Cancer and Metastasis Reviews 19: 281–301, 2000.
© 2001 Kluwer Academic Publishers. Printed in the Netherlands.
6 Patterns of metastasis
6.1. Introduction
One of the oldest problems in metastasis concerns the
distinct and different patterns of target organ involve-
ment, by different types of metastasizing primary
cancers growing in different anatomic sites. In his
own important paper, Stephen Paget (1889) cited both
Langenbeck and Billroth as raising the question of
specific dissemination patterns of different types of
cancer.
Present day concepts of the mechanisms underlying
patterns of metastasis to different sites are conveniently
considered in terms of two distinct, but not mutu-
ally exclusive hypotheses: The “mechanical” and the
“seed-and-soil” hypotheses. The first is mainly based
on the anatomy of the dissemination-routes and focuses
on the effects of differential delivery of cancer cells,
while the second focuses on patterns due to differential
arrest and proliferation of cancer cells “seeds” in dif-
ferent anatomic sites “soils”, and is therefore largely
concerned with differential arrest and events occurring
after cancer cell delivery.
6.2. The “Mechanical” or “Hemodynamic”
hypothesis
6.2.1. Lymphogenous metastasis
Metastasis may be initially confined to the lymphatic
system or to natural cavities; however, the presence
of discrete, extra-nodal metastases indicates embolic
spread via the blood-stream.
In reviewing the history of concepts of metastatic
patterns, it is noteworthy that the association of axillary
swelling and breast tumors goes back to antiquity, long
before recognition of axillary lymph nodes or breast
cancer. This was extended to surgical practice so that
by the fourteenth century, Guy de Chauliac (cited by
Wider, 1956) advised removing “rests” together with
breast cancers, and in the sixteenth century Severinus
removed axillary lymph nodes at mastectomy. By the
eighteenth century, LeDran (1757) recognized that can-
cer spread via the lymphatics to the regional lymph
nodes, and then to the general circulation. Later precise
anatomic descriptions of lymphatic dissemination were
given by Klinger (1857), Hoggan (1878), Heidenhain
(1889), Stiles (1899) and many others.
Following Sappey’s extended studies (1874/1885), it
became clear that the pattern of lymphogenous metas-
tasis could be generally accounted for by lymphatic
anatomy. An example was provided in the report of
an autopsy performed by Thiersch (1865) on a case of
uterine carcinoma, with widespread metastases in the
pelvic lymph nodes, external iliac veins and other sites.
In addition, clusters of cancer cells were described in
the thoracic duct. The entire metastatic pattern was
explicable on the basis of the then well-known cir-
culatory anatomy in relation to dissemination routes.
Hoggan (1878) explicitly associated observed organ
patterns of metastasis in his paper “On cancer and
its relationship to lymph vessels”. A good example
of pattern is seen in patients with carcinoma of the
stomach with involvement of the left subclavicular
lymph node (Zeidman, 1955), named after Virchow by
Troisier (1886). The importance of the thoracic duct as
a connection between lymphatic and blood-borne dis-
semination was emphasized by Stevens (1907) and his
predecessors.
Unusual patterns of lymphogenous metastasis were
also accounted for by perturbations in lymphatic flow.
Thus, Virchow (1845) suggested that retrograde flow
accounted for the involvement of the lower lumbar
lymph nodes in cases of carcinoma of the pancreas
and stomach, and of the inguinal nodes in carci-
noma of the uterus. The concept of the so-called
“Retrograde lymphatic embolism” was emphasized by
von Recklinghausen (1885), Vogel (1891) and Vierth
(1895), and was correctly interpreted to occur when,
due to a combination of pathologic obstruction of some
lymphatics and dilation of collateral vessels, the direc-
tion of lymphatic flow is reversed (Zeidman, 1959).
Many documented examples of the effects of retro-
grade lymphatic embolism are given by Willis (1952;
pp. 24–26).
Therefore, as also noted by Sugarbaker (1982), in a
sense the stage was set for the “mechanical” (anatomic)
hypothesis of hematogenous metastatic patterns, by
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well-substantiated observations on the anatomic basis
of lymphogenous metastatic patterns.
6.2.2. Hematogenous metastasis
Apart from metastases in the lungs and liver, which are
initially seeded via the portal vein and systemic veins
respectively, and skeletal metastases seeded via the
paravertebral venous plexus of Batson (1940, 1956),
hematogenous metastases are for the most part, seeded
via arteries.
Although cancer cells are delivered to the liver and
lungs via the hepatic and bronchial arteries respec-
tively, in advanced disease it is often difficult or
impossible to discriminate between arterial metastases
in these organs, and those seeded via the portal or
systemic veins. As the common starting point for can-
cer cells generating arterial metastases to other organs
is the left ventricle, it is expected that if circulatory
mechanics were the only or major determinant of pat-
tern, then the incidence of metastasis in various target
organs should correlate with the blood-flow to them.
An early mechanical approach to arrest was raised
by Moore (1860), who asked “Is the material of cancer
carried, as pus is supposed to be carried in pyaemia, and
arrested by accident of its size, in one or other vessel?”
This analogy with bacterial emboli was also made by
Paget (1889) and Simon (1878) stressed that cancerous
materials “. . . pass on with the blood till they become
fixed as emboli in smaller vessels.”
As part of his significant contribution to the
widespread acceptance of the seed-and-soil hypoth-
esis, Stephen Paget (1889) necessarily made some
valid criticisms of the mechanical hypothesis: “If the
remote organs . . . are all alike passive . . . all equally
ready to receive and nourish any particle of the primary
growth . . . brought to them, – then the distribution of
cancer throughout the body must be a matter of chance.
But if we can trace . . . any relation between the char-
acter of the primary growth and the situation of the
secondary growths derived from it, then the remote
organs cannot be altogether passive or indifferent as
regards embolism.”
Nowadays, the “mechanical” hypothesis is com-
monly associated with James Ewing (1866–1943), who
was an influential figure in the development of oncol-
ogy in the United States. In his text-book, “Neoplastic
Diseases: A Treatise on Tumors”, Ewing (1919) wrote:
“ ‘Genius loci’ or the particular susceptibility of a tissue
to develop secondary tumors is an interesting phase
of the study of metastases. Familiar examples are the
predominance of pulmonary metastases in chorioma,
which is simply explained by the intravascular posi-
tion of this tumor; the bone-marrow metastases of
hypernephroma and cancer of the prostate; and the mul-
tiple cutaneous tumors secondary to lymphosarcoma
testis. The mechanism of the circulation will doubtless
explain most of these peculiarities, for there is as yet no
evidence that any one parenchymatous organ is more
adapted than others to the growth of embolic tumor
cells. The spleen however, seems to escape with pecu-
liar frequency.” That Ewing realized that circulation
mechanics does not fully account for metastatic pattern,
is evident from the preface to his book: “ . . . the signif-
icant facts about tumors are not of general application,
but are best revealed in the study of special tumor
groups or even special cases.” In common with other
contemporary oncologists, Ewing knew that different
cancers in different sites have different metastatic pat-
terns, and would have been aware of Paget’s (1889)
paper; however, he must have thought that at that time
direct evidence for the “seed-and-soil” hypothesis did
not account for many of the observations on pattern,
but that many observations could to a large extent
be accounted for in terms of circulatory mechanics.
Ewing’s statement is repeated in the 1928 edition of his
book, but is at variance with his comments also made
in 1928, at a conference in London where, according to
Willis (1952; p. 16), he emphasized the individual prop-
erties of different types of tumors: “The predilection
of metastases for particular organs may be due to spe-
cial nutritive requirements dependent on varying cell
metabolism.” In the 1940 edition of his book, Ewing
terminates his comment on “Genius loci . . . ” with no
additional comment on underlying mechanisms.
Cancer cells can disseminate along any anatomic
pathway; in the blood-stream, passage is subject to
restraints on entry, cancer cell size and hemodynamic
considerations. An extreme case of anatomic oppor-
tunism in this respect, is the dissemination of an
optic glioma to the peritoneal cavity via a ventriculo-
peritoneal shunt inserted in a young boy to relieve
hydrocephalus (Trigg et al., 1983).
