Acta Medicn Scnndinnvicn. Vol. CLIV, fwc. I, 1956.

From the Department of Medicine (Head: E. Ask-Upmark) of the Royal Academic Hospital, Upsala, Sweden.

Metastatic Tuniours of the Brain and their Localization. BY

ERIK ASK-UPMARK, M. D.

(Submitted for publication November 3, 1955.)

Numerous studies have been devoted to the metastatic tumours of the central nervous system. Among the outstanding contributions during recent years, parti- cular mention may be made of the investigations of Lesse and Netsky (1954) and of Stortebecker (1954), where references are to be found. The present paper will attempt to assess whether the metastatic deposits are apt to present any predilec- tion with regard to their localization.

Material.

During the decade 1945-1954 there have been registered in our department some 190 verified cases of tumour of the brain, in 14 of whom the tumours were metas- tases. The material is thus of limited size but may nevertheless serve as a kernel for the discussion. All 14 cases were observed post mortem; in one case only had an attempt a t surgical removal been made as well. Out of 14 cases 8 were males, 6 females. The details are given in the following table.

It will be seen that the site of the primary tumour was in 5 cases the lung, in 5 cases the female genital system (3 breast, 1 uterus, 1 ovary) and in 4 cases various other organs (pancreas. intestinum tenui, Grawitz and melanosarcoma of unknown primary localization). In 5 instances the metastases in the brain were multiple, in 9 cases solitary. Supratentorial structures alone were affected in 10 cases, infratentorial structures alone in 2 cases, both supra- and infratentorial structures in 2 cases. The frontal and the occipital lobes were each represented by 6 cases, the cerebellum by 4 cases, the parietal lobe by 2 , the temporal lobe by 2 cases and the brain stem (pons) by one case. In one case the localization was the clau- strum.

2

M M IIL III M F F

E R I K ASK-UPMARK.

Table 1.

66 60 29 63 70 58 66

Case ~ Sex 1 Agc - 1

2

3 4 5 6 7 8 9

10 11 12 P I 54 _ _ 13 F SO 14 1 P 1 40

Primary tumour

Intcstinum jejuni

Mclanosarcoma orig. inc.

Pancreas Bronchial carcinoma

)) 0 I) ))

)) I)

Grawitz tumour Cervix uteri Ovary Bronchial carcinoma Carcinoma mamm.

D 1)

) s

Localization of metastases

Left frontal lobe, left occipital lobe, right tempora

Left occipital, right occipital, right pons, cercbellum.

Anterior part of claustrum. Right occipital. Left frontoparietal, left Sylvian fissure. Left frontal. Left frontal. Cerebellum (roof IVth vcntriclc). Right parietal. Right occipital. Left occipital. Left cerebellum. Left frontal, right cerebellum. Left parietal, right temporal.

lobe.

Comment and Discussion.

The following questions will be briefly discussed. 1. The frequency of metastatic brain tumours. 8. The sites of the primary tumours. 3. The occurrence of solitary metastases. 4. The localization of the metastases. 5. The clinical behaviour of the metastatic tumours.

ad (1). The frequency of metastatic tumours among a material of brain tumours depends essentially on the character of the clinical department concerned. On the one hand the neurosurgical clinics are apt to present rather few instances of metastatic tumours, owing to the selective principles directing the admission. A representative figure in such instances is reported by Stortebecker, who among 4,444 patients with verified brain tumours a t Serafimerlasarettet in Stockholm found metastatic tumours in 152 instances, i. e. 3.5 yo. At the other end of the scale are departments where perhaps the neurosurgical activity is less pronounced but where the patients are allowed to stay for a long time, frequently usque ad mortem. Such is the case with the material reported from Montefiore Hospital in the study of Lesse and Netsky where, owing to such selective factors, the metastatic deposits represented 58 % of all brain tumours. In an average hospital, covering various specialities, the frequency of metastatic tumours of the brain is apt to amount to some 10 %, as estimated from the necropsies (Dandy). Our own material is in fairly good correspondence with this figure, the frequency being about 7 yo.

ad (2). Bruilner (1936) held that about 1/3 of all metastatic brain tumours are delivered from bronchial carcinomas, another 1/3 from other carcinomas and about 113 from sarcomas (the frequency of sarcomas: carcinomas being given as

