Document KG3JdOKQDYRaGakYqDqqXwL1x

FILE NAME: Kent (KNT) DATE: 1953 Nov DOC#: KNT128 DOCUMENT DESCRIPTION: Journal Article - Case Reports: Asbestosis and Bronchogenic Carcinoma - American Journal of Medicine Case Reports Asbestosis and Bronchoogenic C arcinom a' /;/ A/ o f One Autopsied Case and Review o f the Available Literature J . I sski i j achf.k , m .d ., H a n n a K i .a u s , m .d . and H a r r i k t L . H a r d y , m .d . Boston, Massachusetts f~ \ --O i a re several reasons for presenting I in c r ia i! a case, report and a review of the _A_ av A.iable liter,ituic dealing with the :Aoi-.oshr betw een oempaiiunal exposure to - -.>:<.>> reel respit atory tract malignancy. T he am.wen: increase in bronchogenic carcinoma, c o r i a i i e in males, reported in the. pas! decade !-.*d i scrutins- of respirable dusts as possible v v . M ost English observers' "* are satisfied :: c: tie. : is a statistically significant increase t-ul; t. m ary m alignancy among asbestos curtains and clothing. The chief operations are disintegration of the crude mineral, carding tine fiber, separating tine more useful long from the short fiber, spinning, plaiting and weaving the asbestos, often with cotton. Insulating material is produced by mixing magnesia, diatom.aceous earth and other materials with .asbestos to make cements or fillings for insulating boilers, engines and pipes. Other non-textile asbestos products so made include asbestos cement, sheets, brake and dutch linings, electrodes and switchboard Mo t s . Some' A m erican writers consider that panels. i \ p : ienc;' to date does not support this : t e r . i t 5 ' I he work of G r a h a m ,f`i' Doll and : H : . ' ar 5 O o h s n e H '10 has created m uch interest the correlation of cigarette smoking with . r.cltcconic c a rcinom a. E. R., whose case is . rein tresentech was exposed to harmful r.o tn o of asbestos dust and was a chain -an:war. f inis prosifies spculaiion as to the t'.ssi'ile role of two tiologie agents. l ew renorted cases of lime cancer related to asbestos exposures pro\ ide data on t ::c c h a ra c te r and quantity of dust exposure. ; Ms is a serious deficit in exact studs of tiologie : ciM anon. In the clinical report presented -.-rein Stale authorities have determined bv . easiirem em that tire asbestos dust exposure : A.is m a n d u rin g bis twelve Years of work was : ciskhAVihly above the safe level, which is con-' Asbestos is a hydrated magnesium silicate. The chief supplies arc in Canada, Cape Province, h a lf, Rhodesia and Russia. Asbestos dust given off in manufacturing processes consists of frag ments of fillers and small rounded or angular particles. Actual studies in industry show the size and shape of the particles of asbestos to be such as max' gain entrance into the bronchioles.11 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 safe working eoneemration. Some operations because of their dustiness are more hazardous than others in asbestos manufacturing. Bagging the. asbestos, separating the. long from the short fibers, carding, spinning and weav ing show a greater statistical evidence of asbestosis than do other operations. As might A cred to lie five million particles per cubic : ol a ir for an e ight-hour working flay. It :s pertinent to this presentati-; that there ..re p r o b a b ly a b o u t 10.000 worker.-, engaged in .ce miially hazardous asbestos manufacturing : ra tio n s in tine U nited States.11 Middleton - - ports the nu m b er in Great Britain as between r . ' hi 5 . 0 0 0 . M ost of the industry is engaged or asbevios textile manufacturing producing ns.tax in g mattresses, brake linings, fire proof lie expeded, the longer the duration of exposure the greater the num ber of cases. In the Mvrcwether 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 CASE R E PO R T E. R. (M G H #735586),16 a forty-one year old asbestos mill worker, entered the Massachusetts General Hospital in April, 1951. The chief F i o r a t h e F). p a r t m e n t s o f M e d i c i n e a n d P a t h o l o g y , a n d t h e O c c u p a t i o n a l M e d i c a l Clin ic, M a s s a c h u s e t t s G e n e r a l : r p : o l . F e s t o n , "Mass. T h i s w ork v s s u p p o r te d in p a r t b y t h e N a t i o n a l Institu tes of H e a l t h , D ivision of R e se a r c h : v i v. {.k , 19 5 3 72T Asbcstosis, Bronchogvnic Carcinoma I.ssdbachcr d al. tions 30, and tem perature 99r. orally, His e.liest was thin and showed poor expansion. There were dullness and reduced breath sounds at both lung bases with stick) inspirator) crackling rales over the region of the left lower lobe. The 1 left border of cardiac dullness was 10 cm. to the j J ABLE I i P CI M ON A K Y H ' X C I I O N s r c n i l . s * B E F O R E AXIS A S T E R A C T I l f Kcfoi c AC n i After ACTH Approvt- mate Nru ni.il Values}*' ! C.:,- J ig . 1. X - r a y o f ches t. T h e lo w e r lobes a r c r e d u c e d in size a n d sh o w a " h o n e y r . o m l r ' p a t l r m . T h e r e is a n in crease in l i n e a r a n d n o d u l a r m a r k i n g s . A density is M e.n in t h e rci on u f t h e l i n g u l a w i t h e n l a r g e m e n t of lym ph nodes in the left hm g tool, suggesting a tum or in that area. complaint was progressive low back pain which had been pretent 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, feverish ness and a 10-pound weight loss. H e 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 i till 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 lr. authorities to be considerably above the safe level. H e 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 lie 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 dyspn<*ic m a n w ith evidence of weight loss and cyanosis of the lips and nail beds. T he blood pressure was 110/75, pulse 96, respira- Vi Alt I tp,;<in (I- . ) ........ M.ni:: jtn bu ad im: t up it*ilS' (i-./ Vn.) . RrxMu ':! \u!l|lllC ( i - > . .. r.fTrcm *abet Ia1 sernila ion ('./ Ah ml: r pO. (111 11. H e ) . Anen.i 1 pO: fimn lie) . ArtciD , , c o . (mm HtO Ai ttrLi O: v.i tn 11Oil (' ) ................. Set uiTi p H . . . Ahr.,I. r-.'ttici O: <1ifie ellCf fmm Hr). 24 32 3 1 575 7 63 115 0 88 0 36 0 97 3 7 43 27 2 18 79 5 1 49 5 48 H)5 0 76 0 42 0 94 4 7 42 29 3.9 103 1.30 5.02 105 107 95 97 40-43 95-97 7.39 10. 15 '1 h c -r ct ti'! if> u t i (- po: b : met I b v D r . .folin A Held t, I.K p art m en t o f Pmslolo-v. J !:jt \ a id -Vlwol of Public Health, j A C J H I ' D nt'g. in n .U71H u iil.n ]y fo r leu d a\i.. XIV.th nitbue ;iir;i sv.;x1.62 Mj. m. left of the midstema! line in the fifth interspace; there were occasional extra systoles; P 2 was greater than Ag 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 rescaled 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, C 0 2 29.4 m E q./L ., alkaline phosphatase 4.9 Bodansky units. Repealed examinations of the sputum were negative for acid-fast organ isms, asbestosis bodies and m alignant cells. T w o bronchoscopies revealed obstruction of the left lower lobe bronchus. The. patient was given a trial of A C T H 100 mg. daily intramuscularly AMERICAN JOURNAL OF MEDICI NE sbi'stusis, Bronchogenic Carcinoma Jsulhachcr cl al. 723 len days. (.'.linically there was no change for euphoria. Pulmonary function and tut reIinc catheterization studies were performed i f f o r r a n d after AC'.TH and likewise showed no significant changes. (Tables t .and it.) Cardiac catheterization did reveal chronic cor pulmonale blood count was 6,300, hemoglobin 11.5 gm. per cent. It was believed that the patient had pneu monitis in the right lower lobe and earl)* cor pulmonale with congestive failure. He was digitalized, given mercurial diuretics, anti- T able n C A R D IA C C A T H K l L L IZ A T IO X S TU D IE S* U LTO RE A M A LTER ACUTI f i " o,. Cai p a r i t y O. Content (cc./m in./ fq. in.) Radial Radial ! Artery Artery ! (er./100 cc.) ! (rc./100 cr.) Co .Satura tion Radial Artery (hi)' kwlinonary A tery IT e.sujre (min. Hg) Mean Pulmonary Artery Pressure, (nun. Hg) Cardiac Index (I../m in./ sq. m.) Approximate noiana.l v a l u e s 30 145 R fore R e s t ...................( 180 A G T H ! M ild exercise ' I (2 m in .). . I 370 After f R e s t ...................j 156 A G T H I M ild exercise ; l (2 m in .). . 349 20.0 19.3 17.4 19.0 18.1 16.6 96 30/10 15 94 36/14 21 43/14 28 95 38/15 23 52/22 36 3.2 4.47 5.55 4.02 6.97 * T h e se studie; u ri c perfni ined by tin: C a rd iac C a th e te rizatio n U n it o f the M assachusetts i n c l u d i n g R rs. G . S. M y e r c A. 1>. lTR clich, T R . O . N e i i l , G. C o h e n a w l .1. G . S c h n w l l . t A G T H 100 mg. intiv.niusoilarly for ten days. General Hospital, with slight pulm onary hypertension; after biotic.s (penicillin and streptomycin), and was exercise the pulmonary hypertension increased in an oxygen tent most of the time. Chest x-rays ~s and significant arterial oxygen unsaturation now were suggestive of lymphatic spread of appeared. tumor. In spite of all therapeutic measures fever, Before: discharge from the hospital he received dyspnea and evanosis grew worse. H e became radiation (1,200 r) to the lum bar spine with no confused and died on the thirty-fourth hospital relief of the back pain. day. For several weeks after discharge the patient At necropsy the patient was emaciated; the seemed somewhat better and returned to light thorax was lengthened in the anteroposterior work, llowcvei, lhe cough increased markedly diameter. T here was clubbing of the fingers and and he had sex ere dyspnea at rest so that after toes. two months he had to be readmitted. Physical On opening the thorax the lungs did not examination on re-entry revealed a temperature collapse but remained inflated, complete])' of 100.4T. rect.illy, pulse of 120-144, respirations filling both pleural cavities. The majority of 30 per minute. He h ad marked tachypnea, the pleural space was obliterated bilaterally by m o d e ra te cyanosis and such dyspnea that it was dense fibrous adhesions between the visceral very difficult for him to speak. T here were many and parietal layers. Both the visceral and inspiratory and expiratory wheezes throughout parietal pleurae were markedly thickened, gray the lung fields. At the right base there were moist fibrous m em branes measuring up to 0.3 cm. bubbling rales together with dullness, reduced thick. T here were 100 cc. of clear straw-c.olorcd tactile fremitus and increased vocal fremitus, fluid loculated in the left base. T h e interlobar d'he left bo rd e r of ca rd ia c dullness now' extended fissures were obliterated by fibrous tissue. out 12 cm. from the midsternal line. P 2 was Scattered throughout the adherent layers of the m uch louder than A 2. T h e liver was percussed dia phra gm a tic pleura, especially on the right, down two and a half fingcrbrc.ndths and there were a number of whitish gray, shins plaques was 2 plus ankle edema. At this time the white 0.5 cm. long; these resembled similar plaques N O V r. M B k k , 1 9 5 3 ! - '< ;i/ J i 7-4 Asbr.stosis,/ Brow h oO-cn ic C arcin o m a Jssrlhac.hn cl al. I i1> 1 1I i ii F ig. 2. C u t surface of left lung nficr fuiiAaFn fixation. N ote difi use p u l m o n a r y fibrosis a n d m a r la.