- Author: Winston W Tan, MD, FACP; Chief Editor: Jules E Harris, MD, FACP, FRCPC more...
Malignancies involving mesothelial cells that normally line the body cavities, including the pleura (see the image below), peritoneum, pericardium, and testis, are known as malignant mesothelioma. Asbestos, particularly the types of amphibole asbestos known as crocidolite and amosite asbestos, is the principal carcinogen implicated in the pathogenesis of malignant pleural mesothelioma.
Signs and symptoms
Dyspnea and nonpleuritic chest wall pain are the most common presenting symptoms of malignant pleural mesothelioma, with at least 1 of these occurring in 60-90% of patients. Other common accompanying symptoms are as follows:
On physical examination, findings of pleural effusion are usually noted upon percussion and auscultation. Patients may also be asymptomatic, with evidence of a pleural effusion noted incidentally on physical examination or by chest radiograph.
See Clinical Presentation for more detail.
More than 90% of patients with pleural mesothelioma present with pleural effusion that decreases after thoracentesis
Typically, the pleural fluid findings are nondiagnostic, with < 1000 leukocytes/μL, few erythrocytes, elevated protein levels, and normal lactate dehydrogenase levels
Pleural fluid cytologic findings are diagnostic in only 32% of patients and are suggestive in 56%
FISH to distinguish malignant mesothelioma from reactive mesothelial cells in effusions had 79% sensitivity 
Thoracoscopically guided biopsy
Indicated if mesothelioma is suggested
Diagnostic in 98% of cases
Routinely stained biopsy preparations are the most valuable diagnostic tool in malignant mesothelioma. Diagnostic features that distinguish malignant mesothelioma from adenocarcinoma include the following:
Negative results for periodic acid-Schiff stain, mucicarmine stain, carcinoembryonic antigen, and Leu M1
Positive test results for calretinin, vimentin, and cytokeratin
Soluble mesothelin (the current reference biomarker)
Megakaryocyte potentiating factor
Findings in malignant pleural mesothelioma include one or more of the following:
Obliteration of the diaphragm
Nodular thickening of the pleura
Decreased size of the involved chest
Radiolucent, sheetlike encasement of the pleura
A loculated effusion (> 50% of patients), with opacification of a major portion of the pleura
See Workup for more detail.
Currently, no therapy is considered standard. Treatment options for the management of malignant mesothelioma include the following:
Surgery (reasonable when disease is confined to the pleural space)
Chemotherapy [2, 3]
Radiation (provides significant palliation of chest pain and chest wall metastasis in 50% of patients)
Generally used chemotherapy regimens include the following:
Cisplatin – Standard for single-agent therapy
Pemetrexed/gemcitabine – For patients who cannot take cisplatin
Malignancies involving mesothelial cells that normally line the body cavities, including the pleura, peritoneum, pericardium, and testis, are known as malignant mesothelioma. The 3 major histologic types are sarcomatous, epithelial, and mixed. The condition may be localized or diffuse. (See Etiology.)
Primary sites for malignant mesothelioma include the pleura (87%), the peritoneum (5.1%), the pericardium (0.4%), and the right side of the thorax (more so than the left side, by a right-to-left ratio of 1.6:1). (See Etiology, Presentation, and Workup.)
Among patients with malignant pleural mesothelioma, 77% have previously been exposed to asbestos. Diagnosis is difficult because results from fluid analysis of the tumor’s effusion are not usually diagnostic. Death from malignant mesothelioma is usually due to infection or respiratory failure from the progression of the disease. (See Etiology, Presentation, and Workup.)
Malignant pleural mesothelioma
Malignant pleural mesothelioma usually begins as discrete plaques and nodules that coalesce to produce a sheetlike neoplasm. Tumor growth usually starts at the lower part of the chest. The tumor may invade the diaphragm and encase the surface of the lung and interlobar fissures.
The tumor may also grow along drainage and thoracotomy tracts. As the disease progresses, it often extends into the pulmonary parenchyma, chest wall, and mediastinum. Malignant pleural mesothelioma may also extend into the esophagus, ribs, vertebra, brachial plexus, and superior vena cava.
Asbestos, particularly the types of amphibole asbestos known as crocidolite and amosite asbestos, is the principal carcinogen implicated in the pathogenesis of malignant pleural mesothelioma. Exposure to chrysotile asbestos is also associated malignant mesothelioma, but at a lower incidence than occurs with the other types. (The rod-shaped amphiboles are more carcinogenic than the chrysotile.)
