Document mqM3VjX30pMno39b5Z2YmLxeO
FILE NAME Kent KNT
DATE 1953 Nov
DOC KNT128
DOCUMENT DESCRIPTION Journal Article - Case Reports Asbestosis and Bronchogenic Carcinoma - American Journal of Medicine
s
Case Reports
Asbestosis and Bronchogenic Carcinoma
odes
Report of One Autopsied Case and Review of the Available Literature
Ky
Ky J. BACHER M.D. HANNA Klaus m.D. and Harriet L. Hardy M.D.
Boston Massachusetts
donal * a
The
AL
are several reasons for presenting
Ceruil a case report and a review of the
asalable literature dealing with the
elatoship between between occupational exposure to
curtains and clothing The chief operations are disintegration of the crude mineral carding the
fiber separating the more useful long from the
short fiber spinning plaiting and weaving the
Piaeds
.
and respiratory tract malignancy The
asbestos often with cotton Insulating material
increase in bronchogenic carcinoma
is produced by mixing magnesia diatomaceous
in males reported in the past decade
earth and other materials with asbestos to make
:
os
eres
led to scrutiny of respirable dusts as possible ology Most English observers are satisfied
cements or fillings for insulating boilers engines and pipes Other textile asbestos products
there is a statistically significant increase
so made include asbestos cement sheets brake
;
chri
malignancy among asbestos
and clutch linings electrodes and switchboard
chri
pee -
rkers Some American writers consider that
thesperience thesperience to date does not support this 4.5 The work of Graham Doll and
Hand
Hand Ochsner has created much interest
panels
Asbestos is a hydrated magnesium silicate
The chief supplies are in Canada Cape Province
Italy Rhodesia and Russia Asbestos dust given
>
. a
Le very
tha
. tha
thas
.
that
10-
-I
in
rele,
vepie
vepie
tere:
correlation of cigarette smoking with schogenic carcinoma E. R. whose case is
off in manufacturing processes consists of fragiments of fibers and small rounded or angular
rein
presented was exposed to
of asbestos dust and was
harmful a chain
particles Actual studies in industry show the size and shape of the particles of asbestos to be
:
:
This provides speculation as to the
such as may gain entrance into the bronchioles.14bronchioles.14
:
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
ustrial asbestos exposures provide data on
of small enough size to be respirable to be the
character and quantity of dust exposure
a serious deficit in exact study of etiologic
5
In the clinical report presented
safe working concentration Some operations because of their dustiness
are more hazardous than others in asbestos
State authorities have determined by
manufacturing Bagging the asbestos separating
Measurement that the asbestos dust exposure
the long from the short fibers carding spinning
f
It
are
man during his twelve years of work was considerably above the safe level which is con to be five million particles per cubic
air
for an eight working day is pertinent to this presentati that there probably about 10,000 workers engaged in
and weaving show a greater statistical evidence of asbestosis than do other operations As might
be expected the longer the duration of exposure
the greater the number of cases In the Mercwether and Price series there was one case under
four years exposure and up to 53.6 per cent
potentially hazardous asbestos manufacturing
with fifteen to nineteen years exposure
by
by
operations in the United States Middleton
REPORT
ro poris the number in Great Britain as between
10 5.000.12 Most of the industry is engaged
CASE
R. MGH 735586 a forty year old
asbestos textile manufacturing producing - asbestos mill worker entered the Massachusetts
nsalating mattresses brake linings fire proof
General Hospital in April 1951. The chief
From
the
Departments
of Medicine
and
Pathology
and
the
Occupational
Medical
Clinic
Massachusetts
General
Hispital Beston Mass This work was supported in part by the National Institutes of Health Division of Research
NOVEMB .k 1953
721
^'!
FRAO
srngan se
tions 30 and temperature 99 orally His chest
was thin and showed poor expansion There
were dullness and reduced breath sounds at
|
both lung bases with sticky inspiratory crackling
ates
rales over the region of the left lower lobe The
ey
left border of cardiac dullness was 10 cm to the
ceae
steee
regan TABLE I
PULMONARY FUNCTION STUDIES BEFORE AND AFTER AFTER ACTH
met: Approxi
Before
After
mate
ACTH
| ACTI
| mial
Valoestr
'
capacity L oe
Maximum bacarking
)
Residual
volume L.
alveolar ventilation
cee. capacity
2.4
(
\
52.5
'
1.375
2.18
79.5 1.49
3.9
105 1.30
for ten
except cardiac before .
