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'S. Asbestosis and Bronchogenic Carcinoma* Report of One Autopsied Case and Review of(fie Available Literature Kurt J. Issf.i.uachf.r. m.d., Hanna Ki.aus, m.d. and Harriet L. Hardy, m.d. Boston, Massachusetts here arc several reasons for presenting curtains and clothing. The chief operations are Tin detail a case report and a review of the disintegration of the crude mineral, carding the available literature dealing with the fiber, separating the more useful long from the relationship Ik-tween occupational exposure stohort fiber, spinning, plaiting and weaving the asbestos and respiratory- tract malignancy. The asbestos, often with cotton. Insulating material apparent increase in bronchogenic carcinoma, is produced by mixing magnesia, diatomareous especially in males, reported in the past decade earth and other materials with ashestos to make has led to scrutiny of respirable dusts as possible cements or fillings for insulating boilers, engines etiology. Most English observers1-1 are satisfied and pipes. Other non-textile asl>estos products that there is a statistically significant increase so made include ashestos cement, sheets, brake in pulmonary malignancy among asbestos and clutch linings, electrodes and switchl>oard wotkers. Some American writers consider that panels. the experience to date does not support this Asbestos is a hydrated magnesium silicate. contention.4,1 The work of Graham,8,7 Doll and The chief supplies are in Canada, Cape Province, Hill.'4 and Orhsncr11'1 has created much interest Italy, Rhodesia and Russia. Asbestos dust given in the correlation of cigarette smoking with off in manufacturing processes consists of frag bronchogenic carcinoma. E. R., whose case is ments of filters and small rounded or angular herein presented, was exposed to harmful particles. Actual studies in industry show the amounts of asbestos dust and was a chain size and shape of the particles of asbestos to be smoker. This provides speculation as to the such as may gain entrance into the bronchioles.14 possible role of two etiologic agents. Experience has led to the acceptance - of five Few reported cases of lung cancer related to million particles of asbestos per cubic foot of air, industrial asbestos exposures `provide data on of small enough size to be respirable, to be the the character and quantity of dust exposure. safe working concentration. This is a'serious deficit in exact study of etiologic Some operations because of their dustiness correlation. In the clinical report presented are more hazardous than others in asbestos herein State authorities have determined by manufacturing. Bagging the asbestos, separating measurement that the aslrestos dust exposure of this man during his twelve \cars of work was considcrabl. a`x>vr the safe level, which is con sidered to lx- five million particles per cubic foot of air for an eight-hour working day. It is pertinent to this presentation that there are probably about 10,fK)0 workers engaged in potentially hazardous asl>estos manufacturing operations in the United States.11 Middleton the long from the short fibers, carding, spinning and weaving show a greater statistical evidence of asbestosis than do other operations. As might he expected, the longer the duration of exposure the greater the numi>er of cases. In the Merewether and Price series there was one case under four years' exposure, and up to 53.6 per cent with fifteen to nineteen years' exposure.11 reports the number in Great Britain as between CASE REPORT },b00 to 5,ODD.'1 Most of the industry is engaged in asbestos textile manufacturing producing insulating mattresses, brake linings, fire proof E. R. (MGH i*`7355861.;n a forty-one year old asbestos mill worker, entered the Massachusetts General Hospital in April, 1951. The chief From the Departments of Medicine and Pathology, anil the Occupational Medical Clinic-, Massachusetts Genet Hospital, Boston, Man. This work was supported in part by the National Institutes of Health. Division of Resear Grant*. HOVtHltt, 1953 721 Ropr-nted from the November, ioi3 issue of The American Journal of Medicine Moot-hiy by The Ancncjn Jinirnl of Mediant, luc,, NTM York Voi. Wt No. pa^es 721-751. Cop>rieht, 1953. 1_8_007305~7 NOTE: THIS DOCUMENT DID NOT COMjE.FROM PPG FILES 1 1 .^ 722 .\>l>estosis, Bronchogenic Carcinoma--Isselbachcr ct at. tions 30, and temperature 99f. orally. His chest was thin and showed poor expansion. There W'ere dullness and reduced hreath sounds at both lung bases with sticky inspiratory crackling rales over the region of the left tower lobe. The left lxjrder of cardiac dullness was 10 cm. to the Table i PUt MONARY FUNCTION STUDIES* BEFORE AND AFTER ACTH f Before At.TH I Approve | A/tee mate ACTH Normal 1 Vlluct* Vital capacity (I. )......................... .. Maximum breathinf capacity <L./min.)............................. . . Residual volume ft..)