Document m7X1n6arKGKxrgZZbXDyzVMg

is they are claimed to 1 iiis as a possible source noting that in our series** males who had had, their ', as the average age tises, ||r: ;s, average age 51.7, have ] ;; cancer of breast eases, ^ ze 13% appendectomies; i, average age 63.0, have The control series shows ad. ,, jf our observations and.. iible errors of McKay's ! s ve referred, we conclude T ,7 ent evidence to support"P ;en previous appendec- | development of maemf" RENCE he appendix in relation-'to-^ire-- 17:929-37, 1964. ASBESTOS, AN EXTRINSIC FACTOR IN THE PATHOGENESIS OF BRONCHOGENIC ... CARCINOMA AND MESOTHELIOMA Ward M. O'Donnell, md, Richard H. Mann, md, and John L. Grosh, md In 55 asbestos textile workers who had pathologically proven asbestosis, 28 malignant neoplasms were found--23 bronchogenic carcinomas and 5 meso theliomas of peritoneum or pleura. Of the 28 patients with neoplasms, 26 had been exposed to asbestos dust before 1936; the medium total occupational exposure was 20 years. The interval from initial exposure until the recognition of the neoplasms varied from 20 to 40 years. Thirteen of the individuals no longer were employed in the industry when evidence of the neoplasms ap peared. The primary anatomical site of the carcinomas was in the lower lobes of the lungs in 22 patients and in one instance was multicentric in origin. In the morphologic classification of the neoplasms, 10 were the squamous cell variety; 7 were anaplastic; 5 were adenocarcinoma and one was bronchiolar. The frequent association of pulmonary asbestosis with bronchogenic carcinoma (42%) and mesothelioma (8%), as seen in this study, lends further support to the opinion that asbestos is a carcinogen in susceptible individuals after critical exposure in the textile phase of the industry. he causal role of asbestos in the de hazard. Thomson reported finding asbestos Tvelopment of bronchogenic carcinoma bodies in lung smears in 26% of the routine and mesothelioma has been a subject of ina utopsies performed in Cape Town13 and in creasing concern during the past decade. Re 27% of those performed in Miami.11 In Pitts cent reports from South Africa,12-14 Eng burgh Cauna2 and others found 41% of the land1- 4 and the United States3-5-9 have individuals autopsied to have asbestos bodies incriminated the asbestos fiber as an etiologic in lung smears. These observations suggest agent which can induce neoplasia in exposed that asbestos fibers are widely encountered in individuals. Current interest in this associa our atmospheric environment today. tion has been stimulated by the Conference Occupational exposure due to the inhala cm Biological Effects of Asbestos, presented in tion of finely divided asbestos fibers is limited New York, in October 1964.11 in geography to those areas where the textile The 8-fold increase in world consumption manufacturing phase of the industry exists or of this mineral during the past generation, the to those occupations where individuals handle increase in the number and variety of indus the finished asbestos product. We have had trial products utilizing this material, the fact the unusual opportunity to study this disease that the fiber itself is practically indestructi- in patients who had been employed in an b e> aD have lead to a more widespread ex asbestos textile factory in a small community posure of our population to asbestos. in Pennsylvania. This report will be con Evidence now is being presented to impli- cerned with patients studied by us in the cate the asbestos fiber as a modern urban Lancaster General Hospital and there will be a special effort to evaluate the relationship between asbestosis and neoplasia as seen in - the Deoartments o Pathology and Medicine, Lancaster General Hospital, Lancaster, Pa. Received for publication November 15, 1963. these workers. Part of this material had been presented as a preliminary report in a Sym posium on Diseases caused by Environmental 1143 1144 Cancer August 1966 Twenty-three Asbestos Workers Who Developed Bronchogenic Carcinoma Vol. 19 No. 8 Asbestos j Table 1. Name Year of established morphologic W.P. 4033 H.T. A-48-114 L.F. A-50-140 R.G. A-50-53 H.B. A-S2-165 l.S. S-52-2097 W.B. A-S3-61 J.T. A-S3-96 H.F. S-53-507 B.B. O-A-54-48 I.F. S-S5-3600 S.D. A-56-164 C.N. A-56-76 R.F. A-57-34 