Document 87e7qY98znQYVbX6ZQ5NROZe

PlAWTffPS EXHIBIT 416 ACS-1 18 Edited by David M. Spain. MD Asbestosis and Pulmonary Carcinoma fRANK It. DUTRA. MI>. AND JOHN D. CARXKV. MD. CASTRO VAU.EY. CAUK Although asbestosis, a disabling industrial disease, has beett recognized for only some 50 years, the mechanism by which the dust particles produce tissue alterations in this condition is better understood than for any of the other pneumoconioses. Asbestos, a hydrated magnesium silicate, evokes cliaractcristic abnormalities of the bronchi and bronchioles, alveoli, and pleura as a result of mechanical irritation, ami in some 10% to 15% of persons with asbestosis the changes progress to malignant neoplasms.1 Asbestosis usually affects persons from whom a history of industrial cxjxjsure to asbestos dusts is readily obtained, but in stances of the disease occur with increasing frequency in which the circumstances of ex posure arc not known to the physicians or even to the patient. Suianitud tor publication Oct S. 1964. Accepted for publication Oct 2S, 1964. Editorial Comment by David M. Spam. MD. and Case Presentation by Frank K. Dutra. MD, Pathol ogist anti Director of laboratories. F.dcn 1 |o-pii.l. Castro Valley, Associate Clinical Professor f Pathology. University of California. San I'rnneiseo. anti John D. Carney. MD. Pathologist. F.dcn Hos pital, Castro Valley, Clinical Instructor in Palludogy, University of California Medical School, San Francisco. Reprint requests to nrookilale Hospital Center. Unden Blvti and Rockaway Fkwy, nr#'oklyn, NY 11212 (Dr. Spain). Report of Case A104X4. .Vo* /nmruro /V/tmux /lifMiiiu/nifum Hospital.--Yl*e patient was a 70-year-old white man wlm complained of the insidious progressive citnv.'i* ness of the left upper extremity, first noted thrsv weeks Wtore admission. The patient Itad been di abetic for at least five years ami was being treated witli insulin zinc suspension (I.cttte Ilctin) (5 units per day). The only recorded occupational his tory is tliat lie had been a pipe filter; no details were given. He was an alert, chronically ill man in tin acute distress. Jllond pressure was 155 systolic ami SO diastolic, |si1sc. 82 tier minute ami irregular, Postcroanterior diameter ot the chest was increased, there was diffuse hyncrrrsminnee. ami scattered inspiratory rales were heard over the haws. A grade ll systolic apical murmur was noted ami auricular fibrillation was present. IV liver edge was palpable 2 cm below the costal margin. Strength was dimin ished in tltc left up|tcr extremity and flattening of the left nasolabial fnl.l was noted. Chest films (Fig 1 and 2) showed moderate pulmonary emphysema with some increase m hrouchovaseular markings. Hematoiocic findings: Hub. 17.A gut/100 ml. VVHC 11.000/ cu mm, and normal diucrcmr.d. CUvul chem istry aualytiral results: HUN. 16 mg and b'RS 220 mg/lGfl ml. Urinalysis: 1-r albumin, 1 to 6 white blond cells jer Inch-power field. He seemed to be improving in the hospital mml the llth hospital day when he suddenly became "e:k and semienmatose. He did not respond to miravenous glucose and died approximately 20 nmmtcs later. Autopsy: Death had Wen caused by tliro*nWis of intracranial ami coronary arteries with acute cerebral ami myocardial infarction. The lungs Arch Environ Health--Vot JO, March, 1965 V .% ASUFSTOSlS dr CAKClXOMA--nura.-l .r CAUSI.Y 417 T)ciir.| 1.1W1 cm iocimUt .xwl llrf tu'u'ai sur faces were ami llivl.s were not present. lit tiu* lateral !* ir iivum tl*c upper lnle <*i Uk.* leit hme "'.x* a Mil-pleural Jl'licfiol ma** nvaMirinc 1.5 rm * lUaon-trr. Tlih filmtNts .m<i in part t* the pleural tls.ekemng; in advanced cases plcural-pcricardi.d a*lUo>*un and fii>ri>MS may become so pmummeed that a characicriMic "j-oiCupinc- was ruvrrrtl l>f imiUiicaUii pleural Minarc. Iteavl slvulmv" results.