........................ Effective alveolar vennlaikm (l../mtn)............. ................. Alveolar pO imm, Hf),. Arterial pO (mm. Hf).................. Artcnal pCOt (mm. Hai.............. Arterial Ot saturation ("i).. . .... Serum pH..................... ............................ Alveolar>iierul Of difference (nun. Hg)............................................... 2.4 1 t; 5 1 575 2 14 79 5 1.49 7 *1 IIS 0 * 0 w.o >7 3 7,45 5 4* 105 0 76.0 *10 94,4 7.42 29. 5.9 IAS 1.30 5 02 105-107 95-97 40-43 95-97 7.39 to. F;c. 1. X-rav cf ch*-*t. The lower lobe* are reduced in size ar.d show z "honeycomb'* pattern. There is an increase in linear and nodular marking*. A density is TH**e itudtet wttr performed by Dr. John Affeldt* Ikpirtmnt of Phyamtofy. Harvard School of Public Health, t ACTH 100 04. intramusriiUriv tin* tea da*t, seen in the region of the lingula with enlargement of J Body mnacc Area 1.62 tq. m. lymph nodes in the left lung root, suggesting a tumor in that area. left of the midsternal line in the fifth interspace; there were occasional extra systoles; P* was complaint was progressive low back pain which greater than A*; there was some pulsus para had been present for four months and was only doxus. Liver and spleep were not felt. There partially relieved by aspirin. In addition, one was tenderness of the spine over L-4 with spasm month before admission the patient noticed of the lumbar musculature. He had extreme increasing dyspnea on exertion, a worsening of clubbing of fingers and toes. his chronic productive cough, night sweats, - Laboratory data revealed a normal urinalysis. anorexia, feverishness and a 10-pound weight Hemoglobin was 14.0 gm. per cent and the loss. He had worked in an asbestos mill for white count was 5,700, with a normal differen l about.^g^Lvears but had stopped working tial. Chest x-ray revealed the lower lobes reduced | there for two years prior to this hospital admis- in size and showing a honeycomb pattern. \ sion. In the mill he had spent one year in the (Fig. 1.) There appeared to be a homogenous `'picker room" where, crushing, grinding and density in the lingula with enlargement of sorting of long asbestos fibers was carried out. lymph nodes in the left lung root suggesting a He also worked live years in the carding room tumor in the region of the left lower lobe. Films where the concentration of fibers had been of the spine indicated areas of increased and determined by authorities to be considerably decreased density in the fourth lumbar vertebra above the safe levei. He used one can of snuff giving the appearance of metastatic malignancy. and smoked on an average of one to tw*o packs Electrocardiogram showed non-specific T wave of cigarettes daily for many years. For seven changes. Non-protein nitrogen was 27 mg. per or eight years he had been aware of clubbing cent, CO; 29 4 mEq./'L., alkaline phosphatase of his fingers: one flight dyspnea was present for 4.9 Bodansky units. Repeated examinations of about tw-o years. There had hren no hemoptysis. the sputum were negative for acid-fast organ Physical examination revealed a chronically isms. asbestosis bodies and malignant ceils. Two ill and dvspneic man with evidence of weight bronchoscopies mealed obstruction of the left loss and cyanosis of the lips and nail beds. The lower lobe bronchus. The patient was given a blood pressure was 110/75, pulse 96, respira trial of ACTH K'tl mg. daily intramuscularlv AMERICAN JOURNAL OF MEDICINI ( : TM5$ DID i^OME FROM PPG FILES -------------------------------| BB 0007306 l M S .... w Asbestosis, Bronchogenic Carcinoma--Isselbacher et al. 7*3 for ten days. Clinically there was no change except for euphoria. Pulmonary function and cardiac catheterization studies were performed Ik-fore and after AO.TH and likewise showed no significant chances. (Tables i and ti.) Cardiac catheterization did reveal chronic cor pulmonale blood count was 6,500, hemoglobin 11.5 gm. per cent. ' It was believed that the patient had pneu monitis in the right lower lol>e and early cor pulmonale with congestive failure. He was digitalized, given mercurial diuretics, anti- Tabi.e u CARDIAC; CATHETERIZATION STt'UIKS* BEFORE AND AFTER ACTHt Approximate t 1 o. Consumption O, Capacity (cc./tnin./ *q. m.) Radial Arterytec./100 cc.) i i O, Ot i Satura Content tion Radial Radial Artery ; (cc.; too cc.) 1 Arterv (%)' !1 Pulmonary' Mean Artery Pressure i Pulmonary Artrry linni. Hr) ' Pressure (mm. Hg) . 1 ( if 1i normal values*11........... Before (Rest............... US 180 20 0 19.3 19 0 18.1 26- 1 30/10 1 94 ' 36/14 ' 15 21 ACTH | Mild exercise ' ' f ~t2 min.).. 370 ' 43/14 28 After f Rest............... ACTH J Mild exercise 1 [2 mm.). . 156 349 P.4 16.6 ' 95 . 