Document K6LrK1NbNExjxG2kzL94DLaow

FILE NAME: Asbestos Cement Pipe and Sheet (ACPS) DATE: 1953 Nov DOC#: ACPS007 DOCUMENT DESCRIPTION: Published Journal Article Case Reports Asbestosis and Bronchogenic Carcinoma' Hrpurl o f One Autopsied Case and Review o f the Available Literature K r .- .v J . IsiF .i uA G iiF kj m .d ., H a n n a K l a u s , m .d . a n d H a r r ie t L . H a r d y , m .d . Boston, M assachusetts f--x--C tr re are several reasons for presenting curtains and clothing. The chief operations are I in c.r-iAil a case report and a review of the disintegration of the crude mineral, carding the A - available literature dealing with the fiber, separating the more useful long from the .'ntionship between occupational exposure to short fiber, spinning, plaiting and weaving the . - rstos ar.d respiratory tract malignancy. The asbestos, often with cotton. Insulating material _pp.:rent increase in bronchogenic carcinoma, is produced by mixing magnesia, diatomac.vous viai'y in males. reported in the past decade earth and other materials with asbestos to make ..:s 'vd ; :>scrutiny of respirable dusts as possible cements or fillings for insulating boilers, engines nol'-^y. Most English observers1-* are satisfied .and pipes. Other non-textile asbestos products tie. :v is a statistically significant increase so made include asbestos cement, sheets, brake tulin.-nary malignancy among asbestos and dutch linings, electrodes and switchboard rkt i'. Some American writers conside; that panels. t \pe: ience to date docs not support this Asbestos is a h\dialed magnesium silicate. . v.er.iio-,.1' The work of Graham,*' Doll and The chief supplies tire in Canada, Cape Province, --i.il.' ;tn:i Ochsnet <`,ir' has created much inteiest Italy, Rhodesia and Russia. Asbestos dust given .-. the cc'trelation of cigarette smoking with off in manufacturing piocesses consists of frag . nchoceoic carcinoma. E. R., whose case is ments of fibers and small rounded or angular . rein 'presented, was exposed to harmful particles. Actual studies in industry show the r.o.-.rus of asbestos dust and was a chain size and shape of the particles of asbestos to be -m.cxer. This provides speculation as to the such as may gain entrance into the bronchioles.11 .cssible role of two etiologic agents. Experience has led to the acceptance of five Few reported cases of lung cancer related to million particles of asbestos per'cubic fool of air, .ndi.ftrial asbestos exposures provide data on of small enough size to be respirable, to be the '-he character and quantity of dust exposure. safe working concentration. : is a serious deficit in exact stucb of etiologic Some operations because of their dustiness . `r:elation. In tbe clinical report piesented are more hazardous than others in asbestos -.-rein State authorities have determined by manufacturing. Bagging the asbestos, separating : easuremem that the asbestos dust expos.ire the long from the short fibers, carding, spinning '.'".is man during his twelve years of work was and weaving show a greater statistical evidence : .Ttsiderably above the safe level, which is con-- of asbestosis than do other operations. As might ~.::e:ed to be five million particles per cubic be expected, the longer tire duration of exposure ot air for an eight-hour working day. the greater the number of cases. In the Mere- It is pertinent to this presentatr. that there wether and Price scries there was one case under -re nrobablv about 10,(100 workers engaged in four years', exposure, and up to 53.6 per cent p.ceniially hazardous asbestos manufacturing with fifteen to nineteen years' exposure.1* .Derations in the United States.11 Middleton : -ports the number in Great Britain as between C\SE REPORT ' to 5.000.15 Most of the industry is engaged E. R. (MGH #735586),1Sa forty-one year old --- asbestos textile manufacturing producing r:;.daiir.g mattresses, brake linings, fire proof asbestos mill worker, entered the Massachusetts General Hospital in April, 1951. The chief ' From the D epartm ents of Medicine and Pathology, and tbe O ccupational Medical Clinic, M assachusctts General aspiial, Boston, M ass. This work was supported in part by the N ational Institutes of H ealth, Division of Research v : v u i s r . s , 193 721 / Asbrstosis. Bronchogenic Carcinom a-- Issclbacltcr cl ul. 