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ASBESTOSIS AND CARCINOMA OF THE LUNG Juan F. Cordova, m.d., Henry Tesluk, m.d., and Kenneth P. Knudtson, m.d. he increasing incidence of pulmonary the cases we have seen. In the review of our Tcarcinoma has stimulated considerable own surgical and autopsy material we were interest in the search for possible causativaeble to find 6 cases of bronchogenic carcinoma agents, especially those of the inhalant type. associated with pulmonary asbestosis. Five ad There now exists considerable data to sup ditional cases were obtained from the files of port the contention that pulmonary asbes- the Armed Forces Institute of Pathology, tosis has a definite role in the development of Washington, D.C. neoplastic change in the respiratory system. In general, the question as to whether specific Case Reports pneumoconiosis predisposes to carcinoma of the lung is of considerable medicolegal impor tance, and in spite of extensive experimental and clinical research, none of the agents studied have been clearly implicated except uranium in the case of the Schneeberg miners in Germany. Bridge and Henry2 formulated Case 1. P.K.E. was a 58-year-old hod carrier who had worked with insulating material for 20 years. He was a heavy smoker. A routine chest roentgenogram at Virginia Mason Hos pital, Seattle, Wash., showed an unsuspected lesion in the middle lobe of the right lung. Right pneumonectomy was carried out. A the following specific conditions as necessary white, firm, slightly gelatinous, well-demar for the acceptance of industrially acquired cated, 2x3-cm. tumor was found in the middle cancer: (1) the rate of incidence in the occupa tion under review should exceed that in the general population to a significant extent, and (2) in the occupation concerned, there would be sufficient association of the worker with a substance proved experimentally to have carcinogenic properties. Although there is a statistically proved high incidence of pul monary carcinoma in asbestosis, it is readily apparent that these postulates have not as yet been fulfilled. Indeed, it should be pointed out that a study by Jacob and Bohlig18 indi lobe. Another small firm area was at the apex. The lesion was an adenocarcinoma with growth along alveolar walls. The stroma was densely fibrous and contained numerous as bestos bodies (Fig. 1). Of particular interest was the finding of a separate focus of tumor in the apical scar, which also contained as bestos bodies (Fig. 2). Case 2. J.W. was a 46-year-old ironworker admitted to Virginia Mason Hospital with mild congestive heart failure. He had been a heavy smoker for many years. A chest roent genogram showed a right upper lobe lesion. cated that the incidence of carcinoma in as An exploratory operation revealed a well- bestos workers in Dresden was not increased. In view of the fact that the role of asbestosis in the pathogenesis of carcinoma of the lung remains unproved, we felt it would be worth while to review the existing evidence and present clinical and pathological findings on defined tumor in the posterior segment of the right upper lobe, extending through the inter lobar fissure into the right lower lobe. Pneumo nectomy was performed. A separate malignant tumor was found in the right apex. Both tu mor nodules were surrounded by firm areas of fibrosis. Microscopically, the tumors were ter minal bronchiolar carcinoma. There was From the departments of Pathology, Virginia Mason Hospital, 1101 Terry Ave., Seattle 1, Wash., the Vet erans Administration Hospital, and the University of Washington Medical School, Seattle, Wash. We are Indebted to the Armed Forces Institute of Pathology, Washington, D.C., for their permission to use 5 cases from their files and also to Dr. Alexander Breslow for 2 cases obtained from Firland Sanatorium, Seattle, Wash. The photomicrographs were made by Mr. Paul New man. Chief of Medical Illustration, Veterans Adminis tration Hospital, Seattle, Wash. Received for publication Jan. 2S, 1962. marked pulmonary fibrosis, and typical as bestos bodies were found in areas of fibrosis. Case 3. G.M.G. was a 55-year-old Negro shipyard worker admitted to Firland Sana torium with hemoptysis and wheezing. A roentgenogram