cancer research · cancer research volume 21 october 1961 number 9 patterns of metastasis in lung...

CANCER RESEARCH

VOLUME 21 OCTOBER 1961 NUMBER 9

Patterns of Metastasis in Lung Cancer- d Review*

WiLsoN I. B. ONwmBot

(Department ~Jf Pathology, University qf Olaxgow and lFestern Ir~firmary, Glasgow, Scotland)

I N T R O D U C T I O N Scientific methodology emphasizes the impor-

tance 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, supra- renals, 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 teach- ings of the old masters (95).

Fif ty years ago, Levin and Sittenfield (8~2) made a comment of considerable relevance to the problem of metastasis: "This proof of the transporta-

* Aided in part by a grant from the University of Glasgow. t Research student, on study leave from the Ministry of

Health, Eastern Nigeria.

Received for publication _March ~20, 1961.

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 Ander- son (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 mar- shaled--(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. In order to be in a position to harmonize these discordant notes in the theme of hematogenous metastasis, the variations characteristic of lymphogcnous metastasis are next elabo- rated. I t is shown that lymphogenous metastases tend to be (a) limited in extent; (b) centrifugal in sequence; (c) selective in distribution; (d) ipsi-

1077

Research. on June 27, 2020. © 1961 American Association for Cancercancerres.aacrjournals.org Downloaded from

http://cancerres.aacrjournals.org/

1078 Cancer Research Vol. ~1, October 1961

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 harbor- ing 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.

U N E X P E C T E D P A T T E R N S 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 my study of 6,000 cases of lung cancer recorded in ~8 Teaching Hos- pitals (99), note was made of the presence of metastases in eight organs. In as many 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 enor- mous vaseularity of the lung is taken into account

~2. Centrifugal metastasis.--We expect, as did Carnett (s and Cohnheim (~7), tha 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

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 col- lect 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 tha t lung cancer tends to spread centrifugally. This pattern is contrary to our expecta- tion tha t opportunities for invasion of both far and near organs are equal in this condition.

3. Selective metastasis.--Since the days of Hodg- kin (69), the fact tha t a tumor seems, on occasion, to select a particular organ for at tack 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 com- mentary comes from Robbins (107) : "For obscure reasons, bronchogenic carcinoma sometimes sin- gles out the adrenals as sites of spread."

This problem would have been easy of solution on the theory of soil susceptibility if adrenal selec- tivity had been all tha t demanded explanation. However, as a number of contributors recognize (9, 15, 70, 1~0), other organs including the brain, heart, liver, pancreas, and kidney may also be selectively involved.

Since hmg cancers show considerable poly- morphism 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 undif- ferentiated-cell types (160) have all been indicted for their proclivity to spread to this organ, although Halpert (59) is emphatic in denying tha t the cell type bears any relation to the frequency of intracranial metastasis. I t would seem, therefore, tha 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



ONumBo---Metastasis in Lung Cancer: A Review 1079

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 ter- tially 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 recta- static 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 simul- taneously to the ensuing cancerous bombardment daily.

Let us, therefore, compare the deposits found in

the adrenal gland on either side. Gillespie (51) discovered on making this comparison that the one growth is usually larger than the other. So con- spicuous 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 Lon- don 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 hid- den 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 in- nocent 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 dis- similarities--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 quanti ty of cancer-contain- ing blood received by an organ is not correlated with its metastatic frequency. Since blood flow to the adrenals per unit weight of tissue is high (81), their relatively high rate of metastasis may con- ceivably be due to this fact. However, this argu- ment 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 exhib- its metastases half as often as the cerebrum. This




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 avail- able 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 em- phasis 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 com- mensurate 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 per- tinence 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 LYMPHOGENOUS 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 "con- firming instances" of another theory. We begin by delineating topographical patterns which char- acterize 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-

ticular, in neoplastic diseases the nodes act as in- terrupters 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 pro- pensity 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) de- picted, lung cancers "often exhibit discrete deposits in the abdominal and cervical glands, these di- minishing in centrifugal order." Figures 1, 2, and 4 illustrate this fact. We deduce, in consequence, that centrifugal metastasis is one of the character- istics of lymphogenous invasion.