* MieroscupieaMy, the jmlutMiMry alvclr spare* at well at (Ik* Iwoocliial liuonia cmtlaimtl jraiiiTfil clusters ; ;-icmrf>t-laloi marroplwevs aiul a low atlwMoiit Italics. I'jnplty.wnit ,wa main Jett liy stretched, tUutuetl, ail broken alveolar septa treat ing tmall cystic spare*. There was tMTOvaseutar, periitroot'iiial, ami nodular interstitial ftiirnds. Tlic filtrurie areas contained a smaicratc amount of aiithracoiic pigment ami mmtrrcm* typical bother Micrmcopically, the mass in the upper 1<*5< of the left Urny wat a tumor which orientated in au cetane bronciiu*. It extended in a liapharard ami stellate C<uw<.mh:mt with tlic development of tihniMN, h>tnrtiim and emphysematous en largement of many alveoli lcc*me prominent, llmuehtus and bronchiolitis become chronic atul often lead to bronchiectasis. The tlcjvudeut :ovtumN of the lungs arc usually more profoundly affectvtl than the tipper halves. This serves as a gross diagnostic jtmuc in differentiating astaMnsts from the more widespread and nodular alterations of sdieosis. fashion into tlic adjacent pulmonary parenchyma. TItc architecture wa* comprised nt immature ami atypical soitamous cells among winch kcratm ami intracellular bridge* were not demonstrable. The nuclei were large atul vesicular: some were ot rela A>bestiis bodies arc essential to the microscopic diagnosis ot the condition. Some of these structures max* iic free in alveoli, 'out most of than arc embedded in fibrous tissues tively gigantic proi*ortiom with irrrmilarly dumped of the walls of alvcoii or bronchioles. A few chromatin and distinct, wrinkled nuclear membrane*. Tlic cytoplasm ranged from colorless to finely granular and amphophilic. Typical asiKstosis itodies wrcrc numerous both in ami about the ttimor mass ' may be surrounded by giant ceils of iorcign body tyjtc. These bodies arc comprised of asltcstos fibers surrounded by albuminous (Fig J). material, calcium salts, and iron salts. The Pathology of Asbestosis etuis arc usually knobbed, while the central regions may be notched. The color is yellow The crystalline asbestos fibers become to pinkish red m the usual histologic prepara wedged in tlic lumens of the rcsjnnnory tions. A few arc as small as Ip in length but bronchioles, and with the inspiratory narrow the Majority arc 10/t to 60/* long. ing-elongation ami expiratory widemngshortening of these tubes through each Clinical Findings respiratory cycle the fibers arc worked into Dyspnea is usually the first sign of disease, the walls of the bronchioles. This mechanical and it seldom occurs with an industrial cx- irritation accounts for the fibrosis, which at jvisurc to asbestos dusts of less than five first is jicribronchioltr. As the disease years. Iaiss of weight is often marked. Dry progresses, irregular diffuse fibrosis occurs cough is common.and more thau half of the throughout the pulmonary tis>ucs with efface- ivtticms cNjKX'tomte small amounts of blood- ment of alveoli in the areas of fully developed streaked sputum sometime during their ill disease. Ultimately, the reactive tissue inter ness. Asbestosis bodies may be found in the feres with lymphatic drainage of the lung ami sputum of most patients by microscopic ex stasis ]>ccotncs an additional factor predis amination. posing fibroplasia. Increasing flow of lymph The chest becomes emphysematous, and toward the subplctiral lymphatic network fine crackling rales arc present over tlic lower tends to produce irritation of the pleura with lobes. Cyanosis and clubbing of the nails are attendant pleural thickening ami adhesions to frequently present m patients wuh moderate the parietal pleura. ly advanced disease, and cor pulmonale is The "ground glass" appearance of the lung often a late complication. Asbestosis does not shallows in films of patients with aslxrstosis prcdisjtosc to tuberculosis, differing in this may in part be due to diffuse parenchymal respect from silicosis.1 Ar(K nfirtm Health--Vol JO. March, 7965 as .'l.Y/J/;.YT0i7.V 0- CAlta,\-OM.