Document M4vmVkjJndDG0e87YVkn8nyX9
FILE NAME: Smoking (SMOK) DATE: 1953
DOC#: SMOK005
DOCUMENT DESCRIPTION: Journal Article - Case Reports Asbestosis and Bronchiogenic Carcinoma
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 e t L . H a r d y , m .o . Boston, Massachusetts
f~ \ --O i a re several reasons for presenting curtains and clothing. T h e chief operations are
f in dm A! a case, report and a review of the disintegration of the crude mineral, carding the
_A_ as .dial ale literature dealing with the fiber, separating the more useful long from the
:laii-.inshir) b e tw e e n occupational exposure to short fiber, spinning, plaiting and weaving the
- '.'.'tos reel respiratory tract malignancy. Tire asbestos, often with cotton. Insulating material
rjii.e/cn; increase in bronchogenic carcinoma, is produced by mixing magnesia, diatom.uceous
'-./retailc in m ales, reported in the. pas! decade earth and other materials with asbestos to make
!-.*d t a *cru:inv of respirable (lusts as possible cements or fillings for insulating boilers, engines
.ic-'-v v . M ost English observers' "* are satisfied and pipes. O th e r non-textile asbestos products
:: r: ile.: e is a statistically significant increase so made include asbestos cement, sheets, brake
i uli r.. -nary m alignancy among asbestos and d u tc h linings, electrodes and switchboard
rkers. Some' American writers consider that panels.
i \ p ricnec to date does not support this
Asbestos is a hydrated magnesium silicate.
:c.er. it o r .5 ' I he work of G r a h a m /'-1Doll and T he chief supplies arc in C a na da , Gape Province,
.-Ed.' ar d O ohsneA -10 has created much interest Italv, Rhodesia and Russia. Asbestos dust given
lire correlation of cigarette smoking with off in manufacturing processes consists of frag
:. :,c .enic c a rcinom a. E. R., whose case is ments of fillers and small rounded or angular
. w in '.r e s e n te d , was exposed to harmful particles. Actual studies in industry show the
m o u n t ; of asbestos dust and was a chain size and shape of the particles of asbestos to be
- m e r e r . T h is prosifies speculation as to the such as may gain entrance into the bronchioles.11
m ssiole role of two eliologic. agents.
Experience has led to the acceptance of five
l ew renortvd cases of lime cancer related to million particles of asbestos per'cubic foot of air,
mmufirial asbestos exposures pro\ ide data on of small enough size to be respirable, to be the
me c h a ra c ter and quantity of dust exposure, safe working concentration.
i is a serious deficit in exact study of ctiologic
Some operations because of their dustiness
: u ueA hon. In the clinical report presented are more hazardous than others in asbestos
mein Stale authorities have determined by manufacturing. Bagging the. asbestos, separating
. e n siirem em tha t tire asbestos dust exposure the. long from the short fibers, carding, spinning
: Ans r u n d u rin g his twelve w a r s of work was and weav ing show a greater statistical evidence
: .m sid w a h ly above the safe level, which is con-' of asbestosis than do other operations. As might
-A c re d to lie five million particles per cubic lie expe d e d , the. longer the duration of exposure
at ol air for an eight-hour working flay.
