CANCER RESEARCH
VOLUME 21
OCTOBER 1961
NUMBER 9
Patterns of Metastasis in Lung Cancer- d Review*
WiLsoN I. B. ONwmBot
(Department ~JfPathology, University qf Olaxgow and lFestern Ir~firmary, Glasgow, Scotland)
INTRODUCTION
Scientific methodology emphasizes the importance of any discrepancies between an accepted
theory and the observed facts. The present study
aims to focus attention on the metastatic patterns
of lung cancer which are at variance with current
concepts.
The accepted theory of lung cancer metastasis
was clearly stated by Aekerman and Regato (1):
"The lymphatic spread is the most common, and
involvement of mediastinal, peritracheal lymph
nodes almost always takes place . . . . If tumor
grows into the pulmonary veins, systemic dissemination becomes inevitable and brain, bone, suprarenals, and liver become the site of metastases."
This statement reveals the present dual concept of
metastasis: first, lymphogenous spread to the
lymph nodes; secondly, hematogenous spread to
the organs. As Batson (11) pointed out, this dual
concept is held by Willis, Walther, and other authorities. The blood stream, according to Fried
(46), is looked upon as the essential mode of spread
of tumor cells to the distant organs. This view is
deducible from Coman's (~8) review of metastatic
mechanisms. In nay opinion the current hematogenous theory of visceral metastasis dates back to
the 19th century (97) and follows the general teachings of the old masters (95).
Fifty years ago, Levin and Sittenfield (8~2) made
a comment of considerable relevance to the problem of metastasis: "This proof of the transporta-
tion of carcinonm cells through blood channels offers a better explanation for certain peculiarities in
metastasis formation, than the purely lymphatic
theory." Today, these peculiarities remain une•
plained in lung cancer. For example, Galluzi and
Payne (47), who assumed that this tumor spreads
hematogenously to the organs, found it so difficult
to harmonize their observations with expectations
from blood flow that they called for detailed study
of unexpected metastatic patterns. Now, as Anderson (3) noted, the very location of lung cancer
with respect to the thin-walled pulmonary veins is
such that 'this tumor gains access to the peripheral
blood stream more readily than most other tumors. Therefore, if a tmnor so richly endowed with
opportnnities for blood-borne dissemination can be
shown to fall short of expectations repeatedly, I
am persuaded that new prospects in cancer research would open.
The plan of this paper is as follows: First, the
various findings which fall short of our expectations on hematogenous dissemination are marshaled--(a) metastases are often not widespread;
(b) they are distributed centrifugally; (c) they appear selectively in certain organs; (d) they are infrequent in the contralateral lung; (e) they are
found wholly or mainly on one side in paired organs; (.f) they show no correlation with the blood
supply; and (g) they predominate in certain parts
of the organs. I n order to be in a position to harmonize these discordant notes in the theme of
hematogenous metastasis, the variations charac* Aided in part by a grant from the University of Glasgow. teristic of lymphogcnous metastasis are next elabot Research student, on study leave from the Ministry of rated. It is shown that lymphogenous metastases
Health, Eastern Nigeria.
tend to be (a) limited in extent; (b) centrifugal in
sequence; (c) selective in distribution; (d) ipsiReceived for publication _March ~20,1961.
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lateral in the main; (e) asymmetrical with respect
to the midline; and (f) predominant in certain
parts of the involved tissue. Then, it is demonstrated by means of analogy that every one of the
unexpected metastatic patterns seen in the organs
is compatible with, and probably attributable to,
one or more of the delineated lyinphogenous patterns. Finally, since tumor cells undoubtedly circulate in numbers in the blood of patients harboring lung cancer, it is urged that attention should
be directed toward the elucidation of the reasons
why lymph-borne rather than blood-borne tumor
cells account for the metastatic patterns in this
disease.
