Document gboN7wkq6Bk5Y8p6QB6dG5o53

Case Reports Asbestosis and Bronchogenic Carcinoma* Report of One Autopsied Case and Review of the Available Literature J. L.Kurt Isselbacher, m.d., Hanna Klaus, m.d. and Harriet Hardy, m.d. Boston, Massachusetts here are several reasons for presenting curtains and clothing. The chief operations are Tin detail a case report and a review of the disintegration of the crude mineral, carding the available literature dealing with the fiber, separating the more useful long from the relationship between occupational exposure stohort fiber, spinning, plaiting and weaving the asbestos and respiratory tract malignancy. Thaesbestos, often with cotton. Insulating material apparent increase in bronchogenic carcinoma, is produced by mixing magnesia, diatomaceous especially in males, reported in the past decade earth and other materials with asbestos to make has led to scrutiny of respirable dusts as possible cements or fillings for insulating boilers, engines etiology. Most English observers1-3 are satisfied that there is a statistically significant increase in pulmonary malignancy among asbestos workers. Some American writers consider that and pipes. Other non-textile asbestos products so made include asbestos cement, sheets, brake and clutch linings, electrodes and switchboard panels. the experience to date does not support this Asbestos is a hydrated magnesium silicate. contention.4,6 The work of Graham,8,7 Doll and The chiefsupplies are in Canada, Cape Province, Hill,8 and Ochsner9,10 has created much interest in the correlation of cigarette smoking with Italy, Rhodesia and Russia. Asbestos dust given off in manufacturing processes consists of frag bronchogenic carcinoma. E. R., whose case is ments of fibers and small rounded or angular herein presented, was exposed to harmful particles. Actual studies in industry show the amounts of asbestos dust and was a chain size and shape of the particles of asbestos to be smoker. This provides speculation as to the such as may gain entrance into the bronchioles.14 possible role of two etiologic agents. Few reported cases of lung cancer related to industrial asbestos exposures provide data on Experience has led to the acceptance of five million particles of asbestos per cubic foot of air, of small enough size to be respirable, to be the the character and quantity of dust exposure. safe working concentration. This is a serious deficit in exact study of etiologic correlation. In the clinical report presented herein State authorities have determined by Some operations because of their dustiness are more hazardous than others in asbestos manufacturing. Bagging the asbestos, separating measurement that the asbestos dust exposure of this man during his twelve years of work was considerably above the safe level, which is con sidered to be five million particles per cubic foot of air for an eight-hour working day. It is pertinent to this presentation that there are probably about 10,000 workers engaged in potentially hazardous asbestos manufacturing operations in the United States.11 Middleton reports the number in Great Britain as between the long from the short fibers, carding, spinning and weaving show a greater statistical evidence of asbestosis than do other operations. As might be expected, the longer the duration of exposure the greater the number of cases. In the Merewether and Price series there was one case under four years' exposure, and up to 53.6 per cent with fifteen to nineteen years' exposure.16 C.ASE REPORT 3,000 to 5,000.12 Most of the industry is engaged in asbestos textile manufacturing producing insulating mattresses, brake linings, fire proof E. R. (MGH #735586),18 a forty-one year old asbestos mill worker, entered the Massachusetts General Hospital in April, 1951. The chief * From the Departments of Medicine and Pathology, and the Occupational Medical Clinic, Massachusetts General Hospital, Boston, Mass. This work was supported in part by the National Institutes of Health, Division of Research Grants. NOVEMBER, 1953 721 SCF-FA-4200 722 Asbestosis, Bronchogenic Carcinoma--Isselbacher et at. tions 30, and temperature 99f. orally. His chest was thin and showed poor expansion. There were dullness and reduced breath sounds at both lung bases with sticky inspiratory crackling rales over the region of the left lower lobe. The left border of cardiac dullness was 10 cm. to the Table i PULMONARY FUNCTION STUDIES* BEFORE AND AFTER ACTH f Before ACTH After ACTH Approxi mate Normal Values*10 Fio. 1. X-ray of chest. The lower lobes are reduced in size and show a "honeycomb" pattern. There is an increase in linear and nodular markings. A density is seen in the region of the lingula with enlargement of lymph nodes in the left lung root, suggesting a tumor in that area. complaint was progressive low back pain which had been present for four months and was only partially relieved by aspirin. In addition, one month before admission the patient noticed increasing dyspnea on exertion, a worsening of his chronic productive cough, night sweats, anorexia, feverishness and a 10-pound weight loss. He had worked in an asbestos mill for about twelve years but had stopped working there for two years prior to this hospital admis sion. In the mill he had spent one year in the "picker room" where crushing, grinding and sorting of long asbestos fibers was carried out. He also worked five years in the carding room where the concentration of fibers had been determined by authorities to be considerably above the safe level. He used one can of snuff and smoked on an average of one to two packs of cigarettes daily for many years. For seven or eight years he had been aware of clubbing of his fingers; one flight dyspnea was present for about two years. There had been no hemoptysis. Physical examination revealed a chronically ill and dyspneic man with evidence of weight loss and cyanosis of the lips and nail beds. The blood pressure was 110/75, pulse 96, respira- Maximum breathing capacity Effective alveolar ventilation Alveolar-arterial Oj difference 24 2 18 3.9 52.5 1.575 79.5 105 1.49 1 .30 7.63 115.0 88.0 36 0 97.3 7.45 5.48 s 5.02 105 0 105-107 76.0 95-97 42.0 94.4 40-43 95-97 7.42 7.39 27. 