classification, and question whether everything new is necessarily better in the clinic. In 1967, the WHO published a lung cancer classification which included four subtypes of SCLC: fusiform, polygonal, lymphocyte-like (oat celled) and other (squamous cell nests, tubules, or giant cells).11 Ten years later, under the chairmanship of Raymond Yesner, MD, and with the participation of other pulmonary pathologists, such as Mary Matthews, the WHO revised the classification and published their revisions in 1981 (WHO-II).12 SCLC subtypes included oat-cell replacing lymphocyte-like, intermediate, and combined oat-cell carcinoma. In particular, the WHO-II classification recognized combined small cell/large cell and labeled it as 22/40 in that system. This tumor contains some large cells with prominent nucleoli and poor nuclear cytoplasmic molding. In 1984, the pathology panel of the International Association for the Study of Lung Cancer proposed a slight variation of the WHO-II subclassification consisting of pure small cell, mixed (small cell and large cell; ie, 22/40) and combined (small cell and squamous cell or adenocarcinoma).13 Furthermore, the 22/40 subtype was aligned with the variant cell line, which grew in culture both as attached layer and free floating in the serum free media, and represented a poorer prognosis subtype. This subtype was labeled variant morphology small cell. An Eastern Cooperative Oncology Group trial carefully evaluated the incidence and outcome of the 22/40 (variant) subtype in extensive stage disease,14 and showed that, while the incidence of 22/40 subtype was fairly low, those patients with the 22/40 subtype fared at least as well as those patients with the classic subtype. This finding argues strongly that these patients should be included in SCLC classification and treatment. However, such mixed subtypes, which include large-cell tumors, may sometimes be difficult to distinguish from poorly differentiated NSCLC. In 1994, the WHO and International Association for the Study of Lung Cancer pathology committees worked together to develop a new revised classification of lung and pleural tumors. The classification was published in 1999.15 In this classification, large-cell neuroendocrine carcinoma is now included as a variant of large-cell carcinoma. This classification defines this subtype as a high grade NSCLC showing histopathologic features of neuroendocrine differentiation. These tumors show positive immunohistochemical staining for neuroendocrine markers and this new classification sets up the stage for the possibility of a travesty of misclassification. Unfortunately, the diagnosis of SCLC is usually made from fine-needle aspiration specimens. Because of the small amount of tissue, distinguishing between SCLC and NSCLC may be difficult.16,17 Neuroendocrine markers are used to help in the diagnosis of SCLC. Unfortunately, these markers (neuron-specific enolase, chromogranin A, symptophysin dense core granules, and neural cell adhesion molecules) are not specific for lung tumors.18 While helpful, these markers might not be able to distinguish between SCLC and NSCLC with neuroendocrine features. This distinction is important because treatment and prognosis are different between the two subtypes of lung cancer. Furthermore, both of us have seen patients whose SCLC disease was initially misclassified as large cell or NSCLC with neuroendocrine features and who were treated with NSCLC chemotherapy regimens. These patients were also likely captured in the SEER database as NSCLC. We believe that there are multiple causes for the decrease in the overall incidence of SCLC. One is clearly based on changes in smoking habits, changes in cigarettes, such as additives or filters, as well as possible environmental and occupational factors. Another, perhaps less well-recognized cause, relates to how pathologists may distinguish between SCLC and NSCLC. This can certainly confuse the incidence data. We further wonder whether the use of the neuroendocrine carcinoma nomenclature is helpful if some patients' disease might be interpreted as NSCLC rather than SCLC, thus impacting on treatment and prognosis. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. Azzopardi JG: Oat-cell carcinoma of the bronchus. J Pathol Bacteriol 78:513-519, 1959[CrossRef][Medline] 2. Cohen MH, Matthews MJ: Small cell bronchogenic carcinoma: A distinct clinicopathologic entity. Semin Oncol 5:234-243, 1978[Medline] 3. Boring CC, Squires TS, Tong T: Cancer statistics, 1993. CA Cancer J Clin 43:7-26, 1993[Medline] 4. Govindan R, Page N, Morgensztern D, et al: Changing epidemiology of small cell lung cancer in the United States over the past three decades: Analysis of the Surveillance, Epidemiologic and End Results Database. J Clin Oncol 24:4539-4544, 2006 5. Brooks DR, Austin JH, Heelan RT, et al: Influence of type of cigarette on peripheral versus central lung cancer. Cancer Epidemiol Biomarkers Prev 14:576-581, 2005 6. International Agency for Research on Cancer Tobacco: A Major International Health Hazard. Lyon, France, International Agency for Research on Cancer, 1986 7. Ingebrethsen B: Aerosol studies of cigarette smoke. Rec Adv Tob Sci 12:54-142, 1986 8. Benhamou S, Benhamou E, Auquier A, et al: Differential effects of tar content, type of tobacco and use of a filter on lung cancer risk in male cigarette smokers. Int J Epidemiol 23:437-443, 1994 9. Augustine A, Harris RE, Wynder EL: Compensation as a risk factor for lung cancer in smokers who switch from nonfilter to filter cigarettes. Am J Public Health 79:188-191, 1989 10. Zang EA, Wynder EL: Differences in lung cancer risk between men and women: Examination of the evidence. J Natl Cancer Inst 88:183-192, 1996[Medline] 11. Kreyberg L, Liebow AA, Uehlinger EA: International Histological Classification of Tumours: No. 1. Histological Typing of Lung Tumours (ed 1). Geneva, World Health Organization, 1967 12. Kreyberg L, Liebow AA, Uehlinger EA: International Histological Classification of Tumours: No. 1. Histological Typing of Lung Tumours (ed 2). Geneva, World Health Organization, 1981 13. Hirsch FR, Matthews MJ, Aisner S, et al: Histopathologic classification of small cell lung cancer: Changing concepts and terminology. Cancer 62:973-977, 1988[CrossRef][Medline] 14. Aisner SC, Finkelstein DM, Ettinger DS, et al: The clinical significance of variant-morphology small-cell carcinoma of the lung. J Clin Oncol 8:402-408, 1990[Abstract] 15. Travis WD, Colby TV, Corrin B, et al: World Health Organization International Histological Classification of Tumours: Histological Typing of Lung and Pleural Tumours (ed 3). Berlin, Springer Verlag, 1999 16. Nicholson SA, Beasley MB, Brambilla E, et al: Small cell lung carcinoma (SCLC): A clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol 26:1184-1197, 2002[CrossRef][Medline] 17. Renshaw AA, Voytek TM, Haja J, et al: Distinguishing small cell carcinoma from non-small cell carcinoma of the lung: Correlating cytologic features and performance in the College of American Pathologists Non-Gynecologic Cytology program. Arch Pathol Lab Med 129:619-623, 2005[Medline] 18. Yesner R: Heterogeneity of so-called neuroendocrine lung tumors. Exp Mol Pathol 70:179-182, 2001[CrossRef][Medline] Related Article
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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