Clinical Study of Asbestos-Related Lung Cancer

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1 Industrial Health 2003, 41, Original Article Clinical Study of Asbestos-Related Lung Cancer Takumi KISHIMOTO 1 *, Kazuo OHNISHI 2 and Yoshiaki SAITO 3 1 Department of Occupational Pulmonary Disease, Okayama Industrial Injury Hospital, Chikkomidorimachi, Okayama , Japan 2 Kobe Industrial Injury Hospital, Kobe, Japan 3 Keihai Industrial Injury Hospital, Fujiwara, Japan Received May 30, 2002 and accepted February 6, 2003 Abstract: We analyzed the characteristics of 120 patients of primary lung cancer supposed to be induced by exposure to asbestos. Most of 120 patients were male and the age ranged from 47 to 87 years with a median of 70 years. No particular tendency was observed in the histological types of the lung cancer in 120 patients. Forty of the 120 patients were heavy smokers. When the occupational history was analyzed, most of the patients had been exposed to asbestos in former Japanese naval shipyard, commercial shipyards, construction industry and ironworks. The term of asbestos exposure was 2 to 60 years with a median 27 years. Lung cancers appeared after 15 to 69 years with a median 43 years from the initial exposure to asbestos. Lung cancer was accompanied by asbestosis in 35 patients and by pleural plaques in 77. Twenty-two patients had both asbestosis and pleural plaques. The number of asbestos bodies per 5 g wet lung tissue for 72 patients whose lung tissues obtained from autopsy or surgery was more than 150 bodies which meant the number of occupational asbestos exposure. As for the kinds of asbestos fibers of 32 patients, 14 patients exposed to crocidolite, 10 patients to amosite and 8 patients to chrysotile. Key words: Asbestos exposure, Lung cancer, Asbestosis, Pleural plaque, Brinkman index, Shipyard worker, Construction worker Introduction Asbestos is known to be carcinogenic, and its use is prohibited in many western countries, because it induces malignant mesothelioma 1) or lung cancer 2). However, asbestos is still produced and used in large quantities in South America and Asian countries. Because of the latency of carcinogenicity of asbestos, many patients of asbestos-related lung cancer are reported in many countries even today 3 5). In Japan, the import of asbestos increased rapidly shortly after World War II and reached a peak of 352,000 tons in As the use of crocidolite or amosite was prohibited in 1995 and the carcinogenicity of asbestos has become known, its import decreased gradually. However, about 110,000 tons of asbestos is still imported to Japan and is used primarily in construction and automobile industries 6). *To whom correspondence should be addressed. For this reason, the incidence of asbestos-related lung cancer is estimated to be increasing by the study for autopsy cases 7), and there have been several reports of the disease in Japan 8 14). In this study, in order to investigate the relationship between asbestos-related lung cancer and the state of asbestos exposure such as occupational histories and the volume of asbestos bodies in the lung tissues, we studied 120 patients encountered at public hospitals including Industrial Injury Hospitals in Japan from 1995 to Subjects and Methods The subjects 120 patients with primary lung cancer considered to have been induced by exposure to asbestos definitively diagnosed at Industrial Injury Hospitals established by Labor Welfare Corporation (Okayama, Chugoku, Kobe, Keihai, Kagawa, Tohoku and Moji Industrial Injury Hospitals) and National Kure Hospital, Kure Kyosai