METASTATIC TUMOURS O F T H E BRAIN AND THEIR LOCALIZATION. 3

5 : 100; hypernephromas are included in the sarcomas). The various materials published are slightly different in this regard: with Stortebecker the percentage of hypernephromas is particularly high, with Globus no mammary carcinomas are included, with Krasting no bronchial carcinomas, and so on. Walther (1948) has made an attempt to estimate the affinity of metastases to the brain in various tumours, the ranking being as follows: melanosarcoma of the skin (76 yo), hyper- nephromas (14 yo), pulmonary carcinomas (9 %), mammary carcinomas (7 .5 %) etc. Brunner found metastases to the brain in 28 yo of necropsies in bronchial carcinomas, in 16 yo of hypernephromas and in 1.6 yo of other kinds of carcinomas, although he rightly emphasizes that the last mentioned figure does not do justice t o the mammary carcinomas, where the cerebral metastases are common. Chris- tensen (1949) points out that in the majority of all metastatic brain tumours the origin is to be found above the diaphragm; an exception is, of course, represented by the Grawitz tumours. The tendency of bronchial carcinomas to metastasize to the brain was also pointed out by Ask-Upmark (1932), in a paper where the general principles of hematogenous metastases were briefly outlined; they were later elaborated by Walther (1948). Brunner ha? i t that neuraxial metastases from bronchial carcinomas should be more commo 1 from carcinomas of the upper pulmonary lobe.

ad (3). How often is the metastatic tumour of the brain a solitary lesion and how often multiple? An attempt to summarize the observations in some of the materials published will be found in table 2.

Table 2.

A u t h o r

1 Krasting ......... 2 Kikuth ..........

1 3 Grant ........... ~ 4 Dunlop . . . . . . . . . . , 5 Elkington ........

6 Hare et al. . . . . . . 7 Minkowski . . . . . . . 8 Globus, Meltzer ...

1 9 Walther ......... 10 Willis . . . . . . . . . . .

1 11 Lesse, R’etsky .... i 12 Stortebecker . . . . . 13 Ask-Upmark . . . . .

In all

- Year

1906 1925 1926 1932 1935 1939 1941 1942 1948 1952

Multiple Solitary 1 ~ 1 1 cases

I I 98 47 1 18 13 1 13 13 I

13 7 1 9 2 1

20 14 1

62 41 1 7 1 5

30 I 20

18 : 11 I 73 I 39 25 I 84 I 1954

1954 1955 5 1 9 1 I -

1 450 1 246 I 696 I

It will be seen that in approximately one case out of three the metastatic deposit in the brain is represented by a solitary lesion. This is in conformity with the observations of Stortebecker but even if a material not neurosurgically selected is considered, such as that of Lesse and Netsky, the occurrence of solitary lesions is still as high as about one in four or one in five cases. Obviously this fact is of

4 ERIK ASK-UPMARK.

outstanding importance from the neurosurgical point of view, all the more since occasionally the solitary cerebral metastatic tumour may represent the only metastasis in the body. Such was the case in 20 out of 39 cases studied by Storte- becker, a proportion which perhaps may not be attained by all authors since so large a percentage of Stortebecker’s material was represented by hypernephromas. However, Lesse and Netsky disagree with the conclusion reached by Willis that metastases from the kidney are particularly liable to produce solitary foci in the nervous system. It should be mentioned, moreover, that cases with leptomeningitis carcinomatosa are not included in table 2; according to Lesse and Netsky such cases are not uncommon, a t least when carcinoma mammae is concerned.

ad (4). With regard to the distribution of metastatic growths in the brain it should be emphasized that the only pattern which can be accepted is one compatible with arterial embolic metastasis. Lymphatics do not exist in the central nervous system. On theoretical grounds the vertebral veins could oc- casionally be responsible along the lines indicated by Batson, although i t can readily be objected that a distribution by means of this route into the cranial cavity is against the direction of the blood stream, and, furthermore, that only meningeal, not parenchymatous localization is to be expected should this route exceptionally become used. From the point of view of the present study, however, the discussion may be confined to the arterial metastases.