significa
cathete
Serum pIE
Alveolig Alveolig
| 24.4 | 95.97 j 7.42 | 7.39
nam g
27
29
10
Fig 1. ray of chest The lower lobes are reduced in
size and show a honeycomb pattern There is an
increase in linear and nodular markings A density is seen in the region of the lingula with enburgerment of
These grudies
were pertotined by Dr. John Abeldi Department of
Physiology Harvard School of Public Health
ACTH 100 ing intramuscularly for ten days # Body surface area was 1.62 sy m
lymph nodes in the left hing root suggesting a tumor in
that area
Jeft of the midsternal line in the fifth interspace
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
there were occasional systoles P was greater than Ag there was some pulsus paradoxus Liver and spleen were not felt There
was tenderness of the spine over L with spasm
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
anorexia feverishness and a pound weight
loss He had worked in an asbestos mill for
Laboratory data revealed a normal urinalysis Hemoglobin was 14.0 gm per cent and the
white count was 5,700 with a normal differen-
about twelve years but had stopped working
tial Chest 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 will he had spent one year in the
Fig 1. There appeared to be a homogenous
ee
ame 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
ae
e He also worked five 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 level He used one can of snuff
giving the appearance of metastatic malignancy
and smoked on an average of one to two packs
Electrocardiogram showed specific T wave
of cigarettes daily for many years For seven
changes 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 une flight dyspnea was present for
4.9 Bodansky units Repeated examinations of
about two years There had been no hemoptysis
the sputum were negative for acid organ-
Physical examination revealed a chronically
isms asbestosis bodies and malignant cells Two
ill and dyspneic man with evidence of weight
bronchoscopies revealed obstruction of the left
loss and cyanosis of the lips and nail beds The
Jower lobe bronchus The patient was given a
blood pressure was 110/75 pulse 96 respira-
trial of ACTH 100 mg daily intramuscularly
AMERICAN JOURNAL OF MEDICINE
Approxi
norm
Before ACTI
After ACT
includin
A
with exercis and s appea
Befo radiati relief
For
seemed
work and hu
two m
exami of 100 30 pc moder very d
inspira
the lur bubbli tactile The le out : much down was 2
NOVE
a
Asbestosis Bronchogenic Carcinoma Isselbacher et al 723
blood count was 6,500 hemoglobin 11.5 gm
ten days Clinically there was no change
;
aa
for cuphoria Pulmonary function and
per cent
believed that the patient had pneu-
except catheterization studies were performed
It was
lower lobe and early cor
cardiac
and likewise showed no
monitis in the right
He was
ca
before and after ACTII
and n Cardiac
pulmonale with congestive failure
anti-
significant changes Tables 1
catheterization did reveal chronic cor pulmonale
digitalized given mercurial diuretics
TABLE 11
;
* ACTH STUDIES BEFORE AND AFTER
+ CARDIAC CATHETERIZATION CATHETERIZATION
CATHERIZATON ae ene
oo
'
5
i
cc./min./ cc./min./ st
|
| Os Content Content
Satura- Pulmonary
_ tion
Pulmonary
tion | Artery
Mean
;
pulmonarpuylmonary
Artery
;
Radial
Radial
i Radial ' Pressure
Artery i Radial Artery
i
Artery
| Artery | min Hg
| ( cc./100 cc cc./100 cc./100 cc % Artery
Hg
Pressure Pressure Pressure
mm Hg
|
Cardinc Index
L./min./ L./min./
m
{
Approximate
|
normal values.
Before Before
Rest
eee '
ACTH
Mil2d
exercise min
After
0 Rest ee {
ACTH
Mil2d
exercise exercise | min
145 180
370 156
349
j
20.0
19.3
|
17.4
19.0 18.1
16.6
|
|
*
224
|
5 224
7
|
>
95
!
|
|
|
30/10 36/14
43/14 38/15
i
: NG
NG
'
NN
:
NN
52/22
W
3.2 4.47
5.55 4.02
6.97
the Cardiac Catheterization Unit
* These studies were perforined by
G. Cohen and J.
L. Friedlich R. O'Neill
including Drs G. Myers
ACTH 100 mg intramuscularly for ten days
of the Massachusetts G. Scaunell
General
Hospital
after biotics penicillin and streptomycin and was
with slight pulmonary hypertension
increased
tent most of the time Chest rays
in an oxygen
lymphatic spread of
exercise the pulmonary hypertension
arterial oxygen unsaturation
now were suggestive of
measures fever
of
and significant
tumor In spite of all therapeutic
worse He became
appeared
from the hospital he received
dyspnea and cyanosis grew
hospital
Before discharge
with no
confused and died on the fourth
radiation 1,200 r to the lumbar spine
relief of the back pain
the patient
day
was emaciated the
At necropsy the patient
in the anteroposterior
For several weeks after discharge and returned to light
thorax was lengthened
and
seemed somewhat better
dianeter There was clubbing of the fingers
work However the cough increased markedly
at rest so that after
and he had severe dyspnea
toes
the thorax the lungs did not
months he had to be readmitted Physical
On opening remained inflated completely
two
examination on entry revealed a temperature
collapse but
of
filling both pleural cavities The majority
bilaterally by
of 100.4 rectally pulse of 120-144 respirations
He had marked tachypnea
was obliterated
the pleural space
the visceral
30 per minute
that it was
dense fibrous adhesions between
moderate cyanosis and such dyspnea
and parietal layers Both the visceral and
difficult for him to speak There were many
very
throughout
were markedly thickened gray
parietal pleurae
to 0.3 cm
inspiratory and expiratory wheezes
moist
fibrous membranes measuring up
the lung fields At the right base there were
thick There were 100 cc of clear colored
bubbling rales together with dullness reduced
loculated in the left base The interlobar
tactile fremitus and increased vocal fremitus
fluid
obliterated by fibrous tissue
left border of cardiac dullness now extended
fissures were
the adherent layers of the
The
out 12 cm from the midsternal line P
was
Scattered throughout
diaphragmatic pleura especially on the right
much louder than Ag The liver was percussed
mmber of whitish gray shiny plaques
and there
were a
down two and a half fingerbreadths
|
these resembled similar plaques
2
ankle edema At this time the white
0.5 cm long
was plus
NOVEMBER 1953
ad
Cosa
wat)
ee
co
Fig 2. Cut surface of left lung after foznalin fixation Note diffuse pulrionary fibrosis and marked pleural thickening which obliterates the interlobar fissure
seen on the upper surface of the liver to be described The lungs weighed 2,710 gm were voluminous and very firm throughout no discrcte nodules could be felt Fig 2. Multiple
sections showed a uniform brownish gray surface
throughout except in the left lower lobe where
there appeared to be a diffuse marked fibrosis
throughout the parenchyma The left lower lobe bronchus was completely occluded 1 cm from its origin by pinkish gray firm tissue for a
distance of 1.4 cm here the bronchus measured
0.7 cm in diameter the firin pinkish gray tissue extended into the parenchyma for a
distance of 1.7 can Similar tissue extended from
this point i. the bronchus to the pleura and into
the wall of the 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
The upper lobe bronchi were rigid and nar-
