Cystic intracranial tumours

Journal of the Neurological Sciences, 1979, 44:77-85 © Elsevier/North-Holland Biomedical Press

77

CYSTIC I N T R A C R A N I A L T U M O U R S Cyst Fluid, Biochemical Changes and Computerised Tomographic Findings

P. PULLICINO1, E. J. THOMPSON 2, I. F. MOSELEY 1, E. ZILKHA1 and R. C. SHORTMAN e 1Lysholm Department of Neuroradiology and 2Department of Clinical Neurochemistry, The National Hospital for Nervous Diseases, Queen Square, London W.C. 1N 3BG (Great Britain)

(Received 8 May, 1979) (Accepted 21 June, 1979)

SUMMARY The concentrations of five biochemical substances were studied in cyst fluid from 49 cystic intracranial tumours and the findings were compared with the computerised tomographic (CT) scan and histological appearances of the tumours. The attenuation of the cyst wall on unenhanced CT was found to be related to cyst fluid alkaline phosphatase levels. Enhancement of the cyst wall with contrast medium was associated with higher levels of protein, cholesterol, alkaline phosphatase, phosphohexose isomerase (PHI) and lactate dehydrogenase (LDH) in the cyst fluid. Lesions of high grade malignancy had higher levels of protein, cholesterol, alkaline phosphatase, L D H and P H I than lesion of low grade malignancy and also higher levels of alkaline phosphatase, L D H and P H I than benign lesions. Oedema around a lesion was associated with increased malignancy.

INTRODUCTION The contents of a cyst within an intracranial tumour are thought to be determined largely by the cells lining the cyst and also by the immediate environment of the cyst cavity; it has been postulated that certain cysts are the results of a breakdown of tumour and brain tissue (Cumings 1944). The analysis of cyst fluid from tumours has been a routine procedure in this hospital since it was first shown that such measurements could be useful (Cumings 1950). Of the parameters that are presently measured, protein is taken as an index of breakdown of the blood-brain barrier, and alkaline phosphatase as a less specific measurement of cell activity. The enzymes L D H and P H I are thought to reflect the degree of destruction of nervous or tumour tissue and have been found to be elevated in the cerebrospinal fluid in central nervous system malignancy (Green et al. 1958; Thompson et al. 1959). Cholesterol may be derived

78 from tumour cells or may indicate breakdown of tumour or brain. It has been shown previously (Cumings 1944, 1950; Szliwowski and Cumings 1968; Ledinsky and St~p~n (1957) that measurements of the above parameters taken in conjunction can be used as a moderately accurate index of the degree of malignancy of cerebral tumours. It therefore seemed possible that the morphological appearances of a cystic tumour, especially the cyst wall as seen on the CT scan, might correlate with the cyst fluid contents and possibly shed light on the mechanism of cyst formation. Furthermore, since measurement of the extent of peritumoural oedema is possible on the CT scan, it appeared possible that one of the measured variables might reflect either the causative mechanism or other changes associated with peritumoural oedema. METHODS Forty-nine patients with cystic tumours were scanned preoperatively with an E M I CT 1000 or CT 1010 scanner, and 43 of these patients were rescanned after i.v. injection of iodinated contrast medium (sodium iothalamate). Scans were assessed for the following criteria: (a) Whether the tumour appeared cystic, multicystic or noncystic. (b) Cyst attenuation; this was measured and the tumours divided into groups

TABLE 1 HISTOLOGICAL GROUP Number of patients Contrast enhancement

Group I

Patients given contrast

Scans showing enhancement

22

22

12 (25 ~)

10

8

13 (26~)

11

49

43

24 (49 %) 20 4

Astrocytoma grade III, IV Secondary carcinoma Group H

Astrocytoma grade I, II Oligodendroglioma Haemangioblastoma Ependymoma Group 111

Craniopharyngioma Meningioma Pituitary chromophobe adenoma Epidermoid cyst Schwannoma Hamartoma Radiation necrosis Haemangioma Total numbers