3. Selective metaslasis.--In addition to recogniz- ing 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 anasto- motie 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



ONUmBo--Metastasis in Lung Cancer: A Review 1081

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 con- fined 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) demon- strate, 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 gov- erned by, and varies according to, the dynamics of lymph flow to the part.

ANALOGY BETWEEN VISCERAL AND NODAL PATTERNS

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 rg~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 thoraco- abdominal 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-

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 intercept- ing cells making for the viscera. The filtering ac- tion 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 provi- sional in nature. Therefore, to attach finality to the results hitherto obtained from experiments on brain lymphatics is erroneous. Rouviere (113) ad- vised 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 "Connec t ions . . . 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 al l --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-




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 acknowledge- ably extensive and yet often remains unilateral, as do lymph node metastases. We expect, then, tha 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 at- tacks 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 pre- ponderance 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 rec- ord, 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 difficul- ties.

F U T U R E 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 ex- plore the possibility that blood-borne cancer cells

are not the effective agents of invasion that they have hitherto been assumed.

I t is not disputed tha 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. I t seems to me that, perhaps, the destruction of these cells in the blood stream may be accom- plished to an extent not even dreamt of. In this connection, the long-enunciated (140) but disputed (30) view, that blood and lymph affect can- eer 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 re- cently 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 sur- vival 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 para- mount importance to orientate chemotherapeutic researches toward discovering drugs which are concentrated in the lymph stream. What is en- visaged is exemplified by the observation of Schach- ter (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.

A C K N O W L E D G M E N T S

I am indebted to my chief, Professor D. F. Cappell, for the facilities which he has generously placed at my disposal; to Dr. A. T. Sandison for invaluable discussions; and to Professor C. V. Harrison for ~lcccss to the records of Hammersmi th Hos- pital, London.



ON~JIGBO---Melastasis in Lung Cancer: A Review 1083

R E F E R E N C E S

1. ACKERMAN, L. V., and REGATO, J. U. del. Cancer: Diagno- sis, Treatment and Prognosis, pp. 83-84. St. Louis: Mosby, 1947.

2. ALLISON, P. R. Carcinoma of the Lung. In: H. G. GAR- LAND and W. PHILLIPS (eds.), Medicine, 1:1870-73. Lon- don: l~Iacmillan, 1953.

3. ANDERSON, W. A. D. Pathology of Carcinoma of the Lung. Wisconsin M. J., 51:1085-86, 1952.

4. ARMST[r G. E., and OERTEL, H. Localization of Tu- mor Metastases. Am. J. M. Sci., 158:354-60, 1919.

5. ASK-UPMARK, ]~,. On the Location of Malignant Metas- tases with Special Reference to the Behaviour of the Pri- mary Malignant Tumours of the Lung. Acta Path. et Microbiol. Scandinav., 9: 939-48, 1939.

6. BAKER, D. M. Primary Carcinoma of the Lung, p. 22. M.D. Thesis, Cambridge University, 1946.

7. BALLANTYNE, A. J.; CLAGETT, O. T.; and ~cDoNALD, J. R. Vascular Invasion in Bronchogenic Carcinoma. Thorax, 12:r 1957.

8. BARriOS, M. P. Bilateral Metastases in the Adrenals. Friuli Med., 9: 239-44, 1954.

9. BARNAnD, W. G. Primary Carcinoma of the Lung: Pa- thology. Postgrad. M. J., 19:38-43, 1943.

10. BATSON, O. V. The Function of the Vertebral Veins and Their Role in the Spread of Metastases. Ann. Surg., 112: 138-49, 1940.

11. - - - - - - . The Role of the Vertebral Veins in Metastatic Processes. Ann. Int. Med., 16:38-45, 1942.

1~. BEATTIE, J. ~{., and DICKSON, E. C. A Text Book of Pathology, 5th ed., 1: 661. London: Heinemann, 1948.