UNEXPECTED PATTERNS IN
VISCERAL METASTASIS
1. Limited metastasis.--Lung cancer cells have
only to penetrate the puhnonary veins to reach the
left ventricle and aorta and so to be dispersed to
organs far and wide. I t is, in consequence, "puzzling" to note, as did Ballantyne and his co-workers
(7), that there is a lack of widespread distribution
of metastases in all patients. In m y study of 6,000
cases of lung cancer recorded in ~8 Teaching Hospitals (99), note was made of the presence of
metastases in eight organs. In as m a n y as 1,978
cases none of these organs was stated to have been
invaded. So infrequent indeed was widespread invasion that only ~.6 per cent of the cases exhibited
secondary deposits in more than four of the listed
organs, the average metastatic frequency being
1.3. Although Rosenblatt (11~) and others contend
that metastases are widespread in lung cancer, this
view was neither corroborated by the necropsy
records studied nor substantiated by an analysis of
published figures.
Furthermore, even when an organ is actually
metastasized, it is not uncommon for one metastatic mass to be detected. In the brain, for instance, the indications are that up to one-third of
the deposits may be solitary (44, 5~, 60, 76). I believe, with Stern (131), that this distribution is difficult to accept as one of pure chance. Admittedly,
some metastases must escape detection. Still, our
expectations are jolted: distant deposits are J,ess
common than might be expected when the enormous vaseularity of the lung is taken into account
~2. Centrifugal metastasis.--We expect, as did
Carnett (s and Cohnheim (~7), t h a t tumor cells
dispersed along the systemic arteries would be
found growing indiscriminately in organs both far
and near. On the contrary, in the experience of
Fried (45), the more remote an organ is from the
puhnonary primary the more remote are its
Vol. ~1, O c t o b e r 1961
chances of being metastasized. For example, there
is a striking scarcity of ovarian secondaries (38,
74). In my survey of the incidence of secondary
deposits in the three bilateral or bilobed upper abdominal organs, the discernible topographical pattern was one in which a centrifugal sequence of
spread could not be ruled out (98). In this connection, the bones are of interest, for the thoracic
vertebrae are those most frequently invaded (5,
~1, ~ ) , the distant bones being less often attacked. Thus, Greene (54) in 1957 was able to collect only ten cases from, and to add one case to, the
literature on phalangeal metastases. The centrifugal trend is also noticeable in subcutaneous metastases (~4). The combined evidence warrants the
conclusion t h a t lung cancer tends to spread centrifugally. This pattern is contrary to our expectation t h a t opportunities for invasion of both far and
near organs are equal in this condition.
3. Selective metastasis.--Since the days of Hodgkin (69), the fact t h a t a tumor seems, on occasion,
to select a particular organ for attack has been a
puzzling feature of metastasis. As early as 1910,
Bramwell (13) wondered whether the selection of
the adrenals in lung cancer was a mere coincidence.
This phenomenon has since been a subject for
curiosity and comment (83, 1~8, 15~). An apt commentary comes from Robbins (107) : " F o r obscure
reasons, bronchogenic carcinoma sometimes singles out the adrenals as sites of spread."
This problem would have been easy of solution
on the theory of soil susceptibility if adrenal selectivity had been all t h a t demanded explanation.
However, as a number of contributors recognize
(9, 15, 70, 1~0), other organs including the brain,
heart, liver, pancreas, a n d kidney may also be selectively involved.
Since hmg cancers show considerable polymorphism under tile microscope (6, 48, 1S6, 144),
it is improbable that the mischief is made by particular cell types singling out particular organs.
Indeed, there are conflicting views on the role of
the cell type in metastasis to individual organs.
Thus, in the case of the brain, squamous-cell (41),
adenocarcinoma (117), small-cell (1~0), and undifferentiated-cell types (160) have all been indicted
for their proclivity to spread to this organ, although Halpert (59) is emphatic in denying t h a t
the cell type bears any relation to the frequency of
intracranial metastasis. I t would seem, therefore,
t h a t unless we can with propriety invoke soil suitability in each lone organ seemingly singled out for
metastasis we are confronted by a distribution pattern least expected from a tumor whose opportunities for widespread dispersal are myriad.