H.M. O-A-57-169 P.Y. A-58-61 M.M. A-59-73 HS S-59-1812 B.W. A-59-143 H.F. A-61-116 C.Y. A-61-183 W.W. A-62-194 1940 1948 1950 1950 1952 1952 1953 1953 1953 1954 1955 1956 1956 1957 ' 1957 1958 1959 1959 1959 1961 1961 1962 >1.0. A-62-154 1962 Years of Total exposure (yr.) Interval from initial exposure to discovery of ca. (vr.) 37 Worked prior to World War I 60 1925-1948 -- 2a -- 23 52 1925-1939 14 25 53 1923-1950 27 27 59 Worked prior to World War I 49 1924-1952 -- 28 -- 28 69 1923-1953 30 30 52 1929-1952 23 24 41 1923-1953 30 30 59 Worked prior to World War I 54 1919-1934 -- 15 -- 36 55 1923-1924 1 33 61 1914-1922 8 42 55 1917-1918 1 40 61 1935-1947 12 22 60 1914-1930 16 44 53 1929-1959 30 30 52 1925-1927 1954-1959 60 1917-1938 11 21 34 42 61 1933-1961 28 28 68 1941 61 1926-1942 .333 16 20 36 51 1935-1962 27 27 Histopathologic classification of neoplasm Anatomic location Anaplastic car cinoma Squamous cell carcinoma Squamous cell carcinoma Squamous cell carcinoma Anaplastic car cinoma Squamous cell carcinoma Adenocarcinoma Lower lobe right lung Lower lobe left lung Lower lobe left lung Lower lobe right lung Lower lobe left lung Lower lobe right lung Lower lobe right lung Squamous cell carcinoma Squamous cell carcinoma Adenocarcinoma Lower lobe left lung Lower lobe right lung Lower lobe left lung Squamous cell carcinoma Adenocarcinoma Lower lobe right lung Lower lobe right lung Squamous cell carcinoma Anaplastic car cinoma Adenocarcinoma Lower lobe left lung Lower lobe right lung Lower lobe left lung Squamous cell carcinoma Squamous cell carcinoma Bronchiolar carcinoma Adenocarcinoma Anaplastic car cinoma Anaplastic car cinoma Anaplastic car cinoma Anaplastic car Lower lobe right lung Lower lobe right lung Lower lobe left lung Lower lobe left lung Lower lobe right lung Lower lobe left lung Multi centric origin Right lung cinoma Name Year of established morphologic diagnosis H.B. O-A-57-169 G.M. A-59-138 R.B. A-64-132 S.B. A-65-41 H.D. A-65-139 1957 1959 1964 1965 1965 exposed to the hazards the first 4 decades of t recognition of this tyj The factory where tf this study had been in after the turn of the ct unit was concerned n and weaving of the fi asbestos. In the early ye was no realization of t inhalation of asbestos i record, the concentratioi of such intensity that s ments previously mentic as "a dust hole" and it h; man could not see beyo in the contaminated are. Pulmonary asbestosis ; of relatively recent orig: Price8 gave the first warn asbestos dusts in 1930. Ly suggested a causal relati bestos and bronchogenic With the recognition of Environmental air pollutic the industry instituted ren jth*-e'- pro'ucueusaasuinigg pl'ant wl orked, effective industry Factors during the meeting of the American Association of Pathologists and Bacteriology in April 1957 in Washington, D.C. ' Material During a 25-year period covering 1940 to 1965 55 patients with pathological proven pulmonary asbestosis were seen in the Lan caster General Hospital. These observations were established at autopsy in 52 cases and in the remaining 3 patients by examination of lungs removed at surgery. Only those cases in mplished between 1935 a : the workers in this ser Iing periods of time. Some mmviauaia o.--- were working in the industry when the symp ent after 1940. It is pos, rvations may be of his tori me intensity of exposure ospective studies are ur is premise.- Results toms developed which necessitated th^ir. . ,i pitalization; other individuals were admitt in 55 patients who had years after they had stopped working 111 " gs 23 individuals had1 ass asbestos plant. Most of the workers had e !nic carcinoma and 5 hat Asbestos Related to Carcinoma and Mesothelioma O'Donnell et al. 1145 :nic Carcinoma Table 2. Five Asbestos Workers Who Developed Mesothelioma stopathologic issification of neoplasm aplastic caroma jamous cell cinoma lamous cell cinoma jamous cell cinoma aplastic caroma lamous cell cinoma enocarcinoma lamous cell cinoma lamous cell cinoma enocarcinoma lamous cell cinoma mocarcinoma lamous cell cinoma iplastic carima mocarcinoma lamous cell cinoma lamous cell cinoma nchiolar cinoma mocarcinoma iplastic car>ma iplastic car>ma iplastic carima .plastic carima Anatomic* location Lower lobe right lung - i Lower lobe " f left lung -- j Lower lobe * left lung I Lower lobt~ ft right lung ' f Lower Vve t left lung- Lower kibe right lung Lower lobe:, right lung / Lower lobe: left lung .... Lower lobe right lung ^ Lower lobes left lung __ Lower fobe^ right lung-- Lower lobe right lung Lower lobe left lung Lower loberight lung Lower lobe left lung ' Lower lobe right lung Lower lobe right lung Lower lobe left lung Lower lobe left lung Lower lobe right lung Lower lobe left lung Multi centric origin Right lung id been established by /ere included in this he patients previously the same textile manun be seen in Table 1, een employed for varySome individuals still dustry when the sympnecessitated their hosviduals were admitted opped working in the the workers had been i Name : r.b. *-64-132 S.B. A-65-41 h.d. -'A-65-139 Year of established morphologic diagnosis 1957 Age 44 1959 60 1964 49 1965 53 1965 51 Years of exposure 1937-1957 -- 1929-1963 1926-1946 1933-1935 Total exposure (yr.) 20 Interval from initial exposure to discovery of ca. (yr.) 20 Histopathologic classification of neoplasm Mesothelioma Anatomic location Peritoneum -- -- Mesothelioma Peritoneum 34 34 Mesothelioma Peritoneum and pleura 20 39 Mesothelioma Peritoneum 1.58 32 Mesothelioma Pleura exposed to the hazards of asbestos dust during the first 4 decades of this century prior to the recognition of this type of pneumoconiosis. The factory where the exposure occurred in this study had been in operation since shortly after the turn of the century. This industrial unit was concerned with carding, spinning and weaving of the fibrous rock known as asbestos. In the early years of operation there was no realization of the danger due to the inhalation of asbestos fibers. As a matter of record, the concentration of asbestos dust was of such intensity that several of the depart ments previously mentioned were referred to as "a dust hole" and it has been stated "that a man could not see beyond an arm's length" in the contaminated areas. Pulmonary asbestosis is a pneumoconiosis of relatively recent origin. Merewether and Price8 gave the first warning of the danger of asbestos dusts in 1930. Lynch and Smith6 first suggested a causal relationship between as bestos and bronchogenic carcinoma in 1935. With the recognition of the danger due to environmental air pollution by asbestos dust, the industry instituted remedial measures. In the processing plant where our patients worked, effective industrial hygiene was ac complished between 1935 and 1940. Only one of the workers in this series began employ ment after 1940. It is possible that our ob servations may be of historical value since the same intensity of exposure no longer exists. Prospective studies are under way to test this premise. Results In 55 patients who had asbestosis of the lungs 23 individuals had associated broncho genic carcinoma and 5 had mesotheliomas (Tables 1 and 2). The remaining 27 patients died of pulmonary insufficiency with or with out the syndrome of cor pulmonale or of somfi unrelated disease. Our observations in this report are confined to those individuals who had asbestosis complicated by neoplasm. Sex and age: Twenty-five of the workers were males and 3 were females. The ages ranged from 37 to 69, with a median of 54 years. Years of exposure: In Tables 1 and 2 the known years of exposure to asbestos dust are recorded for each worker. In 3 individuals the only known data on employment dates were that they had worked prior to World War I. The majority of our patients had been em ployed during the years 1920 to 1950; only one individual began working after 1940. (The occupational history of this man [C.Y., A-61-183] revealed a 4-month exposure during 1941. Since the lungs at necropsy were com patible with those seen in advanced classical asbestosis with many asbestos bodies in the parenchyma, we question the completeness of the exposure history which we were able to obtain.) The number of years of exposure in the remainder of the patients ranged from one to 34. The mean duration of exposure was 20 years in those individuals who devel oped neoplasm. Interval from initial exposure to discovery of neoplasm: In the 25 patients for whom such information was available the time from which the workers first were exposed until the neoplasms were recognized clinically varied from 20 to 44 years. The period of