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Natural History and Epidemiology of Malignant Mesothelioma* Karen H. Antman, M.D. / Asbestos exposure constitutes the primary cause of pleural effectiveness of asbestos removal are controversial.* .... ?. and peritoneal mesothelioma in humans. Risk relates to the Asbestos continues to be used extensively in cement, in duration and intensity of exposure. Thus, those exposed at ceiling and floor tiles, and in automobile, but not airplane, younger ages are at higher lifetime risk, families of asbestos brake linings. Currently, Canadian chrysotile accounts for workers exposed to asbestos on hair and clothing as well as about 90% of the asbestos used in the United States."More to asbestos items brought home from the workplace are carcinogenic types ofasbestos continue to be used, however. also at risk, as are employees working in the same vicinity Amosite, for example, is used in ships because it resists salt as asbestos workers. The public health significance of water and some fillers contain anthophyllite. ' ' exposure from asbestos in public and private buildings remains controversial. Malignant mesothelioma is difficult Carcinogenicity n-.frejfes to diagnose and carries a poor prognosis. Chemotherapy One of the most inert compounds known, asbestos appears with single or multiple agents has thus far been disappoint to provoke carcinogenesis through its physical rather than,; ing, but doxorubicin and cisplatin or mitomycin and cisplatin its chemical composition: A 10:1 length-to-width fiber ratio are probably most active with response rates in measurable is associated with carcinogenesis; additionally, the fibers disease of 25%. Palliative radiotherapy is also problematic must be fairly fine. Indeed, fiberglass and other fibers milled since differences between tumor cytotoxicity and pulmo to this standard are also carcinogenic in laboratory animals, nary tolerance are small and radiation pneumonitis may although the fiberglass is commonly used in homes.3 significantly impair quality of life. Amphiboles are about 10 times as carcinogenic as chrys (Chest 1993; 103:373S:76S) otile. (The fibers with the highest carcinogenic potential are Asbestos: An Overview mined in South Africa and other countries, whereas most chrysotile is mined in Canada.) Crocidolite has been asso The link between asbestos and asbestosis, lung cancer, and mesothelioma is by now well established, although ciated with a high risk of malignant mesothelioma,4 whereas amosite appears to carry an intermediate risk. Chrysotile questions remain about the duration and intensity of expo shows the weakest association with malignant mesotheli sure needed to initiate carcinogenesis. Millions ofAmericans oma.5 Nonetheless, chrysotile has been shown to cause have been occupationally exposed to asbestos. Although mesothelioma in laboratory animals.6 Whether human cases some uses of asbestos have been curtailed, because of the of malignant mesothelioma linked to past chrysotile exposure characteristics that make it attractive industrially and its were caused by the serpentine fiber itself or by amphibole relatively low cost, asbestos is still used widely. Given the contamination8-9 remains controversial since such contami wide occupational exposure and the fact that, until 1972, nation is common. asbestos was sprayed in schools and other public buildings, physicians should be aware of potential public health impli Mechanisms of Carcinogenesis cations. This article will briefly review asbestos use, min Fibers enter the distal airway. About two thirds of the eralogy, and mechanisms of carcinogenicity, and review the daily dose is eliminated by coughing and swallowing, which diagnosis and management of malignant mesothelioma. may be the mechanism for the development of peritoneal Asbestos is the commercial name for a hydrated magne mesotheliomas. As macrophages try to engulf the fibers sium silicate fiber comprising 2 types, the seipentine and remaining in the lung, free radicals and lysosomal enzymes the amphiboles. The serpentine chrysotile fibers are curly are liberated, which probably accounts for the fibrosis that and pliable, whereas the amphiboles (crocidolite, amosite, develops.1 anthophyllite, tremolite, and actinolite) are needle-like.' Regulatory Limits Asbestos Use As the scope of asbestos' effects on health became Prized industrially for its resistance to heat and combus apparent, attempts to limit permissible exposures grew. By tion, asbestos was used abundantly in ships and other combat 1970, the Occupational Safety and Health Administration material during World War II. When the war ended, had established 5 fibers per cubic milliliter of air as the industrial and consumer use increased for insulation. Asbes standard acceptable exposure, which legally exposed asbes tos was also sprayed on the interior structural surfaces of tos workers to up to 4 million fibers a day. By 1976, the many public and private buildings between 1946 and 1972, standard had been reduced to 2 fibers and is currently 0.2 including as many as 10% to 15% of the nation's schools. The fibers per cubic milliliter of air. Above these limits, respira public health significance of this exposure as well as the cost tors, protective clothing, and shower and changing facilities become mandatory. Only exposures to fibers longer than 5 From the Department of Medicine, Dana-Farher Cancer Institute, Harvard Medical School, Boston. p.m are regulated currently, however. Present data do not allow conclusions regarding whether there is a safe threshold CHEST / level for asbestos exposure. Asbestos-related Cancer Risk Asbestos workers are currently at substantially higher risk for cancer than they are for pulmonary disease. About 8% of asbestos workers will die of asbestosis. While the average American has about an 18% chance of developing and dying of any malignancy, for an asbestos worker