4. Cordralateral metaslasis.--Over a century
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ONumBo---Metastasis in Lung Cancer: A Review
ago, the old authors drew attention to the way in
which lung cancer tended to spare the contralateral lung (17, 65). Since then many authorities,
and Osier (101) was among them, have made this
point. In fact, so characteristic is this that Barnard
(9) and Weller (151) both counseled that, when
metastases are present in the contralateral lung, an
extrathoracic primary must needs be excluded.
~ In 1882 Fenwick (43) reviewed published cases
of hmg cancer and discovered that only 13 per cent
had metastasized to the other lung. This same figure was obtained in a recent paper (25), the range
being from 10 to 30 per cent (41, 85, 131,137, 158).
According to Eerland (36) and IIerbut (67),
contralateral pulmonary metastasis is hematogenous. Why, then, do blood-borne emboli fail so
often to flourish in the opposite lung? There are, be
it noted, multifarious blood-vascular routes which
should insure successful transference across the
midline: (a) bronchial branches of the aorta (109),
(b) the vertebral venous system (10), (c) the
thoracic duct either in its role as a conduit (142) or
when it is itself infiltrated (159), (d) the superior
vena cava and its tributaries (49), (e) the venous
radicles of invaded lymph nodes (80), and (f) the
venous return which carries not only emboli tertially liberated by established secondary deposits
(80) but also those which successfully negotiated
the capillaries of distant tissues (163).
Owing to the facilities afforded by these channels, not only the egress of tumor cells from the
lung of origin but also their ingress into the contralateral lung should be easy. Why, then, do primary tumors of the lung show, as Budinger (18)
put it, a "seeming reluctance" to invade the other
lung? Unless it is contested that bronchial and
alveolar soils differ markedly, it is noteworthy that
in the contralateral lung the malignant seeds are
being sown on a soil from which the parent tumor
sprouted. In this respect, the fact that "alveolar
cell" carcinomas of the lung also show a low rectastatic frequency (133) fortifies our suspicion that
in this situation the infrequency of contralateral
metastasis reveals a clash between the hematogenous theory and the observed facts.
5. Asymmetrical metastasis.--Bilaterality of invasion of paired organs has long been accepted as a
point in favor of the theories of hematogenous
metastasis (103, 148) and suitability of soil (53,
75). However, since millions of tumor cells in all
probability circulate in the blood stream daily
(88), it is reasonable to expect that paired organs
would be exposed more or less equally and simultaneously to the ensuing cancerous bombardment
daily.
Let us, therefore, compare the deposits found in
1079
the adrenal gland on either side. Gillespie (51) discovered on making this comparison that the one
growth is usually larger than the other. So conspicuous may the resulting disparity in size become that Beattie and Dickson (12) called attention to this fact thus : "Note the minute secondary
growth in the opposite organ." In a case which I
reported from this hospital the difference in the
weights of the adrenals was 460 gin. (91); in Case
5398 of the Postgraduate Medical School of London the difference was as much as 2,388 gin.
Hitherto, these cases have masqueraded merely
as bilateral metastases, but I would draw attention
to the phenomenon of size disparity which lies hidden behind the facade of bilaterality. Although
each member of such an organ pair had from the
first been open to attack by blood-borne cancer
cells, yet one of them succumbs long before the
other. We may consider the issue from another
angle. Of 400 cases of adrenal metastases collected
from the literature (8, 19, 21, 42, 61, 77, 85, 110,
116), as many as 132, i.e., one-third, were unilateral. Why, we ask, does one adrenal nurture the
invading cells to the point at which deposits are
noticeable, although the other gland is as yet innocent of tumor tissue? The unilateral growth, it
should be noted, need not be small. In one of nay
cases the tumor mass weighed 130 gm., although
the other adrenal was unscathed (94). Senoo's case
attained 80 gin. in similar circumstances (124).
Hence, despite the similarities of paired organs
both in their soil and in their opportunities for
blood-borne invasion, there are nevertheless dissimilarities--and these may be astounding--in
their metastatic involvement.
6. Uncorrelated metastasis.--Although the kidneys receive about one-quarter of the total resting
cardiac output (157), yet lung cancer metastasizes
less often to the kidneys than to the tiny adrenals.