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 caidiac dullness was 10 cm. to the T able i m .M O S A R V FUNCTION STL'DIEs * BEFORE AND AFTER ACTH f Bcfojc AC'III After ACTH Approxi mate N*ri mal Value*:' F ie. 1. X -ray of chest. T h e lower lohes arc reduced in size and show a " honeyointi" pattern. T im e is an in n ease in lineai and n o d u lar markings. A density is seen in the legion of the lingula with enlaigeinent of lym ph nodes in the left hm g loot, suggesting a tum or in that aiea. complaint was progressive low back pain which had been present for four months and was only partially' lclieved 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 tw'O years. There had been no hemoptysis. Physical examination revealed a chronically ill and dyspneic man with evidence of weight loss a n d cy an o sis o f th e lips a n d nail beds. The blood pressure was 110/75, pulse 96, respira Vital taprtiiiv (L.) ............................. Maximum Lrcaihim: <jp.it its (L / m i n . ) ............................................... Jif<it!ual volume ( L .) . . ................ r.flVctivr a h e c la r ventilation (!../min ). . . .... . . . . Alveolar p O : (turn H t ? ) .................. Ai u tu! pO f (mm H ? ) ......................... Artciia! p C O ; (inm Ht?).................... Ai irrial O? xaiuraiuu ( ' i ) ................. Kei uin p H .................................................. Alv t ola r- tru rial O ; ilrfu t nce (mm H ? ) ............................................ 2 4 52 5 1 575 7 63 ns o 88 0 36 0 97 3 7 45 27. 2.18 79 5 1 49 5 48 105 0 76.0 42.0 94 4 7 42 29. 3 9 105 1 30 5 02 105 107 95-97 40-43 95-97 7 39 10. * 'I hc'C Mudic' ' d i e pci* m a l bv Dt John Ailckit, Department of Ph\Kr!os>. Hot \ rod SJ mnl of Public Health f \ ( r i 11 1H0 h i ? imt nmu a tilarly for tenriavs J }ud\ yuibitr aio;* v\a< 1.62 in. left of the midsternal line in the fifth interspace; there were occasional extra systoles; P2 was greater than A; there was some pulsus para doxus. Liter 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 w;ts 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 loot suggesting a tumor in the rc'gion of the left lower lobe. Films of. the spine indicated areas of increased and decreased density in the fourth lumbar vertebra giv ing the appearance of metastatic malignancy. Electrocardiogram showed non-specific T wave changes. Non-protein nitrogen was 27 mg. per cent, CO: 29.4 mEq./L., alkaline phosphatase 4.9 Bodansky units. Repeated examinations of the sputum were negative for acid-fast organ isms, asbesiosis bodies and malignant cells. Two bronchoscopies revealed obstruction of the left lower lobe bronchus. The patient w'as given a trial of ACTH 100 mg. daily intramuscularly A M E R I C A N J O U R N A L OF M ED IC IN E Asbestosis, Bronchogenic Carcinoma--Iwclhachn cl nl. 723 ,,,] ten days. Clinically there was no change lNcept for euphoria. Pulmonary function and c;,rrHac catheterization studies were performed nefore and after ACTII and likewise showed no ,,unificant changes. (Tables r and 11.) Cardiac catheterization did reveal chronic cor pulmonale blood count was 0,500, hemoglobin 11.5 gin. 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, ghen mercurial diuretics, anti- * T able ji * CARDIAC CATHETERIZATION STUDIES* BETRE AND AFTER ACTH f O, C o n sum ption (cc./m in./ sq. m.) O, Capacity K aclial Arteryfee./1 00 cc.) O, Content Radial Artery (cc./100 cc.) O; Satura tion Radial Avterv (7c)' I i Mean Puhnonarv ,, , , A* iutv ' Pu,lm onary7 vr>ie sm r*c ,,Arten*7 (min. Hg) . (nIunnj.ufrieg) C aid iac Index (L ./m in./ sq. m.) Nppioxirnatc norm al values31'........... 145 B> fore (R e s t................ 180 A CTH M ild exercise (2 m in .).. 370 After R e st................ 156 A C T H NXlid exercise (2 m in .). . 