ABSTRACT: Diffuse malignant pleural mesothelioma is a rare and aggressive malignancy of the pleura that is usually caused by exposure to asbestos. Between 2,000 and 3,000 new cases are expected to be diagnosed annually in the United States. Difficulties in diagnosis, staging, and treatment set this disease apart from other malignancies. The variable clinical presentation and problems in establishing a definite histopathologic diagnosis result in significant delays in treatment. Three histologic subtypes of the disease are described in this review: epithelial, sarcomatous, and mixed histologies. The Butchart, International Mesothelioma Interest Group, and Brigham staging systems are the most commonly used staging systems. The disease’s natural history involves aggressive local growth, invasion of vital mediastinal structures, and death within 4 to 12 months without treatment. Single-modality therapy of any kind has failed to substantially alter this natural history. Aggressive, multimodality regimens that include surgery, radiation, and chemotherapy have resulted in improved survival in properly selected patients. However, innovative therapies are still needed to prolong survival in patients with early and advanced disease. [ONCOLOGY 16:907-925, 2002]
Diffuse malignant pleural mesothelioma is a rare malignant tumor with an annual incidence in the United States of 2,000 to 3,000 cases. Its natural history is characterized by local aggressiveness and invasion, which, left untreated, results in a median survival ranging between 4 and 12 months. Although asbestos exposure remains the most important epidemiologic factor in the development of this disease, the importance of the simian virus 40 (SV40) has been recently recognized.
Management of diffuse malignant pleural mesothelioma presents several challenges to physicians, from diagnosis and staging to treatment. The lack of randomized studies and the low incidence of this tumor are responsible for the absence of a consensus on how it should be treated.
Mesothelioma occurs most commonly in males (3:1 male-to-female ratio), is unilateral in most patients (95%) with a slight right-sided preponderance, and develops as a result of exposure to asbestos after a median latency period of 32 years. Although most patients are over age 55 at the time of presentation, cases have been reported in younger patients, including children. Such cases are due to causes other than asbestos exposure. The majority of patients present with symptoms related to pleural effusion, such as dyspnea, cough, and chest pain. Other symptoms such as fatigue, weight loss, fever, and night sweats can also occur.
Initially, dyspnea develops as a result of pleural effusion, but as the tumor grows, it replaces the pleural space, and the lung becomes entrapped. Similarly, the chest pain that occurs due to the presence of pleural effusion is at first poorly localized and dull. As the tumor grows, however, intercostal nerves become entrapped, and the pain becomes localized. Unrelenting tumor growth results in mediastinal and abdominal invasion. Ascites, cachexia, chest and abdominal wall deformity, bowel obstruction, and cardiopulmonary compromise lead to the patient’s demise. Metastases in the brain, bone, and other organs rarely occur. However, such metastases are seen more frequently in patients who have received multimodality therapy.
On physical examination, most mesothelioma patients with early disease manifest only signs of pleural effusion such as decreased breath sounds. With advanced disease, palpable chest or abdominal masses can be present. Abdominal masses are a particularly ominous sign because they indicate transdiaphragmatic involvement and unresectability.
Laboratory tests are not very informative, although thrombocytosis (> 400 × 109/L) is thought to be an indicator of poor prognosis. Laboratory evaluation can reveal other nonspecific findings such as anemia of chronic disease, eosinophilia, and hypergammaglobulinemia.
Standard radiologic evaluation of mesothelioma patients should include a chest x-ray, computed tomography (CT) scan of the chest, and magnetic resonance imaging (MRI). Pleural effusions, plaques, and thickening can be seen on plain chest x-rays. However, resectability is best determined with CT and MRI scans, which can better assess the extent of invasion into the chest wall, mediastinum, and diaphragm. Surgeons debate whether MRI or CT scan offers more information and better precision in determining resectability; we have found MRI to be more informative, but the use of both tests in conjunction is quite effective in determining resectability.
Fluorodeoxyglucose positron-emission tomography (PET) has been used with increasing frequency at our institution, mainly to assess distant occult disease. The increased sensitivity of this modality was documented in a recent study of 18 consecutive patients with diffuse malignant pleural mesothelioma. The PET scan detected the presence of distant disease in two patients despite negative CT scans and was more sensitive than CT in detecting mediastinal adenopathy. Another study correlated survival with intensity of uptake on PET scan, indicating an ability to quantify tumor burden.[8,9]
Two-dimensional echocardiography is another useful test with which to determine resectability. This technique is based on the assessment of pericardial involvement and cardiac function.
When patients present with unilateral pleural effusion, the physician needs to relieve the symptoms (by draining the fluid) and establish the cause of the effusion. The three most commonly used methods for achieving these goals are thoracentesis with cytology, closed pleural biopsy, and open pleural biopsy via video-assisted thoracic surgery.
Thoracentesis is usually employed in the initial evaluation and management of these effusions. The effusion is effectively drained, and the fluid can be sent for cytologic and chemical analysis. Mesothelioma-related effusions are typically clear yellow. Thoracentesis, however, establishes a diagnosis in only 30% to 35% of cases due to its inability to distinguish tumor cells from reactive mesothelial cells. This low diagnostic yield has been improved with the assistance of histochemistry, immunohistochemistry, and electron microscopy.
Closed pleural needle biopsy can be used in an attempt to obtain pleural tissue and improve the diagnostic yield. However, for the most part, this is a blind technique with a high false-negative rate because the malignant mass may be missed and normal pleura biopsied instead. Video-assisted thoracic surgery is a minimally invasive technique that improves visualization, effectively drains all fluid by disrupting loculations, and provides an adequate number of tumor tissue samples for the various stains and electron microscopy.
Regardless of the procedure used, tumor cell seeding occurs at the biopsy sites, and chest wall masses eventually develop. Therefore, it is important to strategically place thoracentesis or biopsy sites so that they can be resected at the time of future cytoreductive surgery.
The three histologic subtypes of diffuse malignant pleural mesothelioma that have been described are epithelial, sarcomatous, and mixed. Patients with the epithelial subtype have a much better prognosis than patients with tumors of the other cell types. For the pathologist, diffuse malignant pleural mesothelioma presents a challenge because of the difficulty in distinguishing it from adenocarcinoma and, occasionally, sarcoma. Table 1 lists the criteria used to differentiate diffuse malignant pleural mesothelioma from adenocarcinoma.[14-16]
Numerous staging systems have been proposed for diffuse malignant pleural mesothelioma, but none have been widely accepted. A staging system should stratify survival and direct therapy. Butchart proposed the first staging system in 1976, based on 29 patients. However, there was no correlation between stage and survival. Two tumor/node/metastasis (TNM) systems have been proposed: the International Union Against Cancer system and the International Mesothelioma Interest Group system (Table 2). These staging systems, however, still need to be validated.
The Brigham/Dana-Farber Cancer Institute staging system, proposed by Sugarbaker and colleagues in 1993 and later revised in 1998, is based on a series of 183 patients who underwent extrapleural pneumonectomy and adjuvant chemoradiation. This system mainly defines resectability and nodal status. Positive resection margins or intrapleural nodes identify the disease as stage II, whereas positive extrapleural nodes or involvement of the diaphragmatic muscle or pericardium indicates stage III disease (Table 3 and Figure 1). Median survival following extrapleural pneumonectomy and adjuvant chemoradiation in patients with stage I, II, and III disease is 25, 20, and 16 months, respectively.