Chapter 36. The Lung: III. Neoplasms

Incidence

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.

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.

Etiology

Cigarette Smoking

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).

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).

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.

Cigarette smoking is most strongly associated with squamous carcinoma and small cell undifferentiated carcinoma and to a lesser degree with adenocarcinoma.

Industrial Carcinogens

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.

Mining of many different heavy metals (eg, uranium, nickel, chromate, gold) is also associated with an increased risk of lung cancer.

Radiation

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.

Urban Pollution

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.

“Scar Cancer”

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.

Classification

(Figures 36-1 and 36-2)

The International Classification of Lung Carcinoma introduced by the World Health Organization recognizes four major and several minor types.

Squamous (Epidermoid) Carcinoma

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.

Adenocarcinoma

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.

Small Cell Undifferentiated (Oat Cell) Carcinoma

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.

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).

Large Cell Undifferentiated Carcinoma

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.

Mixed Types

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.

Pathology

Two distinct gross types of lung carcinoma can be distinguished.

Central (Bronchogenic) Carcinoma (75%)

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.

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.

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.

Peripheral Lung Carcinoma (25%)

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.

Peripheral lung carcinomas tend to be adenocarcinomas and, less commonly, squamous carcinomas. Small cell undifferentiated carcinoma rarely occurs in the periphery.

Spread of Lung Carcinoma

(Figure 36-4)

Local Invasion

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.

Lymphatic Metastasis

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.

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.

Bloodstream Metastasis

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.

Common sites of metastasis of lung carcinoma are the adrenals (50%), liver (30%), brain (20%), bone (20%), and kidneys (15%).

Staging of Lung Carcinoma

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.

Clinical Features

(Figure 36-4)

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.

Bronchial Obstruction

A few patients with central lesions present with features of bronchial obstruction, including unresolving pneumonia, lung abscess, and bronchiectasis.

Local Invasion

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.

Pancoast's Syndrome

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.

Distant Metastases

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.

Paraneoplastic Syndromes

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.

Diagnosis

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.

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.

With all of these techniques, both cytologic and histologic examinations provide not only the diagnosis but also the classification of lung carcinoma.

Treatment & Prognosis

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.

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.

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.

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.

While the term “lung cancer” commonly denotes the types of lung carcinomas described above, one should bear in mind that many other benign or malignant neoplasms as well as inflammatory lesions may present as a mass in the lung.

Bronchial carcinoid tumor, mucoepidermoid tumor, and adenoid cystic carcinoma arise in the bronchi, usually near the hilum of the lung, and are slowly growing neoplasms that infiltrate locally but have a very low incidence of metastasis. They therefore behave like low-grade malignant neoplasms. Bronchial carcinoid tumors arise from neuroendocrine cells and resemble carcinoid tumors of the intestine (Figure 36-5). Rarely, they secrete sufficient amounts of serotonin to cause the carcinoid syndrome (see Chapter 41: The Intestines: III. Neoplasms). Mucoepidermoid carcinoma and adenoid cystic carcinoma are probably derived from bronchial mucous glands and resemble the corresponding tumors in the salivary glands (see Chapter 31: The Oral Cavity & Salivary Glands).

Other tumors of the lung include sclerosing hemangioma and chondroid hamartoma (Figure 36-6). Chondroid hamartoma is a benign hamartomatous lesion composed of a disorganized mass of cartilage, fat, and spaces lined by bronchial epithelium. Pulmonary blastoma and carcinosarcoma are malignant neoplasms involving the lung parenchyma. Inflammatory lesions such as infectious granulomas (Chapter 34: The Lung: I. Structure & Function; Infections), plasma cell granuloma, and inflammatory pseudotumor may all present with mass lesions in the lung. All these lesions are rare and have specific types of biologic behavior. They are mentioned here merely to emphasize that the diagnosis of a mass lesion of the lung requires histologic examination.

Metastatic neoplasms occur commonly in the lung, which acts as the first capillary bed in the systemic circulation for entrapment of tumor emboli. It is often difficult to distinguish metastatic from primary lung neoplasms on the basis of histologic examination alone; a full clinical evaluation of the patient is necessary to make a diagnosis of metastatic carcinoma. Carcinomas, sarcomas, melanomas, and almost any other malignant neoplasm may give rise to lung metastases. Metastatic lung tumors are more common than primary lung cancers.

Pleural Effusion

A pleural effusion is a collection of fluid in the pleural cavity. Simple accumulation of small amounts of fluid in the pleural cavity does not cause any symptoms. Large effusions interfere with lung expansion during inspiration, causing a reduction in vital capacity. The presence of a large pleural effusion can be detected clinically by the absence of chest wall movement, shift of mediastinal structures to the opposite side, decreased breath sounds, and dullness to percussion over the effusion. Small pleural effusions cannot be detected clinically and require radiologic examination. When more than about 300 mL of fluid is present in an adult's pleural cavity, it can be seen on an upright chest x-ray.