the greater the num ber of cases. In the Mcrc-
It :s p e rtine nt to this presentati: that there wethcr and Price series there was one case under
m e p r o b a b ly a b o u t 10.000 worker.-. engaged in four years', exposure, and up to 53.6 per cent
.memially h a z a rd o u s asbestos m anufacturing with fifteen to nineteen years' exposure.16
a;.'-, ra tio n s in the U nited States.11 Middleton i - ports the nu m b er in Great Britain as between
CASE REPORT
r . "' *to 5 . 0 0 0 . Most of the industry is engaged
E. R. (M G H #735586),16 a forty-one year old
uu asbestos textile m anufacturing producing asbestos mill worker, entered the Massachusetts
a? .-.holing mattresses, brake linings, fire proof General Hospital in April, 1951. T h e chief
Fi ora the T1 p a rtin e n ts of Medicine and Pathology, a nd the Occupational Medical Clinic, M assachusetts General
:sp :ta l. Heston, "Mass. T h is \\ ork v s supported in p a rt by the National Institutes of H e a lth , Division of Rese arch
: v i v. i . k , 1 9 5 3
72T
AslK'stosis, Bi'oncliogcnic C a r c i n o m a I.ssclbachcr 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) inspirators crackling rales over the region of the left lower lobe. The I left border of cardiac dullness was 10 cm. to the
j
J ABLE I
i
P CI M OA 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
Kcfot c AC HI
After ACTH
Approvt-
mate Noi mal Values}*'
I
IT.:,-
J ig. 1. X - r a y of chest. T h e lower lobes arc reduced in size and show a " h o n e y c o m b 1' p a t l r n i . T here is an increase in linear a n d n o d u la r markings. A density is Me.n in the ret son of the lingula with enlargem ent of lymph nodes in the left hing tool, suggesting a tumor in that area.
complaint was progressive low back pain which had been present for four months and was only partially relieved by aspirin. In addition, one month before admission the patient noticed increasing dyspnea on exertion, a worsening of his chronic productive cough, night sweats, anorexia, feverishness and a 10-pound weight loss. 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 nil he had spent one year in the " picker room" where crushing, grinding and sorting of long asbestos fibers was carried out. Me 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:.it ( 1i1 *!l> (I-.)........ Maxi:: j?n bie ml im: <..ip nils-
(i-./ Resitlt) t! \ t!ume (i->...
f abet la, ver>ti!;i ion
a ./ Ah cn!; r PO- (m n. He). Ancn.i 1pO: fmm lie) . ArtciD ,,co. (mm HtO Ai trr;.i O: m tn il ion (' ) ................ Set uiri pH .. . AIm nl. r-mici ;,1 O: <bfie eiiCf
fmm IIK).
24
32 3 1 575
7 63 115 0 88 0 36 0 97 3
7 45
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 u r po: b : m e d b v D r . .lolin A Held t, IA p a rt m m t o f Pmxiolo-v. J ! gt \ a id -Vlwol of Public Health,
j A C J H I ' D m'g. imi.i i7i nu n l .n i y for ten dasj..
XIV.th Mitbue mm xv.;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 JO U RN A L OF MEDICI NE
Asbrstusis, 'Bronchogenic C a r c i n o m a Jswlhachcr cl al.
723
, , t en flays, (.'.lir ically there was no change ,.N(i |)t for euphoria. Pulm onary function and i-ardiac catheterization studies were performed iicforr a n d after AC'/J'l] and likewise showed no Penifican! changes. ('J'nl)Ies t and it.) Cardiac catheterization did reveal chronic cor pulmonale
blood count was 6,300, hemoglobin 11.3 gm. per cent.
It was believed that the patient had pneu monitis in the right lower lobe and early cor pulmonale with congestive failure. He was digitalized, given mercurial diuretics, anti-
T able n CARDIAC CATHEIEUIZATIOX STUDIES* HEIORE AM> AFTER ACTH f
i "
(cc./m in ./ sq, in.)
O,.
Ca-,p a r i t y i Radial ! Artery
(ec./'lOO cc.)
O.
Ofintrnt Radial Artery J (ec./lOO cc.)
Os
Satura tion
Ratlial Artery
(A)'
kwlinonary Artery P its*tire
(min l i d
Mean Pulmonary
Artery Pressure, (mm. Jig)
Cardiac Index
(L./inin./
m .)
Approximate
no rm al values30
145
IS- fore ( R e s t ..................(
180
A C T H | Mild exercise '
l (2 inio.). . | 370
After
f R e s t ..................j
156
A CT) I | Mild exercise :
l (2 m i n . ) . ..
