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Lung carcinoma is one of the major problems of modern society. In the United States, it causes about 140,000 deaths annually; in England and Wales, it accounts for 40,000 deaths annually—about one-third of total cancer deaths and almost one-tenth of all deaths from any cause. The incidence has increased markedly since 1950 (approximately fivefold) and continues to increase. Rates of lung cancer vary greatly in different countries, principally due to differences in smoking habits.
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Lung carcinoma is more common in males; the male:female ratio was 7:1 in 1960 but has fallen to about 2:1. Lung cancer has overtaken breast cancer as the leading cause of death by cancer in women. It is a disease of older individuals, being rare under 40 years of age.
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Cigarette smoking is the main cause of lung carcinoma (Chapter 12: Disorders Due to Chemical Agents). Heavy cigarette smokers (over 40 cigarettes a day) have a 20-fold increase in incidence compared to nonsmokers. Cessation of smoking decreases the risk: 10 years after stopping smoking, the risk falls to that of a nonsmoker. The risk is only slightly less with “low-tar” filter cigarettes. Cigar smoking and pipe smoking carry a much lower risk (probably because of less smoke inhalation).
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The mechanism by which smoking causes lung carcinoma is not clear. A large number of potent carcinogens are present in cigarette smoke, including polycyclic hydrocarbons, aromatic amines, and heavy metals such as nickel. Any or all of these may be involved in human carcinogenesis (Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia).
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Cigarette smoking produces changes in the respiratory epithelium of humans. There is loss of cilia and progression from squamous metaplasia through all degrees of dysplasia to carcinoma in situ. Squamous metaplasia alone is not premalignant, but dysplasia is. Dysplasia is very uncommon in nonsmokers. In patients with lung carcinoma, the respiratory epithelium away from the neoplasm frequently shows dysplasia and carcinoma in situ.
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Cigarette smoking is most strongly associated with squamous carcinoma and small cell undifferentiated carcinoma and to a lesser degree with adenocarcinoma.
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Industrial Carcinogens
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The best-known occupational lung carcinogen is asbestos, exposure to which increases the risk of lung carcinoma as documented among World War II shipyard workers (Chapter 35: The Lung: II. Toxic, Immunologic, & Vascular Diseases). The risk of lung cancer following asbestos exposure is compounded by cigarette smoking.
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Mining of many different heavy metals (eg, uranium, nickel, chromate, gold) is also associated with an increased risk of lung cancer.
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Historically, the miners of Jstocáchymov in the Czech Republic and Schneeberg in Germany were described as developing “mountain sickness” for 4 centuries before it was realized that the sickness was lung carcinoma from exposure to natural radioactive elements in the mines.
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The common urban pollutants are ozone and oxides of nitrogen and sulfur. While there is great concern, most studies to date have failed to demonstrate a significant association between lung carcinoma and urban pollutants.
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There is a slightly increased incidence of lung carcinoma—especially peripherally located adenocarcinoma—in areas of scarring due to prior infarcts, granulomas, or diffuse fibrosis.
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The International Classification of Lung Carcinoma introduced by the World Health Organization recognizes four major and several minor types.
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Squamous (Epidermoid) Carcinoma
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Squamous carcinoma arises in metaplastic squamous epithelium of the bronchi. It is characterized by marked cytologic pleomorphism, intercellular bridges (desmosomes) between tumor cells, and keratinization of the cytoplasm (Figure 36-2A). Squamous carcinoma has a strong male predominance, is strongly associated with cigarette smoking, and accounts for 25–35% of all lung cancers. There may be a preceding phase of dysplasia and carcinoma in situ. Squamous carcinoma tends to remain localized more than the other types, resulting in large masses in the lung. Central cavitation is common.
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Adenocarcinoma of the lung, as elsewhere, shows formation of glands or secretion of mucin by the tumor cells (Figure 36-2B). Several different forms of adenocarcinoma are recognized: (1) adenocarcinoma arising centrally in large bronchi, (2) adenocarcinoma arising in peripheral scars in the lungs (scar carcinoma), and (3) bronchioloalveolar carcinoma arising in small bronchioles or alveoli, probably from the surfactant-producing Clara cells or from type II pneumocytes. The tumor cells typically line intact alveoli, producing a striking histologic appearance (Figure 36-2B). Bronchioloalveolar carcinoma may be solitary (good prognosis) or multiple (bad prognosis). The histologic appearance of bronchioloalveolar carcinoma may be mimicked by metastatic adenocarcinoma, especially from the pancreas or ovary. Adenocarcinoma constitutes 25–35% of lung carcinomas, has an equal sex incidence, and is associated with cigarette smoking although not as strongly as squamous carcinoma and small cell undifferentiated carcinoma.
