Mesothelioma: Overview

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Mesothelioma
Author: Winston W Tan, MD, Assistant Professor of Medicine, Mayo Medical School; Consulting Staff, Mayo Group Practices, Contributor Information and Disclosures

Background

Malignancies involving mesothelial cells that normally line the body cavities, including the pleura, peritoneum, pericardium, and testis, are known as malignant mesothelioma, which may be localized or diffuse. Most, but not all, cases of pleural malignant mesothelioma (MM [lung cancer]) are associated with asbestos exposure.1 Of patients with pleural malignant mesothelioma, 77% have been exposed to asbestos in the past. Diagnosis is difficult because the results from fluid analysis of the effusion from the tumor are not usually diagnostic. Mesothelioma is more common in males than in females and it occurs most commonly in the fifth through seventh decades of life. Most cases (~90%) of malignant mesothelioma occur in the pleura.


Pathophysiology

The 3 major histological types of mesothelioma are sarcomatous, epithelial, and mixed. Pleural mesothelioma usually begins as discrete plaques and nodules that coalesce to produce a sheetlike neoplasm. Tumor growth usually begins 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. Pleural mesothelioma may extend into the esophagus, ribs, vertebra, brachial plexus, and superior vena cava.

Asbestos, amphibole asbestos, asbestos-crocidolite, and amosite asbestos in particular, is the principal carcinogen implicated in the pathogenesis. Exposure to chrysotile asbestos is associated with a lower incidence of mesothelioma. The industries associated with asbestos exposure include mining, ship building involving the use of asbestos, asbestos cement manufacture, ceramics, paper milling, auto parts (asbestos brake lining), railroad repair, and insulation. 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 increase the incidence of mesothelioma.

Most malignant mesotheliomas have complex karyotypes, with extensive aneuploidy and rearrangement of many chromosomes. A loss of a single copy on chromosome 22 is the most common abnormality.

Frequency

United States

Approximately 2500-3000 cases are diagnosed per year. 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- to 10-fold compared to nonpolluted areas. Of patients with malignant mesothelioma in the United States, 80% have been exposed to asbestos.

International

Incidence is 0.9 cases per 100,000 persons per year. 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.

Mortality/Morbidity

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 recent 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), 5.8 months for sarcomatous or mixed type (n=28 patients, P=.0001). The causes of morbidity include atrial fibrillation, wound infection, prolonged intubation, pulmonary emboli, myocardial infarction, respiratory failure, deep vein thrombosis, and postoperative bleeding.
Asbestos exposure is linked to at least 50% of patients developing malignant mesothelioma. Approximately 8 million people in the United States have been exposed to asbestos in the workplace. Family members are also exposed to asbestos embedded in the worker's clothing. Alcohol use, dietary factors, and smoking tobacco have no effect on the incidence of pleural mesothelioma.
Race

Mesothelioma has no racial predilection. Asbestos exposure is the most important factor. Race is not a factor.
Sex

Malignant mesothelioma is more common in men, with a male-to-female ratio of 3:1. It can also occur in children; however, these cases are not thought to be associated with asbestos exposure.
For women with mesothelioma, a 1996 case series by Ascoli et al showed 86% of tumors arising from the pleura, of which most were the epithelial type. Of the patients in this series, 75% had a history of exposure to asbestos and more than half developed the malignancy secondary to household contact with a worker exposed to asbestos.2
For men with mesothelioma, the same case series demonstrated 45.5% with a history of exposure to asbestos and 53% with occupational exposure to asbestos. Most who were involved were construction workers, railroad workers, naval mechanics, bakers, explosive workers, and automobile mechanics.2
Age

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.
Clinical

History

Dyspnea and nonpleuritic chest wall pain are the most common presenting symptoms of malignant mesothelioma. (Approximately 60-90% of patients have symptoms of chest pain or dyspnea.)
Chest radiographs show obliteration of the diaphragm, nodular thickening of the pleura, decreased size of the involved chest, radiolucent sheetlike encasement of the pleura, or a combination of these.
A loculated effusion is present in more than 50% of patients, and a major portion of the pleura is opacified by the effusion.
Chest discomfort, pleuritic pain, easy fatigability, fever, sweats, and weight loss are the other common accompanying symptoms.
Patients may also be asymptomatic, with evidence of a pleural effusion noted incidentally on physical examination or by chest radiograph.
Metastatic disease is uncommon at presentation, and contralateral pleural abnormalities are usually secondary to asbestos-related pleural disease rather than metastatic disease.
Despite the ban or reduction of asbestos in the 1960s, incidence of mesothelioma continues to increase because patients develop mesothelioma 20-40 years after asbestos exposure. The long latency period adds to the complexities of early diagnosis and treatment of the condition.
Physical

In patients with malignant mesothelioma, physical findings of pleural effusion are usually noted upon percussion and auscultation.
In rare cases, malignant mesothelioma manifests as cord compression, brachial plexopathy, Horner syndrome, or superior vena cava syndrome. Death is usually due to infection or respiratory failure from the progression of mesothelioma.
Primary sites 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).
Causes

A substantial proportion of patients were exposed to asbestos in asbestos mills, shipping yards, mines, or their homes.
The crocidolite in asbestos is associated with mesothelioma in miners, manufacturers (using asbestos), and heating and construction workers. The rod-shaped amphiboles are more carcinogenic than the chrysotile.
Malignant mesothelioma has also been linked to therapeutic radiation using thorium dioxide and zeolite, a silicate in the soil.
An etiological role for simian virus 40 in malignant mesothelioma has also been suggested. Asbestos exposure alone was associated with malignant mesothelioma, but simian virus 40 alone was not; thus, some epidemiological evidence exists that simian virus 40 is a possible cocarcinogen. Its direct role at this point is still controversial.3
Interleukin 8 has direct growth-potentiating activity in mesothelial cell lines.
Loss of one copy of chromosome 22 is the single most common karyotypic change in malignant mesothelioma. Other chromosomal changes commonly observed include 1p, 3p, 9p, and 6q. Several changes in the tumor suppressor gene p16 (CDKN2A) and p14 (ARF) and loss of function of neurofibromin 2 (NF2) or merlin are altered.4


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