Smoking

Cigarette smoking is the single most important risk factor for the development of carcinoma of the lung. As might be expected, the duration of smoking history, number of cigarettes smoked each day, depth of inhalation, and amount of each cigarette smoked all correlate with the risk for developing lung cancer. As a rough but easy way to quantify prior cigarette exposure, the number of years of smoking can be multiplied by the average number of packs smoked per day, giving the number of “pack years.”

Although the evidence linking smoking with lung cancer is incontrovertible, the responsible component of cigarette smoke has not been identified with certainty. Cigarette smoke consists of a gaseous phase and a particulate phase, and potential carcinogens have been found in both phases, ranging from nitrosamines to benzo[a]-pyrene and other polycyclic hydrocarbons. Filters appear to decrease but certainly do not eliminate the potential carcinogenic effects of cigarettes. A substantially lower risk for lung cancer is associated with cigar and pipe smoking, presumably related to the fact that cigar and pipe smoke is generally not inhaled deeply into the lungs in the same manner as cigarette smoke. Marijuana and cocaine smoking are also associated with the precancerous histologic changes observed among cigarette smokers, and both are believed to be risk factors for lung cancer.

Development of lung cancer due to smoking requires many years of exposure. However, histologic abnormalities before the development of a frank carcinoma are well documented in the bronchial epithelium of smokers with lesser degrees of exposure. These changes, including loss of bronchial cilia, hyperplasia of bronchial epithelial cells, and nuclear abnormalities, may be the pathologic forerunners of a true carcinoma. If a person stops smoking, many of these precancerous changes appear to be reversible. Epidemiologic studies have suggested that the risk for developing lung cancer decreases progressively after cessation of smoking but probably never fully returns to the level in nonsmokers, even after more than 10 to 15 years. In many cases, the initial cellular changes leading to or predisposing to malignant transformation have already developed by the time the patient stops smoking, and it is merely a matter of time before the carcinoma develops or becomes clinically apparent.

Data indicate that the risk of lung cancer is increased for nonsmoking spouses because of their exposure to sidestream or “secondhand” smoke. Although the risk attributable to “passive smoking” is relatively small compared with the risk of active smoking, involuntary exposure to cigarette smoke is likely responsible for some cases of lung cancer occurring in nonsmokers. The comparably small but real risk of lung cancer from passive smoking has been a major justification for legislation prohibiting smoking in shared spaces such as commercial aircraft, restaurants, and offices.

Occupational Factors

A number of potential environmental risk factors have been identified, most of which occur with occupational exposure. Perhaps the most widely studied of the environmental or occupationally related carcinogens is asbestos, a fibrous silicate formerly in wide use because of its properties of fire resistance and thermal insulation. Shipbuilders, construction workers, and those who worked with insulation and brake linings are among those who may have been exposed to asbestos.

Carcinoma of the lung is the most likely malignancy to result from occupational asbestos exposure, although other tumors, especially mesothelioma (see Chapter 21), are also strongly associated with prior asbestos contact. (Low-level nonoccupational exposures to asbestos in schools or among residents living near asbestos mines or processing facilities are of much lesser significance.) The risk for development of lung cancer is particularly high among smokers exposed to asbestos, in which case these two risk factors probably have a multiplicative rather than a simple additive effect. Specifically, asbestos alone appears to confer a twofold to fivefold increased risk for lung cancer, whereas smoking alone is associated with an approximately 10-fold increased risk. Together, the two risk factors make the person who smokes and has an asbestos exposure 20 to 50 times more likely to have carcinoma of the lung than a nonsmoking, nonexposed counterpart. Like other forms of asbestos-related disease, a long time elapses before complications develop. In the case of lung cancer, the tumor generally becomes apparent more than 2 decades after exposure.

A number of other types of occupational exposure have been implicated. Examples include exposure to arsenic (in workers making pesticides, glass, pigments, and paints), ionizing radiation (especially in uranium miners), halo ethers (bis[chloromethyl] ether and chloromethyl methyl ether in chemical industry workers), and polycyclic aromatic hydrocarbons (in petroleum, coal tar, and foundry workers). As is the case with asbestos, there is generally a long latent period of at least 2 decades from the time of exposure until presentation of the tumor.

Genetic Factors

Why lung cancer develops in some heavy smokers and not in others is a question of great importance but with no definite answer at present. The assumption is that genetic factors must place some individuals at higher risk for lung cancer after exposure to carcinogens. The finding of an increased risk of lung cancer among first-degree relatives of lung cancer patients—even after confounding factors have been taken into account—supports this hypothesis.

Candidate genetic factors have primarily included specific enzymes of the cytochrome P450 system. These enzymes may have a role in metabolizing products of cigarette smoke to potent carcinogens, and genetically determined increased activity or expression of the enzymes may be associated with a greater risk of developing lung cancer following exposure to cigarette smoke. One example is the enzyme aryl hydrocarbon hydroxylase, which can convert hydrocarbons to carcinogenic metabolites. This enzyme is induced by smoking, and genetically determined inducibility of this enzyme by smoking may correlate with the risk for lung cancer. Another enzyme of the cytochrome P450 system can be identified by its ability to metabolize the antihypertensive drug debrisoquine. Some data suggest an association between extensive metabolism of debrisoquine and development of lung cancer. Presumably, the action of this enzyme on a potentially carcinogenic substrate from cigarette smoke affects an individual’s risk for developing lung cancer. However, the available data for both of these cytochrome P450 enzymes are inconsistent, and a role for these enzymes is not universally accepted.