20: Lung cancer: Etiologic and pathologic aspects
OUTLINE
Etiology and Pathogenesis, 243
Smoking, 243
Occupational Factors, 244
Genetic Factors, 244
Parenchymal Scarring, 244
Miscellaneous Factors, 245
Concepts of Lung Cancer Pathogenesis, 245
Pathology, 246
Squamous Cell Carcinoma, 246
Adenocarcinoma, 247
Large-Cell Carcinoma, 248
Small-Cell Carcinoma, 248
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. More than 70 years ago, the primary cause of carcinoma of the lung—cigarette smoking—was conclusively identified. Fortunately, the global prevalence of smoking has been falling, albeit gradually, after peaking in the mid-1970s. The World Health Organization (WHO) reports that the number of smokers in the world decreased from 1.397 billion in 2000 to 1.337 billion in 2018. This decline has been driven largely by a reduction in the number of female smokers, but the number of male smokers appears to have reached a plateau and is also starting to decline. In the United States, the percentage of adults who smoke has decreased from 42% in 1965 to 21% in 2005 and 14% in 2019.
Lung cancer has been one of the most common cancers worldwide for several decades. In 2020, there were an estimated 2,200,000 new cases of lung cancer globally. Lung cancer is also the most common cause of cancer-related death worldwide, with an estimated 1,800,000 deaths (18% of all cancer deaths) in 2020. For 2022, the American Cancer Society estimates that 236,740 new cases of lung cancer will be
diagnosed in the United States, and approximately 130,000 individuals will 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 21% of all deaths in the United States attributable to cancer and approximately 5% of all deaths from any cause, killing more people than cancers of breast, prostate, and colon combined.
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; fortunately, it has been decreasing since then. In women, the death rate increased fivefold in the 30 years from 1960 to 1990, and reached a plateau around 2002.
Despite the magnitude of the problem and some innovative new therapies, our ability to treat most carcinomas of the lung has not yet improved dramatically. In the United States, where treatment is available to most patients, 5-year survival has increased from roughly 7% to 22% during the last several decades, making the prognosis of this disease still dismal in the majority of cases. There is some recent cautious optimism as a result of earlier detection by screening of high-risk patients as well as development and use of new tumor genotype-directed therapies and immunotherapies.
This chapter’s discussion of carcinoma of the lung is presented in two parts. First, the etiology and pathogenesis of lung cancer are considered; this is 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 an additional type of neoplastic disease affecting the respiratory system, bronchial carcinoid tumor, along with a consideration of the common problem of the patient with a solitary pulmonary nodule. Malignant mesothelioma, a neoplasm that originates in the pleura, is discussed in Chapter 15, Pleural Disease.
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 (80%–85% according to most 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 components of cigarette smoke have not been identified with certainty. Cigarette smoke consists of a
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gaseous phase and a particulate phase, and at least 69 known carcinogens have been found in both phases, ranging from nitrosamines to benzo[a]pyrene and other polycyclic hydrocarbons. Filters appear to decrease but certainly 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. The smoking of marijuana and cocaine is also associated with the precancerous histologic changes observed among cigarette smokers, and both are believed to be risk factors for lung cancer. The use of e-cigarettes, commonly known as vaping, is still relatively new, and the long-term risk it poses for development of lung cancer is unknown. Although many of the carcinogenic components of cigarette smoke are not found in e-cigarettes, there are still some potential carcinogens in the constituents of the vaping liquid as well as the organic products produced by the e-cigarette device.
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.
In contrast to smoking-related emphysema, which is irreversible, if a person stops smoking many of the precancerous changes begin to regress. Epidemiologic studies have shown that the risk for developing lung cancer begins to decrease within 5 years and continues to decline progressively after cessation of smoking. Case-control studies show that abstinence for more than 15 years reduces the risk of lung cancer in former smokers by 80% to 90%, but unfortunately the risk never fully returns to the level of lifetime nonsmokers. In some 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 for lung cancer 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 15), 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
have a multiplicative rather than a simple additive effect. Specifically, asbestos alone appears to confer a 2- to 5-fold 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 had 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, many years elapse before complications develop. In the case of lung cancer, the tumor generally becomes apparent more than two decades after exposure.
The combined risk factors of asbestos exposure and smoking markedly increase the risk of lung cancer.
