Neoplastic Disease of the Pleura

Henri G. Colt

ETIOLOGY AND PATHOPHYSIOLOGY

Neoplastic disease of the pleura can be primary, arising from the cellular elements of the pleural surface (e.g., mesothelial tissue), or metastatic, arising from either thoracic or extrathoracic sites. Metastatic pleural tumors comprise most pleural neoplasms. These resemble the primary tumor histologically and are usually associated with roentgenographically apparent pleural effusion or thickening.

Primary tumors of the pleura are rare. They are classified as benign mesotheliomas (i.e., solitary or localized fibrous) or diffuse malignant mesotheliomas. Solitary fibrous tumors of the pleura occur equally in men and women with a peak incidence in the fourth to sixth decades. Tobacco smoking and exposure to asbestos do not appear to increase the risk for these benign tumors, which are usually grossly well encapsulated and histologically composed of fibrous elements. Similar lesions have been reported as postinflammatory tumors of the pleura, leading to speculation that they are part of a spectrum of mesothelial cell response to a variety of stimuli. Immunohistochemical, ultrastructural, and tissue culture studies were previously felt to support a mesenchymal origin, but most agree now that these tumors derived from fibroblasts have the potential for multidirectional differentiation.

Malignant pleural mesothelioma (MPM), on the other hand, while also rare, has a well-described relationship with occupational exposures, noted in about 80% of patients with MPM, most of whom report exposure to asbestos. The pathogenesis of other metastatic malignant pleural disease, also referred to as pleural carcinomatosis or secondary pleural metastasis, is less clear. Most frequently caused by lung, breast, and gastrointestinal adenocarcinomas, the prognosis for these tumors is poor, with median survivals of only about 9 months. Other less-common primary tumors are those of the ovary, pancreas, liver, kidney, uterus, adrenal glands, testis, larynx, and thyroid. In addition, benign pelvic tumors can be associated with pleural effusion and ascites (Meigs–Salmon syndrome) that subside following tumor resection. The prognosis for patients with malignant pleural disease from non–small-cell lung cancer is even worse, prompting a recent change in TNM staging from T4 to M1.

CLINICAL PRESENTATION AND DIAGNOSIS

Clinically, 30% to 40% of patients with pleural tumors are asymptomatic at the time of diagnosis; others complain of chest pain, cough, dyspnea, and weight loss in decreasing frequency. Tumors can reach enormous size. They can be attached to the pleura by a pedicle and lead to a sensation of something moving about in the chest after a positional change. Other times they may affect diaphragmatic surfaces. Rarely, they cause lobar collapse or superior vena caval obstruction. They may present as wide-based parietal pleural abnormalities, as well as pleural thickening noted on chest radiographs or computed tomography (CT) scans. Infrequently, tumors involve the visceral pleural surface, presenting radiographically as solitary pulmonary nodules. Secondary pleural metastases are frequently noted at post mortem examinations in patients from cancer but without pleural effusions. These deposits probably result from hematogenous spread, although some investigators emphasize a role for lymphatic obstruction in view of frequently noted swollen lymphatics along the posterior and inferior costal parietal pleura during thoracoscopic inspection.

In patients with benign disease, physical examination is usually unrewarding but may show evidence of clubbing (<20%), or osteoarthropathy or arthropathy (<15%) simulating rheumatoid arthritis. The chest roentgenogram usually reveals a localized mass; pleural effusion occurs in fewer than 15% of cases. In some patients with large tumors, hypoglycemia has been reported. Needle biopsy, pleural fluid cytology, or pleural biopsy may suggest the diagnosis, but definitive diagnosis of solitary fibrous tumors of the pleura usually requires thoracoscopy, CT-guided cutting needle biopsy, or thoracotomy. Preoperative differential diagnoses include malignant mesothelioma, metastatic carcinoma, sarcomas, and bizarre pseudotumors related to the organization of a pleural exudate. Surgical resection is usually curative but can be difficult in cases of gross invasion of contiguous vascular, neural, or mediastinal structures. Recurrences may not appear for years following initial resection. Often, the arthropathy disappears with tumor resection but can recur with regrowth. It can then be relieved by further resection.