-l-nurh'.-l 6- CsUtXl.i Fie 1 (left) and 2 (riplit).---Postcroamerier anil lateral films t chest at time of admission. Evidences of emphysema with regions of increasine density of bronciiovascuiar markings. There were no rctocnitaiiie signs of fibrosis. ami nodularity is absent. Roentgenologic Findings ' Attempts to correlate thcTocntgcnographic citanges with the physical findings ami decree of disability is hazardous in any given ease of any of the dust diseases. This axiom is especially true m asbestosis.4 Pulmonary disability may occur in patients who have the most minimal alterations of the chest films, while others with films reflecting significant pulmonary changes may have little or no rcc-; Fip 2A.--Squamous ceil carcinoma invading tissues of lime. Distorted alveoli containing phago cytes arc in the upper right comer, and several aslicstnsts IkkIics are near the center of the field. Hematoxylin ami eosin; X 192. Arch Etwitnn l{cnitU--Vr*\ JO, March. 7965 ASOSSTOStS c CARCtXOMA--DUTRA O CARSZ't rc ` * A *T >- , ; VO *< . X > u* * S**' > I; * ^ -V V. / -' v; :. . **"`'t* u .. .> vr. * v4c / ' ' - ->-fc ^ l ' 4#V. ./ - ^ r: - I "*U* " * v-v*7* .' . - _v ** ~ ": ^i ** ** : : < >:;r - -r ' .* .. a- .-w-. . ..._ * ^.r._____ < Fig JQ.--Ektacolor print of Fig 3A. * -;*>~ *0/ -- *o *K-<x f ^ . \* > * '- -* ;. V .j*: \ *A v }4 *V. , \n- -'~zp N. fr* c L* u ^ - " *.s\i *. - ' O , *J* S? * O .>.~ A T . y.V"1 ^ ^' * a * * : '. fv. .r.o" r. -< '5 j *i !; ] fro i S' W f ^ . f" *V*> f-"v -- - /* ' : ' - i-" .* A ..A. W V :\ -n - - \'- V./>o*' **., .St -\ !* 3 x ' > *- -o ^1 *v ' r; *I i * -Vi^v Fig. JC--Ekucoior print thowing asbeito* ,bodct beneath pleura. *frri vva Httldk /tsiirsvosis ,v cAuctxOM.-i--uuruA & cakxhv <zi ogtti/ahlc Alteration t* lung ftmcium. Gcucr.illy, the first rocutgctiugfaplnc sign of asIvMoms U dilYttsc haziness over the lower dursl of the lung fields. In more advanced cases this lias progressed to a "ground glass" apjHranmec which obscures the broncho* vascular markings, loiter, the upper portions of the lungs also bcctmic fibmtic, but the up* per areas always remain more radioluccnt tlvm the lower. Asbestosis and Carcinoma of the Lung cmifKcrvicms can lead to squamous carci noma of the uterine cervix through the same series of anatomical progression. Mechanical irritation of the asbestos fibers probably leads to squamous cell metaplasia of the bronchi and to bronchogenic carcinoma in the same way. Summary Asltcstosis is a chronic progressive pul monary disease which results uom irritation of the lungs by crystalline asbestos fibers. In recent years it has become clear that there is a more than fortuitous relationship between asbestosis ami bronchogenic carci* noma. Tins belief is based on the following observations: (1) Approximately U.S/o of patients with asbestosis develop squamous cell carcinoma of the lung,1 an incidence con siderably greater than in persons the same age without other lung diseases or who have other pneumoconioses.6 (2) The cancer is usually iu one of "the lower lobes where the number of asbestos fibers is greatest. This contrasts with the data from eases of bron chogenic carcinoma not associated with asbestosis, in which the greater proportion arc iu the upper lolies.'