Bronchogenic Carcinoma A highly malignant primary lung tumor that accounts for most cases of lung cancer and has a very poor prognosis. Bronchogenic carcinoma accounts for > 90% of all lung tumors. It is the second most common cancer in men (13%) and the third most common cancer in women (13%). It is the leading cause of cancer death among men (32%) and women (25%), and its incidence appears to be rising more rapidly among women. It is most common between the ages of 45 and 70. Etiology Cigarette smoking is the principal cause of bronchogenic carcinoma, accounting for > 90% of cases in men and > 80% of cases in women, with 87% of all lung cancers attributed to tobacco exposure. A strong dose-response relationship occurs in the three most common types of bronchogenic carcinoma: squamous cell, small cell, and adenocarcinoma; the slope of the curve is steepest for small cell carcinoma and least steep for adenocarcinoma. Recent epidemiologic studies support previous data suggesting that smoking cessation may postpone lung cancer occurrence and reduce the risk of specific histologic lung cancers. A small proportion of lung cancers (15% in men and 5% in women) are related to occupational agents, often overlapping with smoking: asbestos, radiation, arsenic, chromates, nickel, chloromethyl ethers, mustard (poison war) gas, and coke oven emissions. The exact role of air pollution is uncertain. Exposure to radon gas within the home was thought to be important in a small number of cases; however, a large nested case-control study in Finland did not demonstrate an increased risk of lung cancer from indoor radon exposure. Occasionally, bronchogenic carcinomas, especially adenocarcinoma and bronchioloalveolar carcinoma, are associated with pulmonary scars. Damage to DNA, activation of cellular oncogenes, and stimulation by growth factors are now thought to be of primary importance in the pathophysiology of lung cancer. Pathology Four histologic types of bronchogenic carcinoma usually are distinguished: squamous cell, commonly arising in the larger bronchi and spreading by direct extension and lymph node metastasis; undifferentiated small cell, often associated with early hematogenous metastases; undifferentiated large cell, usually spreading through the bloodstream; and adenocarcinoma, commonly peripheral, often spreading through the bloodstream. All types also commonly spread via the lymphatics. Bronchioloalveolar carcinoma, a subtype of adenocarcinoma, consolidates airspaces and often does not extend beyond the lungs. Although a solitary form exists, this cancer is sometimes distinguished from other types of bronchogenic carcinoma by its multifocal origin. Symptoms and Signs Manifestations depend on the tumor's location and type of spread. Because most bronchogenic carcinomas are endobronchial, patients typically present with cough, with or without hemoptysis. In patients with chronic bronchitis, increased intensity and intractability of preexisting cough suggest a neoplasm. Sputum arising from an ulcerated bronchial tumor usually is not excessive (although occasionally sputum may be profuse and watery with bronchioloalveolar carcinomas), but it contains inflammatory exudate and is often blood-streaked. Hemoptysis is uncommon in small cell carcinoma. Copious bleeding is uncommon and strongly suggests invasion of large underlying blood vessels. Bronchial narrowing may cause air trapping with localized wheezing and commonly causes atelectasis with ipsilateral mediastinal shift, diminished expansion, dullness to percussion, and loss of breath sounds. Infection of an obstructed lung produces fever, chest pain, and weight loss. Persistent localized chest pain suggests neoplastic invasion of the chest wall. Peripheral nodular tumors are asymptomatic until they invade the pleura or chest wall and cause pain or until they metastasize to distant organs. Late symptoms include fatigue, weakness, decreased activity, worsening cough, dyspnea, decreased appetite, weight loss, and pain. Malignant serosanguineous pleural effusions are common and are often large and recurrent. Horner's syndrome (due to invasion of the cervical thoracic sympathetic nerves) consists of enophthalmos, miosis, ptosis, and ipsilateral facial anhidrosis. Pancoast syndrome (due to infiltration of the brachial plexus and neighboring ribs and vertebrae) consists of pain, numbness, and weakness of the affected arm. The two