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Characteristics of Asbestos and Its Relationship to MPM
Asbestos is a collective term applied to a family of complex hydrated silicates characterized by a fibrous geometry with a high length-to-diameter (aspect) ratio (3,4). These fibers include commercial amphiboles (crocidolite and amosite); noncommercial, contaminating amphiboles (actinolite, anthophyllite, and tremolite); and commercial nonamphiboles or serpentines (chrysotile).
The carcinogenicity of a particular type of fiber is proportional to its aspect ratio and its durability in human tissue. The most tumorigenic fibers are more than 8 mm long and less than 0.25 mm wide and have an aspect ratio of greater than 32 (4). Fiber durability in tissue is also an important factor in tumorigenicity, as some fibers are eliminated from tissue whereas others are retained for prolonged periods. In general, amphiboles are straight, needlelike fibers that penetrate deeply into the lung, are insoluble in water, and accumulate during the patient's lifetime (Figure 1). Because of its high aspect ratio and durability, crocidolite is the most carcinogenic fiber. It accounts for more malignancies than amosite, tremolite, and chrysotile combined (5).
Chrysotile, a nonamphibole or serpentine fiber, accounts for approximately 80% of the asbestos used in the Western World. It is relatively noncarcinogenic because of its physical characteristics: a corkscrew geometry, a low aspect ratio, and poor durability in tissue, where it is broken down into smaller fibers that are eliminated by phagocytes and the mucociliary escalator (Figure 2). Chrysotile is deposited in the proximal airways and is relatively water soluble. It is postulated that exposure to pure chrysotile does not cause MPM. Amphibole contaminants such as tremolite, a noncommercial amphibole, are almost always present in chrysotile and may be responsible for tumor development in individuals exposed to chrysotile (6).
The amount of asbestos exposure needed to produce MPM, or the dose-response relationship, is unknown. There is no recognized "threshold" exposure below which MPM will not occur; on the other hand, there is no proof that low concentrations of asbestos will cause MPM. The number of fibers per volume of lung tissue represents an individual's "asbestos burden," but this parameter of exposure is not correlated with the incidence of MPM (7). However, a dose-response relationship is suggested by the fact that the greater the duration and intensity of exposure, the higher the incidence of MPM (4).
Markers of Asbestos Exposure
The microscopic hallmark of asbestos exposure is the asbestos body, a type of ferruginous body that results from deposition of an iron-protein complex on an asbestos fiber core; this process results in the creation of fusiform, segmented (or "beaded") rodlike structures (Figure 3). The gross pathologic hallmark of asbestos exposure is the pleural plaque, which microscopically consists of dense, hypocellular, undulating collagen fibers that are often arranged in a basket weave pattern, with or without focal or massive calcification (Figure 4a) (8). Asbestos fibers are rarely found within the plaques at histologic analysis but may be detected by means of electron microscopy (8,9). Macroscopically, plaques appear as circumscribed, gray-white, raised lesions that typically affect the parietal pleura; the visceral pleura is rarely affected (Figure 4b) (10). Plaques most commonly occur adjacent to the dependent portions of the lung, at the level of the sixth ribs and below, often following the course of the ribs, and over the posterolateral chest wall and central tendinous portion of the diaphragm. The mediastinal pleura is less commonly affected, and the pleural surfaces of the apex and costophrenic angle are usually spared (3,9).
Radiologically, plaques appear as focal areas of pleural thickening, typically less than 1 cm thick. They commonly exhibit calcification, which is detected at radiographic examination in approximately 25% of cases (reported range, 0%-50%) (11) and at CT in approximately 60% of cases (12). A 20-year interval from the time of exposure is necessary for the calcification in plaques to become visible (12). Plaques are usually multifocal, bilateral, and stable over time. They first appear 20-30 years after the initial asbestos exposure (Figure 5) (13).
Pleural plaques are a unique manifestation of asbestos-related disease because they cause no symptoms. There is no evidence that plaques are premalignant or precursors of MPM. The presence of plaques, however, does suggest an increased probability of MPM occurring (10).
Although the process by which asbestos fibers cause malignancy is poorly understood, pathogenesis may be due to prolonged fiber retention, producing a foreign-body reaction that results in malignant transformation of subserosal cells. The transformed neoplastic cells may differentiate into several morphologic forms that produce the various subtypes of MPM (1).