13. BRAMWELL, B. Malignant Disease of the Lung, Resem- bling Chronic Phthisis. Clinical Studies, 8:984-87, 1910.

14. BRUNN, E. T. Cancer of the Lungs. In: W. PEPPER (ed.). A System of Practical Medicine, pp. 460 and 868. Lon- don: Low, Marston, Searle & Rivington, 1885.

15. BRYSON, C. C. Carcinoma of the Bronchus, pp. 36-85. M.D. Thesis, Cambridge University, 1949.

16. BRYSON, C. C., and SPENCER, H. Carcinoma of the Bron- chus. Quart. J. Med., 20:173-86, 1951.

17. BunD, G. M. On Some of the Effects of Primary Can- cerous Tumours within the Chest. Proc. Med.-Chir. Soc. London, 3:87, 1859.

18. BU1)INGER, J. M. Untreated Bronchogenic Carcinoma. Cancer, 11:106-16, 1958.

19. BVLLOCK, W. K., and HIRST, A. E. Metastatic Carcinoma of the Adrenal. Am. J. M. Sc., 226:5~1-24, 1953.

20. BVRKE, E. M. Tmnors of the Adrenal. Am. J. Cancer, 20:338-51, 1934.

21. BUSlNCO, A. Primary Carcinoma of the Lung: A Survey of Its Pathological Anatomy. Scientia Italica Med., 1: 656-722, 1950.

~2. CAPVELL, D. F. Muir's Text-Book of Pathology, 7th ed., pp. 261, 505. London: Arnold, 1958.

~3. CARNETT, d. B. Malignant Metastases Other Than to the Regional Lymph Nodes. Arch. Snrg., 18:811-18, 1999.

24. CHARACHE, H. Bronchogenic Carcinoma with Sub- cutaneous Metastases. Am. J. Cancer, 37:431-34, 1939,

25. CnlSTOVlCH, A. N., and ZERNOV, A. I. The Pathological Anatomy of Lung Cancer. Probl. Oncol., 3: 398-402, 1957.

26. COATS, J. A Specimen of Cancer of the Lung with Enor- mous Secondary Deposits in the Liver. Trans. Glasgow Path. Clin. Soc., 6:18, 1895.

07. COHNHEIM, J. Lectures on General Pathology, p. 795. London: The New Sydenham Society, 1889.

28. COMA>~, D. R. 5Iechanisms Responsible for the Origin and

48.

49.

-. 50.

51.

59.

53.

54.

55. 56.

Distribution of Bloodborne Tumor Metastases: A Review. Cancer Research, 13: 897-408, 1958.

99. COWDRY, E. V. A Text Book of Histology, 4th ed., p. 994. London: Kimpton, 1950.

30. - - - - . Cancer Cells, p. 34. London: Saunders, 1955. 31. CVSSEN, L. J. Metastasis of Malignant Tumours to the

Adrenal Gland. M. J. Australia, 1: 89-41, 1960. 32. CUTLER, ~ . , and BUSCHKE, F. Cancer: Its Diagnosis and

Treatment , pp. 572-86. London: Saunders, 1938. 33. DONALDSON, J. K. Surgical Disorders of thc Chest, 9d

ed., p. 315. London: Kimpton, 1947. 84. Dow, R. S., and MoRvzzI, G. The Physiology and Pathol-

ogy of the Cerebellum, p. 559. Minneapolis: The Univ. Press, 1958.

85. DRINKER, C. K. The Functional Significance of the Lymphat ic System. Harvey Lectures, Series 33, p. 107, 1987-1938.

36. EERLAND, L. D. Puhnonary Carcinoma. Arch. Neerl. Chir., 2: 919-33, 1950.

37. ENGELL, H. C. Cancer Cells in the Blood. A Five to Nine Year Follow Up Study. Ann. Surg., 149:457-61, 1959.

38. ENTICKNAP, J. B. An Analysis of 1,000 Cases of Cancer with Special Reference to Metastasis. Guy's Hosp. Rep., 101: 973-79, 1952.