*cl p le u r a l thickening winch abliterates the interlobar fissure. seen on the tipper 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 lefi lower lobe where there appeared to be a diflusc marked fibrosis throughout the parenchym a. T he left lower lobe bronchus was completely occluded 1 era. 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 i the bronchus to the pleura and into tlw wall of die 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. T h e u ppe r lobe bronchi were n- ;,! and n a r rowed by a thick, white fibroin v. The right lower and to some extent the i middle and left lo n e r lobe bronchi were dir ..d, and there F io . 3. Asl.n-stosis b r>:!u's in tlie Inn!;. T h e c l u b s h a p e d , b e a d e d a s b e sto s's bodies a i e sciai in the. a l \ c o l a r d u c ts , s u r r o u n d e d b y imicroj>ti;igrs a n d " d u s t cells'1; X 900. w its collapse of the intervening p a r e n c h im a . 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. T h e remaining myo cardium appeared uninvolved and measured 0.6 cm. thick in the right ventricle, 1.3 cm. in the left. T h e endocardium and valves were negative. J he 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. T h e rem aining 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 bod)' appeared to have increased porosity. A M 1. k 1 (I A N J O U K N A 1. O F M U I I C I N K Cm i kC vS .' , l 7>b VTi t 2 tx,-. tyo.] r. ? -..---pi BAB FA s'.-':- LAA "` f rrx-v'*; fr'7. f-V ;. l ie. l The 1 soctionp near th 1 crnl art, be seen > Fibres prolifci'ithe artq and p))' peribro ' apices, . demons ' fibrosis j the hingl areas b > firmed ' A sites t in all s* : fibers 41 some cl ` which s:l prepara/r prepnra, 1 larger, K O V 1; M I ` Asbestosis,> BronchogOenic C a rc in o m a Isselbochcr d al. 7 2 5 ' iV -p T ,-V' *c : / W' t -, .V , , . o ,.'j ' A s . - v O : " - ., T * -It ..'. ^ A g ir ; : W e C f '` A -'; ; . v A .-/'O-i-; ; O--' Tbe - /P * -W--, -: m ~x; a W iV '- v x m a x : : c - v ; X b A x W X m x g s A X x a m X > e ,w m --'r -,-r: C v w v a v x mw-W . V . : , - v . b A :Z A X ? x ^ C S v s . c W T e v : - ' --v - ' * 4 5 F ig . 4. S q u a m o u s m e t a p l a s i a in t h e a l v e o l a r d u c t s ; n o t e also asbestosis b o d ies a n d in terstitial ib?'Osis; X 100. F ig . 5. A d e n o c a r c i n o m a i n v a d i n g th e m y o c a r d i u m ; X too. The line's 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: T h ro u g h o u t the lungs there was proliferation of fibrous tissue around the bronchi, the arteries, alveolar duels; the interlobar septa and pleurae were also thickened. There was peribronchial and alveolar duel fibrosis in both apices, and slight alveolar wall thickening as demonstrated by connective tissue stains. T he fibrosis increased in the remaining portions of the lungs, teas heaviest in the hilar and mid-lobar areas but extended to the periphery. This con firmed the gross impression of diffuse fibrosis. Asbestosis bodies: Asbeslosis bodies were present in ;dl seciions. (Fig. 3.) These were segmented fibers averaging 50/r long, some, straight and some club-shaped, others resembled dum b bells which stained lark brown on hcmatoxylin-cosin preparations, and blue on Prussian blue (iron) preparations. Particles of iron-staining dust and larger, easily identifiable asbestosis body parti- KOVEMW.R, 19 5 3 des, were present in the macrophages. The distribution was equal bilaterally, lacing slight to moderate in tire 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. Scierai aggregations of asbestosis bodies were found in the bronchi. Fragmented asbestos fibers were found mostly in the m acro phages but occasional iron-staining particles were found free on the alveolar walls. M uch, but by no means all, of this material in the macrophages took the iron stain. Inflammatory response: T h e chief inflam m atory cells responding to the irritant were the m acro phages. These cells were seen in abundance in every section; they lined up along the walls of the alveolar ducts, filled the lumina of b ro n chioles and alveoli, and were found throughout the septa and fibrous tissue. Most of these con- // ) /26 Asbestosis, Bronchogenic Carcinoma Isschacher d al. l 'i o . 6. X - i a v diiTrartio n film o f l u n " re sid u e o f 1:'.. K . * T lic linci listed w h e n c o m p a r e d to t h e k n o w n p a t t e r n for asbestos tpvc positive p: o o f t h a t t h e l u n g re s id u e is es sentially asbestos. 4.52 4.20 3.35 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 . : ample of formalized lung tissue was digested in 20 volumes hydrogen peroxide, the digestion being accelerated with gentle healing. T h e residue fiom the digestion was treated with dilute hydrochloric acid, filtered, w a s h e d a n d ign ited at 500f. T h e i g n ite d re s id u e was a n a l y z e d by x -ra y d iffra c tio n by th e m e t h o d d e s r r i b e d in the a r t i c l e b y H a n a u alt, .1. D . , R i n n , H . \V ., F re v el, L . K . , " C h e m i c a l analysis b y x -ray d i f f r a c t i o n , " hulusi. & Brig. Claim., Anal. E 'l . y vol. 10, no. 9, 1933. T h i s w o r k w as clone b y R . 