Apparently, the total quantity of cancer-containing blood received by an organ is not correlated
with its metastatic frequency. Since blood flow to
t h e adrenals per unit weight of tissue is high (81),
their relatively high rate of metastasis may conceivably be due to this fact. However, this argument would leave unexplained the higher incidence in the liver, an organ which is, weight for
weight, very poor in arterial blood supply (125).
Perhaps it is best to compare the metastatic
frequency in two portions of the same organ. In
the brain, for instance, the cerebellum is only
about one-eighth of the size of the cerebrum (105).
However, 38 per cent of brain metastases secondary to lung cancer were found in the cerebellum
(47), a figure suggesting that the cerebellum exhibits metastases half as often as the cerebrum. This
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proportion is borne out by nay collected data (94)
and those of Willis (153) and Meyer and Reah
(87), data being those related to tumors in general.
Although some think that the cerebellum shows
no distinctive metastatic features (34), the available data indicate, as Dorothy Russell states (114),
that the cerebellum must be considered as a site of
predilection. Until it is shown either that the cerebellum offers to blood-borne tumors a soil markedly different from that in the cerebrum or that
the true proportional incidence of cerebellar and
cerebral metastases is not that usually recorded, it
is fair to conclude that the distribution of metastases in the brain is at odds with the current emphasis on arterial dissemination.
The liver may also be considered. This organ is
symmetrical in primitive animals (71). In man the
left lobe is only about one-quarter of the size of the
right lobe (145). Nevertheless, in my study of 0~00
cases of pulmonary and other extra-portal tumors
with hepatic deposits (9~), there was no commensurate concentration of the metastatic masses
in the right lobe. In effect, this lack of correlation
with blood supply belies the current hematogenous
theory of metastasis.
7. Spatial metastasis.--Spatial relationships are
manifest in visceral metastasis. Perhaps the most
widely recognized example is that seen in the
adrenal gland, whose medulla is more often the
seat of secondary deposits than the cortex (20, 31,
111). Medullary localization is of particular pertinence to the theory of hematogenous metastasis,
because the medulla is thought to obtain its blood
supply largely through capillary vessels which
have already passed through the cortex (63).
Therefore, it comes as a surprise that the medulla
rather than the cortex seems to trap tumor emboli
more commonly (1~7). Unless the comparative
frequency of medullary metastases is an erroneous
observation, this distribution pattern conflicts
with the accepted theory of blood flow through the
adrenal.
TOPOGRAPHICAL PATTERNS IN
L Y M P H O G E N O U S METASTASIS
In keeping with methodological principles (156),
I have presented above a number of "falsifying instances" of the theory that hmg cancer spreads to
the organs via the blood stream; we turn now to
the problem of deciding whether these are "confirming instances" of another theory. We begin by
delineating topographical patterns which characterize lymph-borne metastasis.
1. Limited metastasis.--Virchow (147) stressed
the pathological importance of the interruptions
which the nodes offer to the flow of lymph. In par-
Vol. ~1, October 1961
ticular, in neoplastic diseases the nodes act as interrupters and filters (1~3, 139). On this account,
malignant cells are prone to lodge in, but tend to
be localized by, the nodes (50, 108). Consequently,
even with cancers which show considerable propensity for metastasis, only relatively few nodes
are actually involved in most cases (143).
Only one of the 37 cases of lung cancer reported
by Hashem (64) exhibited generalized enlargement
of the lymph nodes. The only case in my series of
25 detailed dissections in which there was generalized lymph node metastasis is shown in Figure 1.
We conclude, therefore, that lymphogenou s metastasis is characterized by, but is not wedded to, limited distribution.
~. Centrifugal metastasis.--Paget (10~) was
aware that cancer is prone to spread to the proximal rather than to the distal lymph nodes. This
centrifugal sequence is apparent in lung cancer
(58, 79). Thus, it is the lower rather than the upper
cervical nodes and, conversely, the upper rather
than the lower abdominal nodes that are more
often metastasized (16, 68). As Willis (154) depicted, lung cancers "often exhibit discrete deposits in the abdominal and cervical glands, these diminishing in centrifugal order." Figures 1, 2, and 4
illustrate this fact. We deduce, in consequence,
that centrifugal metastasis is one of the characteristics of lymphogenous invasion.
