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The Relationship Between Asbestosis and Bronchial Cancer
The Relationship Between Asbestosis and Bronchial Cancer G. K. Sluis-Cremer, M.D.·
This communication addresses the question of whether bronchial cancer in asbestos-exposed persons should be considered a complication of asbestosis or an independent effect of the inhalation of asbestos dust or both. The evidence will be considered under separate headings and then discussed
rate for general German population aged over 50. Finally, in two other autopsy seriesS,g on asbestos workers with lung cancer, asbestosis was invariably present.
EVIDENCE
In a large experiment on rats, Wagner et al l O in 1974 found that after statistical adjustment for survival time, the grade of asbestosis (estimated blind) was strongly related to the presence of lung tumors ( p < .(01). In addition there was an excess of tumors in rats with slight asbestosis (even when the exposure was minimal, te one day). There was no excess of tumors when asbestosis was absent.
FOR AN AsSOCIATION
BETWEEN
AsBESTOSIS
AND BRONCHIAL CANCER IN MAN
The association was first noted in the 193051.2 and
the evidence ably summarized by Hueper et all in
1966 who reported that in various autopsy series on
persons suffering from asbestosis, 12-50 percent were found to also have bronchial cancer. This was in sharp contrast with a reported prevalence of 1.2 percent of bronchial cancer at autopsy in silicotic subjects. 4 Buchanan,I) in a mortality study on subjects certified as having asbestosis, found that during the years 1961-1963, 54.5 percent of 77 cases also had lung cancer (there may have been some mesotheliomas included). Later, a review of 2,044 autopsied cases of asbestosis culled from the literature up to 1974 by Mirabella" revealed that 34.3 percent of those who died between 1955 and 1974 also had an intrathoracic malignancy (including mesothelioma) . Both Buchanan and Mirabella noted a startling secular increase of lung cancer throughout the last four decades. This may be due to the increase in cigarette consumption and/ or due to the fact that sufferers from asbestosis are living longer, the disease having become milder due to improved dust conditions. Bohlig et aI7 in a study of living cases of asbestosis concluded that there is an association between the severity of asbestosis and the prevalence of bronchial cancer, the incidence being 82/10,000 in severe cases and 11/10,000 in minimal cases, while in asbestos workers without disease bronchial cancer occurred in 3.7/10,000 which was not in excess of the -Director, Epidemiology Unit, Medical Bureau for Occupational Diseases, Department of Mines, Johannesburg, Republic of South Africa.
•
G. K. SLUIS-CREMER
Evidence for Association in Animal Experiments
Anatomic Site of Bronchial Cancer in Asbestos Workers Hueper," Bohlig,? Kannerstein and ChurgS and Whitwell et alii have all noted that the relationship between the number of cases in the upper lobes to the lower lobes, usually about 2.5:1, is inverted in asbestosis workers varying from 2:3 to 7:53. It has been proposed that the asbestos fiber entrapped in the region of most marked fibrosis (usually in the lower lobes) concentrates carcinogens from tobacco smoke and other pollutants. In addition, bronchial cancer in asbestos workers tend to be peripherally located and to involve the pleura, making it difBcult to differentiate from mesotheliomas.
