Contrast Enhanced CT Scan and Radionuclide Brain Scan in

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1 Contrast Enhanced CT Scan and Radionuclide Brain Scan in Supratentorial Gliomas ALAN A. BUTLER, 2 ANTHONY M. PASSALAQUA, ALEX BERENSTEIN, AND IRVIN I. KRICHEFF Downloaded from by on 1/2/18 from IP address Copyright ARRS. For personal use only; all rights reserved The preoperative contrast enhanced CT and radionuclide brain scans of 6 patients with surgically verified supratentorial astrocytomas were evaluated and compared. Resufts indicated that the mechanisms of contrast enhancement and radionuclide uptake are Identical In the detection of supratentonal gilomas. These diagnostic methods apparently mirror the integrity of the blood-brain barrier and therefore can be useful in assessing the degree of malignancy of supratentorial gilomas. However, lesions with an intact blood-brain barrier will be missed with radionucllde Imaging. These parenchymal abnormalities and/or the associated mass effect will be dotected with contrast enhanced computed tomography. These findings firmly establish contrast enhanced CT as the primary Investigative tool in the suspected brain tumor. The first description of the clinical results of computed tomography (CT) by Ambrose [1] included a brief discussion of the possibility of enhancing the density of brain lesions by intravenously injecting contrast material. He ascribed the accumulation of the contrast material to a breakdown in the blood-brain barrier. He also mentioned the retention of contrast enhancement at 2 hr in a meningioma. Ambrose and Paxton [2, 3] alluded to possible mechanisms in the extravascular accumulation of contrast material and emphasized that the extent of the abnormal vascularity was one of the major factors responsible for the degree of enhancement. New et al. [4] mentioned that contrast enhancement was dependent on the vascularization of the lesion. They suggested that delayed enhancement was secondary to the residual blood pool concentration of iodine. Ethier et al. [5] also assumed that contrast enhancement was secondary to iodinated contrast material in the vascular pool and referred to tissue density enhancement as computerized angiotomography. Hatam et al. [6] presented the first thorough clinical investigation of contrast enhancement response with time. They concluded that, in part, contrast enhancement was secondary to the extravascular accumulation of contrast material through a defective blood-brain barrier. Gado et ai. [7] determined the tissue-blood ratio of enhancement in pathologic conditions and concluded that there was an extravascular component in contrast enhancement. They emphasized the similarity in the mechanism of contrast enhancement and the abnormal accumulation of radioisotopes in brain lesions. The positive radionuclide brain scan in brain tumors is in great measure secondary to the extravascular accumulation of the radioactive tracer via a local breakdown in the blood-brain barrier [8-13]. There is debate regarding the extent of the contribution of intravascular radioactive tracer in the positive static radionuclide scan, but vascularity does play some role if only to increase the capillary surface area for the extravasation of the diagnostic agent. This investigation evaluates and compares the apparent parallel mechanisms of contrast enhancement and radionuclide uptake in a large group of homogeneous supratentorial gliomas and examines the roles of these diagnostic methods in assessing the degree of malignancy of these tumors. Subjects and Methods All patients with histologically confirmed supratentorial astrocytomas seen at the New York University Medical Center over 3 years were collected from the neuropathology files. Those patients who had high resolution preoperative pre- and postcontrast enhancement CT and radionuclide brain scans within a maximal interval of 4 weeks were included in the evaluation. Sixty patients met these criteria and formed the basis for this study. Tumors were graded histologically according to the criteria of Kernohan et al. [14]. Grades I and II astrocytomas were designated low grade and grades Ill and IV were designated high grade. Grades III and IV correspond to the glioblastoma multiforme with a low and high degree of malignancy respectively [14]. The 6 cases included 46 high grade astrocytomas and 14 lesions of low grade malignancy (table 1). The median age of the patients with low grade gliomas was 38 years and those of high grade malignancy was 58 years. The patients records were reviewed and particular note was made as to whether or not the patients were receiving steroids at the time of the CT or radionuclide brain scans. CT scans were routinely performed with a 13 mm collimator and scan pairs were usually obtained from the base of the skull to the vertex. The contrast enhanced scan was performed immediately after the noncontrast study. Meglumine diatrizoate 3% (2 ml) was infused over a 5-7 mm period. Scanning was started and an additional 1 ml was infused slowly throughout the scan series. Children received 4 mi/kg of body weight to a maximal dose of 2 ml. The pre- and postcontrast CT scans were evaluated by direct viewing of the cathode ray tube, photographs, and the 16 x 16 digital print out. When contrast enhancement was observed, a central region of enhancement of at least 25 picture elements was identified and a mean of this region of interest was calculated. An attempt was made to locate the identical Received January 24, 178; accepted after revision December 12, 178. This work was supported in part by grant no. NOl CM 675 from the National Brain Tumor Study Group. I Department of Radiology, New York University Medical Center, New York, New York Present address: Department of Radiology, Hartford Hospital, Hartford, Connecticut Address reprint requests to A. A. Butler. AJR 132:67-611, April17 17 American Roentgen Ray Society X/7/ $.