2 CLINICAL STUDY OF ASBESTOS-RELATED LUNG CANCER 95 Hospital from 1995 to The diagnostic criteria were a positive history of occupational exposure to asbestos and primary lung cancer in patients with asbestosis or pleural plaques or detection of 150 or more pulmonary asbestos bodies per 5 g of wet lung tissue 15) in patients without asbestosis or pleural plaques. Each patient was evaluated with regard to the gender, age, histological type of lung cancer, occupational history, period of exposure to asbestos, period from initial exposure to the onset of lung cancer, history of smoking, and the presence or absence of asbestosis or pleural plaques. In the patients who underwent surgery or autopsy, pulmonary asbestos bodies were counted according to Matsuda s method 16). Five gram of wet lung tissue was dissolved in sodium hypochlorite over 48 hours, and complete dissolution of the lung tissue was confirmed. The supernatant was discarded, the sediment was dissolved with 10 ml each of chloroform and 50% ethanol, and the solution was centrifuged at 18 g for 5 minutes. The supernatant was discarded, the sediment was dissolved with 95% ethanol, the solution was passed through a 5 µm poresized Millipore filter, and the asbestos bodies on the filter were counted under the light microscope ( 100). In 32 patients whose lung tissues were enough to examine asbestos fibers, the number of asbestos fibers in the lung was examined by transmission electron microscopy ( 4,000), then element analysis was performed by X-ray microanalysis. And the type of asbestos fibers was evaluated from the ratios of element contents. The relative peak heights for seven elements (magnesium, silicon, calcium, sodium, manganese, iron, and aluminum) were measured for each fiber 17). Values for the relative peak-height percentage of these seven elements were plotted on a Gibbs triangular coordinate diagram 18). We classified fibers using a discriminate function analysis technique based on the data from the International Union Against Cancer standard fiber analysis 19). Twenty asbestos fibers were examined for each case and the type of asbestos fiber which was detected most frequently was assumed to be the cause of lung cancer. Statistical analysis was done by Kruskal-Wallis test for the number of asbestos bodies with asbestosis and pleural plaques, with asbestosis without pleural plaque, with pleural plaque only, and without asbestosis and pleural plaque, then p<0.05 was thought to be significant. Results Of the 120 patients with asbestos-related lung cancer, 116 were males and only 4 were females. The age at the onset ranged from 47 to 87 years with a median value of 70 years Table 1. Ages and gender of patients with asbestosrelated lung cancer Ages (years) Males Females Total Total Table 2. Occupational histories of asbestos-related lung cancer Occupational history Shipyards 51 Construction workers 18 Ironworks 15 Slate manufacturing 7 Plumber 6 Automobile industry 4 Steel industry 3 Lagging 3 Welder 3 Repair of brake and clutch 3 Making and repair of furnace 3 Steam locomotive 2 Sprayer 1 Thermal power station (Table 1). The most predominant occupation among patients was ship building, which consisted of 51 persons. They used to be employed at the naval arsenal before the end of World War II and were engaged in rigging, plumbing, and electric work to the post-war era. Among other occupations, 18 were employed in construction industry, 15 at ironworks, 7 in slate manufacturing, followed by 6 plumbing and 4 automobile industry workers (Table 2). The duration of exposure to asbestos for 70 patients ranged from 2 to 60 years with a median of 27 years (Table 3). Other 50 patients had occupational histories of asbestos exposure, but the duration of asbestos exposure was not confirmed. The latency from the initial exposure to the onset of lung cancer for 70 patients ranged from 15 to 69 years and the median latency was 43 years (Table 4). The distribution of histological types of 120 lung cancers was 54 squamous cell carcinomas, 51 adenocarcinomas, 11 small cell carcinomas, and 4 large cell carcinomas.