showed a lesion in the right up per lobe. Because of reduced pulmonary func tion, a right lobectomy only was done. He died the following day. The tumor measured 4x7 cm. and projected into the apical seg mental bronchus. Microscopically, it was a 1 SCF-FA-5270 11 82 Cancer Naventber-Decembcr 1962 Vol. 13 squamous cell carcinoma with marked fibro sis of ihe surrounding tissues. Numerous as bestos bodies were present in alveolar spaces and in peribronchial fibrous tissue. Case 4. H.M.G. was a 71-year-old retired bricklayer admitted to Firland Sanatorium with suspected tuberculosis. Symptoms in cluded hemoptysis, cough, and whce/.ing. A large infiltrate was seen in the left upper lobe and a mottled appearance in the lower lobe by roentgenogram. Cultures were positive for tubercle bacilli. His condition deteriorated over a 3-mont.h period,`and he died. A poly poid, soft, white tumor in the left main bron chus was continuous with a mass in the apicalposterior segment of the left upper lobe. The tumor had infiltrated into the chest wall pos teriorly. There was fibrocaseous tuberculosis of the right lung. Microscopically, the tumor was a poorly differentiated squamous cell carci noma. '.There was moderately severe pulmonary fibrosis with numerous asbestos btxbes present. There were numerous foci of caseation ne crosis associated with the tuberculous gran uloma formation. Case 5. G.J.I1. was a 64-year-old white male pipe iasulator and coverer admitted to the Seattle Veterans Administration Hospital be cause of exertional dyspnea. He had been a heavy smoker for 10 years previously. A chest roentgenogram showed a mass in the right lung and atelectasis of the middle and lower lobes. A right lower lobectomy was carried out, anti a firm infiltrating malignant, tumor was found. Microscopically, this tumor was a mod erately differentiated adenocarcinoma that had infiltrated the mucosa of the main bronchus entering this lobe. There was diffuse fibrosis of lung parenchyma, and numerous asbestos bodies were seen both in the tumor and in the areas of fibrosis. Case 6. H.R.H. was a 69-year-old white man admitted to the Seattle Veterans Administra tion Hospital with symptoms of increasing shortness of breath and chronic pulmonary dis ease. He had worked in an asbestos plant for 48 years. He had been told lie had asbestosis 15 years prior to his admission to the hospital. He hail smoked cigarettes for 20 years. A biopsy of a skin nodule revealed metastatic, anaplastic No. 6 Asbestosis & Carcinoma of Ll'ng Cordova et al. 1183 Fin. 2. Case 1. Microscopic section from separate focus of the tumor in apical scar showing several asbestos bodies. (X4'>0.) carcinoma. Autopsy revealed an anaplastic car cinoma, arising in the right upper lobe bron chus and infiltrating the major portion of that lobe. Metastases were evident in the hilar lymph nodes, liver, and adrenal glands. As bestos bodies were seen within the tumor and in the adjacent fibrous lung tissue. Case 7. E.J.H. was a 65-year-old white man who was admitted to the hospital with a primary complaint of swelling of the right side of the neck of 1 week's duration. He had worked as an asbestos insulator in the Bremer ton Naval Shipyard, Bremerton, Wash., during the past year and prior to that had worked in an asbestos manufacturing plant for 53 years. He had smoked 1 package of cigarettes per day for 40 years. He had progressive dyspnea with rapidly decreasing respiratory function and diecl 3 weeks after his admission to the hospital. Autopsy revealed severe pul monary fibrosis with a squamous carcinoma infiltrating the right upper lobe. Asbestos bodies were prominent within the tumor-bear ing area. Case 8. P.K. was a 62-year-old white man who presented with symptoms of general dis ability and weight loss. A roentgenogram taken on admission to the hospital revealed an area of increased density in the right upper lobe and emphysema. A hilar mass was evi dent on the right. At thoracotomy, a tumor involving the right upper lobe was found. However, the tumor haa, by direct extension, involved the chest wall and was considered inoperable. The patient died 3 days post operatively in respiratory failure. The tumor was for the most part an undifferentiated car cinoma with