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Glioma Recurrence Versus Radiation Necrosis?
Glioma Recurrence Versus Radiation Necrosis? A Pilot Comparison of Arterial Spin-Labeled, Dynamic Susceptibility Contrast Enhanced MRI, and FDG-PET Imaging Yelda Ozsunar, MD, Mark E. Mullins, MD, PhD, Kenneth Kwong, PhD, Fred H. Hochberg, MD, Christine Ament, MD, Pamela W. Schaefer, MD, R. Gilberto Gonzalez, MD, PhD, Michael H. Lev, MD Rationale and Objectives: Distinguishing recurrent glial tumor from radiation necrosis can be challenging. The purpose of this pilot study was to preliminarily compare unenhanced arterial spin-labeled (ASL) imaging, dynamic susceptibility contrast-enhanced cerebral blood volume (DSCE-CBV) magnetic resonance imaging, and positron emission tomographic (PET) imaging in distinguishing predominant glioma recurrence or progression from predominant radiation necrosis in postoperative patients treated with proton-beam therapy. Methods: Patients with grade II to IV glioma previously treated with surgery and proton-beam therapy were enrolled on the basis of new enhancing nodules or masses with primary differential diagnoses of predominant tumor recurrence or progression versus radiation necrosis. ASL, DSCE-CBV, and PET examinations were assessed by visual qualitative and quantitative analysis for the detection of predominant tumor recurrence. Imaging results were correlated with a clinical-pathologic reference standard. Results: Thirty patients were studied, resulting in 33 ASL, 32 DSCE-CBV, and 26 PET examinations. On the basis of visual inspection, the sensitivities of PET, ASL, and DSCE-CBV examinations for detecting high-grade tumor foci were 81%, 88%, and 86%, respectively. The highest sensitivity values for quantitative ASL imaging were obtained using a normalized cutoff ratio of 1.3, resulting in sensitivity of 94% for ASL imaging and 71% for DSCE-CBV imaging. When predominant high-grade tumors with superimposed regions of predominant mixed radiation necrosis were excluded, DSCE-CBV sensitivity improved to 90%, but ASL sensitivity remained unchanged. Conclusions: Compared with DSCE-CBV imaging, ASL imaging may more accurately distinguish predominant recurrent high-grade glioma from radiation necrosis, especially in regions with mixed radiation necrosis, for which DSCE-CBV imaging may underestimate true blood volume because of leakage artifacts. Key Words: Arterial spin labeling; perfusion MRI; brain tumors; glioma; perfusion; radiation necrosis. ªAUR, 2010
P
rimary central nervous system neoplasia is one of the most frequent causes of death between 15 and 35 years of age (1). Gliomas constitute >90% of primary brain tumors diagnosed after the second decade of life (2). Despite treatment with chemotherapy and radiation, including proton-beam therapy (PBT) and other radiosurgery, the majority of these tumors progress and/or recur. Moreover, treatment with radiation remains associated with tissue necrosis that may also lead to clinical deterioration (3,4).
Acad Radiol 2010; 17:282–290 From the Department of Radiology, Adnan Menderes University, School of Medicine, Hastane Caddesi, Aydin, Turkey (Y.O.); the Department of Radiology, Emory University, Atlanta, GA (M.E.M.); the Department of Radiology (K.K., P.W.S., R.G.G., M.H.L.) and the Department of Neurology and Brain Tumor Center (F.H.H.), Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA (K.K., F.H.H., P.W.S., R.G.G., M.H.L.); and Boston University Eye Associates, Trygve Gunderson Eye Center, Boston, MA (C.A.). Received August 31, 2009; accepted October 21, 2009. This study was presented at the 87th Scientific Assembly and Annual Meeting of the Radiological Society of North America in 2001. This project was funded by a Seed Grant from the Radiological Society of North America (Oak Brook, IL) to Dr Lev. Address correspondence to: Y.O. e-mail: [email protected] ªAUR, 2010 doi:10.1016/j.acra.2009.10.024
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When a magnetic resonance imaging (MRI) scan of the brain shows a new enhancing lesion after a patient has undergone surgery and radiation for high-grade glioma, the differentiation of predominant recurrent tumor (or progression of tumor) from predominant radiation necrosis is often crucial, because the two entities have different treatment approaches and prognoses (5). Computed tomographic and conventional MRI findings are relatively nonspecific, although some findings on MRI, especially when presenting in combination, may favor a given diagnosis (5–7). Positron emission tomographic (PET) and single photon-emission computed tomographic imaging provide additional information regarding tumor metabolism (3,8). Although early results with fluorodeoxyglucose (FDG) PET imaging were encouraging, some studies have reported specificities as low as 18%, high cost, and limited availability (3,8). Glioma recurrence or progression and radiation necrosis may be frequently mixed (in terms of pathology), and residual microscopic tumor foci are often present, even in so-called pure necrosis cases, further complicating the situation (9). Recent developments in MRI techniques have made the evaluation of tumor vascularity more accessible (10–13).