latency averaged about 30 years. Interval from cessation of exposure to as bestos dust and development of neoplasm: This period varied from zero to 39 years. Eleven of the workers still were employed in 1146 Cancer August 1966 f Vol. 19 No. 8 Asbestos Re Fig. 1. Case I.F. S-55- 3600. Section of lung showing asbestos bod ies and nests of squa mous cell carcinoma (X160). j i: 3 t Fig. 2. Section of lung from the same case, showing replace ment fibrosis of the parenchyma and sev eral asbestos bodies (Xl60). j the plant when the malignant complication localized to the pleura. The pertinent data l facts made this a w< was discovered. In those individuals no longer are recorded in Tables 1 and 2. association of broncl associated with the industry, 21 years was the mesothelioma in asbes average postemployment interval before the neoplasms were recognized. Comment The high incidence (50%) in our materi; Smoking histories: In 5 of the patients a It had not been our intent in this report variance with the ot definite history was recorded of smoking more to determine the so-called "incidence of lung than one pack of cigarettes daily. Unfortu cancer or mesotheliomas" in asbestos workers. and others who fount cancer of the lungs ai nately, detailed smoking histories were not We recognized that our patients were selected workers handling the available from the clinical records for the from a segment of the asbestos-exposed popu degree of exposure w remaining individuals. In those for whom lation whose hospital admissions were based our group. In Englanc there was no history of smoking we had no on symptoms and signs related to advanced of the Chief Inspecto way of knowing whether they smoked, had pneumoconiosis or complicating neoplasm. year 1947, there was a smoked and stopped or had never smoked. Furthermore, we realized that this was a retro of the association of lui Histopathologic classifications of neoplasms: In the pathologic presentation the 23 lung carcinomas were classified as follows: Squa mous cell--10; anaplastic--7; adenocarcinoma --5; bronchiolar--one. In 22 patients the origin of the carcinoma was found in the lower lobes of the lungs. In the remaining spective study and that the concentration of asbestos dust which existed during the years of exposure of our patients is no longer a hazard of the same degree. Lastly, the asbestos worker has the same nonoccupational liability to develop lung cancer as does the general population. For years we have anatomical site of the ated with asbestosis. 1 bronchogenic carcinon don, the primary lesioi the lungs. In one pat multicentric in origii patient (W.W., A-62-194) the origin was con We had the opportunity to determine the chyma. In contrast, ; sidered to be multicentric. association of neoplasia and asbestosis in hos cryptogenic lung canc The mesotheliomas found in our patients pitalized patients in terminal illness. These lobes of the lungs, have been reported elsewhere.7 In 3 individ individuals had been long-term regularly em unique finding in luns uals the serosal cell tumors originated in the ployed asbestos workers in the same plant in to the fact that the gr peritoneum and were confined to the ab the textile phase of the industry and we were the fiber and resulting dominal cavity. In the fourth patient the able to obtain fairly complete exposure his in the lower lobes of tb mesothelioma developed independently and tories. The individuals lived and died in a did not share our exj perhaps simultaneously in both peritoneum stable community and we had pathologic con 11 cases of asbestos c and pleura. In the fifth case the neoplasm was firmation of our findings. We think the above them originated in the .. 