Background: Mesothelioma is a malignant neoplasm originating from pleural or peritoneal surfaces that is usually associated with occupational exposure to asbestos. Wagner et al connected asbestos to mesothelioma in a classic 1960 study of 33 patients with mesothelioma exposed to asbestos in a mining area in South Africa's North Western Cape Province (Brit J Ind Med 1960; 17: 260-70). Of the patients, 32 had been exposed to crocidolite, the most carcinogenic type of asbestos. Asbestos mining and production peaked from the 1930s-1960s.

Asbestos was used in a variety of products ranging from construction supplies to brake linings. During World War II, hundreds of thousands of civilian and military workers, through their occupations, were exposed to asbestos. Production slowed dramatically in the 1970s as the health risks of asbestos became known. Governmental restrictions were placed on its use, and alternative materials became available. Despite these changes, asbestos continues to be used in the manufacture of some fire safety products.

The clinical latency period between asbestos exposure and mesothelioma development is 35-40 years, and as a result, the number of mesothelioma patients has continued to rise despite decreased asbestos production. In the year 2000, the incidence of mesothelioma in the US was expected to peak at 2800 patients.

Pathophysiology: The 2 subgroups of asbestos are termed amphiboles and serpentines.

Table 1. The "Families" of Asbestos Fibers

 

Serpentine	Amphibole
Chrysotile	Crocidolite *
	Amosite
	Anthophyllite
	Tremolite
	Actinolite

*Strongly associated with mesothelioma

The 3 primary pathologic types of mesothelioma are epithelioid, sarcomatoid, and biphasic.

On gross pathologic examination, mesothelioma is a grayish lobulated pleural tumor that usually spreads by direct extension into adjacent structures such as the lungs, mediastinum, and chest wall. Peritoneal mesothelioma usually occurs as a direct extension of pleural disease across the diaphragm but can be the primary site of disease.

Two of the most common staging systems are the Butchart system (Table 2) and the tumor, node, metastases (TNM) based system (Table 3) introduced by the International Mesothelioma Interest Group.

Table 2. Butchart Staging System for Malignant Pleural Mesothelioma

 

Stage	Location
I	Tumor confined to the ipsilateral pleura, lung, or pericardium
II	Tumor invading the chest wall or mediastinal structures or metastases to thoracic lymph nodes
III	Tumor penetrating the diaphragm to involve the peritoneum or metastases to extrathoracic lymph nodes
IV	Distant blood-borne metastases

Table 3. TNM Staging System for Malignant Pleural Mesothelioma

Stage	Location
T1a	Limited to ipsilateral parietal pleura (including mediastinal and diaphragmatic pleura), with no involvement of visceral pleura
T1b	Ipsilateral parietal pleura (including mediastinal and diaphragmatic pleura), with scattered foci of visceral pleural involvement
T2	Ipsilateral pleural surface has at least 1 of the following: Diaphragmatic muscle involvement Confluent visceral pleural tumor involvement (including fissures) Extension from visceral pleura into pulmonary parenchyma
T3	Locally advanced but resectable tumor; each ipsilateral pleural surface has at least 1 of the following: Involvement of the endothoracic fascia Extension into the mediastinal fat Solitary, completely resectable tumor focus in chest wall soft tissues Nontransmural involvement of the pericardium
T4	Locally advanced, technically unresectable tumor; each ipsilateral pleural surface has at least 1 of the following: Diffuse extension or multifocal chest wall masses with or without rib destruction Direct transdiaphragmatic extension into the peritoneum Direct extension to contralateral pleura Direct extension to 1 or more mediastinal organs Direct extension into spine Extension through to internal surface of pericardium, with or without pericardial effusion or myocardial involvement
NX	Regional lymph nodes not assessable
N0	No regional lymph nodes metastases
N1	Metastases in ipsilateral bronchopulmonary or hilar lymph nodes
N2	Metastases in subcarinal or ipsilateral mediastinal lymph nodes, including ipsilateral internal mammary nodes
N3	Metastases in contralateral mediastinal, contralateral internal mammary, and ipsilateral or contralateral supraclavicular lymph nodes
MX	Distant metastases not assessable
M0	No distant metastases
M1	Distant metastases present

Frequency:

• In the US: Annual incidence of mesothelioma is 7-13 per 1,000,000 male patients with a history of asbestos exposure. Approximately 1 in 1,000,000 North American patients with no asbestos exposure present with mesothelioma per year.