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Vascular proliferation is a major hallmark of malignant gliomas (14). Moreover, it is believed that angiogenesis (15) ultimately determines blood flow, metabolism, and growth rate in irradiated tumor beds (16). Thus, dynamic perfusion-weighted MRI either separately or in combination with fused diagnostic techniques, such as FDG-PET/MRI scanning, has been proposed as a tool to grade and to differentiate high-grade (and therefore likely to be highly vascular) tumors from low-grade tumors and benign lesions (3,17–19). To date, the literature has focused primarily on dynamic susceptibility contrast-enhanced cerebral blood volume (DSCE-CBV) (10,11,17–20) rather than arterial spin-labeled (ASL) cerebral blood flow imaging as a means to achieve this assessment. Unlike DSCE-CBV imaging, which can underestimate vascularity in ‘‘leaky’’ regions of severe blood-brain barrier (BBB) breakdown, ASL imaging provides an assessment of tumor microvascularity less affected by variations in permeability, with low cost and risk for nephrogenic systemic sclerosis, a disease that has been recently linked to the use of gadolinium contrast media in patients with renal insufficiency. Our purpose in this study was therefore to compare these different dynamic brain tumor imaging techniques with regard to their ability to distinguish predominant radiation necrosis from predominant glioma recurrence or progression in posttreatment patients. We investigated this question by qualitatively and quantitatively analyzing ASL, DSCECBV, and FDG-PET data sets. The comparison of the ASL technique with DSCE-CBV and PET imaging in patients with radiated primary brain tumors is not currently well established in the literature. We chose to use the clinically relevant terms ‘‘predominant tumor’’ and ‘‘predominant radiation necrosis’’ to reflect the ‘‘true’’ histologic reference standard.
MATERIALS AND METHODS Patient Enrollment
Inclusion criteria for consecutive patients included (1) histologically proven enhancing primary intra-axial glioma at first presentation (mixed or ‘‘pure’’ World Health Organization grade II, III, or IV), (2) prior total or subtotal resection of abnormally enhancing tumor, (3) prior treatment with PBT, (4) suspicion of new tumor recurrence or progression versus radiation necrosis on the basis of a brain MRI scan showing a new enhancing nodule or mass $6 months following radiation treatment, and (5) proof of predominant recurrence, low-grade tumors, or predominant necrosis on the basis of either direct histology (for proof of predominant tumor recurrence or progression) or $1 year of subsequent clinical and imaging stability (for proof of predominant necrosis). Approval for this study was obtained from the human research committee (internal review board) at our hospital, and written informed consent was obtained prospectively for all ASL
ASL VERSUS DSCE-CBV
studies. The study was compliant with the Health Insurance Portability and Accountability Act. FDG-PET and DSCECBV imaging were performed as part of our clinical routine, and retrospective comparisons among all modalities were subsequently performed. Chemotherapy as well as fractionated and unfractionated radiation treatments were not uniform in this cohort. Doses of radiation were typical of patients at our hospital and consistent with the literature (21,22). All patients received both photon irradiation and PBT. Exclusion criteria were (1) a lack of proof of predominant tumor recurrence or progression versus necrosis either by definitive histology or >1 year of clinical and imaging stability and (2) motion artifacts or otherwise technically unacceptable DSCE-CBV or ASL imaging.
Brain Tumors
In this study, the clinical pathologist classified gliomas as World Health Organization grade II, II, or IV. Oligodendrogliomas were classified as grade II, III (anaplastic), or IV (glioblastoma); mixed gliomas were classified according to the highest grade component. Mixed high-grade tumors with large (subjective) areas of necrosis were also recorded. Grade II tumors were designated as low-grade gliomas and grade III and IV tumors as high-grade gliomas.
Clinical Follow-Up
Clinical follow-up for the determination of nonrecurrence is established as the absence of neurologic symptoms related to primary tumor and the absence of tumor recurrence in radiologic follow-up.
PET Examinations
The interval between MRI and PET exams ranged from 0 to 30 days. FDG-PET imaging (n = 26) was performed using a previously described methodology (23,24). Briefly, PET imaging was performed parallel to the orbitomeatal line. A molded plastic facemask was used to restrict head motion. Images were acquired with either a PC-384 or a PC-4096 PET camera (Scanditronix AB, Uppsala, Sweden). All images were reconstructed using a conventional filtered back-projection algorithm. An analytic attenuation correction assuming a uniform distribution of absorber within the slice contour was applied to the data. All projection data were corrected for nonuniformity of detector response, dead time, random coincidences, and scattered radiation. PET images of glucose uptake were obtained using 18F-labeled FDG. Patients received a 5-mCi to 10-mCi bolus of 18F-labeled FDG injected intravenously over 15 seconds. Imaging was performed 45 minutes later in two (PC-4096; 30 slices) or three (PC-384; 15 slices) bed positions. 283
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MRI Examinations
MRI scans were performed on the same day except in two patients (acquired 2 and 24 days later). MRI scans were performed according to a previously described methodology (20). In brief, all MRI was performed using a 1.5-T Signa scanner (GE Medical Systems, Milwaukee, WI), upgraded by Advanced NMR Systems (Wilmington, MA) for echoplanar imaging. Conventional brain MRI consisted of sagittal T1, axial dual fast spin-echo T2, and postcontrast axial and coronal T1-weighted images. Conventional magnetic resonance and DSCE-CBVand ASL images were acquired during the same imaging session. ASL levels were selected from the precontrast axial T1 T1-weighted images. The intravenous administration of a gadolinium-based contrast agent through an antecubital vein (injection rate, 5 mL/s; dose, 0.2 mmol/ kg), followed by a 12-mL saline flush, was accomplished with a prototype MRI-compatible power injector. Contrast delivery was delayed 16 seconds from the start of echo-planar imaging so that a baseline sequence of images could be obtained. Axial T2-weighted, spin-echo, echo-planar images were acquired using the following parameters: repetition time, 1500 ms; echo time, 75 ms; matrix size, 256 to 128; and field of view, 40 20 cm. Fifty-one sequential images for each of the 10 sections (or, in a few cases, 46 images per section for 11 sections) were acquired during 1 minute 23 seconds. ASL Imaging