19 fio 8 Asbestos Related to Carcinoma and Mesothelioma O'Donnell et al. 1147 Tig. 1. Case I.F. S-55- C - Fig. 2. Section of 3600. Section of lung .j*, lung from the same showing asbestos bod- \ - case, showing replace _mie_s_o_u_asndc..e.n.ileil sts--caorcf-*inm-omgHa ~usTl1ii** ment fibrosis of parenchyma and the sev (Xl60). eral asbestos bodies (Xi SO). a. The pertinent data i 1 and 2. MENT r intent in this report lied "incidence of lung as" in asbestos workers, r patients were selected asbestos-exposed popuadmissions were based is related to advanced implicating neoplasm, ed that this was a retro t the concentration of listed during the years atients is no longer a ree. Lastly, the asbestos noccupational liability :r as does the general inity to determine the i and asbestosis in hoserminal illness. These ong-tenn regularly em s in the same plant in industry and we were .omplete exposure his > lived and died in a we had pathologic confs. We think the above facts made this a worthwhile study of the association of bronchogenic carcinoma and mesothelioma in asbestosis. The high incidence of associated neoplasm (50%) in our material is not necessarily at variance with the observations of Selikoff10 and others who found a 20% association of cancer of the lungs and pleura in insulation workers handling the finished product. The degree of exposure was far more intense in our group. In England in the Annual Report of the Chief Inspector of Factories1 for the year 1947, there was a lower percentage (13%) of the association of lung cancer and asbestosis. For years we have been impressed by the anatomical site of the origin of cancer associ ated with asbestosis. In each of our cases of bronchogenic carcinoma, with but one excep tion, the primary lesion was in a lower lobe of the lungs. In one patient the neoplasm was multicentric in origin in the lung paren chyma. In contrast, approximately 60% of cryptogenic lung cancers arise in the upper lobes of the lungs. We have related this unique finding in lung cancer with asbestosis to the fact that the greatest concentration of the fiber and resulting fibrosis is most marked m the lower lobes of the lungs. Cordova et al.3 did not share our experience since 7 of the U cases of asbestos carcinoma reviewed by them originated in the upper lobes. The 5 mesotheliomas were seen after 1956. There were fifteen bronchogenic carcinomas in our material before the first mesothelioma was recognized. Mesotheliomas have ac counted for 5 of the last 15 malignant neo plasms associated with asbestosis seen since 1956. We have no explanation for this re cently acquired complication of asbestosis, nor can we account for its absence until 1957. As a matter of fact, we first became aware of this complication in a report from the North Western Cape Province of South Africa, in which Wagner, Sleggs and Marchand14 de scribed 33 cases of pleural mesotheliomas in relation to asbestosis. Our first 2 cases (1957, 1959) were found upon review of our material. Three of the' mesotheliomas in our series were confined to the peritoneum. In the fourth case, the mesotheliomas involved the serosal coverings of both peritoneum and pleura and in the last patient the tumor was limited to the pleura. A plausible explanation for the development of peritoneal mesothe lioma is that a chemical carcinogen is released in the lungs and gains access to the serosa of the abdominal cavity through the lymphatics of the diaphragm. Selikoff et al.10 found 10 mesotheliomas among American insulation workers--4 in the pleura and 6 in the peritoneum. There is no indication in their report that any of the pa- 1148 Cancer August 1966 4, Vol. 19 tients had simultaneous involvement of both pleura and peritoneum. The same investiga tors thought Chrysotile type asbestos fibers used primarily in the American asbestos in dustry to be carcinogenic, as well as the with the extent or severity of the pulmonary asbestosis. In some instances in which neo plasm occurred there were few asbestos bodies in the lung sections and fibrosis was minimal. Contrariwise, in patients who did not have a ? MALIC l Crocidolite type asbestos referred to in the South African and British literature.10 We concur with the above opinion. The plant involved in this study used the Chrysotile neoplasm but died of pulmonary insufficiency or unrelated disease there were many ex amples of advanced fibrosis of the lungs with asbestos bodies in practically every micro type of asbestos fiber almost exclusively. The neoplastic hazard results from exposure to as bestos in general rather than to any one par ticular type fiber. In our patients the interval from initial exposure until the neoplasms were diagnosed ranged from 20 to 40 years. This is in accord with the knowledge that an extrinsic factor which serves as the causal agent in neoplasia must be operative for a long period of time. In our study, a year of