CANCER RESEARCH
A M O N T H L Y J O U R N A L OF A R T I C L E S A N D A B S T R A C T S R E P O R T I N G C A N C E R R E S E A R C H
VOLUME 1 APRIL, 1941
The Occurrence and Pathology of Spontaneous
Carcinoma of the Lung in Mice
H. Gideon Wells, M.D., Maud Slye, Sc.D., and Harriet F. Holmes
From the Otho S. A. Sprague Memorial Institute and the Department o/ Pathology, University o~
Chicago, Chicago, Illinois)
(Received for publication March Io, 1941)
Mice share with men the peculiarity of having tu-
mors of the lung among the most common neoplasms.
However, the lung tumors of mice are very different
from the common cancer of the lung in man. The
latter arises in the bronchi, leads to occlusion of the
bronchi with its sequelae of atelectasis, abscess forma-
tion, unresolved pneumonia, fibrosis, and empyema,
and is almost unexcelled in the extent of its wide-
spread metastasis. The tumors of the lung of mice
arise in the subpleural regions from the alveolar epi-
thelium, and invading the bronchi in the form of
papillary ingrowths do not often lead to the wide-
spread necrosis and suppuration common to human
lung cancer.
Of particular importance is the absence of metastasis.
In the recent series of papers on the production of
experimental lung tumors no mention whatever can
be found of the occurrence of metastases, with the
exception of papers by Campbell and by Magnus.
Campbell (2) produced lung tumors by dusting mice
with road dust, and of 26 cases thus produced there
were metastases in three---one in the heart and two
in the kidney. He comments on the fact that these
were the first metastases to be observed in England,
and also that this was the first case of metastasis to
the heart. In a later paper (3) he reports that in io
mice with tumors of the lung induced by extract
of cardboard, one tumor gave rise to metastases in
the mediastinal nodes and pleura. Magnus (5) pro-
duced tumors of the lung by giving 1,2,5,6-dibenzan-
thracene by stomach tube to mice, and observed one
metastasis to the liver and one to the suprarenal.
These are all the cases of induced lung tumors with
metastases that we can find.
Of metastases in spontaneous tumors, the record
seems equally blank, for no metastases are recorded in
the great number of spontaneous tumors observed,
except in a paper published from this laboratory in
i9r 4 (6). Here were reported the spontaneous oc-
259
NUMBER, 4
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currence of 16o lung tumors observed in 6,000 mice,
of which 4 showed metastasis outside the lung. This
was the first, and until recently the only, example of
metastases of lung tumors, and served to establish
them as true neoplasms. Since that time we have
observed many more instances of lung tumors, both
with and without metastases.
Of i47,I32 mice coming to autopsy in the Slye
laboratory, where every mouse is allowed to live out
its span of life, 2,865 mice had lung tumors, or about
2 per cent. Since a considerable proportion of the mice
do not live to tumor age, the figure of mice of
tumor age would be raised to about 3 per cent. Of
these lung tumors, 1o4 showed metastases outside the
lungs, or 3.6 per cent. All these showed metastases in
the mediastinal lymph nodes, many of them also
showed growths along the chest wall and on the
diaphragm. Only Io showed metastases to other lo-
cations; namely, 5 in the kidney, 3 in the heart (Fig.
1), i in the seminal vesicle, and i in the skull.
There were also 284 tumors that were unquestion-
ably malignant, as shown by metastases througho)it the
lung, making a total of 388 malignant growths, or I3.6
per cent of the lung tumors. Of the rest, a considera-
ble number were probably malignant, as shown by
invasion of the bronchi, and it was difficult to de-
cide whether some were multicentric or metastatic and
so were included as multicentric benign growths. The
experimental study of lung cancer has shown that the
growth begins in the alveolar walls, frequently ex-
tends into the bronchi, and presents no sharp dis-
tinction between malignancy and benignancy. There
is equal difficulty in distinguishing between benign
and malignant spontaneous tumors. Sometimes tu-
mors that would be coasidered benign on the basis
of structure and lack of invasive character are found
to give rise to metastasis, while other tumors of wild
growth fail to produce metastatic growth. All ob-
servers comment on the infrequency of mitotic figures,
and the lack of this sort of evidence of malignancy.
260
Furthermore, when present, mitotic figures are not
indicative of malignancy.
In Tyzzer's articles (7, 8) he speaks of "several
cases" of epidermoid cancer of the lung in his series.
In our large series but 7 distinctly presented this
character.
With reference to the origin of these tumors in the
alveolar walls, which is well discussed by Grady and
Stewart (4), and the question whether these cells
Fro. I. Metastasis of c a r c i n o m a of
~)~ 2.{ 5 9
are mesenchymal or epithelial, the behavior of the
metastatic tumors may throw some light. For of the
zo 4 cases with metastasis, no less than 33 of the me-
tastatic growths showed more or less the structure of
a sarcoma (Fig. 2) even when the primary growth
exhibited no sarcomatous elements, although in not
a few primary growths this sarcomatous structure was
apparent (Fig. 3). No primary sarcomas of the lung,
without epithelial elements, have been observed in
our mice.
Campbell has directed attention to this phenomenon
Cancer Research
of sarcoma-like transition in primary lung tumors of
mice in the following words, "The tumors are regarded
as malignant if they give rise to metastases, and also if,
without metastases, they contain infiltrating spindle
cells or spheroidal cancer cells," and shows pictures
of the spindle cell growth. This is a true spindle cell
growth with collagen fibers between the cells, and
not the oat cell growth of undifferentiated lung carci-
noma. It is interesting to consider that Andervont ( i )
the lung in thc hcart. FI(;. 2.--Spindle cell metastasis in chcst wall of primary Downloaded from http://aacrjournals.org/cancerres/article-pdf/1/4/259/2368302/crs0010040259.pdf by University of Valencia user on 13 February 2024
carcinonla of the lung of a mouse. >< 28o.
reports that 4 pulmonary tumors induced in mice by
dibenzanthracene, and one which arose spontaneously,
when transplanted into the subcutaneous tissues be-
came changed to spindle cell sarcomas, although the
parent tumors were definitely adenomatous. Ap-
parently when the cancer cells get away from the
alveolar walls which serve as a framework and per-
haps maintain their epithelial character, they assume
a spindle cell character resembling sarcoma. Perhaps
this may be looked upon as evidence of their mes-
enchymal nature.
 Wells et al.--Carcinoma o[ the Lung in Mice 26r