ASL maps (n = 33) were constructed by the subtraction of nonselective (flow-insensitive) T1-weighted images from selective (flow-sensitive) T1 images, according to the method of Kwong et al (25). In this pulsed ASL technique, tissue signal is nulled by subtraction, whereas flow signal from incoming spins accumulates and simultaneously decays according to the T1 relaxation time of blood (26). This T1-based, absolute flow method involves the tagging of incoming spins with a single inversion recovery pulse followed by imaging a distal slice. Because the T1 shortening effects of gadolinium interfere with the buildup of flow signal, spin-labeled MRI was performed prior to contrast material administration. The single imaging level was chosen from the precontrast, T2-weighted images by guiding a board-certified neuroradiologist. ASL images were acquired using following parameters: repetition time, 3500 ms; echo time, 30 ms; inversion time, 1300 ms; thickness, 6 mm; number of signals acquired, 1; matrix size, 128 64 (3 3 mm in-plane resolution); and imaging time, 4 to 8 minutes. DSCE-CBV Imaging
DSCE-CBV maps were acquired (n = 32) and constructed according to a previously described methodology (20). In brief, either 51 or 46 sequential images per slice, for 11 slices, were acquired over 83 seconds. DSCE-CBV maps were 284
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generated from spin-echo, echo-planar data sets (27). The curve of DR2 versus time for each pixel in each imaged slice was integrated from a time 2 seconds prior to injection through the end of image acquisition. The change in T2 relaxation rate, DR2, is defined as ln(S/S0)(echo time), where S represents signal intensity and S0 the baseline value. The value of DR2 has been shown to be approximately linearly proportional to the concentration of contrast material in tissue (28). By convention, maps were constructed using a standard mathematical ‘‘correction’’ algorithm to compensate for the confounding effects of high-permeability, ‘‘leaky’’ regions of severe BBB breakdown, regions frequently present in necrotic tumor and irradiated tumor beds (28,29). An additional strategy to correct for ‘‘leakiness,’’ also used in this study, has been the administration of a small (4–6 mL) dose of intravenous contrast material just prior to primary data acquisition (28,30–32). Theoretically, this should ‘‘presaturate’’ the peritumoral interstitium in regions of severe BBB breakdown, reducing the distorting effects of subsequent gadolinium ‘‘leakage’’ relative to the baseline T2 signal intensity of such regions (28). Data Analysis
Analyses of magnetic resonance images and the PET results were performed by consensus interpretation by two boardcertified neuroradiologists who were blinded to the tissue diagnosis but unblinded to the earlier conventional prior MRI examinations. DSCE-CBV and ASL images were first rated individually and independently according to the presence or absence of high-grade tumor components, then a consensus was reached for qualitative assessment. ASL and DSCE-CBV images were scored on a three-point scale (0 = definitely no increased perfusion compared to the corresponding contralateral ‘‘normal’’ gray or white matter, 1 = equivocal increased perfusion, 2 = definitely increased perfusion). The quality of ASL images was also rated compared to DSCE-CBV images as inferior, equivalent, or superior with regard to visual conspicuity and lesion boundaries or extent. The technique was defined as superior if better delineation or better coverage of tumor was present or greater sensitivity for small lesions (<3 mm) was found. If the patient had poor contrast in a leaky region or if suboptimal level selection was detected for ASL imaging, the technique was interpreted as inferior. Each modality was independently evaluated in a separate blinded session $2 weeks apart to reduce the potential for bias. Thus qualitative (including conventional MRI) and quantitative interpretations of ASL, DSCE-CBV, and PET imaging were not performed together in the same readout session. For quantitative analyses of the ASL and DSCE-CBV maps, representative 4 4 pixel regions of interest (ROIs) with the lowest possible standard deviation between adjacent pixels were chosen from regions with the highest obtainable signal intensity. This was achieved by manually and repeatedly moving a 4 4 pixel ROI until a region was found that
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had the least standard deviation and minimal partial volume effect between neighboring gray and white matter. Visually definable veins, surgical or presumably necrotic cavities, regions with hemorrhage, and the choroid plexus were specifically avoided. Manually obtained ROIs were normalized by dividing the mean signal intensity of tumor by that of contralateral ‘‘normal’’-appearing brain in a comparable anatomic location. Results were correlated with both the conventional MRI findings and with the clinical-pathologic standard. Specifically, to address the effect of perfusion maps in more ‘‘leaky’’ lesions, patients with mixed high-grade tumor and radiation necrosis, which presumably contain more leaky regions, were separately analyzed. Statistical Analysis
Statistical analyses were performed using a personal computer–based software package (SPSS; SPSS, Inc, Chicago, IL). To compare qualitative data of the nonrecurrence versus recurrence tumor groups, the c2 test was performed for nonparametric analyses. Two-tailed Student’s t tests, assuming unequal variance, were conducted using Microsoft Excel 2000 (Microsoft Corporation, Redmond, WA). P values <.05 were defined as statistically significant. Consistency tests, correlation tests, and Friedman’s tests based on the qualitative analyses (on the three-point scale) were performed for the comparison of ASL, DSCE-CBV MRI, and PET imaging. Binormal receiver-operating characteristic curves were constructed using various cutoff values to define the optimal cutoff values to differentiate radiation necrosis from tumor recurrence.