In patients with suspected malignant mesothelioma, tissue diagnosis is required after obtaining a good occupational history. Pleural fluid cytology results are often equivocal. Recent studies suggest a role for serum mesothelin-related proteins and osteopontin, but these may only support a presumptive diagnosis. Mesothelioma is rare, accounting for less than 1% of all cancer deaths in the general population; however, its incidence is rising because of (1) the delayed effects of an increase in the occupational exposure to asbestos; (2) increased awareness by pathologists of this disease; and (3) more accurate diagnostic methods, such as electron microscopy and immunohistochemistry. Today, it is felt that approximately 2,000 cases are diagnosed yearly in the United States. Tumors must be distinguished from other neoplasms such as soft-tissue sarcoma and leukemia or lymphoma involving the pleura.

Malignant mesotheliomas also occur as primary tumors of the peritoneum and tunica vaginalis of the testes; simultaneous occurrence of pleural mesothelioma with mesothelioma at these other sites has not been described, although patients may have both pleural and peritoneal involvement during the course of their illness. Pathologically, MPM tumor appears early as single or multiple, small, white or gray lesions; later it may produce a thick, gelatinous, gray–pink sheath enveloping the affected lung. It is noteworthy that thoracoscopic appearance can be misleading. Parietal pleura can appear normal, as is often the case in stage 1A malignant mesothelioma, or appear as a conglomeration of small or large nodules involving parietal, visceral, or both pleural surfaces.

Histologically, tumors are composed of epithelial and mesenchymal (fibrosarcomatous) elements and are classified as epithelial (54%), fibrosarcomatous (21%), or mixed (25%). Epithelial mesotheliomas are the most frequently diagnosed histologic type. Seven types of epithelial mesotheliomas are seen, the most common of which is tubulopapillary. Sarcomatoid mesotheliomas account for approximately 20% of mesotheliomas, and are usually positive on keratin staining. This is unlike most sarcomas. Twenty percent of epithelial mesotheliomas produce hyaluronic acid, which can be identified by specific stains. The presence of hyaluronic acid contributes to the increased viscosity often noted in pleural fluid from patients with mesothelioma. Carcinoembryonic antigen (CEA) has been reported as negative in 88% of mesotheliomas. This immunostaining procedure can be helpful in excluding mesothelioma from the diagnosis. Immunohistochemical and ultrastructural analysis of pleural neoplasms can lead to an accurate diagnosis of mesothelioma in most cases, although a careful review of an entire battery of tests often including CEA, Leu-M1, and mucicarmine staining is necessary. Electron microscopy is also helpful when abnormalities such as long, slender microvilli are noted. Increasingly, biologic markers of pleural malignancy are being studied, and differential gene expression between MPM, adenocarcinoma, and normal or benign mesothelium are being assessed.

In some patients, diagnosis can only be made retrospectively after careful review of the exposure history, clinical history, immunohistochemical stains and ultrastructural analyses, clinical and radiographic progressions of disease (usually one of gradual entrapment of the lung with associated pleural thickening, and dyspnea), and autopsy findings. Although the pathogenesis of malignant mesothelioma is unclear, asbestos is the single most important causative agent. This conclusion is based on (1) retrospective studies showing a strikingly higher incidence (300×) of malignant mesothelioma among asbestos workers; (2) studies showing a significantly higher incidence of asbestos exposure among new mesothelioma cases versus controls; and (3) direct measurements of significantly increased asbestos fiber content of the lungs of patients with mesothelioma (95%) with respect to controls. A shift has occurred in exposure history from primary users to end-users of asbestos (handlers of asbestos products, such as workers in the construction industry). A threshold amount of asbestos exposure necessary to induce mesothelioma is unknown but presumed. Cigarette smoking is not a risk factor for malignant mesothelioma, but the addition of smoking to asbestos exposure significantly increases risk for lung cancer. Histologic, biologic, and cellular prognostic factors such as microvessel density of tumor specimens, overexpression of COX-2, levels of MIB-1, and role for Simian SV40 virus (a DNA virus shown to induce mesothelioma in up 100% of hamsters after intrapleural injection) remain controversial.

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