rowed by a thick white fibrou lower and to some extent the i
.The .The right
middle and
left lower lobe bronchi were dil d and there
Fig 3. Asbestosis belies in the hung The shaped beaded asbestosis bodies are seen in the alveolar ducts surrounded by macrophages and dost cells ^ 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 wart weighed 360 gm There
was involvement of the left atrium and auricle
by thick firm grayish pink tissue for an arca measuring 2.3 by 0.7 cm The remaining myocardium appeared uninvolved and measured 0.6 cm thick in the right ventricle 1.3 cm in
the left The endocardium and valves were
n^'gative The diaphragins contained firm grayish pink
areas of plaque 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 confluent areas in Glisson's capsule The remaining organs with the exception of the fourth lumbar vertebra were negative This vertebra appeared opalescent and resembled marble but its consistency was softer than the adjacent vertebrae The body appeared to have increased porosity
AMERICAN JOURNAL OF MEDICINE
section
near the eral ar ' be seen
Fibroz prolifen
the arty
and phy peribro v apices
demons
fibrosis
the lung
areas ba firmed
Asbes t in all st fibers a some cl
which s
prepara
prepara1
larger +
NOVEMT NOVEMT
Asbestosis Bronchogenic Carcinoma Isselbacher et al
Fy a
me
bodies and interstitial fibrosis ^ 100
nat
ducts note also asbestosis
cae
Fig 4. Squamous metaplasia in the alveolar
100
>
Fig 5. Adenocarcinoma invading the myocardium
Or in the macrophages The
we
were sectioned topographically
cles were present
bilaterally being slight
The lungs
taken
distribution was equal
sections from all segmental bronchi were
moderate in the apical segments quite
nelrmine the hilum the lobar and the periph- to
the remainder of the lung and oc-
near
could
marked in
mid-
me eral areas These basic histologic patterns
curring with equal intensity in the hilar
an
;
be seen
Fibrosis Throughout the lungs there was of fibrous tissue around the bronchi
ptrhoeliafretreartiieosn alveolar ducts the interlobar septa
were also thickened There was
and pleurac and alveolar duct fibrosis in both
lymphatics peribronacnhidalslight alveolar wall thickening as The
adpeimcoensstrated by connective tissue stains fibrosis increased in the remaining portions of
the lungs was heaviest in the hilar and lobar
but extended to the periphery This con-
arcas
firmed the gross impression of diffuse fibrosis Asbestosis bodies Asbestosis bodies were present
in all sections Fig 3. These were segmented
fibers averaging 50... long some straight and sone shaped others resembled dumb bells
which stained dark brown on hematoxylin and blue on Prussian blue iron
pprreeppaarraattiioonnss Particles of staining dust and
parti- larger casily identifiable asbestosis body
Snes NOVEMBER 1953
lobar and peripheral zones
While most of the asbestosis bodies were seen in the bronchioles and alveolar ducts a few could be seen in the alveoli and fragments were
and in the
found both in the macrophages
Several aggregations of asbestosis
bodies were found in the bronchi Fragmented
asbestos fibers were found mostly in the macro-
but occasional staining particles
pwheargeesfound free on the alveolar walls Much
but by no means all of this material in the
macrophages took the iron stain
The chief inflammatory
Inflammatory response
the macro-
cells responding to the irritant were
These cells were seen in abundance in walls of
phagessection they lined up along the
etvheeryalveolar ducts filled the lumina of bron-
chioles and alveoli and were found throughout
the septa and fibrous tissue Most of these con-
ee
ren
ee
oo
ka ot
sent
coke deans
ane
Me
Fio 6. ray diffraction film of lung residue of E. * The lines listed when compared to the known pattern
for asbestos give positive
proof that the lung residue is essentially asbestos lung
give positive
Table of B lines
4.52
2.42
1.63
4.20
2.38
1.531
3.35
2.115
1.49
2.98
1.84
1.44
2.67
1.70
1.38
* 68.5 gm sample of formalized lung tissue was digested in 20 vtorleuamteeds whiytdhrodgieluntepehryodxriodcehltohreicdiagecsitdionfilbteeirnegd
accelerated with gentle heating The residue from the digestion was
the method described in the
500 The
residue was analyzed by ray diffraction by
washed and ignited at
ignited H. W. Frevel L. K. Chemical analysis by ray diffraction Indust & Eng Chem
article by Hanawalt D. Rinn
R. I. Chamberlin and A. Woewucki Jr. of the Massachusetts
Anal Ed vol 10 no 9 1938. This work was done by
Bonding and Insurance Company Boston Mass
tained brown pigment granules many of which took an iron stain and portions of asbestosis
bodies were also found in the macrophages
These cells have been called dust cells and are thought to lay down the iron on the asbestos fiber constituting the asbestosis body Anthracotic pigment was also present in the macrophages Multianeleated giant cells of the foreign body type were found in abundance in all arcas many of these contained birefringent asteroidal bodies Few lymphocytes avere seen those present were scattered around the bronchi near the hila A few focal areas of bronchopneu-
monia with polymorphonuclear polymorphonuclear infiltration were present these had no particular relation or location to any grouping of the asbestosis bodies and were undoubtedly a terminal phenomenon
Throughout the lungs many air sacs were dilated and contained a granular cosinophilic
material probably fibrin Some of these plugs were undergoing organization mainly in alveolar ducts this type of fibrosis probably accounts
for a small percentage of the total fibresis seen Bronchi The bronchi of the lower lobes showed
marked bronchiectasis there was dilatation
fibrosis of the muscular coat and peribronchial
fibrosis While the latter was most marked in
the lower lobes it was seen in the hilar and mid-
Bland vessels The arteries and arterioles of the
right middle and both lower lobes showed moderate intimal thickening with hyalinization
and narrowed lumina This was most marked
near the hila but was found occasionally farther
into the periphery Tumor Adenocarcinoma was found originat-
ing in the inferior lingual segment of the left upper lobe bronchus The tumor was present in the sonal area of the apical posterior segment of the left upper lobe the entire lingula and left lower lobe as well as the right middle and lower lobes It had spread by sub-
mucosal and lymphatic routes Sections of the left atrium showed direct extension through the
left hilum into the pericardium and myocar-
dium Fig 5. Metastatic tumor was seen in the
fourth lumbar vertebra
Asbestos granulomas The white plaques described in the diaphrag~-n and Glisson's capsule were made up chiefly of hyalinized connective tissue No asbestosis bodies or giant cells were seen These distinctive areas grossly
suggested granulomas ray diffraction studies were carried out on
a sample of formalized lung tissue The resulting pattern indicated that the lung residue was mostly asbestos Fig 6.
zonal regions of al ist all segments Another
COMMENTS
striking feature was widespread squamous metaplasia of the bronchial epithelium Fig 4.