349
20.0 19.3
17.4
19.0
96
30/10
15
18.1
94
36/14
21
43/14
28
16.6
95
38/15
23
52/22
36
3.2 4.47
5.55
4.02
6.97
* Those studies irerc peifoimed by the Cardiac Catheterization Unit of the Massachusetts General Hospital, including Drs. G. S. M y c r h A. 1>. F i k cilic7\, .7. R. O.N eill, G. Cohen ami .7. G. Scnnnrll.
t A G 7 17 100 mg. intra m u sc u la rly for tun days.
with slight pulm onary hypertension; after biotic.s (penicillin and streptomycin), and was
exercise the pulm onary hypertension increased in an oxy gen 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 rvor.se. 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
co rk , llowcvei, ihe 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
exam ination on re-entry revealed a tem perature collapse lout remained inflated, completely
of lOO.dH. rect.illy. pulse of 120-144, respirations filling both pleural cavities. T he majority of
.30 per m inute. H e h a d m arked 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. Roth the visceral and
inspiratory and expiratory wheezes throughout parietal pleurae were markedly thickened, gray
Iho lung fields. At the rieht 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-colored
tactile fremitus and increased vocal fremitus, fluid loculated in the left base. T h e interlobar
d'he left horde:' of cardiac 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 fingc.rbrcadths and there were a num ber of whitish gray, shiny plaques
was 2 plus ankle edema. At this time the white 0.3 cm. long; these resembled similar plaques
nov r. miskh, 1953
I
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J
ii 7 - 4
Asbcslosis,? Bi oik lujO-cnic C arcin o m a Jssrlhac.hn cl al.
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F ig. 2. C u t surface of left lung nficr funnulin fixation. Note difiuse pulinonary fibrosis and marked pleural thickening which 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 difiusc 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 lube bronchi were rim.! 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 di; ..d, and there
F k;. 3. Asbvstosis b r>:!u's in tlie I n n " . T h e clu b sh aped, beaded asbestos's bodies :ue seen in the. a l\ e o la r ducts, surrounded by imicroj>ti;igrs a n d "dust cells'1; X 900.
was collapse of the intervening parenchyma. The veins and arteries appeared normal.
There were adhesions between the visceral and parietal pericardium both at the apex and the base. The apical adhesions were thin fibrous strands but those at the base were extensions of the firm tissue described in the left lower lobe bronchus. The heart weighed 360 gm. There was involvement of the left atrium and auricle by thick, firm, grayish pink tissue for an area measuring 2.3 by 0.7 cm. 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 bodt' appeared to have increased porosity.
A M K k I Cl A N J O U K N A I . O F M l ' . D I C l N K
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The ' soction-p near th 1 crnl art, be seen >
Filno-^ prulifci'i" the artq and plj' peribro ' apices, .i demons t fibrosis | the lungl areas b > firmed >'
A sites t in all s( : fibers 41 sonte cl ` which s:l
p r e p a r a ::
prepara 1 larger, e
k o v i: m i `
Asbestosis, Bronchogenic C a rc in o m a fsselbac/tcr cl al.
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F ig. 4. Sq u am o u s m etaplasia in the alveolar ducts; note also asbestosis bodies a n d interstitial Jib?'Osis; X 100.
F ig. 5. A denocarcinom a invading the m y o ca rd iu m ; X too.
The lungs were sectioned topographically; sections from all segmental bronchi were taken near the hiluni, 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 all seciions. (Fig. 3.) These were segmented fibers averaging 50/r long, some, straight and some club-shaped, others resembled dum b bells which stained dark brown on hcmatoxylin-cosin preparations, and blue on Prussian blue (iron) preparations. Particles of iron-staining dust and larger, easily identifiable asbestosis body parti-
k o v e m b i .r , 19 5 3
cles, were present in the macrophages. The distribution was equal bilaterally, lacing slight to moderate in the apical segments, quite marked in the remainder of the lung and oc curring with equal intensity in the hilar, midlobar and peripheral zones.
'While most of the asbestosis bodies were seen in the bronchioles and alveolar ducts, a few could be seen in the alveoli, and fragments were found both in the macrophages and in the lymphatics. Several aggregations of asbestosis bodies were found in the bronchi. Fragmented asbestos fibers were found mostly in the 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-
/ /
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/2G
Asbestosis., Bronchogenic Carcinoma Issclbacher cl al.