Histologic Type of Bronchial Cancers Associated with Asbestosis Hueper3 was the first to comment on the greater prevalence of adenocarcinoma among asbestosis-related cancers than expected. Hourihane and McCaughey" confirmed this in a small series, while Kannerstein and Churg did not.S In the most recent large mortality study on workers with asbestosis and bronchial cancer, Whitwell et alii found 34 percent with adenocarcinoma. These workers strike a note of caution, however, pointing
CHEST, 78: 2, AUGUST, 1980 SUPPLEMENT
out that the proportion will vary according to the source of the histologic material, that is, biopsy, or surgical and post-mortem. In the study of Wagner et al,10 in asbestos-exposed rats the cancers which developed were mostly peripheral adenoma, adenomatosis, adenocarcinoma and squamous carcinoma. Thus, the bulk of evidence suggests there is indeed an excess of adenocarcinoma, but that the association with asbestos exposure is not as strong as it is in the case of oat-cell carcinoma in relation to uranium'" and chloremethyl methyl ether'" exposure. Both Hueper" and Wagner et al l O describe the development of premalignant epithelial alterations in areas of fibrosis. The fact that an asbestos worker develops adenocarcinoma would seem to have little medicolegal implication. DISCUSSION
The relationship between asbestosis and bronchial cancer does not appear to be straightforward. The pattern of site distribution and the presence of premalignant changes in the areas of fibrosis in man and animals suggest that cancer is often a complication of the asbestosis. There is also the evidence that bronchial cancer may complicate interstitial fibrosis of many etiologies and asbestosis is only exceptional in the high prevalence of this occurrence. IS The above does not exclude the possibility that asbestos exposure per se may cause bronchial cancer in a dose insufficient to cause fibrosis. This did not, however, happen in the rats in the series of Wagner et al. 16 It may be that the dose-response relationships between asbestos dust on the one hand and cancer and fibrosis on the other hand are similar, and therefore the two responses are frequent in the same individual. In any event, the evidence suggests that asbestos bronchial cancers invariably occur in lungs which are the seat of fibrosis. It should be stressed that this refers to fibrosis detectable at histologic examina-
CHEST, 78: 2, AUGUST, 1980 SUPPLEMENT
tion. Our methods for clinical diagnosis of mild degrees of asbestosis are insensitive and even in the presence of moderately severe degrees of Sbrosis no clinical, physiologic or radiologic abnormality may be detected in an important proportion of the cases. To demand proof of the presence of asbestosis in vivo before attributing a bronchial cancer to the inhalation of asbestos dust would thus seem to be unreasonable.
REFERENCES 1 Gloyne SR. Two cases of squamous carcinoma of the lung occurring in asbestosis. Tubercle 1935; 17:5 2 Egbert DS, Geiger AJ. Pulmonary asbestosis and carcinoma. Am Rev Tuberc 1936; 34: 143 3 Hueper WC. Recent results in cancer research. Berlin: Springer Verlag, 1956; 44 4 Merewether ER. Annual report, chief inspector of factories for the year, 1955 5 Buchanan WD. Asbestosis and primary intrathoracic neoplasms. An NY Acad Sci 1965; 132:5C11 6 Mirabella F. Pleuropulmonary malignancies confirmed by autopsy in asbestosis. Med d. Lavora 1975; 66:192 7 Bohlig H, Jacob G, Miiller H. Die Asbestose der Lunger. Stuttgart: Georg Thieme Verlag, 1960; 60 8 Kannersteing M, Churg J. The pathology of carcinoma of the lung associated with asbestos exposure. Cancer 1972; 30:14 9 Knox JF, Holmes S, Doll R, Hill ID. Mortality from lung cancer and other causes amongst workers in an asbestos textile factory. Br J Ind Med 1968; 25:293 10 Wagner JC, Berry G, Skidmore JW, Timbrell V. The effects of the inhalation of asbestos in rats. Br J Cancer 1974; 29:252 11 Whitwell F, Newhouse MD, Bennett DR. A study of the histological cell types of lung cancer in workers suffering from asbestosis. Br J Ind Med 1974; 31:298 Ii Hourihane D O·B, McCaughey WTE. Pathological aspects of asbestosis. Postgrad Med J 1966; 4i:613 13 Archer VE, Saccomanno G, Jones JH. Frequency of different histologic types of bronchogenic carcinoma as related to radiation exposure. Cancer 1974; 34:2056 14 Weiss W, Auerbach 0, De Fonso LR, Moser RL. The histologic type of lung cancer in chIoromethyl ether workers and its relation to dose. Presented at International Conference on Occupational Lung Disease, San Francisco, February 27-March 2, 1979 15 Stack BHR. Fibrosing Alveolitis. Tubercle 1971; 1;15 16 Wagner JC. Personal communication, 1979
THE RELATIONSHIP BETWEEN ASBESTOSIS AND BRONCHIAL CANCER 381
This communication addresses the question of whether bronchial cancer in asbestos-exposed persons should be considered a complication of asbestosis or an independent effect of the inhalation of asbestos dust or both. The evidence will be considered under separate headings and then discussed
rate for general German population aged over 50. Finally, in two other autopsy seriesS,g on asbestos workers with lung cancer, asbestosis was invariably present.
