The usual gross (large scale) and microscopic features of malignant mesothelioma are well described in many standard texts. This account concentrates on the unusual or controversial, on the still-evolving role of immunohistochemistry for the discrimination between mesotheloma and its look-alikes, and on the differential diagnosis in pleural biopsies.
Malignant pleural mesothelioma
Malignant mesothelioma (MM) has recently attracted the attention of the media because of its relationship with professional and environmental exposure to asbestos. This tumour of the pleura is a disease which has emerged in significant numbers of patients during the last 30 years in the industrialized countries and its increasing incidence makes it of socio-economical interest.
The histological description of MM was first published by E. Wagner in 1870 and later by Klemperer and Rabin. A literature review of pathological cases of lung diseases before 1940 identified 41 out of 46,000 autopsies as possible MM. In this review they mentioned a report from 1767 by Lieutaud who was the first to describe two possible cases of MM in an autopsy study. Since then, a number of case reports were published in which a relationship with asbestos exposure was considered important, but it was the report of J.C. Wagner in 1960 which identified a clear relationship between exposure to crocidolite mining and the development of MM. From that moment the association between asbestos exposure and MM was accepted and a beginning was made to abandon the production and processing of asbestos materials.
Mesothelioma: Cases Associated with Non-occupational and Low-dose Exposures.
Asbestos: Mesothelioma Mesothelioma is a rare cancer of the "mesothelial" cells that make up various membranes in a person's chest or abdominal cavity. This includes the pleura that encases the lungs. The pleura facilitates lung movement during breathing without motion sensation or nerve irritation inside the chest. Mesothelioma is not lung cancer, although it frequently causes respiratory problems as the tumor grows and spreads along the surface of internal organs along serosal membranes. When it develops, mesothelioma is almost always caused by asbestos. It is not caused by smoking of any kind. Mesothelioma most often occurs in two areas, forming extremely serious malignant tumors:
· Pleural Mesothelioma: cancer of the pleura, the membrane that lines the lungs and the chest cavity, and
· Peritoneal Mesothelioma: cancer of the peritoneum, which is the serosal membrane lining of the abdomen.
MesotheliomaTreatment Options:
The tumor encases the lung as it tracks the pleura, causing pain with breathing and creating compromised lung function.
Mesothelioma has a very long "latency" period, i.e., the time between the first exposure to asbestos and the onset of the symptomatic disease. This latency period is usually at least 10 to 15 years, and is reported in the recent medical journals to be as long as over 60 years. A period of 40 years from exposure to diagnosis is not uncommon. Mesothelioma can be caused by very brief, low-dose exposures to asbestos. The risk of contracting mesothelioma increases with any level of exposure. Because there is no "safe" level of exposure, all preventable contacts with asbestos should be avoided.
Mesothelioma: Occupational and Enviornmental Medicine
These comments were made on the behalf of the Art and Creative Materials Institute, a non-profit trade organization that represents the major manufacturers and importers of art materials in the United States. Talc is a common component of these art materials.
Asbestiform Talc
Definition: The draft report discusses the definition of asbestiform fibers. It would be strengthened if it includes NIOSH’s definition of these fibers:. NIOSH (Kullman, et al. 1995) defines asbestiform habit as:
“a specific type of mineral fibrosity in which the growth is primarily in one dimension and the crystals form naturally as long, flexible fibers. Fibers can be found in bundles that can be easily separated into smaller bundles or ultimately into fibrils.”
This definition is important since many of the fibers in asbestiform talc are cleavage fragments. NIOSH’s definition for asbestiform habit contrasts with their definition for the nonasbestiform habit :
“These minerals have … crystal habits where growth proceeds in two or three dimensions instead of one dimension. When milled, these minerals do not break into fibrils but rather into fragments resulting from cleavage along the two or three growth planes. Particles formed by the comminution of these minerals are referred to as cleavage fragments.”