An elegant example of the importance of vascular
anatomy in the determination of metastatic pattern was
provided by Wieberdink’s (1959) study of neonatal
neuroblastomas of the “Pepper” type, in which death at
birth or within several months thereafter, results from
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metastasis. The metastatic patterns including involve- Table 6.1. Reported deaths from primary cancers of different
ment of the liver and fetal part of the placenta, change sites, expressed as percentages of total cancer deaths
abruptly between the pre-natal and post-natal periods, Site Tachou American cancer society
which Wieberdink associated with closure of the patent (1844) (1989)
foramen ovale and ductus arteriosus which previously Male Female
permitted by-pass of the pulmonary circulation, and
Uterus 33% — 4%
closure of the patent ductus venosus which previously Stomach 25% 3% 2%
permitted by-pass of the liver. Breast 13% — 18%
Liver 6% 2% 2%
Colorectal 2% 11% 13%
6.3. The “Seed-and-Soil” hypothesis Oral 1% 2% 1%
Lungs 0.08% 35% 21%
Prostate 0.05% 11% —
Walshe (1846), discussed the “systemic” development
of cancer (p. 92), by which he meant the “. . . condition
of its original localization, encroachment and dissem- Table 6.2. Cases of cancer
ination”. He stated that it had long been known that Limited to one Invading two or
some parts of the body were more prone to [primary] locality more locations
cancer than others, but that relative numerical estimates Walshe 15 63
of organ involvement had only recently been provided Herrick & Popp 25 42
in 1844, by Tanchou, from the Mortuary Registers 40 105
of Paris and two adjacent arrondissements, for 9118 From Walshe (1846; p. 101).
deaths from cancer over the period 1830–1840. Some
of Tanchou’s data are reproduced in Table 6.1, together
with corresponding data for the USA for 1989; differ- to become the primary seat of the disease, secondary
ences such as these, regardless of cause, must be borne development is not observed to occur? . . . Nor am I cer-
in mind when extrapolating from one period to another. tain that any organ is actually exempt from the chance
Walshe then commented “Admitting these numbers to of secondary affection, as an effect of pre-existing
be correct . . . they convey a notion of the disposition disease in distant parts . . . .
to become the seat of cancer, secondary as well as . . . But not only do the organs affected differ accord-
primary, possessed by different textures and organs.” ing as the disease is primary or secondary, but the
An early attempt to establish a numerical basis for parts of those organs attacked vary with the same cir-
metastatic patterns came from Herrick and Popp (1841; cumstance.” In drawing attention to differences in situ
cited by Walshe; p. 93), who noted the distribution of within organs affected by primary cancers of the lungs,
143 cancers in 67 patients dying of cancer. Although liver and kidneys and metastases to these organs,
not enough details are given of primary and metastatic Walshe was in fact providing evidence in favor of
sites to determine pattern, Walshe’s tabulation of his anatomic explanations of intra-organ pattern, as dis-
own and Herrick and Popp’s combined 145 cases give tinct from “proneness”. Walshe was clearly on the track
some idea of the clinical progression of metastatic of a “seed” component to pattern, with his statement
disease in their cases at autopsy (Table 6.2), and led that “The species of disease also influences the local-
Walshe to the conclusion that “. . . in about 27.6 per ization of cancer”, although his emphasis is again on
cent of cases of cancer the disease continues to the primary lesions. In discussing Langenbeck’s experi-
end, in respect of its local manifestations, an isolated ments in which “The detritus and ichor of [human]
affection.” carcinoma have been injected into the veins of ani-
Walshe critically examined the evidence for “prone- mals, but no development of cancer has resulted . . . The
ness” of different organs to cancer, “But in respect perfection of the seed is not enough to secure the devel-
of the localization of cancer, the circumstance of the opment of the plant; the soil, in which it is sown, must be
disease being primary or secondary requires special capable of feeding it”. Of course this refers to irrepro-
consideration” (p. 97). He asked whether there were ducible results of xenotransplants in immunologically
“. . . any structures in which, though they are liable intact hosts.
284
Billroth (1869/1871) commented that “In cancer of
the breast, the localization of the secondary tumors is
very regular, . . . the pleura, liver and bones, are the most
frequent sites of metastatic tumors”. Although this
statement was cited by at least some of Billroth’s con-
temporaries, my own attempts to verify its originality
have proved inconclusive.
Differential resistance to metastasis in target organs
was also discussed by Eve (1883), who after noting
that the lungs of animals showed high resistance to
infection with the fungus penicillium, wrote “Perhaps
the same resisting power is shown by the lungs to the
formation of cancer; secondary deposits being found,
not uncommonly, in the liver, kidney and bones, while
the lungs remain perfectly free, although the cancer
elements must have passed through the pulmonary cir-
culation in order to reach the organs first named . . . The
lungs . . . apparently offer more favorable conditions
for the growth of sarcoma, as they are frequently the
seat of secondary deposits in cases of sarcomas of the
bones.”
Some of the basic tenets of the “seed-and-soil”
hypothesis were also alluded to by Sir James Paget
(1887) in his Morton Lecture to the Royal College of
Surgeons of England. Using the analogy of galls affect-
ing the leaves of oak trees, he made the point that
“. . . even a well-defined virus can produce its appropri-
ate disease only in some exactly appropriate place or
texture. . . . Each virus requires . . . a susceptible and fit-
ting place and substance; and this is a fact confirming
what we believe in the case of many specific diseases,
and as I venture to say in the cancerous. The two con-
ditions must co-exist – the specific material, microbe,
virus or whatever we may name it, in the blood which
will carry it to every part, and the one appropriate part,
texture, or place in which this material can produce the
disease . . . I believe that there are facts in the history
of secondary cancers which cannot be explained by
the merely mechanical process or of embolism. There
are often evidences of other than mechanical relations
between the primary and secondary.”
The earliest, systematic attempt to document human
metastatic patterns in specific terms, appears to have
been made by an ophthalmologist, Fuchs, on the metas-
tasis of melanosarcomata arising in the uveal tract.
Fuchs (1892; pp. 325–326) wrote: “. . . The fourth stage
[which] is that of the generalization of the tumor
by development of metastatic nodules in the inter-
nal organs, most frequently to the liver . . . ”. The
metastases in remote organs arise through embolism.
The blood-current detaches cells from the tumor and
carries them into other parts of the body, where they
develop into independent tumors. Fuchs (1888; pp.
200–202) had previously pointed out that in cases of
uveal melanoma, “There are only two cases known
where there were no liver metastases, but metastases
elsewhere . . . . Virchow said that it is not clear why they
prefer this organ, since embolization is arterial. Certain
organs have a predilection for the development of def-
inite tumor types. This is true not only for the primary
but also for the secondary. Why do secondary cancer
nodules occur so often in the kidney or the liver, but
never in the female breast? Certainly nobody will deny
that the latter has the capacity for tumor development,
yet it is disposed only for primary and not secondary
cancer development. When a melanosarcoma occurs in
the eye, the cancer cells are taken by the bloodstream to
a wide variety of organs in the body, but not everywhere
do they find a favorable soil for their development . . . .”
Stephen Paget (1889) also considered that the dis-
tribution of the secondary growths is not a matter of
chance. He noted the question raised earlier by Langen-
beck and Billroth: “What is it that decides what organs
shall suffer in a case of disseminated cancer?” “If the
remote organs in such a case are all alike passive and,
so to speak, helpless – all equally ready to receive and
nourish any particle of the primary growth which may
“slip through the lungs”, and so be brought to them,
– then the distribution of cancer throughout the body
must be a matter of chance. But if we can trace any sort
of rule or sequence in the distribution of cancer, any
relation between the character of the primary growth
and the situation of the secondary growths derived from
it, then the remote organs cannot be altogether passive
or indifferent as regards embolism. When a plant goes
to seed, its seeds are carried in all directions; but they
can only live and grow if they fall on congenial soil. The
chief advocate of this theory of the relation between
the embolus and the tissues which receive it is Fuchs
(1888, 1892). . . . Cohnheim (1867) is of the opinion
that a healthy organ has a certain ability to resist the
growth of such an embolus; and he speaks of “dimin-
ished resistance” as Fuchs speaks of “predisposition”.
This theory of disposition receives some support from
an examination of the statistics of fatal cases of cancer.
. . . as regards “metastasis.” Here, too, we shall find
evidences of predisposition; we shall see that one
remote organ is more prone to be the seat of secondary

growth than another. In cases of cancer of the breast, it
is strange how often the liver is the seat of secondary
cancer. From different sources, I have 735 necropsies
after cancer of the breast. Of these, 241 had cancer of
the liver, only 17 had cancer of the spleen, and 30 had
cancer of the kidneys or suprarenals. The lungs were
involved in about 70 cases; but it is sometimes impos-
sible to say whether the lungs or only the pleura were
attacked, nor can we doubt that in cancer of the breast
the lungs often suffer, not as remote organs, but by
direct extension from the primary disease.
. . . The same propensity of the liver to become
diseased is shown in cases of cancer of the female gen-
erative organs. In 244 necropsies after cancer of the
uterus, the liver was involved in 35, the spleen in one
only, the lungs in 8, and the kidneys or suprarenals in 6,
one of which was by direct extension. This frequency
of secondary disease of the liver is of course a familiar
fact; but it acquires fresh interest when we contrast it
with the immunity enjoyed by other organs. The spleen
has, so to speak, the same chances as the liver; its artery
is even larger than the hepatic artery; it cannot avoid
embolism. Yet the liver was the seat of cancer in 276
cases; the spleen in 18 only. Such a great dispropor-
tion cannot be due to chance. For in pyaemia no such
disproportion exists. I have tabulated 340 necropsies
after pyaemia, and I find that abscesses of the liver
occurred in 66, and an abscess of the spleen in 39 – a
very different proportion from that of 276 to 18.”
Again, if we take the 735 necropsies after cancer
of the breast, we find that the ovaries, one or both,
were involved in no less than 37 cases; that is to say,
twice as often as the spleen, and about as often as
the kidneys and spleen put together. This can hardly
be by chance. And in two of the cases the ovaries
alone of all the organs were diseased. It is one of
these two cases that Dr Coupland says: “To evoke the
fact of the physiological sympathy of two such widely
removed organs to explain such a case as this is a
view perhaps too fanciful to be entertained, but yet it
is difficult to put such a consideration entirely out of
sight.”