areas of mucus-producing adeno carcinoma. .Asbestos bodies were identified in both the tumor and the areas of pulmonary fibrosis. Case 9. G.S. was a 68-year-old white man who had worked for many years with asbestos and Fiberglas as an insulation worker. His chief complaints were productive cough, ex ertional dyspnea, and weight loss. A roent genogram of the chest revealed interstitial pneumonitis in the right upper lobe. The patient showed progressive pulmonary dif ficulty with cyanosis and died 10 days after admission to the hospital. At autopsy, the left lung revealed multiple firm nodules up to 1.5 cm. in diameter, and the right lung contained a firm but honeycombed area in the right apex. Sections showed a bronchiolar carcinoma with multiple foci throughout both lungs and the hilar lymph nodes. Asbestos bodies were 1184 Cancer November-December 1962 Vol. 15 identified in the tumor and in areas ol pul monary fibrosis. Case 10. W.C.D. was a 60-year-old white man who was admitted to the Seattle Veterans Administration Hospital because of extreme dyspnea, anorexia, and chest pain that had been progressive during the past year. He had worked as an asbestos handler for 40 years. He had noticed hemoptysis 3 months prior to admission. A chest roentgenogram revealed densities in both lower lobes compatible with usbestosis. A needle biopsy of the liver revealed metastatic anaplastic carcinoma. Roentgeno grams revealed osteolytic lesions of the verte brae anil skull and Paget's disease of the left innominate bone. He was given X-ray ther apy to the lungs. The patient died on the third hospital day after progressive dyspnea. Autopsy revealed a malignant tumor appar ently arising in the right lower lobe bronchus and infiltrating the entire right lower lobe. A 3.5-cm. tumor nodule was seen beneath the pleura of the left lower lobe. The remain ing lung parenchyma was replaced by dense fibrous tissue. On microscopic section the tu mor revealed undifferentiated carcinoma with foci of necrosis. Asbestos bodies were iden tified in the tumor-bearing area. Case II. G.B. was a 64-year-old white man who was admitted to the hospital with com plaints of dyspnea on exertion for 3]/g years. He had been exposed to asbestos and mag nesium for the previous 30 years. A roent genogram revealed a circumscribed density in the posterior right lower lobe, with diffuse emphysema. A right lower lobectomy showed a firm but gelatinous tumor lying beneath the pleura. Microscopic examination revealed a mucous adenocarcinoma characteristic of bronchiolar carcinoma. Large club-shaped as bestos bodies were noted throughout the tu mor and in the adjacent fibrotic pulmonary tissue. Results Eleven cases in which asbestosis and car cinoma of the lung coexisted have been re viewed. Five cases were obtained from the Armed Forces Institute of Pathology, Wash ington, D.C.; among 20 cases of asbestosis on file at the Institute, an incidence of 25%. Two cases were included from the files of the Seattle Veterans Administration Hospital, Seattle, Wash.; among 6 cases of asbestosis, an incidence of 33.3%. Two cases were obtained from Firland Sanatorium, Seattle, Wash.: from a total of 6 proved cases of asbestosis, an incidence of 33%. The remaining 2 cases were from the Virginia Mason Hospital, Seattle, Wash. Table 1 summarizes the major findings of interest in this series of patients. The mean age of the patients at the time the diagnosis of carcinoma of the lung was established was 62 years. There were 10 white patients and 1 Negro patient, all of whom were men. The Table 1 CASE HISTORIES OF 11 MALE PATIENTS WITH ASBESTOSIS AND LUNG CANCER Case no. Pi. ini 1:. Pt. Durat, "ge, Pt. expos., yr. race yr. Smoking history Occupation Site ca. Type ca. i RICE. 2 J.W. 58 46 3 G.M.G. 55 4 H.M.G. 71 5 G.J.B. 64 6 H.R.H. 69 7 E.J.H. 8 P.K. 9 G.S. 65 62 68 10 W.C.D. 60 1 1 G.H. 64 W 20 2 pk./dnv 20 yr. Hod carrier vv > 2 pk./dny ? yr. Ironworker Rt. mid. lobe Adenoca. Rt. upp. lobe Term. N> bronchiolar ? Shipyard worker Rt. upp. lobe Squam. cell w 40 1 pk./day ? yr. Ret. bricklayer Ll upp. lobe Squam. cell w 30 2J pk./day 10 Pipe insulator Rt. low. lobe Adenoca. yr.; stopped 8 yr. prior to death w 48 1 pk./day 20 yr. 33 yr. in asbestos Rt. upp. lobe