39. EWING, J. Neoplastic Diseases, 4th ed., pp. 63-65. Lon- don: Saunders, 1940.

40. FAGGE, C. H. The Principles and Practice of Medicine, pp. 77-78. London: Churchill, 1886.

41. FARRER, S. M. Lung Cancer, pp. 40-69. Springfield: Charles C Thomas, 1954.

49. FAROOKI, M. A. Cytodiagnosis of Bronchogenic Car- cinoma. Medicus, 19:149-65, 1960.

43. FENWICK, B. A Case of Intrathoracic Cancer. Trans. Path. Soc. Lond., 33 : 996-300, 1889.

44. FLAVELL, G. Solitary Cerebral Metastases from Bronchial Carcinomata. Brit. M. J., 2:736-37, 1949.

45. FRIED, B. M. Bronchogenic Carcinoma and Adenoma, pp. 85-99. London: Bailliere, Tindall & Cox, 1948.

46. - - - - . Tumors of the Lungs and Mediastinum, p. 161. London: Kimpton, 1959.

47. GALLUZI, S., and PAYNE, P. M. Bronchial Carcinoma: A Statistical Study of 741 Necropsics with Special Reference to the Distribution of Blood-Borne Metastases. Brit. J. Cancer, 9:511-27, 1955. GAZAY~RLI, M. E. Primary Lung Cancer, pp. 50-85. Ph.D. Thesis, Edinburgh University, 1985. GIDDON, R. L., and BRINDLEY, P. Primary Carcinoma of the Lung in Texas. Texas J. Med., 46:888, 1950. GILCHRIST, R. K. Fundamental Factors Governing Lym- phatic Spread of Carcinoma. Ann. Surg., 111:630-89, 1940. GILLESPIE, M. Primary Intrathoracic Growths, p. 27. M.D. Thesis, Glasgow University, 1980. GLOBUS, J. H. Metastatic Brain Tumor with Broncho- genie Carcinoma as the Primary Source. J. Mt. Sinai Hosp., 10:533-64, 1943. GOODALL, J. R. A Further Study of the Clinical and Pathological Properties of Malignancy. J. Obst. & Gy- naec. Brit. Emp., 50:271-77, 1943. GREENE, M. H. Metastasis of Pulmonary Carcinoma to the Phalanges of the Hand. J. Bone & Joint Surg., 39A: 972- 75, 1957. GREEP, R. O. Histology, p. 838. London: Churchill, 1955. GUDERNATSCH, F. In: J. P. SCItAEFFER (ed.), Morris' Human Anatomy, l l t h ed., pp. 1593-94. New York: McGraw-Hill, 1953.




57. GULL, W. The Harveian Oration, pp. 19, 5~2. London: Churchill, 1870.

58. HALI'EI~T, B. Morphological Aspects of Carcinoma of the 88. Lung. Surgery, 8:903-909, 1940.

59. - - - - - - . Biological Behavior of Carcinomas of the Lung as Influenced by Their Cellular Structures. In: Cancer of the Lung- -An Evaluation of the Problem, pp. 209-~12. New 84. York: American Cancer Society, 1956.

60. HALrERT, B. ; EBICKSON, E. E.; and FIELDS, W. S. Intra- 85. cranial Involvement from Carcinoma of the Lung. Arch. Path., 69:93-10~, 1960. 86.

61. IIALPERT, B. ; FIELnS, W. S. ; and ])EBAKEY, M. E. Intra- cranial Metastasis from Carcinoma of the Lung. Surgery, 35: 346-49, 1954. 87.

62. HAM, A. W. Histology, 2d ed., p. 675. London: Lippincott, 1953.

63. HARRISON, R. G., and HOEY, M. J. The Adrenal Circula- 88. tion, p. 22. Oxford: Blackwell, 1960.

64. HASHEM, M. The Pathology of Lung Cancer. J. Egypt. 89. M. Assoc., 40 (Suppl.): 63-72, 1957.

65. HASsE, C. E. An Anatomical Description of the Diseases of the Organs of Circulation and Respiration, p. 371. Lon- 90. don: Sydenham Society, 1846.

66. HAWK, W. A., and HAZARD, J. B. Factors in the Mecha- nism of Metastasis: A Review. Cleveland Clin. Quart., 91. 20: 389-93, 1953.