EVIDENCE
In a large experiment on rats, Wagner et al l O in 1974 found that after statistical adjustment for survival time, the grade of asbestosis (estimated blind) was strongly related to the presence of lung tumors ( p < .(01). In addition there was an excess of tumors in rats with slight asbestosis (even when the exposure was minimal, te one day). There was no excess of tumors when asbestosis was absent.
FOR AN AsSOCIATION
BETWEEN
AsBESTOSIS
AND BRONCHIAL CANCER IN MAN
The association was first noted in the 193051.2 and
the evidence ably summarized by Hueper et all in
1966 who reported that in various autopsy series on
persons suffering from asbestosis, 12-50 percent were found to also have bronchial cancer. This was in sharp contrast with a reported prevalence of 1.2 percent of bronchial cancer at autopsy in silicotic subjects. 4 Buchanan,I) in a mortality study on subjects certified as having asbestosis, found that during the years 1961-1963, 54.5 percent of 77 cases also had lung cancer (there may have been some mesotheliomas included). Later, a review of 2,044 autopsied cases of asbestosis culled from the literature up to 1974 by Mirabella" revealed that 34.3 percent of those who died between 1955 and 1974 also had an intrathoracic malignancy (including mesothelioma) . Both Buchanan and Mirabella noted a startling secular increase of lung cancer throughout the last four decades. This may be due to the increase in cigarette consumption and/ or due to the fact that sufferers from asbestosis are living longer, the disease having become milder due to improved dust conditions. Bohlig et aI7 in a study of living cases of asbestosis concluded that there is an association between the severity of asbestosis and the prevalence of bronchial cancer, the incidence being 82/10,000 in severe cases and 11/10,000 in minimal cases, while in asbestos workers without disease bronchial cancer occurred in 3.7/10,000 which was not in excess of the -Director, Epidemiology Unit, Medical Bureau for Occupational Diseases, Department of Mines, Johannesburg, Republic of South Africa.
•
G. K. SLUIS-CREMER
Evidence for Association in Animal Experiments
Anatomic Site of Bronchial Cancer in Asbestos Workers Hueper," Bohlig,? Kannerstein and ChurgS and Whitwell et alii have all noted that the relationship between the number of cases in the upper lobes to the lower lobes, usually about 2.5:1, is inverted in asbestosis workers varying from 2:3 to 7:53. It has been proposed that the asbestos fiber entrapped in the region of most marked fibrosis (usually in the lower lobes) concentrates carcinogens from tobacco smoke and other pollutants. In addition, bronchial cancer in asbestos workers tend to be peripherally located and to involve the pleura, making it difBcult to differentiate from mesotheliomas.