38/15 1 1I 1 |; j 52/22 25 . i 36 j Cardiac Index (L./min./ sq. m.) 3.2 4.47 5.55' 4.02 6.97 * These studies were performed bv the Cardiac Catheterization Unit of the Massachusetts General Hospital, including Drs. G. S. Myers, A. L. Friedlich, J, R. O'Neill, G, Cohen and J. G. Scanned. _ f ACTH 100 mg. intratnusctilarly for ten days. with slight pulmonary hypertension; after exercise the pulmonary hypertension increased and significant' arterigj 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 twu months he had to be readmitted. Physical examination on re-entry revealed a temperature of 100.4f. rectally, pulse of 120-1-4, respirations 30 per minute. He had marked tachypnea, moderate cyanosis and such dvspnea that it was very difficult lor him to speak. There were mam inspiratory and expiratory' wheezes throughout the lung fields. At the right base there were moist bubbling rales together with dullness, reduced tactile fremitus and increased vocal fremitus. The left border uf cardiac dullness now extended out 12 nu. from die rnidsrc:T.?.l fine. Pj w-as much louder 'dun A . The liver '> oercussed down two ... - .V .'rjiilj-crul'.' -.md if,ere was 2 pei* ;. * . nr w>i- biotics (penicillin and streptomycin), and was in an oxygen tent most of the time. Chest x-rays now were suggestive of lymphatic spread of tumor. In spite of all therapeutic measures fever, dyspnea and cyanosis grew worse, {ic became confused and died on the thirty-fourth hospital day. At necropsy the patient was emaciated; the thorax was lengthened in the anteroposterior diameter. There was clubbing of the fingers and toes. On opening the thorax the lungs did r.ot collapse but remained inflated, completely filling both pleural cavities. The majority of Mu? pleural space was obliterated bilaterally by dt?nse fibrous adhesions betwern the visceral and parietal layers. Both the visceral and parietal pleurae were markedly thickened, gray fibrous memhranes measuring up to 0.3 cm. 1 hick. There were 100 cc, of clear straw-colored fluid loculatcd in the left base. The interlobar fissures were obliterated by fibrous tissue. Scattered throughout the adherent layers of the diaphragmatic pleura, especially on the rigm, were 1 number of whitish grav, shinv plagues ' > cm. long; these resembled similar plaque* r ' '/ ' ? - "i -----i7307*'7  AMH^tosis. Hrt."irfioixemc f bininon u i uj Fie,. 2. (`ul si'ifacr of left l.imr after formaiinTncuioc. Nod- diffuse pubuoiidry librosis and milked pleural thickenim* ivlucli obliterate* the interli'b^j- tiiSiire' seen on the. upper surface of the liver, to he described. T he lungs weighed 2,"10 gm., weie voluminous and verv firm throughout: .no dis-. t-reie nodules could he felt. (Fig. 2.) Multiple sections showed a uniform brownish gras surface throughout except in the left lower lobe where there appeared to he a dilfuse murker 1 filirosis throughout die parencnvina. Tire left !nu Itthe bronchus was Completely occluded 1 cut. from its origin b\ pinkish gray, firm tissue for a distance ul 1.4 cm.: here the bronchus tiausmed it."* em. in diunteter: the firm pinkim grav tissue extended into the pareiiehvtiin im distance ut 1em. Similar tissue extended from this [Hum in the bronchus to the pleuta .mu .mo the wall ul the 1**11 atrium which w.> .ulherent to the pleura at this point: the gross atrial in* viilvetifnt utea.'.uf'tl 2.3 In <" cm m 'nm The tipper lobe l>rtmchi 'uie rigid rowed In a thick, white iibrmi.s iu.m. I '.gm lower and to some extern the rigm im.ibi'- mu left lower lobe bronchi wete dilaled. ami *1 ere Fit,. .*. .VIk-UiTsis ImUie* m 'In lung. 1'tie club-shaped,t.'-lie.uleU .isl*>i.wis limli.s di-- vi-.-n in the aivrci.ir dm MiriiiuuiJeii liv maei'iphuges .inti "dust eeIU'"i A UtHl.^''1', *!"3 a was collapse *1 the intervening parenchvin.ii' The xfinis and arteries appeared uoima!. Huyc were adhesions between the visciral and parietal pericardium both at the apex uncL- .' the base The apical adhesions weir thin fibrous, strands but those at the base were extensions sj._; rT.-.j, the firm tissue described in the left lower lobe ^ o luxfnchui. The heart weighed 36<> em. The*e j ^ i _ was involvement of the left atrium and auricJv^T lw thick, ftrin. grasish [link tissue lor an ari^-^ measuring 2.3 ny b.7 itn. The remaining ms<*^ cardiuin appeared umnoilu-d and measured H.O em. thick in the right \enirirle. 1.3 em. it* the left. "I he endocardium and ..lives were liei'.llise I he diaphragms tommied firm gr.p.tsh pmk areas ol j)lut|ue-likc thickening wl.tch measured u;,' to n.3 cm. m rlt.uti,*-t *r. i'hesc were seen on both ih< pleural anti ocniomal turfices, were apposed and luoseh adherent to similar mn- fluent .ui .it i:t (ilisson s capsule. I he- remaining organs, with die exception ul :he fourth lumbar \ ertei n`a. were ti gative. Thi- ut!(,IiI'a appeared up.ilescetu ant! 'esetul .led m.oble. but as eon- M-.U1K V was sum r than the adiarrm . rn brae. In b.itk appeared to have increased porusits. WII kl('\N |nl,kN M OF M F. ') 1 C I S f _I_BB 000730s" C-C 1531? Aslx*scosis, Bronchogenic Carcinoma-- hselhachrr ft al. 72=> mn m #s=- a?:,s.