Let us now see what is the case as regards the bones
in cancer of the breast. If we consider how favor-
able the lymph glands are to the growth and spread of
cancer, and how close the connexion is between the
lymph glands and the medulla of the bones, we may
look to find something of interest among the cases
where the bones were involved. In the first place, there
285
Table 6.3. Percentages of organs with metastases from primary
breast cancers metastatic sites
Gross (1880) Paget (1889) Pickren (1958–1979)
(100% = 128) (100% = 735) (100% = 1022)
Liver 42.0 32.8 61.3
Lungs 21.9 9.5 66.1
Spleen 2.3 2.3 14.8
Kidneys 3.9 13.1
Adrenals 1.6 4.1 25.2
(Combined)
is reason for believing that a general degeneration of
the bones sometimes occurs in cases of cancer of the
breast, yet without any distinct deposit of cancer in
them. Thus Torock and Wittelshofer, in their analy-
sis of 336 necropsies on cases of cancer of the breast,
say: “Besides the cases where the bones were man-
ifestly diseased, there were 8 cases of that peculiar
brittleness and softness of different bones mentioned by
Rokitansky, Lucke and others, where a cancerous
degeneration could not be made out.”
“. . . The evidence to me seems irresistible that in
cancer of the breast the bones suffer in a special way,
which cannot be explained by any theory of embolism
alone. Some bones suffer more than others; the dis-
ease has its ‘seats of election’.” The autopsy data used
by Paget on cases with a history of breast cancer, may
be compared with the corresponding data recorded by
Gross in 1880, and that collected over the period 1958
to 1979 by my former colleague, the late Dr John
Pickren and communicated personally (Table 6.3). It
appears at first sight that Paget underestimated the inci-
dence of metastasis to specified target organs. However,
the longer survival of patients nowadays, for a whole
variety of reasons, allows more time for detectable
metastases to arise, quite apart from improvements in
autopsy techniques. There are differences in both inci-
dence and relative incidence; for example the ratio of
liver to spleen involvement is 14 : 1 in Paget’s series,
compared to 19 : 1 in Gross’ and 4 : 1 in Pickren’s.
6.4. Metastasis in the spleen and bone marrow
6.4.1. Spleen
In 1846 Walshe wrote (pp. 107–108) “How close is the
relationship of the liver and spleen; yet of eleven cases
of cancer of the liver related by Andral (1823), one
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only was attended with similar formation in the spleen;
though in almost every instance there were other organs
affected with the disease. It is a curious fact too, that in
Velpeau’s celebrated case (1856), while the liver con-
tained several hundred cancers, and hardly a part of the
frame had escaped contamination, the spleen was unaf-
fected. It is true, that, when cancer exists in the spleen,
evidence of the disease is commonly to be found in the
liver; but in explanation of this it must be recollected,
that no matter where the primary disease exists, the
liver is the organ most prone to suffer consecutively.
The idea that the spleen is a uniquely hostile “soil” for
cancer was accepted for many years. In 1934, Warren
and Davis reported an incidence of 4% metastasis in the
spleen in 1140 autopsies on unselected cases of can-
cer, but they also reported a similar incidence (4.6%) of
metastasis in the kidneys, which are not considered to
be an uncommon target site. In their cases with breast
cancer, Warren and Davies reported a 14.5% incidence
of metastasis in the spleen, compared with the 14.8%
reported by Pickren (Table 6.3).
An interesting observation on alteration of splenic
susceptibility to metastasis was made by Foulds (1932)
using the Brown-Pearce tumor in rabbits which, when
transplanted into muscle or given intravenously, pro-
duced a very low incidence of metastases or colonies
in the spleen. However, when the animals received
injections of trypan blue for several days prior to intra-
venous injection of cancer cells, there was an increase
in both the incidence and size of the splenic colonies.
Foulds suggested that; “. . . some organs notably the
spleen, resist the establishment of secondary deposits
by a local mechanism similar to that which opposes
the takes of grafts in laboratory animals.” Much later,
it was shown that injections of trypan blue in fact sub-
stantially reduce the numbers of macrophages; Foulds
observations may therefore have reflected macrophage-
induced suppression.
Other observations relating to the spleen and the
“seed-and-soil” hypothesis were made by Pilgrim
(1969), using a transplantable reticulum cell sarcoma,
which selectively metastasized to the mouse spleen.
When equal numbers of cells were injected into the
kidney and the spleen, growth in the spleen was always
considerably greater than in the kidney. However, in no
case was the mitotic index higher in the spleen than the
kidney. Pilgrim therefore considered that cell loss in
the kidney was greater than in the spleen; however, his
emphasis was on cell migration rather than cell death
within the target organ. Regardless of mechanism,
compared with the spleen, the kidney was therefore
unfavorable “soil” for this tumor, and this was appar-
ently unrelated to growth-rate as determined by mitotic
indices.
6.4.2. Bone-marrow
Bone-marrow involvement usually figures prominently
in any discussion of metastatic pattern. Metastasis to
bone has been well recognized for at least three cen-
turies (Onuigbo, 1981), and the state of the art up to
1981 is covered in “Bone Metastasis” (Eds. Weiss &
Gilbert, 1981).
Wiseman (1676) wrote of cancers “. . . rotting the
bones under them”, as did Norford (1753). Pearson
(1793) described a case of breast cancer with ipsilateral
humeral metastasis, and asked “Whether the cancer-
ous virus, having been deposited upon this spot, had
eroded it?” As noted earlier, “virus” was used to sig-
nify toxic material in general. Bony metastases were
clearly described in the orbital bones (Scarpa, 1818);
in the skull (Travers, 1829) and in the tibia (Walshe,
1846). Local invasion or extension of primary cancers
to bone, as distinct from metastasis, was implicated by
Velpeau (1856) to account for rib involvement by a pre-
viously adherent “fixed” carcinoma of the breast, but
Billroth (1878) describes extension to, and destruction
of local bones, by primary head and neck cancers.
From a clinical viewpoint, the most striking metas-
tases to bone are those associated with pathologic frac-
ture as described by Cooper (1824) and Warren (1837),
among others. Paraplegia as a consequence of verte-
bral involvement was described by Haward (1882), and
hemiplegia due to pressure from skull lesions on the
cerebrum were described by Rolleston (1897), and a
bruit from a metastasis in the scapula from a primary
thyroid carcinoma was described by Haward (1882).
Direct extension from primary cancers to bone was
often confused with metastasis, where discontinuity
from the primary lesion is the essential feature. Direct
extension was defined by Moore (1889), “A new growth
may become adherent to neighbouring structures and
grow into them, and this may be termed ‘growth in
continuity’.” Examples of the confusion are provided
by Finlay (1885), who described a case of lung can-
cer, where “. . . The tumours on the surface of the
chest were connected directly with the intrathoracic
mass, the connections surrounding and eroding the

ribs.” Macewen (1886) considered that “. . . mammary
carcinoma passes into the sheath covering the pec-
toral muscles, next infiltrates the muscular fibres, the
ribs, the intercostal muscles, the pleura, and even the
lungs . . . . All of this occurs by direct continuity of the
growth from the original primary tumour”. In accord
with this view, Williams (1889) described a case in
which the breast region was “. . . extensively infiltrated
by a dense fibroid cancerous growth, which had invaded
the subjacent ribs and sternum by direct extension.”
With a fuller appreciation of metastasis, lymphatic
and venous dissemination of cancer to bone were
considered. Thus, Snow (1898) thought that bone
metastasis was due in part to “. . . ‘regurgitation of
lymph currents’ consequent on stasis in the [lym-
phatic] glands”, and Stephen Paget (1889) thought that
the spread of breast cancer to bone was affected by
“. . . how close the connexion is between the lymph
glands and the medulla of bones.”
Nowadays, it is generally accepted that bone involve-
ment is predominantly by hematogenous (arterial)
metastasis. Hodgkin (1848) invoked some concept
of specificity by “. . . some power which arrest cer-
tain molecules already in the circulation, and that
so-arrested, they become fresh starting points for the
production of morbid growth.”
Snow (1898) wrote “. . . Subsequently, general
blood-infection ensues, with abundant deposit in the
viscera and in distant bones.”, and Villy (1898)
concluded from examinations of bone-marrow that
“. . . bone affliction was due to the deposition of can-
cerous emboli”.
An early suggestion of pattern-specificity came from
Virchow (1860) with his comment that “. . . an ichorous
juice [from a cancer may pass] through the lungs with-
out producing any change [metastasis] in them, and yet
a more remote point, as for example in the bones of a
far distant part, excite changes of a malignant nature.”
Apparent transpulmonary passage of cancer cells was
also recorded by Morgan (1879), and by Eve (1883),
who observed metastases “. . . not uncommonly, in the
liver, kidneys, and bones, while the lungs remain per-
fectly free, although cancer elements must have passed
through the pulmonary circulation in order to reach the
organs first named.” Transpulmonary passage of cancer
cells without metastasis in the lungs, usually repre-
sents a false negative due to either the small size of
pulmonary metastases or inadequate sampling during
autopsy (Weiss & Harlos, 1986).
287
The unusually high or low incidence of metastases
in different target organs is the hallmark of selectivity,
and this has been well-studied with respect to bone.
Sir James Paget (1887) noted that his observation of
the high frequency of bone involvement in cases of
thyroid carcinoma, occurred “. . . as if by selection”,
and Stephen Paget (1889) had concluded that it was
“. . . not a matter of chance what bone shall be attacked
by secondary growth.” Cases in which there was an
apparent absolute or relative restriction of metasta-
sis to bones, suggested a high level of susceptibility
in the bone marrow to Cohnheim and Maas (1877),
Thompson and Keiller (1924), and Onuigbo (1981)
cites other late nineteenth century records of perceived
bone preference in metastasis.