67. HERnUT, P. A. Pathology, pp. 373, 751. London: Kimp- ton, 1955. 92.

68. HII~L, R. M. Intrathoracic Tumours, p. 70. M.D. Thesis, Edinburgh University, 1931. 93.

69. HODGKIN, T. Lectures on the Morbid Anatomy of the Serous and Mucous Membranes, 1:264. London: Sher- 94. wood, Gilbert & Piper, 1836.

70. Hu~PER, W. C. Occupational Tumors and Allied Dis- 95. eases, p. 380. Springfield: Charles C Thomas, 1942.

71. HUNTINGTON, G. S. The Anatomy of the Human Peri- 96. toneum and Abdominal Cavity, p. 144. Philadelphia: Lea, 1903. 97.

7~. IWASA~:I, T. ttistological and Experimental Observations on the Destruction of Tumor Cells in Blood Vessels. J. 98. Path. Bact., 20: 85-105, 1915.

73. JAMIESON, E. B. A Companion to Manuals of Practical 99. Anatomy, 7th ed., p. 678. London: Oxford University Press, 1954. 100.

74. KARSH, J. Secondary Malignant Disease of the Ovaries. 101. Am. J. Obstet. Gynec., 61:154-60, 1951.

75. KARSN~R, It . T. Human Pathology, pp. 348-50. Phila- 10~. delphia: Lippincott, 1938.

76. KING, R. A., and FORD, F. R. A Clinical and Anatomical 103. Study of Neurological Conditions Resulting from Metas- tases in the Central Nervous System Due to Carcinoma of 104. the Lung. Johns Hopkins Hosp. Bull., 70:124-56, 1943.

77. KNIGHTS, E. M. Metastatic Tumors of the Brain and Their Relation to Primary and Secondary Pulmonary Cancer. Cancer, 7: 359-69, 1954. 105.

78. KOLODNY, A. The Relation of the Bone Marrow to the Lymphat ic System. Its Role in the Spreading of Car- 106. cinomatous Metastases Throughout the Skeleton. Arch. Surg., 11:690-707, 1925. 107.

79. LA]USTELLA, E. Regional Lymph Node Metastasis in Pri- mary Bronchogenic Carcinoma. Ann. Chir. et Gynaec. 108. Fenniae, 47 (suppl. 80): 4-39, 1958.

80. I~EAF, C. H. On the Relation of Blood to Lymphatic Ves- sels. Lancet, 1 : 606-8, 1906. 109.

81. LEVER, J. D. The Anatomy of the Adrenal Cortex, p. ~26. M.D. Thesis, Cambridge University, 1954. 110.

82. LEVIN, I., and SITTENFIELD, M. J. On the Mechanism of

Formation of Metastases in Malignant Tumors. J. Exp. Med., 14:148-57, 1911. LORE, J. M. The Pathogenesis of Ascites and a Considera- tion of Pre-Existing Portacaval Shunts in Cirrhosis and Metastatic Carcinoma. Rhode Island M. J., 38:257-59, 1955. LUMSDEN, C. E. Pulmonary Carcinoma. Glasgow M. J., 13 : 57-73, 1939. MAXWELl,, J. Primary Malignant Intrathoracie Tumours. J. Path. Bact., 33:233-49, 1930. MEYER, K. K. Direct Lymphat ic Connections from the Lower Lobes of the Lung to the AbdomeIl. J. Thoracic Surg., 35:726-33, 1958. MEYER, P. C., and REACt, T. G. Secondary Neoplasms of the Central Nervous System and Meninges. Brit. J. Can- cer, 7:438-48, 1953. MooRE, G. E. The Spread of Cancer. Gastroenterology, 33: 313-15, 1957. MOORE, G. E.; ShNDnERG, A. A.; and WATNE, A. L. The Spread of Malignant Cells: A Review. Univ. Michigan M. Bull., 25:191-202, 1959. NOHL, H. C. The Modes of Spread of Carcinoma of the Bronchus and Their Relevance to Surgery, p. 75. I).M. Thesis, Oxford University, 1960. ONI:IGBO, W. I. B. Some Observations on the Spread of Lung Cancer in the Body. Brit. J. Cancer, 11:175-80, 1957.

