Neuro-radiology
Neuroradiology (1992) 34:463-469
DiagnosticNeuroradiology
9 Springer-Verl ag 1992
Magnetic resonance imaging and histopathology of cerebral gliomas M.Watanabe, R. Tanaka, and N.Takeda Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan Received: 8 February 1991
Summary. The correlation of magnetic resonance imaging (MRI) with histopathological findings was analysed in 26 patients with untreated cerebral gliomas. In low-grade gliomas, T2-weighted images demonstrated relatively homogeneous high-intensity lesions involving both the grey and the white matter. In high-grade gliomas, especially grade IV, T2-weighted images demonstrated prominent heterogeneity in signal intensity, which consisted of a hyperintense "core", less hyperintense or normal intensity "rim" and surrounding finger-like areas of high intensity. M a r k e d and irregular contrast enhancement was evident in all but one case of these high-grade gliomas in which gadolinium-DTPA was used. Histological examination revealed t u m o u r cells extending as far as the borders of the high-intensity areas shown on T2-weighted images in both high- and low-grade gliomas, but in 5 of 8 low-grade and 4 of 18 high-grade gliomas, isolated turnout cells extended beyond the hyperintense areas shown on T2-weighted images. Key words: Cerebral glioma - Histopathology- Magnetic resonance imaging - G a d o l i n i u m - D T P A
The sensitivity of magnetic resonance imaging (MRI) in the examination of intracranial tumours has b e e n widely discussed [1-8]. A n u m b e r of groups have assessed the relative effectiveness of CT and M R I for the assessment of histological grading and tumour extent [4, 6, 8-15]. Burger et al. [16] presented evidence that the bulk of neoplastic tissue is within the confines of the contrast-enhancing areas on CT and in the peritumoral areas of low density, but they could not infer the distribution of tumour cells from CT images, since the peritumoral areas could over- or underestimate the extent of the lesion. The degree of correlation between M R I and histological findings has not been sufficiently clarified, nor is it clear whether M R I can discriminate between parenchymal infiltration by tumour cells and o e d e m a t o u s p a r e n c h y m a without t u m o u r cells [14]. The purpose of this investigation was to determine whether there is a correlation between M R I and histo-
pathological findings and to explore whether M R I could enable correct determination the grading of cerebral gliomas and define the histological limits of tumour cell invasion in untreated cerebral gliomas.
Materials and methods Twenty-six patients (15 males and 11 females) with supratentorial gliomas, 8 low-grade (Kernohan grades I-II) and 18 high-grade (grades III-IV), were selected for this study. Each case is summarized in Table 1. Only 3 patients received preoperative radiotherapy at a dose of 20 Gy; the others were untreated at the time of the study. The interval between CF and surgery was 2~50 days (average: low-grade 16.8 days, high-grade 14.8 days). The interval between MRI and surgery was 0-56 days (average: low-grade 23.6 days, highgrade 13.5 days). The MR images were obtained on 1.5 T imager. Axial spin-echo images were obtained with two excitations, 4 mm contiguous slices, 256 x 256 acquisition matrix, and a 25-cm field of view (0.97 mm spatial resolution). The spin-echo sequences were TR/TE 600 ms/15 ms for Tl-weighted images (TlWI), and TR/TE 2000-3500 ms/80-90 ms for T2-weighted images (T2WI). A flow compensation program was used in all cases. Gadolinium (GdDTPA) was administered to 17 patients. Regions of interest (ROI) on CT were correlated with MRI by measuring their position relative to the bicommissural line. In 13 of the 26 patients, en-bloc removal or lobectomy was carried out, and axial sections were prepared for correlation with CT and MRI findings. In 2 cases, CT-guided stereotaxic needle biopsy was performed using the Komai CT-stereotaxic system, while in the others, the location of each specimen was determined intraoperatively based on its depth below the anatomically identified cortex. In addition, biopsies were obtained from the edge of the brain after resection to be correlated with postoperative C-'I"and MRI. Surgical specimens were examined by light microscopy with regard to cellularity, vascular proliferation, pleomorphism of tumour cell nuclei, degree of oedema or demyelination of the white matter, and other degenerative changes. Specimens were fixed in formalin in the operating room immediately after resection, in order to avoid tissue autolysis. Stains were obtained with the haematoxylin and eosin and the Kltiver-Barrera methods. Specimens were classiefied on the basis of histological features (histological ROI) as follows: (1) Tumour tissue proper." the tumor cells are crowded, unaccompanied by intervening normal brain parenchyma, with or without vascular proliferation or microcystic changes; (2) isolated tumour cells: the cells are not in contact
464 Table 1. C l i n i c a l s u m m a r y in 26 p a t i e n t s w i t h c e r e b r a l g l i o m a s Case
Age (y ears)
Sex
Histologic grade
Site of tumour
Interval CE on between surgery CT and CT/MRI
C E on MRI
Preoperative treatment
Surgery
Total removal of H I L on T 2 W I
Recurrence
Days 1.
44
F
Ia
L Frontal
6
3
-
+
-
Partial removal
No
-
2.
59
F
II a
L Temporal
36
14
+
+
-
E n bl oc removal
No
-
3.
49
M
II
R Central
8
35
-
-
-
E n bl oc removal
Yes
-
4.
27
F
II
R Frontal
8
30
-
-
-
Lobectomy
Yes
-
5.
60
6.
29
M
II
R Frontal
20
32
-
NE
I R 20 G y
Lobectomy
Yes
-
M
II
R Frontal
11
25
-
NE
-
Lobectomy
No
+
7.