By the beginning of the twentieth century many
cases had been reported of metastasis to the bone mar-
row associated with anemia (Review: Harrington &
Teacher, 1910). This was exemplified by a report of
a woman with carcinoma of the stomach who pre-
sented with bone pains and had “Anemia of a peculiar
type showing marked diminution of the red cells
[< 2 M/mm3 ], high colour index, granular basophilia,
polychromatophilia, slight poikilocytosis, megalocyto-
sis, and the constant presence of numerous myelocytes
and erythroblasts, the majority of which were mega-
loblasts.” In view of the peculiar type of anemia and
the presence of some bone pains, metastatic inva-
sion of the bone marrow was diagnosed. Autopsy
revealed a large carcinoma of the lesser curvature of
the stomach with widespread lymphatic permeation
and hepatic and pulmonary involvement. “. . . in addi-
tion there was very widespread dissemination through
the bone marrow which could hardly have occurred by
any other route than the blood-stream . . . . [There was]
almost complete disappearance of red marrow . . . and
its replacement by tumour tissue, and the development
of large quantities of red marrow in the medullary cav-
ities of the long bones . . . . The blood picture is due
to stimulation of the bone marrow by the metastatic
tumours . . . probably both defective haematogenesis
and increased haemolysis take part in the production
of anaemia”.
Primary and secondary sites of cancer. In 1887,
Sir James Paget stated that “The organs that are
most frequently the seats of primary cancer are very
rarely the seats of secondary”. This erroneous view
was also stated by Walshe in 1846 and, as late as
288
1940, MacCallum commented that “Virchow made the
statement that in those organs in which tumors are com-
monly primary, metastases rarely occur, while primary
growths are rare in those situations which seem to form
the best soil for secondary nodules. Thus, the stom-
ach and uterus are common sources of primary tumors,
but rarely the seat of metastases, while the reverse is
true of the liver. Although this cannot be said to be
universally true, it introduces the suggestion that cer-
tain tissues form an especially suitable ground upon
which the tumor cells may take root and thrive, and
further, that this is not the same for all types of tumors.
Indeed, there are many tissues, such as the pancreas,
thyroid, heart-wall, muscle etc., which seem especially
unsuited to support the growth of tumor cells, although
these tissues must receive many emboli.” In general,
the reverse resistance or enhancement of growth in pri-
mary and metastatic cancers in the same organs, is
simply not true; the lungs are a common site for both
primary and secondary cancers, and primary cancers
of bone, kidney and thyroid commonly metastasize to
these organs.
6.5. Metastasis of metastases
Provided a patient with metastatic cancer survives long
enough, there is no a priori reason why these metas-
tases should not themselves metastasize to other sites;
metastatic sequences of this nature are referred to as
“metastatic cascades”, and by Willis (1952; p. 46) as
“superimposed metastatic cycles”.
Onuigbo (1981) has drawn attention to a number
of references from the nineteenth century literature on
metastasis of metastases. In 1829, Travers mentioned
the “successive appearance” of metastases; in 1846,
Walshe considered that they “may have occurred by
a successive or by a simultaneous process of devel-
opment; in 1887, James Paget asked whether cancers
“would grow and multiply in distant parts, and in them
be centres for yet further infections”, and in 1883,
Eve considered dissemination from metastases in the
lungs to bone. Although Simon did not understand the
basic mechanisms involved, in 1878 he used the terms
secondary and tertiary deposits.
Willis cites cases of venous invasion at multiple sites,
described by Weigert, Zenker, Kantorowicz and oth-
ers, over the period 1876–1893, which initiate fresh
embolic cycles leading to complex metastatic patterns.
Willis did not make the mistake of assuming that
tumor embolism is identical with metastasis, and con-
sidered that “The behaviour of a neoplasm as regards
its ability to penetrate blood-vessels is perpetuated
in its metastatic progeny, and haemic dissemination,
once begun, tends to proceed in superimposed vicious
cycles.”
In 1902, Berent reported a case in which a primary
squamous cell carcinoma of the jaw metastasized to a
renal cell carcinoma. Since then, approximately fifty
reports have been published of metastasis to cancer
(Dobbing, 1958), and renal cell carcinomas are the
commonest target sites.
The burden of proof lies in determining whether or
not metastatic cascades make a significant contribution
to metastatic pattern. For example, in a patient with
widely disseminated, hematogenous metastases from a
primary colonic carcinoma, did the final metastatic pat-
tern develop by a sequential process of metachronous
seeding, in which secondary metastases from the pri-
mary lesion first developed in the liver; did these
hepatic metastases then seed tertiary metastases in the
lungs which, in turn, generated quaternary (arterial)
metastases in other organs? Alternatively, did the final
metastatic pattern arise by a process of synchronous
seeding, in which the metastases in all sites were seeded
from the primary lesion with progressively decreasing
numbers of cancer cells, possibly with different growth
rates in different target organs, which could account for
their detection in the liver, lungs and other sites at dif-
ferent times? In humans, it may be impossible to detect
micrometastases in random samples of tissues taken
for histologic examination.
The difficulty in determining the chronology of
metastasis was recognized by Walshe (1846; p. 110) in
his discussion of a patient of Récamier with a painful,
non-ulcerating scirrhus of the breast, who died with
apoplectic symptoms and hemiplegia, and at autopsy
was found to have “. . . a tumor the size of a nut, and
possessing the characteristics of carcinoma . . . floating
as it were, in a quantity of diffluent brain”. However,
Walshe briefly describes how the “. . . mammary
growth ceased to be painful, and eventually disap-
peared almost completely”, raising the question of
whether the breast lesion was in fact cancer, and the
brain lesion a metastasis from it! Regardless of this
reservation, and the fact that his discussion was cen-
tered on the basic relationship between primary cancers

and their metastases, under the heading of “simultane-
ous dissemination”, he asked “But, it may be inquired
what absolute demonstration can be furnished that in
all the cases of general dissemination adverted to,
the growths hitherto considered to be developed con-
secutively to another or others, really possess such a
relation thereto? Is it not quite as likely that, in some
instances at least, the presence of cancerous growths
in numerous organs may depend on their simultaneous
development?”.
In two other sections which are relevant to the
metastasis of metastases, Walshe continued: “Relative
tendency of different parts and organs to affect the sys-
tem secondarily. It may be laid down as a principle, to
which there is no exception, that every structure in the
body may, when cancerous, prove the source of gen-
eral contamination; and on the other hand it is equally
certain, that there is no site in which the cancer cannot
run its course to the end without being attended with
similar formation in distant organs.
Order of dissemination: “. . . I have sought in
vain . . . for any semblance of a principle (beyond the
simple one, that wherever the primary disease be
seated, the liver and the lungs are the most common
secondary sufferers), regulating the modes of sequence
observed: combinations of organs, the most perversely
inexplicable, are constantly encountered. And even in
respect of the two organs most frequently thus affected,
though the liver ordinarily suffers more extensively
than the lungs, and though, when the disease exists
in both, its development in the former seems almost
always (when the point is capable of decision) to have
been prior to that in the latter, yet this is by no means
invariably observed.”
At first sight, one approach to the metastatic capa-
bilities of metastases, would be investigation of the
effects of removal of solitary metastases from patients
with resected primary cancers. Where this is not a cura-
tive procedure due to the subsequent development of
other metastases, it may be assumed that these were
seeded prior to surgery and that the initial diagnosis
of “solitary” metastasis was therefore incorrect. How-
ever, if even a small number of patients are cured by
surgical resection, then the initial diagnosis would have
been correct, and a potential metastatic cascade would
have been aborted.
As far as I am aware, the only text dedicated to
solitary metastasis is that of Rubin and Green (1968).
According to which, the first successful resection of a
289
pulmonary metastasis was reported in 1927 by Divis,
and the first report in the American literature of a
5-year survivor following resection of a solitary pul-
monary metastasis from a primary renal cell carcinoma
was by Barney and Churchill in 1939. Although in
the majority of treated patients, death was ultimately
associated with disseminated disease, in a minority,
long-term survival (>20 years) has been reported (e.g.
Tandon et al., 1963). In the majority of cases, increased
survival as distinct from cure, combined with the obser-
vation that a more favorable prognosis is associated
with a delay exceeding two years between detection of
the metastasis (i.e. metachronous metastasis), makes it
impossible to discriminate between slow growth of an
undetected, independently seeded micrometastasis and
dissemination from a generalizing site.
An analogous situation to that in the lung also occurs
with respect to rather rare solitary metastases in the
liver. The first reported case of resection of a liver nod-
ule in a patient with an occult primary lesion was by
Garre in 1888, and Cullen (1905) reported a patient
with a resected primary renal cell carcinoma, who was
alive and well after resection of a liver metastasis. How-
ever, long-term follow-up of this case was not reported,
but the studies of my colleagues and I (Weiss et al.,
1988) indicate a high probability of detectable pul-
monary metastases at death, which could have acted
as generalizing sites for more rapidly growing liver
lesions.
The reviews of Flanagan and Foster (1967) and
Rubin and Green (1968) indicate that as with the lungs,
resection of the primary lesion and a solitary liver
metastasis was associated with improved prognosis
when the hepatic lesion was detected less than two
years after diagnosis of the primary. Patients subse-
quently dying of their cancer usually had widespread
metastases in the liver and other organs. These “fail-
ures”, while of clinical interest, do not exclude seeding
of target organs by the primary cancer prior to its resec-
tion, but perhaps indicate a narrow window of missed
therapeutic opportunity before widespread seeding
occurred from a solitary generalizing site.