this risk is close to 50%, with most ofthe tumors involving the lung. Currently an estimated 3% of all cancers are asbestos-related, most of which are primary in the lung. The incidence of lung cancer in the United States in nonsmoking, non-asbestos-exposed individuals is about one per million man years, and the expected incidence of lung cancer in the population at large is about 7%. In a cohort of asbestos workers, however, the risk of lung cancer increases to approximately 25%.1011 Asbestos, which is directly cytotoxic, efficiently adsorbs hydrocarbons, which probably accounts for the higher risk of lung cancer in persons who have histories of asbestos exposure and cigarette smoking, (Interestingly. there is no ^ssociation_^etween_cigarette_smokin^_andjnali2nantjnes; othelioma, and they may even be negatively correlated. This most likely reflects earlier development of and death from lung cancer in smokers, removing them from the risk pool for mesothelioma.) As noted, the risk of lung cancer in the nonsmoking general population with no asbestos exposure is small. This risk increases about 6-fold in nonsmokers who have been exposed to asbestos, still a fairly small risk. However, conservative estimates of the lung cancer risk in smokers with a history of asbestos exposure suggest that their risk for lung cancer increases almost 60-fold (Table l).12 The incidence of gastrointestinal malignancy is also higher in asbestos workers, but whether asbestos is causally related to these tumors is controversial. Anecdotal reports also detail head and neck tumors and B cell malignancies such as myeloma and lymphoma.1011 Malignant Mesothelioma Not until 1960, with the publication of a series of patients with mesothelioma by an astute internist in South Africa, was the existence of malignant mesothelioma as a discreet clinical entity and its relation to asbestos exposure, both " occupational and bystander risk, established.13 The annual , incidence of malignant mesothelioma in the United States - is not known with certainty because cancer mortality in the United States is reported by site of the primary lesion, not the morphology. The incidence is estimated to be approxi mately 2,200 cases per year or about 12.1 cases per million white men,11 but in asbestos workers, this risk rises to 8% '. to 13%. The incidence appears to be increasing,15 probably reflecting the long latency period from asbestos exposure to clinical disease and the high numbers of workers exposed to , Table 1--Age-Standardized Death Rates per 10" Man \ Years Showing Synergism Between Asbestos Exposure and Smoking for hung Cancer* *Data adapted from Hammond et al," asbestos in the decades following World War II. Risk of developing malignant mesothelioma varies, de pending on the duration and degree of exposure. Because so many people have been exposed to asbestos, the mathe matic risk of developing malignant mesothelioma can actu ally be calculated and equals a constant (which comprises the intensity and duration of the exposure) multiplied by the time since the first exposure to the third or fourth power. Thus, someone exposed at age 20 years has no higher risk er_^eai_jbr_anv given exposure, but accumulates a higher lifetime risk than someone who is exposed to asbestos at aim 50. In fact, given the latency period, which is 20 to more than 40 years, moderate asbestos exposure would probably carry few medical consequences for asbestos workers 55 years or older. Asbestos workers with heavy exposure have a higher risk of developing peritoneal mesothelioma, whereas those exposed for relatively brief periods are at higher risk of developing pleural primaries. Risks to Workers' Families The families of asbestos workers have an approximately 1% risk of malignant mesothelioma. In most cases, this risk arisesbecause_ofasbestoscontamination^woriccJotlKS_or, less frequently, manufactured articles (eg, textiles) workers have brought home. Projections based on the average family size in 1950 suggest that about up to one third of eases of malignant mesotheliomas may develop in family members of asbestos workers. Diagnosis and Management of Malignant Mesothelioma Fatient History: A comprehensive history for natients ^usecte^^fhavingjnalignantjnesothelionmniustfocus_on a period of 20 to 40 years before and should include the occupations of family members living with the patient during this interval. Even the most comprehensive history may fail to. establish asbestos exposure in about 30% of cases. For example, a cluster of cases of malignant mesothelioma with no stated history of asbestos exposure was explained when 2 patients being treated at the Dana-Farber Cancer Institute realized they knew each other. Both had worked at a factory manufacturing asbestos paper filters for cigarettes. When epidemiologists traced the histories of the approximately 50 people who had worked in that plant, they found that most had already died of malignancies, either lung cancers or mesotheliomas.16 Malignant mesothelioma is difficult to diagnose. Most patients come to medical attention when they develop dyspnea, chest pain, or both symptoms. Examination will usually reveal a large, unilateral effusion; only about 5% of patients have bilateral disease at diagnosis. X-Ray Findings: Only about 20% of patients with pleural mesothelioma demonstrate characteristic signs of asbestosis--a low diaphragm, interstitial fibrosis, or even pleural j>Ja2ues_on_^hest_fiImsi Since the development of both malignant peritoneal mesothelioma and asbestosis requires longer asbestos exposures, about 50% of patients with primary peritoneal tumors will demonstrate x-ray evidence of asbestosis and pleural calcifications. Other than being markers for prior asbestos exposure, the calcifications are of no medical significance. Patients with late-stage disease often develop a character- Nalural History and Epidemiology of Malignant Mesothelioma (Karen H. Antman)