This was most marked in the alveolar ducts it
was found in all areas and was not particularly related topographically to the adenocarcinoma
described later
Asbestosis may be defined as a specific occupational disease caused by the inhalation of asbestos fibers and leading to a progressive
fibrosis and scarring within the Jungs.17 It has been demonstrated by Gardner2 and again by
AMERICAN JOURNAL OF MEDICINE
Fo Cary er
+
189
ANA,
mentee
(ely
cat
ce
e
Laer
Vorwald
occur wi concentri
cubic fot
The P inhalatio
to be ch rather th
from fib
The inh
to pass
so they reaction
The pa
consider
desquan
of asbest The l
lining th irritation
mate N
phagocy
asbestos
phages .
asbestos calle from a
particle
|
ing of
course
which irritatio
sputum Their ^ to asbo
an ind The
is the tion c and al
compi in con mary 1 the lo
partic
a fine lower
upper Th
previ
tends
cease
to be
tion
NOVE
aon
sae
was
has
ste bias
Tsselbacher ef al.
427
Carcinoina~
Bronchogenic Asbestosis
-Iselbacher -Iselbacher et . five ta 727
usually the Bronchogenic Bronchogenic
Carcinoma Carcinoma -Isselbacher
to high 727
general general there delay five to seven
Vorwald's
Vorwald's
that less usually the disease will will
not
between there delay delay
occur with fibers
years
high con-
nceut
concentration concentration
concentration
below
than
20
length
particles
centrations
centrations
initial exposure
The dusts the onset
cubic cubic cubic foot
processes resulting ihe
clinical clinical asbesMetrewoethserisThe average interval rc-
TheThe pathologic
particles particles from
ported ported
Merewether asbestosis eleven years While
inhalation inhalation inhalation of asbestos
chemical believed
patients patients patients
most
asbestosis have had an
due due to their
to exposure of ten sixteen
w be to
consequence mechanical nature
that disease has years important
consequence rather, rather
irritation
lodged lodged respiratory mechanical
to realize
occurred with with industrial exposure
som from fibers
general tree.15-20
short industrial
appear years.42 years.42
symptoms
The inhaled particles are general
bronchioles
The
bronchioles
part Usually Usually symptoms
reserve until large
fibrosis.21 te so pass breeyomndairnesthepreirianittoirayte initiate foreign bronchioles
hy part the respiratory
been reduced
by
fibrosis
Merewether
Merewether
has
frequently
frequently
lungs
vo reaction trheaectyion eventually eventually leads The
the
can mented mented how markedly
fairly comfortable affected
sequence events events sequence
However the patient be
comfortable 17
The considered
occurring in stages can
symptoms once
desquamation desquamation occurring
exudation formation
However
when
becomes
becomes
apparent
and
desquamation exudation
asbestosis
fibrosis fibrosis scarring
usually significant dyspnea rapid progression there Then
of The asbestosis bodies and
cells
long traumatize traumatize epithelial
constant
productive definite
weight and
fatigue productive cough anorexica omplaints Death
lining lining
bronchioles bronchioles and
irritation and
eventually the common
intercurrent intercurrent infection
irritation
cause the cells desqua-
results from
mate Macrophages Macrophages pour
effort effort
cor pulmonale
hing many
pour forth in phagocytize fibers
The case herein carcinoma
many phagocytize
bodies bodies fibers In our fragmented macro-
presented demonstrates demonstrates
of the significant
pathogenesis pathogenesis
features features the
asbestosis lymphatics second within symptomatology phages and lymphatics
reaction the
natural course asbestosis asbestosis an
lymphatics second reaction
had natural
asbestos asbestos fiber the body body production of the
The patient having worked twelve years an
so called " asbestosis asbestosis
22-24 This results
atmosphere
concentration concentration of asbestos
from reaction reaction occurring
the asbestos
tissues
known to
particles
sufficient Th produce produce
pathology
only
particle particle and surroundingthe deposition It deposition thicken-
the fiber
its
pulmonary
life However However was
during the last year
cough
ing
protein protein matrix containing along
ing course course of
to containing iron
and weight manifested dyspnea
anorexia
manifested themselves
had been present
themselves
five
which which probably probably
found chronic
Clubbing
downhill least due
bodies may
irritation irritation These
found in the
years
He had
very
rapid downhill
course
lung pleura lymph nodes
sputum
evidence of exposure
be
necessarily
undoubtedly the two associated
the factors --- The
asbestosis and carcinoma
cyanosis and
asbestos presence hbuet bly d themselves themselves are necessarily
findings clubbing clubbing
an indication
not necessarily physical
bases all cyanosis and
The indication of asbestosis 17,27,28
dullness the lung lung
consistent consistent the
to
significant
and most
with asbestosis were the x findings
BCO-
an production
the deposi- deposi-
evidence evidence suggesting
tion
production
production
of
fibroblasts
distal
bronchioles
bronchioles
lus . apart from
severe severe
symptom
is and alveoli about about
which progressive The outstanding
attributed to a
ensues diffuse diffuse compresses compresses compresses
resulting
attributed
combination progressive dyspnea superim- superim-
obliteration alveoli and capillaries resulting pulmo-
in complete
involved
combinaantdiosnprepulmonaary dipnuglmneooplnasam rnyeoplasm pulmonatrhye
This obliteration of
nary
is more pronounced pronounced
infection
finally congestive congestive on the
the lower process
in
cor
there particles most abundant for it
sees
particles
abundant By ray sees
abundant abundant
pulmonale As indicated indicated
ACTH the case
history the ten day
a fine ground glass
in the period
accompanied accompanied only
lower lobes and frequently granular pattern the the
euphoria euphoria therapy was
measurements Fe-
upper lobes frequently or emphysema emphysema in the vealed significant significant objective
was not not
upper
sequence sequence pathologic events
surprising for reasons This
had had
The
of long duration the fibrosis
previously previously
the fibrosis obviously
and therefore therefore
tends progress even after
has
would expect long duration
this at this
this exposure exposure
however animals
and he superimposed change change much
and
broncho-
superimposed ceased
that intercurrent intercurrent seem
is superimposed
be
be the casethe progression progression intercurrent infec- infec-
infec-
carcinoma carcinoma .
with with chronic compare compare compare
results patients
chronic beryllium beryllium
tion contributes
he progression man
NOVEMBER 1953 1953
these results to with
NOVEMBER NOVEMBER
in man."