The question of metastasis of metastases was also
raised by Sugarbaker et al. (1971) during one of the
repetitive cycles of enthusiasm for immunotherapy.
In the immunogenic murine tumor system studied by
them, metastases did not metastasize. In a later paper
(Hoover & Ketcham, 1975), metastasis of metastases
was demonstrated in parabiotic systems in mice, and
290
in this system prior immunization was not protective
against the formation of metastases.
6.5.1. Vascular bypasses and shunts
A factor complicating the identification and assessment
of the importance of metastatic cascades, is that at least
some of the cancer cells released into the blood-stream
from a primary cancer, could effectively avoid a tar-
get organ altogether by means of vascular bypasses, or
be transported through an organ, avoiding arrest in its
microvasculature by means of vascular shunts, thereby
synchronously seeding the next in-line organ.
Roberts (1961) listed four major bypass routes for
whole organs:
(1) The veins of Batson (1940).
(2) Portasystemic venous shunts.
(3) Retrograde venous pathways.
(4) Crossed or paradoxical pathways.
(1) Veins of Batson (Vertebral venous system). Batson
suggested that this system accounted for the presence of
metastases in the bone marrow and brain, from primary
cancers of the breast and pelvic organs, in the absence
of pulmonary metastasis.
Experimental confirmation of this disseminative
bypass was reported by Coman and deLong (1951) who
injected cancer cell suspensions into the femoral veins
of rats and rabbits, while applying light abdominal
pressure. Although cancer foci were later demonstrated
in the vertebral venous system of these animals none
were detected in their arterioles, as would have been
expected if intact cancer cells had passed through the
pulmonary circulation, and had entered the systemic
arterial circulation. In contrast, in “control” animals
injected without abdominal compression, tumors were
subsequently detected in the lungs only – none in the
vertebral venous system. Thus, in addition to indicat-
ing the importance of Batson’s plexus as a bypass,
which was the major focus, these experiments also
indicated that in these systems at least, transpul-
monary passage of cancer cells is comparatively
unimportant.
A convincing test of the validity of Batson’s hypothe-
sis in humans was made by Franks (1954), who injected
radio-opaque suspensions into the dorsal vein of the
penis in cadavers, and demonstrated (in the presence of
the ligatured inferior vena cava) large venous channels
connecting the inferior vena cava with the vertebral
venous plexus. Microscopy of tissue sections revealed
cancer emboli in a prostatic vein together with the
radio-opaque material. Other observations confirming
the importance of Batson’s plexus as a bypass were
reported by Wack et al. (1958).
(2) Portasystemic venous communications. The exis-
tence of a collateral venous circulation to relieve portal
obstruction has been appreciated at least since the nine-
teenth century, and according to “Gray’s Anatomy”
(Goss, 1973), this relief is effected mainly by collaterals
between the gastric and lower esophageal veins which
drain into the azygos system, and collaterals between
the inferior and middle (systemic) and superior hem-
orrhoidal (portal) veins. Other collaterals which play a
minor role are the accessory portal system of Sappey,
which pass in the falciform and round ligaments to
anastomose with the superior and inferior epigastric
and internal thoracic veins, and through the diaphrag-
matic veins with the azygos system; a parumbilical
vein which may pass from the hilum of the liver to
the umbilicus, producing prominent varicosities cen-
tered on the umbilicus, the so-called “caput medusae”;
and the retrocolic venous plexus of Retzius freely
communicates with the perirenal and lumbar veins.
Lore and his colleagues (1955, 1958) reported a
series of formerly unrecognized, pre-existing porta-
caval shunts, demonstrated in “fresh” cadavers, with
and without liver cirrhosis, following the injection of
colored neoprene latex. Of these, porta-pulmonary,
porta-renal and spleno-renal shunts could in theory at
least, account for the dissemination of gastrointestinal
cancers to the lungs, completely bypassing the liver.
In addition, a porta-adrenal shunt was described, in
which a vein from the gastric fundulus drained into
the retroperitoneal plexus where it communicated with
the left adrenal vein, thus providing a possible route
for cells from a gastric carcinoma to seed the lungs,
left adrenal and kidney, and retroperitoneum directly
via systemic veins, while bypassing the liver. In an
analogous manner, a porta-ovarian shunt between the
mesenteric and right ovarian venous plexus could per-
mit direct spread of gastrointestinal tract cancers to the
ovaries.
As with all collateral vessels or shunts demonstrated
by injection under pressure into cadavers, the ques-
tion of their patency under physiological conditions is
always reason for caution in designating them as impor-
tant dissemination routes for circulating cancer cells.

In addition, it is extremely difficult to rule out false
negative reports of metastases in the liver.
(3) Retrograde venous pathways. Under conditions
in which venous blood-flow is permanently or tem-
porarily reversed, abnormal seeding patterns may
occur. Permanent reversal occurs when venous occlu-
sion leads to development of collateral venous path-
ways; in some of which the direction of flow may
be reversed. In the great veins of the thorax and
their major tributaries, temporary reversal may occur,
the underlying cause of which is due to the positive
(+10 mmHg) blood pressure within peripheral veins,
compared with the normally negative pressure (−2 to
−3 mmHg) in the superior vena cava and pleural cavity.
When the intrathoracic pressure becomes positive due
to coughing, sneezing or vomiting, a transient reversal
of blood-flow can occur in the direction of the new pres-
sure gradient, in the veins entering the thorax (Candel &
Ehrlich, 1953).
The early literature on retrograde venous embolism
due to transitory reversal of blood-flow in unobstructed
veins has been critically reviewed by Willis (1952; pp.
42–45). It was first suggested by von Recklinghausen
in 1885, that “. . . respiratory retropulsations of venous
blood . . . ” play a role in unusual distribution patterns
of cancer emboli. In von Recklinghausen’s case, a pri-
mary chondrosarcoma of the tibia had metastasized to
many sites, including the lungs with pulmonary vein
involvement, but no tumors were detected in the infe-
rior vena cava and the distal end of the renal vein.
Von Recklinghausen’s reconstruction of events leading
to metastasis in the kidney was that a tumor embolus
from the femoral vein had been carried up the infe-
rior vena cava to the level of entry of the renal vein,
and had then been carried by retrograde flow into the
renal vein and tributaries, where it was arrested and
grew. He also postulated that the growths in the pul-
monary veins were seeded by retrograde passage from
the tumor in the left atrium. In contrast, Willis con-
sidered that metastasis involving the kidney was more
likely due to arterial metastasis, and implied that the
involvement of the pulmonary vein was probably due to
an undetected extension from the lesions in the lungs or,
if the evidence against this was conclusive, the emboli
in the pulmonary veins could have been fragments dis-
lodged from the atrial lesions by manipulation during
autopsy. I prefer the first explanation! In his charac-
teristic incisive manner, Willis also considered arterial
291
metastasis as the most probable underlying mechanism
for other cases ascribed to retrograde venous embolism,
including Arnold’s (1891) case of mammary cancer
metastatic to the brain; Ernst’s (1898) case of carci-
noma of the kidney with myocardial vein involvement;
Ziegler’s (1919) case of hepatic vein involvement, and
Geipel (1912) and Parsch’s (1913) view that retrograde
carriage of emboli from the liver to the spleen could
occur via the portal and splenic veins.
(4) Crossed or paradoxical pathways. Paradoxical
embolism refers to the occurrence of arterial metas-
tases seeded by cancer cells released into systemic
veins, in the absence of lung metastases. The concept
of “crossed” or “paradoxical” embolism was intro-
duced by Zahn (1889), and was based on Cohnheim’s
(1867) observation that septal defects in the heart
permitted infectious thrombi from leg veins to reach
the brain, while apparently avoiding the lungs. How-
ever, Willis (1952; p. 42) stated that in two of Zahn’s
three cases, pulmonary metastases were in fact present,
which could have served as generalizing sites for sys-
temic metastases without invoking the mechanism of
crossed embolism. In addition, both Zenker (1890) and
Dunger (1905) had previously concluded from their
own studies, that patency of the foramen ovale was
a coincidence, bearing no relationship to metastatic
pattern. In their review of reported cases of paradoxi-
cal embolism, Thompson and Evans (1929) considered
that the lungs had not been examined in enough detail
to exclude small metastases.
In contrast to adults, paradoxical patterns were
convincingly demonstrated by Wieberdink (1957) in
fetuses and neonates with neuroblastomas of the
“Pepper-type”. Excluding those cases in which death
resulted from extensive liver involvement before
metastases were detectable elsewhere, Wieberdink suc-
cessfully accounted for distinctive metastatic patterns
in terms of lung-avoidance, due to patency of the fora-
men ovale and ductus arteriosus, and liver-avoidance
due to a patent ductus arteriosus. The observed pat-
tern changed abruptly at birth, when cardiovascular
anatomy converted to the adult type.
6.5.2. Intra-organ shunts
Vascular shunts have the potential to enable cancer
emboli to avoid interaction with capillary beds after
delivery to a target organ and, by remaining in larger
292
vessels, to avoid arrest and metastasis-seeding or death
and, finally to emerge from the organ in a tumorigenic
state with the potential to seed down-stream organs.