The general trend is to consider the localization within the brain of the metastasis as related to the amount of blood presumed to pass the various structures. Thus Grant, quoting Krasting, maintains that ))the amount of blood passing through the cerebrum is relatively greater than through the cerebellum)). Willis has i t that ))the cerebrum is affected more frequently than the cerebellum, and the cerebellum than the brain stem, differences no doubt proportional to the relative bulks of these structures. Moreover, without giving needless details, I find that the various lobes of the cerebrum are affected with approximately equal fre- quency; there are no preferential areas of metastases,. With Christensen, 80 per cent of the metastases were supratentorial and with Stortebecker the corresponding figure was 78. Walther puts the matter thus: wUber den Sitz der auf dem Blut- wege entstandenen sekundaren Hirntumoren lasst sich keine Regel aufstellen. Es ist wohl so dass die in die Endaste des Art. carotis int. und der Art. vertebralis verschleppten Geschwulstthrombe dem Zufall folgend in den verschiedenen Regionen des Gehirns zu Ruhe kommen.)) Summarizing, the authors already quoted tend to consider the supratentorial structures as more often afflicted with metastases than the infratentorial structures, the reason presumably being the dominance of the carotid arteries in the blood supply of the brain.

On the other hand there are various details which have become the subject of divergent opinions. That the primary localization of an early metastasis is in the grey matter just at its junction with the white matter is of course fairly generally accepted (references to be had in the monograph of Willis). The view that me- tastases occur predominantly in the left hemisphere is held by several authors (Krasting, Brunner, Mc Lean and others; references cited by Ask-Upmark) although disputed by others (Willis, Stortebecker). My own material does not

METASTATIC TUMOURS OF THE BRAIN AND THEIR LOCALIZATION. 5

allow any conclusions in this regard: of strictly one-sided metastases there were 10 on the left, 9 on the right side. It is strikingly often observed that the occipi- tal lobe becomes the seat of metastases. Brunner ranked the various structures thus: occipital lobe, frontal lobe, cerebellum, parietal lobe, temporal lobe. Cour- ville had i t that 50 yo of all occipital tumours are metastatic. With Walther no less than 9 out of 30 cerebral metastases were located to the occipital lobe. In my own small material the occipital lobe was involved in 6 cases out of 14. On the other hand, Stortebecker, in his large and carefully analysed material failed to confirm this favoured localization, nor could Lesse and Netsky confirm it.

With regard, however, to the distribution of the metastases among the cere- brum, the cerebellum and the brain stem, it appears that insufficient consideration has been paid to the size of the structures involved, notwithstanding the thesis of Willis already quoted (p. 4). The weight of the various parts of the brain is as follows. Newborn: cerebrum 92.7 yo, cerebellum 6.5 yo, brain stem 1 . 4 %. 20 years of age: cerebrum 88 yo, cerebellum 10. i yo, brain stem 1.9 %.I

approximately 9 : 1 and the ratio of cerebrum to brain stem 45 : 1.

the following figures.

It will hence be seen that the ratio of the weight of cerebrum to that of cerebduwi i s

However, if cases with solitary metastases are analysed in this regard we ohtain

Tnble 3.

Krasting . . . . . . . . . . . . 36 Grant . . . . . . . . . . . . . . 13 Hare et al. ........ ' 14 ' 8

. . . . . . . . . . . . 30 ii ~ 14 Walther Lesse, Netsky.. ..... . I Minkowski . . . . . . . . . : 1 2

Ask-Upmark . . . . . . . . 9 7

3 3 5 3 ! 9 8 2 I

8

1

2 3

.-

._

-

Cases with multiple metastases are more difficult to evaluate, all the more since i t occasionally may occur that an author compiling material from the literature fails to mention his sources. Thus, one cannot exclude that some of the cases reported by Willis belong to materials already quoted by Krasting now almost 50 years ago. Because of that I have preferred to summarize only three materials: the material studied a t first-hand by Lesse and Netsky, the literature material of Willis, and my own small material.

1 I am indebted to Professor Gunnar Resed at our Department of Anatomy for the figurw just quoted.

6

Lesse and Xetsky . . . I 81 142 28 Willis . . . ........... 168 ~ 129 66

'In all 1 257 1 281 I 96

Ask-Upmark . . . . . . . . 1 5 10 I 2 I

ERIK ASK-UPMARK.

3 32 I

36

Evidently solitary metastases occur in tile cerebrum only 3 t i m e s as frequently as in the cerebellum and only 8 times as frequently as in the brain stem. If cases with multiple metastases are considered much the same proportions will be obtained.

The conclusion seems justified that the frequency of metastases in the infraten- torial structures is far higher than would be expected if the distribution were dependent mainly on the bulk of the structure involved. Even the figures of Stortebecker and of Christensen are not compatible with a distribution according to weight, and the observations of Brunner tend to lend further support to the view here taken.

The predilection of malignant metastases for the cerebellum seems to be a matter of practical importance. As to the explanation of this phenomenon the following possibilities have to be considered.