29. 10. * These studies were performed by Dr. John Affeldt, Department of Physiology, Harvard School of Public Health, t ACTH 100 mg. intramuscularly for ten days. X Body surface area was 1.62 sq. m. left of the midsternal line in the fifth interspace; there were occasional extra systoles; P2 was greater than A2; there was some pulsus para doxus. Liver and spleen were not felt. There was tenderness of the spine over L-4 with spasm of the lumbar musculature. He had extreme clubbing of fingers and toes. Laboratory data revealed a normal urinalysis. Hemoglobin was 14.0 gm. per cent and the white count was 5,700, with a normal differen tial. Chest x-ray revealed the lower lobes reduced in size and showing a honeycomb pattern. (Fig. 1.) There appeared to be a homogenous density in the lingula with enlargement of lymph nodes in the left lung root suggesting a tumor in the region of the left lower lobe. Films of the spine indicated areas of increased and decreased density in the fourth lumbar vertebra giving the appearance of metastatic malignancy. Electrocardiogram showed non-specific T wave changes. Non-protein nitrogen was 27 mg. per cent, CO2 29.4 mEq./L., alkaline phosphatase 4.9 Bodansky units. Repeated examinations of the sputum were negative for acid-fast organ isms, asbestosis bodies and malignant cells. Two bronchoscopies revealed obstruction of the left lower lobe bronchus. The patient was given a trial of ACTH 100 mg. daily intramuscularly AMERICAN JOURNAL OF MEDICINE Asbestosis, Bronchogenic Carcinoma--Isselbacher et al 723 lot ten days. Clinically there was no change except for euphoria. Pulmonary function and cardiac catheterization studies were performed before and after ACTH and likewise showed no significant changes. (Tables i and n.) Cardiac catheterization did reveal chronic cor pulmonale blood count was 6,500, hemoglobin 11.5 gm. per cent. It was believed that the patient had pneu monitis in the right lower lobe and early cor pulmonale with congestive failure. He was digitalized, given mercurial diuretics, anti- Table 11 CARDIAC CATHETERIZATION STUDIES* BEFORE AND AFTER ACTHf Oi Consumption (cc./min./ sq. m.) o2 Capacity Radial Artery (cc./lOO cc.) o2 Content Radial Artery (cc./lOO cc.) o2 Satura tion Radial Artery (7c) Pulmonary Artery Pressure (mm. Hg) Mean Pulmonary Artery Pressure (mm. Hg) Cardiac Index (L./min./ sq. m.) Approximate Before | Rest.............. ACTH | Mild exercise l (2 min.), . After | Rest............... ACTH | Mild exercise \ (2 min.). . 145 180 370 156 349 20.0 19.3 17.4 19.0 18.1 16.6 96 30/10 94 36/14 43/14 95 38/15 52/22 15 21 28 23 36 3.2 4.47 5.55 4.02 6.97 * These studies were performed by the Cardiac Catheterization Unit of the Massachusetts General Hospital) including Drs. G. S. Myert, A. L. Friedlich, J. R. O'Neill, G. Cohen and J. G. Scannell. t ACTH 100 mg. intramuscularly for ten days. with slight pulmonary hypertension; after exercise the pulmonary hypertension increased and significant arterial oxygen unsaturation appeared. Before discharge from the hospital he received radiation (1,200 r) to the lumbar spine with no relief of the back pain. For several weeks after discharge the patient seemed somewhat better and returned to light work. However, the cough increased markedly and he had severe dyspnea at rest so that after two months he had to be readmitted. Physical examination on re-entry revealed a temperature of 100.4f. rectally, pulse of 120-144, respirations 30 per minute. He had marked tachypnea, moderate cyanosis and such dyspnea that it was very difficult for him to speak. There were many inspiratory and expiratory wheezes throughout the lung fields. At the right base there were moist bubbling rales together with dullness, reduced tactile fremitus and increased vocal fremitus. The left border of cardiac dullness now extended out 12 cm. from the midsternal line. P2 was much louder than A2. The liver was percussed down two and a half fingerbreadths and there was 2 plus ankle edema. At this time the white NOVEMBER, 195 3,. biotics (penicillin and streptomycin), and was in an oxygen tent most of the time. Chest x-rays now were suggestive of lymphatic spread of tumor. In spite of all therapeutic measures fever, dyspnea and cyanosis grew worse. He became confused and died on the thirty-fourth hospital day. At necropsy the patient was emaciated; the thorax was lengthened in the anteroposterior diameter. There was clubbing of the fingers and toes. On opening the thorax the lungs did not collapse but remained inflated, completely filling both pleural cavities. The majority of the pleural space was obliterated bilaterally by dense fibrous adhesions between the visceral and parietal layers. Both the visceral and parietal pleurae were markedly thickened, gray fibrous membranes measuring up to 0.3 cm. thick. There were 100 cc. of clear straw-colored fluid loculated in the left base. The interlobar fissures were obliterated by fibrous tissue. Scattered throughout the adherent layers of the diaphragmatic pleura, especially on the right, were a number of whitish gray, shiny plaques 0.5 cm. long; these resembled similar plaques 724 Asbestosis, Bronchogenic Carcinoma--Isselbacher et al. Fio. 2. Cut surface of left lung after formalin fixation. Note diffuse pulmonary fibrosis and marked pleural thickening which obliterates the interlobar