Once the presence of an effusion has been established, aspiration of fluid is helpful to identify its cause. Low specific gravity, low protein concentration, and lack of inflammatory cells identify a transudate. Exudates have a specific gravity over 1.015, a protein level of over 1.5 g/dL, and many inflammatory cells. Bacterial infection commonly produces a frankly purulent exudate (empyema). Hemorrhagic exudates occur in malignant effusions, tuberculosis, uremia, and pulmonary infarction. Cytologic examination of effusion sediment for malignant cells is frequently positive when malignant neoplasia is the cause of the effusion (Table 36-3).

Pleural biopsy provides a core of pleural tissue for histologic examination and is useful in the diagnosis of tuberculosis or cancer.

Chylothorax

Chylothorax is a specific kind of pleural effusion characterized by accumulation of chyle in the pleural cavity. Chyle is a milky fluid of high fat content that is normally present in the thoracic duct. Chylothorax may be differentiated from other turbid pleural effusions by the presence of chylomicrons and a high triglyceride content. The presence of chylothorax is evidence of an abnormal communication between the thoracic duct and the pleura. This may result from injuries to the thoracic duct by trauma and surgery or by infiltration of the thoracic duct by malignant neoplasms.

Pneumothorax

Pneumothorax is the presence of air in the pleural cavity. Pneumothorax may result from trauma, air being sucked in through a chest wall defect or entering via a laceration of the lung surface; or from spontaneous rupture of a bulla on the lung surface into the pleural cavity. Spontaneous pneumothorax may complicate many lung diseases such as bronchial asthma, emphysema, and tuberculosis, or it may occur in healthy, young, muscular individuals and may be recurrent. In this instance, rupture of subpleural blebs is believed to be responsible.

Patients with pneumothorax present with acute onset of chest pain and dyspnea, directly proportionate to the amount of air that accumulates in the pleural cavity. When the pneumothorax is progressive, dyspnea rapidly worsens. Physical examination reveals an absence of chest expansion, mediastinal shift to the opposite side, decreased breath sounds, and a tympanic sound on percussion. The diagnosis is confirmed by chest x-ray.

In most cases, the air in the pleural cavity is reabsorbed, with reexpansion of the collapsed lung. Occasionally, a valve-like effect develops, producing a tension pneumothorax, or spontaneous resorption occurs so slowly that the collapsed lung begins to undergo fibrosis. In these cases, insertion of a chest tube is essential.

Neoplasms of the Pleura

Primary Mesothelial Neoplasms

Benign Fibrous Mesothelioma

Fibrous mesothelioma is a rare benign neoplasm of the pleura, usually discovered incidentally on routine chest x-ray. It appears grossly as a localized growth of firm, dense fibrous tissue on the visceral pleura, often attached to the lung surface by a pedicle. Most fibrous mesotheliomas are small; rarely, they may reach large size. Microscopically, they are composed of fibroblast-like spindle cells and collagen. They do not invade, and the prognosis after surgical excision is excellent.

Malignant Mesothelioma

Malignant mesothelioma is a rare neoplasm strongly related etiologically to asbestos exposure; many cases have occurred in World War II shipyard workers. There is a long lag period (as long as 40 years) between asbestos exposure and tumor development.

Malignant mesothelioma commonly occurs in the over-50 age group. Clinical presentation is with dyspnea and features of pleural effusion. Grossly, the tumor diffusely involves the pleura, encasing large areas of lung as a firm, grayish, gelatinous mass (Figure 36-7). Invasion of both lung parenchyma and chest wall occurs frequently. Microscopically, the tumor is biphasic, with a sarcomatoid spindle cell component and epithelial elements that form tubular and papillary structures. When the epithelial component predominates, differentiation from adenocarcinoma may be difficult.

The prognosis is very poor, with 50% of patients dead within 1 year after diagnosis and few survivals of more than 2 years.

Secondary Pleural Neoplasms

Secondary involvement of the pleura by malignant neoplasms is much more common than mesothelioma. Direct involvement of the pleura by lung carcinoma is the most common secondary pleural neoplasm. Metastases from distant sites such as the breast, colon, kidney, and thyroid also occur. Involvement of the pleura by malignant lymphoma is uncommon.

Secondary pleural neoplasms cause dyspnea and effusion. On x-rays, nodular pleural masses may be identified. The diagnosis may be established by identifying malignant cells in aspirated pleural fluid. The differentiation of secondary pleural neoplasms from malignant mesothelioma on the basis of cytologic features may be difficult. Immunoperoxidase techniques may be helpful; carcinoma is positive for keratin and frequently for other antigens such as carcinoembryonic antigen (CEA), Leu-M1, and BER-Ep4. Mesothelioma is positive for keratin and negative for CEA, Leu-M1, and BER-Ep4.