28
F
II
L Central
35
29
-
-
-
Partial removal
No
-
8.
42
M
II
Bil. c e n t r u m s e m i o v a l ed
11
21
-
•
-
Stereobiopsy
No
-
9.
77
F
III
L Parietal
15
6
+
NE
-
Partial removal
No
-
10.
38
M
III
L Frontal
60
56
-
•
-
En bloc removal
Yes
+
11.
16
M
III
L Temporal
4
29
+
+
-
En bloc removal
Yes
-
12.
55
F
III
L Parietal
5
7
+
+
-
Partial removal
No
-
13.
26
M
III
R Frontald
2
8
+
+
-
Lobectomy
No
+
14.
75
F
III
R Basal ganglia
18
17
+
+
-
Stereobiopsy
Yes
+
15.
63
M
IV
L Temporal
2
9
+
NE
I R 20 G y
Lobectomy
No
+
16.
59
M
IV
L Temporoparietal
3
2
+
+
-
Partial removal
No
+
17.
38
M
IV
R Frontal
3
3
+
NE
-
Partial removal
No
+
18.
70
M
IV
R Occipitop a r i e t a l~
12
8
+
NE
I R 20 G y
Lobectomy
No
+
19.
57
F
IVb
R Occipital
5
5
+
NE
-
Lobectomy
-Yes
+
20.
78
F
IV
R Frontal
31
21
+
NE
-
Lobectomy
No
-
21.
39
F
IV
R Frontald
14
18
+
NE
-
Partial removal
No
+
22.
65
F
IV
L Temporal
15
29
+
+
-
Partial removal
No
+
23.
73
M
IV
L Temporoparietal
55
8
+
+
-
Partial removal
No
+
24.
70
F
IV
L Basal ganglia
13
7
+
+
-
Partial removal
No
+
25.
15
M
IV c
L Temporal
5
0
+
+
-
Partial removal
No
-
26.
73
M
IV
R Temporal
6
10
+
+
-
Lobectomy
No
+
C E , C o n t r a s t e n h a n c e m e n t ; N E , n o t e x a m i n e d ; I R , i r r a d i a t i o n ; ~ o l i g o a s t r o c y t o m a , b p a r t i a l l y c o m p o s e d of s a r c o m a t o u s c o m p o n e n t , c und i f f e r e n t i a t e d g l i o m a ; d h i g h i n t e n s i t y o n T 2 W I e x t e n d s to c o n t r a l a t e r a l h e m i s p h e r e
465 Table 2. Correlation of histological findings and MRI in 8 low-grade
gliomas Histological findings Tumour Isolated tumour cells Isolated tumour cells with oedema Cortical invasion Normal or oedematous brain
Tl-weighted Iso L 1 4 8 1 0 4 4 2
1 0
LL 0 0 1
T2-weighted Iso H 1 3 5 4 0 2
HH 1 0 3
0 0
2 2
0 0
3 0
Iso isointensity, L (LL) (markedly) low intensity, H (HH) (mar-
kedly) high intensity Table 3. Correlation of histological findings and MRI in 18 high-
grade gliomas Histological findings Tumour with VP Tumour with MCC Isolated tumour cells Isolated tumour cells with oedema Cortical invasion Coagulation necrosis Cystic cavity Normal or oedematous brain
Tl-weighted Iso L LL 13 4 0 0 4 1 11 3 0 0 9 1 8 0 0 4
4 5 0 2
0 1 3 0
T2-weighted Iso H 12 5 0 2 4 10 0 5 6 0 0 3
6 2 0 3
HH 0 3 0 5 0 4 3 0
VP vascular proliferation, M C C microcystic change, Iso isointensity, L (LL) (markedly) low intensity, H (HH) (markedly) high intensity
with each other and permeate the largely intact brain parenchyma, without apparent oedema or degenerative changes; (3) isolated tumour cells with oedema: parenchyma infiltrated by sparse tumour cells, with loosening of the white matter, pallor of myelin, and relative paucity of oligodendroglia; (4) corticalinvasion: the cortex is infiltrated by tumour cells; (5) coagulation necrosis; (6) cystic cavities; and (7)normal or oedematous brain tissue without tumour cells.