1. C h a m b e r l i n a n d A . W o r w n c k i , J r . o f th e M a s s a c h u s e t t s Bonding and Insurance Company, Boston, Mass. tamed brown pigment granules m ain' 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 arc thought to Jay down the iron on the asbestos fiber, constituting the asbestosis body.) Anthracotic pigment was also present in the m acro phages. Multi nucleated giant cells of the foreign bode type weie found in abund an ce in all areas; manv of these contained birefringent astcroidal bodies. Few lymphocytes svere 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 p articular relation or location to any grouping of the asbestosis bodies and were undonbtedlv a terminal phenomenon. T hroughout 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 ptrccnoigc of the total fibrosis seen. B nicln: 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 ah; ist all segments. A nother 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 vends: T h e arteries and arterioles of the right middle and both lower lobes showed moderate intimal thickening with hv alinizalion and narrowed lumina. This was most marked near the hila but was found occasionally farther into the periphery. J'umor: 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 hiluin into the pericardium and m yocar dium. (Fig. 5.) Metastatic tum or was seen in the. fourth lumbar vertebra. Asbestos "granulomas": T h e white plaques described in the diaphragm and Clisson's c a p sule were made up chiefly of hyalini/.ed 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. T h e 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 G a rd n e r50 a n d again by A M 1. K 1 C A N J t l V K N A 1. f) r M E D I C 1 N E V orw ahl: occur wt concentre cubic, foe, T h e p, inhalatio, id be di rather, tl from fib The inh. to pass 1, so they i| reaction The pa consider- desquan of asbest T h e 1< lining tl irritatio; mate, h !1 phagoev asbestos pliages . asbestos so-ca!lc from a partich 1 ing of ' course which imtatit sputun Thcir j to a s! n an ind The is the t lion c and al compi in c.on nary t the lo partie a fine luvvcr uppOl Th previ tends ce asi to he tion 1 NOVI / Asbestosis, Bronchogenic Carcinoma - -Isselbachcr rt a/. 7~7 \'u rw n k l's that usually the disease will not occur with fibers less than 2Op in length or a eencentnition below five million particles per. cubic foot of air. The pathologic processes resulting from the inhalation of .-asbestos particles arc believed u> be due not to their chemical n ature but, rather, the consequence of met hanical irritation linm fibers lodged in the respiratory tree.1*"20 The inhaled par.'eles are, in general, too large lu pass beyond the respiratory bronchioles and m> they rem ain 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) desquam ation and exudation, (2) formation of asbestosis bodies and (3) fibrosis and scarring. T he long fillers traumatize the epithelial cells lining the smaller bronchioles and the constant irritation and friction cause the cells to desqua mate. M acrophages pour forth, in an edort to phagocytize the fillers. 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""21 T his results Irom 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.25 These bodies m ay be found in the sputum , Jung., pleura, lymph nodes and spleen.25 T h e ir presence is held to be evidence of exposure to asbestos but by themselves are not necessarily an indication of asbestosis.17'27-25 T h e tliird 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 difluse 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 arc. most abu n d a n t. By x-ray one sees a fine, ground glass or granular pattern in the lower lobes and frequently emphysema in the upper lobes. T he sequence, of pathologic events described previously occurs slowly. In m an the fibrosis tends to progress even after the exposure has ceased; however in animals this does not seem to be the rase. It may be thal intcrc.urrcnt infec tion contributes to the progression in m an.'3 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 Mercwcthe.r is eleven years.17 While, most patients with asbestosis have had an exposure of ten to sixteen years, it is im portant to realize that the disease has occurred with as short an industrial exposure as 0.5 y e a rs.1'2 Usually no symptoms appear until a large p a rt of the. respiratory reserve has been reduced by the fibrosis. Merewether has frequently com mented how marked!) the lungs can be affected and yet the patient be fairly com fortable.17 However, when symptoms once begin and significant dyspnea becomes a p p a re n t, there is usually a definite and rapid progression. Then productive cough, anorexia, weight loss and faligue are the common complaints. Death cventuallv results from intercurrent infection, cor pulmonale or carcinoma of the lung. The ease herein presented demonstrates many of the significant features in the pathogenesis, sympturnatologv and natural course of asbestosis. T he patient had worked for twelve years in an atmosphere having a concentration of asbestos particles known to be sufficient to jmxluec pulmonary pathology. However, it was only during the last year of life that dyspnea, cough, anorexia and weight loss manifested themselves. C lubbing 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. T he physical findings of clubbing, cyanosis and dullness at the lung bases were all consistent with asbestosis as were the x-ray findings in the lu s, 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, puhnonnrv 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) tire fibrosis had obviously been of long duration and therefore one would not expect it to change m u c h at this time; and (2) he hac! superimposed b ro n c h o genic carcinoma. It is of interest to com pare these results to patients with chronic beryllium N o v i. Mn 1-: r , 19 5 3 7 ;?8 A-!