Mesothelioma, Adult Malignant

Introduction

Mesothelioma is a malignant neoplasm originating from pleural or peritoneal surfaces; this condition 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 who were exposed to asbestos in a mining area in South Africa's North Western Cape Province.1 Of the 33 patients, 32 had been exposed to crocidolite, the most carcinogenic type of asbestos.

Asbestos mining and production peaked from the 1930s-1960s, and 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.

Pathophysiology

The 2 subgroups of asbestos are termed amphiboles and serpentines. Amphiboles are long needlelike fibers with high length-to-diameter ratios and are resistant to dissolution. These fibers remain in the tissues for years. Crocidolite is the amphibole most available commercially and is strongly associated with mesothelioma.

Serpentines have a corkscrew shape and are more soluble. Chrysotile, the lone serpentine, accounts for 80-90% of commercial asbestos used in the United States and Canada. Chrysotile is less toxic than crocidolite because of its smaller length-to-diameter ratio, increased tissue solubility, and tendency to deposit in the central airways. Chrysotile that has been contaminated with tremolite (a noncommercial amphibole) has been suggested as the only occupational cause of mesothelioma, although this is not accepted universally. The mechanism by which asbestos fibers cause mesothelioma is not well understood. One possible explanation is that malignant transformation of cells follows a foreign-body reaction that is caused by the insoluble fibers.

The "families" of asbestos fibers are as follows:

• Serpentine - Chrysotile
• Amphibole - Crocidolite (strongly associated with mesothelioma), amosite, anthophyllite, tremolite, actinolite

The 3 primary pathologic types of mesothelioma are epithelioid, sarcomatoid, and biphasic. Patients with epithelioid mesothelioma (55-65%) have a slightly better median survival time. Pathologically, the epithelioid subtype can appear similar to adenocarcinoma. Special staining and immunohistochemical and ultrastructural analysis are necessary to differentiate the 2 diseases. Sarcomatoid mesotheliomas (10-15%) are similar in appearance to true sarcomas. Biphasic mesothelioma (20-35%) has both epithelioid and sarcomatoid features.

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 the peritoneum can be the primary site of disease.

Two of the most common mesothelioma staging systems are the Butchart system and the tumor, node, metastases (TNM)-based system (see Table) that was introduced by the International Mesothelioma Interest Group.

The Butchart staging system for malignant pleural mesothelioma is as follows:

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

TNM Staging System for Malignant Pleural Mesothelioma

Stage	Location
T1a	Ipsilateral parietal pleura only (including mediastinal and diaphragmatic pleura), without visceral pleura involvement
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 the 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 the 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 the contralateral pleura Direct extension to 1 or more mediastinal organs Direct extension into the spine Extension through to internal surface of the pericardium, with or without pericardial effusion or myocardial involvement
NX	Regional lymph nodes not assessable
N0	No regional lymph nodes metastases
N1	Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes
N2	Metastases in the subcarinal or ipsilateral mediastinal lymph nodes, including the ipsilateral internal mammary nodes
N3	Metastases in the contralateral mediastinal, contralateral internal mammary, and the ipsilateral or contralateral supraclavicular lymph nodes
MX	Distant metastases not assessable
M0	No distant metastases
M1	Distant metastases present
Stage	Location
T1a	Ipsilateral parietal pleura only (including mediastinal and diaphragmatic pleura), without visceral pleura involvement
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 the 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 the 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 the contralateral pleura Direct extension to 1 or more mediastinal organs Direct extension into the spine Extension through to internal surface of the pericardium, with or without pericardial effusion or myocardial involvement
NX	Regional lymph nodes not assessable
N0	No regional lymph nodes metastases
N1	Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes
N2	Metastases in the subcarinal or ipsilateral mediastinal lymph nodes, including the ipsilateral internal mammary nodes
N3	Metastases in the contralateral mediastinal, contralateral internal mammary, and the ipsilateral or contralateral supraclavicular lymph nodes
MX	Distant metastases not assessable
M0	No distant metastases
M1	Distant metastases present

Frequency United States

Annually, approximately 1.0-1.1 in 100,000 people present with mesothelioma.The incidence rate of mesothelioma is highest in the Pacific and Mid-Atlantic states and may be related to the location of industries such as shipyards.