Results
In low-grade gliomas, T2-weighted images demonstrated homogeneous and relatively localized high intensity lesions (HIL) involving both grey and white matter on MRI. The H I L tended to be round or oval and their margins were smooth in 6 of the 8 cases. The tumour proper showed variable intensity on both T1 and T2WI (Table 2). There was no apparent correlation between cellularity and signal intensity. One oligo-astrocytoma (case 1) exhibited a marked H I L on T2WI which corresponded to the oligodendroglioma component of the tumour. On T2WI, change in signal intensity of the white matter infiltrated by tumour cells tended to depend not on the cellularity or atypism of those cells, but on the
severity of oedema, demyelination, and other degenerative changes. In addition, T2WI was the most sensitive sequence for assessment of cortical invasion by tumour cells (Table 3). In case 4 (Fig. 1), while T l W I showed only focal low intensity in the superior frontal gyrus, T2WI demonstrated involvement of both grey and white matter in the right frontal lobe, which was diffusely infiltrated by neoplastic cells. In case 8, in which a diffuse, irregular area of high intensity was evident in the white matter of both cerebral hemispheres on T2WI, CT-guided biopsy revealed tumour cells extending into both cerebral hemispheres. In another grade II tumour (case 6), with an irregular H I L in the white matter of the right frontal lobe, a lobectomy was carried out, but the posterior portion of the high intensity area on T2WI was not removed completely. This tumour recurred 7 months after radio- and chemotherapy. In 5 cases in which en-bloc removal or lobectomy was performed, histological examination revealed that neoplastic cells infiltrated the whole area of high intensity on T2WI. In low-grade gliomas, including these 5 cases, isolated tumour cells extended throughout the H I L on T2WI and, in addition, tumour cells had already infiltrated beyond it in 5 of the 8 cases (Table 4). Gd-DTPA enhancement was observed only in one oligoastrocytoma (case2) which showed moderately increased vascularity. Typical appearances for high-grade gliomas on T2WI, especially grade IV, consisted of a central "core" of hyperintensity surrounded by an isointense "rim" with peripheral finger-like hyperintensity, correlated with coagulation necrosis, viable tumour tissue and parenchyma infiltrated by isolated tumour cells with oedema respectively. This general signal heterogeneity, mass effect, and marked, heterogeneous Gd-DTPA enhancement, are the most important predictors with respect to tumour grading. Marked, heterogeneous Gd-DTPA enhancement was present in all high-grade gliomas with the exception of one grade III astrocytoma with numerous microcysts and slightly increased vascularity (Fig.2). Histological examination revealed that areas of enhancement were directly related to neovascularity in tumour tissue proper or dense tumour cell infiltration adjoining it. In high-grade gliomas, dense tumour tissue with vascular proliferation exhibited less hyperintensity or isointensity relative to the cortex, while the tumour proper, with numerous microcysts or micronecrotic loci, demonstrated high intensity on T2WI (Table 3). T2WI changes in signal intensities of the tumour-invading zone depended on the severity of oedema, demyelination, and other degenerative changes. There was no obvious correlation between signal intensity and cellularity or pleomorphism, proposed as important factors in malignancy of glial neoplasms. Including the 8 patients undergoing en-bloc removal or lobectomy, neoplastic cells were identified histologically in 44 of 47 areas of high intensity on T2WI. In case 21, a "finger" of high intensity on T2WI extended to the white matter of the contralateral frontal lobe. Open biopsy revealed that isolated tumour cells infiltrated the H I L of the contralateral side. In case 19 (grade IV), isolated tumour cells were identified in the white matter of the ipsilateral temporal lobe, approximately 6 cm from the edge of the
466
Fig.1. MRI: a TlWI (TR 600/TE 15 ms) b T2WI (3000/90) and c postoperative TlWI of case 4 (grade II). a shows only low intensity loci in the white matter of the right frontal lobe, while b shows a wedge-shaped high intensity lesion involving grey and white matter. Histological examination revealed a small area of solid tumour and diffuse infiltration of tumour ceils throughout the entire specimen (d). H & E xl00
contrast enhancement on CT, and approximately 2.5 cm from the margin of the H I L on T2WI (Fig. 4). Isolated tumour cells extended beyond the margin of the H I L on T2WI in 4 cases (Table 5). For example, despite one patient's (case 10) being treated by en-bloc removal encompassing the H I L on T2WI, the tumour recurred 8 months after the initial treatment. On the other hand, extensive resections and multiple biopsies revealed three "false positive" H I L on T2WI in terms of tumour invasion (cases 10, 15, 18); 2 of these had been treated preoperatively by radiation. Histological examination of these lesions revealed marked degenerative changes in the white matter or cortex. Coagulation necrosis and cystic cavities were uniformly depicted as marked prolongation of both T1 and T2, the latter tending to have much longer T1 values (Table 3).
Discussion
Fig.2. MRI: a TIWI (600/15) after administration of gadoliniumDTPA, b T2WI (3000/90) of case 10 (grade III). Enhancement is not evident. En-bloc removal of the area of high intensity the right superior frontal gyrus on T2WI was performed. Histological examination reveals that the central hypointensity in a corresponded to tumour with microcystic change (c). H & E x 100
Histological grading of cerebral gliomas is required to assess prognosis and to guide clinical management. Some workers have emphasized the use of MRI in predicting the grade of cerebral gliomas [4, 9, 10,13, 15]. Using serial stereotactic biopsies, Le Bas et al. [14] observed a linear relationship between T1 values and water content with the slope related to the tumour grade. Indeed, the relaxation time of various tissues may be directly proportional to the water content, or more precisely, to the free water content [17-20]. Although immature or invasive tissues generally have a higher water content than mature or noninvasive varieties [19, 21], the T1 and T2 values would not generally be proportional to tumour grade [6, 14, 19, 21, 22] but would depend on non-specific changes in tissue components. For example, diffuse vasogenic oedema and necrotic loci generally prolong the T1 and T2 of high-grade gliomas, but the most viable tumour site exhibits less hyperintensity or is isointense on T2WI. Just et al. [6] stated that glioblastomas have a shorter T1 than astrocytomas, oligodendrocytomas, or ependymomas. It is generally accepted that the restricted molecular motion of water caused by binding to membranes and macromotecules plays the principal role in shortening relaxation time [17, 18]. Since highly cellular tissues contain large amounts of membranes and macromolecules, the highly cellular component of cerebral glioma would exhibit less hyperintensity on T2WI [6, 9].
