Lung carcinoma is a malignant lung tumor usually categorized as small cell or non–small cell. Cigarette smoking is the major risk factor for most types. Symptoms include cough, chest discomfort, and, less commonly, hemoptysis, but many patients are asymptomatic and some present with metastatic disease. Diagnosis is suspected by chest x-ray or CT scan and confirmed by biopsy. Treatment is with surgery, chemotherapy, and/or radiation therapy. Despite advances in treatment, the prognosis is poor, and attention is focused on early detection and prevention.

Epidemiology, Pathophysiology, and Classification

An estimated 171,900 new cases of lung carcinoma are diagnosed each year in the US, and the disease causes 157,200 deaths annually. The incidence is rising in women and appears to be leveling off in men. Black men are at especially high risk.
Cigarette smoking, including passive (secondhand) smoking, is the most important cause. Risk differs by age and smoking intensity and duration; risk after smoking cessation declines but probably never returns to baseline. Exposure to radon, a breakdown product of naturally occurring radium and uranium, is the most important environmental risk factor in nonsmokers. Occupational exposure to radon (in uranium miners); asbestos (in construction and demolition workers, pipefitters, shipbuilders, and automotive mechanics); silica (in miners and sandblasters); arsenic (in workers in copper smelting, pesticide manufacturing, and wood-treatment plants); chromates (in stainless steel and pigment manufacturing plants); nickel (in battery and stainless steel manufacturing plants); chloromethyl ethers; beryllium; and coke oven emissions (in steel workers) accounts for a small number of cases per year (see Environmental Pulmonary Diseases). The risk of cancer is greater with combined exposure to occupational toxins and cigarette smoking than with either one alone. COPD and pulmonary fibrosis may increase susceptibility; β-carotene supplementation may increase susceptibility in smokers. Air pollution and cigar smoke contain carcinogens but have never been shown to cause lung carcinoma.
Respiratory epithelial cells require prolonged exposure to cancer-promoting agents and accumulation of multiple genetic mutations before becoming neoplastic. Mutations in genes that stimulate cell growth (K-RAS, MYC ), code for growth factor receptors (EGFR, HER2/neu), and inhibit apoptosis (BCL-2) contribute to proliferation of abnormal cells. So do mutations that inhibit tumor-suppressor genes ( p53, APC ). When enough of these mutations accumulate, lung carcinoma results.
Lung carcinoma is generally classified as small cell (SCLC) and non–small cell (NSCLC). SCLC is a highly aggressive cancer almost always occurring in smokers and causing widespread metastatic disease in 60% of patients by the time of diagnosis. Clinical behavior of NSCLC is more variable and depends on histologic type

Symptoms and Signs
About 25% of lung carcinomas are asymptomatic and are detected incidentally with chest imaging. Symptoms and signs develop from local tumor, regional spread, and metastasis. Paraneoplastic syndromes and constitutional symptoms may occur at any stage.

Local tumor causes cough and, less commonly, dyspnea because of airway obstruction, postobstructive atelectasis, and lymphangitic spread. Fever may occur with postobstructive pneumonia. Up to 1⁄2 of patients report vague or localized chest pain. Hemoptysis is less common, and blood loss is minimal, except in rare instances when tumor erodes a major artery, causing massive hemorrhage and death by asphyxiation.

Regional spread may cause pleuritic chest pain or dyspnea from pleural effusion, hoarseness due to tumor encroachment on the recurrent laryngeal nerve, and dyspnea and hypoxia from diaphragmatic paralysis due to involvement of the phrenic nerve.

Compression or invasion of the superior vena cava (SVC syndrome) can produce headache or a sensation of head fullness, facial or upper extremity swelling, and supine breathlessness and flushing (plethora). Signs of SVC syndrome are facial and upper extremity edema, dilated neck and subcutaneous veins over the face and upper trunk, and facial and truncal plethora. SVC syndrome is more common in patients with SCLC.