/ B ronchogenic C arcin o m a -Jaclhachcr cl al. poisoning who usually show a favorable re sponse to steroid therapy.1'' Two further aspects of this case merit more d.-taded consklci alion and analvsis: (1) the pulmonary function and cardiac catheterization studies; and (2) the significance of the superim posed bronchogenic carcinoma. . R U J.M O N A R Y 1 r , \ . : ! \ A N D C A R D IA C C.Vl'lTn iE K I /A T IO N S J CLUES Table ) indicates, as one might expect, that the. patient had a reduction in vita] and m axi mum breathing capacities. However, the finding of an alveolar-arterial oxygen gradient of 27 mm. Jig demonstrates that uim of the dis turbances in pulmonary function was a defect in the diffusion of oxygen from the alveoli of the lungs to the capillaries. 1} is corresponds to the syndrome of " alveolar-capillary block" de scribed by Baldwin, Command and R ic h a rd s31,32 and again by Austrian ct ?.l."3 T his diffusion defect is not surpiising when one recalls the fibrosis about the alveoli, alveolar duels, capil laries and bronchioles that occurs in asbcslosis. 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 m inute at rest. This compensatory mechanism apparentlv was not adequate during stress or exercise for under those conditions the arterial oxvgcn saturation fell. T here was a considerable degree of pulm o nary hypertension and, as in the Cases of p ulm o nary fibrosis studied by Command and his associates, a rise in the pulmonary alter)' pressure occurred with exercise. (Table n.) The partial pressure of carbon dioxide in the blood (36 mm. llg ) was low normal rather than ele vated. H ad there been a defect in alveolar ventilation, the pCCT would probably have been higher. As Arnot emphasized in discussing this case16 carbon dioxide is not im paired in its transfer from the blood to the alveoli because of its great diffusion capaeitv. This speed of diffusion plus the increased alveolar ventilation no doubt accounted for the lowered p C 0 2value. ASBESTOSIS AND CARCINOMA OF T H E LUNG The association of asbestosis and carcinoma of the lung has been mentioned frequently in the lite ra tu re .1" 3' 3'1'-1'3 Heretofore some authors have believed that the cases were too few in num ber to lie of significance; others, especially Vorwald and Karr, have slated that " inhaled dusts, except 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 ai'm: in I N C I DE S C F . O F A S B L S J O U S A N D C A R C I N O M A O F l.UN'O Author 1 Xo. of Xo. Due to Deaths with Canter of ; A-bcstOsis Lung Jncielenco (%) 235 tV c !!,r; .......... . A 92 Wycrs2............. . . J 115 Lynch. Cannon 7. ., 40 121 ! CiOi 31 13.2 . 1 5 16.3 17 14.8 3 7.5 17 14.1 83 13.8 n o m a .' 4 O u r conclusion at jresent is in favor of the concept that the association of broncho genic. carcinom a with asbestosis is more than coincidence. T h a t there is a significant incidence of bronchogenic carcinom a in asbestosis is apparent from 'fable in. Mcrcwcther has cited the largest series- of 233 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 c e n t.9,1754 In contrast to asbestosis the incidence of bronchogenic carcinoma in silicosis as recorded in the two largest scries has been similar to what might, be expected in the general p o p u la tion. The data compiled by M crcwcther1 and the Miner's Phthisis Medical Bureau of South Africa'1'0 arc based on a total of 6,884 a n d 1,438 autopsied eases of silicosis respectively, and disclose an incidence of lung carcinoma of 1.32 and 0.~0 per cent. Vorwald and K a r r found two lung carcinomas in 136 silicolics (1,47 per cent). K lo tz 56 noted an incidence of 8 per cent, but his series of fifty cases does not seem large enough to be statistically significant. However Gloyne3 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 A M r. R I C A N J O U R N A L O F M E D I C I N E A sbestosis, B r o n c h o g e n ic C a r c in o m a Issr.Ibacher cl a/. 