467
Fig.3. MRI: a Gd-TIWI (600/15) b T2WI (3000/90) of case 16 (grade IV). Irregular ring-enhancement in the left temporal lobe in a. The heterogeneous, less hyperintense or isointense lesion is surrounded by finger-like high intensity in b
On the other hand, it is well recognized that high-grade gliomas tend to undergo haemorrhage, and that haemoglobin metabolites, such as methaemoglobin, shorten T1 relaxation time. In this study, there was no case in which haemorrhage was confirmed histologically. Therefore, T1 or T2 values themselves are insufficient predictors of tumour grading [22]. We must also consider general MR features an important predictor of tumor grading, especially signal heterogeneity on T2WI including the central hyperintense "core", isointense "rim" and finger-like projections of high intensity. We conclude that general and intratumoral signal heterogeneity, with apparent mass effect, is most closely associated with increasing tumour grade and that tumour heterogeneity is demonstrated best on T2WI.
It is still uncertain whether the distribution of the tumour cells of cerebral gliomas can be inferred from MRI. Many authors have described the superior identification, localization and determination of tumour extent due to the greater sensitivity of T2WI than CT [4, 8, 11-15, 2023]. In most of our cases, the areas of hyperintensity revealed by T2WI were larger and more readily discernible than those defined as areas of hypodensity on CT. Recently, however, it has been recognized that changes in relaxation time on both T1 and T2WI are dependent on quite non-specific changes in tissue composition, especially the amount of free water and certain kinds of lipids [20, 22-24]. Le Baset al. [14] stated that T l W I enabled better discrimination between turnout and peritumoral tissues t h a n CT. However, T l W I information is insufficient to distinguish paucicellular involvement from peritumoral oedema. Furthermore, in agreement with our results, Kelly et al. [8] reported that isolated turnout cells of both high and low-grade gliomas usually extended at least as far as the prolongation of T2 on T2WI, if not beyond. Oedema or degeneration of white matter cause prolongation of relaxation times, expecially on T2WI [2, 20, 23, 25], but the extent of oedema fluid is not coterminous with the area of tumour cell infiltration [8], i. e. the most important histological change determining relaxation time is not the presence of tumour cells but the degree of oedema, loss of myelin, or other degenerative change. Therefore, it is difficult to depict the presence of tumour cells without secondary degenerative changes in the parenchyma. It is difficult to discriminate between parenchyma infiltrated by isolated tumour cells and parenchyma altered by oedema and degenerative changes, simply by using the pulse sequences we employed. We were therefore able to conFig.4. MRI: a T1WI (600/15) b T2WI (2800/90) c postoperative contrastenhanced CT of case 19 (grade IV). Extended right occipital lobectomy was performed. Histological examination reveals that the central hyperintense "core" and isointense "rim" correspond to coagulation necrosis and the viable partly sarcomatous component tumor layer (d), respectively.Isolated turnout cells infiltrate the oedematous white matter throughout the area of high intensity on T2WI (e). H & E • 100
468 Table 4. Identification of features in 8 low-grade gliomas on CT and
MRI Histological findings
Number of lesions seen on: T1W, T2W, T2W, CT not CT
T2W, not not TIW seen
Tumour
3
1
i
0
Isolated mmour cells Isolated tumour cells with oedema
0 4
3 1
3 0
5 0
Cortical invasion Normal or oedematous brain
1 0
2 0
2 0
2 2
T1WTl-weightedimaging, T2W T2-weighted imaging
blood-brain barrier, gadolinium p r e s u m a b l y does not enter the extravascular space and n o significant contrast enh a n c e m e n t is o b s e r v e d [26]. T h e precise separation of the z o n e i n v a d e d b y t u m o u r f r o m surrounding o e d e m a remains a drawback. Investigation of this p r o b l e m awaits the use of appropriate pulse sequences or advances in spectroscopy. Turski et al. [28] noted that sodium M R I has potential applications in the study of neoplastic disease, because an increase in imracellular sodium is a p p a r e n t l y necessary to initiate mitosis and maintain cellular proliferation. This potential can be fully realized only w h e n different sodium e n v i r o n m e n t s can be differentiated.
Acknowledgement. We are grateful to Dr. Hitoshi Takahashi (Department of Pathology, Brain Research Institute, Niigata University) for his support and advice.
