Diagnostic

Lymphangitic Spread of Metastatic Radiology

Cancer to the Lung

A Radiologic-Pathologic Classification1
MURRAY L. JANOWER, M.D., and JOHN B. BLENNERHASSETT, M.D.

ABSTRACT-Autopsy diagnosis of pulmonary lymphangitic carcinomatosis

was made in 23 cases in which recent chest radiographs were available. Three
radiologic groups were evident: Group 1-5 cases with both parenchymal nod-
ules and an interstitial linear pattern; Group II-I0 cases with an interstitial
linear pattern only; Group III-8 cases in which the lungs appeared normal.
The radiologic-pathologic correlation was excellent. Lymph nodes contained
metastatic tumor in 11 cases while arterial tumor emboli were identified in 20
of the 23 cases. The pathogenic mechanism of such tumor spread may be pri-
marily vascular embolization rather than retrograde spread from central lymph-
node involvement.
INDEX TERMS: Lungs, cancer. Lymph Nodes, cancer
Radiology 101 :267-273, November 1971

TVMPHANGITIC spread of tumor in the
L lung is a well recognized manifesta-
tion of metastatic disease, in which the
patient's clinical respiratory distress is fre-
quently out of proportion to the abnormali-
ties seen on chest films. Although the
roentgen finding of increased interstitial
lines in the chest films of these patients has
been well described in the radiologic litera-
ture (1, 2), relatively little attention has
been given to the variable radiologic pat-
terns that may exist. This paper relates
the roentgen appearance to pathologic
findings, with the hope that such a correla-
tion will help the radiologist to understand
this process.
BACKGROUND
Peripheral lymphatic channels of the
lung consist of those in the pleura and those
in the lung parenchyma. Lymphatics in
the visceral pleura form a rich network of
vessels, approximately 0.5 mm in diameter,
which can be seen with the naked eye on a
gross pathological specimen, but which
cannot normally be seen on a chest film.
Most of these channels peripherally outline
the interlobular septa, but they may also be
distributed at random over the surface of
1 From the Departments of Radiology and Pathology, Massachusetts General Hospital, Boston, Mass.
sented at the Fifty-sixth Scientific Assembly and Annual Meeting of the Radiological Society of North America
Chicago, Ill., Nov. 29-Dec. 4, 1970.
the lobule. The pleural lymphatics are
more frequent over the lower than the
upper lobes, being present at a ratio of
approximately 3.2: lover the right lung
and 8.2: lover the left lung (3). In many
of these vessels valves direct the flow of
lymph into the lymphatics in the inter-
lobular septa whence it is carried to the
hilar lymph nodes. Although it may be
possible for the pleural lymph to travel
entirely over the surface of the lung to the
hilus, this occurrence is thought to be un-
usual (3).
The lung parenchymal lymphatics form
two major networks; those in the inter-
lobular septa and those found in association
with the vessels or bronchi. The pe-
ripheral lung lymphatics lie in the inter-
lobular septa which form the boundaries
between the polyhedral secondary lung
lobules; in addition to lymphatic vessels,
the septa contain connective tissue and
pulmonary venules (4). The secondary
lobules, which measure between 1 and 2.5
em along a side, are regularly organized at
the periphery of the lung (particularly at
the bases) where they form a layer which
is 2 or 3 lobules in depth, the so-called lung
cortex; the septa of these lobules are fre-
Pre-
a~