Small cell mfg. & 16 yr. as asbestos insulator w +0 1 pk./dny 40 yr. 53 yr. in asbestos Rt. upp. lobe Well-cliff, w None None mfg. Carpenter squam. cell Rt. upp. lobe Undid. known w> 30 yr. Insulation worker; Rt. upp. lobe Term, worked with bronchiolar Fiberglas many yr. w 40 1 i pk./day 46 yr. Asbestos handler Rt. low. lobe Undid. w 30 Occupat. expos, Rt. low. lobe Term. _ to asbestos & bronchiolar magnesium No. 6 Asbestosis & Carcinoma of Lung Cordova el al. 1185 mean duration of exposure to asbestos in 7 patients was 35 years. Carcinoma of the lung occurred most frequently in the right upper lobe (6 cases). Five patients had a history of cigarette smoking for 20 years or longer. There was no predominant cell type of carci noma of the lung in our series. Death was most commonly attributed to bronchopneu monia, lung abscess, and cor pulmonale. Discussion Asbestos is a magnesium silicate that is one of a group of silicate minerals of crystalline fibrillar structure.18 Industrially, the material is found in asbestos mining and in many in dustries engaged in the processing and manu facturing of asbestos products. These include insulating materials (fire resistant cloths, ropes, millboard, wallboard, mortar, and other prod ucts). The principal hazard in these industries consists of inhalation of the asbestos dust. Some regard pulmonary asbestosis as a form of pneumoconiosis not necessarily accom panied by symptoms, whereas others feel the term should be reserved for cases in which clinical manifestations are present.25 The de velopment of pulmonary lesions that are char acterized by fibrosis and the formation of the so-called asbestos body depends upon the dura tion and degree of exposure to asbestos dust.5 Lynch19 provided a careful description of the pathogenesis of the disease and classified it into 4 stages. The lesions may appear after 3 to 15 years' exposure but may not produce symptoms for many years.18 There is con siderable individual variation in susceptibil ity, some individuals developing the disease rapidly while others may be exposed for years without evidence of pulmonary involvement. Symptoms of the disease consist of dyspnea, cough with expectoration, pallor, cyanosis, palpitation, weight loss, and chest pain.28*27 Characteristic changes of pneumoconiosis may be seen on roentgenographic examination. The pathognomonic asbestos bodies are found in the interstitial connective tissue of the lung and in peribronchial and hilar lymph nodes.8*18 They consist of a central translu cent fiber, 10 to 100 p in length and 1 to 12 p in diameter, enclosed in a golden-brown en crusted sheath composed of an iron protein compound. The ends are usually bulbous. The fibers may be surrounded by macrophages or giant cells. The fibrosis that accompanies the deposition of asbestos fibers tends to pro gress even after exposure to inhalation has been discontinued. The exact nature of the association be tween asbestosis and pulmonary carcinoma has been difficult to unravel. Since the first report by Lynch and Smith,21 many observations have been made concerning this relation ship,4* 8-s*10-14 with the use of several different approaches to the problem. It has been shown in a series of studies that there is a statistically proved higher incidence of carcinoma of the lung in patients with as bestosis than in the general population. One such study, the results of which are given in the Annual Report of the Chief Inspector of Factories for the Year 1947 in Great Britain, established that carcinoma of the lung occurs in 13% of cases of asbestosis in contrast to the 2 to 6% incidence in the general popula tion. Doll,4 in similar studies, arrived at the con clusion that the risk of developing carcinoma of the lung was higher in individuals exposed for a long period of time to asbestos inhala tion. Nordmann,28 who published data on 6 cases, went even further to state that carci noma of the lung is an occupational disease among people engaged in asbestos work. This opinion was also expressed by Hornig.12 The second point of interest concerns the multifocal development of cancer in these cases pointed out by Nordmann,28 Gloyne,8 and Hueper.18 This feature has often char acterized the malignant tumors found in