RESULTS Thirty patients who underwent 35 separate evaluations for predominant radiation necrosis versus predominant recurrent brain tumor were enrolled. Primary diagnoses before PBT were World Health Organization grade II in seven patients, grade III in nine patients, and grade IV in 19 patients. Six of the grade II and three of the grade III gliomas were mixed astrocytoma and oligodendroglioma. The age range was 20 to 69 years (mean, 42 11 years); there were eight women and 22 men. For all 35 evaluations after PBT, histopathology revealed seven predominantly radiation necrosis, five predominant low-grade tumors, and 23 predominant high-grade tumors. The time interval between perfusion MRI and biopsy ranged from <1 day to 4 weeks (mean, 6 8 days). For all but three time points, diagnoses were established by surgical pathology. In the three patients for which biopsies were not available, final diagnoses were established by a minimum of 12 months of stable follow-up without clinical signs of high-grade tumor recurrence or progression. A total of 26 PET, 33 ASL, and 32 DSCE-CBVexams were included for qualitative interpretation. Of these, three
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patients had undergone two ASL examinations, and two patients had undergone two DSCE-CBV examinations. For all modalities, the visual (qualitative) distinction between patients with predominant radiation necrosis or low-grade tumor versus those with predominant high-grade tumor recurrence or progression, as measured by the three-point ranking scale, were statistically significant (c2 test, P < .01). Mean ranking scores for each imaging methods are shown in Table 1. Patients with relative increased perfusion (ranking scores of 3 or 4) in treated tumor beds were diagnosed as having local tumor recurrence or progression (Figs 1 and 2). The sensitivity and specificity of PET, ASL, and DSCE-CBV imaging in detecting predominantly high-grade tumor, based on this visual inspection, are shown in Table 1. The quality of DSCE-CBV versus ASL images was rated as superior in 17, inferior in seven, and equivalent in the remaining eight patients. Reasons for the superiority of DSCE-CBV imaging included better delineation of tumor extent, greater sensitivity for the detection of small lesions, and imaging through the ‘‘suboptimal’’ level with the ASL technique. Reasons for the inferiority of DSCE-CBV imaging included noise from cortical vessels, poor contrast in ‘‘leaky’’ areas of severe BBB breakdown, and technical errors during scanning. DSCE-CBV imaging was judged superior to ASL imaging in both anatomic resolution and coverage in two patients. ASL images were better correlated with PET results compared to DSCE-CBV images. Consistency tests, based on the threepoint qualitative scale, showed good correlation between ASL and PET imaging (k = 0.75), whereas comparisons between ASL and DSCE-CBV imaging (k = 0.47) and also between DSCE-CBV and PET imaging (k = 0.56) did not show good correlations. Quantitative analyses were possible in 23 examinations for ASL imaging and in 19 examinations for DSCE-CBV imaging. ROI measurements could not be obtained in the remainder of the patients, because the original source image digital data were unavailable for analysis. On the basis of the quantitative analysis, binormal receiver-operating characteristic curves were constructed to define the optimal cutoff value; a cutoff value of 1.3 provided the optimal sensitivity and specificity values for the detection of high-grade tumor recurrence for both DSCE-CBV and ASL imaging (Fig 3, Table 2). Because DSCE-CBV imaging might underestimate true blood volume because of leakage artifacts, patients with histologic high-grade tumors with radiation necrosis (mixed histology) were subcategorized. When patients with mixed histology were excluded, sensitivity and specificity values were improved (Table 2). Seventeen of 23 ASL measurements and 15 of 19 DSCE-CBV measurements resulted in the correct categorization of predominant high-grade tumor recurrence, using the cutoff value of 1.3. Mean normalized ROI values and their scatterplot representation, stratified according to final diagnoses for each ASL and DSCE-CBV examination, are summarized in Table 3. Differences between the nonrecurrence and high-grade recurrence groups were 285
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TABLE 1. Distribution of Sensitivity and Specificity Values of Predominantly Recurrent or Progressive Versus Nonrecurrent Highgrade Tumor Modality ASL imaging DSCE-CBV imaging PET imaging Histopathology
Total
Nonrecurrence
Recurrence
Sensitivity
Specificity
33 32 26 35
12 (36%) 10 (33%) 12 (46%) 12 (34%)
21 (64%) 22 (67%) 14 (54%) 23 (66%)
88% 86% 81%
89% 70% 90%
ASL, arterial spin-labeled; DSCE-CBV, dynamic susceptibility contrast-enhanced cerebral blood volume; PET, positron emission tomographic. The findings are based on grading scores on three-point scale for ASL, DSCE-CBV, and PET imaging in patients treated with proton-beam therapy (Friedman’s test, P < .01 for all three comparisons). Consensus rating scores of 0 and 1 indicated nonrecurrence, whereas a score of 2 indicated high-grade recurrence.
Figure 1. A 45-year-old man with a history of attempted resection of grade IV glioma, chemotherapy, proton-beam therapy, and subsequent new abnormal enhancing lesion on follow-up magnetic resonance imaging. Positron emission tomographic image (a) shows ring-shaped hypermetabolism in the right frontal lobe (arrow). Contrast-enhanced T1-weighted axial image (b) illustrates a heterogeneously ring-enhancing lesion at the site of lesion. Both axial arterial spin-labeled (c) and dynamic susceptibility contrast-enhanced cerebral blood volume (d) maps show ring-shaped hyperperfusion in the contrast-enhancing lesion, suggesting predominant high-grade tumor recurrence, which was confirmed on histopathology.
Figure 2. A 47-year-old man with a history of attempted resection of grade IV glioma and proton-beam therapy with new abnormal enhancing lesion on follow-up. Positron emission tomographic imaging (a) shows hypermetabolism at the site of the lesion on contrast-enhanced T1 axial imaging (b). Arterial spin-labeled (ASL) (c) and dynamic susceptibility contrast-enhanced cerebral blood volume (DSCE-CBV) (d) images show hyperperfusion that correlates with the axial postcontrast T1-weighted image. Note that the lesion is more conspicuous on ASL than on DSCECBV imaging. Subsequent surgical resection confirmed predominantly tumor recurrence.
not statistically significant. On the basis of a previously published (20) normalized cutoff value of 1.5 for detection of native, untreated high-grade tumors, sensitivity was found to be 83% for ASL imaging and 80% for DSCE-CBV imaging. When patients with mixed predominantly high286
grade tumors and radiation necrosis were excluded, the sensitivity of DSCE-CBV imaging for predominant tumor improved to 92%, but the sensitivity of ASL imaging did not significantly change. Using quantitative analyses and a cutoff of 1.5, ASL and DSCE-CBV imaging had two
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Figure 3. Receiver-operating characteristic curves for arterial spin-labeled (ASL) and dynamic susceptibility contrast-enhanced cerebral blood volume (DSCE-CBV) images obtained using mean region-of-interest measurement (95% confidence interval for ASL imaging, 0.42–0.97; 95% confidence interval for DSCE-CBV imaging, 0.34–0.97).