267
268 l\1URR.\.Y L. }.:\NOWER AND JOHN B. BLENNERHASSETT
T ABLE I: SITES OF ORIGIN OF TUMORS
Breast
Adeno- Other Adenocarcinoma
carcinoma
Group I 2 Prostate
Endometrium
Group II 7 Fallopian tube
Cervix
Group III 4 Endometrium
Colon
quently perpendicular to the chest wall.
The secondary lobules are considerably
less well separated by septa near the inner
portion of the lung, the medulla (5). The
septa and lymphatics within them extend
centrally to become continuous with the
connective tissue around major vessels and
bronchi, forming a perivascular and peri-
bronchial network which points toward
the hilus.
METHOD
Twenty-three patients whose chest radio-
graphs were taken within three months of
death form the basis of this study; the
autopsy diagnosis in all was lymphan-
gitic spread of tumor. The following ob-
servations were made from the chest
roentgenograms: presence or absence of an
interstitial linear pattern; degree and dis-
tribution of this pattern; presence or
absence of other parenchymal densities;
enlarged lymph nodes; pleural fluid. Sim-
ilar observations were then made from the
autopsy reports, photographs of gross
specimens, and histological slides. In ad-
dition, the histological nature of the tumor
infiltrate was determined.
The chest radiographs were divided into
three categories. Group I consisted of
those cases in which parenchymal nodules
were evident, as well as a linear pattern.
In Group II cases only an interstitial linear
pattern was seen, and in Group III cases
the lungs appeared normal. The cases
were next arranged in decreasing order of
involvement within each category. The
pathological findings were then reviewed
to see if a correlation existed between them
and the findings on the chest films.
RESULTS
Of the 23 cases, 5 were in Group I, 10
November 1971
(23 CASES)
Other Tumor Total
1 Bladder 1 5
1
1 Cervix 1 10
1
1 Esophagus 1 8
1 Bladder 1
were in Group II, and 8 were in Group III.
The sites of origin of the tumors are shown
in TABLE I.
Group I (5 Patients): Gross paren-
chymal nodularity was evident on the
chest films in 4 cases (Fig. 1) while in one
only a few scattered small nodules were
seen. A markedly prominent linear pat-
tern could be noted between the nodules in
all cases, and the degree of lymphatic in-
volvement was proportional to the degree
of parenchymal involvement. The mark-
ings measured several millimeters in thick-
ness and seemed to have a hazy border
rather than a sharp margin (Fig. 2).
Radiographic evidence of lymphadenop-
athy was noted in 2 cases, and implants of
metastatic tumor in the pleura or pleural
fluid were seen in 3.
The gross specimens of lung correlated
with the parenchymal nodularity as assessed
radiologically; in addition, there was ex-
tensive lymphatic involvement in all cases
(Fig. 3). In 4 cases, the tumor involved
peribronchial, perivascular, septal, and
pleural lymphatics to a marked extent,
grossly accentuating these structures. The
degree of enlargement of the broncho-
vascular and interlobular septal spaces was
comparable with that to be described in
Group II below. In 2 of these 4 cases,
mediastinal and tracheobronchial lymph
nodes were extensively invaded by tumor.
The remaining case showed less obvious
gross tumor, but microscopy revealed in-
filtration of the same lymphatics, without
hilar lymph node metastases.
In all 5 cases, the predominant mass in-
creasing the bronchovascular and septal
spaces was composed primarily of tumor
cells in the lymphatics and adjacent con-
nective tissue with relatively little stromal
Vol. 101 LYMPHANGITIC SPREAD OF METASTATIC CANCER TO LUNG 269 Diagnostic
Radiology

Fig.1. Chest radiograph demonstrating multiple nodules and enlarged lymph nodes. A prominent background
linear pattern can be identified.
Fig. 2. Detail film of the right lower lung field (same case as Fig. 1) revealing thick white lines with hazy
borders between the nodules.
Fig. 3. Cut section of the right lung. Multiple nodules of metastatic tumor in the lower and middle lobes are
almost confluent. In the upper lobe tumor can be seen thickening the walls of the bronchi and vessels (arrows);
nodules are present in the anterior segment.
Fig. 4. A small pulmonary artery is surrounded by lymphatics distended with tumor cells (arrows). A large
tumor nodule is present in the upper right of the photograph. H & E X 25