* Squamous metaplasia of the membranes lining the Imoichi and bronchioles is often observed in asbestosis, The disease is often unsuspected clinically Ijccnusc the occupational exjmsure to dust containing asbestos fibers has not been elicited, and because the chest films may not he diagnostic even in the presence of dis abling abnormality. Iu asbestosis. pulmonary and subpleural fibrosis distort the lungs ami lead to respira tory insufficiency. Squamous metaplasia of the bronchial epi thelium is induced by the irritating fibers, and in some eases there is progression to squamous cell carcinoma of the lung. Pleural mesothelioma is also reported, particularly in eases of asbestosis in South Africa. REFERENCES ' and the mctaplastie cells frequently are atypical with appearances suggesting transi tion toward carcinoma. It has also been suggested that asbestosis may predispose to mesothelioma of the pleura. Thirty-three eases of this tumor were observed over a period of four years among South African workers in asbestos mining operations, ami one ease of asbestosis com plicated by pleural mesothelioma has been 1. Telisehi. M,, ami Rnhenstonc, A. I.: Pulmo nary Asl<sto*is. Arch Path 72:234-243, 1961. 2. Gardner, L. TJ.: Pneumoconioses. Med Clin N Amcr 1239-1200 (July) 1942. 3. Al>esto*is: Report of The Section on Nature ami Prevalence Committee on Occupational Diseases of tlic Chest, American College of Chest Physi cians. Dis Chest 45:107-tlt. 19. 4. Wright. G. W.: Functional Abnormalities of IiKiiistrial Pulmonary Fibrosis, AMA Arch Jmhiscf Health 11:196-203, 1955. described in this country.7 . 5. GloyiK, S. K.: Pneumoconiosis: Histologic At the present time, the mechanism by which asbestosis prcdis|Kcs to neoplasm of the lung or pleura is unknown. Squamous metaplasia of bronchial columnar epithelial cells, predisposing to carcinoma, is known to occur as a result of chronic inflammation front ihe smoking of cigarettes as chronic Survey of Necropsy Material in 1.205 Cases. Lancet 1:810-R14. 1951. 6. Isseltachcr, K. J.; Klaus, H.; and Hardy, If. I..: Asheunsis ami JUouchoccnic Carcinoma. Amcr J Med lS:721-732. 19S3. 7. Case Records of Massachusetts General Hos pital, neujninin Castlcman, vtl.. Case 62-196J. New F.g J Med 269:747-754, 196J. ArcU liniirfin IIcailU--Va/ 10, 3fr</, 1965 AZZ .isnr.STOsrs C-ikcixoma--outha c.-ixxr.y Editorial Comment This, ease presentation excellently illustrates many aspects of the relationship of asbestosis h> pulmonary carcinoma. An especially pertinent statement is made in reference to clinical history of previous cxjiosurc tn nd>c>to*. and well worth re peating "hut instances of the disease occur with increasing frequency in which the circumstances of exposure arc not known to the physicians or even the patients." rcrltnps a positive history of exposure would be obtained mure often if the ques tioner, who is trying to obtain a previous history of cx{*stirc to aslicstos, was mure fully aware of the various industrial processes or products in which a worker might be exposed to aslicstos fillers. Aslicstos fillers consist of silicate minerals often re ferred to as amphiboles. Ten percent of the mined rock consign of these mineral filters which contain complex silicates. The best known sources arc located in Canada (about three fourths of the world supply), KhMle>ia. South Africa, and the USSR. The complex mineral fillers arc removed from the powder and then the long fibers arc separated from the short ones. It is during these processes that the most dangerous exposure occurs. The long fibers arc used for the manufacture of asbestos cloth ami gaskets, while the short ones arc used for paper, heat resistant boards, filter pads, and brake blocks and linings, and arc increasingly found in plastics. Each year new uses for these fillers arc constantly being developed. In the currently reported case, the only occupational history is that the