349 20.0 19.3 17.4 19.0 96 30/10 15 18.1 94 36/14 21 43/14 28 16.6 93 38/15 23 52/22 36 3.2 4.47 5.55 4 02 6 97 * T hese studies were perform ed by tlie C ardiac C atheterization U nit of die M assachusetts Gene-ini Hospitalincluding Drs. G. S. M yers. A. l,, Friedlich, .1. R. O 'Neill, G. Cohen and J G. Sc.mnell. f A C 'l H 100 mg. intram usculai ly 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 rescaled a temperature of 100.4cr. 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 wlieczcs 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 midstcrnal 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 SOVF.M BEH, 19 5 3 biotics (penicillin and streptomycin), and was in an oxy gen 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 -fuui ih 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 die 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 loculnted in the left base. The interlobar fissures were obliterated by fibrous tissue. Scattered throughout the adherent laycts 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 Asbestos's, Bronchogenic Carcinom a- Issrlbacha cl al. Fic. 2. Cut suifacc of left lung after foirualin fixation. N ote dilTusc pulm onary fibrosis and m arked 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 front this point i . the bronchus to the pleura and into the wall of .he left atrium which was adherent to the pleura al this point; the gross atrial in volvement measured 2.3 by 0.7 cm. in extent. The upper lobe bronchi were ri-dd and nar rowed by a thick, white fibrou'- The right lower and to some extent the 1 . middle and left lower lobe bronchi were dii. d, and there was collapse of the intervening parencln ma. 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 In 0.7 cm. The remaining ni)ocardium appeared uninvolvcd and measured 0.6 cm. thick in the right ventricle, 1.3 cm. in the left. The endocardium and \alvcs were negatis e. 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 \crtcbra appeared opalescent and resembled marble, but its con sistency was softer than the adjacent vertebrae. The body appeared to have increased porosity. A M K K IC A N J O U R N A L OF M C D l C l X t Asbcstoris, Bronchogenic Carcinom a-- Isselbacher et al. I 2:) 4 5 F ic. 4. Squam ous m etaplasia in the alveolar ducts; note also asbestosis bodies and inteistiti.il librons; X 100. F ig. 5. A denocarcinom a invading the. m yocardium ; X 100. 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/i 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, 1 9 5 3 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, mid lobar 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 marro ' phages but occasional iron-staining particles were found free on the alveolar walls. Much, but by no means all, of tins 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- 4.52 4.20 2.55 2.98 2.67 Table of " D' 2.42 2.38 2.115 1.84 1.70 lines: 1 .61 1.531 1.49 1.44 1.38 * A 68.5 gm. sam ple of form alized lung tissue was digested in 20 volumes hydrogen p n oxide, the digestion being accelerated with gentle heating. T h e residue fiom the digestion was treated with dilute hydiochloric acid, filtered, w ashed and ignited at 500f. T he ignited residue was analyzed by x-ray diffraction by the m ethod described in the article by H anaw alt, J. D ., R inn, H . W ., Ficvel, L. K ., " C hem ical analysis by x-ray diffraction," Indus!. & Eng Chem., Anal. Ed., vol. 10, no. 9, 193S. This w otk was done by R. I. C ham berlin and A. W oew uefi, Jr. of the Massachusetts Bonding and Insurance Com pany, Boston, Mass. tained brown pigment granules many of which took an iron stain, and portions of ashestosis bodies wore 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 ashestosis body.) Anthracotic pigment was also present in the macro phages. Multinuclcatcd giant cells of the foreign body type were found in abundance in all areas; many of these contained birefringent astcroidal 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 ashestosis 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. Bionchi: 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 mid zonal regions of ah; ust all segments. Another striking feature was widespread squamous metaplasia of the bronchial epithelium. (Fig. 4.) This w'as most marked in the alveolar ducts; it was found in all areas and was not p a r tic u la r ly related topographically to the adenocarcinoma described latcT. Blood vessels: The arteries and arterioles of the right middle and both lower lobes sSiowcd moderate intimal thickening with hyalinization and narrowed luminn. 