Background: Diffuse malignant pleural mesotheliomas (DMPMs) are highly lethal tumors that are becoming more common. Standard management approaches have provided limited effectiveness.
Methods: The literature on management has been revised, and the authors

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<!-- Inject Script Filtered --> present their data on outcomes for 120 patients treated with an aggressive trimodality approach.
Results: An aggressive trimodality approach including extrapleural pneumonectomy followed by chemoradiation produces low mortality and acceptable morbidity. The five-year survival rate in patients with epithelial histology and negative nodes approaches 40%.
Conclusions: Nodal status and histologic subtype are major predictors for survival in patients with early DMPM. A uniformly accepted staging system would allow comparison of treatment approaches from various institutions. More effective management interventions are required.

 

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Introduction

Mesotheliomas of the pleural cavity are relatively rare tumors. Generally, two types of pleural tumors can be referred to as mesotheliomas. The less common is the solitary (or localized) fibrous tumor of the pleura, previously known as "benign mesothelioma." This slow-growing, commonly benign, well-circumscribed tumor is pedunculated on a pleural-based pedicle and often is cured by resection. The tumor appears to originate from submesothelial rather than mesothelial or epithelial cells.¹ The more common variety is the diffuse malignant pleural mesothelioma (DMPM), a true mesothelial malignancy that is locally aggressive, invasive, and almost universally fatal. This multicentric tumor infiltrates the pleural space, results in a pleural effusion, and mechanically compresses the surrounding structures. Though distant metastatic lesions may be seen in up to 30% of cases in autopsy series, most patients die of locoregional invasion and compression of vital structures. The median survival for patients with DMPM is between four and 12 months, depending on the stage at presentation.

Etiology

Asbestos exposure is the best known and most common risk factor associated with DMPM.² Asbestos has commonly been used for insulation, and it also has been used in the shipbuilding industry and in construction. The amphibole type of asbestos is inhaled and collected in the peripheral alveoli during unprotected exposure. It eventually erodes and reaches the subpleural space where it continuously stimulates inflammation and carcinogenesis.² However, a history of asbestos exposure is elicited in only 80% of patients who present with mesothelioma. Other factors that may promote DMPM include chronic lung infections, tuberculous pleuritis, radiation, and some mineral fibers.^2,3 The simian virus 40 (SV40) has been implicated as a potential etiologic factor after sequences corresponding to its T antigens were isolated from human samples of diffuse malignant mesothelioma but not from adjacent normal lung.^4,5 Furthermore, tumors histologically identical to malignant mesothelioma have developed when SV40 DNA material is injected into the pleural cavities of hamsters.⁶ Cigarette smoking does not appear to be related to the development of mesothelioma, although the relationship among smoking, asbestos exposure, and lung cancer is clear.

Epidemiology

In the United States, 2,000 to 3,000 patients are diagnosed with DMPM each year, representing a 50% increase in the number of cases over the last decade. This increase probably reflects the long latency period between the asbestos exposure in the 1940s to 1960s and the clinical manifestation of DMPM.^7? The appearance of a new etiologic factor (eg, SV40-contaminated polio vaccines) is also a possible reason for the increase. Women are less likely to be affected than men, possibly due to women韘 scarce asbestos exposure resulting from different employment patterns. The disease is most common in the sixth decade of life.

Presentation and Diagnosis

The majority of the patients (60% to 90%) present with dyspnea and chest discomfort.³ The dyspnea is usually caused by an expanding pleural effusion that eventually becomes loculated. Inevitably, the pleural space fills with tumor that invades and compresses all the adjacent structures and thus limits lung expansion. The chest discomfort is usually dull and nonspecific at presentation. Once the chest wall and intercostal nerves are invaded by tumor, the pain is more localized and severe, which indicates advanced disease. Less common symptoms include fever, night sweats, cough, malaise, and weight loss.

In cases of advanced disease, the patient may present with ascites, cachexia, or chest and abdominal wall deformity. Thrombocytosis is a relatively common finding and may be associated with a poorer prognosis.¹⁰ Other associated paraneoplastic abnormalities include hypoglycemia, hypercalcemia, thrombocytosis, pulmonary embolism, autoimmune hemolytic anemia, hypercoagulability, and syndrome of inappropriate secretion of antidiuretic hormone (SIADH). These complications are extremely rare.