-sw?* o i<?3j 4 "3 la;. 4. .Squamous metaplasia in the alveolar ilutts; note also asbestosis bodies and interstitial librims: X 100 Kir.. 5. Adenocarcinoma invading the myocardium; X 100. * Tito litns;s were sectioned 'topographically; sections from all segmental bronchi wen: taken near the hilum, the mid-lohar and the periph eral areas. These basic histologic patterns could he 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 perilmmchtal and alveolar duct fibrosis in both apices, and slight alveolar wall thickening as demonstrated hv connective tissue stains. The fibrosis increased in the remaining portions of Che lungs, was heaviest in the hilar and mid-lobar areas but extended to the peripherv. This confinned the gross impression of diffuse fihrosis. Asbestnsu Indies: Ashestosis bodies were present in all sections. Tig. 3 i These wert: segmented libers averaging 5bji long, some straight and some club-shaped, others resembled dumb hells which stained dark brown on hcmaloxylin-eosm preparations, and blue on Prussian blue (iron) preparations. Particles of iron-staining dust and larger, easilv identifiable ashestosis body parti- \OVlMHER, l') 5 3 cles, were present in the macrophages. The distribution was equal bilaterally, being slight to moderate in the apicai segments, quite marked in the remainder of the lung and oc curring with equal intensity in the tiiiar miciiobar and peripheral zones. While most of the ashestosis bodies were seen in the bronchioles and alveolar ducts, a few could be seer, in the alveoli, and lraemt*:u.s were found lioih in the macruphaecs ana in the Ivmphntics. Several aggregations ;;f tsbestosis bodies were found in the bronchi, fragmented asbestos libers were lound mostly in the macro phages but ccasiona: iron-staining particles were found free on the "dveoiar walls. Much, hut Iiv no means all, of this material in the macrophages took the iron stain. lnflammatnr\ ro/amse: The chief inflantm.uorv cells p spunnmg to the irritant were me macro phages. These cells were seen in abundance m every section; they lined up along the watis ' lie alveolar ducts, tilled the lumina of bron chioles and ah'-iili, and were lound throughout the septa and fibrous tissue. Most of these con- J BB 0007309 | GG Ib3l CO 720 Aslx'siosis. Bronc hogenic Carrinoma- -Isselluchtr ft al. I i*. i . X-r.ie .litlrai iiihi lilm of !inw n-xiilur ul I'.. R. ' llir liui'a li-irtl wi.cu i iitnpabtl to (In* known p.iturii Im .t-ls-ai*. irivi* [Vhinw prm>l (li t( iih- lunit midtn* i* rxxciiu.illv ai*lw'iu. 4.52 4 2> 2.35 2,`t 2.6" Tahir nt "1)'" lull**: 2.42 2 38 2.115 1.84 1 Ah 1 '.1 1 53! 1 4V 1 44 1 .38 ' A <>8.5 '/in. sample nf I(iriiiiiii7.cii lung tiviif was dii'cs'.i'd in 20 vulumo*. liyUriittcjt peroxide, the digestion being .nx'-lriauil mh centlr hi-atuig. ITie rrsidur from thi: tiiif-xtion was irruuit with dilute hydrochloric acid, tillered, vijjhnl and Ignited at sOo > rhe igimed residue was analvzrd by <-rnv dirirartton hv the method described in the/' aiiirle by Haoawalt, J, I). Kinn, H, W , Frrvel. f.. K., `"Clhetniral onalvsis hv x-ray dill'rac lion." b'd'i't. Jf Eng, Chrtn , la.it. Eil., vnl.-lll, no. ), I'l38. I'liis woik was done liy R I. C.hamlarlin and A. Woewueki. .Ir. of the M.uwachuwtt/. P-inding and Iiisur.iiii'i- Company, Boston. Mass i.iii.i-tl limwi; I'lL'ineiit granules mnnv of which tiKik tin irmt statu. am! portions ul asln-stosis imUies ui'ir -i 1st found hi the macrophages. tTht'sr ceils have been called dust cells ;m<l are thought (<i la\ down the iron im the asbestos liber, constituting the asbestosis !>odv.) Anthracotic pigment was also piexnil in the macro* ph.tires. Molliluii Ic.itrtl giant Celia of the lor'eign bocK t\pc were found in abundance in all areas: many of these contained birrfringent asteroidal bodies. Few lymphoc> ies were seen: those present were scattered around the bronchi ne.u the hila. A lew- focal areas of bronchopneu monia with poK morphnnuclear infiltration were present:' the^e hail no particular relation or location to anv grouping of the asbestosis bodies and were nndoubiedlv a terminal phenomenon. Throughout rhe lungs many air sacs were dilated anti contained a granular eosinophilic material, probably fibrin. Some ot tliesc plugs were undergoing nruuni/atinn, mainly in alve olar ducts; this type ol fibrosis probably accounts lor a small percentage of the total fibrosis seen. Hn nehi: The bronchi of the lower lolies showed mat keel bronchiectasis: there was dilatation, fibrosis ol the muscular coat and peribroiu iliai fibrosis. Uliile the latiei was most marked in the ||.W;-!' lobes it was see:i in the hilar and Illid/nu..I regions ol almost all segments. Anorhct sinking leatMre was widespread M|ii.titiimi m.