Lung cancer is the most common cause of cancer death and the second most common cancer in both men and women (not counting skin cancer).[1] 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.

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

• Cough, which occurs in about 93% of lung cancer patients. When the tumor erodes the lung capillaries, the cough is often accompanied by hemoptysis.
• Recurring infections, such as bronchitis and pneumonia.
• Generalized weakness and fatigue.
• 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, which is often a late symptom, caused by airway obstruction or compression.
• Axillary, latero-cervical, or supraclavicular lymphadenopathy; hoarseness, which is caused by the compression of the laryngeal recurrent nerve in the mediastinum.
• Dysphagia, which occurs when tumor invades or compresses the esophagus.[2]

Lung cancer can also cause a variety of paraneoplastic syndromes such as hypercalcemia, syndrome of inappropriate antidiuretic hormone secretion (SIADH), neurologic syndromes, polymyositis and dermatomyositis, Cushing’s syndrome, Lambert-Eaton myasthenic syndrome, and a variety of hematologic abnormalities, such as anemia, leukocytosis, thrombocytosis, and hypercoagulable disorders.[3][4][5]

Signs and symptoms of metastatic disease vary according to the organ or site affected. These can include bone pain; neurologic changes, such as weakness or numbness, dizziness, or recent seizure onset; jaundice; and masses that may appear near the surface of the body due to cancer spreading to the skin or to regional lymph nodes.

The two major types of lung cancer are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).[6] NSCLC accounts for about 85% of all lung cancers and includes:

• Adenocarcinoma, which is the most common form of lung cancer in the US and accounts for about 50% of cases. It is an invasive tumor that has five different growth patterns. These include lepidic, which grows along the alveolar walls; acinar, which forms round/oval glands; papillary and micropapillary, both of which have fibrovascular cores; and solid, which is sheets of tumor cells. The lesions are peripheral or central, arising from the epithelium of small airways and showing evidence of glandular activity (sometimes producing mucin).
• Squamous cell carcinoma (SCC) makes up about 25% of lung cancer cases. This invasive carcinoma arises from the squamous cells and is characterized by atypical, pleomorphic squamous cells. SCC also has subtypes including basaloid, clear cell, papillary and spindled, each with a different degree of aggressiveness. SCC is usually found centrally in the lung affecting larger bronchi. It can compress the pulmonary artery and vein.
• Large cell (undifferentiated) carcinoma (about 10% of cases) is a bronchogenic tumor with large pleomorphic cells containing prominent nucleoli. This tumor is generally located in the periphery of the lungs and is a diagnosis of exclusion as the cells are so poorly differentiated that they do no show morphologic or immunohistochemical evidence of glandular, squamous, or neuroendocrine differentiation. These tumors generally have a poor prognosis and are typically larger than 5 cm.

SCLC comprises about 10-15% of lung cancers. This form involves the wall of a major bronchus, arising from specialized neuroendocrine cells in the lungs, which show extensive mitotic activity and foci of necrosis. The tumor is commonly a central, perihilar mass, and 70% of patients have metastasis at time of diagnosis. Virtually all small cell cancers are attributable to tobacco use.

Risk Factors

Smoking. 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 dysplastic transformation, the cancer invades bronchial and pulmonary tissues and subsequently metastasizes hematogenously or via lymphatics.

Secondhand smoke. Epidemiologic evidence suggests an increased risk of approximately 20-25% in nonsmokers regularly exposed to secondhand smoke.[7]

Environmental toxins. Exposure to asbestos, 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 the risk of bronchopulmonary cancer.[8] Exposure to radon, a naturally occurring radioactive gas, can also cause lung cancer. According to the Environmental Protection Agency, radon is the second leading cause of lung cancer in the US.