2 68 BUTLER ET AL. AJR:132, April 17 Downloaded from by on 1/2/18 from IP address Copyright ARRS. For personal use only; all rights reserved TABLE 1 Summary of Supratentorial Gliomas (grades 1 and2) (grades 3 and4) No.cases,... Sex: Male...,,..,...,,... 3 Female Median age (range) (3-6) 58 (31-78) Location: Frontal,..., Parietal,,..,.,,..., Occipital Temporal... 2 Precontrast CT appearance: Hyperdense Isodense...,,...,...,..,. 1 2 Hypodense region of interest on the noncontrast scan, and this area was evaluated in a similar manner. The mean of the region of interest on the contrast scan was divided by the mean of the region of interest on the noncontrast scan. The resultant factor was designated the index of contrast enhancement. The intensity of contrast enhancement was evaluated according to the following scale: slight enhancement was equivalent to an index between 1.1 and 1.5; moderate enhancement represented an index factor of 1.6 to 2.4; marked enhancement indicated an index of 2.5 or greater. Static radionuclide brain scans were obtained with the gamma camera 1 hr after intravenous administration of 15 mci of Tc pertechnetate. All patients received 4 mg of KCLO4 prior to the scans. Images were obtained in the anterior, posterior, Towne, and right and left lateral projections. On rare occasions, vertex views were obtained. The radionuclide brain scans were evaluated by one of us (A. P.) without prior knowledge of the results of the CT scan or the histologic type or grade of the glioma. The intensity of the positive scans was graded from slight to marked by visually comparing the activity in the tumor with that of the superior sagittal sinus. Slight uptake was faintly seen; moderate uptake was well defined, but of less intensity than the superior sagittal sinus. Marked radionuclide uptake represented an intensity equal to or greater than the superior sagittal sinus. Selective internal carotid cerebral angiograms were available in all 14 cases of the low grade astrocytomas and 4 of 46 cases of the high grade (Kernohan s III and IV) gliomas. The angiograms were divided into two groups: nonvascular and vascular. The criteria used for inclusion in the vascular category was the presence of either a capillary blush, neovascularity, or early filling veins. Results The results are summarized in tables 1-4. There were 14 astrocytomas of low grade malignancy. In nine of these cases there was no contrast enhancement and the radionuclide brain scans were falsely negative (table 2). The majority of nonenhancing low grade astrocytomas were seen as parenchymal lucencies on the pre- and postcontrast CT scan. In addition to the parenchymal abnormalities, the associated mass effect and ventricular size were clearly demonstrated. There was contrast en- TABLE 2 Contrast Enhanced CT Compared with Radionuclide Brain Scanning TABLE 4 Angiographic Findings in the Series of (grades3 and 4) Contrast enhancement: Positive 5 46 Negative... False negative Aadionuclide scanning: Positive Negative False negative TABLE Comparison of Intensity of Contrast Enhanced CT Scan and Aadionuclide Brain Scan Contrast enhancement: Negative... Slight Moderate.,,... Marked Aadionuclide Negative Slight Moderate Marked scanning: No. % 5 (grades 3 and 4) (grades 3 and 4) Vascular Avascular Lesion missed hancement in five low grade astrocytomas. In each case the intensity of uptake was slight. In four of these tumors the intensity of radionuclide uptake was moderate and in the other case the intensity of uptake was slight. There was contrast enhancement in all 46 of the high grade gliomas (Kernohan s grade Ill and IV). The index of contrast enhancement was moderate in 25 cases and marked in 21 cases. Tumor mass was clearly separable from surrounding edema. The radionuclide brain scan was also positive in all of the high grade gliomas. The uptake of radionuclide was marked in 31 cases and moderate in 15 cases. Slight accumulation of iodine or radioactive tracer was not seen in any of the high grade No.