Table5. Identification of features in 18 high-grade gliomas on CT
and MRI Histological findings
Number of lesions seen on: TlW, T2W, T2W, T2W, CT notCT notTlW
not seen
17
0
0
0
4
0
0
0
Isolated tumour cells Isolated tumour cells with oedema
4 10
6 0
7 0
4 0
Cortical invasion Coagulation necrosis
3 6
3 0
2 0
6 0
Cystic cavity Normal or oedematous brain
3 1
0 1
0 1
0 3
Tumour with VP Tumour with MCC
VPvascular proliferation, MCCmicrocystic change weighted imaging, T2W T2-weighted imaging
References
TIWT1-
elude that in u n t r e a t e d cerebral gliomas, H I L on T 2 W I should be at least considered as p a r e n c h y m a infiltrated by isolated t u m o u r cells and should b e c o v e r e d in the field of radiation therapy. W h e n we treat recurrent or previously treated cerebral gliomas, we must also be aware that r a d i o t h e r a p y or surgery m a y cause d e g e n e r a t i o n of the white m a t t e r leading to p r o l o n g a t i o n o f T2 values irrespective of the p r e s e n c e of t u m o u r cells [24], G a d o l i n i u m e n h a n c e d T l W I visualizes t u m o u r loci m o r e clearly than c o n t r a s t - e n h a n c e d C T because of its superior contrast resolution [1, 2, 26]. It is considered n o t only to reveal b l o o d - b r a i n barrier disruption but also to reflect the extent of invasion by t u m o u r in gliomas and metastatic brain t u m o u r s [27, 28]. T a n a k a et al. [25] reported the usefulness o f gadolinium e n h a n c e m e n t in studying vasogenic o e d e m a in an experimental cold-injury model. As long as " g a d o l i n i u m e n h a n c e m e n t " corresponds principally to disruption of the b l o o d - b r a i n barrier [23, 26, 29], however, it is impossible to discriminate b e t w e e n the z o n e invaded b y t u m o u r and o e d e m a t o u s p a r e n c h y m a n o t infiltrated by t u m o u r cells, We have shown that gadolinium e n h a n c e m e n t is directly related to neovascularity of the tumour. In low-grade gliomas with little or no alteration o f
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Neuroradiology (1992) 34:463-469
DiagnosticNeuroradiology
9 Springer-Verl ag 1992
Magnetic resonance imaging and histopathology of cerebral gliomas M.Watanabe, R. Tanaka, and N.Takeda Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan Received: 8 February 1991
Summary. The correlation of magnetic resonance imaging (MRI) with histopathological findings was analysed in 26 patients with untreated cerebral gliomas. In low-grade gliomas, T2-weighted images demonstrated relatively homogeneous high-intensity lesions involving both the grey and the white matter. In high-grade gliomas, especially grade IV, T2-weighted images demonstrated prominent heterogeneity in signal intensity, which consisted of a hyperintense "core", less hyperintense or normal intensity "rim" and surrounding finger-like areas of high intensity. M a r k e d and irregular contrast enhancement was evident in all but one case of these high-grade gliomas in which gadolinium-DTPA was used. Histological examination revealed t u m o u r cells extending as far as the borders of the high-intensity areas shown on T2-weighted images in both high- and low-grade gliomas, but in 5 of 8 low-grade and 4 of 18 high-grade gliomas, isolated turnout cells extended beyond the hyperintense areas shown on T2-weighted images. Key words: Cerebral glioma - Histopathology- Magnetic resonance imaging - G a d o l i n i u m - D T P A
The sensitivity of magnetic resonance imaging (MRI) in the examination of intracranial tumours has b e e n widely discussed [1-8]. A n u m b e r of groups have assessed the relative effectiveness of CT and M R I for the assessment of histological grading and tumour extent [4, 6, 8-15]. Burger et al. [16] presented evidence that the bulk of neoplastic tissue is within the confines of the contrast-enhancing areas on CT and in the peritumoral areas of low density, but they could not infer the distribution of tumour cells from CT images, since the peritumoral areas could over- or underestimate the extent of the lesion. The degree of correlation between M R I and histological findings has not been sufficiently clarified, nor is it clear whether M R I can discriminate between parenchymal infiltration by tumour cells and o e d e m a t o u s p a r e n c h y m a without t u m o u r cells [14]. The purpose of this investigation was to determine whether there is a correlation between M R I and histo-
pathological findings and to explore whether M R I could enable correct determination the grading of cerebral gliomas and define the histological limits of tumour cell invasion in untreated cerebral gliomas.
Materials and methods Twenty-six patients (15 males and 11 females) with supratentorial gliomas, 8 low-grade (Kernohan grades I-II) and 18 high-grade (grades III-IV), were selected for this study. Each case is summarized in Table 1. Only 3 patients received preoperative radiotherapy at a dose of 20 Gy; the others were untreated at the time of the study. The interval between CF and surgery was 2~50 days (average: low-grade 16.8 days, high-grade 14.8 days). The interval between MRI and surgery was 0-56 days (average: low-grade 23.6 days, highgrade 13.5 days). The MR images were obtained on 1.5 T imager. Axial spin-echo images were obtained with two excitations, 4 mm contiguous slices, 256 x 256 acquisition matrix, and a 25-cm field of view (0.97 mm spatial resolution). The spin-echo sequences were TR/TE 600 ms/15 ms for Tl-weighted images (TlWI), and TR/TE 2000-3500 ms/80-90 ms for T2-weighted images (T2WI). A flow compensation program was used in all cases. Gadolinium (GdDTPA) was administered to 17 patients. Regions of interest (ROI) on CT were correlated with MRI by measuring their position relative to the bicommissural line. In 13 of the 26 patients, en-bloc removal or lobectomy was carried out, and axial sections were prepared for correlation with CT and MRI findings. In 2 cases, CT-guided stereotaxic needle biopsy was performed using the Komai CT-stereotaxic system, while in the others, the location of each specimen was determined intraoperatively based on its depth below the anatomically identified cortex. In addition, biopsies were obtained from the edge of the brain after resection to be correlated with postoperative C-'I"and MRI. Surgical specimens were examined by light microscopy with regard to cellularity, vascular proliferation, pleomorphism of tumour cell nuclei, degree of oedema or demyelination of the white matter, and other degenerative changes. Specimens were fixed in formalin in the operating room immediately after resection, in order to avoid tissue autolysis. Stains were obtained with the haematoxylin and eosin and the Kltiver-Barrera methods. Specimens were classiefied on the basis of histological features (histological ROI) as follows: (1) Tumour tissue proper." the tumor cells are crowded, unaccompanied by intervening normal brain parenchyma, with or without vascular proliferation or microcystic changes; (2) isolated tumour cells: the cells are not in contact
464 Table 1. C l i n i c a l s u m m a r y in 26 p a t i e n t s w i t h c e r e b r a l g l i o m a s Case
Age (y ears)
Sex
Histologic grade
Site of tumour
Interval CE on between surgery CT and CT/MRI
C E on MRI
Preoperative treatment
Surgery
Total removal of H I L on T 2 W I
Recurrence
Days 1.