reaction (Fig. 4). In the case showing the
most obvious fibrous reaction to tumor,
approximately half the bulk of increased
tissue was made up of tumor cells, the re-
maining 50% being reactive fibrous tissue.
The grossly visible tumor nodules, on the
other hand, had disrupted normal anatomy
to such an extent that an origin from either
lymphatic or blood vessel was not dis-
cernible. Tumor emboli were quite ex-
tensively present in small arteries and
arterioles in 4 of the 5 cases.
Group II (10 Patients): The chest
radiographs in this group revealed a
classic interstitial linear pattern without
parenchymal nodularity (Fig. 5). The ex-
tent of pleural involvement varied but it
was present in all cases, while enlarged
270 MURRAY L.
Fig. 5. Chest radiograph revealing a prominent interstitial linear pattern.
Fig. 6. Detail film of the left upper lobe (same case as in Fig. 5), demonstrating the clarity of the interstitial
lines.
lymph nodes were recognized in only 3 cases.
All portions of the lungs were uniformly in-
volved, allowing for the fact that there is
considerably more lung parenchyma at the
lung bases than the apices. The markings
were predominantly linear in type, radiat-
ing toward the hilus; punctate nodularity
could be discerned in many. Careful in-
spection usually showed perpendicular
thickened septal lines at the costophrenic
angles, but a reticular, lace-like pattern was
unusual. The lines varied in thickness
from 1 to 3 mm but were generally fine in
texture with sharp clear margins (Fig. 6);
they were so numerous that they could not
be confused with vessels. In 3 cases, the
lines appeared more prominent and were
particularly well seen; the size of these
patients and the technique of the films
were similar to those of the other patients
in this category.
At autopsy, 1 of the 10 cases in this
group showed a few parenchymal nodules
measuring up to a maximum of 1.2 ern in
diameter. In the remaining 9 cases, paren-
chymal nodules larger than 5 mm were not
found, although small pleural nodules were
seen in 4 and more diffuse pleural thicken-
ing was present in another 4. The remain-
ing patient had bilateral pleural effusions,
but no pleural tumor masses were seen.
JANOWER AND JOHN B. BLENNERHASSETT November 1971
All patients in this group showed a
grossly visible combination of marked
peribronchial and perivascular tumor ac-
centuating the size of the bronchovascular
space, thickening of the peripheral inter-
lobular septa up to 2-3 mm, and accentua-
tion of pleural lymphatics (Fig. 7). On
microscopic examination, tumor was seen
in the lymphatics and appeared to focally
disrupt these and invade adjacent septal
connective tissue (Fig. 8). In the medial
and central zones the bronchovascular
space was thickened by an increment of up
to 5 mm, while more peripherally this
tended to be less marked, apart from focal
zones in which tumor was growing in a
nodular fashion adjacent to the lymphatics.
Again, stromal reaction to the tumor in
bronchovascular and interlobular areas was
absent or mild in 5 (Fig. 9) and only
moderate in 5 (Fig. 10), tumor cells them-
selves making up the bulk of the mass.
Though differences in degree of involve-
ment by tumor were difficult to grade
accurately because of lack of uniformity of
microscopic sampling, it was clear that the
3 patients whose radiological markings
were most prominent also showed more
prominent involvement grossly.
In 8 of the 10 patients, in addition to the
lymphatic spread of tumor, emboli were
Vol. 101 LYMPHANGITIC SPREAD OF METASTATIC CANCER TO LUNG 271 Diagnostic:
Radiology

Fig. 7. Cut surface of the formalin-inflated lung (upper) and pleural surface of the fresh lung (lower). Pleural
lymphatic vessels (arrow) distended with tumor cells outline the secondary lobules. Toward the hilar region of the
cut section tumor distends the peribronchial-perivascular areas and can be seen thickening bronchial and vascular
walls inferiorly.
Fig. 8. Four subsegmental bronchial branches are cut in cross section. The submucosal and peribronchial
areas are markedly thickened by tumor (arrows). H & E X 10
Fig. 9. A small peripheral blood vessel is surrounded by lymphatic spaces (arrows) which are distended by
tumor cells. H & E X 130
Fig. 10. The perivascular space is thickened by tumor cells which are inciting a fibrous stromal reaction. H &
EX 50
Fig. 11. A small pulmonary artery contains an impacted tumor embolus (double-tailed arrow) which shows
peripheral fibrous organization. Tumor is growing in the perivascular connective tissue space and in lymphatics
(arrows). H & E X 10