36

79 with low, isodense or raised aaenuation. (c) The cyst attenuation values before and after contrast medium injection. (d) The maximum anteroposterior and transverse diameter of the cyst. (e) The attenuation, thickness and regularity of the tumour capsule and whether or not the capsule enhanced after intravenous contrast medium. (f) Peritumoural oedema; the cases were divided into 3 groups showing: O -- no oedema + = slight local oedema, ÷ - ~ = marked extensive oedema. All patients underwent craniotomy following the scan, at which the cystic nature of the lesion was confirmed. Cyst fluid was removed and its volume measured in most cases, and material was taken for histological examination. The cyst fluid was analysed with respect to the following substances: by the methods indicated. (a) Total protein (Greenberg 1929). (b) Total cholesterol (King 1946). (c) Alkaline phosphatasec (Alk. Pase) (King 1946). (d) Lactate dehydrogenase (LDH) (Wroblewski and Ladue 1955). (e) Phosphohexose isomerase (PHI) (Bodansky 1954). Tumour biopsy tissue removed at operation was classified into 3 malignancy grades: (Table 1) (1) Astrocytoma Kernohan grades III and IV (glioblastoma) and metastatic tumours; (2) Astrocytoma grades I and II, oligodendrogliomas and haemangioblastoma; (3) Benign tumours. The means of the 5 biochemical values were correlated with the CT scan features noted above and with the histological data. The latter were also correlated with the CT variables. RESULTS Of the 49 cystic tumours analysed, 43 were situated above the tentorium, and the remainder were infratentorial. As judged by the CT appearances, 35 (71 ~/o) of the lesions were obviously cystic and a further 9 (18 ~o) were multicystic. The remainder (11%) were not originally thought to be cystic although all proved to be so at operation. The mean attenuation coefficients of the cysts on CT scan, prior to contrast enhancement, varied between 8 and 39 EMI units, with the majority lying between 12 and 28 EMI units. There was no obvious correlation between these attenuation coefficients of the cysts before contrast enhancement, and the concentrations of the chemicals in the cyst fluid. The mean attenuation coefficients for the 3 histological groups (Table l) were: high malignancy group 17.38 EMI units, low malignancy group 17.5 EMI units, benign group 19.7 EMI units. One of the cysts, histologically a pinealoma, was isodense with the surrounding brain prior to contrast medium administration (Fig. 1) and a further cystic tumour (an epidermoid), was of increased attenuation (39 EMI units) (Fig. 2). A small amount of raised attenuation debris was present in the dependent part of 4 of the tumours before contrast enhancement but this finding was not reflected in a typical concentration of

80

Fig. 1. Isodense cystic pinealoma causing hydrocephalus. Contrast not given. Fig. 2. Hyperdense cystic epidermoid tumour. Contrast not given.

Fig. 3. A: astrocytoma prior to contrast administration; B: same case after i.v. contrast administration, revealing the cystic nature of the lesion.

81 TABLE 2 CYST FLUID CHEMISTRY VERSUS ENHANCEMENT OF CYST WALL (ALL TUMOUR TYPES)

Non-enhancing cyst wall (standard deviation) Enhancing cyst wall (standard deviation)

Protein (g/l)

Cholesterol Alkaline LDH mmol/1 phosphatase (IU/I) (tu/l)

PHI ([U/1)

27.8 (15.3) 39.5 (13.0)

2.6 (1.71) 3.3 (2.34)

62.2 (81.2)** 3,842 (7,746)

12.2 (5.4)* 26.2 (29)

53.6 (42.2)* 1,892 (4,626)

* P < 0.025; ** P < 0.01. any of the substances studied. Forty-three patients were given intravenous contrast medium and in 36 of these there was cyst wall enhancement (Table 1). Five of the lesions were not thought to be cystic on the unenhanced CT scan, but contrast enhancement of the capsule in two of these case cases suggested their cystic nature (Fig. 3). The average total attenuation o f the cyst contents did not increase after i.v. contrast in any case although layering of contrast medium in the dependent part of the cyst was seen in 5 cases, 4 of which were malignant lesions. The mean levels of all the chemical substances analysed were higher in those lesions whose capsule enhanced on the CT scan than in those which showed no enhancement, but those differences were significant only in the cases of alkaline phosphatase, L D H and PHI (Table 2). Seven of the multicystic tumours were malignant although they were not found to be markedly necrotic lesions at operation. There were 8 tumours which were noted by the pathologist to be necrotic and all were astrocytomas of grades III or IV. Nine tumours had a recognisable nodule in the cyst wall at CT, and these were equally divided between the 3 histological groups. The size of the cyst did not appear to be related either to the degree of malignancy or to any of the concentrations of the cyst fluid constituents. There was, however, general agreement between the size of the cyst and the volume of fluid removed at operation. Levels of cholesterol, alkaline phosphatase, L D H and PHI were found to be significantly higher in the high malignancy group than in the low malignancy group, but only in the case of L D H and PHI were the mean levels in the high malignancy group significantly above those of the benign tumours. There were no significant differences in protein concentration in the different histological groups nor was there a significant difference between low malignancy tumours and benign lesions in any of the concentrations of cyst fluid substances (Table 3). Three cases of haemangioblastoma were studied and showed mean values of the chemical constituents mostly well below those for all the 3 main histological groups (Table 3). None of the average values of the chemicals studied in the 4 cystic secondary