3. Selective metaslasis.--In addition to recognizing the centrifugal nature of lymphatic metastasis,
Paget (10r knew also that at times metastases
appear in distant rather than in proximate lymph
nodes. Herbut (67) and Kolodny (78), among
others, refer picturesquely to this phenomenon as
"skip" metastasis. Lymph node skipping, a general neoplastic manifestation (39, 104, 149), is reported in lung cancer (~, 14, 135). I t is discernible
in Figures 1 and ~. The significance of this phenomenon should be clear: it shows that tumor cells
spreading lymphogenously may be conducted past
some nodes en route before attacking a more remote node. We may generalize: in lymphogenous
metastasis certain tissues along the line of spread
may be skipped over and a more distant tissue selectively invaded on account of the existence of
direct lymphatic connections.
4. Contralateral metastasis.--Although anastomotie lymph vessels link up both hemithoraees
(146), experience shows that for some time at least
only the nodes on one side of the chest are attacked in lung cancer (15, 3~). Figures ~ and 3
exemplify this trend. Despite the proximity of the
nodes of either side, whereas the ipsilateral groups
suffer, the eontralateral nodes are often spared. We
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ONUmBo--Metastasis in Lung Cancer: A Review
infer, consequently, that low frequency of contralateral metastasis is a lymphogenous phenomenon.
5. Asymmetrical metastasis.--Since metastasis
commences on one side, the final metastatic pattern tends to be asymmetrical. As Fagge (40) argued, "For obvious reasons the disease is then confined to one side, or at least far more marked on
one side than on the other." This size disparity is
noticed not only in the proximal nodes (1~1) but
also in those more distant (130). Figures 1 and 4
are illustrative. Hence, we deduce that asymmetry
in metastatic development is a hall-mark of lymphatic spread.
6. Spatial metastasis.--Spatial relationships are
manifest in lymph node metastases. As the textual
figures of Cappell ( ~ ) and Willis (154) demonstrate, in the node the earliest tumor deposits are
found in the subcapsular (peripheral) sinus, except
in cases of retrograde metastasis in which the earliest deposits may be found in the hilum (medulla)
of the node (~r 15r These localization peculiarities were confirmed by the experiments of Zeidman
(161, 16~), who demonstrated that the locus in
which a deposit develops in a node is determined
by the manner of arrival of the current of lymph.
Therefore, we conclude that in lymphogenous metastasis the site of earliest deposit formation is governed by, and varies according to, the dynamics of
lymph flow to the part.
ANALOGY B E T W E E N VISCERAL
AND NODAL P A T T E R N S
Having scrutinized the metastatic patterns not
only in the viscera but also in the nodes, let us seek
for analogies between them. All lymph nodes offer
fertile soils to tumor emboli (189, 154), just as all
nodes receive nutrient arterial blood supply. Now,
the blood of lung cancer patients must carry emboli to the lymph nodes. Therefore, it is revealing
that the fertile soils of distant lymph nodes seldom
exhibit metastases in lung cancer. Are blood-borne
cancer cells ineffective agents of invasion of lymph
nodes? If they are ineffective, ought we not to
question their effectiveness as invaders of the organs? I t would seem that we should draw analogy
between the fact that near nodes are most often
metastasized and the fact that near o r g ~ s suffer
most often.
As was long suspected (~26), the abdominal
nodes are usually invaded lymphogenously from
the chest (154). I t is easy to picture lung cancer
cells as they travel retrogradely in the thoracoabdominal lymphatics, but it is difficult to imagine
them discriminating between one lymph vessel and
another by entering those vessels which lead toward the nodes but adroitly avoiding similar yes-
1081
sels which lead equally retrogradely to the organs.