Histologic Type of Bronchial Cancers Associated with Asbestosis Hueper3 was the first to comment on the greater prevalence of adenocarcinoma among asbestosis-related cancers than expected. Hourihane and McCaughey" confirmed this in a small series, while Kannerstein and Churg did not.S In the most recent large mortality study on workers with asbestosis and bronchial cancer, Whitwell et alii found 34 percent with adenocarcinoma. These workers strike a note of caution, however, pointing
CHEST, 78: 2, AUGUST, 1980 SUPPLEMENT
out that the proportion will vary according to the source of the histologic material, that is, biopsy, or surgical and post-mortem. In the study of Wagner et al,10 in asbestos-exposed rats the cancers which developed were mostly peripheral adenoma, adenomatosis, adenocarcinoma and squamous carcinoma. Thus, the bulk of evidence suggests there is indeed an excess of adenocarcinoma, but that the association with asbestos exposure is not as strong as it is in the case of oat-cell carcinoma in relation to uranium'" and chloremethyl methyl ether'" exposure. Both Hueper" and Wagner et al l O describe the development of premalignant epithelial alterations in areas of fibrosis. The fact that an asbestos worker develops adenocarcinoma would seem to have little medicolegal implication. DISCUSSION
The relationship between asbestosis and bronchial cancer does not appear to be straightforward. The pattern of site distribution and the presence of premalignant changes in the areas of fibrosis in man and animals suggest that cancer is often a complication of the asbestosis. There is also the evidence that bronchial cancer may complicate interstitial fibrosis of many etiologies and asbestosis is only exceptional in the high prevalence of this occurrence. IS The above does not exclude the possibility that asbestos exposure per se may cause bronchial cancer in a dose insufficient to cause fibrosis. This did not, however, happen in the rats in the series of Wagner et al. 16 It may be that the dose-response relationships between asbestos dust on the one hand and cancer and fibrosis on the other hand are similar, and therefore the two responses are frequent in the same individual. In any event, the evidence suggests that asbestos bronchial cancers invariably occur in lungs which are the seat of fibrosis. It should be stressed that this refers to fibrosis detectable at histologic examina-
CHEST, 78: 2, AUGUST, 1980 SUPPLEMENT
tion. Our methods for clinical diagnosis of mild degrees of asbestosis are insensitive and even in the presence of moderately severe degrees of Sbrosis no clinical, physiologic or radiologic abnormality may be detected in an important proportion of the cases. To demand proof of the presence of asbestosis in vivo before attributing a bronchial cancer to the inhalation of asbestos dust would thus seem to be unreasonable.
REFERENCES 1 Gloyne SR. Two cases of squamous carcinoma of the lung occurring in asbestosis. Tubercle 1935; 17:5 2 Egbert DS, Geiger AJ. Pulmonary asbestosis and carcinoma. Am Rev Tuberc 1936; 34: 143 3 Hueper WC. Recent results in cancer research. Berlin: Springer Verlag, 1956; 44 4 Merewether ER. Annual report, chief inspector of factories for the year, 1955 5 Buchanan WD. Asbestosis and primary intrathoracic neoplasms. An NY Acad Sci 1965; 132:5C11 6 Mirabella F. Pleuropulmonary malignancies confirmed by autopsy in asbestosis. Med d. Lavora 1975; 66:192 7 Bohlig H, Jacob G, Miiller H. Die Asbestose der Lunger. Stuttgart: Georg Thieme Verlag, 1960; 60 8 Kannersteing M, Churg J. The pathology of carcinoma of the lung associated with asbestos exposure. Cancer 1972; 30:14 9 Knox JF, Holmes S, Doll R, Hill ID. Mortality from lung cancer and other causes amongst workers in an asbestos textile factory. Br J Ind Med 1968; 25:293 10 Wagner JC, Berry G, Skidmore JW, Timbrell V. The effects of the inhalation of asbestos in rats. Br J Cancer 1974; 29:252 11 Whitwell F, Newhouse MD, Bennett DR. A study of the histological cell types of lung cancer in workers suffering from asbestosis. Br J Ind Med 1974; 31:298 Ii Hourihane D O·B, McCaughey WTE. Pathological aspects of asbestosis. Postgrad Med J 1966; 4i:613 13 Archer VE, Saccomanno G, Jones JH. Frequency of different histologic types of bronchogenic carcinoma as related to radiation exposure. Cancer 1974; 34:2056 14 Weiss W, Auerbach 0, De Fonso LR, Moser RL. The histologic type of lung cancer in chIoromethyl ether workers and its relation to dose. Presented at International Conference on Occupational Lung Disease, San Francisco, February 27-March 2, 1979 15 Stack BHR. Fibrosing Alveolitis. Tubercle 1971; 1;15 16 Wagner JC. Personal communication, 1979
THE RELATIONSHIP BETWEEN ASBESTOSIS AND BRONCHIAL CANCER 381