Lung Cancer

Etiologic and Pathologic Aspects

Carcinoma of the lung is a public health problem of immense proportions. It has been a source of great frustration to individual physicians and the medical profession in general. Half a century ago, the primary cause of carcinoma of the lung—cigarette smoking—was identified beyond a shadow of a doubt. Fortunately, the prevalence of smoking in developed countries has been falling gradually after peaking in the mid-1970s. Unfortunately, any optimism is tempered by the following concerns: (1) about 20% of all American adults still smoke; (2) although smoking prevalence declined substantially in the years before 1990, it has changed only slowly since then; and (3) tobacco use is continuing to increase in developing countries, where the tobacco industry is focusing its marketing efforts.

A few statistics put the magnitude of the problem of lung cancer into perspective. Worldwide in 2008, there were an estimated 1,600,000 new cases of lung cancer and an estimated 1,380,000 deaths. In the United States, nearly 220,000 new cases of lung cancer are diagnosed annually, and approximately 160,000 individuals each year die as a result of the disease. For many years, carcinoma of the lung has been the leading cause of cancer deaths among men, and in 1985 lung cancer surpassed breast cancer as the leading cause of cancer deaths among women. Lung cancer is responsible for 25% to 30% of all deaths attributable to cancer and approximately 5% of all deaths from any cause, killing more people than cancers of breast, prostate, colon, liver, kidney, and melanoma combined. It is sobering to realize that during the last 5 years, more Americans died from lung cancer than were killed in all of the wars in U.S. history.

The number of cases and the number of deaths related to lung cancer have increased dramatically over the last several decades. For no other form of cancer has the increase approached that of lung cancer. For men, the death rate appears to have reached a peak in 1990 and fortunately has been decreasing since then. In women the death rate increased fivefold in the 30 years from 1960 to 1990 but more recently appears to be reaching a plateau. Despite the magnitude of the problem, our ability to treat carcinoma of the lung has improved only minimally. Five-year survival has increased from roughly 7% to 14% during the last several decades, making the prognosis of this disease still dismal in the vast majority of cases.

The discussion of carcinoma of the lung is presented in two parts. This chapter considers what is known about the etiology and pathogenesis of lung cancer, followed by a description of the pathologic aspects and classification of the different types of tumors. Chapter 21 continues with a discussion of the clinical aspects of the disease, including diagnostic and therapeutic considerations. Chapter 21 concludes with a brief discussion of two additional types of neoplastic disease affecting the respiratory system, bronchial carcinoid tumor (bronchial adenoma) and mesothelioma, along with a consideration of the common problem of the patient with a solitary pulmonary nodule.

Etiology and Pathogenesis

For no other common cancer affecting humans have the causative factors been identified as well as for lung cancer. Cigarette smoking clearly is responsible for the vast majority of cases (>85%, according to some estimates), and additional risk factors associated with occupational exposure have been identified. This chapter begins with a discussion of the two major risk factors—cigarette smoking and occupational exposure—and considers genetic factors as a potential contributor to lung cancer risk. Next is a brief description of the importance of previous scarring within the pulmonary parenchyma, which has been implicated in the development of “scar carcinomas,” and several miscellaneous proposed risk factors are mentioned. Finally, the role of oncogenes and tumor suppressor genes in the pathogenesis of lung cancer is discussed.

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.

Smoking-induced histopathologic abnormalities in bronchial epithelium precede the development of carcinoma.

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.

The combined risk factors of asbestos exposure and smoking markedly increase the risk of lung cancer.

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.