Respirable fiber size: Although the draft report notes that a respirable fiber has a diameter of 3-4 mm this is for fibers with a density of 1. Talc has a specific gravity of 3 and, consequently the equivalent aerodynamic diameter of respirable talc fibers would be 1/3 of this, on the order of 1 mm (Wylie, et al. 1993). This finding is particularly important in that the fibers in asbestiform talc are primarily wider than 1 mm with only 10-11% of fibers in commercial talcs being <1 mm in diameter.
Fiber size and cancer risk: There are excellent animal models for the relationship between fiber dimension and risk of both mesothelioma and lung cancer. For mesothelioma risk, fibers with a dimension of 0.25 mm in diameter and >8 mm long appear to present the greatest risk (Stanton, et al., 1981; Oehlert, 1991) with almost no risk presented by short fibers (Davis, et al. 1986). Most amphibole fibers in a asbestiform talc mine are shorter than 10 mm (Kelse and Thompson, 1989) and would not be expected to present a risk of mesotheliomas. Similarly, lung cancer risk also depends on fiber dimensions. Based on asbestos inhalation studies, Berman et al (1995) found that potency for lung cancer rested with fibers that were longer than 10 mm and less than 0.3 mm in diameter. Their model found that fibers that were <10 mm long and had widths from 0.3-5.0 mm were not associated with a lung cancer risk. Lippmann (1988) performed as similar analysis. He found that fiber retention drops rapidly as fiber diameter increases from 0.8 to 2.0 mm. No lung cancer risk was associated with fiber length less than 5 mm. Lung cancer risk was associated with fibers with a diameter of 0.3-0.8 mm and a substantial fraction >10 mm in length.
Animal Studies: Although IARC considered a number of studies involving the carcinogenicity of talc in experimental animals, they did not have access to identification information concerning several of the fibrous talcs. This is particularly important because talcs form the Grouvenor Talc Company (GTC), the mine most studied for cancer risk, have been examined in a number of animal models and have been found to be non-carcinogenic. Stanton, et al. (1981) examined two asbestiform talcs from the Grouvenor talc district including one from GTC (Stanton talc #6) in their pleural implantation rat model. Neither of these talcs induced mesotheliomas although based on particle dimensions, a 60% incidence of mesotheliomas would have been expected with the GTC talc. Oehlert (1991) re-analyzed the Stanton data, breaking out potency assessments not only by particle size but by mineral type. When compared to asbestos, the author found that talcs were 1/135,000 as potent for causing pleural tumors. This re-analysis included both the asbestiform talcs and 5 non-asbestiform talcs studied by Stanton, et al.
Smith, et al. (1979) also studied one GTC talc (FD14) in their hamster pleural mesothelioma model. This talc, as well as another talc containing amphibole fibers, was negative in their model.
Wylie, et al. (1997) studied the FD14 talc from the Smith et al. study in an in vitro system. It was not cytotoxic and did not induce cell proliferation. Talc samples not containing quartz were not cytotoxic where asbestos was both cytotoxic and induced proliferation.
Epidemiology: non-asbestiform amphiboles: The primary components of asbestiform talcs, other than talc, are cleavage fragments of anthophyllite and tremolite. Since exposure to these cleavage fragments may be a factor in cancer risk from exposure to asbestiform talc, a review of epidemiological studies of workers exposed to nonasbestiform amphiboles is in order and will strengthen this report. Kusiak et al (1991) looked at a cohort of 54128 gold and nickel miners with potential exposure to nonasbestiform amphibole fibers. They found an excess cancer risk in pre-1945 workers but no relationship between cancer excess and exposure to mineral fibers. The concluded that the excess was probably related to exposures to arsenic and radon decay products (radon daughters). Steenland and Brown (1995) studied 3328 gold miners from South Dakota. There was no significant increase in lung cancer risk in this cohort though there was evidence of excessive quartz exposure including elevated deaths from immunological diseases, renal disease and tuberculosis.