International

The incidence rate of mesothelioma varies greatly among nations and is difficult to document in countries without mesothelioma registries. Crude incidence rates are highest in Australia, Belgium, and Great Britain (about 30 cases per million annually).6 The incidence rates of mesothelioma tend to be high in industrialized countries where asbestos was widely used; however, for unknown reasons, the incidence rates have also been reported to be low in some countries where there was wide use of asbestos.

Mortality/Morbidity

Malignant mesothelioma is usually fatal. Death generally occurs within 18 months of symptom onset.

Race

No racial predisposition is recognized.

Sex

The incidence rate of mesothelioma is much lower in women than in men, probably because fewer women than men worked outside the home in the mid-20th century; therefore, they were less exposed to asbestos. Between 4- to 6-fold more men than women are affected by mesothelioma.

Age

Mesothelioma is most commonly diagnosed at age 50-70 years, with the greatest incidence rates at age 65 and older in both sexes.

Presentation

Mesothelioma usually appears 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 as follows:

• Recent onset of shortness of breath (31%)
• Recent increase in shortness of breath (30%)
• Chest pain (43%)

Other symptoms include the following:

• Cough (35%)
• Weight loss (23%)
• Weakness (18%)
• Increased sputum production (18%)

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

Patients with peritoneal involvement experience symptoms as follows:

• Abdominal pain (60%)
• Anorexia (27%)
• Weakness (12%)
• Nausea (11%)

The most common signs of peritoneal mesothelioma include the following:

• Abdominal distention (56%)
• Ascites (37%)
• Weight loss (38%)
• Abdominal mass (11%)

Adams et al 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 such 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 was a factory in Nottingham, England, where women manufactured gas masks during World War II using asbestos that was 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 that another environmental mineral fiber is also implicated as a risk factor for this tumor. Nearly 50% of deaths in 3 Turkish villages in central Cappadocia, where a mineral fiber termed erionite was found in the rocks, resulted from mesothelioma Interestingly, there is no association between smoking and mesothelioma.

The diagnosis of mesothelioma should be made with care. A clinical history of asbestos exposure and radiologic findings that are 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 studies. Other more common diseases such as benign asbestos-related pleural disease and metastatic adenocarcinoma can look radiographically identical to mesothelioma. 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 treatment 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 is usually 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 is often seen along the diaphragmatic and mediastinal pleura.

EPP is an en bloc resection of the parietal and mediastinal pleura, lung, hemidiaphragm, and ipsilateral pericardium to remove all gross disease. EPP is indicated for stage I tumors without involvement of the mediastinal lymph nodes. No difference in overall long-term survival is seen between pleurectomy and EPP, but the disease-free survival period is improved with pleurectomy. 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 is usually palliative or adjunctive to surgery. Because mesothelioma is resistant to radiation, a dose of 4000 cGy is usually 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 of mesotheliomas 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 are undergoing evaluation 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 γ -interferon.

Photodynamic therapy is also 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

• Chest radiography is the initial screening examination.
• Computed tomography (CT) scanning is preferred for staging the tumor.
• Magnetic resonance imaging (MRI) complements CT scanning in some patients. MRI provides better delineation of soft tissues (better soft-tissue contrast) and allows imaging in the sagittal and coronal planes.
• Positron emission tomography (PET) scanning may also be useful in delineating the extent of tumor or metastases.

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 is frequently underestimated in radiographs.

CT scanning provides more and better information than plain radiography with regard to tumor characteristics and extent. Although MRI is superior to CT scanning in some areas, this advantage did not change the surgical treatment in a 1999 study by Heelan et al.11 Neither CT scanning nor MRI provides an unequivocal diagnosis of mesothelioma; tissue biopsy is required for the definitive diagnosis.

Differential Diagnoses

• Asbestos-Related Disease
• Congestive Heart Failure
• Empyema
• Localized Fibrous Tumor of the Pleura
• Lung, Metastases
• Renal Cell Carcinoma

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)
• Tuberculous pleural thickening

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