82 carcinoma lesions differed significantly from the values obtained from the astrocytomas grades III and IV. The mean of the cholesterol values (4.89 mmol/1) from the 6 cases of cystic craniopharyngioma was not significantly higher than that of the other benign lesions. On comparing the attenuation levels of the cyst wall, as seen on CT scan, with the concentrations of the chemical constituents of the cysts, it was found that apart from the alkaline phosphatase levels there were no significant correlations. With alkaline phosphatase, cysts with high attenuation walls were found to have lower levels of this substance (mean value = 13.61 U/I) as compared with the mean values found in cyst walls of either low or mixed attenuation. The mean alkaline phosphatase levels for these were 351 U/1 and 33.16 U/I, respectively. These differences in alkaline phosphatase levels are significant (P < 0.02 and P < 0.05, respectively). The thickness of the cyst capsule as seen on CT scan was also compared with the concentrations of the cyst chemicals, but no significant correlations resulted. Mean cyst levels of L D H were higher in lesions with marked peritumoural oedema (2635 IU/I, SD 5806) than in lesions with slight oedema (2349 IU/I, SD 5196) and lesions with slight oedema had higher mean values of L D H than lesions with no oedema (750 1U/l, SD 995). Mean cyst levels of PHI were also higher in the marked (3982 IU/1, SD 7332) and slight (5557 IU/1, SD 10566) oedema groups than in the group without oedema (1127 1U/l, SD 953). None of these differences however reached statistical significance. The presence of a cyst in a tumour of high grade malignancy was associated with more peritumoural oedema than was seen with the less malignant (P < 0.01) or benign (P < 0.001) lesions. The only benign lesion with marked peritumoural TABLE 3 CYST F L U I D CHEMISTRY VERSUS M A L I G N A N C Y Histological group

Protein (g/l)

Cholesterol mmol/1

Alkaline phosphatase

LDH (IU/I)

PHI (IU/1)

(tu/l) I Astrocytoma grade III and IV, secondary carcinoma (standard deviation) Significance (I and II) I1 Astrocytoma grade I and II, oligodendroglioma, haemangioblastoma, ependymoma (standard deviation) Significance (II and III) III Benign lesions (standard deviation) Significance (I and iii) Haemangioblastoma (3 cases)

38.5 (9.9) NS 32.7

3.2

31.8

5358.4

(1.11)

(33.5)

(5490)

P -- 0.01

P < 0.02

P = 0.025 P < 0.05

2.0

11.3

(13.5)

(.1.38)

(11.9)

NS

NS

NS

50.7 (32.4)

4.6 (4.8)

20.5 (13.7)

NS

NS

NS

37.4

2890.8

1.54

4.6

214.8

(389) NS

(9181)

778.1

(1851) NS

307.4 (729)

390.3 (516)

P < 0.05

P < 0.025

26

30.8

83 TABLE 4 CAPSULE THICKNESS AND IRREGULARITY AGAINST HISTOLOGICAL GROUPS Histological group

Capsular width thin thick

Capsular regularity regular irregular

I High malignancy II Low malignancy 1I[ Benign

37% 80~ 78%"

14~ 40 °/ 67- /o~o

63%* 20~* 22%

86%** 60% o ~,,, 33/,

m

* I and lI 0.1 0.05; ** I and III < 0.025; other differences not significant.

oedema was a case of radiation necrosis. Turnouts of high grade malignancy showed enhancement of their walls on postcontrast CT scans in all 22 cases. This incedence was significantly higher than the numbers of benign lesions which showed enhancement (P < 0.005) (Table 1). In addition 86 ~ of highly malignant cysts had irregular capsules on CT and 63 o / h a d thick capsules in contradistinction to the less malignant or benign lesions which tended to have thin regular capsules (Table 4). DISCUSSION