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Small Cell Undifferentiated (Oat Cell) Carcinoma
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Small cell undifferentiated carcinoma is composed of small round to oval cells with scant cytoplasm, a high nuclear:cytoplasmic ratio, and hyperchromatic nuclei that do not have prominent nucleoli (Figure 36-2C). Small cell undifferentiated carcinoma is believed to arise from neuroendocrine cells in the bronchial mucosa (Figure 36-1); it stains positively with neuroendocrine immunologic markers such as chromogranin and neuron-specific enolase and has neurosecretory granules in the cytoplasm on electron microscopy. Small cell undifferentiated carcinoma is highly malignant. Bloodstream metastasis occurs early in the course of the neoplasm.
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Small cell undifferentiated carcinomas account for 10–25% of lung carcinomas and are strongly associated with smoking. They are more common in males. They almost always occur in the large bronchi near the hilum of the lung (Figure 36-3).
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Large Cell Undifferentiated Carcinoma
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This tumor type comprises 5–20% of lung carcinomas and is composed of large cells that show no squamous or glandular differentiation on light micros-copy. In some cases, immunohistochemical or electron microscopic examination is able to detect early glandular, squamous, or neuroendocrine differentiation. Pleomorphic giant cell carcinoma is a highly malignant variant with numerous multinucleated giant cells.
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Mixtures of the above histologic types are common (eg, adenosquamous carcinoma), leading to the hypothesis that lung carcinoma arises from a primitive cell that has the capability to differentiate in several directions.
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Two distinct gross types of lung carcinoma can be distinguished.
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Central (Bronchogenic) Carcinoma (75%)
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Central carcinomas arise in the first-, second-, or third-order bronchi near the hilum of the lung (Figure 36-3) and tend to be hidden in chest x-rays during their early growth phase. They can, however, be seen and biopsied at an early stage by bronchoscopy. All histologic types occur, but the majority are squamous or small cell undifferentiated carcinomas.
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The earliest clearly malignant lesion is carcinoma in situ, which on bronchoscopy may produce no visible change or simply a plaque-like mucosal thickening. However, cytologic examination of sputum shows malignant cells. The term occult carcinoma is used when sputum cytology shows malignant cells and no tumor can be found by radiography and bronchoscopy.
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From its mucosal origin, the neoplasm grows into the bronchial lumen (causing ulceration, bleeding, or obstruction) and infiltrates the bronchial wall and adjacent lung parenchyma. Infiltration tends to occur very early. Rarely, tumor growth is mainly endobronchial; in most cases, there is extensive invasion of the bronchial wall and lung parenchyma, forming a large hilar mass with areas of necrosis and hemorrhage.
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Peripheral Lung Carcinoma (25%)
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Peripheral carcinomas arise in relation to small bronchi, bronchioles, or alveoli. These neoplasms are visible on chest x-ray at an early stage as a circumscribed mass but cannot be seen by bronchoscopy.
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Peripheral lung carcinomas tend to be adenocarcinomas and, less commonly, squamous carcinomas. Small cell undifferentiated carcinoma rarely occurs in the periphery.
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Spread of Lung Carcinoma
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With central lung carcinomas, invasion involves vital mediastinal structures such as the superior vena cava and pericardium. Peripheral lung carcinomas tend to extend locally in the lung, with involvement of the pleura occurring early.
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Lymphatic metastasis to lymph nodes occurs early in all types of lung carcinoma, most commonly in small cell undifferentiated carcinoma and least frequently in well-differentiated squamous carcinoma. Involvement of the hilar and scalene lymph nodes (Figure 36-4) is present in 50% of cases at presentation.
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Retrograde permeation of pleural lymphatics (pleural lymphatic carcinomatosis) occurs in advanced lesions, leading to multiple pleural nodules, pleural effusion, and a typical reticular appearance on chest x-ray.
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Bloodstream Metastasis
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Hematogenous metastasis also occurs early, and patients with lung carcinoma frequently present with a distant metastasis. In small cell undifferentiated carcinoma, distant metastases are almost invariably present at the time of diagnosis. Hematogenous metastases occur later in the course of non-small cell carcinomas.
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Common sites of metastasis of lung carcinoma are the adrenals (50%), liver (30%), brain (20%), bone (20%), and kidneys (15%).
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Staging of Lung Carcinoma
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The tumor node metastases (TNM) (T = tumor, N = node, M = metastases) staging system has been recommended for classification of lung carcinoma (Table 36-1). Using this system, lung carcinoma is divided into four clinical stages that are derived from combinations of T, N, and M criteria (Table 36-1). Precise staging preoperatively by computer tomography (CT) scan and bronchoscopy determines operability and the treatment modalities that will be used. Pathologic staging of any resected specimen determines prognosis and indications for postoperative radiation and chemotherapy.
