Overview and Risk Factors

Lung cancer is the most common cause of cancer death for men and women worldwide. It is the most frequently occurring cancer in men and the third most frequent in women. Lung cancer usually develops within the epithelium of the bronchial tree and subsequently invades the pulmonary parenchyma. In advanced stages, it invades surrounding organs and may metastasize throughout the body.

The most common histological types are:

Epidermoid (squamous cell) carcinoma (about 40% of lung cancer cases). This is the most common form, located centrally in the lung. The carcinoma arises from a dysplastic epithelial focus in one of the bronchi, presenting the cytological and nuclear features of atypia. Eventually, it invades the pulmonary parenchyma.

Adenocarcinoma (about 25% of cases). The lesions are peripheral or central, arising from the epithelium of small airways and showing evidence of glandular activity (sometimes producing mucin). Adenocarcinomas have a characteristic growth pattern along the alveolar septa, without destroying the underlying lung architecture.

Small cell (oat cell) carcinoma (about 20% of cases). This form involves the wall of a major bronchus, arising from specialized neuroendocrine cells (K cells) in the lungs, which show extensive mitotic activity and foci of necrosis. The tumor is commonly a central, perihilar mass. Virtually all small cell cancers are attributable to tobacco use.

Large cell (undifferentiated) carcinoma (about 15% of cases). This is a bronchogenic tumor with large pleomorphic cells containing prominent nucleoli. The cells are poorly differentiated and metastasize early.

Risk Factors

Tobacco smoking accounts for approximately 90% of lung cancers. Initially, tobacco smoke irritates the bronchial epithelium and paralyzes the respiratory cilia, depriving the respiratory mucosa of its defense and clearance mechanisms. The carcinogens in tobacco smoke then act on the epithelium, giving rise to atypical cells, which form the first stage of cancer: carcinoma in situ. After metaplastic transformation, the cancer invades bronchial and pulmonary tissues, and subsequently metastasizes hematogenously or via lymphatics. Additional risk factors include:

Passive smoking. Epidemiologic evidence suggests an increased risk of approximately 20% to 25% in nonsmokers regularly exposed to secondhand smoke.¹

Occupation. Regular exposure to manipulated asbestos (1 of 5 deaths is due to lung cancer), chromium and nickel (heavy metals), benzopyrene, acroleine, nitrous monoxide, hydrogen cyanide, formaldehyde, nicotine, radioactive lead, carbon monoxide, insecticides or pesticides containing arsenic, glass fibers, and coal dust increases workers' risk of bronchopulmonary cancer.

Family history. Investigations show a 14-fold higher frequency of lung carcinomas in smokers with a family history of lung cancer.² Risk is also increased in individuals with Li-Fraumeni syndrome, resulting from an inherited mutation in the p53 gene.³

Immunosuppression. The risk of oncogenesis increases with conditions that weaken the immune system (eg, immunosuppressive medications, diseases, or malnutrition).

Air pollution. The mortality rate from lung cancer is 2 to 5 times higher in industrialized areas than in less polluted rural areas.

Inflammation. Chronic and recurrent respiratory diseases act as chronic irritants and play an oncogenic role (eg, tuberculosis, chronic bronchitis, recurrent pneumonias).

Ionizing radiation. Radiation exposure (x-rays, radon gas) increases carcinogenic risk in dose-dependent manner. Lung cancer is 10 times more frequent in uranium miners than in the general population.

Diet and nutrition. See Nutritional Considerations.

Diagnosis

Primary Symptoms

Lung cancer has an insidious onset, and the disease is usually well developed by the time of diagnosis. Clinical signs and symptoms that suggest lung cancer are:

• Generalized weakness and fatigue. 
• Cough. About 93% of lung cancer patients complain of an initial cough, which gradually worsens. Chronic irritation of the bronchial epithelium will cause a persistent cough that can be dry, productive, spastic, and refractory to symptomatic treatment. When the tumor erodes the lung capillaries, the cough is often accompanied by hemoptysis.
• Chest pain, which is often pleuritic. This commonly occurs when the tumor invades the pleural folds or the thoracic wall and ribs, causing pleural effusion.
• Loss of weight and appetite.
• Persistent fever.
• Clubbing of fingers and toes.
• Dyspnea. This is a late symptom, caused by airway obstruction or compression.
• Atelectasis.
• Lymphadenopathy in the axilla, latero-cervically, or supraclavicularly.
• Hoarseness. This symptom is caused by the compression of the laryngeal recurrent nerve in the mediastinum by the tumoral growth.
• Dysphagia. It occurs when the tumor invades or compresses the esophagus.
• Pericardial complications. These are frequent and due to direct invasion and metastatic spread.
• Recurring infections, such as bronchitis and pneumonia, with moderate fever.