TABLE 2. Test Characteristics for the Detection of Predominant Recurrent or Progressive High-Grade Glioma in PBT-treated Patients, Based on Quantitative ROI Analyses, Applying a Cutoff Ratio of 1.3 ASL Imaging
Variable Sensitivity Specificity PPV NPV
DSCE-CBV Imaging
With Mixed Histology
Without Mixed Histology
With Mixed Histology
Without Mixed Histology
(n = 23)
(n = 18)
(n = 19)
(n = 15)
94% 50% 88% 12%
92% 50% 85% 15%
71% 40% 77% 15%
90% 40% 75% 16%
ASL, arterial spin-labeled; DSCE-CBV, dynamic susceptibility contrast-enhanced cerebral blood volume, NPV, negative predictive value; PBT, proton-beam therapy; PPV, positive predictive value; ROI, region of interest. The second and fourth columns represent patients excluding mixed high-grade tumor and radiation necrosis.
TABLE 3. Mean Normalized ROI Values Based on Quantitative ROI Analyses of the Perfusion Map Values, Stratified According to Clinical-pathologic Diagnoses Normalized ROI
Histopathology
ASL Imaging
DSCE-CBV Imaging
(n = 23)
(n = 19)
Predominant radiation 2.0 1.4 (n = 5) 2 1.5 (n = 5) necrosis/low-grade tumor Predominant high-grade 3.9 5 (n = 13) 2.6 1.8 (n = 10) tumor recurrence Radiation necrosis with 4.3 1.6 (n = 5) 1.2 0.3 (n = 4) mixed high-grade tumor The differences between the nonrecurrence and predominantly highgrade recurrence for histopathologic subgroups were not statistically significant (Student’s t test).
false-positive diagnoses of high-grade recurrence, for what were histologically proven to be oligodendrogliomas. In one case of predominant radiation necrosis, ASL measurement was truly negative for high-grade recurrence (0.7), whereas the DSCE-CBV measurement was falsely positive (1.5) (Fig 4).
DISCUSSION Our pilot data confirm previous literature that has suggested that both susceptibility-based DSCE-CBV and ASL MRI techniques may be of value in assessing tumor grade on the basis of neovascularity. These methods provide high sensitivity for distinguishing predominant recurrent malignant glioma from predominant radiation necrosis, with values comparable to or surpassing those of PET imaging (1,20,29,33–38). Our data extend the literature by documenting that the ASL technique may provide higher sensitivity and specificity values than DSCE-CBV imaging in some patients. Comparison of ASL technique to DSCE-CBV and PET imaging in patients with irradiated primary brain tumors has not previously been emphasized in the literature. In our study, qualitative analyses of ASL images provided higher sensitivity (88%) and specificity (89%) compared to both DSCE-CBVand PET imaging in detecting predominant tumor recurrence in patients after treatment with PBT. When quantitative analyses were performed, the sensitivity values were increased. The low sensitivity of DSCE-CBV findings likely arose from vascular leakage, probably caused by radiation necrosis (Fig 4). Radiation therapy has been shown to induce breakdown of the BBB and vascular leakage (6). In instances of approximately equally mixed combined 287
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Figure 4. A 58-year-old man with grade IV glioma and a history of attempted resection, proton-beam therapy, and with a new enhancing lesion on follow-up magnetic resonance imaging. Positron emission tomographic imaging (not shown) shows hypometabolism at the site of the abnormally enhancing left parieto-occipital lesion on contrast-enhanced T1-weighted axial image (a). Whereas the arterial spin-labeled (ASL) image (b) shows hypoperfusion, the dynamic susceptibility contrast-enhanced cerebral blood volume (DSCE-CBV) image (c) shows hyperperfusion of the enhancing lesion that is surrounded with hypoperfused region due to vasogenic edema. Histopathology of this lesion confirmed radiation necrosis. This case therefore demonstrates ‘‘true-negative’’ ASL and ‘‘false-positive’’ DSCE-CBV findings.