Willis took the view that as he only rarely failed
to discover cancer emboli or small metastases in the
lungs in cases with arterial metastases, transpulmonary
passage of cancer cells was infrequent. The more rel-
evant question here is whether or not enough cancer
cells make transpulmonary passage to generate arterial
metastases in other organs, regardless of the presence
of pulmonary metastases and, if they do directly seed
metastases in the other organs, could these be discrim-
inated from those generated by cascade processes, that
is metastases from pulmonary metastases?
Arteriovenous shunts are well-accepted. For exam-
ple, Daniel and Prichard (1951a,b) demonstrated many
intrahepatic pathways between the portal vein and
the inferior vena cava in animals. Transorgan pas-
sage of glass spheres was demonstrated by Prinzmetal
et al. (1948); spheres of up to 440 µm diameter passed
through the vasculature of the kidney, up to 390 µm
through the lungs, up to 370 µm through the spleen,
and 180 µm through the liver. Tobin and Zariquiey
(1950) also demonstrated passage of spheres of up to
500 µm diameter, through specimens of human lungs,
with considerable regional variation. On the assump-
tion that the rigid, non-deformable beads did in fact
provide a non-traumatic demonstration of pre-existing
vascular shunts which prevent the entry of cancer
emboli in smaller vessels, the question remained of
the patency of these shunts under physiologic and
pathologic conditions.
In order to provide direct evidence for transorgan
passage, Zeidman and Buss (1952) injected cancer cells
into the ear veins of rats and rabbits and immediately
afterwards sampled aortic blood. They then performed
bioassays by injecting the blood intravenously into
fresh animals, in which pulmonary tumors subse-
quently developed. They also noted that the amount
of transpulmonary passage varied between different
types of cancer cells. Although there can be no doubt
about the validity of these particular observations,
more recent studies have tended to downplay the
importance of transorgan passage. Thus, in his dis-
cussion of transpulmonary passage, Cameron Wallace
(Wallace et al., 1978) observed that: “The phenomenon
of transpulmonary passage has attracted interest ever
since it was demonstrated convincingly by Zeidman
and Buss . . . . It is likely, however, that the perspective
on this problem has been distorted . . . the experience of
many investigators including ourselves, is that extra-
pulmonary metastases after intravenous injection into
the caval system of veins, while they can occur, are
rare, and that the vast majority of most types of tumor
cells are arrested in the lungs. Possibly, of those pass-
ing the capillary bed, too few are sufficiently viable
to initiate a metastasis . . . ”. Later work was in accord
with Wallace’s views.
The existence of various by-passes and shunts could
have accounted for some of the apparent deviations
from the joint concepts of metachronous seeding and
metastatic cascades. However, these deviations could
for the most part be accounted for by incorrect reports
of metastatic non-involvement of large organs, partic-
ularly the liver and lungs.
6.6. Some additional experimental data
The experiments, discussed earlier, of Holtfreter,
Moscona, Trinkaus and others, on confronted embry-
onic tissue fragments, or reaggregating, dispersed cells
from embryonic tissues, indicated the ability of cells to
“home” in specific positions or sites raised the question
of whether some sort of “homing” process accounts for
the diversity of metastatic patterns.
Possible support for this “homing” hypothesis came
from P. Weiss and Andres’ (1952) observation that
when melanoblast suspensions prepared from embry-
onic chickens of a pigmented variety were injected
intravenously into embryos of a non-pigmented type,
some 8% of the recipients developed pigmented
patches exclusively in sites of normal pigmentation
in the donors. They offered two explanations of their
results, which are at the heart of mechanisms of
metastatic patterns, namely: trapping of cells in spe-
cific sites, where proliferation occurred subsequently
or, alternatively, random trapping of cells with subse-
quent proliferation in specific sites. On the basis of
these experiments, a choice could not be made between
the two possible mechanisms, because the cells could
only be identified by standard histologic techniques
some two weeks after injection, when they had prolif-
erated to form identifiable colonies, when correlation
between differential survival and original cell-trapping
pattern could no longer be examined.
By the use of improved techniques involving injec-
tion of radiolabeled cells into chicken embryos, and
their identification by autoradiography, Burdick (1968)

showed that their initial distribution was independent of
their organ source. Additional experimental evidence
against homing in embryonic cells was also provided
by Hollyfield and Adler (1970).
In contrast to at least some tissue cells from and in
embryos, lymphocytes do exhibit organ-specific migra-
tion patterns, which to some extent are associated
with maturity. Mature small lymphocytes recirculate
from the blood to the lymph by migration through the
endothelium of the post-capillary venules. Lympho-
cytes from peripheral lymph nodes preferentially return
to peripheral lymph nodes, and lymphocytes from the
gut preferentially migrate to Peyer’s patches and to the
lamina propria of the gut (Gowans & Knight, 1964).
The work of Butcher and his colleagues (Butcher &
Weissman, 1980) shows that in some way arrest of
mature lymphocytes in specific locations is associated
with their capacity to “recognize” the endothelium in
high-endothelial venules (HEV). The metastatic pat-
terns of lymphoreticular tumors may reflect loss or gain
in this capacity.
Coman and his colleagues (1951) took the view that
the scarcity of metastasis in certain target organs could
be due on the one hand to low tumor susceptibility (i.e.
unfavorable “soil”) or, on the other hand, due to failure
of sufficient numbers of cancer cells to reach the organ
in question. Voluntary muscle is a relatively uncom-
mon site for metastasis; however, when suspensions
of V2 carcinoma cells were injected into the femoral
artery of rabbits, the muscles of the lower limbs became
massively infiltrated by cancer, showing that if enough
cancer cells were delivered to voluntary muscle, even
this reputed unfavorable site will support their growth.
In these experiments, when cancer cells were injected
into the left side of the heart, they produced tumors in
all organs, and injections into the right side of the heart
produced tumors in the lungs only, as the “. . . result of
screening by the lungs.” It was therefore concluded that
“. . . the scarcity of metastasis in an organ is explain-
able by the scarcity of tumor cells reaching that organ.
Under the conditions of these experiments, no organ
proved to be an unfavorable soil.”
In another study made by this extraordinarily pro-
ductive group in the University of Pennsylvania
(deLong & Coman, 1950), tumor fragments were
directly transplanted into the kidney, liver, adrenal,
spleen and muscle of mice, rats and rabbits. Tumors
developed in all organs tested, and no differences were
detected between the weights of tumors growing in the
293
different organs, although in rabbits the tumors grow-
ing in the spleen were generally larger than those in
the other organs. It was concluded that the scarcity of
metastases in certain organs depends on factors other
than the inability of these organs to support tumor
growth. Among other possible factors considered were
failure of tumor emboli to reach the organs; their failure
to be arrested in them, and the inability of the arrested
cells to extravasate.
Coman and his colleagues (1951) made a notable
attempt to directly relate cancer cell delivery via the
arterial system to the subsequent pattern of organ col-
onization. It is important to remember that in 1951,
suitable radiolabels were not generally available to
study this type of cancer cell traffic, radiolabeled beads
were not available to estimate target organ blood-flow,
and antibodies coupled to appropriate markers were not
available for cancer cell detection. In view of the large
amount of recent experimental work with the trans-
plantable B16 melanoma in mice (Fiddler, 1970), and
studies involving the use of radiolabels (Baserga et al.,
1960; Fisher & Fisher, 1967; Hofer et al., 1969), it is of
interest that Godlee (1874) anticipated the use of mark-
ers in studies of metastasis by suggesting that the black
pigmentation of melanomas provided “. . . an unusually
good opportunity for studying the earliest methods” of
metastasis development. Coman et al. (1951) made a
notable attempt to overcome cancer cell identification
problems by mechanically dissociating Brown-Pearce
rabbit tumors into single cancer cells, which were then
fixed in formalin and stained with iron hematoxylin
to make them visible in eosin-stained sections of tar-
get organs. Suspensions of these rigid, “labeled” cells
were then injected into the left side of the heart; ani-
mals were killed within 3 min, and the densities of
cancer cells in sections of the different organs were
determined together with their arteriolar and capillary
distribution. Matching animals received injections of
fresh, tumorigenic cancer cells. “When the total num-
ber of stained cells reaching an organ was compared
with the numbers of tumors in that organ, correspon-
dence was only fair. However, if only those embolic
cells that lodged in the capillaries were considered, cor-
respondence was excellent. Thus, the greatest number
of emboli per square centimeter was found in the iris,
pituitary, adrenals, and kidneys; the smallest number
in muscle, thyroid and spleen. The same frequency of
distribution was found for the tumors. These results
with the tumor and species studied, are in agreement
294
with the hypothesis that the distribution of metastases
is adequately accounted for by the mechanics of circu-
lation and the consequent distribution of embolic tumor
cells. In the organs studied, the role played by local
‘soil’ factors is evidently a minor one, if it exists at all.”
However, later observations on mice and men have not
confirmed these conclusions.
Reticuloendothelial system tumors were the focus
of some of the initial studies, because in mice and
rats they tend to be more overtly metastatic than nat-
urally occurring or transplantable solid tumors. For
example, in the mouse lymphocytic cancers generally,
selectively involve the lymph nodes, spleen and liver
(Dunn, 1954), and histiocytomas the lymph nodes and
liver (Cloudman, 1947; Dunn, 1954). It was noted that
this selective pattern was observed when tumors were
implanted subcutaneously or when cancer cells were
injected intravenously, and therefore could not be dis-
missed as artifactual. Transplantable plasmacytomas
selectively metastasized to bone marrow, where they
produced “punched-out” lesions of the type seen in
humans (Potter et al., 1957; Siegler & Rich, 1966).