  The incidence of mesothelioma is highest in the Pacific and mid-Atlantic states and may be related to the location of industries such as shipyards.

• Internationally: The incidence of mesothelioma in women is 2/1,000,000/year and in men is 10-30/1,000,000/year in industrialized countries where asbestos was used widely. The incidence of mesothelioma varies greatly among nations and is difficult to document in countries without mesothelioma registries. In France, an estimated 950 new patients are seen per year. In the United Kingdom (where a mesothelioma registry exists), incidence is expected to peak in the year 2020 at 2700 deaths per year and is expected to decline rapidly thereafter.

Mortality/Morbidity: Malignant mesothelioma usually is fatal. Death usually occurs within 18 months of symptom onset.

Race: No known racial predisposition exists.

Sex: The incidence of mesothelioma is lower in women than in men, probably because fewer women than men worked outside the home in the mid-20th century; therefore, they were exposed less to asbestos.

Age: Mesothelioma most commonly is diagnosed at age 50-70 years.

Clinical Details: Mesothelioma usually presents 35-40 years after asbestos exposure. The onset of symptoms is insidious, and patients often experience symptoms for 4-6 months before the diagnosis is made. The most common symptoms are the following:

Other symptoms include the following:

The most common findings on physical examination (79%) are signs of pleural effusion (eg, dullness to percussion or decreased breath sounds).

Patients with peritoneal involvement experience symptoms as follows:

The most common signs of peritoneal mesothelioma include the following:

Adams et al (Cancer 1986 Oct 1; 58(7): 1540-51) also described decreased chest excursion (15%), palpable lymph nodes (12%), and a palpable liver (9%).

The primary risk factor for mesothelioma is asbestos exposure. Occupations with the highest risk of exposure include insulation work, asbestos production, the heating trades, shipyard work, and construction. In some patients, no specific asbestos exposure can be found. Frequently, these patients have worked in a job where the exposure was not recognized.

An interesting example of unrecognized asbestos exposure is the Boot factory in Nottingham, England where women manufactured gas masks during World War II using asbestos imported from Australia. Not until 1965, when the first patient from the factory was diagnosed with mesothelioma, did an astute doctor begin to suspect the etiology of her disease. By 1996, of the 1200 women, 67 were diagnosed with malignant mesothelioma.

Other predisposing factors include sharing households with asbestos workers and living near asbestos mines and factories. Nevertheless, mesothelioma without asbestos exposure does occur. In a study of 80 children with mesothelioma, only 2 were known to have been exposed to asbestos.

Although industrial asbestos exposure accounts for most instances of mesothelioma, reports indicate another environmental mineral fiber implicated as a risk factor for this tumor. Nearly one quarter of deaths in a Turkish village in central Cappadocia, where a mineral fiber termed erionite was found in the rocks, resulted from mesothelioma.

Interestingly, no association exists between smoking and mesothelioma.

The diagnosis of mesothelioma should be made with care. A clinical history of asbestos exposure and radiologic findings consistent with mesothelioma warrant inclusion of mesothelioma in the differential diagnosis, but it is important to stress that a diagnosis of mesothelioma cannot be made exclusively with imaging. Other more common diseases such as benign asbestos-related pleural disease and metastatic adenocarcinoma can look identical to mesothelioma radiographically. Biopsy with special staining and immunohistochemical and ultrastructural analysis are absolutely essential for the accurate diagnosis of mesothelioma.

Mesothelioma is very difficult to treat. The current treatment for mesothelioma is usually surgical, although other treatment options such as chemotherapy and radiotherapy are used. The 2 primary surgical interventions are pleurectomy and extrapleural pneumonectomy (EPP).

Pleurectomy usually is a palliative procedure to relieve chest wall pain and prevent recurrent pleural effusions by stripping off the visceral and parietal pleura. Extensive debulking is possible, but incomplete resection often is seen along the diaphragmatic and mediastinal pleura.