729 ilie pneumoconioses as a whole. In tliis same series 8.3 per cent of eases without any pn e u m o coniosis had cancer of the lung. Merewethei' and (i)ovnc's eases were analyzed over a com parable period of time so th a t it seems unreasonable to interpret the figure of 6.9 per cent as reflecting the increase of lung carcinoma in the general populations'-The discrepancy in the data proba ble is explained by the fact tha t Gloync's material was selected from the pneumoconioses in which 1he histories and x-rays were, " unusual." Oloync noted th a t 14.1 per cent of patients with asbrstosis had lung carcinoma. This figure parallels the observations of previous workers and is significantly above th at recorded for silicosis. As has been mentioned the asbestos particle probably acts as a mechanical irritant while, ti e p u lm o n a ry changes in silicosis are considered due to the chemical properties of silica.,!v:0 Carci io n of the lung appears to be promi nent in females w ith asbeslosis. O f M crcw cthcr's thirty-one eases nine were females, or 29 per cent, and in G loync's series of seventeen eases the incidence was 41 per cent. In the published autopsy reports data as to the sex of the patient arc available in tw enty-three, of which five (21 per cent) were females. In contrast, the incidence of bronchogenic carcinoma in females in the general p opulation is considerably lower. Lindskog noted an incidence of 4.0 per c e n t/7 G r a h a m 7 5.4 per cent, Doll and IIill^ 8.4 per cent and O c h s n e r 10 10.3 per cent. T h e higher figure in asbestosis supports the theory that asbestos particles act as carcinogens. Experimental production of neoplasms has demor strated that chronic irritation of body tissues by m echanical means may predispose to the development of malignancy. Asbestos par ticles when lodged in the finer bronchioles s a v e 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 carcinom a/* A " lag period" between the exposure to a possible carcinogen and the onset of malignancy is characteristic. N orc!m ann,s noted in his rases that the average, duration between the initial exposure to asbestos and the development of bronchogenic carcinoma was about eighteen years. Similarly M c re u e th e r' 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 " ad e q u a te " exposure nay be followed by pulmonary malignancy nan)' sears later. In M e re w e th e r's series is the case of a w om an who was an asbestos worker for only six months yet later developed lung carcinoma. G loyncsr' reported the ease of a woman with an exposure of nineteen months who died fifteen years later at the age, of ses entyonc with a squamous cell carcinom a 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 eases bas e been added to the list compiled by I lo m burgvT'6 in 1943. I t is noted tha t in about fourfifths of the eases in which the prim ary site is indicated the origin of the neoplasms was in the lower lobes. Tins is in contrast to the general population whore bronchogenic carcinoma seems to be more frequent in the upper lobes. In LindskogV'9 series there was an incidence of 57 per cent in the u ppe r lobes, 26 per cent in the lower lobes. O c h sn e r10 found 56 per cent in the upper lobes and 35 per cent in the lower lobes. No conclusions should be draw n from the small number of eases listed in T able iv. Nevertheless, since asbestos particles lodge to a greater extent in the lower 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 (lingual) seg ment of the left u p p e r lobe, was in an area significantly involved by the fibrosis and in flammation of asbestosis. It is also noted in T a b le iv th a t twelve of the nineteen previously recorded eases had lesions of the squamous cell type. T h e incidence of squamous cell carcinom a is said to b e high in male cigarette smokers with pulmonary malig nancy.6 At autopsy our patient showed both squamous metaplasia and adenocarcinoma of the. lingula. It m ay be of significance tha t he was a chain smoker for over twenty years in view of the observation by Wyndcr and G raham 7 that males with adenocarcinoma of the lung arc N O V h M h H R , 19 5 3 730 Asbestosis, Bronchogenic Carcinoma- Js.u.Harhcr cl 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 tha t it is not unusual to find several cellular tvpcs in various sections of the same tu m o r .5* Therefore' morphologic carcinoma in 13.S per cent of the eases cited in the literature. In silicosis the incidence is con siderable less than this. T h e asbestos particle may serve as. a carcinogen because of the chronic mechanical irritation it produces. 5. Since there are approxim ately 10,000 T a i u .e i v sp.MMARY or pfi;i.isin;n case reports in which ai'torsy data are cued ^ r a t and Aar Occupation Duration of JNpnsutc (yr.) rI rcf'.i'o in j1 fiorii Pxposutc .Vatu t ><_-ft>i c I >cath ! Primary Site L\ nt h, S m it h 31...................... 1035 M. 3"* j Wea ver Glo\ IH'1' .................................. G l o y n e ..................................... Lgbcrt. Geiger97 .................... N o i i l n m n n ^ ........................... N< ! d n i a t i n .............................. I.\ ncli,*11S m i t h ..................... 1935 1933 1936 1936 1938 1938 1 `>39 K, 33 S p in n er l \ 71 Mattress and open- | ing departments M . 41 : Weaver M . 39 . Packer. stores de- 1 partmrnt K. 33 G a id c r, sp mncr, j weaver M . 33 Pi redlining j assemble ruotn M, 30 Weaver i 11 ollrb,44 Augi 1st.................. 194] M . 32 j Pipe iri'ulanir J J>>1Ir 1>. Aug ris i..................... E M 1 M . 30 . Pipe in-.idator I .ttl/ll.H'll, Wedlei*.............. iB-micnlcs rt al. 43................. D c ' n c n l b , e? a l ..................... H u m b u i r c r 4* . . . 1941 1941 1941 1942 1942 1942 M . 61 ! M. 3~ M ac h i n e adjustor M . 30 Bagecr M. 43 No- i nowti > , 49 N o i ;;<>\vn to rn ac i with asbestos ( iure ion 19................................ Owe n ''1..................................... Stoll. Ra>s. Angrisi12........... 