Epidemiology
MPM is strongly linked to an occupational exposure to all major commercial forms of asbestos (7). This association was established in 1960 by Wagner et al (14) in a landmark study that described 33 patients with MPM who were from the northwestern Cape Province of South Africa; 32 of these patients were exposed occupationally to crocidolite. Since then, a dose-response relationship between asbestos exposure and MPM has been established, indicating a higher incidence of MPM in those patients with greater intensity and duration of exposure. The incidence of MPM is also higher in patients with continuous exposure than in those with intermittent exposure (4,15). However, brief, heavy exposures and indirect exposures (such as contact with the clothing of an asbestos worker) may also produce MPM (16,17).
A history of occupational exposure to asbestos is found in only 40%-80% of patients with MPM (17). Occupations with the highest risk include insulation work (spray insulation, manufacture of insulating textiles), asbestos production and manufacture (mining and milling of chrysotile, work with asbestos cement products, factory use of asbestos), heating trades (manufacture of heat-protective clothing, installation or repair of furnaces or boilers, steam fitting, plumbing, welding), shipyard work, construction (building trades, building demolition, painting), and automotive brake-lining manufacture and repair (17).
The rise in the incidence of MPM during the past 3 decades is related to the increased use of asbestos since the 1930s and the high levels of employment and high turnover rates in shipyards during World War II (2). Repair of steam locomotive engines also resulted in occupational exposure to asbestos in the United States until the advent of the diesel engine in the 1950s (18).
The latency period for development of MPM is at least 35-40 years after initial exposure. The peak incidence of MPM occurs later than asbestos-related lung cancer (25-35 years) and somewhat earlier than asbestosis (40-45 years) (19). Unlike lung cancer and asbestosis, the incidence of MPM does not decline after reaching its peak but remains steady.
Approximately 2,000-3,000 cases of MPM occur in the United States each year (20). Men are more frequently affected, and the male to female ratio is 2-6:1; however, the incidence of MPM in women is increasing (21). Peak occurrence is in the 6th to 7th decades of life (21,22). Nearly 10% of individuals occupationally exposed to asbestos die of mesothelioma, either the pleural (40%-60%) or peritoneal (40%-60%) form (2,23). The incidence in the general population, based on necropsy series, varies between 0.01% and 0.24% but has increased since 1960 (2,24).
Hypotheses regarding the occurrence of MPM in patients with no history of occupational exposure to asbestos and low asbestos body counts in the lung (less than 20 asbestos bodies per gram of wet lung tissue) have been proposed. Theoretically there is no threshold level of asbestos exposure below which MPM will not occur; therefore, a small percentage of tumors may develop secondary to environmental contamination or undetected occupational or environmental exposure to submicroscopic fibers that do not readily form asbestos bodies. In addition, asbestos may act synergistically with other agents; thus, a lesser asbestos exposure may lead to the development of MPM (25).
Other Etiologic Factors
Many patients with MPM do not have a documented history of asbestos exposure (range, 0%-87%). Other etiologic factors, including exposure to other mineral fibers, chronic inflammation, heredity, irradiation, viruses, and exposure to other nonfibrous minerals and organic chemicals, have been implicated in these patients (26).
Zeolite (erionite) is a nonasbestos mineral fiber that has been identified as the probable cause of an epidemic of malignant mesothelioma in Karain, a small village in the Anatolian region of Turkey. Essentially no asbestos was found in the village, a finding which suggests that the ubiquitous airborne, respirable erionite was the etiologic factor (27,28,29).
MPM has been reported in association with chronic inflammation and scarring, as in cases of tuberculosis and empyema (30). The occasional reports of familial cases of MPM have all been associated with documented asbestos exposure; however, because only 3%-8% of asbestos workers develop MPM, the occurrence of this tumor in families suggests that genetic factors may be important (23). The sporadic occurrence of mesothelioma in children has not been linked to asbestos exposure. These tumors may represent an entity entirely different from adult MPM (22).
Radiation has been implicated in patients with MPM who have a history of radiation therapy for Hodgkin disease. In addition, one patient with an "opacity" in the right costophrenic angle received 9.5 rad (95 mGy) during 26 years of frequent, routine chest radiography and later developed MPM at the same location (26).
Other causes of MPM have been suggested in experimental animal studies (26). Nickel and silica dust have been reported to cause malignant mesothelioma in rats, but no causative relationship has been proved in humans. Certain strains of viruses and several chemical compounds, including polyurethane, ethylene oxide, and polysilicone plastics, have also been shown to induce malignant mesothelioma in animals (26).
Cigarette smoking interacts with asbestos; smoking greatly increases a patient's risk of developing plaques by impairing bronchial clearance mechanisms; however, the risk of developing MPM is independent of smoking habits (10).
Etiology and Epidemiology of MPM