F ig. 6. X-ray clifTraclion film o f luni; residue o f 1:'.. K. * Tin- liner listed whe n com p a red to the known p attern for asbestos p \'t' positive proof th at the lung residue is essentially 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 fo rm al ize d lung tissue was digested in 20 volumes h y drogen peroxide, th e digestion being accelerated with gentle heating. T h e residue fiom the digestion was treated with dilute hydrochloric arid, filtered, washed and ignited at 500r. The ignited residue was analyzed by x-ray diffraction by the method described in the article by H a n a u a l t , .1. D., F i n n , H. \V., Frevel, L. K ., " Chemical analysis by x-ray diffraction," Indus!. & Brig. Cleon., Anal. E d.y vol. 10, no. 9, 1933. T his w ork was clone by R. 1. C ha m be rlin and A. W orwucki, dr. of the Massachusetts Bonding and Insurance Company, Boston, Mass.
taim 'd brown pigment granules m a in ' of which
Blood vessels: T h e arteries and arterioles of the
took an iron stain, and portions of asbestosis right middle and both lower lobes showed
bodies were also found in the macrophages. moderate intimal thickening with hyalinizalion
!
(These cells have been called dust cells and arc and narrowed lumina. This was most marked
1
thought to Jay down the iron on the asbestos near the hila but was found occasionally farther
fiber, constituting the asbestosis body.) Anthra- into the periphery.
cotic pigment was also present in the m acro
J'umor: Adenocarcinoma was found originat
phages. Multi nucleated giant cells of the foreign ing in the inferior lingua] segment of the left
budv type weie found in abund an ce in all areas; upper lobe bronchus. T he tum or was present
manv of these contained birefringent asteroidal in the mid-zonal area of the apical posterior
I
bodies. Few lymphocytes were seen; those segment of the. left upper lobe, the entire
present were, scattered aro u n d the bronchi lingula and left lower lobe, as well as the right
near the hila. A few focal areas of bronchopneu middle and lower lobes. It had spread by sub
monia with polymorphonuclear infiltration were mucosal and lymphatic routes. Sections of the
present; these, had no p articular relation or left atrium showed direct extension through the
location to any grouping of the asbestosis bodies left hiluin into the pericardium and m yocar
a n d were undonhtedlv a term inal phenom enon. dium. (Fig. 5.) Metastatic tum or was seen in the.
T hroughout the lungs many air sacs were fourth lumbar vertebra.
dilated and contained a granular eosinophilic
Asbestos "granulomas": T h e white plaques
m aterial, probably fibrin. Some of these plugs described in the diaphragm and Glisson's c a p
t
were undergoing organization, mainly in alve sule ware made up chiefly of hyalinizcd con
olar ducts; this type of fibrosis probably accounts nective tissue. No asbestosis bodies or giant
for a small percentage of the total fibrosis seen.
cells were seen. These distinctive, areas grossly
Broucln: T h e bronchi of the lower lobes showed suggested granulomas.
marked bronchiectasis; there was dilatation,
X-ray diffraction studies were carried out on
fibrosis of the muscular coat and peribronchial a sample of formalized lung tissue. T h e resulting
fibrosis. While the latter was most marked in pattern indicated that the lung residue was
the. lower lobes it was seen in the hilar and mid- mostly asbestos. (Fig. 6.)
zonal regions of ah; ist all segments. A nother striking feature was widespread squamous
COMMENTS
metaplasia of the bronchial epithelium. (Fig. 4.)