Physical examination reveals diminished breath sounds on the affected side due to the effusion and atelectasis. In advanced disease, palpation of a chest wall mass is an indication of thoracic wall invasion. Abdominal fullness also may be present. Such transdiaphragmatic invasion often results in ascites and renders the tumor unresectable. Bowel obstruction is observed in 30% of the patients once transdiaphragmatic invasion has occurred.

A thorough radiologic evaluation is performed to determine the stage of tumor and to help in the design of therapy. Posteroanterior and lateral chest radiograph, computed axial tomography scan of the chest and upper abdomen and, in some centers, magnetic resonance imaging (MRI) of the chest constitute the requisite staging and evaluation. The chest radiograph typically reveals a pleural effusion with or without pleural calcifications. In our institution, we routinely obtain a computed tomography scan and MRI of the chest and upper abdomen. These studies allow greater accuracy in determining whether tumor has surpassed the confines of the ipsilateral pleural space.¹¹ Radiologic criteria of unresectability include invasion of mediastinal structures, transdiaphragmatic involvement, and metastatic disease. Examination of the sagittal sections of the involved chest by MRI allows for a sensitive determination of mediastinal and diaphragmatic invasion.

We have also found two-dimensional echocardiography (2D ECHO) to be useful in searching for pericardial effusions and tumor infiltration through the pericardium. This modality is also helpful in determining whether the patient韘 baseline myocardial function and pulmonary artery pressure will allow an aggressive resection.

The pleural effusion may be examined via thoracentesis. The pleural effusion associated with mesothelioma is usually yellow and thus different from the blood-containing effusion that is characteristic of adenocarcinoma. A diagnosis of DMPM is rarely possible by cytology because malignant cells are seldom seen in these effusions; when they are present, it is often difficult to correctly identify the malignancy. Therefore, to establish a definite diagnosis, it is usually necessary to perform a pleural biopsy. The closed pleural biopsy, widely used in the past, is helpful only when the results are positive. Negative pleural biopsies should be interpreted with caution and, if clinically suspicious, should be followed by open biopsies. Thoracoscopy or pleuroscopy, therefore, is the best approach to obtain pleural tissues in patients with suspected mesothelioma. In this manner, generous biopsies of the involved areas in the pleura are obtained, and frozen section analysis can confirm that the material is sufficient for final diagnosis. Thoracentesis, pleuroscopy, and thoracoscopy should all be performed through strategically placed incisions because mesothelioma cells can easily seed the tracts of the incisions used for the diagnostic biopsy. We usually place one or, at most, two thoracoscopy ports on the patient's chest in an area that will be included in a subsequent resection. Planning avoids recurrence in the port sites. In cases of obliterated pleural space where a thoracoscope cannot be inserted, an open pleural biopsy is performed.

Pathogenesis and Histology

The earliest pathologic findings are small nodules that are present in parietal pleura. The tumor crosses the pleural space to involve the visceral pleura, coalesces, and replaces the pleural space. As the tumor mass becomes locally advanced, it constricts the underlying normal pulmonary parenchyma. Late in the disease process, the tumor invades the pericardium and mediastinum and may metastasize elsewhere. Patient death is usually caused by compression of the heart and the lung.

DMPM derives from mesothelial stem cells that are, by definition, pluripotential. The cells differentiate into epithelial or mesenchymal elements. It is common to find both cell types in the same tumor specimen. The dominant histology classifies DMPM as having epithelial (50%), sarcomatous (35%), and mixed (15%) histologic groups. This histologic classification has prognostic implications. Several studies have demonstrated that epithelial-type mesothelioma has a better prognosis than the sarcomatous and mixed types.^12,13

The histopathologic diagnosis of mesothelioma can be difficult. Common diagnostic dilemmas for the pathologist include differentiation between adenocarcinoma and tubulopapillary mesothelioma (Table 1),¹⁴ between reactive mesothelial hyperplasia and early mesothelioma, and between desmoplastic mesothelioma and benign pleuritis or plaquing. Use of immunochemistry stains by an experienced pathologist who has access to sufficient fresh and formalin-fixed tissue will optimize results.