Apical tumors, usually NSCLC, can invade the brachial plexus, pleura, or ribs, causing shoulder and upper extremity pain and weakness or atrophy of the ipsilateral hand (Pancoast's tumor). Horner's syndrome (ptosis, miosis, enophthalmos, and anhidrosis) results when the paravertebral sympathetic chain or cervical stellate ganglion is involved. Spread of tumor to pericardium may be asymptomatic or lead to constrictive pericarditis or cardiac tamponade (see Pericarditis: Anatomy and Pathophysiology). Rarely, esophageal compression causes dysphagia.
Metastases always eventually cause symptoms that vary by location. Metastases to the liver cause GI symptoms and ultimately hepatic insufficiency. Metastases to the brain cause behavioral changes, confusion, aphasia, seizures, paresis or paralysis, nausea and vomiting, and, ultimately, coma and death. Bone metastases cause severe pain and pathologic fractures. Lung carcinoma commonly metastasizes to the adrenal glands but rarely leads to adrenal insufficiency.

Paraneoplastic syndromes are not caused by cancer directly (see Overview of Cancer: Paraneoplastic Syndromes). Common paraneoplastic syndromes in patients with lung carcinoma include hypercalcemia (caused by tumor production of parathyroid hormone-related protein), syndrome of inappropriate antidiuretic hormone secretion (SIADH), finger clubbing with or without hypertrophic osteoarthropathy, hypercoagulability with migratory superficial thrombophlebitis (Trousseau's syndrome), myasthenia (Eaton-Lambert syndrome), and a variety of neurologic syndromes, including neuropathies, encephalopathies, encephalitides, myelopathies, and cerebellar disease. Mechanisms for neuromuscular syndromes involve tumor expression of autoantigens with production of autoantibodies, but the cause of most others is unknown.

Constitutional symptoms most commonly include weight loss and fatigue and are sometimes the first indication of underlying malignancy.

Diagnosis

Chest x-ray is the initial test. It may show clearly defined abnormalities, such as a single mass or multifocal masses or a solitary pulmonary nodule (see Approach to the Patient With Pulmonary Symptoms: Solitary Pulmonary Nodule), or more subtle changes, such as an enlarged hilum, widened mediastinum, tracheobronchial narrowing, atelectasis, nonresolving parenchymal infiltrate, cavitary lesion, or unexplained pleural thickening or effusion. These findings are suggestive but not diagnostic of lung carcinoma and require follow-up with high-resolution CT (HRCT) and cytopathologic confirmation.

CT demonstrates many characteristic patterns and appearances that may confirm the diagnosis. CT also can guide needle biopsy of accessible lesions and is useful for staging.
The method used to obtain cells or tissue for confirmation depends on the accessibility of tissue and the location of suspect lesions. Sputum or pleural fluid cytology is the least invasive method. In patients with productive cough, sputum specimens obtained on awakening may contain high concentrations of malignant cells, but yield for this method is about 50% overall. Pleural fluid is another convenient source of cells, but effusions accompany ≤ 1⁄3 of all lung carcinomas; nevertheless, a malignant effusion immediately stages a cancer as at least stage IIIB (see Table 3: Tumors of the Lungs: International Staging System for Lung Cancer) and is a poor prognostic sign. In general, false-negative cytology readings can be minimized by obtaining as large a volume of sputum or fluid as possible early in the day and sending the sample to the pathology laboratory immediately to minimize delays in processing, which lead to cell breakdown. Percutaneous biopsy is the next least invasive procedure. It is more useful for metastatic sites (supraclavicular or other peripheral lymph nodes, pleura, liver, and adrenals) than for lung lesions because of a 20 to 25% risk of pneumothorax and the risk of false-negative results unlikely to change the perceived need for treatment.

Bronchoscopy is the procedure most often used for diagnosing lung carcinoma. In theory, the procedure of choice for obtaining tissue is the one that is least invasive. In practice, bronchoscopy is often performed in addition to or instead of less invasive procedures, because diagnostic yields are greater and because bronchoscopy is important for staging. A combination of washings, brushings, and fine-needle aspiration of visible endobronchial lesions and of paratracheal, subcarinal, mediastinal, and hilar lymph nodes yields a tissue diagnosis in 90 to 100% of cases. Mediastinoscopy is a higher-risk procedure and is usually used before surgery to confirm or exclude the presence of tumor in enlarged mediastinal lymph nodes of undetermined significance (see Tumors of the Lungs: Staging).
Open lung biopsy, performed via open thoracotomy or using video assistance (VATS—see Diagnostic and Therapeutic Pulmonary Procedures: Thoracoscopy and Video-Assisted Thoracoscopic Surgery), is indicated when less invasive methods do not provide a diagnosis in patients whose clinical characteristics and radiographic features strongly suggest resectable tumor.
Staging