malignant tumor recurrence superimposed on radiation necrosis, vascular leakage may be exaggerated, and this may not be fully compensated for during CBV map construction by our standard mathematical correction algorithms. Quantitative analyses of astrocytomas have also documented that tumor DSCE-CBV is reduced after radiotherapy compared to pretreatment levels and that this reduction is dose dependent (19). Other possible reasons for falsely low DSCECBV sensitivity are intratumoral susceptibility artifacts due to recent hemorrhage (deoxyhemoglobin) or chronic hemosiderin deposition (39–41). Mixed primary brain tumor with radiation necrosis after surgery, chemotherapy, and radiation therapy is relatively common. In one study, an even mix of tumor recurrence and radiation necrosis was found in 33% of patients with gliomas who received external-beam radiotherapy and subsequently underwent biopsy to distinguish tumor recurrence from radiation necrosis (42). ASL imaging may be of benefit for high-grade tumor detection in these instances because it is theoretically less likely to be affected by the BBB breakdown, which is exceedingly common within these patients (20); the correlation (k = 0.75) between ASL and PET imaging may support this hypothesis. We did not report the individual specificity values for the visual interpretation of the ASL, DSCECBV, and PET maps because visual interpretation of these functional maps was of necessity performed in conjunction with that of conventional MRI findings, and thus we felt that it could not be interpreted separately from these data. Quantitative analyses of ASL provided the highest sensitivity (94%) for differentiating nonrecurrence from malignant recurrence using a cutoff value of 1.3. Using the same normalized threshold value of 1.3, ASL showed only one false-negative result. A DSCE-CBV cutoff value of 1.5 has provided 288
high sensitivity for grading native glial tumors in the literature (20,27). In other studies that have focused on grading native tumors using perfusion imaging (12,38,43–45), relative DSCE-CBV values greater than 1.3 (46) 1.5 (45), 1.7 (35), and 1.8 (47) have also been shown to indicate high-grade tumors. Using a threshold value of 1.5 for ASL imaging, we identified three patients with false-positive results, including one with predominant radiation necrosis and two with lowgrade tumors. When the quality of ASL and DSCE-CBV images was compared, DSCE-CBV images were found to be superior. Relative CBV provided both better delineation of tumor borders and greater sensitivity for the detection of small lesions, in part related to the higher intrinsic spatial resolution of DSCE-CBV compared to ASL maps. However, the DSCE-CBV images appeared to falsely underestimate tumor extent relative to ASL specifically in leaky regions of BBB breakdown (Fig 1). The ASL technique has limitations. The single-slice method used for this study, despite a high signal-to-noise ratio, has lower spatial resolution than DSCE-CBV imaging. Other limitations of spin-labeled techniques include long imaging times (4–8 min/slice) and the inability to image following gadolinium administration. ASL imagin cannot be performed after gadolinium administration because it shortens the T1 of blood and therefore reduces the buildup of inflowing signal, causing a severe degrading of signal-to-noise ratio in the subtracted image. Another confounding factor is the ‘‘amplification’’ of flow signal proportional to the difference in T1 between blood and tissue, because incoming blood contains spins that relax more slowly than those in adjacent tissue. Different tissues such as gray and white matter are amplified differently, which distorts quantitative flow maps. Also, partial
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volume averaging of cerebrospinal fluid with brain parenchyma results in an underestimation of flow values (48). Ours is a preliminary pilot study and had limitations. The sample size was small, and multislice ASL imaging was not technically possible at the time of our study. Therefore, we obtained only one image slice, which could have introduced selection bias. New studies are needed to address our hypothesis with high-quality multislice ASL techniques that can be acquired using whole-brain or near-whole-brain coverage pulsed ASL or continuous ASL methods. The technical variations may potentially cause bias. We also had a relatively small number of nonrecurrence patients (n = 5 for both ASL and DSCE-CBV imaging), which may have introduced error into the specificity calculation. This was a retrospective study without standardization of chemotherapy, PBT, or photon radiotherapy, although our patient group likely reflects our daily clinical practice, the very common clinical issue of ‘‘patient with history of glioma, after surgery and/or radiation therapy with a new enhancing abnormality.’’ Moreover, because of the nature of gliomas, the brain tissue being imaged is likely to contain residual tumor in most, if not all, patients, even those with predominant radiation necrosis. Because wide surgical margins were not uniformly obtained, sampling error may also have occurred. Because not all patients had surgical pathologic correlation, our assumption that clinically stable patients (without imaging or clinical evidence of progression on long-term follow-up) were without significant recurrent or progressive tumor cannot be validated. Further studies using a larger group of more standardized patients with direct pathologic correlation, multilevel new ASL techniques (49), especially with higher magnetic strength enabling shorter scanning times (50), may be indicated on the basis of our pilot results.
CONCLUSION In this small and highly selected preliminary cohort of PBTtreated patients with gliomas, the ASL technique provided more conspicuous differentiation of predominant recurrent high-grade glioma from predominant radiation necrosis, compared to both DSCE-CBV MRI and PET imaging. The greater sensitivity for detection of recurrent high grade glioma compared to DSCE-CBV imaging may in large part relate to the underestimation of DSCE-CBV in regions of marked BBB breakdown (‘‘leakiness’’) with the use of the DSCE-CBV technique. Increased cerebral blood flow on ASL imaging for newly enhancing lesions within a previously irradiated field strongly suggests predominant tumor recurrence as opposed to predominant radiation necrosis. Thus, despite the limitations of our pilot study, our results support the hypothesis that ASL imaging may have advantages over conventional MRI, DSCE-CBV MRI, and FDG-PET imaging in glioma follow-up. The addition of ASL MRI to the diagnostic imaging surveillance of treated brain tumors likely warrants further study based on our pilot results.