Approximately 8 million people in the United States have been exposed to asbestos in the workplace. A substantial proportion of patients with malignant pleural mesothelioma were exposed to asbestos in asbestos mills, shipping yards, mines, or their homes. The crocidolite in asbestos is associated with mesothelioma in miners, manufacturers who use asbestos, and heating and construction workers. Family members of workers exposed to asbestos can also be at risk of exposure if asbestos becomes embedded in the workers’ clothing.
The industries associated with asbestos exposure include the following:
Ship building involving the use of asbestos
Asbestos cement manufacture
Auto parts (asbestos brake lining)
In Turkey, the use of the fibrous substance erionite (similar to amphibole asbestos) in building construction has led to an epidemic of pulmonary mesothelioma. Environmental exposure to asbestos in areas polluted by the substance may also increase the incidence of mesothelioma.
Alcohol, dietary factors, and tobacco smoke have no effect on the incidence of pleural mesothelioma.
Other sources of mesothelioma
Interleukin-8 has direct growth-potentiating activity in mesothelial cell lines. Malignant mesothelioma has also been linked to therapeutic radiation using thorium dioxide and zeolite, a silicate in the soil.
An etiologic role for simian virus 40 in malignant mesothelioma has been suggested. However, although asbestos exposure alone has been associated with malignant mesothelioma, simian virus 40 alone has not. Thus, some epidemiologic evidence exists that simian virus 40 is a possible cocarcinogen. Its direct role at this point is still controversial.
Most malignant mesotheliomas have complex karyotypes, with extensive aneuploidy and the rearrangement of many chromosomes. Loss of 1 copy of chromosome 22 is the single most common karyotypic change in malignant mesothelioma. Other chromosomal changes commonly observed include deletions in the chromosome arms 1p, 3p, 9p, and 6q. Several changes in the tumor suppressor genes p16 (CDKN2A) and p14 (ARF) and loss of function of neurofibromin-2 (NF2) have also been noted.
Occurrence in the United States
Approximately 3000 cases of malignant mesothelioma are diagnosed annually. In the absence of occupational exposure to asbestos, the incidence is 0.1-0.2 per 100,000 population in both sexes. The risk is increased in polluted areas by 2-10 fold compared with nonpolluted areas. Of patients with malignant mesothelioma in the United States, 80% have been exposed to asbestos.
Incidence of malignant mesothelioma is 0.9 case per 100,000 persons annually. Marked variability exists in the incidence of malignant mesothelioma in different countries. In some countries, the incidence is low even though asbestos exposure is high. The reasons for these differences are not known.
Sex- and age-related demographics
Malignant mesothelioma is more common in men than in women, with a male-to-female ratio of 3:1.
Malignant mesothelioma has a peak incidence 35-45 years after asbestos exposure. Two thirds of cases of malignant mesothelioma develop in the fifth to seventh decade of life.
Malignant mesothelioma also occurs in children; however, these cases are not thought to be associated with asbestos exposure.
Without treatment, malignant mesothelioma is fatal within 4-8 months. With trimodality treatment, some patients have survived 16-19 months. A few have survived as long as 5 years, with rates of 14% for all types and 46% for the epithelial type. However, numbers are small.[10, 11] The tumor recurrence rate is 50% for patients treated with surgery.
Median survival for patients with malignant mesothelioma is 11 months. It is almost always fatal. Median survival based on histologic type is 9.4 months for sarcomatous, 12.5 months for epithelial, and 11 months for mixed. Approximately 15% of patients have an indolent course.
In a review of 64 patients undergoing pleurectomy, the overall survival rate was 43%, 28%, and 10% at 1, 2, and 3 years, respectively. The overall median survival with epithelial histology was 21.7 months (n=56 patients); it was 5.8 months for patients with sarcomatous or mixed type mesothelioma (n=28 patients). The causes of morbidity include atrial fibrillation, wound infection, prolonged intubation, pulmonary emboli, myocardial infarction, respiratory failure, deep vein thrombosis, and postoperative bleeding.
Based on many clinical factors, 2 separate groups, the Cancer and Leukemia Group B and the European Organization for Research and Treatment of Cancer, identified the following poor prognostic factors[12, 13] :
Performance status of 2 or greater
Age older than 75 years
High platelet count
Lactate dehydrogenase greater than 500 IU/L
High white count
The pattern of nodal metastasis is different from that of lung cancer. The mechanism of spread of the disease to the hilar nodes may be through lung invasion and not due to spread directly from the pleura. In a study of 49 patients who underwent surgery, only 7 had no lung invasion and none had positive hilar nodes. In the postpneumonectomy patients, 6 of 14 had positive hilar node and mediastinal nodes.
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