The authors suggest that a slight excess in lung cancer rates might be related to the smoking habits of miners: they smoke more then the general population. Cooper et al (1992) studied 3444 taconite miners exposed to silica and nonasbestiform amphibole fibers. The standardized mortality rate (SMR) for lung cancer was less than expected at 67 and was not related to duration of employment, exposure level or latency. When Cooper, et al. eliminated those workers with less than 3 months of employment from the analysis, the SMR for lung cancer actually decreased as duration of employment increased.
Epidemiology: asbestiform talc: The association between exposure to asbestiform talc and lung cancer risk is primarily based on the findings of increased cancer risk in workers exposed to asbestiform talc in the Grouvenor talc district (GTD) of upstate New York. A more detailed description of these studies, as well as inclusion of the latest (Dezell et al, 1995) study would be in order. Kleinfeld, et al. (1967, 1974) found a 10 pulmonary and pleural tumors among a study of all GTD workers. All cases occurred in workers who were exposed prior to the introduction of exposure control measures ca. 1945. Twenty-nine of the workers died of pneumoconioses, including 5 who died of a complication of quartz exposure, tuberculosis. This study had the short coming that it did not take into account exposures other then to talc, did not take into account smoking history and did not relate exposure levels to outcome. Recent data developed by NIOSH (1980) can be used to estimate respirable quartz exposures to workers in this study. NIOSH found that for the average dust exposure of 2.9 million particles per cubic foot (mppcf) in GTC mills, the average respirable quartz exposure was 11 mg/m3 and that for the average dust exposure of 8.1 mppcf in the GTC mine the average quartz exposure was 12.4 mg/ m3. Dust exposure measurements were made for GTD mines and mills in the Kleinfeld, et al. study. These exposures can be translated to average respirable quartz exposures as follows:
Pre-1945 1945-1965
Mppcf Qartz (mg/m3) Mppcf Quartz (mg/m3)
Mines: drilling 818 1250 5 8
Mines: other 129 190 5-9 8-14
Mills 69-278 260-1050 27-37 102-140
Exposure levels prior to 1945 were sufficiently high, in both mines and mills, to result in the pneumoconioses cases described above with quartz levels in air as great as 10 fold higher than today’s permissible exposure limit for respirable quartz of 100 mg/m3. Respirable quartz is a known human lung carcinogen, with elevated risks particularly when exposures are sufficient to result in silicosis. That respirable quartz exposures were a concern has been confirmed by autopsy studies performed by Dr. Jerrold Abraham of 8 GTD workers. Two of the 5 workers with a history of more than 20 years of talc mining had silicosis.
The second study that has been used to implicate a risk between exposure to asbestiform talc and lung cancer is the NIOSH 1979 study of Grouvenor Talc Company workers. GTC went into operation in the late 1940’s using a wet drilling method that would have suppressed exposure to respirable quartz dust as noted in the above table. The NIOSH study has been criticized because of a number of short comings. It would be important to highlight these short comings since they have been addressed in later epidemiological studies of these workers. Specific concerns with this study included its small size; inclusion of all workers, including those that had only worked days; lack of assessment of the contribution of prior exposures; no study of exposure-lung cancer relationships; and no adjustment for smoking effects (Brown, et al, 1983). Any prior mine work among GTC employees would have likely involved high level exposures to quartz dust. Stille and Tabershaw (1982) were able to nearly double the size of the cohort. They found that the SMR for lung cancer among workers who had only worked at GTC was less than expected (76) and that tuberculosis, a disease associated with silicosis, was a significant finding (SMR 680). This study did not correct for smoking history, exposure or identify non-GTC exposures that many have been a concern.
Lamm, et al. (1988) presented a re-analysis of the Stille and Tabershaw (1982) data set in which the occupational histories of workers dying of lung cancer were presented. 8 of 11 workers who died of lung cancer had worked in mines other than talc mines or in quarries elsewhere than at GTC. The SMR for lung cancer in mill workers was 72 for those workers who had worked at least one year at GTC. For those for workers who worked less than one year and had first worked to GTC 20-24 years prior to their death, the SMR for lung cancer was 1111. The latter group would have included workers with prior exposures to mine dust prior to the putting in place of dust control technologies.