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 "gianulomas": The white plaques described in the diaphragm and Glisson's cap sule were made up chiefly of hyalinized con nective tissue. No ashestosis bodies or giant cells were seen. These distinctive areas grossly suggested granulomas. X-ray diffraction studies were cairied out on a sample of formalized lung tissue. The resulting pattern indicated that the lung residue was mostly asbestos. (Fig. 6.) COMMENTS Ashestosis may he 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 Gardner50 and again by A M r. K I C A N J O U R N A L O !' M IJ I C 1 N K Asbcstosis, Bronchogenic Carcinoma- -Isselhacha cl al. TV Vorwald1'* that usually the disease will not In general there is a delay of five to sc\cn occur with fibers less than 20ft in length or a years between the initial exposure to high con concentration below five million particles per. centrations of asbestos dusts and the onset of cubic foot of air. . clinical asbcstosis. The average interval re The pathologic processes resulting from the ported by Mcrewethcr is eleven years.17 While inhalation of .-asbestos particles arc believed most patients with asbcstosis have had an 10 be due not to their chemical nature but, exposure of ten to sixteen years, it is important nithcr, the consequence of mechanical irritation to realize that the disease has occurred with as fmin fibers lodged in the respiratory trcc.,s~2ft short an industrial exposure as 0.5 years.1,2 The inhaled particles are, in general, too large Usually no symptoms appear until a large io pass beyond the respiratory bronchioles and part of the respiratory reserve has been reduced mi they remain there to initiate a foreign body by the fibrosis. Mcrewethcr has frequently com reaction which eventually leads to fibrosis.21 mented how markedly the lungs can be affected J'he pathologic sequence of events can be and \ct the patient be fairly comfortable.17 considered as occurring in three stages: (1) However, when symptoms once begin and desquamation and exudation, (2) formation significant dyspnea becomes apparent, there is of asbcstosis bodies and (3) fibrosis and scarring. usually a definite and rapid progression. Then The long fibers traumatize the epithelial cells productive cough, anorexia, weight loss and lining the smaller bronchioles and the constant fatigue arc the common complaints. Death irritation and friction cause the cells to desqua eventually results from intcrcurrcnt infection, mate. Macrophages pour forth in an effort to cor pulmonale or carcinoma of the lung. phagocytizc the fibers. In our case fragmented The case herein presented demonstrates many asbcstosis bodies were also seen within macro of the significant features in the pathogenesis, phages arid lymphatics. A second reaction to the symptomatology and natural course of asbcstosis. asbestos fiber in the lung is the production of the The patient had worked for twelve years in an so-called " asbcstosis body." 22- 24 This results atmosphere having a concentration of asbosto' from a reaction occurring between the asbestos particles known to be sufficient to pioduce particle and surrounding tissues. It is a thicken pulmonary pathology. However, it was only ing of the fiber due to the deposition along its during the last year of life that dyspnea, cough, course of a protein matrix containing iron anorexia and weight loss manifested themselves. which probably serves to reduce the chronic Clubbing had been present for at least five irritation.5* These bodies may be found in the years. lie had a very rapid dow nhill com sc, elite sputum, lung, pleura, lymph nodes and spleen.25 undoubtedly to the two associated factors--the. Their presence is held to be evidence of exposure asbcstosis and