fissure. seen on the upper surface of the liver, to be described. The lungs weighed 2,710 gm., were voluminous and very firm throughout; no dis crete nodules could be felt. (Fig. 2.) Multiple sections showed a uniform brownish gray surface throughout except in the left lower lobe where there appeared to be a diffuse marked fibrosis throughout the parenchyma. The left lower lobe bronchus was completely occluded 1 cm. from its origin by pinkish gray, firm tissue for a distance of 1.4 cm.; here the bronchus measured 0.7 cm. in diameter; the firm pinkish gray tissue extended into the parenchyma for a distance of 1.7 cm. Similar tissue extended from this point in the bronchus to the pleura and into the wall of the left atrium which was adherent to the pleura at this point; the gross atrial in volvement measured 2.3 by 0.7 cm. in extent. The upper lobe bronchi were rigid and nar rowed by a thick, white fibrous coat. The right lower and to some extent the right middle and left lower lobe bronchi were dilated, and there Fig. 3. Asbestosis bodies in the lung. The club-shaped, beaded asbestosis bodies are seen in the alveolar ducts, surrounded by macrophages and "dust cells"; X 900. was collapse of the intervening parenchyma. The veins and arteries appeared normal. There were adhesions between the visceral and parietal pericardium both at the apex and the base. The apical adhesions were thin fibrous strands but those at the base were extensions of the firm tissue described in the left lower lobe bronchus. The heart weighed 360 gm. There was involvement of the left atrium and auricle by thick, firm, grayish pink tissue for an area measuring 2.3 by 0.7 cm. The remaining myo cardium appeared uninvolved and measured 0.6 cm. thick in the right ventricle, 1.3 cm. in the left. The endocardium and valves were negative. The diaphragms contained firm grayish pink areas of plaque-like thickening which measured up to 0.5 cm. in diameter. These were seen on both the pleural and peritoneal surfaces, were apposed and loosely adherent to similar con fluent areas in Glisson's capsule. The remaining organs, with the exception of the fourth lumbar vertebra, were negative. This vertebra appeared opalescent and resembled marble, but its con sistency was softer than the adjacent vertebrae. The body appeared to have increased porosity. AMERICAN JOURNAL OF MEDICINE Asbestosis, Bronchogenic Carcinoma--Isselbacher et al. 725 The lungs were sectioned topographically; sections from all segmental bronchi were taken near the hilum, the mid-lobar and the periph eral areas. These basic histologic patterns could be seen: Fibrosis: Throughout the lungs there was proliferation of fibrous tissue around the bronchi, the arteries, alveolar ducts; the interlobar septa and pleurae were also thickened. There was peribronchial and alveolar duct fibrosis in both apices, and slight alveolar wall thickening as demonstrated by connective tissue stains. The fibrosis increased in the remaining portions of the lungs, was heaviest in the hilar and mid-lobar areas but extended to the periphery. This con firmed the gross impression of diffuse fibrosis. Asbestosis bodies: Asbestosis bodies were present in all sections. (Fig. 3.) These were segmented fibers averaging 50>* long, some straight and some club-shaped, others resembled dumb bells which stained dark brown on hematoxylin-eosin preparations, and blue on Prussian blue (iron) preparations. Particles of iron-staining dust and larger, easily identifiable asbestosis body parti NOVEMBER, 1953 cles, were present in the macrophages. The distribution was equal bilaterally, being slight to moderate in the apical segments, quite marked in the remainder of the lung and oc curring with equal intensity in the hilar, midlobar and peripheral zones. While most of the asbestosis bodies were seen in the bronchioles and alveolar ducts, a few could be seen in the alveoli, and fragments were found both in the macrophages and in the lymphatics. Several aggregations of asbestosis bodies were found in the bronchi. Fragmented asbestos fibers were found mostly in the macro phages but occasional iron-staining particles were found free on the alveolar walls. Much, but by no means all, of this material in the macrophages took the iron stain. Inflammatory response: The chief inflammatory cells responding to the irritant were the macro phages. These cells were seen in abundance in every section; they lined up along the walls of the alveolar ducts, filled the lumina of bron chioles and alveoli, and were found throughout the septa and fibrous tissue. Most of these con- 726 Asbestosis, Bronchogenic Carcinoma--hselbacher et al. Fig. 6. X-ray diffraction film of lung residue of E. R. * The lines listed when compared to the known pattern for asbestos give positive proof that the lung residue is essentially asbestos. 4.52 4.20 3.35 2.98 2.67 Table of "D" lines: 2.42 2.38 2.115 1.84 1.70 1.61 1.531 1.49 1.44 1.38 * A 68.5 gm. sample of formalized lung tissue was digested in 20 volumes hydrogen peroxide, the digestion being accelerated with gentle heating. The residue from the digestion was treated with dilute hydrochloric acid, filtered, washed and ignited at 500V The ignited residue was analyzed by x-ray diffraction by the method described in the article by Hanawalt, J. D., Rinn, H. W., Frevd, L. K., "Chemical analysis by x-ray diffraction," Indust. & Eng. Chem., Anal. Ed., vol. 10, no. 9, 1938. This work was done by R. I. Chamberlin and-A. Woewucki, Jr. of the Massachusetts Bonding and Insurance Company, Boston, Mass. tained brown pigment granules many of which took an iron stain, and portions of asbestosis bodies were also found in the macrophages. (These cells have been called dust cells and are thought to lay down the iron on the asbestos fiber, constituting