-iapl.iMa of llie'bronel.i.ii cpitheiittm. (l ie J. This wt- most marked in the nhroUr ducts: it wax lotmil in all areas and wax not partienl.u l\ reiateti inringr ajihic.ilb to :i-,e ailetiot arcit'ii::'t 'leseribed laiei. HIwhI Till- arteries ami artetioles o! the right middle and both lower lolies showed moderate imimal thickininc with hyalinbuiion and narrowetl luimna. This w;,s most marked near the hila but was found net axionallv farther into the periphery. 'lumtii; Adenoetirrinoma wax found originat ing in die inferior lingual segment ul the hit upper lobe bronchus. The limit it was present in the mid-zonal area of tm* apical jxwtrrior segment of the lelt upper lube. *thc entire lingula and hit lower lobe, as will as the right middle and lower lobes. It had spread In xuli- muco.sal ami lymphatic routes 'set tioii.x ol the V left atrium xhnwt,d direct extension through left hilmti into tbt* pericairliui.t ami tusoear- dititti. (Fig. s.! Metastatic tumor was seen in tin* fourth lumbar vertebra. '.'"runi.inmaf`, l he white plaques described in the diaphragm and (hixsons cap sule were made up clmlb of h\ tlinized Con ner'ivi tissue. No asbestosis iiodies or giant cells were seen. 1 le xe Hist inch, r areas grosslv xuggeso'd aranul'>tnas. liillraeli'.n Modi-' wete i arried nut on a 'ample ol fiinnalizeo" lung iissn* i he n-ulting pat!":Ti indicated rh.u tin lung residue was moxii-. axuestos : Fie i i immi- \ :s A<be-;osis rna b** defined ,is i specific occttpaii.'tta! tii'f.ie e.m.si'd li\ tin- inhalation ol asbesti/x hi'erx and lending to a progresxiv** fiiirosis :'iii! scirring wahm t!:e lungs.1' It tiax been iemnnuiaied t a C i.irdneiand again I., \ M t N i i \ N |"FhN \1 'ip M I l> ! i' J N * i--__^0731o'T A.s!>rsuwis. Broiwhoiicnir Carcinoma Is\rli.achrt el al. Vurwald'* ill.11 usualli the disease will not *jO'iir wiili fila-rs less than 2ttyi in length ut .1 < nnrenti.ition hefow tin- million particli*s jx*r nil lie I. K>( of air. I !>' pathologic processes resulting from the inh.il.ition of al>fstos particle* arc tielicvrd to t.e line not to their eh* mienl n.itnn: hut. i .11 her, the consequence of mech.mirul irritation Irotn Itl>cr> lodged in the texpiratorv tree.1' " I In inhaled particles are, in general. too large to pass hcintul the respirntoi\ hmnehiolcs and ut they rein.tin there to initiate .1 foreign I tody rear lion which "\entna)l\ leads to lihrosis.-1 `Hie palhohigit. setptenci ol events can he coii'idi red as i>< earring in ' thnt* stages. il. dt'stpuimaiion atul exudation. '.2' formation ol asItoitiMs bodies anti (5 til'msis and scarring. The tnt.e IiIkts traumatize the epithelial cells Iniinu the smaller bionihiolrs and the ( oust,mi irritation .inti litction cause the cells to destpta- inate. Macrophages jioiir forth ill an elfort to phaunetti/c `.he fillers. In our case fragmented .tsliesiiisis Imdirs were also wen within macro phage' .cid Is mphntics. A second reaction to the asoesms liber in die limt; is the production of the so-railed "as! Hstosis isidv."'-- This results Iriitti a reaction nemtring lictwccn the aslicstos panicle and surrounding tissues. It is a thicken- ina (die (iher due tit the deposition along iis ttmrse of a o` ro* tein matrix containing iron width probably sci\cs to reduce the thnmic irritation.5* These bodies rnav he ITiund* ih the sputum. lung, pleura, lymph nodes and spleen.1* f'iteir presence is held to he ev iclence of exposure to asbestos hut hv themselves are not necessarily an indication of .ishestusis.'"-7-5' "I he third and must significant tissue response ts t!ie production of tihrohla.sts atid the rirjiusi'ti<>n ot 'collagen alxmt the distal bronchioles and .menu. Then ensues a dillusc It I n-tasis whiih compresses the alveoli and capillaries. resulting in comp!-. :e uhliterauon of the involved pulmo nary tissue. This process is more pronounecd in the lower lohes of die lung for it is there ihat tie- particles are most ahumlani. Tfi x-ra\ or-' s< es a lute, ground c!a or granular patieru in me low-r lohes anti lrer;ucmt\ mphisenia in the :;:!'.ee lol.es, lit:; scqnenre of padinlocii oleins i!"mi died pn .lou'h ut cm * *!ow |\. In m.m tie- ta.uii':' teial.s to pi-ogress on alt-T t',e esjsisiti'i u.rs I'c.ised. Ii.iwimi l't .: t' i 1' i. * I. tills due* not - : 11 '.e : 1' 1 ,i-e t ,i,.i, . :f.,i* -i:rt**ii .ti - - i al rootrihii'e- * *. * pi. .m'essn >:. 'a ttt in s 1 v k 11. *; ! In general there is a delay of five to seven wars between the initial exposure to high eon- ct-i 1 trainm.s ol ashestos dusts and the (inset of elitiieal tshestusis `The average interval re- |stried h\ Merewether is eleven wars.While must patients with asliestosis hast; had 'in exjioMitv of ten to sixteen years, it is important to reali/.e tlui tin disease has occurred with as >hon an industrial exposure as 0.5 years.1-* 1`.'italic no symptoms appear until a large part of the respirators' reserve has hecn reduced hy the tihrosis. Mercwerher has frcqucmly cnm- luemcd how markedly the lungs can he affected anil yet the patient he fairly comfortable.'Y However, when s\ mptoms once begin and2 significant tlvspnea liecomes apparent, there iji", usu.iHv a detmite and rapid progression. 