Asbestosis may he defined as a specific, occu
This was most marked in the alveolar ducts; it pational disease caused by the inhalation of
was found in all areas and was not particularly asbestos fibers and leading to a progressive
related topographically to the adenocarcinom a fibrosis and scarring within the lungs.17 It has
described later.
hc.cn demonstrated by G a rd n e r50 a n d again by I A M 1. R I C A N J O V K N A I. O !' M E D I C 1 N E
Vorwald: occur wi concentre cubic, foe,
T h e p, inhalatio, to he cli lather, tl from fib The inh. to pass 1, so they i) reaction The pa consider (k'squan of asbest
T h e 1< lining tl irrilalioj mate, h phagocs asbestos phages. asbestos so-calle from a particle ing of ' course which irritatie sputun Their j to a sin an ind
The is the lion c and al compi in con nary t the lo partic a fine lower uppoi
Th pro i lends cease to he tion
x a v i
/
Asbestosis, B ronchogenic C a rc in o m a - -Issdbaihcr rt at.
7~7
\'u rw n k l's that usually the disease will not occur with fibers less th an 20/je in length or a eencentnition below five million particles per. ,-ubie 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 iu 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 f iction 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 Irani 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 comjire.sses 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 intcrcurrcnt infec tion contributes to the progression in m an.'3
N o v i . M n 1-: r , 19 5 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. Mcrewcther 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 ]mxluee 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
7;?8
Asbestosis. 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 u t a d e d c o n s k l o i oXion a n d a n a l v s i s : ( 1) t h e
pulmonary function and cardiac catheterization studies; and (2) the significance of the superim posed bronchogenic carcinoma. .
r It] . MON ARY 1r , \ . : ! \ A N D CARDIAC C . V n T l C l E K ] / A T I O N S J UDIES
Table ) indicates, as one might expect, that the. patient had a reduction in vital and m axi mum breathing capacities. However, the finding of an alveolar-arterial oxy gen 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 longs to the capillaries. This corresponds to the syndrome of " alveolar-capillary block" de scribed by Baldwin, Command and R ic h a rd s31,32 an d again by Austrian ct a l.33 T his diffusion defect is not snrpiising when one recalls the fibrosis about the alveoli, alveolar duels, capil laries and bronchioles that occurs in asbeslosis. 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. Tin? 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 pulm onary artery pressure occurred with exercise. (Table n.) The partial pressure of carbon dioxide in the blood (36 mm. 1Jg) was low normal rath er 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 capacitv. This speed of diffusion plus the increased alveolar ventilation no doubt accounted for the lowered p C 0 2value.
ASBESTOSIS AND CARCINOMA OF THE 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 b e r to Ire of significance; others, especially Vorwald and Kang have slated that " inhaled dusts, except those containing recognized carci nogenic substances (as radium and tar) cannot in general be considered as etiologic factors in the development of primary pulmonary carci-
T.M'i.i: in
INCIDENT.!. OF AOiLsTOUS AND CARCINOMA OF I.UNO
Author
1 Xo. of Xo. Due to
i Deaths with Canter of
: Asbestosis
Lung
Jncitlencc
(7c)
235
WcillcT5.......... . .7
92
Wycrs2............. . . J 115
Lynch. Cannon 1. .,
40
121
! CiOi
31
13.2 .
1 5
16.3
17
14.8
3
7.5
17
14.1
83
13.8
nom 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 Table 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.9,17'54
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 popula 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 silieotics (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. Howc.vcr 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 \1 F R I C A N J O U R N A L O F M E D I C I N E
Asbestosis, B ronchogenic C arc in o m a Issr.1bac.her cl a/.
729
the 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. Merewetbei' and Glovnc'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."
Oloyne noted th a t 14.1 per cent of patients with asbestosis had lung carcino m a. 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 loma of the lung appears to be promi nent in females w ith asbestosis. 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 particle's act as carcinogens.
Experimental production of neoplasms has demorstrated 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 serve as mechanical irritants to the bronchial epi thelium. The squamous metaplasia of the lungs found frequently in asbestosis is presumably a consequence of prolonged irritation in the lower respiratory tract. Some pathologists consider squamous metaplasia as an alteration in the cellular structure, that may precede or be the initial step towards the development of squamous cell 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 eases that the average, duration between the initial exposure to asbestos and the development of
NO V h Mh HR , 19 5 3
bronchogenic carcinoma was about eighteen years. Sim il a rly M crew ether' 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 may be followed by pulmonary malignancy man)' years 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 have, 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 where 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 l o n e r 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 may be of significance that 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
730
Asbestosis, B ronchogenic C arcinom a- Js.u.Warhcr d a!.