SCLC is categorized as limited-stage and extensive-stage disease. Limited-stage disease is cancer confined to one hemithorax (including ipsilateral lymph nodes) that can be encompassed within one tolerable radiation therapy port, excluding the presence of pleural or pericardial effusion. Extensive-stage disease is cancer outside a single hemithorax and presence of malignant pleural or pericardial effusion. About 1⁄3 of patients with SCLC have limited-stage disease; the remainder often have extensive distant metastases.

NSCLC staging involves determining tumor size, tumor and lymph node location, and the presence or absence of distant metastases

Thin-section CT from the neck to upper abdomen (to detect cervical and supraclavicular and hepatic and adrenal metastases) is the first staging test for both SCLC and NSCLC. However, CT often cannot distinguish postinflammatory from malignant intrathoracic lymph node enlargement or benign from malignant hepatic or adrenal lesions (distinctions that determine stage). Thus, other tests are usually performed when CT abnormalities are present in these areas. PET scanning is an accurate, noninvasive test used to identify malignant mediastinal lymph nodes and other distant metastases (metabolic staging). Integrated PET-CT, in which PET and CT images are combined into a single image by scanners in a single gantry, is more accurate for NSCLC staging than CT or PET alone or than visual correlation of the two tests. The use of PET and PET-CT is limited by cost and availability. When a PET scan is unavailable, bronchoscopy and, less commonly, mediastinoscopy or video-assisted thoracoscopy can be used to biopsy questionable mediastinal lymph nodes. Without PET scanning, suspect hepatic or adrenal lesions must be evaluated by needle biopsy.

MRI of the chest is slightly more accurate than high-chest HRCT for staging apical tumors and cancers close to the diaphragm.

Patients with headache or neurologic abnormalities should undergo head CT or MRI and evaluation for SVC syndrome. Patients with bone pain or elevated serum Ca or alkaline phosphatase should undergo a radionuclide bone scan. These imaging tests are not indicated in the absence of suspicious symptoms, signs, or laboratory test abnormalities. Other blood tests, such as CBC, serum albumin, and creatinine, play no role in staging but provide important prognostic information about the patient's ability to tolerate treatment.

Prognosis
Prognosis is poor, even with newer treatments. On average, untreated patients with advanced NSCLC survive 6 mo, whereas 5-yr survival for treated patients is about 9 mo. Patients with extensive-stage SCLC do especially poorly, with a 5-yr survival rate < 1%. The median survival time for limited-stage disease is 20 mo, with a 5-yr survival rate of 20%. In many patients with SCLC, chemotherapy prolongs life and improves quality of life enough to warrant its use. The 5-yr survival rate of patients with NSCLC varies by stage, from 60 to 70% for patients with stage I to virtually 0% for those with stage IV disease; recent evidence suggests improved survival in early-stage disease with a platinum-based chemotherapy regimen. Given the disappointing results in late-stage disease, efforts at reducing mortality have increasingly focused on early detection and active interventions to prevent disease.

A screening chest x-ray in high-risk patients detects lung carcinomas at early stages but does not decrease mortality. A screening CT is more sensitive for detecting tumors, but more false-positive readings increase the number of unnecessary invasive diagnostic procedures needed to verify CT findings. Such procedures are costly and risk complications. A strategy of yearly CT screening of smokers with follow-up PET scan or HRCT to evaluate indeterminate lesions is being studied. So far, this strategy does not seem to lessen mortality and cannot be recommended as routine practice. The future of screening may lie in a combination of molecular analysis for genetic markers (such as K-ras, p53, EGFR), sputum cytometry, and detection of cancer-related volatile organic compounds (eg, alkane, benzene) in exhaled breath.

Treatment
Treatment generally involves assessment of eligibility for surgery followed by choice of surgery, chemotherapy, and/or radiation as appropriate, depending on tumor type and stage. Many nontumor-related factors affect eligibility. Poor cardiopulmonary reserve; malnutrition; frailty or poor physical performance status; comorbidities, including cytopenias; and psychiatric or cognitive illness all may lead to a decision for palliative over curative treatment or for no treatment at all, even though cure might technically be possible.