syndromes may coexist. A tumor may extend directly into the esophagus, producing obstruction, sometimes complicated by a fistula. Phrenic nerve invasion usually causes diaphragmatic paralysis. Clinical features of cardiac involvement include arrhythmias, cardiomegaly, and pericardial effusion. Superior vena cava obstruction and left recurrent laryngeal nerve paralysis (causing hoarseness) are produced by direct extension of the tumor or by extension of the tumor from neighboring lymph nodes. In the superior vena cava syndrome, obstruction of venous drainage leads to dilation of collateral veins in the upper part of the chest and neck; edema and plethora of the face, neck, and upper part of the torso, including the breasts; suffusion and edema of the conjunctiva; breathlessness when supine; and CNS symptoms (eg, headache, visual distortion, disturbed states of consciousness). Although a dramatic clinical situation, this syndrome requires urgent but not emergency care. Most importantly, a histologic diagnosis should be made if an undiagnosed mediastinal mass is present. Intrapulmonary spread of primary or secondary cancer may cause lymphangitic carcinomatosis with subacute cor pulmonale, worsening hypoxemia, and severe dyspnea. Secondary hematogenous nodular metastases within the lungs are common, but secondary bronchial invasion is rare. Hematogenous metastatic spread to the liver, brain, adrenals, and bone is common and may occur early, resulting in symptoms at those sites before obvious pulmonary symptoms. Paraneoplastic syndromes of lung cancer, which are numerous, are extrapulmonary, remote effects of tumors. They lead to metabolic and neuromuscular disturbances unrelated to the primary tumor or metastases. They may be the first sign of occurrence or recurrence, but they do not necessarily indicate that a tumor has spread outside the chest. In hypertrophic pulmonary osteoarthropathy (the best known), clubbing of the fingers and toes and periosteal elevation of the distal parts of long bones occur. All levels of the nervous system may be affected--principally causing encephalopathy, subacute cerebellar degeneration, encephalomyelitis, the Eaton-Lambert syndrome, and peripheral neuropathy. Polymyositis and dermatomyositis or metabolic syndromes due to production of substances with hormonal activity may develop. Small cell carcinomas may secrete ectopic ACTH, resulting in Cushing's syndrome, or ADH, causing water retention and hyponatremia, and are also associated with the carcinoid syndrome (flushing, wheezing, diarrhea, and cardiac valvular lesions). Squamous cell carcinomas may secrete parathyroid hormone-like substances that produce hypercalcemia. Other endocrine syndromes associated with primary lung carcinomas include gynecomastia, hyperglycemia, thyrotoxicosis, and skin pigmentation. Hematologic disorders, including thrombocytopenic purpura, leukemoid reaction, myelophthisic anemia, polycythemia, and marantic thrombosis, may also occur. Diagnosis The principal sources of diagnostic information are the history, which raises the suspicion of tumor and provides early localizing information, and the chest x-ray, which shows the lesion, its location, and its anatomic effects. However, large-scale studies at several cancer centers did not demonstrate any advantages for lung cancer screening using chest x-rays and sputum sample analysis. Although cancers were occasionally detected earlier using these methods, early detection did not appear to affect the overall survival of patients. When lung cancer is suspected, the next step after chest x-ray is to obtain tissue for histologic confirmation of the diagnosis. Physical examination is usually nonspecific. Signs of metastatic disease (enlarged lymph nodes or hepatomegaly) may be found occasionally. Other extrapulmonary physical manifestations are discussed above. X-ray patterns depend on the site of involvement. In asymptomatic patients, a peripheral nodular mass is often seen on chest x-ray. Lesions cannot be detected if they are < 5 to 6 mm in diameter. Previous x-rays are valuable for discerning new growth. With smaller solitary nodules, overpenetrated x-rays and chest CT may show calcification; the amount of calcification must be more than a fleck to diagnose a benign tumor or chronic granulomatous process and to exclude lung cancer. CT may also show small lesions invisible with other techniques and may be useful in staging