as bestosis and has also been noted in 2 of the cases presented in this report. Finally, the age-time exposure relationship has supported the idea of a causal relation ship. The longer the exposure to asbestos, the greater the risk of developing a malignant tumor; and the younger the individual when first exposed to asbestos dust, the earlier is the development of the pulmonary carcinoma. However, this relationship is not invariably found. As shown in the cases presented, 4 of the individuals had no known history of direct exposure to asbestos dust, and the diagnosis of asbestosis was made based entirely on the histological findings of pulmonary fibrosis as sociated with the presence of asbestos bodies. There are no documented cases in the litera ture to our knowledge of cases of asbestosis associated with carcinoma of the lung in which the patient had not been exposed at one time or another directly to asbestos dust, either in I IBM Canckr Novernber-December 1962 Vol. 15 the mines, in the crude processing oE the fibers, or in other phases oE the manufactur ing.:i- )0-11 However, it is well known that asbestos is now being utilized to a greater degree in the manufacture of products that uparcntly bear no direct relationship to asbestos, such as in insulating material, rope, wallboard, mortar with cement, and plaster of paris. If we accept the cases presented as nsbestosis, then these individuals, even though known exposure is lacking in the history, have lieen exposed to asbestos dust in some form and for prolonged ]>eri(xls of time to induce changes compatible with nsbestosis and the subsequent development of pulmonary carci noma. The fact that no known exposure ex isted in -1 cases indicates that the disease can occur without prolonged exposure to known sources. The average time lapse from the ini tial exposure to asbestos dust to the develop ment of asbestosis is 9 years according to Egbert and Geiger,5 although this figure varies according to different authors, and much shorter exposure times with development of asbestosis have been recorded. In individuals who base developed carcinoma of the lung, the asbestos exposure time averages 15 years, with a range of 3 to 27 years.13-14 and with latent periods of from 15 to 22 years between the initial exposure to the asbestos dust and the development of a malignant, tumor.8 There have been cases, however, in which an unusually short exposure time was re corded. In a case cited by Owen,84 pulmonary carcinoma developed in an individual exposed to asbestos dust for only 12 months, approxi mately 20 years after the exposure. The majority of the lung carcinomas as sociated with asbestosis recorded have been of the squamous cell type. In our series, bronrhiolar carcinoma and undifferentiated carci noma were present in equal numbers. Localization of the tumor in these cases is of some interest. Carcinoma of the lung usu ally occurs more frequently in the upper lobes, whereas in asbestosis, approximately 80% of the cases reported txcurred in lower lobes where the pneumoconiosis is most severe.17 Our cases showed a majority of the malignant tumors occurring in the upper lolres (Table !) Other agents that are believed to be related to cancer of the lung are uranium, chromium, and possibly nickel. In the case of asbestos, although experimental proof is lacking, there appears to be sufficient clinical pathological evidence to make it highly probable that this is a carcinogenic agent.20 It must be admitted that the carcinogenic stimulus is a weak one, and the mode of action is still obscure. Par ticle size is apparently of importance in the production of asbestosis. Those fibers less than 20 p in length have no apparent deleterious effect.15 The fibrotic reaction in the lung is produced by both physical anti chemical changes secondary to the asbestos fiber.8-17 The fibrosis is a progressive phenomenon, with progression after exposure has ceased.13 Multifocal areas of metaplasia of the broo ch iolar epithelium have been described in the areas of fibrosis and the suggestion made that these represent early stages in carcinogenesis.20 The silicate portion of the fiber is apparently not responsible for this activity. Carcinoma of the lung occurs in only 1.3% of