44
F
Ia
L Frontal
6
3
-
+
-
Partial removal
No
-
2.
59
F
II a
L Temporal
36
14
+
+
-
E n bl oc removal
No
-
3.
49
M
II
R Central
8
35
-
-
-
E n bl oc removal
Yes
-
4.
27
F
II
R Frontal
8
30
-
-
-
Lobectomy
Yes
-
5.
60
6.
29
M
II
R Frontal
20
32
-
NE
I R 20 G y
Lobectomy
Yes
-
M
II
R Frontal
11
25
-
NE
-
Lobectomy
No
+
7.
28
F
II
L Central
35
29
-
-
-
Partial removal
No
-
8.
42
M
II
Bil. c e n t r u m s e m i o v a l ed
11
21
-
•
-
Stereobiopsy
No
-
9.
77
F
III
L Parietal
15
6
+
NE
-
Partial removal
No
-
10.
38
M
III
L Frontal
60
56
-
•
-
En bloc removal
Yes
+
11.
16
M
III
L Temporal
4
29
+
+
-
En bloc removal
Yes
-
12.
55
F
III
L Parietal
5
7
+
+
-
Partial removal
No
-
13.
26
M
III
R Frontald
2
8
+
+
-
Lobectomy
No
+
14.
75
F
III
R Basal ganglia
18
17
+
+
-
Stereobiopsy
Yes
+
15.
63
M
IV
L Temporal
2
9
+
NE
I R 20 G y
Lobectomy
No
+
16.
59
M
IV
L Temporoparietal
3
2
+
+
-
Partial removal
No
+
17.
38
M
IV
R Frontal
3
3
+
NE
-
Partial removal
No
+
18.
70
M
IV
R Occipitop a r i e t a l~
12
8
+
NE
I R 20 G y
Lobectomy
No
+
19.
57
F
IVb
R Occipital
5
5
+
NE
-
Lobectomy
-Yes
+
20.
78
F
IV
R Frontal
31
21
+
NE
-
Lobectomy
No
-
21.
39
F
IV
R Frontald
14
18
+
NE
-
Partial removal
No
+
22.
65
F
IV
L Temporal
15
29
+
+
-
Partial removal
No
+
23.
73
M
IV
L Temporoparietal
55
8
+
+
-
Partial removal
No
+
24.
70
F
IV
L Basal ganglia
13
7
+
+
-
Partial removal
No
+
25.
15
M
IV c
L Temporal
5
0
+
+
-
Partial removal
No
-
26.
73
M
IV
R Temporal
6
10
+
+
-
Lobectomy
No
+
C E , C o n t r a s t e n h a n c e m e n t ; N E , n o t e x a m i n e d ; I R , i r r a d i a t i o n ; ~ o l i g o a s t r o c y t o m a , b p a r t i a l l y c o m p o s e d of s a r c o m a t o u s c o m p o n e n t , c und i f f e r e n t i a t e d g l i o m a ; d h i g h i n t e n s i t y o n T 2 W I e x t e n d s to c o n t r a l a t e r a l h e m i s p h e r e
465 Table 2. Correlation of histological findings and MRI in 8 low-grade
gliomas Histological findings Tumour Isolated tumour cells Isolated tumour cells with oedema Cortical invasion Normal or oedematous brain
Tl-weighted Iso L 1 4 8 1 0 4 4 2
1 0
LL 0 0 1
T2-weighted Iso H 1 3 5 4 0 2
HH 1 0 3
0 0
2 2
0 0
3 0
Iso isointensity, L (LL) (markedly) low intensity, H (HH) (mar-
kedly) high intensity Table 3. Correlation of histological findings and MRI in 18 high-
grade gliomas Histological findings Tumour with VP Tumour with MCC Isolated tumour cells Isolated tumour cells with oedema Cortical invasion Coagulation necrosis Cystic cavity Normal or oedematous brain
Tl-weighted Iso L LL 13 4 0 0 4 1 11 3 0 0 9 1 8 0 0 4
4 5 0 2
0 1 3 0
T2-weighted Iso H 12 5 0 2 4 10 0 5 6 0 0 3
6 2 0 3
HH 0 3 0 5 0 4 3 0
VP vascular proliferation, M C C microcystic change, Iso isointensity, L (LL) (markedly) low intensity, H (HH) (markedly) high intensity
with each other and permeate the largely intact brain parenchyma, without apparent oedema or degenerative changes; (3) isolated tumour cells with oedema: parenchyma infiltrated by sparse tumour cells, with loosening of the white matter, pallor of myelin, and relative paucity of oligodendroglia; (4) corticalinvasion: the cortex is infiltrated by tumour cells; (5) coagulation necrosis; (6) cystic cavities; and (7)normal or oedematous brain tissue without tumour cells.