the asbestosis body.) Anthracotic pigment was also present in the macro phages. Multinucleated giant cells of the foreign body type were found in abundance in all areas; many of these contained birefringent asteroidal bodies. Few lymphocytes were seen; those present were scattered around the bronchi near the hila. A few focal areas of bronchopneu monia with polymorphonuclear infiltration were present; these had no particular relation or location to any grouping of the asbestosis bodies and were undoubtedly a terminal phenomenon. Throughout the lungs many air sacs were dilated and contained a granular eosinophilic material, probably fibrin. Some of these plugs were undergoing organization, mainly in alve olar ducts; this type of fibrosis probably accounts for a small percentage of the total fibrosis seen. Bronchi: The bronchi of the lower lobes showed marked bronchiectasis; there was dilatation, fibrosis of the muscular coat and peribronchial fibrosis. While the latter was most marked in the lower lobes it was seen in the hilar and midzonal regions of almost all segments. Another striking feature was widespread squamous metaplasia of the bronchial epithelium. (Fig. 4.) This was most marked in the alveolar ducts; it was found in all areas and was not particularly related topographically to the adenocarcinoma described later. Blood vessels: The arteries and arterioles of the right middle and both lower lobes showed moderate intimal thickening with hyalinization and narrowed lumina. This was most marked near the hila but was found occasionally farther into the periphery. Tumor: Adenocarcinoma was found originat ing in the inferior lingual segment of the left upper lobe bronchus. The tumor was present in the mid-zonal area of the apical posterior segment of the left upper lobe, the entire lingula and left lower lobe, as well as the right middle and lower lobes. It had spread by sub mucosal and lymphatic routes. Sections of the left atrium showed direct extension through the left hilum into the pericardium and myocar dium. (Fig. 5.) Metastatic tumor was seen in the fourth lumbar vertebra. Asbestos "granulomas": The white plaques described in the diaphragm and Glisson's cap sule were made up chiefly of hyalinized con nective tissue. No asbestosis bodies or giant cells were seen. These distinctive areas grossly suggested granulomas. X-ray diffraction studies were carried out on a sample of formalized lung tissue. The resulting pattern indicated that the lung residue was mostly asbestos. (Fig. 6.) COMMENTS Asbestosis may be defined as a specific occu pational disease caused by the inhalation of asbestos fibers and leading to a progressive fibrosis and scarring within the lungs.17 It has been demonstrated by Gardner*0 and again by AMERICAN JOURNAL OF MEDICINE Asbestosis, Bronchogenic Carcinoma--Isselbacher et al. 727 Vorwald18 that usually the disease will not occur with fibers less than 20/t in length or a concentration below five million particles per cubic foot of air. The pathologic processes resulting from the inhalation of asbestos particles are believed to be due not to their chemical nature but, rather, the consequence of mechanical irritation from fibers lodged in the respiratory tree.18-20 The inhaled particles are, in general, too large to pass beyond the respiratory bronchioles and so they remain there to initiate a foreign body reaction which eventually leads to fibrosis.21 The pathologic sequence of events can be considered as occurring in three stages: (1) desquamation and exudation, (2) formation of asbestosis bodies and (3) fibrosis and scarring. The long fibers traumatize the epithelial cells lining the smaller bronchioles and the constant irritation and friction cause the cells to desqua mate. Macrophages pour forth in an effort to phagocytize the fibers. In our case fragmented asbestosis bodies were also seen within macro phages and lymphatics. A second reaction to the asbestos fiber in the lung is the production of the so-called "asbestosis body."22-24 This results from a reaction occurring between the asbestos particle and surrounding tissues. It is a thicken ing of the fiber due to the deposition along its course of a protein matrix containing iron which probably serves to reduce the chronic irritation.28 These bodies may be found in the sputum, lung, pleura, lymph nodes and spleen.28 Their presence is held to be evidence of exposure to asbestos but by themselves are not necessarily an indication of asbestosis.17'27,28 The third and most significant tissue response is the production of fibroblasts and the deposi tion of collagen about the distal bronchioles and alveoli. There ensues a diffuse fibrosis which compresses the alveoli and capillaries, resulting in complete obliteration of the involved pulmo nary tissue. This process is more pronounced in the lower lobes of the lung for it is there that the particles are most abundant. By x-ray one sees a fine, ground glass or granular pattern in the lower lobes and frequently emphysema in the upper lobes. The sequence of pathologic events described previously occurs slowly. In man the fibrosis tends to progress even after the exposure has ceased; however in animals this does not seem to be the case. It may be that intercurrent infec tion contributes to the progression in man.13 NOVEMBER, 1953 In general there is a delay of five to seven years between the initial exposure to high con centrations of asbestos dusts and the onset of clinical asbestosis. The average interval re ported by Merewether is eleven years.17 While most patients with asbestosis have had an exposure of ten to sixteen years, it is important to realize that the disease has occurred with as short an industrial exposure as 0.5 years.1,2 Usually no symptoms appear until a large part