Several other occupational exposures have been associated with an increased risk of lung cancer. Examples include exposure to arsenic (in workers making pesticides, glass, pigments, and paints), ionizing radiation (especially in uranium miners), haloethers (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 latent period of at least two 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 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.
In some families with high rates of lung cancer in nonsmokers, germline mutations in the epithelial growth factor receptor (EGFR) have been identified and are postulated to be a risk factor for lung cancer. Other as yet unidentified genetic factors potentially affect susceptibility to environmental carcinogens and may include the activity of tumor suppressor genes. If such factors are eventually recognized, then preventing susceptible individuals from being exposed to the known environmental carcinogens or targeting more aggressive screening techniques toward the populations at greatest risk may be possible.
Parenchymal scarring
Scar tissue within the lung can be a locus for the subsequent occurrence of lung cancer, called a scar carcinoma. The scarring may be either localized (e.g., resulting from an old focus of tuberculosis or another infection) or diffuse (e.g., from pulmonary fibrosis, whether idiopathic or associated with a specific cause). Mechanistically, it is thought that fibrosis and malignancy share some dysregulated pathways of cell proliferation, although the precise relationship is uncertain. Most frequently, scar carcinoma of the lung is a peripherally located adenocarcinoma.
Although it is easy to consider carcinomas occurring within or adjacent to scar tissue to be scar carcinomas, adenocarcinomas of the lung may also develop fibrotic areas within the tumor. Therefore, in
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some cases, it may be impossible to know whether the scar preceded or followed development of the carcinoma.
Miscellaneous factors
Exposure to radon, a gas that is a decay product of radium-226 (itself a decay product of uranium-238), is a clear risk factor for the development of lung cancer. Epidemiologic studies of uranium miners exposed to high levels of radon working in the United States and Europe prior to the 1980s, when the risk was identified, demonstrated an increased incidence of both small-cell and squamous cell carcinoma (see discussion of pathology further on). The risk appears to be mitigated by improved working conditions and ventilation in mines.
Exposure to much lower levels of this known carcinogen may occur indoors in homes built on soil that has a high radium content resulting in release of radon into the surrounding environment. The finding of unacceptably high levels of radon in some home environments has sparked concern about the risk of lung cancer and interest in widespread testing of houses. Household levels of radon never come close to the level experienced by miners, so some uncertainty remains about the overall risk posed by exposure to household radon. However, most authorities agree there is a small but real increased risk of lung cancer associated with elevated home levels. It has been suggested that radon is the second most important factor contributing to lung cancer and is potentially responsible for 20,000 lung cancer deaths per year in the United States.
Some evidence suggests that dietary factors may affect the risk of lung cancer. Several studies have reported an association between low intake and serum levels of β-carotene, the provitamin form of vitamin A, with an increased risk of lung cancer. However, the data relating to this issue are controversial. An increased risk associated with low dietary intake of β-carotene, if it exists, is relatively minor compared with the risk posed by cigarette smoking. Three large randomized trials have failed to demonstrate a protective effect of β-carotene, α-tocopherol, or retinoid supplementation on lung cancer risk. The issue is further complicated by data suggesting an increase in the incidence of lung cancer in some trials of individuals given supplements.
Human immunodeficiency virus (HIV) infection increases the risk of lung cancer; this association has become more important as effective antiretroviral treatment has decreased mortality from infectious causes in this population. Patients who have received radiation therapy to the thorax (e.g., as treatment for breast cancer or Hodgkin lymphoma) are at increased risk for lung cancer. Finally, in developing countries, chronic exposure to wood smoke is believed to be responsible for a sizable fraction of lung cancers, particularly among women.
Concepts of lung cancer pathogenesis
There has been a great deal of interest in identifying the cell or cells of origin (i.e., histogenesis) of the various types of lung cancer and elucidating the genetic changes involved in malignant transformation of these cells. For many years it was assumed that the different histopathologic types of lung cancer (described in the section on pathology, further on) were each associated with a different cell of origin. It was thought that previously well-differentiated normal cells underwent a process of dedifferentiation and unrestricted growth when exposed to a carcinogenic stimulus. However, based in part on the common finding of cellular heterogeneity (i.e., more than one cell type within a single tumor), it is currently believed that many if not all types of lung cancer arise from a relatively undifferentiated precursor or stem cell. During this cell’s malignant transformation, it differentiates along one or more particular pathways that determine its ultimate histologic appearance—that is, its cell type or types.
Alterations in genes that code for proteins controlling or regulating cell growth have been found in a