1. The predilection may be more apparent than real since a localization to the cerebellum is apt to interfere a t an early stage with the free circulation of fluid and hence to cause clinical symptoms. In the cerebrum, on the other hand, silent regions may easily become involved and if no symptoms from the nervous system have been reported during life the necropsy may perhaps overlook the brain. This explanation seems in itself sound enough and is well compatible with the high frequency of brain stem metastases, since a growth in the brain stem hardly can fail to produce symptoms during life. It cannot be excluded that this factor may be of some importance a t least as regards the frequency of brain stem metastases. Nevertheless, as a whole, this interpretation must be discarded owing to the ex- tremely careful analysis performed by Lesse and Netsky a t the Montefiore Hospital with its large neurologic and neoplastic divisions and its diligent post mortem examinations.

2. The predilection of the metastatic deposits for the cerebellum may tend to suggest that the vertebral arteries are more apt to carry metastases than the carotid artery. Such, however, cannot be the case. For one thing, the vertebral arteries are smaller than the carotid arteries and have yet to supply important supra- tentorial structures as well (occipital and part of temporal lobe). Secondly, to the best of my knowledge there is no evidence of any outstanding difference between the arterial blood supply of the cerebellum and that of the cerebrum. Thirdly, we know from the anatomy that the right vertebral artery has a recurrent course which may invite the introduction of a catheter from below, as performed

METASTATIC TIJMOURS O F THE BRAIN A N D THEIR LOCALIZATION. 7

so skilfully by Radner, but which by no means invites the transportation of em- bolies. It is instructive that the Wallenberg syndrome is so much more frequent on the left side than on the right. Whereas the cerebrum may get its supply from both large carotids (and the basilar artery), the cerebellum mainly depends on the left vertebral artery as far as blood-borne embolies are concerned. True, the involvement of the occipital lobe, considered as frequent by some authors at least, is suggestive of a mechanism involving the vertebral arteries. But 011 the one hand this involvement is denied by those authors who have covered the largest materials. On the other hand it cannot be sufficiently emphasized how important it is, when dealing with such questions, always to record the features of the circle of Willis. I t is, for example, not unusual that the posterior cerebral artery 011 one or both sides is derived not from the vertebral arteries, but by means of enlarged posterior communicating arteries from the carotid, an older type from the evolutionary aspect. In the future this matter will have to be observed in all cases of metastatic lesions to the brain. With regard to the vertebral artery there is still another point which may be discussed. The vertebral artery leaves the subclavia almost a t the same level as the internal mammary artery. Since i t has been rightly emphasized, by Christensen, that there is a tendency for the supradiaphragmatic tumours to metastasize to the brain it should not be forgotten that such tumours - breast carcinomas, bronchial carcinomas - are apt t o involve the lymph nodes accom- panying this artery. Provided that this involvement could penetrate into and obliterate this artery it would be easy to imagine how a growing neoplastic throm- bosis might dispatch embolic material to the artery in front of its origin, i . e. the vertebral artery. Such a sequence of events must, however, be considered as extremely unlikely since arteries are apt to escape neoplastic engagement even when passing through a compact mass of tumour. Nevertheless, an examination of the internal mammary artery in such instances seems easy to perform post mortem and may be suggested.

3. On theoretical grounds the recumbent position of the posterior cranial fossa - and of the occipital lobes -- in a person lying supine in his bed might invite a metastasis by means of the cerebrospinal fluid, originating perhaps from the chorioid plexus, to settle in the structures here concerned. In one of my own cases a cerebellar metastasis is reported as being located in the roof of the 4th ventricle, a position entirely compatible with such an explanation. Metastases t o the chorioid plexus have been observed repeatedly (for references see Willis), the artery of delivery obviously being the anterior chorioidal artery from the carotid. It seems relevant to pay attention henceforth to the chorioid plexus also, in order to elucidate the question here concerned. Nevertheless, since the majority of the cerebellar metastases are located in the parenchymatous tissue itself, it is hardly likely that the cerebrospinal fluid factor can be of any particular im- portance, except perhaps in some rare instances.