The Spread of Extra-Portal Tumours to the Liver. West African M. J., 6:175-80, 1957.

The Spread of Lung Cancer to the Kidneys. Can- cer, 11: 737-39, 1958.

The Spread of Lung Cancer to the Brain. Brit. J. Tuberc., 52:141-48, 1958.

An Historical Criticism of Tumor Metastasis. J. Hist. Med., 13:5~9-30, 1959.

Lung Cancer--Metastat ic Theory and Surgical Practice. J. Thoracic Surg., 37:771-73, 1959.

Lung Cancer in the 19th Century. Medical His- tory, 3:69-77, 1959.

Centrifugal Metastasis in Lung Cancer. Brit. J, Dis. Chest, 55:86-90, 1961.

The Limitation of Metastasis in Lung Cancer. Tubercle, 42: 248-51, 1961. - - - - . Cerebral Lymphatics. Brit. M. J., 1:505-6, 1961. OSLER, W. The Principles and Practice of Medicine, p. 556. Edinburgh: Pentland, 189~. PAGET, J. Lectures on Surgical Pathology, 3d ed, p. 821. London: Longman, 1870. PARSONS, J. H. Metastatic Carcinoma of the Orbit. Ophthalmic Hosp. Rep., 15:286-91, 1903. PnnnoT, J. W. Advances in the Anatomical Investigation of the Lymphatic System with Special Reference to Some Pathological Applications. Edinburgh M. J., 61:50-63, 1954. REID, J. Physiological, Anatomical and Pathological Re- searches, p. 385. Edinburgh: Sutherland & Knox, 1848. RicE, G. J. The Distribution of Metastatic Tumors in the Cerebrum. Arch. Neurol. & Psychiat., 23:742-49, 1930. ROBmNS, S. L. Textbook of Pathology, p. 1181. London: Saunders, 1957. ROBERTS, O. W. Notes on Malignant Tumours, with Special Reference to 692 Cases, p. 8~. M.S. Thesis, Lon- don University, 1928. ROBINSON, A. Cunningham's Text-Book of Anatomy, 5th ed., p. 1095. London: Hodder & Stoughtou, 1922. ROGERS, W. L. Primary Carcinoma of the Lung. Arch. Int . Med., 49:1058-77, 193~.



ONUIGBO--Metastasis in Lung Cancer: A Review 1085

1~3.

124.

111. ROLLESTON, SIR H. D. The Endocrine Organs in Health and Disease, p. 381. London: Oxford University Press, 1936.

112. ROSENBLATT, M. B. Cancer of the Lung: Facts and Fal- lacies. J. Kentucky M. A., 56:131-36, 1958.

113. ROUVIEnE, H. Anatomy of the Human Lymphatic Sys- tem, pp. 208, 238. Michigan: Edward, 1938.

114. RUSSELL, D. S. The Pathology of Intracranial Tumours. Postgrad. M. J., 26:124-25, 1950.

115. RUSZNYAK, I. ; FOLDI, M.; and SZABO, G. Lymphatics and Lymph Circulation, p. 156. Oxford: Pergamon, 1960.

116. SAHAGIAN-EDWARDS, A., and HOLLAND, J. F. Metastatic Carcinoma to the Adrenal Glands with Cortical Hypo- function. Cancer, 7:1242-45, 1954.

117. SAMSON, P. C. The Relation of Cell Type to Metastasis in Bronchogenic Carcinoma. Am. J. Cancer, 23:754-61, 1935.

118. SCHACHTER, R. J. Fate and Distribution of Penicillin in the Body. 1. Circulation of Penicillin in the Lymph. Proc. Soc. Exper. Biol. & M ed., 68:~9-34, 1948.