Family history. Investigations show a 14-fold higher frequency of lung carcinomas in smokers with a family history of lung cancer.[9] Risk is also increased in individuals with Li-Fraumeni syndrome, resulting from an inherited mutation in the p53 gene.[10]

Immunosuppression. The risk of oncogenesis increases with conditions that weaken the immune system, such as HIV infection.[11]

Air pollution. The mortality rate from lung cancer is 2-5 times higher in industrialized areas than in less polluted rural areas.[12]

Inflammation. Chronic and recurrent respiratory diseases act as chronic irritants and play an oncogenic role (e.g., tuberculosis, chronic bronchitis, recurrent pneumonias).[13] Individuals with diffuse pulmonary fibrosis also have an increased risk of lung cancer.[14]

Ionizing radiation. Environmental and diagnostic/therapeutic radiation exposure (radon gas, x-rays) increases carcinogenic risk in a dose-dependent manner. Lung cancer is 10 times more frequent in uranium miners than in the general population. Radiation therapy (RT) used to treat other malignancies, such aslymphoma and breast cancer, has also been shown to increase risk, especially in smokers. ,[15][16]

Diet and nutrition. See Nutritional Considerations below.

Screening

Screening for lung cancer with chest radiography and sputum cytology has not been shown to reduce mortality from lung cancer. Screening with computed tomography (CT), however, has been shown to detect early-stage tumors, which have a favorable prognosis. The National Lung Screening Trial compared CT screening with chest x-ray and demonstrated a 20% decrease in lung cancer mortality in heavy smokers who were screened annually for 3 years. The U.S. Preventive Services Task Force recommends annual screening for lung cancer with low-dose CT in adults aged 50 to 80 years who have a 20 pack-year smoking history, and who currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.[17]

Diagnosis

Patients with signs or symptoms of lung cancer should initially undergo chest radiography. Any abnormal findings, such as a new or enlarging lesion, pulmonary nodules, enlarged hilar or paratracheal lymph nodes, persistent pneumonia, lobar atelectasis, or pleural effusion, should be further evaluated with contrast-enhanced chest CT. For patients suspected of having NSCLC, the CT should include both the chest and upper abdomen. When chest imaging is suspicious for lung cancer, patients should also have laboratory studies including a complete blood count, electrolytes, liver function tests, and a serum calcium performed. Evaluation of extra-pulmonary or paraneoplastic signs or symptoms should be clinically directed.

Ultimately the diagnosis of lung cancer is made by cytology or tissue biopsy. Cytologic specimens can be obtained from the lung from bronchoscopic washings, brushings, or needle aspiration; sputum; or transthoracic needle aspirates. Specimens can also be obtained by transthoracic, transbronchial, or transesophageal lymph node aspirates, from pleural fluid, or from needle aspirates of metastatic tissue. Similarly, tissue for histopathologic examination can be from lung tissue, lymph nodes, or metastatic tissue by endobronchial biopsy, transbronchial biopsy, transthoracic needle biopsy, surgical biopsy, mediastinoscopy, or core tissue biopsy. If multiple lymph nodes appear enlarged on imaging studies, a pulmonologist will perform an endobronchial ultrasound bronchoscopy, a minimally invasive but highly effect procedure to diagnose lung cancer and other diseases in enlarged lymph nodes.

Panels of histochemical stains help further subclassify NSCLC (adenocarcinoma versus squamous cell carcinoma). Often adenocarcinomas are tested for molecular mutations such as EGFR, KRAS, ALK, ROS1, and BRAF, which can assist with targeted therapies when indicated.

Metastatic evaluation. Once lung cancer is diagnosed, a metastatic evaluation should be performed based on clinical signs and symptoms and may include laboratory testing, PET scanning, or MRI scanning. The TNM (tumor, node, metastasis) classification is the preferred system for tumor staging.

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 is the main treatment for NSCLC, 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. For some patients, video-assisted thoracoscopy is associated with decreased operative morbidity and a faster recovery.

Chemotherapy is the primary treatment for small-cell cancer and is used as adjuvant therapy in more advanced stages of NSCLC. However, it has serious side effects, such as myelosuppression, neutropenia with infection, thrombocytopenia, nausea, vomiting, and alopecia, without significant improvement of life expectancy and survival rate.

Radiation therapy 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. Stereotactic body radiation therapy may allow more targeted radiation treatment compared with conventionally fractionated radiation therapy.

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 due to a coagulopathy can be treated with procoagulants, such as vitamin K. Sleep disorders due to pain, lack of appetite, dyspnea, cough, and asthenia may also respond to focused treatment. Superinfections are common and should be treated with appropriate antibiotics, antifungals, and expectorants.