of the respiratory reserve has been reduced by the fibrosis. Merewether has frequently com mented how markedly the lungs can be affected and yet the patient be fairly comfortable.17 However, when symptoms once begin and significant dyspnea becomes apparent, there is usually a definite and rapid progression. Then productive, cough, anorexia, weight loss and fatigue are the common complaints. Death eventually results from intercurrent infection, cor pulmonale or carcinoma of the lung. The case herein presented demonstrates many of the significant features in the pathogenesis, symptomatology and natural course of asbestosis. The patient had worked for twelve years in an atmosphere having a concentration of asbestos particles known to be sufficient to produce pulmonary pathology. However, it was only during the last year of life that dyspnea, cough, anorexia and weight loss manifested themselves. Clubbing had been present for at least five years. He had a very rapid downhill course, due undoubtedly to the two associated factors--the asbestosis and carcinoma of the lung. The physical findings of clubbing, cyanosis and dullness at the lung bases were all consistent with asbestosis as were the x-ray findings in the lungs, apart from the evidence suggesting neo plasm. The outstanding symptom, the severe and progressive dyspnea, was attributed to a combination of pulmonary fibrosis, superim posed and spreading lung neoplasm, pulmonary infection and finally congestive failure on the basis of cor pulmonale. As indicated in the case history, the ten-day period of ACTH therapy was accompanied only by euphoria but objective measurements re vealed no significant changes. This was not surprising for two reasons: (1) the fibrosis had obviously been of long duration and therefore one would not expect it to change much at this time; and (2) he had superimposed broncho genic carcinoma. It is of interest to compare these results to patients with chronic beryllium 728 Asbestosis, Bronchogenic Carcinoma--Isselbacher et al. poisoning who usually show a favorable re sponse to steroid therapy.29 Two further aspects of this case merit more detailed consideration and analysis: (1) the pulmonary function and cardiac catheterization studies; and (2) the significance of the superim posed bronchogenic carcinoma. PULMONARY FUNCTION AND CARDIAC CATHETERIZATION STUDIES Table 1 indicates, as one might expect, that the patient had a reduction in vital and maxi mum breathing capacities. However, the finding of an alveolar-arterial oxygen gradient of 27 mm. Hg demonstrates that one of the dis turbances in pulmonary function was a defect in the diffusion of oxygen from the alveoli of the lungs to the capillaries. This corresponds to the syndrome of "alveolar-capillary block" de scribed by Baldwin, Cournand and Richards31'92 and again by Austrian et al." This diffusion defect is not surprising when one recalls the fibrosis about the alveoli, alveolar ducts, capil laries and bronchioles that occurs in asbestosis. In order for the patient to maintain a near normal arterial oxygen saturation, a high alveolar oxygen was necessary; and this ap parently was accomplished in part by hyper ventilation. The patient had an average respiratory rate of 40 per minute at rest. This compensatory mechanism apparently was not adequate during stress or exercise for under those conditions the arterial oxygen saturation fell. There was a considerable degree of pulmo nary hypertension and, as in the cases of pulmo nary fibrosis studied by Cournand and his associates, a rise in the pulmonary artery pressure occurred with exercise. (Table 11.) The partial pressure of carbon dioxide in the blood (36 mm. Hg) was low normal rather than ele vated. Had there been a defect in alveolar ventilation, the pCC>2 would probably have been higher. As Amot emphasized in discussing this case16 carbon dioxide is not impaired in its transfer from the blood to the alveoli because of its great diffusion capacity. This speed of diffusion plus the increased alveolar ventilation no doubt accounted for the lowered pCC>2 value. ASBESTOSIS AND CARCINOMA OF THE LUNO The association of asbestosis and carcinoma of the lung has been mentioned frequently in the literature. 1-9,94~63 Heretofore some authors have believed that the cases were too few in number to be of significance; others, especially Vorwald and Karr, have stated that "inhaled dusts, except those containing recognized carci nogenic substances (as radium and tar) cannot in general be considered as etiologic factors in the development of primary pulmonary carci- Table m INCIDENCE OF ASBESTOSIS AND CARCINOMA OF LUNG Author No. of No. Due to Deaths with Cancer of Asbestosis Lung Inci dence <%) Merewether1........... Wedler44................. Wyers*.................... Lynch, Cannon47. . Gloyne*.................. Total....................... 235 92 115 40 121 603 31 13.2 15 16.3 17 14.8 3 7.5 17 14.1 83 13.8 noma."4 Our conclusion at present is in favor of the concept that the association of broncho genic carcinoma with asbestosis is more than coincidence. That there is a significant incidence of bronchogenic carcinoma in asbestosis is apparent from Table in. Merewether has cited the largest series--of 235 cases of asbestosis there were thirty-one with bronchogenic carcinoma, or 13.2 per cent.1 An average of the five analyses recorded in the literature is 13.8 per cent. This is considerably higher than the incidence of lung carcinoma in routine necropsies, which in a comparable period (1935-1948) ranged from 0.8 to 2.4 per cent.9'47-64 In contrast to asbestosis the incidence of bronchogenic carcinoma in silicosis as recorded in the two largest series has been similar to what might be expected in the general popula tion. The data compiled by