Metastatic Symptoms

Signs and symptoms vary according to the organ or site affected.

• Bone pain and limitations of use occur with bony metastases.
• Neurological changes (such as weakness or numbness, dizziness, or recent seizure onset) occur when tumors invade or compress nerves. 
• Jaundice results from metastatic invasion and/or compression of the liver and biliary canals.
• Masses may appear near the surface of the body due to cancer spreading to the skin or to regional lymph nodes.

Laboratory Tests and Clinical Procedures

Chest x-ray can detect lesions up to 2 years before symptoms appear. It defines tumor size and location and can track progression or remission.

Bronchoscopy facilitates diagnosis through tissue biopsy. Bronchoscopic lavage allows for cytologic and histologic analysis, which can detect cancer before radiologic changes.

Computed tomography (CT) accurately reveals tumor location and size.
CT-guided percutaneous fine-needle aspiration of pulmonary nodules allows for cytological examination.

Erythrocyte sedimentation rate (ESR) is usually elevated in malignant disease. It is a nonspecific finding, however, as ESR is also commonly elevated in tuberculosis and other pulmonary infections.

Ultrasound examination allows differentiation of cystic versus solid tumors. It also allows guidance of thoracentesis needle.

Radioactive pulmonary scan, with radioisotopes injected into the bloodstream, is better than x-ray for precise and extended visualization of tumoral lesions.

Bronchography with contrast dyes allows visualization of distal bronchi, stenosis, and infarcts.

Phlebography allows visualization of axillary or subclavicular enlarged lymph nodes. Phlebography through the vena cava and azygos vein reveals mediastinal compression and infiltration.

Pleuracentesis gives the diagnosis in 80% of cases where pleural invasion occurs.

Lymph node biopsy is of great diagnostic value when enlarged lymph nodes are present and accessible.

Mediastinoscopy allows for a biopsy of hilar and mediastinal ganglia and is positive in nearly 40% of all lung cancer cases. It allows direct visualization of possible mediastinal invasions that could contraindicate surgery.

 Treatment

Medical treatment of lung cancer involves combinations of surgery, radiation, and chemotherapy. Treatment is largely palliative, although early detection and treatment of the cancerous process may significantly improve prognosis and prolong survival.

Surgery. The main treatment for squamous cell carcinoma, adenocarcinoma, and large cell cancer is surgery, unless the tumor is unresectable, or the patient is not a surgical candidate. Surgery can involve partial removal of diseased lung areas (segmentectomy, lobectomy, bronchopulmonary resection with bronchoanastomosis), or total lung removal (simple or radical pneumonectomy), with removal of metastatic lymph nodes.

Chemotherapy. Chemotherapy is the primary treatment for small cell cancer and an adjuvant for the other types. However, it has serious side effects, such as myelosuppression, neutropenia with infection, thrombocytopenia, nausea, vomiting, and alopecia, without improving significantly the life expectancy and survival rate. Doxorubicin may cause cardiomyopathy, vincristine and cisplatin are potentially neurotoxic, and cyclophosphamide may cause hemorrhagic cystitis.

Radiation therapy. Radiation may reduce tumor bulk to allow surgical resection. Radiation is usually recommended in early stages of cancer if surgery is contraindicated, or as an adjunct to surgery. A serious side effect is the "irradiated lung," with symptoms of radiation pneumonitis (dyspnea, cough, chest pain, fever, and malaise) and later pulmonary fibrosis, with severe alteration of pulmonary parenchyma. Irradiation also depresses immune function.

Three-dimensional conformal radiation therapy. 3D CRT, a new and innovative therapeutic technique, increases the radiation dose delivered to a tumor and improves local control, allowing less irradiation of adjacent tissues than the conventional two-dimensional technique.

Fast-neutron radiotherapy. This therapy leverages high linear energy transfer to increase the effectiveness of radiation.

Symptomatic Treatments. An important part of the therapeutic plan is treatment of the symptoms that accompany lung cancer and its metastatic manifestations. Pain may be mild or severe, and requires analgesic anti-inflammatory drugs or opioid derivates. Pain in the thoracic wall can be treated with infiltrations of affected nerves with anesthetic substances or alcohol. Hemoptysis can be treated with procoagulants, such as vitamin K. Sleep disorders due to pain, lack of appetite, dyspnea, cough, and asthenia can also respond to focused treatment. Superinfections are common and should be treated with appropriate antibiotics, antifungals, and expectorants.