Gamble (1993) performed a nested case control study on NIOSH’s second evaluation of 710 GTC workers (NIOSH, 1990) to address concerns of confounding. They found that when using fellow GTC workers as controls, all of the excess lung cancer risk could be ascribed to smoking. When looking at past exposures they found that essentially all talc exposure could be ascribed to work at GTC. They were able to give more complete exposure histories for the lung cancer cases: 8 of the 22 cases had worked as drillers at mines or quarries other than GTC and 17 had worked in metal mines prior to working at GTC. Work in mines would have been expected to be associated with exposure to either quartz dust (exposures would have likely been even higher in metal mines than in talc mines because of quartz content of base rock) or radon daughters, a known cause of excess lung cancer risk in metal miners. That drillers may be at particular risk of quartz exposure has been noted by Rubino, et al. (1976) who found that dust generated from drilling operations my contain up to 18% quartz, even though talc itself is relatively free from quartz. In metal mines, drilling dust can contain up to 39% quartz (McDonald, et al., 1978).
Dezell, et al. (1995) further expanded the cohort to 818 workers and increased the latency time to an average of 21 years for GTC workers. They were able to address the concern that prior studies did not address incorporate an exposure-response analysis by estimating respirable dust exposures. When compared to past dust measurements, there was an excellent correlation between the two with a correlation coefficient of 0.78. They found no relationship between dust exposure at GTC and lung cancer. Increases in lung cancer were limited to workers hired prior to 1955 with deaths from non-malignant respiratory disease concentrated in this group as well. When adjusting for exposure they found an inverse relationship between lung cancer and exposure to all subjects, to those workers who were first employed prior to 1955 and to those workers who had worked at GTC for more than one year. The Gamble and Dezell, et al. studies discount the finding of an exposure-related risk of lung cancer for GTC workers with smoking and/or prior exposures to cancer-causing quartz dust or radon being likely contributors to the risk.
Asbestos and Cancer: An Overview of Current Trends in Europe
Maria Albin,1 Corrado Magnani,2 Srmena Krstev,3 Elisabetta Rapiti,4 and Ivetta Shefer1*
1Department of Occupational and Environmental Medicine, Lund University Hospital, Lund, Sweden; 2Cancer Epidemiology Unit - CPO Piemonte, S. Giovanni B. Hospital and University of Torino, Torino Italy; 3Institute of Occupational and Radiological Health, Belgrade, Yugoslavia; 4Osservatorio Epidemiologico Regione Lazio, Rome, Italy
Abstract
This review assesses the contribution of occupational asbestos exposure to the occurrence of mesothelioma and lung cancer in Europe. Available information on national asbestos consumption, proportions of the population exposed, and exposure levels is summarized. Population-based studies from various European regions on occupational asbestos exposure, mesothelioma, and lung cancer are reviewed. Asbestos consumption in 1994 ranged, per capita, between 0.004 kg in northern Europe and 2.4 kg in the former Soviet Union. Population surveys from northern Europe indicate that 15 to 30% of the male (and a few percent of the female) population has ever had occupational exposure to asbestos, mainly in construction (75% in Finland) or in shipyards. Studies on mesothelioma combining occupational history with biologic exposure indices indicate occupational asbestos exposure in 62 to 85% of the cases. Population attributable risks for lung cancer among males range between 2 and 50% for definite asbestos exposure. After exclusion of the most extreme values because of methodologic aspects, most of the remaining estimates are within the range of 10 to 20%. Estimates of women are lower. Extrapolation of the results to national figures would decrease the estimates. Norwegian estimates indicate that one-third of expected asbestos-related lung cancers might be avoided if former asbestos workers quit smoking. The combination of a current high asbestos consumption per capita, high exposure levels, and high underlying lung cancer rates in Central Europe and the former Soviet Union suggests that the lung cancers will arise from the smoking-asbestos interaction should be a major concern. -- Environ Health Perspect 107(Suppl 2):289-298 (1999).
http://ehpnet1.niehs.nih.gov/docs/1999/Suppl-2/289-298albin/abstract.html