Surgery is performed only on patients who will have adequate pulmonary reserve once a lobe or lung is resected. Patients with preoperative forced expiratory volume in 1 sec (FEV1) > 2 L generally tolerate pneumonectomy. Those with FEV1 < 2 L should undergo a quantitative radionuclide perfusion scan to determine the proportion of function the patient can expect to lose from resection. Postoperative FEV1 can be predicted by multiplying percent perfusion of the nonresected lung by the preoperative FEV1. A predicted FEV1 > 800 mL or > 40% of the predicted normal FEV1 suggests adequate postoperative lung function, though studies of lung volume reduction surgery in COPD patients suggest that patients with FEV1 < 800 mL can tolerate resection if the cancer is located in poorly functional bullous (generally apical) lung regions. Patients undergoing resection at hospitals that perform more resections have fewer complications and are more likely to survive than those who undergo surgery at low-volume hospitals.

Multiple chemotherapy regimens exist for treatment of lung carcinoma; no one regimen is proven superior. Choice of regimen, therefore, often depends on local practice, contraindications, and toxicities. Treatment options for disease that recurs after treatment vary by location and include repeat chemotherapy for local recurrence, radiation therapy for metastases, and brachytherapy for endobronchial disease when additional external radiation cannot be tolerated.
Radiation treatment carries the risk of radiation pneumonitis when large areas of lung are exposed to high doses of radiation over time. Radiation pneumonitis can occur up to 3 mo after treatment. Cough, dyspnea, low-grade fever, or pleuritic chest pain may signal the condition, as may rales or pleural friction rub. Chest x-rays may be nonspecific; CTs may show nonspecific infiltration without discrete mass. The diagnosis is often one of exclusion. Radiation pneumonitis is treated with 60 mg prednisone for 2 to 4 wk followed by a gradual taper.

Because many patients with lung carcinoma die, the need for end-of-life care should be anticipated. Symptoms of breathlessness, pain, anxiety, nausea, and anorexia are especially common and can be treated with parenteral morphine; oral, transdermal, or parenteral opioids; and antiemetics

SCLC: SCLC of any stage is typically initially responsive to treatment, but responses are usually short-lived. Surgery generally plays no role in treatment of SCLC, although it may be curative in the rare patient who has a small focal tumor without spread (such as a solitary pulmonary nodule).

In limited-stage disease, a combination of etoposide and a platinum compound (either
cisplatin or carboplatin) in 4 to 6 cycles is thought to be most effective, although
combinations with other drugs—including vinca alkaloids (vinblastine, vincristine, vinorelbine), alkylating drugs (cyclophosphamide, ifosfamide), doxorubicin,taxanes (docetaxel, paclitaxel), and gemcitabine—are also commonly used.
Radiation further improves response; the very definition of limited-stage disease as disease confined to a hemithorax is based on the significant improvement in survival observed with radiation. The use of cranial radiation to prevent brain metastases is advocated by some experts; micrometastases are common in SCLC, and chemotherapy does not cross the blood-brain barrier.
In extensive-stage disease, treatment is the same as with limited-stage disease but without concurrent radiation. Replacing etoposide with topoisomerase inhibitors (irinotecan or topotecan) may improve survival. These drugs alone or in combination with other drugs are also commonly used in refractory disease and in cancer of either stage that has recurred. Radiation is often used as palliative treatment for metastases to bone or brain.
In general, recurrent SCLC carries a poor prognosis, although patients who maintain a good performance status should be offered a clinical trial.

NSCLC: Treatment of NSCLC depends on the stage. For stage I and II disease, the standard is surgical resection with either lobectomy or pneumonectomy combined with mediastinal lymph node sampling or complete dissection. Lesser resections, including segmentectomy and wedge resection, are considered for patients with poor pulmonary reserve. Surgery is curative in about 55 to 75% of patients with stage I and in 35 to 55% of patients with stage II disease. Adjuvant chemotherapy is probably helpful in early-stage disease (stages Ib and II). An increase in 5-yr overall survival (69% vs 54%) and disease-free survival (61% vs 49%) occurs with cisplatin
plus vinorelbine. Because the improvement is small, the decision for adjuvant chemotherapy should be made on an individual basis. The role of neoadjuvant chemotherapy in early-stage NSCLC is under investigation.