119. SCARFF, R. W. The Morbid Anatomist and Cancer Re- search. Proc. Roy. Soc. Med., 42:19-24, 1949.

120. SCHUSTER, N�9 H. Aetiology and Pathology of Primary Lung Tumours. J. Path. Bact., 32:799-811, 1929.

121. - - - - . Primary Carcinoma of the Lung. J. State Mud., 37: 278-88, 1929.

1~2. SELLORS, T. H. In: LORD HORDER (ed.), The British En- cyclopaedia of Medical Practice. 5~edical Progress 1954, p. 43. London: Buttcrworth, 1954. SENN, N. The Pathology and Surgical Trcatmcnt of Tu- mors, 2d ed., p. 75. Philadelphia: Saunders, 1900. SENOO, T. I~letastasis of 400 Necropsy Cases of Broncho- genie Carcinoma: Statistical and Morphological Studies. Osaka Univ. M. J., 7:515-37, 1956.

1~5. S~tERLOCK, S. Diseases of the Liver and Biliary System, p. 577. Oxford: Blackwell, 1955.

126. SHIK, R. G. Bronchogenic Carcinoma. Am. Rev. Soviet Med., 4:142-47, 1946.

127. SIMrSON, C. K. Pathology of the Adrenal Gland in Rela- tion to Sudden Death. Lancet, 1:851-56, 1937.

1~8. SMITH, L. W., and GAULT, E. S. Essentials of Pathology, Sd ed., p. 422. Philadelphia: Blakiston, 1948.

1~9. SMITHERS, D. W. A Clinical Prospect of the Cancer Prob- lems, p. 65. Edinburgh: Livingstone, 1960.

130. SFENCER, H. The Development and Spread of Lung Can- cer, pp. 121-86. Ph.D. Thesis, London University, 1954.

1S1. STERN, R. O. The Morbid Anatomy of Carcinoma of the Bronchus: An Analysis of 87 Cases with Special Reference to Solitary Cerebral Metastases. Brit. J. Cancer, 8:412- 19, 1954.

132. STIRRAT, J. H. Concerning the Mode of Spread of Car- cinoma, p. 87. M.D. Thesis, Glasgow University, 1945.

133. STOREY, C. F.; KNUDSTON, K. P.; and LAWRENCE, B. J. Bronchiolar ("alveolar cell") Carcinoma of the Lung. J. Thoracic Surg., 26:331-403, 1953.

134. STORTEBECKER, W. P. Metastatic Tumors of the Brain from a Neurosurgical Point of View. J. Neurosurg., 11: 84-111, 1954.

135. STOUT, A. P. Human Cancer, p. 769. London: Kimpton, 1932.

136. STRANG, C. Bronchial Carcinoma, pp. 57 ft. M.D. Thesis, Durham University, 1949.

187. STRAUSS, B., and WELLER, C. Bronchogenic Carcinoma: A Statistical Analysis of Two Hundred Ninety-Six Cases

144.

145.

146.

147.

148.

\ '349:

150�9

151.

152.

153.

154.

155.

156.

i 6 2 . - - - - - -

with Necropsy as to Relationship between Cell Types and Age, Sex, and Metastasis. Arch. Path., 63:602-11, 1957.

138. STRAUSS, J. F., and SAPHIR, O. The Possible Significance of Altered Blood Coagulability on the Spread of Car- cinoma Cells. Proc. Inst. ivied. Chicago, 17:263, 1949.

139. SUGARBAKER, E. D. The Surgical Problem of Cancer in Lymph Nodes. Surgery, 12: 608-19, 1945.

140. SYMMERS, D. The Metastasis of Tunlors. Am. J. M. Sc., 154: 225-40, 1917.

141. SYMONDS, SIR C., and CAIRNS, Silt H. Brain Tumour. In: LORD HORDER (ed.), The British Encyclopaedia of Medi- cal Practice, 2d ed., 3: 96. London: Butterworth, 1950.