1948 1931 1931 L, 3 . Pipe <<>\ et er \ | M. 39 Asbestos worker M. 40 Pipe covein I't t-seni a u d - o r s ..................... 1932 M 4] Asbesto*, mil! ! worker ; sorter 1 21 8 in 17 1 0 '-2 4 mo. 9 yr. 15 yr. 2 vr. ? jno. Squ.imotH veil Sq u am o u s cell Stji, .mo*ts f ell Glandolar O.it (ell K.L.L. K.L.L. R.L.L. L.b.L. L.L.L. M ;vi\ nodules in R 1. L. Pleura None Widespi ead L.ll.L. and pleura 7 9 yr. Sq u am o u s ecll I. I . . ! . . 1,i\ er, k idneys 7 12 yr. S q u a m i n e cell L.L.L. Widesp: cad 13 3 yr. Stp. t moiis wi tli R.L .L . Pleura, medi- glandular astinal nodes features 23 9 w. N o n-1. e ia '.mix- R . l ' . L . Mediastinal nodes, ing squamous adienal, kidney relied 23 If \r. O at cell R Lb. Widespread, including brain > 3 Not Vno^n Squamom tell R.L.L. None 23 1 mo. Alveolar cell L. lung Pleura 22 4 mo. S qu am ou s cell R. lung Pleura 5 1 VI. Sq u am o u s cell R. lung Diapluagm 20 17 mo. Anaplastic I..I..K- Pleura Not know n Scoiamoti' tell R . lung Liver, adrenal, stomach, hilar Jvmph nodes 7 13 yr. Sq u am o u s cell L.L.L. Pi-ncaiduim, liter, kidney, ovaries, femur 1 20 vi. Adenoeai rinoma R. lung None 6 About 4 u. 3 vr. Anaplastic No definite Kidness. brain. site liver 12 2 vr. Adenoeatcitioma I.impila M\ or.mbum , peri- ca idiuni, spine, regional nodes differences in cell arrangem ents may not really represent different ctiologic varieties of cancer. SUMMARY AM) CONCLUSIONS 1. A ease of asbestosis with superimposed adenocarcinoma of the lung with metastascs, following documented harmful industrial ex posure, is preiented. 2. A C T H (adrenocorticotrophic hormone) was given with no objective changes in the patient's clinical course. 3. Pulm onary 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 eases of asbestosis. From the evidence presented a higher incidence of bronchogenic carcinoma should he expected in this group. Addendum: Since the submission of this 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 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. A M E R I C A N J O U R N A I. O I- M K D I C I N II Asbestosis,J B ro n c h o go e n ic C arcin o m a-- Issrlhachcr cl al. 731 At autopsy the lungs were firm and weighed 3.350 gm. T here was a poorly difierentifued adenocarcinoma arising from the left lower lobe bronchus, almost eompletrly replacing `the left with reference to p u lm o n a ry asbestosis. Tubercle, 11; 131, 1930. 20. G a KD.VKK, 1-, L . I 'l i u l o o y o f pi-u'UinoCOniOSK. J . A. M . A., 111: 1923, 1938. 21. GAku.NKk, L. G. a n d C cmminos, )). L. Stu d ies on lower lobe. T h e tu m o r had spread to the. left e x p e r i m e n t a l p n e u m o c o n i o s is : V). I n h a l a t i o n of upper lobe, hilum, pericardium, pleura and diaphragm; and had metastasized to the right lung and ^adrenal. T h e remaining lung tissue asbestos du-U; its effect u p o n p r i m a r y t u b e r c u l o u s infection. J, ludust. Ilyg., 13; 65, 97, 1931. 22. O ookl, W . L. Asbestos dust a n d the curious bodies found in p u lm o n a ry asbestosis. Bril. M . 2; 578, showed peribronchial fibrosis, focal alveolar wall 1929. thickening and num erous asbcsto.sis bodies, sur rounded by m acrophages filled with asbestosis hod\' particles and foreign body giant cells. The asbestosis bodies were seen in ecpial distribution 23. M cD unai i), S. Histology of p u lm o n a r y asbestosis. Brit. M . J . , 2: 102.3, 1927. 24. S i l w a r t , M . .1. a n d H a d d o w , A. C. D e m o n s t r a t i o n of the peculiar bodies of p u lm o n ary asbestosis (adx-stosis bodies) in material obtained by Jung in all parts of the lungs not completely involved puncture and in the sputum . Rath. Ci B od., 32: by tumor. 172, 1929. 23. G i.o y n k , S. K . T h e p r e se n c e o f a sb esto s fib re in t h e KKl KRI.XCKS lesions of asbestos workers. Tubercle, 10: 404, 19 2 9 . 20. .Sj k w a k t , H . L ., B r r e m . k , C. L. a n d G oldm an, 1. M ehewkth e r , K. R. A. A nnua l R e p o rt of the- Chief L. H . Asbestosis, tw o cases. Aich. 7V;//.., 12: 909, Inspector of Factories. London, 1947. H. M. 1931. SuitioiKuy OfTire. 27. W o o d , \V. B. a n d S l o y n k . S. R . P u l m o n a r y 2. W yers, H. Asbestosis. Post. Grad. Al. J ., 25: 631, a.-be.stosis. Lancet, 2: 1383, 1934. 1 949. 28. L y n c h , K. M . Pulm onary asbestosis. J . A. M . A., 3. O e o y ne, S. R. Pneum oconiosis. A histologic sm vey 109: 1974,1936. of netiropsy m aterial in 1205 cases. Lance!, 1: 810, 29. Symposium on the treatm ent of chronic beryllium 19.51. poisoning w ith A G T H and cortisone. Arch, Indnst. 4. Y okw ai.d , A. .1. a n d K a r r , .1. \V. I'nenmoeoniosis Ilyg., 3; 343. 1931. and pulm o n a ry carcinom a. Am. ./. Path., 14: 49, 30. Ba i d w j n , L, D i d '., G o u u n a n d , A. a n d R i c h a r d s , 1 938. D. \ \ \ , .Ik . P u l m o n a r y iusufTieiency. i. P hysiologi- 5. V< RWAi.ii, A. J . Personal c o m m unica tion, 1952. cal classification, clinical methods of analysis, 6. G raham, L. A. P r i m a r y c an c er of the lung with standard values in normal subjects. Medicine, 27: special c o n sidera tion of its etiology. Hull. Acw 243, 1948. York Acad. M ed., 27: 261, 1951. 31. Ba l d w in , D . D r i b , C o l r n a n d , A. a n d R ichards, 7. WvxiiER, E. L. a n d G r a h a m , E. A. T o b ac co sm ok D. \ \ \ , J r. Pulm onary insufficiency, n. A study of ing as a possible eliologic factor in bronchogenic thirty-nine cases of p u lm o n ary fibrosis. Medicine, carcinoma. ./. A. Al. A., 143: 329, 1950. 