individual had been a pipe fitter. It is conceivable that part of his work was concerned with the use of asbestos-containing coverings for these pipes. Tins might have been the possible source of exposure in tlut it may have l>ccn necessary for him to saw through this asbestos material and thus produce a certain amount of asliestosis-coniaining dust. In this case, the carcinoma was of the squamous tyj>c. There seems to he a difference of opinion as to the most prevalent h'stologic type of carcinoma that is found in association with asbestosis. In this report, it is stated that squamous cell carcinoma is the usual form, whereas Spencer 1 states that adenocarcinoma is the most frequent form. It has become increasingly apjiarcnr that pulmonary cancers arising in scars arc more frequent titan was formerly believed. These are generally adenocarcinomas. Whether or not some substance or substances, as for instance the iron in the asbestosis body, is specifically carcinogenic nr whether carcinoma arises because of the nonspecific alterations produced by the aslicstos remains to be de termined. With the squamous cell carcinoma, it is conceivable that the squamous metaplasia, the bronchiectasis, and the fibrosis caused by the asbestos fibers might impair the lung's ability to effectively rid itself of other carcinogens, ami by this process cnltaitcc the development of carcinoma. In jeirticular, it would be important to note what proportion of individuals with asbestosis and pulmonary carcinoma were cigarette smokers. At any rate, the incidence of pulmonary carcinoma In in dividuals with aslicstosis in various rcjwrts has ranged from 13/o-20/o. Statistically, this is a highly significant relationship. Of more immediate interest arc the eases of mesothelioma of the pleura tlut occur in individuals with asbestosis. In a most recent rcf*>rt 3 from Liverpool. England, evidence of exposure to aslicstos was noted in \4 of 16 consecutive cases of pleural mesothelioma. Asbestosis bodies were present in lung tissue in ten of these ctscs. In another study on two patients with mesothelioma, one individual had not been in contact with asbestos for 20 years and in the oilier ease the exposure had been only intermittent ami slight. In all individuals with mesothelioma careful search should now be made for asbestosis bodies and fibers in the lung and tumor tissue. It Ar(k Environ UaailU--Vet IQ, March, WtS . ' AStWSTOStS A CAKaS'OMA-miTKA fr C.lXSr.Y 423 is suggested that thick frozen sections be used because adjestusb ixidics may easily l< missed in thin sections' l-'ilnosis of the pleura with adhesions lo surrounding struc tures is commonplace in asi>csto>i>. The nshcsloMs Unites produce alterations in the periphery of the lung whereby these Imdics gain entrance to die pleural tissues via *lc peripheral lymphatics in the lung. because of the occurrence of mesothelioma in association with asbestosis, it is likely that substances in asbestos iilcrs are spe cifically carcinogenic- It is unlikely that other iniialcd carcinogens would gain access to the pleura and produce carcinoma m tissue previously rendered less resistant by the asbestos- A ease cf asbestosis in which the individual had both bronchogenic and gastric carcinomas and in which die latter tumor contained rcfractilc granules lends support to lids concept of the specific carcinogenicity of the asbestos fibers. REFERENCES t. S;ci*cer, M-: Pathology of Lung, New York: Tle Macmillan Co., 1962, pp 618-610. 2. Owen, W. C-: DI/Tujc Mesothelioma and Asbestos Exposure in Merseyside, Brit Med ) 2:214, 1964. 2. Fowler, V. E. S.; Slopcr, J. S-; and Warner, F. C: Exposure to Asbestos and Mesothelioma of Pleura, Brit Med J 2:211,1964. Arch Environ tlealdv~ol IQ, b(arch, 1965 ^ \