Epidemiology of malignant pleural mesothelioma

INTRODUCTION — Mesothelioma is an insidious neoplasm arising from the mesothelial surfaces of the pleural and peritoneal cavities, the tunica vaginalis, or the pericardium. Eighty percent of cases are pleural in origin. The predominant cause of malignant mesothelioma is inhalational exposure to asbestos, with approximately 70 percent of cases of pleural mesothelioma being associated with documented asbestos exposure.

This topic will discuss the epidemiology and risk factors of pleural mesothelioma.

●The pathology, clinical presentation, evaluation, and staging, and treatment of malignant pleural mesothelioma are discussed separately. (See "Presentation, initial evaluation, and prognosis of malignant pleural mesothelioma" and "Pathology of malignant pleural mesothelioma" and "Initial management of malignant pleural mesothelioma".)

●Peritoneal mesothelioma is discussed separately. (See "Malignant peritoneal mesothelioma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging" and "Malignant peritoneal mesothelioma: Treatment".)

EPIDEMIOLOGY — The annual incidence of mesothelioma in the United States is estimated to be approximately 3300 cases per year [1]. The incidence of mesothelioma in the United States peaked around the year 2000 and is now declining, secondary to control of exposure to asbestos [2].

The incidence is increasing in many other places in the world, particularly in Great Britain and Australia [3,4]. The rate has been predicted to peak around 2015 in England, and mesothelioma rates are expected to drop gradually thereafter. These changes are attributed to an understanding of the relationship of mesothelioma to asbestosis and reduced exposure in the workplace and the general environment. In contrast, mesothelioma incidence rates are predicted to increase dramatically in resource-limited settings secondary to poor regulation of asbestos mining and the proliferation of industrial and household utilization of asbestos [3,5,6].

RISK FACTORS — Asbestos exposure is the most important risk factor associated with subsequent development of pleural mesothelioma, and asbestos exposure is responsible for the bulk of the mesothelioma burden worldwide.

Asbestos exposure — Asbestos is the commercial name for a group of hydrated magnesium silicate fibrous minerals. Asbestos occurs in soil and rock as long fibers. There are two major types: serpentine and amphibole. About 95 percent of the asbestos produced and used worldwide is chrysotile, which is a serpentine fiber that is reportedly less carcinogenic [3,7]. However, even chrysotile asbestos has been linked to the development of pleural mesothelioma [7].

Asbestos is valued in industry for its resistance to heat and combustion. It is used in cement, ceiling and pool tiles, automobile brake linings, and in shipbuilding. In addition to occupational exposure, environmental exposure to asbestos from natural sources may contribute to the mesothelioma burden.

Occupational exposure — Efforts to control occupational exposure to asbestos can result in a significant decrease in the incidence of mesothelioma. The latency period after exposure to asbestos is very prolonged, with almost all cases appearing 15 or more years after exposure [8], and the risk persists for many decades. However, the very prolonged latency between exposure and disease development means that a decrease in the incidence of mesothelioma occurs very slowly.

As an example, in the United States, as many as eight million living persons in the have been occupationally exposed to asbestos over the past 50 years. The Occupational Safety and Health Administration (OSHA) initially established 5 fibers/mL of air as the standard acceptable exposure. This level has since been reduced to 0.1/mL, but this applies only to fibers longer than 5 micrometers [9]. Workers exposed to higher concentrations of regulated fibers are mandated to use protective clothing, respirators, and showers.

Asbestos workers are at significant risk for the development of both non-malignant and malignant pulmonary disease.

●Approximately 8 percent of asbestos workers will die of respiratory failure secondary to asbestosis. (See "Asbestos-related pleuropulmonary disease".)

●The average asbestos worker has a 50 percent chance of dying from a malignancy, compared with around 18 percent for the average American. The vast majority of cancers in asbestos workers involve the lung, either primary lung carcinoma or mesothelioma.

●The lifetime risk of developing mesothelioma among asbestos workers is thought to be as high as 10 percent [10]. There is a latency period of approximately 30 to 40 years from the time of asbestos exposure to the development of mesothelioma.

●There appears to be a dose-response relationship between asbestos exposure and mesothelioma. This was illustrated in cohort study of 4659 people who resided in an Australian city that produced crocidolite asbestos but who did not directly participate in its mining or milling; the incidence of mesothelioma increased significantly with greater environmental exposure, based upon the neighborhood and duration of residence [11]. In a cohort of textile workers with heavy exposure to asbestos, the risk of pleural mesothelioma was increased and was proportional to the latency period [12]. Unlike asbestosis, even a brief intense exposure to asbestos can result in mesothelioma.