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 produce's.
5. Since there are approxim ately 10,000
T aiu.e iv summary or pfi;i.isin;n cask reports in which aitorsy data are cued
^ ea t and Age
Occupation
Dmation of Lsposutc
(yr.)
rI rce dioin
fto:;i F.xposuic t ><_-ft>i c I >cath
1j
;X atu j
Primary Site
J.\nth, Smith31............
Glennt'3*................... Gloyiic.....................
Kghcrl. Geiger97............
Nonliiiann^............... Nuitlmann.................
1.\ihIi,*5Smith............ 11olleb,44Angiisi.......... I!.>!Jf1>. Augcist............ iIB.m-'ztihi.cinvFleis, Weleal!l.e43i."................
Dc'i'ieiile.-. c?a!............ Homlnm-cC* . . .
(hireion19.................. SOtnolcl.mF-1la.>.s...A..n..g.r.i.s.i1..5.............
I'teseni authors............
103s M. 3"*j Weaver
11993353)
lK\, 7313
.Spinner Mattiess andopen-
11993366 MM..4391:.1|WPpmaeacgakrvtedmerer.npaisttrotmicsendtse-
1938 K. 33 ('aider, spinner,
1938 M. 33jPwit-eSapvienrning
1`>39 M, 30jiWaessaevmerble ruotn
1941 M.32j Pipe in'tilanir
1,1,1 M.301. Pipeiri-.olator
111999444111 MMM...63310~!BMaagcgheirneadjustor
111999444222
M>., 4439
No. i nowti No : ;jo\vn contact
with asbestos
1948 L, 3 . Pijif <<>\<iei 11993311 MM.. 4390||Al'ispbeesctoosvewinojker 1932 M 41 Asbestos mill
!1 workoi;sorter
21
8
m
17 10'. 2*
7
4 mo.
9 yr. 15 yr.
2 vr. ? mo.
9 yr.
ScjO.imotH well
Sq u a m o u s cell Scii. -m oo s cell
Glandular O a t t ell
S q u a m o u s ecll
K.L.L.
K.tLL. K.L.L.
1..L.L. L.L.L.
I.I..!..
M a n ) nodules in R 1. L.
Pleura None
W idespi eatl L.U.L. and pleura
1,i\ e r, k i d ney s
7
12 yr.
Sq u a m o u s ecll L I. L
Widesp: ead
13
23
23 > 3
23 22
5 20
7
1 6 12
3 yr.
9 w.
If \r.
Not known 1 mo. 4 mo. 1 VI. 17 mo.
Not know n
Sqi. a moiis witli glandular features
N o n - k e i a '.mixing M]ii.'!inous relied
O a t cell
Squ a m ot.' cell Alveolar cell S qua m ous cell S q u a m o u s cell Anaplastic Squamous tell
K.L.L.
K .l'.L .
R I. L. K.L.L. L. lung R. lung R. lung R . lung
13 yr.
S q u a m o u s cel! L .L.L .
20 vi.
About 4 u. 3 vr.
2 vr.
Adenoeai einoma Anaplastic
Adenoeaicinoma
R. lung No definite
site Lingula
Pleura, modiastinal nodes
M ediastinal notles, a d i e n a !, k i d n e y
Widespiead, including brain
None Pleura 1'leura Diaphragm Pleura Liter, adrenal,
stomach, hilar Ivmpih nodes Pcricauluim, liter, kidney, ovaries, femur None Kidness, brain. liver M \ orardinm , periea idiuin, 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 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 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 1) ] C 1 N II
Asbestosis,J B ro n c h o go e n ic C arcin o m a-- Is s c lh a c h c r cl a l.
731
At autopsy the lungs were firm and weighed 3.350 gm. T here was a poorly difRrentimed adenocarcinoma arising from the left lower lobe bronchus, almost eompletcly replacing `the left
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l '
'4 A M L R I C A N J O U R N A L O V M E D 3CI N E