Results
In low-grade gliomas, T2-weighted images demonstrated homogeneous and relatively localized high intensity lesions (HIL) involving both grey and white matter on MRI. The H I L tended to be round or oval and their margins were smooth in 6 of the 8 cases. The tumour proper showed variable intensity on both T1 and T2WI (Table 2). There was no apparent correlation between cellularity and signal intensity. One oligo-astrocytoma (case 1) exhibited a marked H I L on T2WI which corresponded to the oligodendroglioma component of the tumour. On T2WI, change in signal intensity of the white matter infiltrated by tumour cells tended to depend not on the cellularity or atypism of those cells, but on the
severity of oedema, demyelination, and other degenerative changes. In addition, T2WI was the most sensitive sequence for assessment of cortical invasion by tumour cells (Table 3). In case 4 (Fig. 1), while T l W I showed only focal low intensity in the superior frontal gyrus, T2WI demonstrated involvement of both grey and white matter in the right frontal lobe, which was diffusely infiltrated by neoplastic cells. In case 8, in which a diffuse, irregular area of high intensity was evident in the white matter of both cerebral hemispheres on T2WI, CT-guided biopsy revealed tumour cells extending into both cerebral hemispheres. In another grade II tumour (case 6), with an irregular H I L in the white matter of the right frontal lobe, a lobectomy was carried out, but the posterior portion of the high intensity area on T2WI was not removed completely. This tumour recurred 7 months after radio- and chemotherapy. In 5 cases in which en-bloc removal or lobectomy was performed, histological examination revealed that neoplastic cells infiltrated the whole area of high intensity on T2WI. In low-grade gliomas, including these 5 cases, isolated tumour cells extended throughout the H I L on T2WI and, in addition, tumour cells had already infiltrated beyond it in 5 of the 8 cases (Table 4). Gd-DTPA enhancement was observed only in one oligoastrocytoma (case2) which showed moderately increased vascularity. Typical appearances for high-grade gliomas on T2WI, especially grade IV, consisted of a central "core" of hyperintensity surrounded by an isointense "rim" with peripheral finger-like hyperintensity, correlated with coagulation necrosis, viable tumour tissue and parenchyma infiltrated by isolated tumour cells with oedema respectively. This general signal heterogeneity, mass effect, and marked, heterogeneous Gd-DTPA enhancement, are the most important predictors with respect to tumour grading. Marked, heterogeneous Gd-DTPA enhancement was present in all high-grade gliomas with the exception of one grade III astrocytoma with numerous microcysts and slightly increased vascularity (Fig.2). Histological examination revealed that areas of enhancement were directly related to neovascularity in tumour tissue proper or dense tumour cell infiltration adjoining it. In high-grade gliomas, dense tumour tissue with vascular proliferation exhibited less hyperintensity or isointensity relative to the cortex, while the tumour proper, with numerous microcysts or micronecrotic loci, demonstrated high intensity on T2WI (Table 3). T2WI changes in signal intensities of the tumour-invading zone depended on the severity of oedema, demyelination, and other degenerative changes. There was no obvious correlation between signal intensity and cellularity or pleomorphism, proposed as important factors in malignancy of glial neoplasms. Including the 8 patients undergoing en-bloc removal or lobectomy, neoplastic cells were identified histologically in 44 of 47 areas of high intensity on T2WI. In case 21, a "finger" of high intensity on T2WI extended to the white matter of the contralateral frontal lobe. Open biopsy revealed that isolated tumour cells infiltrated the H I L of the contralateral side. In case 19 (grade IV), isolated tumour cells were identified in the white matter of the ipsilateral temporal lobe, approximately 6 cm from the edge of the
466
Fig.1. MRI: a TlWI (TR 600/TE 15 ms) b T2WI (3000/90) and c postoperative TlWI of case 4 (grade II). a shows only low intensity loci in the white matter of the right frontal lobe, while b shows a wedge-shaped high intensity lesion involving grey and white matter. Histological examination revealed a small area of solid tumour and diffuse infiltration of tumour ceils throughout the entire specimen (d). H & E xl00
contrast enhancement on CT, and approximately 2.5 cm from the margin of the H I L on T2WI (Fig. 4). Isolated tumour cells extended beyond the margin of the H I L on T2WI in 4 cases (Table 5). For example, despite one patient's (case 10) being treated by en-bloc removal encompassing the H I L on T2WI, the tumour recurred 8 months after the initial treatment. On the other hand, extensive resections and multiple biopsies revealed three "false positive" H I L on T2WI in terms of tumour invasion (cases 10, 15, 18); 2 of these had been treated preoperatively by radiation. Histological examination of these lesions revealed marked degenerative changes in the white matter or cortex. Coagulation necrosis and cystic cavities were uniformly depicted as marked prolongation of both T1 and T2, the latter tending to have much longer T1 values (Table 3).
Discussion
Fig.2. MRI: a TIWI (600/15) after administration of gadoliniumDTPA, b T2WI (3000/90) of case 10 (grade III). Enhancement is not evident. En-bloc removal of the area of high intensity the right superior frontal gyrus on T2WI was performed. Histological examination reveals that the central hypointensity in a corresponded to tumour with microcystic change (c). H & E x 100
Histological grading of cerebral gliomas is required to assess prognosis and to guide clinical management. Some workers have emphasized the use of MRI in predicting the grade of cerebral gliomas [4, 9, 10,13, 15]. Using serial stereotactic biopsies, Le Bas et al. [14] observed a linear relationship between T1 values and water content with the slope related to the tumour grade. Indeed, the relaxation time of various tissues may be directly proportional to the water content, or more precisely, to the free water content [17-20]. Although immature or invasive tissues generally have a higher water content than mature or noninvasive varieties [19, 21], the T1 and T2 values would not generally be proportional to tumour grade [6, 14, 19, 21, 22] but would depend on non-specific changes in tissue components. For example, diffuse vasogenic oedema and necrotic loci generally prolong the T1 and T2 of high-grade gliomas, but the most viable tumour site exhibits less hyperintensity or is isointense on T2WI. Just et al. [6] stated that glioblastomas have a shorter T1 than astrocytomas, oligodendrocytomas, or ependymomas. It is generally accepted that the restricted molecular motion of water caused by binding to membranes and macromotecules plays the principal role in shortening relaxation time [17, 18]. Since highly cellular tissues contain large amounts of membranes and macromolecules, the highly cellular component of cerebral glioma would exhibit less hyperintensity on T2WI [6, 9].