metastases o u t s i d e t h e l u n g s . All of these s h o w e d

metastases in t h e m e d i a s t i n a l l y m p h n o d e s ; m a n y
also s h o w e d g r o w t h s a l o n g t h e chest wall a n d o n t h e
d i a p h r a g m . O n l y io s h o w e d metastases to o t h e r or-
g a n s ; n a m e l y , 5 in t h e k i d n e y , 3 in t h e heart, i in
t h e s e m i n a l vesicle, a n d i in t h e skull.
O f t h e io 4 cases w i t h metastases, 33 of t h e m e t a s t a t i c
g r o w t h s s h o w e d m o r e or less the s t r u c t u r e of a
s a r c o m a . T h i s was t r u e even w h e n n o s a r c o m a t o u s

Downloaded from http://aacrjournals.org/cancerres/article-pdf/1/4/259/2368302/crs0010040259.pdf by University of Valencia user on 13 February 2024

e l e m e n t s w e r e seen in t h e p r i m a r y g r o w t h . A l t h o u g h
in a n u m b e r of p r i m a r y l u n g t u m o r s this s a r c o m a t o u s
s t r u c t u r e was a p p a r e n t , no p r i m a r y s a r c o m a s of t h e
l u n g , w i t h o u t epithelial e l e m e n t s , h a v e b e e n o b s e r v e d
in these mice.
T h e m e s e n c h y m a l or epithelial o r i g i n of these l u n g
t u m o r s is discussed.

REFERENCES
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2. CA~IPBELL, J. A. Effects of Road Dust "Freed" from Tar
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FXG. 3.--Sarcoma-like area in primary carcinoma of the lung the Incidence and Inheritability of Spontaneous Tumors
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SUMMARY AND CONCLUSIONS
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