carcinoma of the lung. The to asbestos but by themselves are not necessarily physical findings of clubbing, cyanosis and an indication of asbcstosis.n,27,2S dullness at the lung bases were all consistent The third and most significant tissue response with asbcstosis as were the x-ray findings in the is the production of fibroblasts and the deposi lu :s, apart from the evidence .suggesting neo tion of collagen about the distal bronchioles plasm. The outstanding s; upturn, the severe and alveoli. There ensues a diffuse fibrosis which and progressive dyspnea, was attributed to a compresses the alveoli and capillaries, resulting combination of pulmonary fibrosis, superim- in complete obliteration of the involved pulmo ' posed and spreading lung neoplasm, pulmonary nary tissue. This process is more pronounced in infection and finally congestive failutc on the the lower lobes of the lung for it is there that the basis of cor pulmonale.. particles are most abundant. By x-ray one sees As indicated in the ease history, the ten-day a fine, ground glass or granular pattern in the period of ACTH therapy was accompanied only lower lobes and frequently emphysema in the by euphoria but objective measurements re tipper lobes. vealed no significant changes. This was not The sequence of pathologic events described surprising for two reasons: (1) the fibrosis had previously occurs slowly. In man the fibrosis obviously been of long duration and therefore tends to progress even after the exposure has one would not expect it to change much at this ceased; however in animals this does not seem time; and (2) he had superimposed broncho to be the ease. It may he that intcrcurrcnt infec genic carcinoma. It is of interest to compare tion contributes to the progression in man.11 these results to patients with c h ro n ic beryllium n o v k m n i: r , 19 5 3 7-28 Abbc.stOis. Bronchotrcnic Carcinoma---Jssclhacher et al. poisoning who usually show a favorable rc(spouse to steroid therapy.5' . Two further aspects of this case merit more detailed consideration 2 nd analysis: (1) the pulmonary function and cardiac catheterization studies; and (2) the significance of the superim posed bronchogenic carcinoma. . P U L M O N A R Y FU N C T IO N .AND C A R D IA C c i a t i Te t e r i z vriox s t u d i e s 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 oxygon from the alveoli of the lungs to the capillaries. This corresponds to the syndrome of " alveolar-capillary block" de scribed by Baldwin, Cournand and Richards31,32 and again by Austrian ct al.33 This diffusion defect is not stirpiising when one recalls the fibrosis about the alveoli, alveolar ducts, capil laries and bronchioles trial occurs in asbestosis. In order for the patient to maintain a near normal arterial ox\gen 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 company Uory mechanism apparently was not adecpiatc during stress or exercise for under those conditions the arteria.1 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 n.) 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 pCO; would probably have been higher. As Arnot emphasized in discussing this ease10 carbon dioxide is not impaired in its transfer from the blood to tire alveoli because of its great diffusion capacity. This speed of diffusion plus the increased alveolar ventilation no doubt accounted for the lowered pCCh value. ASBESTOSIS AND CARCINOMA OF 1 HE LUNG The association of asbestosis and carcinoma of the lung has been mentioned frequently in the literature.1' 3'34" 53 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, c.xccpt those containing recognized carci nogenic substances (as radium and tar) cannot in general be considered as tiologie factors in the development of primary pulmonary carci- T aiux. hi INCIDENCE. OF ASBF.S/l OMS AND CARCINOMA OF LUNG A uthor 1 ! Xo. of j D eaths with j .Vbestoiis 1 i M erew ether1......... 235 W cdlcr44................ .' 92 W yers*................... ! 115 Lynch, C a n n o n 41. .1 40 G lo )n e 3................. i 121 T o ta l...................... . ! 