 Nutritional Considerations

Although environmental exposures (particularly tobacco smoke and, to a lesser extent, air pollution, asbestos, and radon) are the chief causes of lung cancer, diet also plays a surprisingly important role. Research on the relationships between diet, smoking, and lung cancer risk is complicated by the fact that smokers tend to have lower intakes and/or lower blood levels of many protective nutrients, compared with nonsmokers. Nonetheless, certain patterns have emerged.

Overall, evidence suggests that individuals (eg, Seventh-Day Adventists) eating plant-based diets, rich in vegetables and fruits, may be at lower risk for lung cancer, independent of tobacco use. The aspects of the diet associated with reduced risk are avoiding meat and saturated fat, consuming antioxidant-rich fruits and vegetables, and limiting alcohol, as described below:

Avoiding meat and saturated fat. Some studies suggest that vegetarian diets are associated with lower risk for lung cancer.⁴ Increased risk is also associated with red meat,⁵ particularly ham, sausage, and liver,⁶ saturated fat,⁷ and dairy products.^{8, 9}

Consumption of fruits and vegetables. Several studies show that individuals with diets rich in vegetables and fruits have reduced risk for lung cancer, independent of smoking. Nutrients that appear responsible for these protective benefits include carotenoids (as opposed to vitamin A found in animal products); vitamin C;^{10, 11} sulfur compounds incruciferous vegetables (broccoli, cauliflower, cabbage);¹² flavonoids;¹³ and folic acid.^{14, 15} A comprehensive antioxidant index that summarized the collective intake of carotenoids, flavonoids, vitamins E and C, and selenium among male smokers found that those with the highest antioxidant consumption had a significantly lower risk for lung cancer than those with the lowest antioxidant intakes.¹⁶ There appears to be no decrease in lung cancer incidence in persons taking antioxidant supplements, with the exception of individuals with poor selenium status who take selenium supplements.¹⁷ Beta-carotene supplements may actually raise lung cancer risk, at least in certain subgroups.^{18, 19}

Limiting alcohol intake. Intake of higher amounts of beer and spirits in particular appears to increase lung cancer risk up to 3 times that of nondrinkers.^{20, 21} One reason may be that acetaldehyde, an alcohol metabolite, is a known carcinogen. In contrast, several studies suggest that moderate consumption of wine lowers the risk for lung cancer.^{21, 22} However, part (though not all) of the increased risk for alcohol may be due to its association with smoking.

Orders

Smoking cessation.

Lung cancer prevention: See Basic Diet Orders chapter.

Treatment of lung cancer: There are as yet no specific guidelines for dietary interventions associated with improved survival. However, see Diet during Cancer Treatment chapter for general guidelines.

What to Tell the Family

In the case of lung cancer, prevention is clearly the most effective strategy. Family members and the patient should be encouraged to quit smoking. Smoking is the primary risk factor for lung cancer, and those who quit smoking experience a gradual risk reduction over time. This lower risk may be enhanced in persons who avoid alcohol and eat a diet low in saturated fat and high in fruits and vegetables.

References

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15. Voorrips LE, Goldbohm RA, Brants HA, et al. A prospective cohort study on antioxidant and folate intake and male lung cancer risk. Cancer Epidemiol Biomarkers Prev. 2000;9:357-365.

16. Wright ME, Mayne ST, Stolzenberg-Solomon RZ, et al. Development of a comprehensive dietary antioxidant index and application to lung cancer risk in a cohort of male smokers. Am J Epidemiol. 2004;160:68-76.

17. Reid ME, Duffield-Lillico AJ, Garland L, Turnbull BW, Clark LC, Marshall JR. Selenium supplementation and lung cancer incidence: an update of the nutritional prevention of cancer trial. Cancer Epidemiol Biomarkers Prev. 2002; 11:1285-1291.

18. Goodman GE, Thornquist MD, Balmes J, et al. The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. J Natl Cancer Inst. 2004;96:1743-1750.

19. Albanes D, Heinonen OP, Taylor PR, et al. Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. J Natl Cancer Inst. 1996;88:1560-1570.

20. Bandera EV, Freudenheim JL, Vena JE. Alcohol consumption and lung cancer: a review of the epidemiologic evidence. Cancer Epidemiol Biomarkers Prev. 2001;10:813-821.

21. Prescott E, Gronbaek M, Becker U, Sorensen TI. Alcohol intake and the risk of lung cancer: influence of type of alcoholic beverage. Am J Epidemiol. 1999;149: 463-470.

22. Kubik AK, Zatloukal P, Tomasek L, et al. Dietary habits and lung cancer risk among non-smoking women. Eur J Cancer Prev. 2004;13:471-480.