Cysts in intracranial tumours may be divided into two general types; firstly, those which are lined by epithelium, as in some benign tumours, (e.g. craniopharyngioma) (Calvo 1971a); and secondly those rapidly growing tumours in which a cystic space (or pseudocyst) appears as a result of a haemorrhage or necrosis. Our cases followed this pattern in that the benign lesions tended to have thin regular capsules and the more malignant lesions tended to have thick irregular capsules and to be multicystic. The contents of the first type of cyst appear to be produced by the cells lining the cyst whereas the contents of the second type will depend on the relative contributions of transudation of fluid from the bloodstream and breakdown of the lining cells (Cumings 1950). The concentrations of the constituents of the fluid in this type of cyst therefore depend on these relative contributions. The normal blood levels of L D H and PHI are too low to affect the cyst concentrations, except by dilution. The levels of" protein, cholesterol and alkaline phosphatase may, however, be increased by serum transudation, as the levels of these substances usually found in cysts are below the normal blood levels. We have found that tumours of higher malignancy enhance after injection of sodium iothalamate contrast medium more often than less malignant tumours, confirming previous reports (Claveria et al. 1976; Steinhoff and Aviles 1976a). Sodium iothalamate is a compound of molecular weight 635.9 which is not protein-bound and is readily excreted through the kidneys (Cattell 1970) and does not cross the blood-brain barrier in significant quantities in normal brain (Phelps et al. 1973; Zilkha et al. 1976). In many pathological states marked by contrast enhancement of the lesion

84 this is due to an extravascular component (Gado et al. 1975) presumably as a result of increased permeability of the blood vessels. It appears therefore that sodium iothalamate acts as a marker of increased permeability and that this is seen more often in lesions which are of high malignancy, where there may be frank leakage of the contrast medium into the cavity of a cystic tumour. Furthermore, the free leakage of contrast medium into the cyst and pericystic areas from the blood in these malignant tumours may indicate the mode in which such cysts enlarge once they are formed, supporting the suggestions of Cumings (1950). Previous investigators (Cumings 1950; Szliwowski and Cumings 1961 ; Ledinsky and ~t~p~n 1957) measured the concentrations of several different constituents in fluid aspirated from cystic tumours, in an attempt to determine the degree of transudation from the bloodstream as well as the origin of the cyst fluid contents. There has also been some success at predicting the degree of malignancy of a lesion from the cyst fluid contents (Szliwowski and Cumings 1961). Our results (Table 3) generally support their findings although we have not found protein levels to be of diagnostic significance and we have not been able to differentiate low grade malignant lesions from benign tumours by this method. It is of some interest, although not altogether surprising, to find that cysts which show enhancement on post-contrast CT scans have higher levels of alkaline phosphatase, L D H and PHI; cysts with walls of low or mixed attenuation on CT also tend to show higher levels of alkaline phosphatase. These findings are thought to indicate that in the region of the cyst wall abnormal rapidly multiplying cells necrose and leak their enzymes into the cyst cavity. The areas of necrosis in the cyst wall region may in turn lead to increased permeability of the glomerular capillary formations known to be present in these areas (Calvo 1971b), possibly by loss of local support, which could then be followed by increased permeability to contrast medium. Our finding that there was significantly more oedema associated with cystic tumours of high malignancy agrees in general with previous reports (Grumme et al. 1976; Steinhoff and Aviles 1976b; Claveria et al. 1977). Although the correlation between the extent of oedema and the mean L D H and PHI levels did not reach significance this might have been due to insufficient numbers. We have also confirmed that on CT scan cystic lesions may appear either isodense or even hyperdense with respect to normal brain. Our one case (Fig. 2) of a cyst of raised attenuation on CT had an unusually high cholesterol level of 14.2 mmol/1, but the cholesterol levels in the cystic craniopharyngiomas in the present series bear no apparent relationship to their CT attenuation levels, and the cause of this high attenuation remains unknown. Similarly, Isherwood et al. (1977) were unable to correlate the hyperdensity of colloid cysts shown on CT scans with any of the chemical constituents of the lesions and concluded that hyperdensity was probably due to a high electron density of the constituents. These observations thus demonstrate that the distrubance of the blood-brain barrier in the wall of a cystic malignant tumour, as evidenced by contrast enhancement on the CT scan, is related to the levels of at least 3 enzymes in the cyst fluid. More generally, the usefulness of combining CT observations (including behaviour with

85 c o n t r a s t m e d i u m ) w i t h b i o c h e m i c a l f i n d i n g s is r e a d i l y a p p a r e n t , as it offers a m e t h o d of comparing ante-mortem biochemical, pathophysiological and morphological data.

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