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The earliest symptoms of bronchogenic carcinoma are cough, hemoptysis, dyspnea, chest pain, and weight loss. Unfortunately, these occur at a relatively advanced stage. A minority of cases of lung carcinoma are detected at an asymptomatic stage by routine chest x-ray.
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Bronchial Obstruction
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A few patients with central lesions present with features of bronchial obstruction, including unresolving pneumonia, lung abscess, and bronchiectasis.
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Patients with lung carcinoma may also have symptoms due to local invasion of nearby structures by the neoplasm. Direct invasion of the pleura and pericardium results in pleural and pericardial effusion. The finding of carcinoma cells in aspirated effusion fluid is one method of diagnosis of lung carcinoma. Involvement of the thoracic duct at the lung hilum may result in chylothorax, and superior vena caval obstruction causes edema and congestion of the face and brain (superior vena caval syndrome). Large hilar neoplasms may invade the esophagus, causing dysphagia and tracheoesophageal fistula.
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This is a specific clinical presentation of lung carcinoma resulting from an apical lung carcinoma (usually squamous) that invades the apical pleura. The tumor causes destruction of the T1 intercostal nerve and leads to a T1 motor and sensory deficit—weakness and wasting of small muscles of the hand and numbness on the medial side of the arm—and the cervical sympathetic trunk, causing Horner's syndrome—ptosis of the eyelid, pupillary constriction, and absent sweating on the side of the lesion.
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A significant number of patients with lung carcinoma present with evidence of lymph node or hematogenous metastases. Cervical lymph node enlargement, pathologic fractures due to bone metastasis, and brain masses are common presenting features.
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Paraneoplastic Syndromes
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A minority of patients present with a variety of signs or symptoms that cannot be attributed to the direct effects of destruction by primary or metastatic tumors; these conditions are referred to as paraneoplastic syndromes (Table 36-2). These include the effects of secretion of hormones by the neoplasm (ectopic hormone syndromes). The mechanisms that cause many of the other paraneoplastic syndromes are largely unknown, although autoimmune phenomena have been postulated.
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Lung carcinoma must be considered a possibility when a patient presents with any of the protean clinical manifestations described above. This is particularly so if there is a strong smoking history. Chest x-ray and computerized tomography are effective for demonstrating the presence of a mass in the lung, but they do not predict the pathologic diagnosis and have a significant failure rate in detection of small hilar lesions.
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The diagnosis of lung carcinoma must in every case be substantiated by pathologic examination. In addition to cytologic examination of sputum for malignant cells, bronchoscopy is useful for visualization of central lung cancers, direct biopsy, recovery of brush specimens for cytologic examination, and taking of transbronchial needle biopsies from peripheral lung masses. Percutaneous needle aspiration biopsy may be done under radiologic guidance when a mass lesion is visible on chest x-ray or CT scan. Open lung biopsy may rarely be necessary for diagnosis, especially in peripheral lesions. Biopsy of metastatic lesions in other organs frequently provides the first evidence of a previously undiagnosed lung carcinoma. Aspiration of pleural effusions and biopsy of enlarged cervical lymph nodes and brain masses are examples.
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With all of these techniques, both cytologic and histologic examinations provide not only the diagnosis but also the classification of lung carcinoma.
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Treatment & Prognosis
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The overall 5-year survival rate of patients with lung cancer is a dismal 10–20%. Recent chemotherapeutic regimens combined with aggressive surgery have shown an improving trend.
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Small cell undifferentiated carcinoma is treated primarily by chemotherapy, which has improved median survival from less than 6 months to about 2 years. Surgery is contraindicated because this type of tumor is almost invariably stage III or IV at the time of presentation. Few patients survive 5 years.
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Non-small cell carcinoma (squamous carcinoma, adenocarcinoma, and large cell undifferentiated carcinoma) tend to remain localized to the lung for longer periods, and surgical resection is possible in about 30% of cases. Five-year survival rates are as follows: patients with surgically resected stage I tumors, 50%; patients with surgically resected stage II tumors, 20–30%; patients with stage IIIA tumors, 5–10%; and patients with stage IIIB or IV tumors, close to zero.
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The prognosis is similar for squamous carcinoma, adenocarcinoma, and large cell undifferentiated carcinoma, which all have overall 5-year survival rates of about 20–30%. Bronchioloalveolar carcinoma has a better prognosis, with a 60% survival rate at 5 years. Chemotherapy for squamous carcinoma and adenocarcinoma is largely palliative.