Merewether1 and the Miner's Phthisis Medical Bureau of South Africa66 are based on a total of 6,884 and 1,438 autopsied cases of silicosis respectively, and disclose an incidence of lung carcinoma of 1.32 and 0.70 per cent. Vorwald and Karr found two lung carcinomas in 136 silicotics (1.47 per cent). Klotz66 noted an incidence of 8 per cent, but his series of fifty cases does not seem large enough to be statistically significant. However Gloyne9 in reviewing necropsy material from 1929 to 1949 (796 cases) also described the surprisingly high incidence of lung carcinoma in silicosis of 6.9 per cent, and 7.7 per cent in AMERICAN JOURNAL OF MEDICINE Asbestosis, Bronchogenic Carcinoma--Isselbacher ei al. 729 the pneumoconioses as a whole. In this same series 8.3 per cent of cases without any pneumo coniosis had cancer of the lung. Merewether and Gloyne's cases were analyzed over a comparable period of time so that it seems unreasonable to interpret the figure of 6.9 per cent as reflecting the increase of lung carcinoma in the general population. The discrepancy in the data proba bly is explained by the fact that Gloyne's material was selected from the pneumoconioses in which the histories and x-rays were "unusual." Gloyne noted that 14.1 per cent of patients with asbestosis had lung carcinoma. This figure parallels the observations of previous workers and is significantly above that recorded for silicosis. As has been mentioned the asbestos particle probably acts as a mechanical irritant while the pulmonary changes in silicosis are considered due to the chemical properties of silica.1820 Carcinoma of the lung appears to be promi nent in females with asbestosis. Of Merewether's thirty-one cases nine were females, or 29 per cent, and in Gloyne's series of seventeen cases the incidence was 41 per cent. In the published autopsy reports data as to the sex of the patient are available in twenty-three, of which five (21 per cent) were females. In contrast, the incidence of bronchogenic carcinoma in females in the general population is considerably lower. Lindskog noted an incidence of 4.0 per cent,67 Graham7 5.4 per cent, Doll and Hill8 8.4 per cent and Ochsner10 10.3 per cent. The higher figure in asbestosis supports the theory that asbestos particles act as carcinogens. Experimental production of neoplasms has demonstrated that chronic irritation of body tissues by mechanical means may predispose to the development of malignancy. Asbestos par ticles when lodged in the finer bronchioles serve as mechanical irritants to the bronchial epi thelium. The squamous metaplasia of the lungs found frequently in asbestosis is presumably a consequence of prolonged irritation in the lower respiratory tract. Some pathologists consider squamous metaplasia as an alteration in the cellular structure that may precede or be the initial step towards the development of squamous cell carcinoma.68 A "lag period" between the exposure to a possible carcinogen and the onset of malignancy is characteristic. Nordmann38 noted in his cases that the average duration between the initial exposure to asbestos and the development of bronchogenic carcinoma was about eighteen years. Similarly Merewether1 found that patients dying of carcinoma of the lung had a longer mean exposure to asbestos (16.5 years) than those dying with no evidence of malignancy (13.4 years). Finally, a short but "adequate" exposure may be followed by pulmonary malignancy many years later. In Merewether's series is the case of a woman who was an asbestos worker for only six months yet later developed lung carcinoma. Gloyne86 reported the case of a woman with an exposure of nineteen months who died fifteen years later at the age of seventyone with a squamous cell carcinoma of the right lower lobe. Table iv summarizes the pertinent informa tion of the twenty cases of asbestosis with lung carcinoma that have been autopsied and re corded in the available literature. Four cases have been added to the list compiled by Homburger46 in 1943. It is noted that in about fourfifths of the cases in which the primary site is indicated the origin of the neoplasms was in the lower lobes. This is in contrast to the general population where bronchogenic carcinoma seems to be more frequent in the upper lobes. In Lindskog's69 series there was an incidence of 57 per cent in the upper lobes, 26 per cent in the lower lobes. Ochsner10 found 56 per cent in the upper lobes and 35 per cent in the lower lobes. No conclusions should be drawn from the small number of cases listed in Table iv. Nevertheless, since asbestos particles lodge to a greater extent in the lower respiratory tree where the changes of asbestosis are also more pronounced, a higher incidence of carcinoma in this location should be expected if an etiologic relationship exists. In our case the asbestosis was widespread and severe, and the tumor, which originated in the inferior (lingual) seg ment of the left upper lobe, was in an area significantly involved by the fibrosis and in flammation of asbestosis. It is also noted in Table iv that twelve of the nineteen previously recorded cases had lesions of the squamous cell type. The incidence of squamous cell carcinoma is said to be high in male cigarette smokers with pulmonary malig nancy.6 At autopsy our patient showed both squamous metaplasia and adenocarcinoma of the lingula. It may be of significance that he was a chain smoker for over twenty years in view of the observation by Wynder and Graham7 that males with adenocarcinoma of the lung are NOVEMBER, 1953 730 Asbestosis, Bronchogenic Carcinoma--Isselbacher et al. frequently chain smokers. However, it is our belief that the presence of an adenocarcinoma rather than one of the squamous cell type may be explained by the fact that it is not unusual to find several cellular types in various sections of the same tumor.68 Therefore morphologic carcinoma in 13.8 per cent of the cases cited in the literature. In silicosis the incidence is con siderably less than this. The asbestos particle may serve as a carcinogen because of the chronic mechanical irritation it produces. 