Hon contributes to the progression
1953 NOVEMBER,
e
cen
ee
cenm
te
ae
728
Asbestosis BronchogenicBronchogenic Carcinoma Isselbacher et al
e
poisoning who usually show a favorable rc-
number to be of significance others especially
sponse to steroid therapy
Vorwald and Karr have stated that inhaled
Two further aspects
consideration
consideration
detailed consideration consideration
of this case merit more
and analysis ) the
dusts except those containing recognized carci-
nogenic substances as radium and tar cannot
pulmonary function and cardiac catheterization
in general be considered as ctiologic factors in
studies and 2 the significance of the superin- the development of primary pulmonary carci-
eet
posed bronchogenic carcinoma
PULMONARY FUNCHON FUNCHON AND CARDIAC CATHETERIZATION CATHETERIZATION STUDIES
Table i indicates as one might expect that the patient had a reduction in vital and maxi-
,
Sel TAFLE HI
ASBENTOSIS AND CARCINOMA OF LUNG
| CIE |
No. of
No. Due
Inci
ONO
Author
1 Deaths with | Cancer of | dence
ne
1 Asbestosis
Laing
%
an
breathing capacities However the finding
of an alveolar oxygen gradient of ne
27 mm Hg demonstrates that one of the dis-
Merewether 02. i Wedlert ee...
235 92
31
13.2
15
16.3
turbances in pulmonary function was a defect
Wyers ?. :
115
17
14.8
in the diffusion of oxygen from the alveoli of the
Lynch . Cannon .;
40
3
7.5
longs to the capillaries This corresponds to the
Gloyne ?.
121
17
14.1
ee. syndrome of capillary block de-
scribed by Baldwin Cournand and Richards132 Total . :
603
83
13.8
and again by Austrian cal cal This diffusion
defect is not surprising when one recalls the fibrosis about the alveoli alveolar ducts capil-
nona Our conclusion at present is in favor of the concept that the association of broncho-
laries and bronchioles that occurs in asbestosis
genic carcinoma with asbestosis is more than
In order for the patient to maintain a near
coincidence That there is a significant incidence
normal arterial oxygen saturation a high
of bronchogenic carcinoma in asbestosis is
alveolar oxygen was necessary and this ap-
apparent from Table 1
parently was accomplished in part by hyperventilation The patient had an average respiratory rate of 40 per minute at rest This compensatory mechanism apparently was not
Merewether has cited the largest series of
235 cases of asbestosis there were
with
thirty bronchogenic
carcinoma average of the
five
or 13.2 per cent An
analyses recorded in the
adequate during stress or exercise for under
those conditions the arterial oxygen saturation
literature is 13.8 per cent This is considerably higher than the incidence of lung carcinoma
fell There a was considerable degree of pulmo-
nary hypertension and as in the cases of pulmo-
comparable in routine necropsies which in a
period 1935-1948 ranged from 0.8 to 2.4 per
nary fibrosis
_ an associates a
studied rise in
by Courmand and his the pulmonary artery
cent 9,47.54
In contrast to asbestosis the incidence of
pressure occurred with exercise Table 11. The
bronchogenic carcinoma in silicosis as recorded
partial
of carbon dioxide in the blood
pressure 36 mm
Had vated
Hg was low normal rather than ele-
there been a defect in alveolar
discussing ventilation the pCO would probablpyrobably have
been higher As Arnot emphasizedin
this case,, carbon dioxide is not impaired in
its transfer from the blood to the alveoli because
of its great diffusion capacity This speed of
diffusion plus the increased alveolar ventilation
no doubt accounted for the lowered pCO2 value
in the two largest series has been similar to what might be expected in the general population The data cosupiled by Merewether and
the Miner's Phthisis Medical Bureau of South
Africa are based on a total of 6,884 and 1,438 antopsied cases of silicosis respectively and disclose an incidence of lung carcinoma of
1.32 and 0,70 per cent Vorwald and Karr found
two lung carcinomas in 136 silicotics 1.47 -- -- cent Klotz55 noted an incidence of 8 per cent
ASBESTOSIS AND CARCINOMA OF THE LUNG
The association of asbestosis and carcinoma
of the lung has been mentioned frequently the literatu1-r 3,34-e 83 Heretofore some authors
have believed that the cases were too few in
but his series of fifty cases does not seem large enough to be statistically significant However Gloyne 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
AMERICAN JOURNAL OF MEDICINE
the pne series 8
coniosis 1
Cloyne'L |
period
interj
the incr
populat bly is 1
materia
which
Gloyi
with asil
:
parallel i
and is
silicosis
particle
while t conside
n||
silica.:s
Carc
nent in
thirty i
cent as
the inci
autopsy
are av
21 pc :: inciden
in the
Lindskij Grahag
cent an
figure
asbesto
Expq
demon
tissues
the de
ticles w
as mey
thelium found !