603 No. Due to C anter of Lung 31 15 17 3 17 83 Incidcncc (7c) 13 2 16.3 14 8 7.5 14 1 13 8 noma." 4 Our conclusion at present is in favor of the concept ihat 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 ill. Merewether has cited the largest scries --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.9,47,54 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 Africa55 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). Klotz56 noted an incidence of 8 per cent, but his series of fifty cases docs not seem large enough to be statistically significant. However Gloyne3 in reviewing necropsy material from 1929 to 1949 (796 eases) also described the surprisingly high incidence of lung carcinoma in silicosis of 6.9 per cent, and 7.7 per cent in A M E R I C A N J O U R N A L OF M ED ICIN E .1 Asbcslosis, Bronchogenic Carcinoma--Issclbachcr cl al. 729 the pneumoconioses as a -whole. In this same scries 8.3 per cent of cases without any pneumo coniosis had cancer of the lung. Merewether and Gloync's eases 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.sThc discrepancy in the data proba bly is explained by the fact that Gloync'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.ls,:o Carcinoma of the lung appears to be promi nent in females with asbestosis. Of Mcrcwcthcr's thirty-one eases nine were females, or 29 per cent, and in Gloync's series of seventeen cases the incidence was 41 per cent. In the published autopsy reports data as to the sex of the patient arc 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,57 Graham7 5.4 per cent, Doll and Hill6 8.4 per cent and Ochsncr10 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.55 A "lag period" between the exposure to a possible carcinogen and the onset of malignancy is characteristic. Nordmann*5noted in his cases that the average duration between the initial exposure to asbestos and the development of bronchogenic carcinoma was about eighteen years. Similarly Merewether' 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 Mcrcwcthcr's scries is the ease of a woman who was an asbestos worker for only six months yet later developed lung carcinoma. Gloyne'5 reported the ease 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 eases 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 Homburg.r46 in 1943. It is noted that in about fourfifths of the eases 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's5* series there was an incidence of 57 per cent in the upper lobes, 26 per cent in the lower lobes. Ochsncr10 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 eases listed in Table iv. Nevertheless, since asbestos particles lodge to a greater extent in the low'cr respiratory tree where the changes of asbestosis arc also more pronounced, a higher incidence of carcinoma in this location should be expected if an ctiologic relationship exists. In our case the asbestosis was widespread and severe, and the tumor, which originated in the inferior (lingua!) 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 die nineteen previously recorded eases 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 Wyndcr and Graham7 that males with adenocarcinoma of the lung arc NOVtMIiKR, 1 9 5 3 730 Asbestosis, Bronchogenic C arcinom a hsdbar.her el al. frequently chain smokers. However, it is our belie! that the presence of an adenocarcinoma r at h er t han one of the s qu a mo u s cell type may. he explained by the fact t hat it is not unusual to find several cellular types in various sections o! the same t u m o r . 3- 'J herefore' morphologic ca rc inoma in 13.S ter cent of the eases r iled in the literature. In silicosis the incidence is c on siderably less t han this. T h e asbestos particle may serve as. a carcinogen because of the chronic mechanical irritation it produces. 5. Since there arc ap p r ox i ma te ly 10,(100 " T a k i.e iv SySlMAKY o r J'UBI.ISHKD CASE RETORTS l.\ WHICH At/TOCSV DATA ARE CITED ;i ttd Atftr Oi cupatron Dm ation of INposiue (>r.) . S m i t h ' 1.........................i Cl(>\ lie'*"1. . . (Iloyuc . . . . hg ltcri, Cc\- Cioync:t. . . N o r d t u m m 1' ............. X.udmaun . ............. I.-. iu-fi,-vl St: ............. 