by suggesting the presence or absence of nodal spread. MRI of the chest is occasionally needed; it is most helpful in imaging chest wall and vertebral body extension of apical Pancoast tumors. In symptomatic patients, the chest x-ray may show bronchial narrowing and irregularity, parenchymal infiltration, or atelectasis. Cavitation may be visible in an obstructed area or within a peripheral tumor. Obstructive emphysema is not common. Rarely, x-rays show zones of infiltration or obstruction in separate lobes that cannot be explained by a single neoplastic focus but result from diffuse submucosal lymphatic permeation of the bronchial tree. Pleural effusions are often associated with infiltrating or peripheral tumors; cytologic examination of pleural fluid or pleural biopsy may provide the diagnosis. Rarely, sputum is positive for tumor cells when there is no demonstrable focus of disease. The use of thoracic MRI is experimental in lung cancer diagnosis and treatment. MRI may provide a more accurate definition of tissue planes before surgical resection of lung cancers. Bronchoscopy is used to visualize and biopsy bronchial tumors. With a rigid bronchoscope, the visual field is limited to the major bronchi and their primary divisions, but the extent of the tumor can be effectively determined by carinal and random biopsy, and the resistance produced by extrabronchial masses can be sensed. With a flexible bronchoscope, the subsegmental bronchi can be explored to demonstrate and to sample tumors by washings, brushings, and biopsy. Many surgeons perform a preoperative mediastinoscopy to evaluate the mediastinal and hilar lymph nodes, to confirm the diagnosis, and to separate operable from inoperable tumors. Exploratory thoracotomy is required in < 10% of cases to establish the diagnosis and resectability of lung cancer. Contraindications include distant or mediastinal metastases and cardiorespiratory insufficiency. Exploration is unnecessary when metastases are demonstrated by mediastinoscopy, by parasternal mediastinotomy (which has largely replaced scalene node exploration), or by pleural or liver biopsy. Palpable lymph nodes and metastatic skin nodules provide important diagnostic material. Staging lung cancer is useful in prognosis as well as in comparison and selection of treatment. Staging may be done clinically but is more accurate with procedures that yield information about the extent of local and systemic disease, especially thoracotomy. CT may detect metastases in the liver, brain, and adrenal glands. Radionuclide scans may indicate skeletal involvement due to metastasis. Conventional bone x-rays or MRI is often used to confirm abnormal bone scan findings. Cytologic studies of sputum and tissue biopsy may directly establish the presence of primary tumors and metastases. The TNM (tumor, node, metastasis) system is a standard staging classification for non-small cell carcinoma. Small cell carcinoma has usually metastasized by the time it is diagnosed; it is staged as either limited (confined to one hemithorax with or without involvement of mediastinal and ipsilateral supraclavicular lymph nodes) or extensive (spread beyond this point). Differential Diagnosis Differential diagnosis of pulmonary nodules includes foreign bodies, nonsegmental pneumonia, and endobronchial and focal pulmonary manifestations of TB, systemic mycoses, autoimmune disease, and metastatic disease caused by an extrathoracic primary cancer. Solitary pulmonary nodules are particularly difficult to differentiate. A solitary pulmonary nodule is a single lesion, regardless of size, surrounded by lung parenchyma on at least 2/3 of its circumference, not touching the hilum or mediastinum, and without associated atelectasis or pleural effusion. Important causes include neoplasms, infections, and collagen vascular diseases. About 40% of solitary pulmonary nodules are malignant; 90% of these are bronchogenic carcinoma. The most common infectious cause may be Coccidioides immitis, Histoplasma capsulatum, or Mycobacterium tuberculosis, depending on the geographic location. Of collagen vascular diseases, RA and Wegener's granulomatosis are the most common causes. Solitary pulmonary nodules should first be evaluated by comparison with previous chest x-rays, if available. A lesion that has not enlarged in >= 2 yr suggests a benign etiology. CT scanning helps detect calcification (usually a sign of a benign etiology) and