5. Since there are approximately 10,000 Table iv SUMMARY OF PUBLISHED CASE REPORTS IN WHICH AUTOPSY DATA ARE CITED Authors Year Sex and Age Occupation Duration of Exposure (yr.) Freedom from Exposure Nature of Tumor before Death Primary Site Metastases Lynch, Smith34................... 1935 M, 57 Weaver Gloyne*3............................... Gloyne................................. Egbert, Geiger37.................. Gloyne33............................... Nordmann*8........................ Nordmann........................... Lynch,3* Smith................... 1935 1935 1936 1936 1938 1938 1939 F, 35 F, 71 M, 41 M, 59 F, 35 M, 55 M, 50 Spinner Mattress and open ing departments Weaver Packer, stores de partment Carder, spinner, weaver Prespinning assembly room Weaver Holleb,44 Angrist................ 1941 M, 52 Pipe insulator Holleb, Angrist................... 1941 M, 50 Pipe insulator Linzbach, Wedler4'............ Desmeules et al.43............... Desmeules et al................... Horoburger43....................... Homburger.......................... Homburgcr.......................... 1941 1941 1941 1942 1942 1942 M, 61 M, 57 M, 50 M, 45 M, 43 F, 49 Machine adjustor Bagger Not known Not known No known contact with asbestos Cureton49............................. 1948 F, 37 Pipe coverer Owen31................................. 1951 M, 39 Asbestos worker Stoll, Bass, Angrist3*........... 1951 M, 40 Pipe coverer Present authors................... 1952 M, 41 Asbestos mill worker; sorter 21 4 mo. Squamous cell R.L.L. Many nodules in R.L.L. 8 9 yr. Squamous cell R.D.L. Pleura 15 yr. Squamous cell R.L.L. None 17 ion 2 yr. ? mo. Glandular Oat cell L.L.L. L.L.L. Widespread L.U.L, and pleura 7 9 yr. Squamous cell L.L.L. Liver, kidneys 7 . 12 yr. Squamous cell L.L.L. Widespread 13 3 yr. Squamous with R.L.L. Pleura, medi glandular astinal nodes features 25 9 yr. Non-keratin iz- R.U.L. Mediastinal nodes, ing squamous adrenal, kidney celled 25 10 yr. Oat cell R.L.L. Widespread, including brain >3 Not known Squamous cell R.L.L. None 25 1 mo. Alveolar cell L. lung Pleura 22 4 mo. Squamous cell R. lung Pleura 5 1 yr. Squamous cell R. lung Diaphragm 20 17 mo. Anaplastic L.L.L. Pleura No t known Squamous cell R. lung Liver, adrenal, stomach, hilar lymph nodes 7 15 yr. Squamous cell L.L.L. Pericardium, liver, kidney, ovaries, femur 20 yr. Adenocarcinoma R. lung None 6 About 4 to 5 yr. Anaplastic No definite Kidneys, brain, site liver 12 2yr. Adenocarcinoma Lingula Myocardium, peri cardium, spine, regional nodes differences in cell arrangements may not really represent different etiologic varieties of cancer. SUMMARY AND CONCLUSIONS 1. A case of asbestosis with superimposed adenocarcinoma of the lung with metastases, following documented harmful industrial ex posure, is presented. 2. ACTH (adrenocorticotrophic hormone) was given with no objective changes in the patient's clinical course. 3. Pulmonary function and cardiac catheter ization studies were performed before and after ACTH. They revealed an alveolar diffusion defect and pulmonary hypertension. 4. Asbestos is associated with bronchogenic workers engaged in potentially hazardous asbestos operations in this country, it is reason able to assume that there are many unrecognized cases of asbestosis. From the evidence presented a higher incidence of bronchogenic carcinoma should be expected in this group. Addendum: Since the submission of this manu script a similar case has been observed by us (MGH #778205). The patient was a forty-six year old contractor's helper whose work since age seventeen consisted of cutting and sawing asbestos board to insulate pipes, boilers and refrigerators. For years he had smoked one package of cigarettes daily. He died after a year of illness during the last four months of which he received 5,000 r of deep x-ray to the left chest. AMERICAN JOURNAL OF MEDICINE Asbestosis, Bronchogenic Carcinoma--Isselbacher et al. 73* At autopsy the lungs were firm and weighed 3,350 gm. There was a poorly differentiated adenocarcinoma arising from the left lower lobe bronchus, almost completely replacing the left lower lobe. The tumor had spread to the left upper lobe, hilum, pericardium, pleura and diaphragm; and had metastasized to the right lung and adrenal. The remaining lung tissue showed peribronchial fibrosis, focal alveolar wall thickening and numerous asbestosis bodies, sur rounded by macrophages filled with asbestosis body particles and foreign body giant cells. The asbestosis bodies were seen in equal distribution in all parts of the lungs not completely involved by tumor. REFERENCES 1. Merewether, E. R. A. Annual Report of the Chief Inspector of Factories. London, 1947. H. M. Stationery Office. 2. Wyers. H. Asbestosis. Post. Grad. M. J, 25: 631, 1949. 3. Gloyne, S. R. Pneumoconiosis. A histologic survey of necropsy material in 1205 cases. Lancet, 1: 810, 1951. 4. Vorwald, A. J. and Karr, J. W. Pneumoconiosis and pulmonary carcinoma. Am. J. Path., 14: 49, 1938. 5. Vorwald, A. J. Personal communication, 1952. 6. Graham, E. A. Primary cancer of the lung with special consideration of its etiology. Bull. New York Acad. Med., 27: 261, 1951. 7. Wynder, E. L. and Graham, E. A. Tobacco smok ing as a possible etiologic factor in bronchogenic carcinoma. J. A. M. A., 143: 329, 1950. 8. Doll, R. and Hill, A. B. Smoking and carcinoma of the lung. Preliminary Report. Brit. M. J., 2: 739, 1950. 9. Ochsner, A. and DeBakey, M. E. Carcinoma of the lung. Arch. Surg., 42: 209, 1941. 