●Asbestos exposure acts synergistically with cigarette smoking to increase the risk of developing lung cancer 60 times over that of a similarly matched non-smoking, non-asbestos-exposed cohort. (See "Cigarette smoking and other possible risk factors for lung cancer".)

●Asbestos workers may also be at increased risk of non-mesothelioma gastrointestinal malignancies [5,6,13,14].

●Because of heavy asbestos use in Italy until 1992 when it was banned, there was an epidemic of asbestos-related diseases. The Italian National Registry of Malignant Mesotheliomas collects data of mesothelioma incidence with a regional structure. The type of exposure was an occupational exposure in almost 70 percent of evaluated cases [15]. The Italian surveillance experience has been key in assessing and monitoring the public health impact of occupational and/or environmental exposures, allowing for the implementation of preventive interventions.

Nonoccupational exposure — Environmental, nonoccupational exposure to asbestos also can contribute to an increased risk of mesothelioma [16-21].

As examples:

●In certain rural areas in Greece, Turkey, and Bulgaria, soil contains remarkably high levels of tremolite asbestos fibers, and many cases of mesothelioma in these regions appear to be secondary to long-term nonoccupational asbestos exposure [16-19,22].

●A role for nonoccupational exposure to asbestos was also supported by a study from California in which an increased incidence of mesothelioma was associated with proximity to naturally-occurring asbestos deposits [20].

●Inhalation of other fibrous silicates, such as erionite, has also been implicated as a potential cause of malignant pleural mesothelioma, as shown in epidemiologic studies of a region in Turkey (Cappadocia), which show an abnormally high incidence of pleural mesothelioma [23].

●Fluoro-edenite is a naturally-occurring mineral that forms amphibole asbestos fibers. Unpaved roads in Biancavilla, Sicily, Italy, are a source of airborne fibers and have been linked epidemiologically with the development of mesothelioma, in the absence of occupational exposure [24].

●Despite the decrease in asbestos production and the recognition of the connection between asbestos and MPM, there remains the possibility of environmental exposure, an area where the relationship with MPM has not been extensively explored. This potential connection is all the more difficult to establish due to lack of reliable assessment of type and amount of exposure, smaller sample size, and smaller effect sizes compared with those seen in occupational studies. One review summarizes the most recent studies on the relationship between environmental exposure to asbestos and MPM in an attempt to identify features associated with this type of exposure and quantify the association with MPM [25].

A literature review and meta-analysis that looked at 18 studies from 12 countries concluded that the risk of MPM from nonoccupational asbestos exposure is consistent with the fiber-type potency response observed in occupational settings. This relationship allows for a better evaluation of the risk of MPM in communities with ambient asbestos exposures from industrial or other sources [26].

The epidemiology of sex differences in mesothelioma incidence has not been well studied, recognizing that the majority of occupational exposure occurs among males. In a study of mesothelioma in Italy utilizing an national register epidemiologic surveillance system, cases among females are due mainly to nonoccupational asbestos exposure. Occupational exposures among women mainly are related to work in the chemical and plastic industry in addition to work in the non-asbestos textile sector [27].

Radiation — Ionizing radiation to supradiaphragmatic fields may be a risk factor for the subsequent development of mesothelioma, with a long latent period between the initial treatment and the diagnosis of the second malignancy.

●Two large studies from the Surveillance, Epidemiology, and End Results (SEER) database found that survivors of Hodgkin lymphoma and non-Hodgkin lymphoma were at increased risk for mesothelioma [28,29]. The increased risk was limited to those who had received radiation as part of their treatment.

●A population-based series of over 40,000 men treated for testicular cancer between 1943 and 2001 and followed long-term found 10 excess cases of pleural mesothelioma (relative risk 4) for men treated with radiation therapy alone [30].

●The data for patients with breast cancer are conflicting. An analysis of 22,140 patients treated in 11 National Surgical Adjuvant Breast Project (NSABP) trials identified three cases of mesothelioma, all occurring in women who had received radiation therapy to the ipsilateral thorax [31]. In contrast, a SEER database cohort of over 250,000 could not identify a link between radiation therapy and subsequent development of pleural mesothelioma [32].