3 96 T KISHIMOTO et al. Table 3. Duration of asbestos exposure and the asbestos-related pulmonary or pleural changes in chest radiography Duration of Asbestosis Asbestosis & Pleural plaque asbestos exposure only pleural plaque only none Total 10 years Unidentified Total Table 4. Latency period of the appearance of lung cancer after the initial exposure to asbestos The appearance of lung cancer after the initial exposure to asbestos 20 years Table 5. Numbers of asbestos bodies or fibers in the lung of patients with lung cancer No. of asbestos bodies/5 g wet lung tissue , , ,001 50, , The number of pulmonary asbestos bodies was more than 150/5 g of wet lung tissue in all 72 patients examined, and ranged 160 to 244,500 with a median of 12,680 asbestos bodies/5 g of wet lung tissue and asbestos fibers ranged from to with a median of asbestos fibers (Table 5). The number tended to increase, as the duration of exposure became longer. In 32 patients, the number of asbestos fibers was also 150,000/5 g wet lung tissue or higher. Concerning the type of asbestos detected in each patient, crocidolite was observed alone in 14 patients, amosite alone in 10 patients, and chrysotile alone in four patients. In the remaining four patients, chrysotile was the most frequently detected fiber, and crocidolite and amosite were detected additionally in three and one, respectively (Table 6). Complications were searched by chest radiography, CT, or histopathological examination in all 120 patients. The presence of asbestosis was demonstrated in 35 patients. Among them, 25 patients had relatively mild asbestosis with a Profusion Rate (PR) 1 on chest radiography, but 7 patients had typical asbestosis with PR 2 and 3 patients had severe asbestosis with PR3 (Table 7). Pleural plaques were confirmed in 77 patients. In 64 of them, a pleural plaque or plaques were detected by chest radiography. There were a No. of asbestos fibers/5 g wet lung tissue total of 13 patients whose pleural plaques were not from chest x-ray and/or chest CT but observed by autopsy or surgery. Calcification was noted in 46 patients and a pleural plaque or plaques were detected by chest radiography in 64 patients. Twenty-two cases had both asbestosis and a pleural plaque or pleural plaques. Thirty patients had neither asbestosis nor pleural plaques but had asbestos bodies in the lung tissue more than 150/5 g of wet lung tissue. The mean number of asbestos bodies for patients with asbestosis and pleural plaques was 16,712 ± 13,564/5 g of wet lung tissue, that of asbestosis without pleural plaques was 22,529 ± 20,238/5 g of wet lung tissue, and that of patients with pleural plaques only was 4,651 ± 6,904/5 g of wet lung tissue, and that of patients without asbestosis and pleural plaques was 2,325 ± 5,178/5 g of wet lung tissue (Fig. 1). The number of asbestos bodies for patients suffering from asbestosis, in conjunction with or without pleural plaques shows a Industrial Health 2003, 41,

4 CLINICAL STUDY OF ASBESTOS-RELATED LUNG CANCER 97 Table 6. Asbestos fibers detected in the lung tissue Most dominant No. of Detection of other types of asbestos type of asbestos patients None Crocidolite Amosite Chrysotile Crocidolite Amosite Chrysotile Table 7. Numbers of patients of asbestosis and/or pleural plaques with lung cancer Asbestosis PR1 PR2 PR3 Total Pleural plaque (13*) (13*) *Pleural plaques were detected by autopsy or surgery. 85 (13*) (13*) Fig. 1. Comparison of mean asbestos body concentration in lung tissue among four groups; asbestosis with pleural plaque, asbestosis without pleural plaque, pleural plaque only, and neither asbestosis nor pleural plaque. significant (p<0.0001) increase comparing with that of patients suffering only from pleural plaques or those patients with neither asbestosis nor pleural plaques. But, there is no significant difference in average numbers of asbestos bodies between pleural plaques only and without asbestosis and pleural plaques. Smoking habit was examined and there were only 4 nonsmokers including 2 female. Among 54 smokers, the Brinkman index (BI) was ranged from 450 to 2,400 with a median as 900 and 46 were heavy smokers, whose BI were more than 600 or greater. Discussion Diagnostic criteria for asbestos-related lung cancer are not completely among researchers. While only lung cancer complicated by asbestosis used to be called asbestos-related lung cancer 21), there have been reports that lung cancer