cases of silicosis in contrast to 13% in cases of asbes tosis.4'14-15 It has even been suggested that silicosis may be a deterrent or even offer pro tection against carcinoma of the lung. Summary Eleven cases of asbestosis associated with carcinoma of the lung are presented. A known exposure to asbestos dust was obtained in 7 of these cases. In at least 2 cases, evidence is described for multifocal origin of the tu mor. Typical asbestos bodies were identified in the tumor-bearing area of the lung in each case. The passible relationship of asbestos bodies as a carcinogen in the production of cancer of the lung is discussed. RF.FF.RFNCF.S 1. Anderson. J,, ami Campacna, T. A.: Asbestosis and carcinoma of lung; case report and review of literal urc. Arch. Environ. H. 1: 27-32,1960. 2. Rriocf., J. C., and Henrv, S. A.: Industrial can cers. In Report of the International Conference on Cancer, London, 17th-20th July. 1928. Baltimore, Md. William Wood & Company. 1928; pp. 258-268. 3. Ciireton, R. j. R,: Squamous cell carcinoma oc curring in nslxstosis of lung. Brit. J. Cancer 2: 249-258, 1948. 4. Don., R.: Mortality from lung cancer in aslrcstos workers. Brit. J. Indust. Med. 12: 81-86, 1955. 5. Egbert, D. S., and Geiger, A. J.: Pulmonary asItcstosis and carcinoma; report of case with necropsy findings. Am. Her. Tubeir. 34: 143-150, 1936. 6. Gardner, L. U., and Cummings, D. F..: Studies on experimental pneumonokoniosis; inhalation of as bestos dust; its effect upon primary tuberculous in fection. J. Indust. Hyg, IS: 65-81, 1931. 7. Gi.oyne, S. R..: Morbid anatomy and histology No. 6 Asbestosis & Carcinoma of Lung Cordova et al. 1187 of asbestosis. Tubercle 14: 445-451, 1935. 8. Gloyne, S. R.: Case of oat cell carcinoma of lung occurring in asbestosis. Tubercle 18: 100-101, 1936. 9. Great Britain, Ministry of Labour and Na tional Service: Annual Report of the Chief Inspector of Factories for the Year 1947. London, England, His Majesty's Stationery Office. 1949. 10. Holleb, H. B., and Ancrist, A. A.: Bronchogenic carcinoma in association with pulmonary asbestosis; report of 2 cases. Am. J. Path. 18: 123-135, 1942. 11. Homburcer, F.: Co-incidence of primary carci noma of lungs and pulmonary asbestosis; analysis of literature and report of 3 cases. Am. J. Path. 19: 797 807, 1943. 12. Hornig, F.: Klinische Betrachtungen zur Frage des Berufskrebses der Asbcstarbeiter. Ztschr. Krebsforsch. 47: 281-287, 1938. 13. Hueper, W. C.: Occupational Tumors and Allied Diseases. Springfield, 111. Charles C Thomas. 1942; pp. 403-405. 14. Hueper, W. C.: Environmental lung cancer. Indust. Med. 20: 49-62, 1951. ' 15. Isselhacher, K. J.; Klaus, H,, and Hardy, H. L.: Asbestosis and bronchogenic carcinoma; report of 1 autopsied case and review of available literature. Am. J. Med. 15: 721-732, 1953. 16. Jacob, G., and Bohlig, H.: fiber HSufigkeit und Besonderheiten des Lungenkrebses bei Asbestose. Arch. Gewerbepath. u. Gewerbehyg. 14: 10-28, 1955. 17. Linzbach, A. J., and Wedler, H. W.: Beitrag zum Berufskrebs der Asbestarbciter. Virchows Arch, path. Anal. 307: 387-409, 1940-1941. 18. Lynch, K. M.: Pulmonary asbestosis; asbestos body and similar objects in lung. ]. A. M. A. 109: 1974 1978,1937. 19. Lynch, K. M.: Pathology of asbestosis. Arch. Indust. H. 11: 185-188, 1955. 20. Lynch, K. M., and Pratt-Thomas, H. R.: Car cinoma of lung in asbestosis; report of 2 additional cases. South. M. J. 48: 565-569, 1955. 21. Lynch, K. M., and Smith, W. A.: Pulmonary asbestosis III; carcinoma of lung in asbesto-silicosis. Am. J. Cancer 24: 56-64, 1935. 22. Lynch, K. M., and Smith, W. A.: Pulmonary asbestosis; report of bronchial carcinoma and epi thelial metaplasia. Am. J. Cancer 36: 567-573, 1939. 23. Nordmann, M.: Der Berufskrebs der Asbestarbeiter. Ztschr. Krebsforsch. 47: 288-302, 1938. 24. Owen, T. K.: Carcinoma and asbestosis of lung; report of case. Brit. J. Cancer 5: 382-383, 1951. 25. Sander, O. A.: Asbestosis as differentiated from other pneumoconioses. Arch. Indust. H. 11: 208-211, 1955. 26. Stoll, R.; Bass, R., and Angrist, A, [A.]: As bestosis associated with bronchogenic carcinoma. A. M. A. Arch. Int. Med. 88: 831-834,1951. 27. Wiese, E. R., and Hall, W. E. B.: Asbestosis; re port of case. Dis. Chest 30: 229-230, 1956.