exposure was sufficient scopic field. The individual who develops a malignant process must possess a susceptibility to the specific carcinogenic activity present and survive long enough to develop a malig nant neoplasm. Since there is no constant relationship be tween the severity of asbestosis and the lia bility to neoplasia, the lesser degrees of ex posure seen in workers handling the finished asbestos product, those exposed intermittently in the building trade and the residents of 4 V t , ) f; ' 1 i Malignolipi: "all malign; objectively < cancer diagi nolipin extr a 25.0% ont tion of Mali cancer and value of this time for 2 individuals to inhale adequate numbers of fibers to develop subsequently asbestosis and neoplasm. Thirteen of the pa tients had stopped working in the mill with an average postemployment of 21 years elaps ing before the neoplasms were clinically evi dent. The inhaled fiber is a life-long inde structible material in the lung and the fibrosis and carcinogenic change is a reaction of its presence. The exposed worker must live with his personal pulmonary contaminant long after he has ceased to be employed in the industry. We were not able to correlate the origin of the bronchogenic carcinomas or mesotheliomas cities, takes on added significance. It is even possible that less protracted and intense ex ) posure to the fiber, as occurs in the modern textile plant, still may play a carcinogenic role in susceptible workers even though the classical type of pulmonary asbestosis may dis appear. This is a problem for cancer epi demiology in the future. At the present time, however, we believe : that bronchogenic carcinoma and mesothe liomas are endemic occupational diseases, as seen in the asbestos textile worker, since the frequent association (50%) of these neoplasms with asbestosis can be explained only by a causal relationship. j: f: r r 4 ; RELIABLE SEROLOG A ligancy would be f mankind. Numerous < over the years for th< specific substance in tl ing patients,8' -8'12'8 have been either un specific to warrant cl: cancer diagnostic adjt In 1960 Kosaki et a tion of a specific phosj of patients bearing a 23,25,26 They named nolipin." They and REFERENCES T reported many of its | chemical and immuno 1. Annual Report of the Chief Inspector of Factories for the Year 1947 in Great Britain. London, H. M. Sta tionery Office, 1948. 2. Cauna, C., Totten, R. C., and Groso, P.: Asbestos bodies in human lungs at autopsy. JAMA 192:371-373, 1965. 3. Cordova, J. F., Tesluk, H., and Rnudtspn, K. P.: Asbestosis and carcinoma of the lung. Cancer 15:1181 1187, 1962. 4. Doll, R.: Mortality from lung cancer in asbestos workers. Brit. J. Ind. Med. 12:81-86, 1955. 5. Isselbacher, K. J., Klaus, H., and Hardy, H. L.: Asbestosis and bronchogenic carcinoma. Am. J. Med. 15:721-732, 1953. 6. Lynch, K. M., and Smith, W. A.: Pulmonary as bestosis--Carcinoma of lung in asbestos-silicosis. Am. J. Cancer 24:56-64, 1935. 7. Mann, R. H., Grosh, J. L., and O'Donnel, W. M.: Mesothelioma associated with asbestosis. Cancer 19: 521-526, 1966. 8. Merewether, E. R. A. and Price, C. W.: Reports on Effects of Asbestos Dust on the Lungs. London, H. M. Stationery Office, 1930. 9. Selikoff, I. J., Churg, J., and Hammond, E. C.: Asbestos exposure and neoplasia. JAMA 188:22-26, 1964. 10. -------- , Churg, J., and Hammond, E. C.: Rela tion between exposure to asbestos and mesothelioma. New Eng. J. Med. 272:560-565, 1965. 11. Thomson, J. G.: Asbestos, an urban dweller. Read before the Conference on Biological Effects of Asbestos, New York, October 19, 1964. 12.-------- : Mesothelioma of pleura or peritoneum and limited basal asbestosis. S. Afr. Med. J. 36:759 760, 1962. 13. -------- , Kaschula, R. O. C., and MacDonald, R. R.: Asbestos as modern urban hazard. Ibid. 37:77 81, 1963. 14. Wagner, J. D., Sleggs, C. A., and Marchand, P.: Diffuse pleural mesothelioma and asbestos exposure in the north western cape province. Brit. J. Ind. Med. 17:260-271, 1960. | ^ | S :: ' : * -: " AS* Biological properties ( 1. It is specific for, malignant tissues;23' 2. It never is in nc neoplastic tissues, m tissues or embryonic 3. It is found in th< patients with early but never in the b From the Surgery Branch National Institutes of Hea Department of Health, Ec thesda, Md. Received for publication -- IrVT.:: '