associated nodules. Determining the etiology of enlarging or new lesions requires culture and histologic examination. Culture specimens and tissue can be obtained by transthoracic needle aspiration, transbronchial biopsy, thoracoscopy, or thoracotomy. A lesion should be considered benign only when a specific diagnosis is obtained. Benign diseases rarely cause the superior vena cava syndrome, although TB, fungal infections, retrosternal thyroid, and aortic aneurysms may. Malignant neoplasms, including lymphoma, Hodgkin's disease, small cell carcinoma, squamous cell carcinoma, germ cell tumors, and breast cancer, frequently cause the syndrome. Prognosis and Prophylaxis Bronchogenic carcinoma has a poor prognosis. On average, patients with untreated bronchogenic carcinoma survive 8 mo; about 10 to 35% of tumors are resectable, but the overall 5-yr survival rate is approximately 13%. In patients with well-circumscribed, slow-growing tumors, the 5-yr survival rate after excision ranges from 15% in patients with stage IIIA non-small cell carcinoma to 70% in patients with stage I non-small cell carcinoma. Best results are obtained in patients with peripheral nodular lesions treated by lobectomy. Second primary lung cancers develop in 6 to 12% of survivors. Because small cell carcinoma has almost always spread beyond the primary site at the time of diagnosis, it is usually inoperable. Rarely, early-stage small cell carcinoma can be surgically resected, but because tumors are likely to recur, adjuvant chemotherapy with cisplatin and etoposide is usually recommended. A second primary cancer develops after treatment of early-stage small cell carcinoma in 25 to 50% of cases. Prevention of bronchogenic carcinoma includes avoiding tobacco and exposure to potentially carcinogenic substances in industry. Studies of the chemoprophylaxis of second primary cancers are ongoing. Treatment Surgery is the treatment of choice for non-small cell carcinoma stages I and II; patients who have stage IV or IIIB carcinoma with a malignant pleural effusion are not candidates for surgery. Patients with cancer classified as T3N0M0 or T3N1M0 (because of chest wall invasion) should be considered for surgical resection. Resection should be performed in the absence of contraindications, namely, evidence of spread beyond the lung, endobronchial location of tumor too close to the trachea, and other serious conditions (eg, coronary artery disease or the inadequate lung function of COPD). A CT scan of the chest and upper abdomen (including liver and adrenal glands) should be obtained for all patients being considered for surgery. An MRI scan or a CT scan of the brain should be obtained for all patients being considered for surgery if there are any abnormal neurologic signs and symptoms, such as cranial nerve palsies, changes in visual fields, decreased level of consciousness, or concentration deficits. A radionuclide bone scan is needed if a patient complains of bone pain or tenderness or if serum alkaline phosphatase is elevated due to an increased bone fraction. Elderly patients should not be excluded from surgical resection. Lung cancer is a highly aggressive tumor in the elderly. Patients with untreated lung cancer usually survive < 8 mo, compared with an average normal life expectancy in the USA of 11.1 and 14.8 yr, respectively, for men and women aged 70 yr. The limiting factor for survival is the tumor, not age. Central endobronchial lesions usually require pneumonectomy and removal of neighboring lymph nodes to provide a safe plane of bronchial division proximal to the tumor. Tumors extending into the chest wall can be removed en bloc; preoperative radiation has been reported to be beneficial in apical Pancoast tumors. The use of neoadjuvant chemotherapy in stages II, IIIA, and IIIB non-small cell carcinoma is promising. When administered before surgery in stage II or IIIA and before definitive radiation therapy in stage IIIA or IIIB, neoadjuvant chemotherapy can significantly reduce tumor burden and improve disease-free and overall survival. Some studies of adjuvant chemotherapy show promise; however, mixed results have prevented formation of a consensus on its role in surgically resected or definitively radiated non-small cell carcinoma. Pulmonary function assessment does not provide clear-cut answers to the question of operability, but there are some simple rules for performing a thoracotomy. The