4. The remaining explanation seems to be that the cerebellar tissue for some unknown reason represents a more fertile soil for metastatic deposits. We do not know why the liver or the adrenals represent favoured organs where blood-borne metastases are concerned but we know that such is the case. With regard to the

8 ERIK ASK-UPMARK.

cerebellum there are two relationships which perhaps should be recalled. On the one hand the size of the cerebellum in the adult is proportionally larger than in newborns (vide supra): the cerebellum is growing more rapidly during adolescence than the cerebrum and it is the main site of primary brain tumours in children. On the other hand, Sir Russell Brain has called attention to the peculiar relation- ships between cancer elsewhere in the body, notably so in the ovary, and the appearance of degenerative cerebellar conditions with pronounced ataxia, which has nothing to do with metastases.

ad (5). The clinical behaviour of the metastatic tumours. The present material confirms the general view that there are no symptoms or

signs per se, characteristic for metastatic tumours. If a person has had a malig- nant tumour apt to metastasize and subsequently develops symptoms of a n intracranial tumour the conclusion will of course easily be derived that a secondary deposit is present. The following points should, however, be stressed.

1. The intracranial tumour may be primary and not metastatic. 2. If i t is a metastatic tumour it may be the only blood-borne metastasis in the

body or a t least solitary in the brain and accessible to neurosurgical intervention. 3. Even if i t should be a metastatatic tumour and other metastases should be

about, the situation is not entirely without hope and i t would be wrong to give up. A sudden onset, with headaches, mental confusion, Jacksonian fits and impair-

ment of visual ability as early symptoms, is often considered fairly common when metastatic brain tumours are present. The symptoms may become exaggerated by the frequently considerable collateral oedema. It has been emphasized by Lesse and Netsky that these patients are not apt to present extrapyramidal symp- toms in spite of the fact that the basal ganglia commonly are involved.

Summary and Conclusions.

1. A material of 14 metastatic brain tumours is reported, representing some 7 yo of all brain tumours observed in the clinic.

2. The organs of delivery were in accord with general experience: 5 bronchial carcinomas, 5 genital cancers (breast and gynaecological), 4 other tumours.

3. I n this material the metastatic tumour was solitary in 9 cases and multiple in 5. If other materials are added the frequency of solitary metastases is about one case out of three.

4. Attention is called to the predilection of the cerebellum (and the brain stem) for the localization of the metastatic deposits.

5. This matter is discussed and the conclusion reached that the cerebellum, for unknown reasons, may represent a more fertile soil for metastatic deposits. Additional factors are discussed.

6. Some related problems are briefly outlined and the clinical behaviour of the metastatic tumours is recalled.

METASTATIC TUMOURS OF THE BRAIN AND THEIR LOCALIZATION. 9

I wish to express my gratitude to my friends and colleagues in the Department of Pathology; Professor Robin FBhreeus, Professor Nils Gellerstedt, whose un- timely death we regret, Professor Gosta Hultquist and Ass. Professor Stig Ran- strom. They have put material a t my disposition and given me much helpful advice.

References.

Ask-Upmark, E.: 1) Acta Pathol. et Microbiol. Scand. 9: 239, 1932. - 2) Acta Med. Scand. 152: 433, 1955. - Brunner, W.: Ztschr. ges. Neurol. u. Psych. 154: 793, 1936. - Christensen, Erna: Acta Psych. et Neur. 24: 353, 1949. - Courville, C. B.: 1937, Quoted by Stortebecker 1954. - Dunlop, H. F.: Annals of Int. Med. 5: 2: 1274, 1932. - Elking- ton, J. St. C.: Proc. Roy. SOC. Med. 15, 1935. - Globus, J. F. and Meltzer: Ann. Int. Med. 48: 163, 1942. - Grant, F. C.: Annals of Surg. 84: 635, 1926. - Hare, C. and G. A. Schwartz: Arch. Int. Med. 64: 542, 1939. - Kikuth, W.: Virchows Arch. 255: 107,192.5. - Krasting, K.: Zschr. f. Krebsforsch. 4: 315, 1906. - Lesse, S. and M. G. Netsky: Arch. Neur. Psych. 72: 133, 1954. - Mc Lean, A. J.: Bomke u. Foersters Handbuch Neurol. 14: 131, 1936. - Minkowski, M.: Schweiz. Arch. f. Neur. u. Psych. 46: 41, 1940. - Stortebecker, T. P.: J. Neurosurg. 8: 185, 1951; J. Neurosurg. 11: 84, 1954. - Walther, H. E.: Krebsmetastasen. Benno Schwabe Co. Base1 1948. - Willis, R. A.: The Spread of Tumours in the Human Body, Butterworth Co., - Mosby Co. London - St. Louis 1952.