467
Fig.3. MRI: a Gd-TIWI (600/15) b T2WI (3000/90) of case 16 (grade IV). Irregular ring-enhancement in the left temporal lobe in a. The heterogeneous, less hyperintense or isointense lesion is surrounded by finger-like high intensity in b
On the other hand, it is well recognized that high-grade gliomas tend to undergo haemorrhage, and that haemoglobin metabolites, such as methaemoglobin, shorten T1 relaxation time. In this study, there was no case in which haemorrhage was confirmed histologically. Therefore, T1 or T2 values themselves are insufficient predictors of tumour grading [22]. We must also consider general MR features an important predictor of tumor grading, especially signal heterogeneity on T2WI including the central hyperintense "core", isointense "rim" and finger-like projections of high intensity. We conclude that general and intratumoral signal heterogeneity, with apparent mass effect, is most closely associated with increasing tumour grade and that tumour heterogeneity is demonstrated best on T2WI.
It is still uncertain whether the distribution of the tumour cells of cerebral gliomas can be inferred from MRI. Many authors have described the superior identification, localization and determination of tumour extent due to the greater sensitivity of T2WI than CT [4, 8, 11-15, 2023]. In most of our cases, the areas of hyperintensity revealed by T2WI were larger and more readily discernible than those defined as areas of hypodensity on CT. Recently, however, it has been recognized that changes in relaxation time on both T1 and T2WI are dependent on quite non-specific changes in tissue composition, especially the amount of free water and certain kinds of lipids [20, 22-24]. Le Baset al. [14] stated that T l W I enabled better discrimination between turnout and peritumoral tissues t h a n CT. However, T l W I information is insufficient to distinguish paucicellular involvement from peritumoral oedema. Furthermore, in agreement with our results, Kelly et al. [8] reported that isolated turnout cells of both high and low-grade gliomas usually extended at least as far as the prolongation of T2 on T2WI, if not beyond. Oedema or degeneration of white matter cause prolongation of relaxation times, expecially on T2WI [2, 20, 23, 25], but the extent of oedema fluid is not coterminous with the area of tumour cell infiltration [8], i. e. the most important histological change determining relaxation time is not the presence of tumour cells but the degree of oedema, loss of myelin, or other degenerative change. Therefore, it is difficult to depict the presence of tumour cells without secondary degenerative changes in the parenchyma. It is difficult to discriminate between parenchyma infiltrated by isolated tumour cells and parenchyma altered by oedema and degenerative changes, simply by using the pulse sequences we employed. We were therefore able to conFig.4. MRI: a T1WI (600/15) b T2WI (2800/90) c postoperative contrastenhanced CT of case 19 (grade IV). Extended right occipital lobectomy was performed. Histological examination reveals that the central hyperintense "core" and isointense "rim" correspond to coagulation necrosis and the viable partly sarcomatous component tumor layer (d), respectively.Isolated turnout cells infiltrate the oedematous white matter throughout the area of high intensity on T2WI (e). H & E • 100
468 Table 4. Identification of features in 8 low-grade gliomas on CT and
MRI Histological findings
Number of lesions seen on: T1W, T2W, T2W, CT not CT
T2W, not not TIW seen
Tumour
3
1
i
0
Isolated mmour cells Isolated tumour cells with oedema
0 4
3 1
3 0
5 0
Cortical invasion Normal or oedematous brain
1 0
2 0
2 0
2 2
T1WTl-weightedimaging, T2W T2-weighted imaging
blood-brain barrier, gadolinium p r e s u m a b l y does not enter the extravascular space and n o significant contrast enh a n c e m e n t is o b s e r v e d [26]. T h e precise separation of the z o n e i n v a d e d b y t u m o u r f r o m surrounding o e d e m a remains a drawback. Investigation of this p r o b l e m awaits the use of appropriate pulse sequences or advances in spectroscopy. Turski et al. [28] noted that sodium M R I has potential applications in the study of neoplastic disease, because an increase in imracellular sodium is a p p a r e n t l y necessary to initiate mitosis and maintain cellular proliferation. This potential can be fully realized only w h e n different sodium e n v i r o n m e n t s can be differentiated.
Acknowledgement. We are grateful to Dr. Hitoshi Takahashi (Department of Pathology, Brain Research Institute, Niigata University) for his support and advice.
Table5. Identification of features in 18 high-grade gliomas on CT
and MRI Histological findings
Number of lesions seen on: TlW, T2W, T2W, T2W, CT notCT notTlW
not seen
17
0
0
0
4
0
0
0
Isolated tumour cells Isolated tumour cells with oedema
4 10
6 0
7 0
4 0
Cortical invasion Coagulation necrosis
3 6
3 0
2 0
6 0
Cystic cavity Normal or oedematous brain
3 1
0 1
0 1
0 3
Tumour with VP Tumour with MCC
VPvascular proliferation, MCCmicrocystic change weighted imaging, T2W T2-weighted imaging
References
TIWT1-
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