'Hiett,. productive cough, anorexia, weight loss and fatigue arc the common complaints. lX-ath rvctiiually results from intcrcurrent inlcrtiou, cor pulmonale or carcinoma of the lung. I If case herein presented demonstrates many ol the signilieant features in the pathogenesis. s> inptomatologv and natural course ot a.shestosis.. Hu' patient had worked lor twelve wars in an aimii'|iht ie having a concentration of aslicstos. pat tides known to he sufficient to produce" pulmonary paihologv, However, il was onh * during the last war of life that dvspnea. cough, anorexia and weight loss manifested Mintijicfces. dubbing had hecn present for at least, five wars. He hail a very rapid dowuluil course, due undmihledlv to die two associated 'factors - the ashestoMs and carcinoma of 'in- lung. The pliisic.il findings of riuhhine, nanosts and dullness at the lung liases were all consistent with a.shestosis as were the \-r;v finding* in the lungs., apart from the <:\ idem e .suggesting neo plasm. The outstanding symptom, 'he mv't .mil progressive dvspne.i. was aonhuicii to a touihioation of puhnunari M-ii so, siiperirn- jiii'iI mb spreading lung r!cnni,i:u, pi'linunarv infection and finallv t nn-"'srivi~ die h.i'is of cor pulmonale As indicated in the as*; I istms. `m (''n-tlai jjt i uni ol \( ' Ilf themps, was act ou.o.imcd onlv 01 euphoria hui oiijcetc.e nmieiuems re- .aied no sieniticatu changes. T],.* w mu sta :>ris;ug t if t.'Vii r'-.iSor.S' Hi tie' libiosi' had o'.. uni'll :.eeti ol long duration .mb diicetore 1 ,ft*1 would tint expert i' to change inudi at this uua', and '2 in' fi.nl sujiciimpiis.il hronchu- C' r:a f *' lUuit.a 1* ,s nl i:.'."reo to I'Oiaj'air thesi i.'iili' to p.iM-iu with 'iro'iii hen Ilium GG 15320 | BB 0007311 ( 728 Asbestosis, Bronchogenic Carcinoma--hselbacher et at. poisoning who usually show a favorable re** sponse to steroid therapy.** Two further aspects of this case merit more detailed consideration and analysis: (1) the pulmunary function and cardiac catheterization studies: and (2) the significance of the superim posed bronchogenic carcinoma. PULMONARY FUNCTION AND CARDIAC CATHF.TERIZATION STUDIES Table i 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 oxveen from the alveoli of the lungs to the capillaries. This corresponds to the syndrome of "alveolar-capillary block" de scribed by Baldwin, Cournand and Richards*1,15 and again by Austrian ct al." This diffusion defect is not surprising when one recalls the fibrosis ai>out the alveoli, alveolar ducts, capil laries and bronchioles that occurs in asbestosis. In order for the patient to maintain a near normal arterial oxygen saturation, a high alveolar oxygen was necessary; and this ap parently was accomplished in part by hyper ventilation. The patient had an average respiratory rate of 40 per minute at rest. This compensatory mechanism apparently was not adequate during stress or exercise for under those conditions the aj-terial oxygen saturation fell. There was a considerable degree of pulmo nary hypertension and, as in the cases of pulmo nary fibrosis studied by Cournand and his associates, a rise in the pulmonary artery pressure occurred with exercise. (Table 11.) The partial pressure of carbon - dioxide in the blood (36 mm. Hg) was low normal rather than ele vated. Had there been a defect in alveolar ventilation, the pCO- would probably have been higher. As Arnor emphasized in discussing this case'* carbon dioxide is not impaired in its transfer from the blood to the alveoli because of its great diffusion capacitv. This speed of diffusion plus tin* increased alveolar ventilation 110 doubt accounted for the lowered pCO- value. ASBESTOSES VNl) C ARCIN''VtA OF THF. LUNti The association of asbestosis and carcinoma of the lung has been mentioned frequently in the literature. '- 'Heretofore some authors have believed that the eases wre too few in number to lx* of significance; others, especially Vorwald and Karr, have stated that "inhaled dusts, except those containing recognized carci nogenic substances (as radium and tar) cannot in general lx* considered as etiologic factors in the development of primary pulmonary carci- Table ui INCIDENCE nr ASBESTOSIS AND CARCINOMA OE LU.NO Author | No. of j No. Due to | Inci Deaths with 1 Cancer of j dence Asbestosis I Lung (%) Merewcther*........... Wrdlrr**............... Wyers*..................... Lynch, Cannoni;. (rloyne1................... Total... 235 92 115 40 121 603 31 13.2 15 . 16.3 17 14.8 3 ! 7.5 17 14.1 83 1 13.8 noma."4 Our conclusion at present is in favor of the concept that the association of bronchogrnic carcinoma with aslx'stosis is more than coincidence. That there is a significant incidence of bronchogenic carcinoma in asbestosis is apparent from Table in. Merewcther lias cited the largest series--of 235 cases of aslxtstosis 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.