EPP is an en bloc resection of the parietal and mediastinal pleura, lung, hemi-diaphragm, and ipsilateral pericardium to remove all gross disease. EPP is indicated for stage I tumors with no involvement of the mediastinal lymph nodes. No difference in overall long-term survival is seen, but the disease-free survival period is improved. EPP is a technically demanding surgery with significant morbidity.

The surgical complications of pleurectomy and EPP include pneumonia, bronchopleural fistulae, bronchial leaks, empyema, chylothorax, respiratory insufficiency, myocardial infarction, congestive heart failure, hemorrhage, cardiac volvulus, subcutaneous emphysema, incomplete tumor removal, and vocal cord paralysis.

Radiotherapy usually is palliative or adjunctive to surgery. Since mesothelioma is resistant to radiation, a dose of 4000 centigray usually is required to achieve adequate palliation. Brachytherapy (intrapleural implantation of radioactive isotopes) delivers high-dose radiation locally to the pleural space and is used for recurrent pleural effusions or diffuse miliary seeding of the pleura. Postoperative radiation therapy can prevent recurrence within chest wall incision sites. Complications of radiotherapy include nausea and vomiting, radiation hepatitis, esophagitis, myelitis, myocarditis, and pneumonitis with deterioration of pulmonary function.

Response to chemotherapy has been disappointing. Comparison of chemotherapy regimens has been difficult because of the relative rarity of the disease. Doxorubicin, one of the more commonly used single agents, has had response rates of 0-16%.

Several new therapies currently are being evaluated for the treatment of mesothelioma. Immunotherapy has shown promise, particularly in patients with stage I disease. In one study, 38.4% of patients with stage IA disease demonstrated complete response after intrapleural administration of g-interferon.

Photodynamic therapy is an adjuvant treatment under investigation. A light-activated photosensitizing drug is instilled intrapleurally and is excited by light of a certain wavelength to produce oxygen free radicals that cause tumor necrosis.

Preferred Examination:

Limitations of Techniques: Chest radiography has limited usefulness. The radiographic findings of mesothelioma are nonspecific and observed in other diseases, including metastatic carcinoma, lymphoma, and benign asbestos disease. Small malignant pleural effusions may not be observed on standard radiographs. Alternatively, large pleural effusions can obscure pleural thickening or masses; therefore, disease extent frequently is underestimated.

CT provides more and better information than plain radiography on tumor characteristics and extent. Although MRI is superior to CT in some areas, this advantage did not change the surgical treatment in a 1999 study by Heelen et al. Neither CT nor MRI provides an unequivocal diagnosis of mesothelioma. Tissue biopsy is required for definitive diagnosis.

DIFFERENTIALS

Congestive Heart Failure
[Localized Fibrous Tumor Of The Pleura]
Lung, Metastases

Other Problems to be Considered:

Adenocarcinoma (lung, breast, ovarian, gastric)
Lymphoma
Thymoma
Leukemia
Myeloma
Renal cell carcinoma
Asbestos-related benign pleural disease
Infection (tuberculosis, fungal, bacterial)
Empyema
Tuberculous pleural thickening

X-RAY

Findings: The most common finding is unilateral, concentric, plaquelike, or nodular pleural thickening. Pleural effusions are common, and may obscure the presence of underlying pleural thickening. Tumor frequently extends into the fissures, which become thickened and irregular in contour. A slight right-sided predominance is observed, possibly because of a larger pleural surface area. The tumor can rigidly encase the lung, causing compression of lung parenchyma, diaphragm elevation, intercostal space narrowing, and mediastinal shift toward the tumor. Calcified pleural plaques are present in 20% of patients with mesothelioma and are usually related to the prior asbestos exposure.

Lung nodules and hilar masses usually result from direct tumor extension into lung parenchyma and mediastinal structures, such as lymph nodes, the pericardium, and the heart. Mechanical distortion of the hemithorax, chest wall masses, periosteal rib reaction, or rib destruction by tumor are signs of advanced disease. Although usually unilateral, direct extension across the mediastinum into the contralateral hemithorax does occur.

Degree of Confidence: Although a definite diagnosis cannot be made based on plain film findings, new unilateral pleural thickening or effusion in a patient who has been exposed to asbestos is highly suggestive of mesothelioma.