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24. Aronen HJ, Pardo FS, Kennedy DN, et al. High microvascular blood volume is associated with high glucose uptake and tumor angiogenesis in human gliomas. Clin Cancer Res 2000; 6:2189–2200. 25. Kwong KK, Chesler DA, Weisskoff RM, et al. MR perfusion studies with T1weighted echo planar imaging. Magn Reson Med 1995; 34:878–887. 26. Petersen ET, Zimine I, Ho YC, Golay X. Non-invasive measurement of perfusion: a critical review of arterial spin labelling techniques. Br J Radiol 2006; 79:688–701. 27. Aronen HJ, Gazit IE, Louis DN, et al. Cerebral blood volume maps of gliomas: comparison with tumor grade and histologic findings. Radiology 1994; 191:41–51. 28. Weisskoff R, Rosen BR. Functional magnetic resonance imaging. Acad Radiol 1995;(suppl):133–135. 29. Lev MH, Rosen BR. Clinical applications of intracranial perfusion MR imaging. Neuroimaging Clin North Am 1999; 9:309–331. 30. Provenzale JM, Wang GR, Brenner T, Petrella JR, Sorensen AG. Comparison of permeability in high-grade and low-grade brain tumors using dynamic susceptibility contrast MR imaging. AJR Am J Roentgenol 2002; 178:711–716. 31. Covarrubias DJ, Rosen BR, Lev MH. Dynamic magnetic resonance perfusion imaging of brain tumors. Oncologist 2004; 9:528–537. 32. Song CW, Lokshina A, Rhee JG. Implication of blood flow in hyperthermic treatment of tumors. IEEE Trans Biomed Eng 1984; 31:9–16. 33. Sadeghi N, Salmon I, Tang BN, et al. Correlation between dynamic susceptibility contrast perfusion MRI and methionine metabolism in brain gliomas: preliminary results. J Magn Reson Imagin 2006; 24:989–994. 34. Spampinato MV, Smith JK, Kwock L, et al. Cerebral blood volume measurements and proton MR spectroscopy in grading of oligodendroglial tumors. AJR Am J Roentgenol 2007; 188:204–212. 35. Knopp EA, Cha S, Johnson G, et al. Glial neoplasms: dynamic contrastenhanced T2*-weighted MR imaging. Radiology 1999; 211:791–798. 36. Uematsu H, Maeda M, Sadato N, et al. Blood volume of gliomas determined by double-echo dynamic perfusion-weighted MR imaging: a preliminary study. AJNR Am J Neuroradiol 2001; 22:1915–1919. 37. Aronen HJ, Perkio J. Dynamic susceptibility contrast MRI of gliomas. Neuroimaging Clin North Am 2002; 12:501–523. 38. Warmuth C, Gunther M, Zimmer C. Quantification of blood flow in brain tumors: comparison of arterial spin labeling and dynamic susceptibility-
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P
rimary central nervous system neoplasia is one of the most frequent causes of death between 15 and 35 years of age (1). Gliomas constitute >90% of primary brain tumors diagnosed after the second decade of life (2). Despite treatment with chemotherapy and radiation, including proton-beam therapy (PBT) and other radiosurgery, the majority of these tumors progress and/or recur. Moreover, treatment with radiation remains associated with tissue necrosis that may also lead to clinical deterioration (3,4).
Acad Radiol 2010; 17:282–290 From the Department of Radiology, Adnan Menderes University, School of Medicine, Hastane Caddesi, Aydin, Turkey (Y.O.); the Department of Radiology, Emory University, Atlanta, GA (M.E.M.); the Department of Radiology (K.K., P.W.S., R.G.G., M.H.L.) and the Department of Neurology and Brain Tumor Center (F.H.H.), Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA (K.K., F.H.H., P.W.S., R.G.G., M.H.L.); and Boston University Eye Associates, Trygve Gunderson Eye Center, Boston, MA (C.A.). Received August 31, 2009; accepted October 21, 2009. This study was presented at the 87th Scientific Assembly and Annual Meeting of the Radiological Society of North America in 2001. This project was funded by a Seed Grant from the Radiological Society of North America (Oak Brook, IL) to Dr Lev. Address correspondence to: Y.O. e-mail: [email protected] ªAUR, 2010 doi:10.1016/j.acra.2009.10.024
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When a magnetic resonance imaging (MRI) scan of the brain shows a new enhancing lesion after a patient has undergone surgery and radiation for high-grade glioma, the differentiation of predominant recurrent tumor (or progression of tumor) from predominant radiation necrosis is often crucial, because the two entities have different treatment approaches and prognoses (5). Computed tomographic and conventional MRI findings are relatively nonspecific, although some findings on MRI, especially when presenting in combination, may favor a given diagnosis (5–7). Positron emission tomographic (PET) and single photon-emission computed tomographic imaging provide additional information regarding tumor metabolism (3,8). Although early results with fluorodeoxyglucose (FDG) PET imaging were encouraging, some studies have reported specificities as low as 18%, high cost, and limited availability (3,8). Glioma recurrence or progression and radiation necrosis may be frequently mixed (in terms of pathology), and residual microscopic tumor foci are often present, even in so-called pure necrosis cases, further complicating the situation (9). Recent developments in MRI techniques have made the evaluation of tumor vascularity more accessible (10–13).
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Vascular proliferation is a major hallmark of malignant gliomas (14). Moreover, it is believed that angiogenesis (15) ultimately determines blood flow, metabolism, and growth rate in irradiated tumor beds (16). Thus, dynamic perfusion-weighted MRI either separately or in combination with fused diagnostic techniques, such as FDG-PET/MRI scanning, has been proposed as a tool to grade and to differentiate high-grade (and therefore likely to be highly vascular) tumors from low-grade tumors and benign lesions (3,17–19). To date, the literature has focused primarily on dynamic susceptibility contrast-enhanced cerebral blood volume (DSCE-CBV) (10,11,17–20) rather than arterial spin-labeled (ASL) cerebral blood flow imaging as a means to achieve this assessment. Unlike DSCE-CBV imaging, which can underestimate vascularity in ‘‘leaky’’ regions of severe blood-brain barrier (BBB) breakdown, ASL imaging provides an assessment of tumor microvascularity less affected by variations in permeability, with low cost and risk for nephrogenic systemic sclerosis, a disease that has been recently linked to the use of gadolinium contrast media in patients with renal insufficiency. Our purpose in this study was therefore to compare these different dynamic brain tumor imaging techniques with regard to their ability to distinguish predominant radiation necrosis from predominant glioma recurrence or progression in posttreatment patients. We investigated this question by qualitatively and quantitatively analyzing ASL, DSCECBV, and FDG-PET data sets. The comparison of the ASL technique with DSCE-CBV and PET imaging in patients with radiated primary brain tumors is not currently well established in the literature. We chose to use the clinically relevant terms ‘‘predominant tumor’’ and ‘‘predominant radiation necrosis’’ to reflect the ‘‘true’’ histologic reference standard.