Until it is shown that the mechanism of retrograde
lymph flow toward an organ is different from that
toward a node, we cannot but accept that retrograde lymphatic metastasis occurs not only to the
nodes but also to the viscera. Hence, if the lymph
nodes intercept tumor cells traveling toward more
distant nodes, they must in this way be intercepting cells making for the viscera. The filtering action of lymph nodes not only limits the number of
lymph nodes attacked but also the number of organs invaded.
Why are brain metastases commonly solitary'?
What underlies the curious position which the
cerebellum occupies in the hierarchy of intracranial metastases? According to Symonds and
Cairns (141), the lower half of the brain is the more
common seat of secondaries. This is what we
would expect from centrifugal metastasis along
lymphatic pathways; but many believe that the
brain is without lymphatics and so cannot be invaded by way of this system (33, 84, 106, 13~,
134). Elsewhere (100), I have argued against this
opinion; here, I should like to reiterate, as did Gull
(57) in the Harveian Oration for 1870, that the
negative results of scientific experiments stultify
progress when they impose limits that may not
really exist. As Wisdom (155) emphasized, the results of scientific experiments are inherently provisional in nature. Therefore, to attach finality to
the results hitherto obtained from experiments on
brain lymphatics is erroneous. Rouviere (113) advised us not to dismiss the possibility of the existence of lymph vessels in the central nervous system. We now have the comprehensive review of
Rusznyak, Foldi, and Szabo (115), who concluded
that " C o n n e c t i o n s . . . exist between the central
nervous and the lymph vascular system, connections that are highly significant anatomically,
physiologically and pathologically." In my view
such lymphatic connections must be postulated
before the distribution patterns of intracranial
metastases become meaningful (94).
Why is one organ selectively involved, even
though all are showered with malignant cells? Let
us hypothesize that the selected organ received its
potent invaders not through the blood stream--a
channel open to all--but through the lymph
stream--a channel that has special connections.
This hypothesis does no violence to, but takes a
leaf from, orthodox teaching. Thus, today it is assumed (118) that, when one organ is selected, as it
were, for metastasis, all the other organs had failed
to nourish their own blood-borne emboli. I t is,
therefore, but a simple extension of this idea if we
also assume that the organ selectively metasta-
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sized failed, too, to nourish its blood-borne emboli
but was attacked by retrograde metastasis via its
lymphatics. I t is noteworthy that the lymphatic
system does provide the means of effecting selective metastasis. Thus, the clinical sign, Virchow's
node, is essentially the selective invasion of a
supraclavicular node in the absence of general
lymph node metastases in the neck. Here, the
thoracic dust is the metastatic pathway (161).
Bearing in mind the role of this well defined channel, we should look for less obvious channels in
other sites. For instance, there are direct lymphatic connections between the adrenals and intrathoracic nodes (~0, 56, 73, 1113). Accordingly, lung
cancers can selectively attack the adrenals. Other
organs may have similar direct lymphatic connections (86); these organs in like manner could be
attacked selectively.
The one-sided tendency in lymphogenous metastasis is seen when lung cancer causes pulmonary
lymphangitis carcinomatosa (45, 1130). Now, this
undeniably lymphogenous process is acknowledgeably extensive and yet often remains unilateral, as
do lymph node metastases. We expect, then, t h a t
the less florid manifestation, namely, discrete lymphogenous metastasis, would also tend to be unilateral. In other words, the striking low frequency
of contralateral pulmonary metastases in lung
cancer is what we should expect if this tumor attacks organs and nodes lymphogenously more often than not.
Similarly, the asymmetrical nature of lymphogenous spread is such that disparity in the size
of bilateral deposits is to be expected. The preponderance of deposits in one of a pair of organs is,
therefore, in accord with lymphatic metastasis.
The common location of metastases in the
medulla of the adrenal is analogous to the medullary localization of retrogradely transported lymph
node deposits. Although diverse views are on record, the weight of opinion leans to the conclusion
that adrenal lymph emerges from the medulla (29,
55, 6~). If this assessment is the correct one, deposits are likely to develop first in the medulla
after retrograde lymph carriage. Thus, as with the
other metastatic patterns discussed, it is the lymphogenous theory that resolves the known difficulties.