Most patients with locally advanced or metastatic lung cancer are offered immunotherapy, either as a single agent or in addition to chemotherapy. Most immunotherapy agents for lung cancer target the PD-L1 receptor on the surface of the cancer cell. Expression of this antigen can be assessed via basic immuno-histologic analysis and can be predictive of response. Side effects of immunotherapy include virtually any autoimmune disorder. The most commonly encountered are thyroiditis, pneumonitis, colitis, and dermatitis. The more dangerous side effects include hypophysitis, hepatitis, encephalitis, myocarditis, and nephritis. The treatment of autoimmune dysregulation generally consists of corticosteroids, such as prednisone, and holding the medication.

Approximately 50% of nonsmokers will have an actionable mutation that can be tested for, and targeted by, specific medications. The most common mutation found in nonsmokers with adenocarcinoma affects the epithelial growth factor receptor, which is constitutionally activated but can be "turned off" by oral tyrosine kinase inhibitors such as Erlotinib. Other activating mutations that are commonly tested for, primarily in adenocarcinomas, include ALK and ROS. These mutations can also be treated with FDA-approved, specific targeted medications. These drugs have fewer side effects than traditional chemotherapy, but common side effects include skin rash, diarrhea, and visual disturbances.

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.

Certain dietary patterns have emerged as being protective against lung cancer. In the NIH-AARP (National Institutes of Health–American Association of Retired Persons) Diet and Health study, higher scores on one of several healthy eating classification schemes (the Healthy Eating Index–2010, Alternate Healthy Eating Index–2010, alternate Mediterranean Diet score, and Dietary Approaches to Stop Hypertension) were linked with reduction in lung cancer risk by 14-17%.[18] The common threads among these diets are listed below.

Replacing red meat with legumes. Although a meta-analysis found a 35% higher risk in individuals who consume the most meat, the relationship is likely explained by both the risks posed by red meat and the benefits of foods that replace it.[19] Consumption of legumes, particularly soy products, has been associated with a significantly lower risk for lung cancer.[20][21]

Consumption of fruits and vegetables. Two recent meta-analyses found significantly lower risk for lung cancer in individuals consuming the most fruits and vegetables, compared with the lowest amount. One of these concluded the risk was roughly 15% lower, while another suggested risk reductions of between 20% and roughly 25%.[22][23] Nutrients that appear responsible for these protective benefits include carotenoids (as opposed to vitamin A found in animal products), vitamin C, sulfur compounds in cruciferous vegetables (broccoli, cauliflower, cabbage), and several other compounds found in plant foods.[24][25][26][27]

It is important to note that beta-carotene supplementation appears to increase the risk of lung cancer in adults who are otherwise at high risk because of smoking or exposure to asbestos.[28] This risk applies only to supplements, not to beta-carotene-rich foods, and may be due to the tendency of beta-carotene, when given at high (nonphysiologic) doses, to suppress absorption of other carotenoids.

Limiting alcohol intake. A comprehensive meta-analysis found a 15% higher risk for developing lung cancer only among heavy alcohol consumers.[29] It remains unclear whether these associations represent cause and effect. The link between high alcohol intake and lung cancer may reflect an association with smoking or a carcinogenic effect of acetaldehyde, an alcohol metabolite, and the ability of alcohol to activate carcinogens through an increase in cytochrome P450.[30]

Maintaining adequate vitamin D status. Two meta-analyses have concluded that higher blood levels of vitamin D offer significant protection against lung cancer. One of these found an inverse association between vitamin D and lung cancer risk, while the other observed the greatest reductions at blood levels of 25(OH)D at nearly 53 nmol/L, a level higher than currently recommended by the Institute of Medicine.[31][32][33][34]

Orders

Smoking cessation.

CT screening as indicated.

Lung cancer prevention: See Basic Diet Orders chapter.

During treatment of lung cancer: 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. Evidence suggests that this risk reduction may be modestly enhanced in persons who avoid alcohol and eat a diet high in fruits and vegetables, and low in meat. Family members can encourage each other to follow a healthful diet. In the process, everyone benefits.

References