conseq respira
squama cellula
initial 4
cell ca A
possib is cha that th exposi
t
NOVEN
ee Tore
al a in
unusual a favor
auchothan
idence ssis is
pa fol
with An
ES in the
crably
inoma
cna narable
2.4 per
nce of corded ilar to
sapula-
rand rand South
-I 1,438
% and ma of e found 47 per r cent
a large
Cowever al from d the cinoma
cer
- Isselbacher et
729
Asbestosis Bronchogenic Carcinoma
carcinoma was about eighteen
as whole In this same
bronchogenic Merewether found that patients
the moconioseosf cases without any pneumo-
years Similarly
of the lung had a longer
series 8.3 per cent of the lung Merewether and
dying of carcinoma asbestos 16.5 years than
coniosis had cancer
over a comparable
mean exposure to
of malignancy
Gloyne's cases were analyzed
unreasonable
time so that it seems
those
13.4
dying with no
years Finally
evidence a short but
by
adequate pulmonary
pteoriinotderoprfet the figure of 6.9 per cent as reflecting in the general
be followed exposure may
Merewether's
the increase of lung carcinoma in the data proba-
many years later In
asbestos
malignancy
who was an
population The discrepancyfact that Gloyne's
series is the case of woman
later developed
bly is explained by the
worker for only six months yet of
material was selected from the pneumoconioses
carcinoma Gloyne reported the case
which the histories and rays were
lung
of nineteen months with an exposure
in
noted that 14.1 per cent of patients
Gloyne
carcinoma This figure
a worgan
of seventy-
who died fifteen years later at the age
carcinoma of the right
with asbestosis had lung of previous workers
one with a squamous cell
parallels the observations that recorded for
lower lobe
informa-
and is significantly above
Table 1 summarizes the pertinent
silicosis As has been mentioned the asbestos
of asbestosis with lung tion of the twenty cases
acts as a mechanical irritant
particle probably
in silicosis are
changes
carcinoma corded in
that have been autopsied and re-
the available literature Four cases
while the pulmonary
of
considered due to the chemical properties
been added to the list compiled by Hom-
have
It is noted that in about four-
silica.18.00 silica.18.00
of the lung appears to be promi-
burger in 1943.
site is
in which the primary
Carcinoma
Of Merewether's
fifths of the cases
was in the
nent in females with asbestosis
indicated the origin of the neoplasms
cases nine were females or 29 per
This is in contrast to the general
thirty
series of seventeen cases
and in Gloyne's
lower lobes
where bronchogenic carcinoma seems
cent
41
cent In the published population
in the upper lobes Ju
the incidence was
per
data as to the sex of the patient
to be more frequent
incidence of
Lindskog's series there was an
in
autopsy reports
of which five
available in twenty
cent in the upper lobes 26 per cent
are cent were females In contrast the
in females
21 per
carcinoma
57 per the lower
lobes
Ochsner found 56 per cent
cent in the lower
incidence of bronchogenic
in the upper lobes and 35 per
is considerably lower
in the general population
lobes No conclusions should be drawn from
noted an incidence of 4.0 per cent
number of cases listed in Table iv
Lindskog
5.4
cent Doll and Hills 8.4 per
the small
since asbestos particles lodge to a
Graham
per
and Ochsner 10.3 per cent The higher
cent
the theory that
Nevertheless
tree
extent in the lower respiratory
greater
also more
figure in asbestosis supports
where the changes of asbestosis are
mteL asbestos particles act as carcinogens
has pronounced a higher incidence of carcinoma
production of neoplasms
this location should be expected expected if an etiologic
in
Experstirmaetnetdalthat chronic irritation of body
exists In our case the asbestosis
demor
to relationship
tissues by mechanical means may predispose
widespread and severe and the tumor
of malignancy Asbestos par-
was
in the inferior lingual seg-
the development in the finer bronchioles serve ticles when lodged
bronchial epi-
which originated
ment of the left
upper
lobe
was in fibrosis
an arca
and in-
as mechanical irritants to the
of the lungs significantly involved by the
thelium The squamous metaplasia
flammation of asbestosis
found frequently in asbestosis is presumably a
It is also noted in Table 1 that twelve of the
irritation in the lower
consequence of prolonged
nineteen previously recorded cases had lesions
tract Some pathologists consider |
cell type The incidence of
respiratory metaplasia as an alteration in the
be the
of the squcaelmloucsarcinoma is said to be high in
squamous
malig-
sceqlulauilnaor usstructure that may precede or
male cigarette smokers with pulmonary
initial step towards the development development of squamous
nancy At autopsy our patient showed botohf
cell carcinoma
metaplasia and adenocarcinoma
A lag period between the exposure to a
squamous
that was
the lingula may be of significance
carcinogen and the onset of malignancy
in view of smoker for over twenty years
possible
Nordmann's noted in his cases
is characteristic
the initial
a chain
and Graham that
the observation by Wynder
of the lung are
that the average duration between
of males with adenocarcinoma
to asbestos and the development
exposure
Die
E
NOVEMBER 1953
730
Asbestosis Bronchogenic Carcinoma Carcinoma Isselbacher et 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 types in various sections of the same tunnor 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
Since there are approximately 10,000
TABLE IN
SUMMARY OF PUBLISHED GASE REPORTS IN WHICH AUTOPSY DATA ARE CHIED
ep
Anthops
Yeat
Yeat
vee
oo
Sex Sex
Occupation
and
Occupation
Duration Duration
Duration | of Exposure
Ficedom
Exposure
Stora Exposure
a.
Natue Tumor
| Natue of Tumor
: Age
yr
before Death
i
we
eee
-
oo:
wee tee
-
' ~
|
tee ne
--
Primary
SSiite te
Metastases
Lynch Smith .
Gloyne . coc
eee
Gloyne . eee ee
1935 M. 57 Weaver
\
1935 F. 35 Spinner |
1935 . 71 Matress and open-
.
ing
departments
:
ing departments
21
8
1
4 10
D yr,
XT
cell
Squamous cell
Squamous '
Squamous Squamous cel
R.L..L
K.U.L. R.J..L
Many nodules in
R.L..L
Pleur
.
None
Egbert Geiger^d6... f 1936
:
Glagues . 1936 |
17
10
2 yr ? 10
Oat Glandular Oat cell
!
1
1.L..I
1..3..L
; '
Widespread LUL and pleura
Nordmann15
oo.
ccc
eae
Nordmann . eee eres
1938
.
35 Caider
io weaver
1938 M.
| 7
...st ...st
Squamous cell I .... ....
Liver kidneys
7
12 YT
Sqgutzaninus celt
I.
Widespread
Lynch, Smith
20...
f
Holleh, Angrist 2...
Holleby Angrist
2.00022.
07
1939 1941 1941
M. 50 Weaver
50:
M.
Pipe insular~-irnsular~-r
,
'
+
t
M. Pipe imparator
i
L^ncbachWedler oo 00.
cules Desa
al.43
8
Detrienes et al
wesc,
1941 1941 1941
Rendburger 2.
f 1942 1942
Hamlanger
ce
ee
ee
ee
eg
1942
Corcion ee
Owenee
Stoll Bass Angrist .