Also in the mouse, both lymphocytic lesions origi-
nating in the thymus and those resembling Hodgkin’s
lymphoma, tend to metastasize to all lymphoid organs
(Siegler & Rich, 1966). Pilgrim (1969) commented
that these metastatic patterns were constant enough to
permit tumors lines to be identified by them.
6.6.1. Experiments using neonatal organ transplants
A series of experiments on organ preference were ini-
tiated by Kinsey and Smith (1959) who observed that
the transplantable S91 Cloudman melanoma sponta-
neously metastasized exclusively to the lungs in mice.
Further, when single S91 cell suspensions were injected
into the tail artery, the tail vein, the left ventricle, the
portal vein or the carotid artery, overt tumors were
again only observed in the lungs. Kinsey (1960) stud-
ied this lung preference in a most ingenious manner.
Thus, lung fragments from new-born DBA/2 mice were
implanted into the right thigh muscles of adults of the
same strain, and fragments of kidney, liver, spleen, thy-
roid, heart or skin were inserted on the left. All of
the grafts except the liver were well-vascularized by
7 days, and survived for the duration of the experi-
ment. Ten days after organ transplantation, each animal
received an injection of S91 cells into the tail vein,
the left ventricle, tail vein or artery (retrograde); after
21–28 days, tumors were found in the lungs of all
(8/8) animals which had received tail vein injections,
and in 2 of 8 lung grafts. More striking evidence of
lung preference was found in animals receiving retro-
grade arterial injections, where tumors were found in
the lungs of all of 40 mice, and also in 37 of 40 lung
grafts, but in no other sites. Although the experiments
using organ grafts provided support for the “seed-and-
soil” hypothesis, and were interpreted as demonstrating
that lung preference was not due to differential, cancer
cell trapping in the lungs, but rather the “. . . inability
of these cells to implant and grow” in the other organs.
However, Kinsey and Smith had previously reported
that following their direct injection, S91 cells grew in
every tested site; this observation favors differential
delivery and hence, the mechanical hypothesis. This
apparent contradiction could only have been resolved
by dynamic studies, using quantitative techniques of
cancer cell delivery which were not available in 1959.
An important variation of the Kinsey and Smith
experiments was made by Sugarbaker and his col-
leagues (1971), using 3-methylcholanthrene sarcomas
in syngeneic mice. In these experiments, two days after
receiving intramuscular injections of cancer cells, the
animals received subcutaneous transplants of neona-
tal lung, spleen, and kidney. After some weeks during
which, the “primary” tumors were resected, 18 of 167
animals had pulmonary metastases, but none were
detected in other “normal” sites; among these mice,
6 of 7 had tumors in the lung-transplants, but none
were observed in the spleen or kidney transplants.
These experiments are thus consistent with the “seed-
and-soil” hypothesis, although their relevance to the
human situation is difficult to assess on the basis of the
reported data, because metastatic patterns of tumors
with venous drainage into the inferior vena cava usually
occurs first in the lungs. Therefore the natural metasta-
sis apparently confined to the lungs may have indicated
preferential delivery of cancer cells, and that within the
time-frame of animal survival, the resulting pulmonary
metastases had no time to seed detectable tertiary
metastases in other organs. The relationship of pref-
erential colonization of the neonatal lung transplants
to either preferential delivery or to preferential growth
cannot be determined on the basis of the reported
results, bearing in mind the limited techniques available
to Sugarbaker and his colleagues at the time.
More complete experiments along the general lines
of those reported by Kinsey and Sugarbaker, were

reported by Hart and Fidler (1980), using low doses
(104 ) of B16.F10 melanoma cells in mice. In these
experiments an attempt was made to quantitate cancer
cell delivery to transplants by using radiolabeled cells;
however, the resulting near-background, low radioac-
tivity counts made over the course of several days,
are also difficult to assess, and the role of differential
cancer cell delivery requires clarification. Coman and
Sheldon (1946) showed that transplants of embryonic
tissues excited a progressive hyperemia in mice. If it
occurred, a differential hyperemic response could have
favored differential arrest of injected cancer cells, and
their subsequent growth would presumably have been
enhanced by the subsequent angiogenesis.
A critical discussion of the neonatal transplant exper-
iments, with all the advantages of hind-sight, is given
elsewhere (Weiss, 1985; pp. 237–240), but this should
not obscure the importance of these various attempts
to explore the basis of metastatic patterns in the best
experimental systems available at the time.
6.6.2. Cancer cell selection and metastatic pattern
Attempts to select in heterogenous tumors for sub-
populations of cancer cells which exhibit different
metastasis-related properties, are described in Chapters
X and XI. Early experiments to obtain sub-populations
expressing specific metastatic patterns, were made by
Fidler and Nicolson (1976). Using B16 melanoma cells
originally taken from lung colonies, resulting from
tail vein injection in mice, cells were then propagated
in vitro. When these cultured cells were radiolabeled
and injected into the tail veins of fresh mice, more were
detected in the lungs than after injection into the left
ventricular cavity. However, 14 days after injection,
equal numbers of pulmonary colonies were detected
regardless of injection site. This was interpreted as
demonstrating lung preference, independently of arrest
in the lungs. This interpretation treated the lungs
as uniform structures in the context of “soil”, and
ignored lung vascularization, because tail vein injec-
tions seed the lungs via the pulmonary arteries which
predominantly supply the alveoli, whereas left ven-
tricular injections seed them via the bronchial arteries
which supply the bronchial tubes, interlobular alveolar
tissues, bronchial lymph nodes etc.
More definitive experiments on selection for pattern
were made by Brunson and Nicolson (1978), using the
295
RAW117 lymphosarcoma line. Following injection,
tumor nodules were removed from the livers of mice,
grown in vitro for two passages, and then injected intra-
venously into fresh recipients; this cycle was repeated
10 times to yield the RAW117-H10 line which, on
intravenous injection gave rise to approximately 200
times more liver tumors than the original RAW117
line. This enhancement of colonization potential was
not observed in the lungs, and indicated a surprising
expression of stability of these cells.
Analogous results were reported by Tao et al. (1979)
by injecting B16 melanoma cells into the portal vein,
harvesting the resulting liver tumors, culturing and
injecting them into fresh mice, and repeating this cycle
8 times. Following either tail vein or left ventricular
injection, the “selected” B16 cells gave rise to many
more tumors in the liver than the corresponding unse-
lected parental lines. These results indicated inheritable
organ-preference, following the stated selection proce-
dures. However, the key unanswered questions were
whether the occurrence of liver metastasis was exclu-
sively due to “dedicated”, pre-existing sub-populations
of cancer cells within the original tumor, which
expressed liver-preference, or whether expression of
this trait was a result of growth in the liver, as distinct
from its cause: cancer cells are subject to reversible
and irreversible, environmentally induced, metastasis-
related change (Weiss, 1991). The work of Shearman
and Longenecker (1980) provides a final example of
experiments designed to clarify this exceptionally dif-
ficult problem of the role of cancer cell selection or
organ-specificity in producing metastatic patterns. In
these experiments, chicks were given intraperitoneal
injections of a virus (Marek’s) – transformed, non-
producer cell, line; spleens were removed from mori-
bund animal and injected into fresh recipients. After the
fifth injection cycle, there was an increased virulence
of the cells, expressed as shortened survival. Attempts
were then made to select for liver- and ovary-specific
metastasis from these virulent cell by sequential allo-
transplantation of liver- and ovary-derived cells. There
was a doubling in the number of liver lesions in animals
receiving liver-selected cells. Liver specificity was also
demonstrated in chick embryos following intravenous
injection into the chorio-allantoic membrane, using the
technique pioneered by that experimentalists’ exper-
imentalist, Leighton (1963). From these experiments
it was concluded that liver preference was not due
to selective trapping of cancer cells in the first organ
296
encountered. That the successful at liver selection did
not represent a general case, was indicated by the lack
of success in attempts to select an ovary-specific cell
line using analogous procedures.
During their liver selection procedures, Shearman
and Longenecker used in vitro passage, but they later
demonstrated that liver preference developed sponta-
neously in vitro, in cell lines not obtained by in vivo
selection (Shearman & Longenecker, 1981).
In summing-up studies of this type of selection for
organ-preference in general, it should be emphasized
that cancer cell lines have been obtained which indeed
exhibit this trait, which is heritable for a variable num-
ber of passages in vivo and in vitro. However, as
discussed in Chapter 10, the relationship of these obser-
vations to naturally-occurring, organ-specificity is not
at all clear. In this context, it should be noted that renal
clear cell carcinomas in humans, which might reason-
ably be expected to be kidney-selected, do not in fact
preferentially metastasize to the contralateral kidney
(Weiss et al., 1988).
6.7. Some present and future directions
Reviews of metastatic pattern have been prepared by
Hart (1982), Sugarbaker (1982), Weiss (1992) and
Nicolson (1988), and a highly selected bibliography
representing a very small fraction of recent work is
cited below.
Using a rat sarcoma model, Proctor (1976) injected
cancer cells into the portal venous or vena caval sys-
tems. He observed that cancer cells were retained
almost exclusively in the liver or lung respectively, and
that tumor growth was limited to these organs. In con-
trast, following systemic arterial injection, cancer cells
were distributed to many organs, with different subse-
quent growth patterns; fewer cancer cells were required
to produce tumors in the adrenal glands than in the
lungs, apparently because there is a much higher rate
of cancer cell loss in the latter. This work indicates that
both mechanical and seed-and-soil processes play non-
exclusive roles in this model of the post-dissemination
phases of metastasis.
