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Non-Small-Cell Lung Cancer

Non-Small-Cell Lung Cancer


Lung cancer has been the leading cause of cancer death among men in the United States for years and since 1988, it has become the number-one cause of cancer death among women. An estimated 224,390 new cases of lung cancer and 158,080 deaths due to this disease will occur in 2016, representing roughly 27% of all cancer deaths. This exceeds the combined number of deaths from cancer of the next leading sites (breast, prostate, and colon). Lung cancer accounts for 6% of all deaths in the United States.

Lung cancer develops from pulmonary parenchymal or bronchial supportive tissues. Although multiple cell types are often found within a single lung tumor, one type usually predominates. Based on the therapeutic approach, there are two major subdivisions of lung cancer: small-cell lung cancer (SCLC) and non–small-cell lung cancer (NSCLC). Non–small-cell tumors account for approximately 85% of all lung cancers. The three major tumor types included under this category are adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma.

This chapter provides basic information on the epidemiology, etiology, screening, prevention, and signs and symptoms of lung cancer in general and then focuses specifically on the diagnosis, staging, pathology, and treatment of NSCLC, as well as on the pulmonary evaluation of lung cancer patients and follow-up of long-term survivors.

A separate chapter provides information on the staging, pathology and pathophysiology, and treatment of the far less common SCLC and concludes with brief discussions of mesothelioma and thymoma.



In the United States, the estimated number of new lung cancer cases for 2016 is 117,920 for men and 106,470 for women. Although the incidence of lung cancer had been rising in women, the figures have stabilized and begun to decline recently. The incidence is decreasing in men.


The age of patients at which lung cancer is diagnosed varies widely, but the median age at diagnosis is approximately 70 years. The likelihood of lung cancer in patients younger than 40 years of age is low, with less than 1% of all lung cancers occurring in patients under age 40.


In the United States, the highest incidence of lung cancer in men and women is found in African Americans (93.4/100,000 for men and 51.4/100,000 for women), followed by Caucasians (79.3/100,000 for men and 58.7/100,000 for women).


There are geographic variations in the incidence of lung cancer, with the highest rates worldwide observed in North America and Eastern Europe; in the United States, the highest rates are found in northern urban areas and along the southern coast from Texas to Florida. The state with the highest incidence of lung cancer is Kentucky, with an incidence of 120.4/100,000 in men and 80.7/100,000 in women.


The overall 5-year survival rate for lung cancer is 17%; this has improved from a rate of approximately 12% in the 1970s.

Etiology and Risk Factors

Cigarette Smoking

Approximately 87% of all cases of lung cancer in the United States are related to cigarette smoking. Tobacco smoke contains more than 40 known carcinogens. There is a relatively strong dose-response relationship between cigarette smoking and the development of this cancer. The greater the number of cigarettes smoked on a daily basis and the greater the number of years of smoking, the greater is the risk of lung cancer. An individual who smokes one pack of cigarettes daily has a 20-fold increased risk of lung cancer compared with a nonsmoker.

The overall incidence of cigarette smoking decreased from 1974 through 1992. Smoking cessation decreases the risk of lung cancer, but a significant decrease in risk does not occur until approximately 5 years after discontinuation, and the risk remains higher in former smokers than in nonsmokers for at least 25 years. The benefit of smoking cessation is greater if it occurs at a younger age.

Smoking cessation is difficult. Recent data have suggested that a variety of hereditary factors increase the risk of addiction to nicotine among some individuals. Nevertheless, millions of former smokers have quit successfully. Smoking cessation programs that address both physical withdrawal from nicotine and psychological dependence appear to be more effective than either of these approaches alone. In addition, continued efforts are needed to prevent adolescents and preadolescents from beginning to smoke and to encourage them to quit after a brief period of experimentation.

Several cancer centers have recently reported that more than half of their patients with newly diagnosed lung cancer are former smokers, having quit more than 1 year before diagnosis. Healthy ex-smokers represent a large group of individuals who may benefit from effective tools for early detection and/or chemoprevention of lung cancer.

Secondhand Smoke

Not only is smoking risky for those who smoke, it also poses a hazard to nonsmokers who either live or work with smokers. It is estimated that approximately 3,000 lung cancer deaths per year in the United States are due to secondhand smoke. Individuals who live in a household with a smoker have a 30% increase in the incidence of lung cancer compared with nonsmokers who do not live in such an environment.

Asbestos Exposure

Exposure to asbestos is another risk factor for lung cancer. Cigarette smokers who are exposed to asbestos develop lung cancer at an extremely high rate. There is a 90-fold increase compared with unexposed individuals. Exposure to asbestos is also a major risk factor for the development of mesothelioma (see discussion of this cancer in the chapter on small cell lung cancer).

Radioactive Dust and Radon Exposure

Uranium miners who have been exposed to radioactive dust and radon gas also have an increased incidence of lung cancer. Although there has been some controversy about the risk posed by exposure to residential radon gas, a study conducted in Sweden showed an increased incidence of lung cancer in individuals who were exposed to a high level of radon in their homes. Ten percent of lung cancer cases appear to be associated with radon exposure.


Human papilloma virus (HPV) has been implicated as a cause of NSCLC; nearly 25% of cases in nonsmokers may be associated with the virus. Recurrent respiratory papillomatosis (RRP) is a disease typically found in young patients with laryngo-tracheobronchial HPV polyps. RRP may cause cough and obstruction, and may eventually degenerate into malignancy. HPV 16/18 infection is associated with the p53 mutation. Human immunodeficiency virus (HIV) infection increases the risk of lung cancer by 2- to 11-fold. It is the most common non–AIDS-associated cause of death, accounting for 16% of deaths. Treatment with antiretrovirals has not changed the risk or virulence of lung cancer. Stage-for-stage, NSCLC is far worse for the HIV patient than for patients without AIDS.


Family history has been considered a risk factor, and often a smoking-related history is uncovered. More recently, inheritable mutations have been discovered. One in particular is T790M, a germline mutation of EGFR gene that is associated with adenocarcinoma.

Air Pollution

Particulate matter in air pollution has been shown to increase the risk of lung cancer, especially adenocarcinoma. The risk is associated with the size and volume of the particulate matter. Outdoor pollution may account for 1% to 2% of lung cancer cases.

Chronic Lung Inflammation and General States of Inflammation

Lung cancer has been associated with idiopathic pulmonary fibrosis and many other inflammatory lung diseases; chronic obstructive pulmonary diseases; tuberculosis; and systemic states of inflammation such as rheumatoid arthritis, Crohn’s disease, and other chronic inflammatory conditions.


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