Piesean authors i
1948
1951 1951 1952
H
37. Pipe coveter
i
:
: !
M. M. Asbestos worker worker
M. Pipe coverei
:
1
1
0 M.
!
13
25
25 >
25 22
S 20
7
1 6 12
yr
yr
10 56
Not know know 1 mo mo 1.90 17 mu
Not known
|
;
Squamens with
glandular
features i keratiniz-
Non
{
t
1
Oat cell
{
Squamous cell
Squamous 1
t Alveolar cell
| Squamous
Squamous Squamous
Anaplastic
V
Squamous
cell cell
cell
....
t ....
i |
1..1
4 ....
1. lung 5 R. Jong R. lunglung i I..L .. : R. Jung
\
15 yr
Sqramous cell
I..L..I
| 20 yr,
j
Adenora
cinoma
"
About 4 10 5 yr Anaplastic
| Adenocarcinoma
R. lung
No definite site
Lingula
Peura mediastinal nodes
Mediastinal nodes adrenal kidney
Widespread Widespread including main
None Pleura
Picura Diaphragm
Liver adrenal stomach hilar lymph nodes
Pericardium liver kidney ovaries Temur
None
> Kidneys brain
liver
Myocardium pericardium spine regional 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 hung with metastases following documented harmful industrial exposure is presented
ACTH adrenocorticotrophic hormone was given with no objective changes in the
patient's clinical course
patient's3. Pulmonary function and cardiac catheter-
ization studies were performed before and after
ACTH They revealed an alveolar diffusion defect and pulinonary hypertension
4. Asbestos is associated with bronchogenic
workers engaged in potentially hazardous asbestos operations in this country it is reasonable 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 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 received5,0005,000 r of deep ray to the left chest
AMERICAN JOURNAL OF MEDICINE
>
entero nares
pee a
wae
e
Aa de,
Og
ee cee
ae ne
aoe
serne
At
3,350
adenoc bronch lower 1 upper
diaphr lung a
showed thicker rounde
body 4
asbesto in all |
by tun
5. Ve 6. G
7.
10. O
13. h 14
ny Nee ere Tee Rm eee tt esa gape
PRT Ge TNT, SOT TENT EE AE '
dat a at merece
Ta
me woe
al
Con-
aticle
of the
30,000 30,000
bikx in
vad
pel pleura
Keys Keys vat prvekle sales inal mediese
1. Fileey
azardous azardous
s reason-
vegnized Besented
rcinoma
is manu-
ed by us forty
ork since
i sawing
Alers and
oked one
ter year of which
left est
-
MID
NF
Carcinoma 'Isselbacher et al
731
Asbestosis Bronchogenic
asbestosis Tubercle
with reference to pulmonary
At autopsy the lungs were firm and weighed
There was a poorly differentiated
3,350 gm gm 3,350
arising
from the left lower lobe
adenocarcinoma arising
the left
bronchu abnost complethealdy srperpelaacdintgo the left
lower lobe The tumor
and
upper Jobe hilum pericardium pleura
and had metastasized to the right
diaphragm
The remaining lung tissue
lung anpdearidbrreonnachlial fibrosis focal alveolar wall
showed
asbestosis bodies sur-
thickening anmdacnruompehraoguess filled with asbestosis
rounded by and foreign body giant cells The
body particles
seen in equal distribution
asbestosis bodies were
involved
in all parts of the lungs not completely
by tumor
REFERENCES
R. A. Annual Report of the Chief
1. MEREWETUER of
Factories
London
1947.
H.
M.
Juspector
Stationery Office
Grad M. J. 25 631
2. WYERS H. Asbestosis Post
1949
R. Premioconiosis A histologic survey
3. GLOYNE S.
1205 cases Lancet 1 810
ef necropsy material in
20.
21.
22.
G1AR1DN1E5R1 1.9. 30U. Etiology of pneumoconiosis
J. M. A. 111 1925 1938
L. U. and CuMMixes CuMMixes D. E. Studies on
GARDNER
vi Inhalation of
experimental pneumoconiosis
tuberculous
asbestos dust its effect upon primary
J. Indust Hyg 13 65 97 1931
infection
dust and the curious hodies
Cooke W. E. Adestosasbestosis Brit M. J. 2 578
found in pulmonary
:
1929
of pulmonary asbestosis
McDonald S. Histology
23.
Brit M. J. 2 1025 1927
M. and HaDnow A. C. Demonstration Demonstration
24. Stewart
asbestosis
of the peculiar bodiesmatoefripaullmoobntaairnyed by lung
asbestosis bodies in
J. Path & Bart 32
and in the sputum
puncture
172 1929
of asbestos fibre in the
25. G OYNER. The presence Tubercle 10 404 1929
Jesions of asbestos workers
H. L. BUTCHER C. L. and Corsas
26. Stewart
Arch Path 12 909
E. H. Asbestosis two cases
1931
B. and SLOYNE S. KR Pulmonary
Woon W.
asbestosis Lauret 2 1383 a1sb9e3s4tosis J. A. M. A.
Lyxan K. M. Pulmonary
109 1974 1936 on the treatment of chronic beryllium
29. Symposium with ACTH and cortisone Arch Indust poisoning
1951
A. J. and Karr J. W. Pneumoconiosis
4. VORWALD
carcinoma Am J. Path 14 49
and pulmonary
Medicine 5. Ve1r9w38ald A. J. Personal communication 1952with
5.
E. A. Primary cancer of the lung
6. Graham
of its etiology Bull New
special consideration
York Acad Med 27 261 195E.1 A. Tobacco smok-
7. Wynder E. L. and Graham 7.
in bronchogenic
ing as a possible etiologic factor
J. A. M. A. 143 329 1950
ney carcinoma
and carcinoma
8.
Do R. and
Hn
A. B.
Smoking
Brit
M.
J.