28: 1, 1949. 8. D u x , R. a n d H i i x , A. B. S m oking a n d carcin om a 32. Ba l d w i n , L. D f.F., O o u r n a .v o , A. a n d R i c h a r d s , of the lung. P re lim in ary R e p o rt. Hril. Al. 2: D. \W. J r . Pulm onary insufficiency, ill. A study 739, 1950. of 122 cases of chronic, pulm onary em physem a. 9. OcnsNKK, A. a n d D eB akey, M. K. C arcinom a of the Medicine, 28: 201, 1949. lung. Arch. Sure., 42: 209, 1941. 33. A u s t r i a n , R . , M c C u '.m e n t , J . H . , R l.nv. f.t f i , A. D., 10. OciiSNi.R, A., P eB akey, M . 17, O e C amp, P. T . and D o n a l d . K . W .. K ii .e v , R . L. 'Did O o u k .n a n d . A. R av, C. .1. Bronchogenic c arcin o m a. .1. A. A l. A ., Clinical and physiologic features of some types of 148: 691, 1952. pulm onary diseases with im pairm ent of alveolar 11. Kan/.a , A. J. Personal c o m m u n ica tio n , 1952. capillary diffusion. Am. J . Med., 11: 667, 1931. 12. L anza, A. .1. Silicosis and Asbestosis, p. 386. New 34. L y n c h . K. M . and S m it h , W . A. P u lm o n a ry y! York, 1938. Oxford Univ. Press. . asb' .uosis m . C a rc in o m a of lung in a^bcslo- ed 13. Idem , p. 327. siheosis. Art. ./. Cancer, 24: 36, 1933. na 14. tV o o n , \V. B. a n d G r o y n e , S. R. P ulm onary 35. G i oynk. S. R. T wo cases of s q u a m o u s c a n inoina of asbestosis. Laurel, 1: 445, 1930. the lung in asbestosis. Tubercle. 17: 5, 1935. 15. \ 1 ekkwi;th i;k , E. R. A. a n d P rice, O. \V. R e p o rt 36. G loynl, S. R. A case of o a t cell c a rc in o m a < - h m g on the E.fTccts of Asbestos Dust on the Lungs and o c c u r r in g in asbestosis. Tubercle, 18: 100. 19 39 -37. us Dust Suppression in the Asbestos Industry. 37. L chu.h t , D. S. a n d G liof.r , A. J . P u l m o n a r y a s b e s six London, 1930. H. M . Stationery Office. tosis and carcinom a. R eport of a case with 16. Case R ecords of the M assachusetts General Hospital necropsy findings. Am. Rev. Tubnc., 34: 143, 1936. (case 38221). .Vc;c England .1. M ed., 246: 867, 1952. 38. K ordm ann, M . D er Bcrufskrcbs d er Asbestosai boi 17. M er e w et h ek , E. R . A. A m em o ra n d u m on asbes- ler. Z h c h r .J . Krcbsfatsch., 47; 288, 1938. tosis. Tubercle, 15: 69, 109, 193.3; Tubercle, 15: 152, 39. L y n c h , K.. M . a n d S m i t h , W . A. P u l m o n a r y 1934. asbestosis. v. A report of bronchial carcinom a 18. ,VouwAt.n, A. .1., D cr kan, T . M . a n d Pratt, D. O. a n d e p ith e lia l m e t a p l a s ia . A m . J . Cancer, 36: E x p erim en tal studies on asbestosis. Arch. Indus!. 567, 1939. Ilyg., 3: 1, 1951. 40. K of.lsoh, )7, L u n g e n k r c b s u n d B e m f . ZerAuiUd. / . si. 19. G i.oy.nk, S. R . R e ac tio n of tissues to asbestos fibre, C nm brhyg., 27: 32, 1940. : 1 n o v i n m r . k , 19 5 3 732 Asbcslosis,? B ro n c h o gOe n ic C a r c in o m a lssclbacher cl at. i 41. LiNVRAnii, A. J. a n d W u u . r . R , H . \V. Asbestos u n d ring in asbcslosis of t h e lu n g . Prit. J . Cancer, 2: E u n g c n k r o b s Aich. f . j>ath. Ana/., 307: 387, 1941. 249. 1948. 42. N okumann, M a n d So r g e , A. E u n g c n k re b s d u rch A sbcststaub im T iervcrsueh. Zlschr. f . htcbsfmwch., 50. S m it h , 1.. P n e u m o c o n i o s i s a n d l u n g c a n c e r . Comjmns. Med., 2: 3, 1949. 31: 163, 1941. 51. O ut \ , T. K. C a rcin o m a a n d asbcslosis of the lung: 43. D i.smkui.ks, R . , R oussf.a u , L . , G i r o u x , M . a n d R e p o rt of a case. Prit. J . Cancer, 5: 382, 1951. S irois, A. A m i a n l o s e r t c a n c e rs p u h n o n a i i cs. 52. S io i.l , R ., B ass, R. a n d A n g k ist, A. A. Asbestosis Laval wed., 6 97, 1941. 44. TIo u .kb, FR a n d A n g k is t , A. B r o n c h o g e n i c c a r c i a s e r i a t e d with b r o n c h o g e n ic c a rc in o m a . Arch. t Pit. Med., 88: 831, 1951. nom a with p u lm o n a ry asbcslosis. Am. J. Path., 13: 53. IluM'KR, \V. C. E m h d n m c n t a l lung c a n c e r. PiduU. 123,1942. Med., 20: 49. 1951. 45. Wi oi.Ku, H . \ \ . As bestos m i d E u n g c n k r e b s . Deutsche 54. R e g iu r a r -C e n o ab Statistical Review of E ngland rued. Wchmchr., 69: 575, 1 943; a b s t r a c t e d in: an d W ales for the. Y e a r 1948. L o n d o n , 1950. Hull. Jlyg., 19: 363, 1944. H, M . Slationciy Office. 46. H ov.b u r g e r , 1 . C o i n c i d e n c e o f p r i m a r y c a r c i n o m a 55. R eport: M iners P hrhids M edical Bureau. U n io n of of lungs and pulm onary asbcslosis. Analysis of South Africa., P retoria, 1936. literature arid report of three cases. Am. J . Path., 56. K i . o r / , M . O . Association of silicosis a n d c a r c in o m a 19: 797, 194b of lu ng. Am. J . Cancer, 35: 38, 1939. 47. L ynch, K. M and C annon, \V. M . Asbcslosis vj. 57. E indsk' h*;, G . F. a n d Ki .o o m k r , W . 19. B r o n c h o g e n i c Analysis o f forty nccro p sicd eases. DP. Chest., 14: carcinoma. Cancer, 1: 234, 1948. 874, 1948. 58. W n .i is, R . A. P a th o lo g y of T u m o r s . St. L o u is , 1948. 48. H u k pfr , W . C. E n v iro n m en tal a n d occupational C. V. Mosby Co. cancer. P ub H ealth R e p ., Supp. 209, 1948. 59. J jnt>s>;o g . C. F. B r o n c h o g e n i c c a r c i n o m a . Ann. Sing.. 49. C urkton, R. 4. R. S q u a m o u s cell c a rc in o m a o c c u r 124:667,1946. [/ '4 A M L R I C A N J O UR N A L O V M E I)ICI N E