Stage III disease is one or more locally advanced tumors with regional nodal involvement but no distant metastases. For stage IIIA tumors with occult mediastinal nodal metastases discovered at the time of surgery, resection results in 20 to 25% 5-yr survival. Radiation therapy with or without concurrent chemotherapy is considered standard for unresectable clinically staged IIIA disease, but survival is poor (median survival, 10 to 14 mo). Recent trials suggest slightly better results with preoperative chemotherapy plus radiation followed by surgery and subsequent chemotherapy. This remains an area of investigation.

Stage IIIB patients with contralateral mediastinal nodal disease, supraclavicular nodal disease, or malignant pleural effusions are offered radiation or chemotherapy or both. The addition of radiation-sensitizing chemotherapeutic drugs, such as cisplatin, paclitaxel, vincristine, and cyclophosphamide, improves survival slightly. Patients
with locally advanced tumors invading the heart, great vessels, mediastinum, or spine usually receive radiation. In select cases (T4N0M0 tumors), surgical resection with either neoadjuvant or adjuvant chemoradiation may be feasible. The 5-yr survival rate for treated stage IIIB patients is 5%.

In stage IV disease, palliation of symptoms is the goal. Chemotherapy and radiation may be used to reduce tumor burden, treat symptoms, and improve quality of life. However, median survival is only 9 mo; < 25% of patients survive
1 yr. Surgical palliative procedures may be required and may include thoracentesis and pleurodesis of recurrent effusions, placement of indwelling pleural drainage catheters, bronchoscopic fulguration of tumors involving the trachea and mainstem bronchi, placement of stents to prevent airway occlusion, and, in some cases, spinal stabilization for impending spinal cord compression.

Several novel biologic agents specifically target lung tumors. Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, may be used in patients who have not responded to platinum and docetaxel
therapy. Other biologic agents under investigation
include other EGFR inhibitors, antisense oligonucleotides to EGFR mRNA (messenger RNA), and farnesyl transferase inhibitors.

It is important to distinguish between recurrent NSCLC, an independent 2nd primary tumor, locally recurrent NSCLC, and distant metastatic NSCLC. The treatment of an independent 2nd primary tumor and locally recurrent NSCLC follows the same guidelines as for primary tumor stages I to III. If surgery was used initially, radiation therapy is the main modality. If recurrence manifests as distant metastases, patients are treated as stage IV with a focus on palliation.

Complications: Initial treatment of malignant pleural effusion is with thoracentesis. Asymptomatic effusions require no treatment; symptomatic effusions that recur despite multiple thoracenteses are drained through a chest tube. Infusion of talc (or occasionally, tetracycline or bleomycin) into the pleural space (a procedure called pleurodesis)
scars the pleura, eliminates the pleural space, and is effective in > 90% of cases (see Mediastinal and Pleural Disorders: Malignant pleural effusion).
Treatment of SVC syndrome is the same as treatment of lung carcinoma: with chemotherapy (SCLC), radiation therapy (NSCLC), or both (NSCLC). Corticosteroids are commonly used but are of unproven benefit. Treatment of apical tumors is with surgery with or without preoperative radiation or with radiation with or without adjuvant chemotherapy. Treatment of paraneoplastic syndromes varies by syndrome (see Overview of Cancer: Paraneoplastic Syndromes).
Prevention
No active interventions are proven effective except for smoking cessation. Remediation of high radon levels in private residences removes known cancer-promoting radiation, but a reduction in lung cancer incidence is unproven. Increasing dietary intake of fruits and vegetables high in retinoids and β-carotene appears to have no effect on lung carcinoma incidence. Vitamin supplementation is either unproven (vitamin E) or harmful (β-carotene) in smokers. Preliminary evidence hinting that NSAIDs and vitamin E supplementation may protect former smokers from lung carcinoma requires confirmation. New molecular approaches targeting cell signaling and cell cycle pathways and tumor-associated antigens are under investigation.