2
of the lung Preliminary Report
739 1950
M. E. Carcinoma of the
er 9. Ochsner A. and DEBA--"ey
Arch Surg 42 209 1941
lung
M. E. DECamp T. and
10. OCHSNER A. DEBAKEY
J. A. M. A.
Ray C. Bronchogenic carcinoma
148 691 1952
A. Personal communication 1952
11. Lanza
Asbestosis p 386. New
12. Lanza A. S^>licosis and
York 1938. Oxford Univ Press :
13. 14. 15.
Hospital 1936 16.
17.
Idem p 327
S. R. Pulmonary
Woon W. B. and GloYNE
asbestosis Lancet 1 445 1930
E. R. A. and Price C. W. Report
MEREWETEBffEeRcts of Asbestos Dust on the Lungs and
on the
in the Asbestos Industry
Dust Suppression
Office
London 1930. H. M. Stationery General
Cast Records ofNtehwe MEansgslaacnhduJs.etMte s d 246 867 1952
asbes-
case 38221 R. A. A memorandum on
MEtRosEiWs ETTubHeErckle 15 69 109 1933 Tubode 15 152
1934
T. M. and Pra^flrC.
18. Vorwald A. J. Durkan asbestosis Arch Indust
Experimental studies on
fibre Hyg 3 19R5e3action of tissues to asbestos
19. GLOYNE S. R.
Hyg 3 543. 1951
and Richards
E. Dr.F. Cournand A.
30. Baldwin
insufficiency 1. Physiologi-
D. W. JR Pulmonary
methods of analysis
cal classification clinical
27
standard values in normal subjects
243 1948
A. and Richards
31. BALDWIN D. DEF COURinNsAufNfDiciency 11. A study of
D. W. Jk Pulinomary
fibrosis Medicine
thirty cases of pulmonary
28 1 1949
E. DEF COURNAND A. and Richards
32. BALDWIN
insufficiency m A study
D. W. Jk Pulmonary
of 122 cases of chronic pulmonary emphysema
Medicine 28 201 1949
R. McCLEMENT J. H. RENZETTI RENZETTI D.
Austrian DONALD K. W.
Riley R. L. and COURNAND A. of
features of some types
Clinical and physiologic
of alveolar
diseases with impairment
pulmonarydiffusion Am J. Med 11 667 1951
capillarKy. M. and SMITH W. A. Pulmonary
LYNCH
Carcinoma of lung in asbesto-
astratosis
astratosis 121
Am J. Cancer 24 56 1935
silicosis
silicosis
carvinoina carvinoina of
GLOYNE S. K. Two cases of squamous
35.
in asbestosis Tubercle 17 5 1935
the lung
of oat cell carcinoma of lang
Glovne S. R. case
36.
18 100 1936 -37
occurring in asbestosis Tubarle
asbes-
D. S. and Gricer A. J. Pulmonary
37. EGBERT
of a case with
tosis and carcinoma Report
Am Rev. Tuberc 34 143
necropsy fiMn.diDngesr Berufskrebs der Asbestosarbri-
38. NORDMANN
47 288 1938
ter Ztschr f Krebsforsch
K. M. and SuITH W. A. Pulmonary
39. LYNCH
A report of bronchial carcinoma
asbestosis v
Am J. Cancer 36
and epithelial metaplasia
567 1939
und Beruf Zentralbl f
40. KOELSCH F Lungenkrebs
Gacabehyg 27 32 1940
NOVEMBER 1953
ae
et .
me ETT
re ...
.
EE UR OT CR
nas ae;
732
Asbestosis Bronchogenic Carcinoma et Isselbacher al
41 Lanzrach A. J. and WIDLER W. Asbestos und
ring in asbestosis of the lung Brit J. Cancer 2
Lungenkrebs Arch f path Anat 307 387 1941 42. NORDMANN M. and Sorge A. Lungenkrebs durch
249 1948
50. SMITH L. Purumoconiosis and lung cancer Compens
Asbeststaub im Tierversuch Ztschr f Krebsforsch
Med 3 1949
ee .
51 168 1941 43. 43. 43. Desmeules R. Rousseau L. Giroux M. and
|
51. Ows T. K. Carcinoma and asbestosis of the lung Report of a case Brit J. Cancer 5 382 1951
pulmonaires SIROIS A. Amiantose et cancers
Laral m^'d6 97 1941
-
52. STOLL R. Bass R. and ANGRIST A. A. Asbestosis
.
associated with bronchogenic carcinoma Arch
a
44. Holleb H,and Angrisr A. Bronchogenic carci-
Int Med 88 831 1951
ee
noma with palaionary asbestosis Am J. Path 18
53. Hupper W. Environmental lung cancer Indust
123 1942 palionary Asbestos
Me 20 49d 1951
ade
45. Widler H. Asbestos und Lungenkrebs Drutsche
54. Registrar Statistical Review of England
med Wchschr 69 575 1943 abstracted in
and Wales for the Year 1948. London 1950
eee Bull Hyg 19 363 1944
46. HOMBURGER F. Coincidence of primary carcinoma of lungs are pulmonary asbestosis Analysis of
e literature and report of three cases Am J. Path
M. Stationery Office 55. Report Miners Pathisis Medical Bureau Union of
South Africa Pretoria 1936
56. Klotz M. Association of silicosis and carcinoma
19 797 1943 47. Lyxch K. M and CANNON W. M. Asbestosi vi
of lung Am J. Cancer 35 38 1939 , Landskog G. F. and Bloomer W. D. Bronchogenic
Analysis of forty necropsied cases Dis Chest 14 874 1948
carcinoma Cancer 1 234 1948 58. Wilius R. A. Pathology of Tumors St. Louis 1948
48. HUEPER W. C. Environmental and occupational cancer Pab Health Rep Supp 209 1948
C. V. Mosby Co. Lasussoo G. F. Bronchogenic carcinoma Ann Sung
49. CURETON R. R. Squamous cell carcinoma occur-
124 667 1946
AMERICAN JOURNAL OF MEDICINE
N th app enti
primary
nary di
granulo
pneumc discase groups somewh
general
matter
abando Missou dust dust fri old ch
pigeon
tower in an
said n Thi
grippe
a dif appea and st be sto protra mont sisten chest filtrai
rema
clear
curre SCVCI
T defir find
onc
NOV