5 98 T KISHIMOTO et al. accompanied by pleural plaques should also be regarded as asbestos-related lung cancer 22 24) so we have applied this criterion as well. Concerning the number of pulmonary asbestos bodies, Churg et al. 25) advocated 500/5 g of wet lung tissue as a criterion of positive occupational exposure to asbestos. Among our 72 patients examined, 50 patients met or exceeded Churg s level. Among the remaining 22 patients, 18 patients had a pleural plaque or plaques, which is a leading indicator of asbestos exposure. Because of this evidence, we also have used the Japanese criterion (150 or more/5 g of wet lung tissue) for this study. Our 120 patients were diagnosed as asbestos-related lung cancer on these bases and have been enrolled in this study. Our patients are roughly 10% of all patients having been reported as asbestos-related lung cancer in academic papers in Japan 6, 8 13, 26, 27). Ninety seven percent were male and 83% were aged 60 years or above at the onset. These characteristics of patients were similar to earlier reports 8). Since many of the patients were from the Seto Inland Sea area, nearly half the patients had occupational background as shipyard worker (42.5%), followed by construction worker (15%), ironworker (12.5%), slate manufacturing worker (5.8%), plumber (5.0%), automobile industry worker (3.3%) etc. Reports on asbestosrelated lung cancer used to be frequent in ship building industry 28, 29), but lung cancer has also been reported recently among workers of construction industry 14, 30), and of clutch plate manufacturers in automobile industry 31), indicating an association with changes in the use of asbestos. According to our data, those with an occupational background of construction, slate manufacturing, and automobile industry occupy a considerable percentage of our patients unlike our report 12 years ago 8) which was only treated ship building industry around Kure area. Therefore, the occupational distribution of patients with asbestos-related lung cancer in Japan may be changed. The median duration of exposure to asbestos was 27 years and tended to be longer than the median value of 20 years among the patients with malignant mesothelioma 32). Also, the median latency from the initial exposure to the onset of lung cancer was 43 years, which was longer compared with 20 years among asbestos cement workers with malignant mesothelioma, who had exposed to high concentration of asbestos 33). The incidence of adenocarcinoma and squamous cell carcinoma were 42.5% and 45%, respectively. The results appeared to be generally in agreement with earlier report 34) showing that adenocarcinoma was 37% and squamous cell carcinoma was 31%. As for the type of asbestos, we previously reported that chrysotile also had carcinogenicity 8). In the patients evaluated in this study, the frequencies of detecting fibers of chrysotile, crocidolite, and amosite have no big differences. Chrysotile was most frequently detected in 8 patients, 4 of them (50%) were detected in mixed form with crocidolite or amosite and the number of patients detected chrysotile is lower than the patients of crocidolite or amosite. These results were consistent with the report by Landrigan et al. 35) that the carcinogenicity of asbestos is comparable among the above 3 types. But the incidence of lung cancer induced by chrysotile is seemed to be not so high as crocidolite. As for the history of smoking, 46 patients were heavy smokers with BI of 600 or greater, and only 4 were nonsmokers. Therefore, smoking is considered likely to be involved in the development of lung cancer 36). In Japan, workers compensation is granted generally to patients who have worked in an environment where asbestos has been used for about 10 years or longer and in whom the severity of asbestosis is PR 1/0 or higher or pleural plaques can be confirmed by chest radiography 37). It has also been granted without these findings if asbestos bodies have been demonstrated in the lung 37). Although all 120 patients enrolled in this study fulfilled these conditions, only 10 had applied for workers compensation. There may be several reasons. One might be that their attending physicians had not recognized these rules, another is that they either failed to take a sufficient occupational history or interpreted fibrous lesions in the chest as idiopathic interstitial pneumonia rather than asbestosis. Workers who have handled asbestos themselves are aware of exposure to asbestos, but workers in ship building industry, who have been exposed to asbestos that was used by other workers, for example, are unaware of the fact of their asbestos exposure. Therefore, education of physicians about asbestosis is considered to be needed so that they may be able to diagnose the condition correctly in patients presenting findings as pleural plaques. References 1) Wagner JC, Sleggs CA, Marchand P (1960) Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J Ind Med 17, ) Selikoff IJ, Hammond EC, Churg J (1964) Asbestos exposure and neoplasia. JAMA 188, ) Pang ZC, Zhang Z, Wang Y, Huaquiang Z (1997) Mortality from a Chinese asbestos plant: Overall cancer mortality. Am J Ind Med 32, ) Martuzzi M, Comba P, De Santis M, Iavarone I, Di Paola M, Mastrantonio M, Piratsu R (1998) Asbestosrelated lung cancer mortality in Piedmont, Italy. 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