142. TAUCHI, H. On the Pathology of Primary Cancer of the Lung. Nagoya M. J., 3:25-43, 1955.

143. TAYLOR, G. W., and NATHANSON, I. T�9 Lymph Node Metastases, p. 10. London: Oxford University Press, 1942. TELHNG, M. The Earlier Recognition of Bronchial Neo- plasm, p. 63. D.M. Thesis, Oxford University, I942. THOREK, M. In: J. B. FIELD (ed.), Cancer: Diagnosis and Treatment , p. 228. London: Churchill, 1959. TomN, C. E. Human Pulmonic Lymphatics. Anat. Rec., 127:611-24, 1957. VIncHOW, R. Cellular Pathology, pp. 158, 184. London: Churchill, 1860. WALSHE, W. H. The Nature and Treatment of Cancer, p. 106. London: Taylor & Walton, 1846. WARREN, S. Neoplasms. In: W. A. D. ANDERSON (ed.), Pathology, p. 443. London: Kimpton, 1953. WATANABn, S. The Metastasizability of Tumor Cells. Cancer, 7:215-223, 1954. WEZLER, C. V. The Pathology of Primary Carcinoma of the Lung. Arch. Path., 7:478-519, 1929. WHITE, C. P. The Pathology of Growth: Tumours, pp. 166, 170. London: Constable, 1913. WILLIS, R. A. The Spread of Turnouts in the Human Body, pp. 196, 256, 294. London: Butterworth, 1952. . . . . . Pathology of Tumours, 3d ed., pp. 167-172, $75. London: Butterworth, 1960. WmDOM, J. O. Foundations of Inference in Natural Sci- ence, pp. 6, 7, 50. London: Methuen, 1952. WRmHT, G. H. VON. A Treatise on Induction and Prob- ability, pp. 86, 245. London: Routledge & Kegan Paul, 1951.

157. WnmnT, S. Applied Physiology, 9th ed., p. 25. London: Oxford University Press, 1952.

158. W~;, C. Necropsy Studies in 16 Cases of Bronchogenic Cancer Treated by 2 Million Volt Roentgen Ray. J. Phil- ippine M. A., 33:643-59, 1957.

159. YOUNG, J. M. The Thoracic Duct in Malignant Disease. Am. J. Path., 32: 253-59, 1956.

160. YOUNG, R. D. Bronchial Carcinoma as Seen in North Bedfordshire 1947 to 1956, p. 54.3/I.D. Thesis, Edinburgh University, 1958.

161�9 ZEIDMAN, I. Experimental Studies on the Spread of Can- cer in the Lymphat ic System. III . Tumor Emboli in Thoracic Duct. The Pathogenesis of Virchow's Node. Cancer Research, 15:719-21, 1955.

�9 Experimental Studies on the Spread of Cancer in the Lymphat ic System. IV. Retrograde Spread. Ibid., 1 9 : 1 1 1 4 - 1 7 , 1959.

163. . The Fate of the Circulating Tumor Cells. 1. Passage of Cells through Capillaries. Ibid., 21:38-39, 1961.



ii~ii �84 ~i~

iii~iiiii iiii~iiiii iii

!i I ~i ~ !~ i

~ i ~ii i �84

11 ~�84184184 %!~ ~i~ �84 ~ii? ~'!i i!~iiiiiii~iill ~IIIIIII~III~I~IIIII~I~

~ i i i~i~i �84 ~ii~ �84184184

~~i i'~' ! ~ '~""!iii!'i'i'~i"i',~iii!i'i'i ~'~i~iii~"i~ i~,~!ii

~"~'~'~!~!~iiiiiiii~'~ ~iiii~i~ii i~ ~iiiiiii~ ~iilil ~



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 Y- shaped chain of metastasized nodes, most of the members di- minishing 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.



1961;21:1077. Cancer Res Wilson I. B. Onuigbo

A ReviewPatterns of Metastasis in Lung Cancer:

Updated version

http://cancerres.aacrjournals.org/content/21/9/1077.citation

Access the most recent version of this article at:

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

[email protected] at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

Permissions

Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerres.aacrjournals.org/content/21/9/1077.citationTo request permission to re-use all or part of this article, use this link



http://cancerres.aacrjournals.org/cgi/alerts

mailto:[email protected]



cancer research · cancer research volume 21 october 1961 number 9 patterns of metastasis in lung...

Documents