3 AJA:132, April 17 CONTRAST CT AND RADIONUCLIDE BRAIN SCANS 6 Downloaded from by on 1/2/18 from IP address Copyright ARRS. For personal use only; all rights reserved gliomas. Moderate and marked accumulation of contrast material was uniformly seen in the high grade astrocytoma. Moderate accumulation of radioisotope was encountered in one-third of the high grade gliomas, but also in four low grade gliomas. Marked accumulation of radioisotope was uniformly seen in the high grade glioma. Angiographic vascularity was demonstrated in 31 of 4 (78%) of the high grade gliomas and two of 14 (14%) of the low grade tumors (table 4). Those lesions which were not vascular were identified by vascular displacements. Discussion The extravascular accumulation of iodine and radioactive tracer is largely responsible for the detection of intracranial tumors with contrast enhancement CT and radionuclide brain scanning [8-13]. There is debate regarding the extent of the contribution of intravascular tracer, but tissue vascularity may play a role, particularly during the early phase of imaging [1-12]. The capillaries in normal brain are different from nonneural capillaries in that their junctions are fused and this prevents the free exchange of substances between the intravascular and extravascular compartments ven,,..,tr displacement. B, Enhanced ment. Fig. 2.-Low grade astrocytoma. right frontal area. A, Nonenhanced CT scan. Area of decreased absorption right frontal area. B, Enhanced CT scan. Slight central homogeneous enhancement. C, Right lateral radionuclide brain scan. Area of increased activity vaguely seen in right frontal area (arrow). [11, 13]. These tightjunctions form the structural basis for the concept of the blood-brain barrier. The lack of capillary junctional fenestrations normally prevents the extravascular accumulation of iodine and radioactive tracer. However in astrocytomas, these endothelial junctions are frequently patent and become progressively so as the malignancy of the tumor increases [15, 16]. This continuum in capillary abnormalities allows a progressive increase in the extravascular accumulation of these diagnostic agents [13]. In low grade gliomas the capillary endothelial cells are close to normal and junctional gaps are not present [15, 16]. These minor alterations in the blood-brain barrier may not allow or may significantly retard the extravascular accumulation of contrast media or radioisotope. The evaluation of 14 low grade gliomas with contrast enhancement CT and radionuclide brain scanning is consistent with these neuropathologic observations. There was no contrast enhancement and no radionuclide uptake in nine of the low grade gliomas. In all of these cases the radionuclide brain scan was normal. All of these nonenhancing lesions were seen with CT as unchanging parenchymal abnormalities on the pre- and postcontrast CT brain scans (fig. 1). In the five enhancing low grade gliomas there was slight accumulation of iodine (figs. 2A and 2B). The minimal contrast enhancement probably reflected minor alterations in capillary permeability [13]. The radionuclide brain scan was positive in these lesions with an intensity evaluated as slight in one case (fig. 2C) and moderate in the other four. The most important point in these observations is the strong correlation between the presence of contrast enhancement and radionuclide uptake in these tumors. The criteria used for the evaluation of the intensity of accumulation of these tracers was different and one would not expect a definitive one to one correlation when comparing transmission CT and conventional emission radionuclide imaging. However, in relatively superficial lesions, there was a strong correlation between the intensity of uptake of iodine and radionuclide. The parallel mechanisms of contrast enhancement and radionuclide uptake were clearly seen in this series of high grade gliomas. There was contrast enhancement in all of these tumors. The index of contrast enhancement

4 61 BUTLER ET AL. AJR:132, April 17 Fig. 3.-High grade astrocytoma, left frontal area. A, Nonenhanced CT scan. Discrete area of decreased absorption in left frontal area. B, Enhanced CT scan. Thick rimlike area of enhancement. C, Left lateral radionuclide brain scan. Intense region of increased activity in left frontal area. Downloaded from by on 1/2/18 from IP address Copyright ARRS. For personal use only; all rights reserved Fig. 4.-Bifrontal high grade astrocytoma. A, Enhanced CT scan. Bifrontal rimlike enhancement. B, Right lateral radionuclide brain scan. Marked uptake of radionuclide with central zone of decreased activity. was moderate in 25 cases and marked in 21 cases. Radionuclide imaging was positive in all 46 of the high grade gliomas. The intensity of uptake in the radionuclide brain scans was moderate in 15 cases and marked in 31 cases. Marked accumulation of iodine and radiopharmaceutical was always encountered in the high grade astrocytoma (fig. 3). Despite the frequent occurrence of ring enhancement with CT, there was only one case in which decreased central activity was seen on the radionuclide brain scan (fig. 4). Moderate accumulation of radioisotope was seen in the high grade as well as the low grade glioma. Our