Epidemiology of Lung Cancer

A J Alberg and J M Samet, Johns Hopkins

Bloomberg School of Public Health, Baltimore, MD,

© 2005 Elsevier Ltd. All rights reserved.

At the start of the twentieth century, lung cancer was a rare disease, whereas by its end it had become a leading cause of death and the most common cause of cancer death in the United States. The occurrence of most cases can be explained by environmental agents; cigarette smoking was identified as its predominant cause in the 1950s. With the role of smoking well established, research on lung cancer has focused on environmental and genetic factors that may determine lung cancer risk in smokers. Genetic factors have been the subject of increased scrutiny because the risk of cancer may be determined in part by interindividual variation in the metabolism and detoxification of environmental agents, such as cigarette smoke, as well as variation in susceptibility to DNA damage and in DNA repair capability.

The role of diet as an environmental factor that may determine lung cancer risk in smokers remains a topic of considerable interest. Studies on diet and lung cancer in humans began in the 1970s as part of a broader search for factors determining susceptibility to the carcinogenic effects of tobacco smoke. Early animal studies showed that vitamin A depletion caused loss of differentiation of the respiratory epithelium, a histopathological state analogous to the dysplasia found in cigarette smokers at risk for lung cancer. In animal studies, these changes reverted with nutrient repletion, raising the prospect that dietary interventions could reduce lung cancer risk in cigarette smokers. Early epidemiological studies indicated that indices of vitamin A consumption were associated, in the expected protective direction, with lung cancer risk. An influential 1981 publication by Buckley and colleagues shifted emphasis to /3-carotene rather than retinol, and by the early 1980s clinical trials of ^-carotene as a chemopreven-tive agent had been initiated. Observational evidence continued to show that measures of vitamin A and carotene intake were inversely associated with lung cancer risk; the weight of evidence favored fruits and vegetables as the carriers of the chemopreven-tive agents. In the mid-1990s, the hypothesis that ^-carotene and retinol were protective was disproved in large clinical trials that unexpectedly showed increased risk in smokers randomized to the active agents. Hypotheses concerning specific carotenoids and other dietary components have since been advanced along with more general theories involving dietary antioxidants and oxidant stress from smoking and other factors.

Lung Cancer Respiratory Carcinogenesis

The term 'lung cancer' refers to a histologically and clinically diverse group of malignancies arising in the respiratory tract, primarily but not exclusively from cells lining the airways of the lung. Beginning with the trachea, the airways branch dichotomously through 20 or more generations. Most cancers arise in the larger airways of the lung, typically at the fourth through the eighth generations. There, the airways are lined by a ciliated epithelium that includes secretory cells and glands and also neuroepithelial cells. The specific cells of origin of lung cancer are unknown; candidates include the secretory cells, plur-ipotential basal cells, and neuroepithelial cells. Only a small proportion of lung cancers in smokers have been considered as originating in the lung's periphery, but with the current trend of increasing adenocarci-noma this proportion may be increasing.

Lung cancer is thought to arise from a sequence of genetic changes that move a cell from a normal to a malignant state. Diverse genetic changes in onco-genes and tumor suppressor genes have been found in lung cancers, although the specific longitudinal sequence of these changes has not been characterized. Nonetheless, our evolving understanding of respiratory carcinogenesis, as a sequential progression from normal cell to clinical cancer, implies that there may be multiple points for interrupting the sequence and thereby preventing cancer.

Risk Factors for Lung Cancer

The increase in the incidence of lung cancer during the first half of the twentieth century prompted intensive epidemiological investigation of the disease, with the identification of a number of causal agents. Cigarette smoking is by far the most prominent cause of lung cancer, and the worldwide epidemic of lung cancer is largely attributable to smoking. However, occupational exposures have placed a number of worker groups at high risk and there is evidence that indoor and outdoor air pollution also increases lung cancer risk generally. The observed familial aggregation of lung cancer suggests that genetic factors may also determine risk. Extensive research is in progress on the specific genes that may determine risk in smokers; experience to date has supplied some leads but the evidence has been mixed for most of the genes studied.

In smokers, the risk of lung cancer depends largely on the duration of smoking and the amount smoked; risk increases exponentially with both, but more steeply with duration than amount. A safe level of smoking has not been shown, and even the secondhand tobacco smoke involuntarily inhaled by non-smokers increases lung cancer risk. Fortunately, lung cancer risk declines in those who stop smoking, although not to the level of those who have never smoked; risk is present even after 30 years of abstention and currently in the United States approximately half the lung cancer cases occur in former smokers.

A number of occupational exposures increase lung cancer risk; the substances involved include radon (found in underground mines), arsenic, asbestos, chromium, chloromethyl ethers, nickel, and polycyc-lic aromatic hydrocarbons. For these agents, risk increases with the level of exposure, and synergism with smoking has been shown for several, such as asbestos and radon. Many other agents are suspected occupational carcinogens.

Indoor and outdoor air also contains respiratory carcinogens. Combustion sources contaminate outdoor air with polycyclic aromatic hydrocarbons and radionuclides, and outdoor air pollution is thought to contribute to a few percent of lung cancers in general. Carcinogens in indoor air vary with the setting but may include radon, tobacco smoke, smoke from wood or coal burning, and cooking fumes. In the United States, radon is estimated to cause approximately 14 000 lung cancer deaths annually.

Lung Cancer Histopathology

As assessed by the clinical approach of light microscopy, primary cancer of the lung occurs as multiple histological types, the most common being squa-mous cell carcinoma (epidermoid carcinoma), ade-nocarcinoma, large cell carcinoma, and small cell carcinoma. The other malignancies include adeno-squamous carcinomas, carcinoid tumors, and bronchial gland carcinomas. The pathogenetic bases of the four principal histological types are uncertain, and various cells of origin and pathways of differentiation have been hypothesized. In addition, a careful examination of multiple sections from the same case shows tumors to be frequently heterogeneous, with elements of several histological types. Observer variation in classifying histological types of lung cancer is well documented and should be considered when interpreting research findings on a histological basis.

Few links have been made between specific histolog-ical types and particular etiological agents. Cigarette smoking increases risk for squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and small cell carcinoma, although the risks tend to increase less steeply with extent of smoking for adenocarcinoma, the most common type in never-smokers. Most occupational carcinomas are not associated with risk for a particular histological type of lung cancer. The evidence for specific links is strongest for chloromethyl ether and radon progeny. Some studies of diet and lung cancer risk have provided analyses stratified by histo-logical type, but these histology-specific analyses provide no specific biological insights.

Although knowledge of the etiological and pathological bases of the different types of lung cancer remains limited, trends of lung cancer histology have been monitored in the general population. A trend of increasing proportion of adenocarcinoma has been documented in many regions throughout the world. For example, in the United States during the past three decades adenocarcinoma remained the most common type of lung cancer in women and increased in men so that it is now also the most common histo-logic type of lung cancer in men. The hypothesis has been advanced that this shift reflects temporal changes in the carcinogens delivered by smoking as well as a changing topography of smoking.

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