*47-4* 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 M crew ether1 and the Miner's Phthisis Medical Bureau of South Africa45 arc 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 (1.4* per cent). Riot/.4* noted an incidence of 8 per cent, but his series ot fifty cases does not seem large enough to be stnbsticnllv significant. However Glovnc* in reviewing necropsy material from 1029 to 1949 : 96 cases 1 also described the surprisingly high incidence of lung carcinoma in silicosis of 6.0 per cent, and 7.* per cent in SUIKICAN JOURNAL jF VI F t> I C i N F | BB 0007312 | Asbestosis, Bronchogenic Carcinoma--Isselbacher et al. 729 die pneumoconioses ns a whole. In this same series 8.3 per cent of caws without any pneumo coniosis had cancer of the lung. Merewether and Gloync's cases were analyzed over a comparable [xviod of time so that it seems unreasonable to interpret the figure of 6.9 per cent as reflecting the increase of lond carcinoma in the general population. The 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. .\s has been mentioned the asliestos particle probably acts as a mechanical irritant while the pulmonary changes in silicosis are considered due to the chemical properties of silica.1'r" Carcinoma of the lung appears to be promi nent in females with asliestosis. Of Merewethcr's thirty-one cases nine were females, or 29 per cent, and in Glovne'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,*7 Gratiam7 5.4 pec cent, Doll and Hill* 8.4 per cent and OchsneE10 10?3 per cent. The higher figure rn asliestosis supports the theory that asbestos panicles 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 partides when lodged in the finer bronchioles serve as mechanical irritants to the bronchial epi thelium. Tlie 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 tow ards the development of squamous cell carcinoma.*' A "lag period" between the exposure to a possible carcinogen and the onset of inalignaiic> is characteristic. Nurdmnmr' noted in his cases that the average duration between the initial exposure to asbestos and the development of Inonchogenic carcinoma was alxmt eighteen years. Similarly Merewether1 found that patients tlying of carcinoma of the lung had a longer mean exposure to asbestos (16.5 years! than those dying w-itli no evidence of malignancy (13.4 years;. Finally, a short but "adequate" exposure may be followed by pulmonary malignancy many years later. In Merewethcr's series is the case of a woman who was an aslrestos worker for only six months yet later developed lung carcinoma. Gloyne1* reported the case of a woman with an exposure of nineteen months who died fifteen years later at the age of seventyone with a squamous cell carcinoma of the right lower lobe. Table tv summarizes the pertinent informa tion of the twenty cases of asbestosis with lung carcinoma that have been autopsied and re corded in the available literature. Four cases have been added to the list compiled by Hornburger4* in 1943. It is noted that in airout fourfilths of the cases in which the primary site is indicated ihc origin of the neoplasms was in the lower lobes. This is in contrast to the general population where bronchogenic carcinoma seems to he more frequent in the upper lobes. In I.indskog s"* series there was an incidence of 57 per cent in the upper lobes, 26 per cent in the lower lobes. Ochsner1" found 56 per cent in the upper lobes and 35 per cetit in the lower lobes. No conclusions should be drawn from the small number of cases listed in Table iv. Nevertheless, since asbestos particles lodge to a greater extent in the lower respiratory tree where the changes of asbestosis are also more pronounced, a higher incidence of carcinoma in this location should be expected if an etiologic relationship exists. In our ease the asbestosis was widespread and severe, and the tumor, which originated in the inferior (lingual) seg ment of the left upper lobe, was in an area significantly involved by the fibrosis and in flammation of asbestosis. It is also noted in Tabic rv that twelve of the nineteen previously iccorded cases had lesions of the squamous cell type. The incidence of squamous cell carcinoma is said to be high in male cigarette smokers with pulmonary malignar.cv.1* At autopsy our patient showed both squamous metaplasia and adenocarcinoma of the lingula. It may he of significance that he was a chain smoker for over twenty vrars in view of ihr observation hv Wynder and Graham7 that males with adenocarcinoma of the lung are MIVLHUK, 10S.S : r; NGTr-. - iiC 1 li-V-O | BB 0007313 | CG 153cl 7^0 Aslx*stosis, Bronchogenic Carcinoma--Isselbackcr ct al. frequently chain smokers. However, it is our belief that the presence of an adenocarcinoma rather than one of the squamous cell type may be explained by the fact that it is not unusual to find several cellular types in various sections of the saute minor.