10. Ochsner, A., DeBakey, M. E., DeCamp, P. T. and Ray, C. J. Bronchogenic carcinoma. J. A. M. A., 148: 691, 1952. 11. Lanza, A. J. Personal communication, 1952. 12. Lanza. A. J. Silicosis and Asbestosis, p. 386. New York, 1938. Oxford Univ. Press. 13. Idem, p. 327. 14. Wood, W. B. and Gloyne, S. R. Pulmonary asbestosis. Lancet, 1: 445, 1930. 15. Merewether, E. R. A. and Price, C. W. Report on the Effects of Asbestos Dust on the Lungs and Dust Suppression in the Asbestos Industry. London, 1930. H. M. Stationery Office. 16. Case Records of the Massachusetts General Hospital (case 38221). New England J. Med., 246: 867, 1952. 17. Merewether, E. R. A. A memorandum on asbes tosis. Tubercle, 15: 69, 109, 1933; Tubercle, 15: 152, 1934. 18. Vorwald, A. J., Durkan, T. M. and Pratt, D. C. Experimental studies on asbestosis. Arch. Indust. Hyg., 3: 1, 1951. 19. Gloyne, S. R. Reaction of tissues to asbestos fibre, with reference to pulmonary asbestosis. Tubercle, 11: 151, 1930. 20. Gardner, L. U. Etiology of pneumoconiosis. J. A. M.A.,\\\: 1925, 1938. 21. Gardner, L. U. and Cummings, D. E. Studies on experimental pneumoconiosis: vi. Inhalation of asbestos dust; its effect upon primary tuberculous infection. J. Indust. Hyg., 13: 65, 97, 1931. 22. Cooke, W. E. Asbestos dust and the curious bodies found in pulmonary asbestosis. Bril. M. J., 2: 578, 1929. 23. McDonald, S. Histology of pulmonary asbestosis. Brit. M. J., 2: 1025, 1927. 24. Stewart, M. J. and Haddow, A. C. Demonstration of the peculiar bodies of pulmonary asbestosis (asbestosis bodies) in material obtained by lung puncture and in the sputum. J. Path. & Bad., 32: 172, 1929. 25. Gloyne, S. R. The presence of asbestos fibre in the lesions of asbestos workers. Tubercle, 10: 404, 1929. 26. Stewart, H. L., Butcher, C. L. and Coleman, E. H. Asbestosis, two cases. Arch. Path., 12: 909, 1931. 27. Wood, W. B. and Sloyne, S. R. Pulmonary asbestosis. Lancet, 2: 1383, 1934. 28. Lynch, K. M. Pulmonary asbestosis. J. A. M. A., 109: 1974, 1936. 29. Symposium on the treatment of chronic beryllium poisoning with ACTH and cortisone. Arch. Indust. Hyg., 3: 543, 1951. 30. Baldwin, E. DeF., Cournand, A. and Richards, D. W., Jr. Pulmonary insufficiency, l. Physiologi cal classification, clinical methods of analysis, standard values in normal subjects. Medicine, 27: 243, 1948. ' 31. Baldwin, D. DeF., Cournand, A. and Richards, D. W., Jr. Pulmonary insufficiency, n. A study of thirty-nine cases of pulmonary fibrosis. Medicine, 28: 1, 1949. 32. Baldwin, E. DeF., Cournand, A. and Richards, D. W., Jr. Pulmonary insufficiency, m. A study of 122 cases of chronic pulmonary emphysema. Medicine, 28: 201, 1949. 33. Austrian, R., McClement. J. H., Renzetti, A. D., Donald, K. W., Riley, R. L. and Cournand, A. Clinical and physiologic features of some types of pulmonary diseases with impairment of alveolar capillary diffusion. Am. J. Med., 11: 667, 1951. 34. Lynch, K. M. and Smith, W. A. Pulmonary asbestosis in. Carcinoma of lung in asbesto- silicosis. Am. J. Cancer, 24: 56, 1935. 35. Gloyne, S. R. Two cases of squamous carcinoma of the lung in asbestosis. Tubercle, 17: 5, 1935. 36. Gloyne, S. R. A case of oat cell carcinoma of lung occurring in asbestosis. Tubercle, 18: 100, 1936-37. 37. Egbert, D. S. and Geiger, A. J. Pulmonary asbes tosis and carcinoma. Report of a case with necropsy findings. Am. Rev. Tubeic., 34: 143, 1936. 38. Nordmann, M. Der Berufskrebs der Asbestosarbei- ter. Ztschr. /. Krebsforsch., 47: 288, 1938. 39. Lynch, K. M. and Smith, W. A. Pulmonary asbestosis. v. A report of bronchial carcinoma and epithelial metaplasia. Am. J. Cancer, 36: 567, 1939. 40. Koelsch, F. Lungenkrebs und Beruf. Zentralbl. f. Gewerbehyg., 27: 32, 1940. NOVEMBER, 1953 732 Asbestosis, Bronchogenic Carcinoma--Isselbacher et al. 41. Linzbach, A. J. and Wedler, H. W. Asbestos und Lungenkrebs. Arch. f. path. Anal., 307: 387, 1941. 42. Nordmann, M. and Sorce, A. Lungenkrebs durch Asbeststaub im Tierversuch. Ztschr. f. Krebsforsch., 51: 168, 1941. 43. Desmeules, R., Rousseau, L., Giroux, M. and Sirois, A. Amiantose et cancers pulmonaires. Laval mid., 6: 97, 1941. 44. Holleb, H. and Angrist, A. Bronchogenic carci noma with pulmonary asbestosis. Am. J. Path., 18: 123, 1942. 45. Wedler, H. W. Asbestos und Lungenkrebs. Deutsche med. Wchnschr., 69 : 575, 1943; abstracted in: Bull. Hyg., 19: 363, 1944. 46. Homburoer, F. Coincidence of primary carcinoma of lungs and pulmonary asbestosis. Analysis of literature and report of three cases. Am. J. Path., 19: 797, 1943. 47. Lynch, K. M. and Cannon, W. M. Asbestosis vi. Analysis of forty necropsied cases. Dis. Chest., 14: 874, 1948. 48. Hueper, W. C. Environmental and occupational cancer. Pub. Health Rep., Supp. 209, 1948. 49. Cureton, R. J. R. Squamous cell carcinoma occur ring in asbestosis of the lung. Brit. J. Cancer, 2: 249, 1948. 50. Smith, L. Pneumoconiosis and lung cancer. Compens. Med., 2: 3, 1949. 51. Owen, T. K. Carcinoma and asbestosis of the lung: Report of a case. Brit. J. Cancer, 5: 382, 1951. 52. Stoll, R., Bass, R. and Angrist, A. A. Asbestosis associated with bronchogenic carcinoma. Arch. Int. Med., 88: 831, 1951. 53. Hueper, W. C. Environmental lung cancer. Indust. Med., 20: 49, 1951. 54. Registrar-General. Statistical Review of England and Wales for the Year 1948. London, 1950. H. M. Stationery Office. 55. Report: Miners Phthisis Medical Bureau. Union of South Africa, Pretoria, 1936. 56. Klotz, M. O. Association of silicosis and carcinoma of lung. Am. J. Cancer, 35: 38, 1939. 57. Lindskoo, G. F. and Bloomer, W. D. Bronchogenic carcinoma. Cancer, 1: 234, 1948. 58. Wilus, R. A. Pathology of Tumors.. St. Louis, 1948. C. V. Mosby Co. 59. Lindskoo, G. F. Bronchogenic carcinoma. Ann. Surg., 124: 667, 1946. AMERICAN JOURNAL OF MEDICINE