evident microscopically in pulmonary ar- Autopsy in 3 cases disclosed lymphatic

tery branches (Fig. 11). These were
mostly small arteries and arterioles, but in
some cases vessels up to about 2 mm diam-
eter were involved. In 6, hilar nodes were
enlarged by tumor; no mediastinal tumor
was found in the remaining 4 cases.
Group III (8 Patients): The chest films
in these cases revealed no evidence of
parenchymal disease or of an increase in
the background linear pattern. Two pa-
tients showed pleural effusions and 2 differ-
ent patients had pleural disease.
spread of tumor similar to that seen in
Group II. This could be appreciated on
gross examination of the lung. Tumor
emboli were present in small arterial
branches. In addition, 2 of these 3 cases
showed parenchymal tumor nodules up to
1.5 em in diameter, and in 2 hilar nodes
contained metastatic carcinoma. In the
remaining 5 patients tumor was present
microscopically in the lymphatics, but in
all it was relatively minor and distributed
irregularly in focal areas rather than being
272 MURRAY L. JANOWER AND JOHN B. BLENNERHASSETT
uniform throughout the parenchyma. The
tumor in these cases was within both blood
vessels and lymphatics without any obvious
distension of the perivascular-peribronchial
area or of the septa. Only 1 of these 5
patients had tumor in hilar lymph nodes.
DISCUSSION
The major radiologic observation con-
sisted of an increase in the linear back-
ground pattern of the lung fields. The
lines varied in length, thickness, and
clarity, but they appeared to radiate pre-
dominantly from the hili. The anatomic
location of the lymphatics within the lung
will determine the distribution of the
linear shadows. If viewed tangentially,
the well organized interlobular septa in the
cortex at the bases of the lung will appear
as short lines perpendicular to the chest
wall. If viewed tangentially elsewhere,
such as toward the apices of the lung or
toward the hilus, the lymphatics in the
interstitial septa as well as the pleural,
perivascular, bronchial lymphatics will
appear as lines radiating from the hili. If
these structures are seen en face, a reticular
lace-like pattern will result because of over-
lap. Although thickened septa perpendic-
ular to the lower lateral thoracic wall could
be seen in most cases if carefully looked for,
this was not a major finding; likewise, a
reticular lace-like pattern was unusual.
The abnormal linear pattern was quite uni-
form in most patients, and it seems likely
that any variation within a given patient
or between patients is a function of the
quantity of tumor present and overlapping
of shadows rather than a difference in basic
disease pattern.
The corresponding major pathologic
observation consisted of tumor distending
the perivascular-peribronchial lymphatics
and adjacent connective tissues and the
interlobular septa with or without paren-
chymal nodules. Microscopically, tumor
could often be seen within these lymphatics,
distending them sometimes up to 2 or 3
mm in diameter. In many areas, in
addition to being present within the lym-
phatics themselves, tumor appeared to have
November 1971
invaded the adjacent connective tissues,
forming small nodules. When tumor was
within the lymphatic vessels, little fibrous
stromal reaction could be appreciated.
When it had invaded through the lym-
phatic wall and was present in adjacent con-
nective tissue, the stromal reaction was
often more extensive with an irregular
margin but seldom made up more than half
the total bulk of increased tissue. How-
ever, nodules within the parenchyma often
incited a considerable fibrous stromal
reaction, particularly when they were in
the pleural and subpleural regions. It
follows, therefore, that the linear pattern
seen on chest films in patients with so-
called lymphangitic spread of tumor does
not result solely from involvement of the
lymphatics; the connective tissue in which
the lymphatics course also participates in
the formation of the roentgen image. Fur-
thermore, the hazy outline of the linear
shadows and a suggestion of punctate
nodularity seen in some cases are explained
by the irregular growth pattern of the
tumor, as described above.
The correlation between the radiologic
and the gross and microscopic pathologic
findings was generally excellent, with re-
spect to both parenchymal nodules and
lymphangitic spread. The site of the
primary tumor was not an influencing
factor in the grouping of these patients.
I t was impossible to predict from the radio-