** Therefore morphologic carcinoma in 13.8 per cent of the cases cited in the literature. In silicosis the incidence is con siderably less than this. The asbestos particle may serve as a carcinogen because of the chronic mechanical irritation it produces. 5. Since there are approximately 10,000 Table tv SUMMARY OK PUBLISHED CASE REPORTS IN WHICH AUTOPSY DATA ARE CITED Author* .......................... ' Sn 1 War * ami Mt ' Ofcupaiioft i Duration 1 Freedom 1 jf F.apOMirr from Eaptwire 1 Nature of lumur (yr.) tirforc Death t j ..- -- .. Primary Site * t Meiwain 1---------------------------- 1 vik h, Smith** . ... . . 193* . M. ` Wmcr 1r (dm hr** llnv fte . ... ......... hehert. Getter*7. ..... Lilovnp*1 ... Norrimann*4 Ntinimann Ia it h.*4 South. 1135 1 F, 35 Sptititer , ms J r.7i Mattirw and oprfa me (InMrlmrfill . PH . M. 41 Weaver 113$ 1 M. 5i Packer, wm dei piutneni !93S F. Ji (larticr, apinfier* weaver . 1138 . M. 55 P?captaining amembiv rt**m 1134 1 M. 5o Weaver Afwrwi. 1V4| , M. 52 Pipe inuiLitor Hollrb, Ancnai. . . 1141 M. 50 Pipe uiaulmtor t tn/Htff h. V\fiJlrr*t . . Dettneulei et ah*4 , . Devineulo ct al. . . Hv burger*.............. Hrtrtiburfn*................ Hamburger................ . . 1041 . M. 61 1141 M. 57 . . 1141 M, 50 1 1942 M. 45 . i 1742 M, 43 . ,| 1942 1 F. 49 i ; Machine ailjitnte Niti known Not known No known contact with aahe*tot Cumtrti4*. .... . ` 1948 F,37 Pipe t ovrrer ;- Owen**.......................... Stoll. R**a, Anarrui** - - Promt author*....... . ` 1951 M, 39 . 1951 1 M, 40 ti . .. 1952 ,M, 41 Ailieatm worker Pipe coverer^ Aabmtn* null * workrr; muir - * "t 17 IfMj i 4 om. i \r 15 vi 2 VT .* mn. Squamous cell St|uaAoui cell Sqiuntu* cell Glandular 0*1 .HI R.L.I. R.U.I.. R I..L.I. LL l,, * Mint Bgdula in R.L.L. Pleura None I ! 'V i<|e*pfC*d ; L.U L and pleura 7 'f- 1 Si|uammu nil L.LL . Liver, kidneys n 12 yi ! S<|ttaiiHMt cell I..L.t_ ' Widespread t* 13 |-Squ4iftntt* with R.L 1.. Pleura, modi* t aUnduUr aitmal nods reaturn 25 ? u. , Non>kerjtmu> K.L.L, Mediastinal node*. me iquiuitoui adrenal, kidney 1 t rlieti 25 to yr. i Oai cell R.I.L , Widespread, including brain >J Vni known , Sqtiamou* cell R N<*ne 25 1 mn Alveolar cell 1. lull* Pleura IT 4 mu ^qiiainoui cril ' R. lunt Pleura 5 1 *`f. .squamous tell K tutu: Diaphragm, 111 I7 mo. Anaplastic 1. L.l,,. Pleura Not known . 15 vr. ( Squamous cell i | Squamous tell R. hm i ' 1..I..I.. I.ivrt, adrenal, stomach, hilar 1 Ivuiph nodes JVncitdium, liver, , .> ft * ! , 20 vr. ' Ariruocarvimmta' R. luna About 4 to 5 vr Anaplastic : No tlchnt'e : *ue knlocv. uvanes, femur .NtHir kuintv*. brain, liver u 3 vr. ; AdriHN in inisiiia . Linvulj Mvocardigm. pen- i caidium, spine, reHHial nodes . differences in cell arrangements may -not really represent different etiologic' varieties of cancer. SUMMARY AND CONCLUSIONS 1. A case of asbestosis with superimposed adenocarcinoma of the lung with metastases, following documented harmful industrial ex posure, is presented. 2. ACTH (adrenocorticotrophic hormone) was given with--na^t>bjective changes in the patient's clinical course. ' 3. Pulmonary function and cardiac catheter ization studies were performed before and after ACTH. They revealed an alveolar diffusion defect and pulmonary hypertension. 4. Asbestos is associated with bronchogenic workers engaged in potentially hazardous asbestos operations in this countrv, it is reason able to assume that there are many unrecognized cases of asbestosis. From the evidence presented a higher incidence of bronchogenic carcinoma should be expected in this group. Addendum: Since the submission of this manu script a similar case has been observed by us (MGH 778205). The patient was a forty-six year old contractor s helper whose work since age seventeen consisted of cutting and sawing asbestos board to insulate pipes, trailers 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 p of deep x-ray to the left chest. AMERICAN JOURNAL OK MEDICINE '07; TH'7 nor-M'-vtsit WOT fcli 4 f Li.;3 GG 15323 'j BB 0007314 | Asbestosis, Bronchogenic Carcinoma--Isselbacher et al. 731 At autopsy the lungs were firm and weight'd 3,350 gm. There was a poorly differcnttaied adenocarcinoma arising from the left lower lohe bronchus, almost completely replacing the left lower lobe. The tumor had spread to the left up|>er lolte, hiluni, pericardium, pleura and diaphragm; and had metastasized to the right lung and adrenal. 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Association of silicosis and carcinoma of lung. Am. J. Cancrr. 35: 38. 1939. 5". Lindskijg, G. K. and Bloomer, W. D. Bronchogenic carcinoma. Cancer, 1: 234. 1948. 58. Willis. R. A. Paihologv of Tumors. St. Louis, 1948. C. V. Nlosby Co. 59. Lindseoo, G- F. Bronchogenic carcinoma. .4mt, Sing., 124: 667. 1946. AMERICAN JOURNAL OF MEDICINE I he American Journal oe Medicim1, Inc., 49 West 45th St., New York Primed in the United States of America l-_07316~j GG 15325