physician should keep in mind that the extent of resection can be determined only at operation, and pneumonectomy may be needed. The functional criteria for pneumonectomy are a forced expiratory volume in 1 sec (FEV1) of > 2 L and equal to > 50% of the observed forced vital capacity plus a partial pressure of arterial CO2 (PaCO2) that is normal at rest. If any of these criteria is not met, regional lung function should be assessed by a quantitative differential perfusion scan. (The predicted postoperative FEV1 equals the percent of perfusion to the nonresected lung multiplied by the preoperative FEV1.) If these studies indicate that the patient's FEV1 will still be > 800 mL or > 30 to 40% of the predicted normal FEV1 after pneumonectomy, the risk can be considered acceptable; the closer the value comes to either of these criterion, the more limited the patient's activity will be. Radiation therapy is of proven benefit for controlling bone pain, certain tumor types in the superior vena cava syndrome, spinal cord compression, brain metastasis, hemoptysis, and bronchial obstruction. The use of postoperative radiation therapy does not appear to benefit or to be justified in patients with stage I or II carcinoma. Sometimes radiation therapy is used instead of surgery when thoracotomy is contraindicated because of cardiorespiratory insufficiency or another serious disease. For 3 mo after radiation, patients should be closely monitored for x-ray and clinical signs of radiation pneumonitis (including cough, dyspnea, and fever), which may be controlled by giving prednisone 60 mg/day po for about 1 mo, then gradually tapering it off. Prophylactic cranial radiation therapy should be reserved for patients with small cell carcinoma who have shown a complete response to treatment. It decreases subsequent brain metastasis but has not been shown to prolong overall survival. Brachytherapy can be effective in the treatment of endobronchial lesions and, when they obstruct major bronchi, in their palliation. Chemotherapy with multiple drugs, particularly cisplatin and topoisomerase inhibitors--with or without radiation therapy--has yielded higher survival rates than surgery has in patients with small cell carcinoma; cures are rare. Some improved results with drugs have been reported, but studies to determine the most effective chemotherapeutic combination for bronchogenic carcinoma are ongoing. Chemotherapy in unresectable stage IIIA, IIIB, or IV non-small cell lung carcinomas appears to improve median survival by 6 to 12 wk on average and can effectively ameliorate symptoms of the disease in patients who respond. Drugs active in this disease include platinum compounds (cisplatin and carboplatin), vinca alkaloids (vinorelbine, vincristine, and vinblastine), taxines (docetaxel and paclitaxel), and various topoisomerase inhibitors. Bronchodilator drugs, O2, laser bronchoscopy, and physiotherapy may be needed for airway obstruction. Antibiotics are given to treat complicating infections. Solitary metastasis or, occasionally, multiple metastases to the lungs have been excised after removal of the primary tumor; the 5-yr survival rate is about 10%. Anxiety and persistent pain are common in patients with incurable lung cancer. Sedatives, narcotics, and other drugs in combination are required. Because many patients with lung cancer die, terminal care must be anticipated. In the end stages, high-dose morphine via IV drip may be required to alleviate the distressful sense of air hunger and pain. Advances in palliative care, including the development of potent transdermal drugs (such as fentanyl), have led to improvement in terminal care, with an increasing number of patients able to peacefully die at home. If a histologic diagnosis of superior vena cava syndrome is made, therapy consists of chemotherapy (for small cell carcinoma, lymphoma, or germ cell tumors) or radiation therapy (for breast cancer, squamous cell carcinoma, or lymphoma). When this syndrome is due to lung cancer, corticosteroids are less useful than when it is due to other diseases, such as lymphoma, but they may be of some benefit. Benign bronchial tumors should be surgically removed because of the adverse effects of location, possibility of growth, and potential for malignant transformation. Most benign peripheral tumors are not diagnosed until surgical exploration and excision.
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