FUTURE PROSPECTS
This review spotlights the viewpoint that the
metastatic patterns of lung cancer are concordant
with lymph-borne spread but discordant with
blood-borne invasion. There is need, then, to explore the possibility that blood-borne cancer cells
Vol. ~1, O c t o b e r 1961
are not the effective agents of invasion that they
have hitherto been assumed.
It is not disputed t h a t hematogenous metastasis
can occur. However, as the work of Engell (37) and
others suggest, the fate of the circulating cancer
cell is still unknown. Moore and his associates (89)
hazarded a guess and put the percentage of these
cells which are "promptly destroyed" as high as 95
to 99. It seems to me that, perhaps, the destruction
of these cells in the blood stream may be accomplished to an extent not even dreamt of. In this
connection, the long-enunciated (140) but disputed (30) view, that blood and lymph affect caneer cells differently, calls for concerted reappraisal.
Long ago, Armstrong and Oertel (4) surmised
that not only the quantity but also the quality of
metastasizing cells may be of account. Factors
which are thought to be of importance have recently been reviewed by Hawk and Hazard (66).
To my mind, the problems which may repay further investigation include (a) the effect of the size
of the malignant embolus (90, 150) ; (b) the role of
coagulation and thrombosis in preventing metastasis (72, 138); (c) the relationship between survival of blood-borne cancer cells and duration of
the parent tumor (53, 129) ; and (d) the topographical relationship between the seat of the primary
tumor and the location of the secondaries (91-94,
96, lg6).
I agree with Drinker (135) that the functional
significance of the lymphatic system is probably
underrated. If it is ultimately shown that the
lymph stream is more important than the blood
stream in the dissemination of tumors to both the
lymph nodes and the organs, it would be of paramount importance to orientate chemotherapeutic
researches toward discovering drugs which are
concentrated in the lymph stream. What is envisaged is exemplified by the observation of Schachter (119) that penicillin level is more prolonged in
lymph than in blood, an observation adjudged to
be of therapeutic interest because of the premier
role of the lymph stream in infective diseases. I t
may be conjectured, in like manner, that if the
lymph stream also occupies a premier position in
neoplastic diseases then the drugs of choice in cancer therapy may well be those which attain a
higher concentration in the lymph than in the
blood stream.
ACKNOWLEDGMENTS
I am indebted to m y chief, Professor D. F. Cappell, for the
facilities which he has generously placed at m y disposal; to Dr.
A. T. Sandison for invaluable discussions; and to Professor
C. V. Harrison for ~lcccss to the records of H a m m e r s m i t h Hospital, London.
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A Statistical Analysis of Two Hundred Ninety-Six Cases
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FIG. 1.--Dissected specimen of lung cancer removed en bloc
at autopsy. The primary tumor is left-sided; the larynx,
thyroid, parts of the lungs, esophagus, and adrenals are left i n
situ. Note the widespread lymph node deposits which diminish
in size distally. Also noteworthy are the lower para-esophageal
nodes which remain small, having apparently been "skipped."
On the whole, the metastatic deposits are larger on the left than
on the right side from the angle of the jaw right down to the
aortic bifurcation.
FIG. ~.--A left-sided lung cancer from which extends a Yshaped chain of metastasized nodes, most of the members diminishing in size centrifugally. The exceptions are the nodes at
the top of each arm of the Y. These nodes have probably been
"selectively" attacked. Note that the right mediastinal nodes
are spared.
FIG. 8.---A large right-sided lung cancer which has infiltrated the neighboring nodes, sparing the contiguous contralateral nodes.
Frs. 4.---A right-sided lung cancer which has invaded all the
nodes from the carina right up to the lower poles of the thyroid.
Note that the deposits diminish in size centrifugally and that
they are larger on the right than on the left side.
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Research.
Patterns of Metastasis in Lung Cancer: A Review
Wilson I. B. Onuigbo
Cancer Res 1961;21:1077.
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