graphs whether the linear pattern was due
entirely to increased thickness by tumor
cells alone or whether both tumor and
stromal reaction were responsible. I t is
clear from many of these cases, however,
that tumor cells alone can be responsible
for the radiologic pattern of lymphangitic
spread. Of the 8 cases in which the chest
roentgenogram appeared normal, lym-
phangitic tumor was visible on naked eye
examination of the lung in 3, but, in the
remaining 5, tumor invasion of lymphatics
was relatively minor and appreciable only
on microscopic examination.
The term lymphangitic spread of tumor
within the lung carries the connotation of
a primary and predominant lymphatic role
Vol. 101 LYMPHANGITIC SPREAD OF METASTATIC CANCER TO LUNG
in the spread of tumor (1). To many, it
also implies that the pathogenetic mecha-
nism is one of replacement of hilar lymph
nodes by metastatic carcinoma which then
spreads centrifugally in the lymphatic
channels which surround the bronchi and
vessels. Of the 23 patients in this study,
only 11 in fact had metastatic tumor in the
hilar lymph nodes, and in some of these
the tumor was present only as small, focal
deposits. I t is evident, therefore, that
massive mediastinal lymph node involve-
ment is not a necessary prerequisite for
lymphatic spread of tumor in the lungs.
On the other hand, in 20 of the 23 cases,
there were obvious tumor emboli micro-
scopically visible in blood vessels, usually
arterioles and small arteries, but occasion-
ally in arteries up to 1 or 2 mm in diameter.
In the remaining 3 cases, in which no
tumor emboli were seen, the sampling of
lung tissue for microscopic examination
was inadequate to exclude the possibility
of local tumor embolization. It seems likely,
then, that an alternative hypothesis is more
tenable; that is, that tumor usually
reaches the lung by vascular spread with
embolization in small peripheral vessels (6).
If tumor remains viable, then local growth
may form a parenchymal tumor nodule or
tumor may invade through the wall of the
blood vessel into the adjacent lymphatics
and then spread by way of the path of least
resistance by permeation into the peri-
bronchial-perivascular interlobular septal
and pleural lymphatics. In this way, the
hilar lymph nodes may subsequently be-
come the seat of metastatic tumor as a
result of the lymphangitic pulmonary
spread. The fact that hematogenous
metastases to other organs were present in
all cases adds further support to this
hypothesis. We have no explanation why
273 Diagnostic
Radiology
some tumors spread in pulmonary tyro-
phatics rather than form the much more
usual parenchymal nodularity without im-
pressive lymphatic involvement. However,
it is notable that over half the cases in this
study had primary adenocarcinoma of the
breast.
While involvement of the lung vascula-
ture by tumor embolization is probably in
large part responsible for the physiological
abnormalities observed in these patients,
it is the involvement of the various groups
of lymphatics and adjacent connective
tissue by tumor which produces the radio-
logical abnormalities characteristic of so-
called lymphangitic carcinomatosis. It is
therefore only at a late stage in this type
of pulmonary involvement that radiological
abnormalities become evident.
ACKNOWLEDGMENT: The authors are pleased to
acknowledge that the original stimulus for this
paper came from the late Dr. Felix G. Fleischner.
We are also grateful to Dr. Jeffrey H. Newhouse who
participated in the early stages of this project.
Department of Radiology
Massachusetts General Hospital
Boston, Mass. 02114
REFERENCES
1. Mueller HP, Sniffen RC: Roentgenologic ap-
pearance and pathology of intrapulmonary lymphatic
spread of metastatic cancer. Amer J Roentgen 53:
109-123, Feb 1945
2. Trapnell DH: Radiological appearances of
lymphangitis carcinomatosa of the lung. Thorax 19:
251-260, May 1964
3. Trapnell DH: The peripheral lymphatics of
the lung. Brit J RadioI36:660-672, Sep 1963
4. Heitzman ER, Ziter FM Jr, Markarian B, et al:
Kerley's interlobular septal lines : roentgen pathologic
correlation. Amer J Roentgen 100:578-582, July 1967
5. Heitzman ER, Markarian B, Berger I, et al:
The secondary pulmonary lobule: A practical concept
for interpretation of chest radiographs. 1. Roentgen
anatomy of the normal secondary pulmonary nodule.
Radiology 93: 507-512, Sept 1969
6. Morgan AD: The pathology of subacute cor
pulmonale in diffuse carcinomatosis of the lungs. J
Path Bact 61:75-84, Jan 1949