1933 ' M. I Wt-av 1935 1935 1936 1936 193R 19 K 19 39 F, 35 , F , 71 M .41 . M , 59 . F. M. M, Spinner M ouiyss ;md open ; iny departm ents W eaver . P a c k e r . >;orc.s d r - i partrtirni , Candor, spinner, weaver P: e-pi on ing ; assembly room 8 Ua 17 lO.'.-i 7 7 13 ............. ! ' M ! M . 25 ............. cli, W e d l e i W .............. Ii ;11c> ci a lri R . ............. <') ole.-, ci a J ___ ............. J K m i h u i v y*i )i'inbiir II oinhurv ............. ............. ............. ^ 194 > H'4; 194 1 194 2 194 2 1942 M. M. M . 5" Ma>Iit; aditisior M. M . 4 5 Xtv. kn o w n M. 43 Xo. 1iiuwrt i , 49 No - era n i oritaet writ .-ixbestos 25 > 3 5 20 Free- ,!jrn from Fx'yisure l/cfoic Ib.lltl N a t ;i i r o f I t m m r T r i m a , y Stic ------ ------- RE... 9 yr. 15 vr. i S q u . n o o n s <ell j S<11. nitons cell KARR. R.I..F. : mo. 9 yr. ( l.ifidu la r O ut toil ; S q u .im o m cell R.R.R. 12 sr. ; S'.p::: rn on*- cell ' Sot'.ltllM'jS \ I glandular j features Xon-le ratio | iny Mjtiomous K . !.. L. k.r.L . \ R I. F. 1 :no 4 mo. 1 \t. 17 n.o. ' S^ju.trmni- i ell : A b e* cell [S^u. :dl ' Squamous cell 1 (rll ' A napi.'j'U it K.I. !.. I. 11; u `4 R Rm y R. lune; K . limy y:. : Sqtt.i mon*' ( rll R.R.R. On S u d J , iK,>s, A n g r i i l 4" Pi t.seiii .ruti.ms . . . . 105 M. 1951 M . .Asbestos v.ojkcr Pipe c o v u n >S mil! i ; s o iicr !Aboo y i . Adenuc.ti einoinu R. Iuni; 6 > u* 5 yr. j A n a p l a s t i c No definite site 12 r. AcU n o c a t e t n o m a F i11y 111a MdmU.asrs - --------M :,, K 1. !.. Pleur.i \unr Wit l.-spi c .nl R A M . . ; ul pltuti RK or, kit ne>s W nlrsptead Pleura, medi- Merit tsti ,.ri ,-rs!, ad ; cmi! k i d n C) W it 1t -p: c ad. None Fit-ura >i.tpl;t . ni l.ivei, ad emtl, stom ach. hilar !\ m pii i odes kh'nev, ov.u icy fen iUr Nunc Kidness. Main. liver M i oc.ird :tm, pc eaitiiun , spin;:, t. m ,<!<.. diflerenccs m cell a r r a n g e m e n t s ma y not really represent different etiolocdc varieties of cancer. ' SUMMARY AND ("ONCi.l'SlONS 1. A case of asbestosis with superimposed adenocarcinoma of the lung with niftastascs, billowing d o cu m e n te d It armful industrial ex posure. is presented. 2. A C T H ( a d re n oc o ni co t r o ph i c hor mone) teas given with no objective changes in the patient's clinical course. 3. Pul monar y function a nd cardiac c at he t er ization studies were performed before and after AC I'l l. T h e y res caled an alveolar diffusion defect and pulmonary hypertension. 4. Asbestos is associated with bronchogenic workers engaged in potentially hazardous asbestos operations in tins eountrv, it is . c a e m afile to assume that there are ma ny um.-cegnized cast's of asbestosis. From the evidence presented a higher incidence of bronchogenic cart inoma should lie expected in this group. Aridcnuum: Since the submission of litis m a n u script a similar case has been observed by us (M G H =778205). T h e patient was a forty-six year old contractor's helper whose work since age seventeen consisted of rutting and sawing asbestos board to insulate pipes, boilers and refrigerators. For years be had smoked one package of cigarettes daily. He died after a year of illness during the last four months of which be received a,000 r of deep x-ray to t he lef; chest. AsbestosiSj Bronchogenic C arcin o m a....Issclbachrr et al. yyi At autopsy the lungs were firm a nd weighed A350 gm. T h e r e was a poorly differentiated ad en oc ar ci no ma arising from the left lower lobe bronchus, almost completely r e p l a c i n g 'the left lower lobe. T h e t u m o r h a d spread to the left upper Jobe, hilum, pericardium, pleura and diaphragm; and had metastasized to the right Jung and ^adrenal. T h e remaining lung tissue showed pe ri bronchi al fibrosis, focal alveolar wall thickening and numerous nsbestosis bodies, sur rounded by macrophages filled with asbestosis body particles a nd foreign bod)' giant cells. T h e asbestosis bodies were seen in equal distribution in all parts of the lungs not completely involved by tumor. RKVHRCNCKS b M e r e w e t u e r , F,. R. A. 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