●Although prophylactic mediastinal irradiation is no longer used in testicular germ cell tumors and its use has been sharply curtailed in patients with Hodgkin lymphoma and non-Hodgkin lymphoma, there are a substantial number of cancer survivors who remain at risk for the late development of mesothelioma. (See "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma".)

Malignant mesothelioma developing after therapeutic irradiation may have somewhat different features compared with those due to asbestos exposure. In one report, 22 patients who developed mesothelioma following chest irradiation as part of their treatment for Hodgkin disease or non-Hodgkin lymphoma were compared with 1596 cases associated with asbestos exposure [33]. Patients with treatment-related mesothelioma were significantly younger (median age 45 versus 64 years) and had a significantly longer overall survival (32.5 versus 12.7 months).

The development of malignant pleural mesothelioma has also been associated with other sources of radiation exposure. In one study, exposure to external radiation at nuclear facilities was associated with a significant increase in mesothelioma risk [34]. In rare cases malignant pleural mesothelioma has been associated with intrapleural thorium dioxide (Thorotrast), a radioactive contrast agent in the 1930s and 1940s [35].

Carbon nanotubes — Carbon nanotubes share similar dimensions and chemical properties with asbestos [36]. Studies in animal models have shown that these particles can induce mesothelioma-like changes in susceptible strains of mice following intraperitoneal administration [37,38].

Carbon nanotubes are being used in an increasing array of applications in the workplace. Epidemiologic vigilance will be required to ensure that these are not a new etiologic source of malignant mesothelioma [36].

Viral oncogenes — Simian virus 40 (SV40) is a polyomavirus with oncogenic potential in humans. Its actions in mesothelioma are thought to be due to the complex formation of viral tumor antigens (Tag) and p53 [39]. (See "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections".)

The relationship between SV40 and mesothelioma remains uncertain. Several studies identified SV40 nucleic acids in a large proportion of mesothelioma cases (some of which did not have obvious asbestos exposure) [40-42]. However, a number of epidemiologic studies have failed to confirm these observations [43-45].

Genetic factors — Familial clustering of pleural mesothelioma has been noted, with one study describing an elevated risk for mesothelioma among those whose parents or siblings were diagnosed with the disease of 3.9- and 12.4-fold, respectively [46].

Regarding specific genes that have been implicated, inactivation of the nuclear deubiquitinase BAP1 is associated with malignant mesothelioma [47]. BAP1 appears to regulate key histones and transcription factors related to the development of tumors [48,49]. In an initial study, inactivating mutations of BAP1 were found in about one-quarter of mesothelioma tumor tissues tested [50]. More recent data suggest that somatic mutations of BAP1 may be present in up to 60 percent of mesotheliomas. In addition, germline mutations in BAP1 were identified in two families with a high incidence of mesothelioma [51]. Loss of BAP1 may predispose to cancer after asbestos exposure; testing for mutations in this gene might eventually be used to identify patients at high risk who could be targeted for early intervention. Loss of BAP1 seems to be part of a larger familial cancer susceptibility syndrome, most often associated with ocular melanoma.

Other possible causes — Most cases of mesothelioma not related to asbestos are idiopathic. However, in certain geographic areas, mineral fibers other than asbestos (eg, erionite, fluoro-edenite) have been linked to mesothelioma [52,53]. Therapeutic radiation for other malignancies is another risk factor [53].

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Asbestos exposure (The Basics)")

SUMMARY

●The predominant cause of asbestosis is inhalational exposure to asbestos. There is a very prolonged latency period between exposure to asbestos and the development of mesothelioma. (See 'Asbestos exposure' above.)

●Recognition of the relationship between asbestos exposure and mesothelioma and other lung malignancies led to sharp restrictions in environmental exposure to asbestos. In the United States, these restrictions have led to a gradual decrease in the total number of cases. In other areas, such as Great Britain, the number of cases continues to increase, and the peak incidence has not yet been reached. (See 'Asbestos exposure' above.)

●Exposure to ionizing radiation to supradiaphragmatic fields in the treatment of malignancy (Hodgkin lymphoma, non-Hodgkin lymphoma, testicular cancer) has also been associated with a statistically significant increase in the risk of mesothelioma, although this accounts for only a small fraction of the mesothelioma cases diagnosed. (See 'Radiation' above.)

●A genetic predisposition for mesothelioma has been identified (mutation in the gene BAP1) that has been associated with other cancers, especially ocular melanoma. (See 'Genetic factors' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Steven M Albelda, MD, who contributed to an earlier version of this topic review.