findings with contrast enhancement CT in low grade gliomas are similar to those of Tchang et al. [17]. However, these observers only included Kernohan s grade I gliomas in the low grade category, whereas we included Kernohan s grade I and II gliomas in the low grade group. These different neuropathologic groupings might explain any varying results. Contrast enhancement in supratentorial astrocytomas is highly correlated with microscopic vascularity and necrosis [18]. Isolated increases in pleomorphism and cellularity are generally not associated with contrast enhancement [18]. This observation may explain why some so-called anaplastic astrocytoma may not accumulate iodine. Furthermore, in our experience, these tumors do not accumulate radioisotope. The absence of contrast enhancement and radionuclide uptake in this series was singularly seen in the low grade astrocytoma. The contrast enhanced low grade gliomas clearly accumulated contrast media less intensely than the high grade gliomas. Although in a large series there may be some overlap, it seems that the intensity of contrast enhancement reflects qualitative abnormalities in the blood-brain barrier and can therefore be useful in assessing the degree of malignancy of these tumors. As experience accumulates, these findings may assume even greater significance because of the limited tissue sampling afforded by needle biopsy and subtotal resections. Contrast enhanced CT which sampies the entire tumor may supply useful prognostic and therapeutic information. Radionuclide imaging was falsely negative in nine low grade astrocytomas. The radionuclide brain scan is often normal in the low grade glioma [1-22]. In brain tumors the radionuclide brain scan evaluates the integrity of blood-brain barrier and possibly intrinsic vascularity. Contrast enhanced CT monitors these pathophysiologic parameters and, in addition, CT uniquely evaluates pathologic anatomy. Steroid therapy has been associated with diminution in the intensity of radioisotope uptake and contrast enhancement in brain tumors [1, 23]. On occasion, the uptake of radioisotope may actually be prevented by steroid therapy [23]. None of the patients with low grade gliomas were on steroid therapy at the time of the CT or radionuclide brain scans. Nearly half of the patients with highly malignant gliomas were on therapeutic doses of steroids at the time of one or both of these diagnostic studies. One cannot speculate as to whether or not the intensity of the scans was diminished, since no serial scans were obtained with and without steroid medication. High resolution cerebral angiography failed to demonstrate abnormal vascularity in 22% of the high grade gliomas (table 4). This finding is consistent with those of other observers [21]. The degree of malignancy of a glioma is more highly correlated with a positive radionuclide brain scan than it is with abnormal angiographic vascularity [21]. Furthermore, even magnification angiography with subtraction may fail to demonstrate very small abnormal vessels. Angiographic vascularity was demonstrated in two of 14 cases (14%) of low grade gliomas in this series. This is consistent with the observations of others [21]. In each case there was no contrast enhancement and no uptake

5 AJR:132, April 17 CONTRAST CT AND RADIONUCLIDE BRAIN SCANS 611 Downloaded from by on 1/2/18 from IP address Copyright ARRS. For personal use only; all rights reserved of radioisotope. These two cases lend support to the concept that contrast enhancement and radionuclide uptake are in great measure secondary to the extravascular accumulation of these diagnostic agents. This study was confined to gliomas of the supratentorial region because these tumors are of a different clinicopathologic entity than gliomas in the posterior fossa [24]. Therefore, the uptake of iodine and radioactive tracer have difterent histologic and biologic implications in the supra- and infratentorial regions. Intense contrast enhancement is often seen in low grade postenor fossa tumors [18]. Rarely a juvenile astrocytoma, which originates in the region of the third ventricle, or a cerebellarlike astrocytoma, which occurs in the cerebral hemispheres, may be encountered [24]. These are histologically benign tumors which often have increased vascularity and this could possibly be reflected in a positive contrast enhancement CT and radionuclide brain scan. We did not encounter such tumors in this series. Conclusions The strong correlation between the degree of contrast enhancement and radionuclide uptake demonstrated in this series of astrocytomas offers significant corroborative evidence that the mechanisms of contrast enhancement and radionuclide uptake are identical. Contrast enhanced CT and radionuclide brain imaging mirror the integrity of the blood-brain barrier and therefore can be useful in assessing the degree of malignancy of supratentorial astrocytomas. However, in the presence of an intact blood-brain barrier (low grade glioma), the radionuclide brain scan will be normal. In these cases there will be no accumulation of contrast media, but the parenchymal abnormality and/or the associated mass effect will be seen with CT. 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