An analytic technique has also been developed by
Weiss (1992) for use on human autopsy data, to
discriminate between the roles of delivery and the
seed-and-soil effects in arterial metastasis. Cancer cell
delivery is proportional to arterial blood-flow to the
different organs, and the analyses revealed a trend for
the incidence of involvement of nine target organs by
metastases from 16 different classes of metastasizing
primary cancers, to follow cancer cell delivery, in broad
accord with the mechanical hypothesis. However,
within this framework, the ratios of incidence of arte-
rial metastasis and delivery revealed three (decades)
groups of target organs; a middle group, and two groups
in which the incidence of metastasis was either higher
or lower. The former indicated a “friendly” soil, and the
latter, a “hostile” soil; the numerical variations within
each of the three groups indicated more subtle degrees
of “soil” differences in the different types of primary
cancers, in accord with the seed-and-soil hypothesis.
According to analyses of this type, the most favor-
able soil for metastases from primary cancers of the
breast, colorectum and lung is the uveal tract (posterior
choroid) of the eye, even though the absolute inci-
dence of metastases in this site is low (Weiss, 1993).
In Table 6.4, an example of this type of analysis in
primary carcinoma of the breast is given, where the var-
ious target organs are grouped according to metastatic
efficiency index (MEI) which equals per cent incidence
of involvement/organ arterial blood-flow. Estimates of
MEI for the lungs and liver were not given because can-
cer cells may also reach these organs via the pulmonary
and portal veins respectively, and other routes.
The vexing question of false negative reports of
metastasis is being at least partially resolved by the
use of immunocytochemical and immunohistological
techniques in combination with flow cytometry and
automated microscopy. The prospects of using such
probes and markers for the non-invasive detection of
small metastases in patients has so far proved some-
what disappointing in the present context, because
the techniques of state-of-the-art ultrasound, scinti-
graphic scanning, X-ray tomography and magnetic
resonance imaging cannot directly detect cancers less
than several millimeters in diameter in the absence
of local tissue change, including microcalcifications
associated with breast cancer. However, some improve-
ment in their capabilities through the development of
image-enhancers is probable. If utilizable biochemi-
cal differences between cancer and normal tissue cells
can be identified (Chapter 9), then the powerful tool of
positron emission tomography could also prove to be a
sensitive detection technique.
Many of the key events in hematogenous metas-
tasis involve the interactions between cancer cells

Table 6.4. Metastatic efficiency indices (Incidence of metastasis/ target organ blood flow) for specified target
organs in primary human breast cancer
Kidneys Skeletal Brain
muscle
MEI 0.017 0.028 0.030
Blood flow∗ 1000 560 750
Incidence (%) 17.0 15.5 22.8
of metastasis
∗Blood-flow ml/min.
Data sources cited in Weiss (1993).
and the microvasculature (Orr et al., 1991); there are
many advantages in studying some of these interac-
tions in vitro, where the effects of individual factors
can be isolated. In 1975, Nicolson and Winkelhake
described the selective adhesion of cultured melanoma
cells to monolayers of endothelial cells derived from
different organs, or to sub-endothelial matrix. These
and additional experiments by Nicolson and others
confirmed much earlier histologic studies showing
that when cancer cells made contact with endothe-
lial cells, the latter retracted exposing the underlying
subendothelium to which they adhered. Auerbach et
al. (1987) demonstrated the specificity of adhesion
between certain cancer cells and capillary endothe-
lium derived from different organs in vitro, which in
these systems correlated with cancer cell trapping and
metastasis in vivo. Thus, these various in vitro exper-
iments focus on selective adhesion of cancer cells to
specific sites, and in some cases related metastatic pat-
terns to cancer cell delivery, which is in accord with
the “mechanical” hypothesis. However, one obvious
drawback to these experiments utilizing endothelial
monolayers is that they emphasize the chemistry of
the interactions, but ignore the geometry and hence
the mechanical trapping of cancer cells in small blood
vessels in vivo (Chapter 4 (4)). The main role of adhe-
sion of cancer cells to the microvasculature may not
be in cell trapping per se, but in regulating cancer cell
growth.
The differential effects of cancer cell lodgement sites
on growth has been described by Bellamy and Hinsull
(1978), Kawaguchi et al. (1982), Nicolson and Dulski
(1986), Yamori et al. (1988) and Chan et al. (1988)
among others.
Additional complexity in the mechanisms of
metastatic pattern are indicated by Kahan’s (1987)
297
Skin Heart Bone Thyroid Adrenals Eye
marrow
0.049 0.051 0.103 0.240 0.347 13.5
400 200 600 100 90 0.628
19.5 10.3 61.8 24.0 31.2 8.5
observations on embryonal mouse carcinoma lines,
grown in vitro and injected into different sites in mice.
These indicated that neither local growth responses, nor
initial attachments accounted for the patterns of tumor
colony development seen after arterial injection.
A novel approach to metastatic pattern was described
by Arguello et al. (1992), in their study of the inci-
dence and distribution of tumor colonies, following the
injection of cancer cells into mutant mice with geneti-
cally defective organ microenvironments. Experiments
of this type will hopefully enable the powerful tech-
niques of molecular genetics to be brought to bear on
defined “soil” features of metastatic patterns.
Following the work of Bross and his colleagues
(Bross and Blumenson, 1976), metastasis of metas-
tases, or metastatic cascades, have probably been
demonstrated in humans at autopsy, in primary can-
cers of the colorectum (Viadana et al., 1978; Weiss
et al., 1986), kidney (Weiss et al., 1988) and pan-
creas (Weiss et al., 1993). The demonstration that
metastatic patterns apparently develop in a step-wise
manner raises the possibility of using local therapy,
with the advantages of high local dose to metastases
in the liver or lungs and minimizing systemic toxicity
(Weiss, 1989).
6.8. Cell adhesion molecules and
metastatic patterns
Local variations in the vascular endothelium in relation
to metastasis were reviewed by Belloni and Nicolson
(1991), who concluded that:
(1) The adhesion of cancer cells to the microvascular
endothelial cells in different organ sites is important
in the development of metastatic patterns.
298
(2) The dynamic properties of normal and activated
endothelial cells underlies the marked heterogene-
ity of the microvasculature.
(3) The kinetics of cancer cell adhesion to monolayers
of endothelial cells in vitro, differs among different
sub-populations of cancer cells and often correlates
with their in vivo “metastatic” properties.
(4) The differential expression of organ-associated
microdomains on microvessel endothelial cells,
serves as tissue “addressins” in the prefer-
ential tissue localization of circulating cancer
cells.
(5) Multiple molecular interactions, including involve-
ment of integrin complexes, is involved in cancer
cell adhesion to endothelial cells.
(6) The growth of arrested cells in different target
organs also determines organ preference in metas-
tasis. Growth is determined by cell/cell; cell/ECM
and cell/soluble molecular interactions.
As far as they go, the conclusions of Belloni and
Nicolson are in accord with much experimental evi-
dence. Organotypic endothelial cell surface molecules
were also implicated in organ preference in metasta-
sis by Pauli et al. (1991), but particularly with respect
to organ-specific extracellular matrix-associated tumor
attachment modulators (TAMs). Their major relevant
observation was that cancer cell lines selected in vivo to
metastasize or colonize specific target organs, showed
higher binding affinities for bovine aortic endothelial
cell monolayers grown on TAMs of the preferred tar-
get organ than for monolayers grown on TAMs of any
other organ which was not preferentially colonized by
the cancer cells in question. This suggested that expres-
sion of selective binding properties by endothelial cells,
was a consequence of signals received by them from
the ECM (sub-endothelium). The specificity of the
endothelial cells as receptors of these signals was indi-
cated by Pauli and his colleagues’ failure to observe
the preferential attachment for any of the metastatic
cell lines, when skin fibroblasts were substituted for
the endothelial cells in the binding assays. The data
of Pauli et al. are consistent with the observations of
Simionescu et al. (1982) that lectin-binding sites on the
microvascular endothelial cells are quantitatively sim-
ilar from one species to another, yet vary considerably
from organ to organ. It now appears that organ speci-
ficity did not directly or invariably correlate with initial
arrest to any major extent.
Clearly, metastasis in vivo cannot occur in the
absence of cell adhesion to vessel walls, and cell
adhesion molecules stabilize these adhesions, but their
relationship to specific metastatic patterns is compli-
cated. It is therefore interesting that injections of the 3
amino acid sequence Arginine–Glycine–Aspartamine
(RGD) simultaneously with intravenous injection of
cancer cells, blocked the development of lung colonies
(Humphries et al., 1986). However, while these and
similar experiments implied that receptor/ligand inter-
actions between cancer cells and vessel walls can
promote site-specific metastasis, they did not indicate
whether the effects were mediated through differential
adhesion per se, or differential growth.
It presently appears that metastatic patterns are in
part due to the differential delivery to, and arrest at
target sites of enough tumorigenic cancer cells, and
their differential growth in these sites. Thus, while the
mechanical and seed-and-soil hypotheses are not mutu-
ally exclusive, neither in itself accounts for metastatic
patterns. In surveying the evidence, it is to be borne in
mind that a full-blown hematogenous metastatic pat-
tern can only develop if the patient or laboratory animal
survives long enough, and that the pattern may be
distorted by treatment or death.
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