MATERIALS AND METHODS Patient Enrollment
Inclusion criteria for consecutive patients included (1) histologically proven enhancing primary intra-axial glioma at first presentation (mixed or ‘‘pure’’ World Health Organization grade II, III, or IV), (2) prior total or subtotal resection of abnormally enhancing tumor, (3) prior treatment with PBT, (4) suspicion of new tumor recurrence or progression versus radiation necrosis on the basis of a brain MRI scan showing a new enhancing nodule or mass $6 months following radiation treatment, and (5) proof of predominant recurrence, low-grade tumors, or predominant necrosis on the basis of either direct histology (for proof of predominant tumor recurrence or progression) or $1 year of subsequent clinical and imaging stability (for proof of predominant necrosis). Approval for this study was obtained from the human research committee (internal review board) at our hospital, and written informed consent was obtained prospectively for all ASL
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studies. The study was compliant with the Health Insurance Portability and Accountability Act. FDG-PET and DSCECBV imaging were performed as part of our clinical routine, and retrospective comparisons among all modalities were subsequently performed. Chemotherapy as well as fractionated and unfractionated radiation treatments were not uniform in this cohort. Doses of radiation were typical of patients at our hospital and consistent with the literature (21,22). All patients received both photon irradiation and PBT. Exclusion criteria were (1) a lack of proof of predominant tumor recurrence or progression versus necrosis either by definitive histology or >1 year of clinical and imaging stability and (2) motion artifacts or otherwise technically unacceptable DSCE-CBV or ASL imaging.
Brain Tumors
In this study, the clinical pathologist classified gliomas as World Health Organization grade II, II, or IV. Oligodendrogliomas were classified as grade II, III (anaplastic), or IV (glioblastoma); mixed gliomas were classified according to the highest grade component. Mixed high-grade tumors with large (subjective) areas of necrosis were also recorded. Grade II tumors were designated as low-grade gliomas and grade III and IV tumors as high-grade gliomas.
Clinical Follow-Up
Clinical follow-up for the determination of nonrecurrence is established as the absence of neurologic symptoms related to primary tumor and the absence of tumor recurrence in radiologic follow-up.
PET Examinations
The interval between MRI and PET exams ranged from 0 to 30 days. FDG-PET imaging (n = 26) was performed using a previously described methodology (23,24). Briefly, PET imaging was performed parallel to the orbitomeatal line. A molded plastic facemask was used to restrict head motion. Images were acquired with either a PC-384 or a PC-4096 PET camera (Scanditronix AB, Uppsala, Sweden). All images were reconstructed using a conventional filtered back-projection algorithm. An analytic attenuation correction assuming a uniform distribution of absorber within the slice contour was applied to the data. All projection data were corrected for nonuniformity of detector response, dead time, random coincidences, and scattered radiation. PET images of glucose uptake were obtained using 18F-labeled FDG. Patients received a 5-mCi to 10-mCi bolus of 18F-labeled FDG injected intravenously over 15 seconds. Imaging was performed 45 minutes later in two (PC-4096; 30 slices) or three (PC-384; 15 slices) bed positions. 283
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MRI Examinations
MRI scans were performed on the same day except in two patients (acquired 2 and 24 days later). MRI scans were performed according to a previously described methodology (20). In brief, all MRI was performed using a 1.5-T Signa scanner (GE Medical Systems, Milwaukee, WI), upgraded by Advanced NMR Systems (Wilmington, MA) for echoplanar imaging. Conventional brain MRI consisted of sagittal T1, axial dual fast spin-echo T2, and postcontrast axial and coronal T1-weighted images. Conventional magnetic resonance and DSCE-CBVand ASL images were acquired during the same imaging session. ASL levels were selected from the precontrast axial T1 T1-weighted images. The intravenous administration of a gadolinium-based contrast agent through an antecubital vein (injection rate, 5 mL/s; dose, 0.2 mmol/ kg), followed by a 12-mL saline flush, was accomplished with a prototype MRI-compatible power injector. Contrast delivery was delayed 16 seconds from the start of echo-planar imaging so that a baseline sequence of images could be obtained. Axial T2-weighted, spin-echo, echo-planar images were acquired using the following parameters: repetition time, 1500 ms; echo time, 75 ms; matrix size, 256 to 128; and field of view, 40 20 cm. Fifty-one sequential images for each of the 10 sections (or, in a few cases, 46 images per section for 11 sections) were acquired during 1 minute 23 seconds. ASL Imaging
ASL maps (n = 33) were constructed by the subtraction of nonselective (flow-insensitive) T1-weighted images from selective (flow-sensitive) T1 images, according to the method of Kwong et al (25). In this pulsed ASL technique, tissue signal is nulled by subtraction, whereas flow signal from incoming spins accumulates and simultaneously decays according to the T1 relaxation time of blood (26). This T1-based, absolute flow method involves the tagging of incoming spins with a single inversion recovery pulse followed by imaging a distal slice. Because the T1 shortening effects of gadolinium interfere with the buildup of flow signal, spin-labeled MRI was performed prior to contrast material administration. The single imaging level was chosen from the precontrast, T2-weighted images by guiding a board-certified neuroradiologist. ASL images were acquired using following parameters: repetition time, 3500 ms; echo time, 30 ms; inversion time, 1300 ms; thickness, 6 mm; number of signals acquired, 1; matrix size, 128 64 (3 3 mm in-plane resolution); and imaging time, 4 to 8 minutes. DSCE-CBV Imaging
DSCE-CBV maps were acquired (n = 32) and constructed according to a previously described methodology (20). In brief, either 51 or 46 sequential images per slice, for 11 slices, were acquired over 83 seconds. DSCE-CBV maps were 284
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generated from spin-echo, echo-planar data sets (27). The curve of DR2 versus time for each pixel in each imaged slice was integrated from a time 2 seconds prior to injection through the end of image acquisition. The change in T2 relaxation rate, DR2, is defined as ln(S/S0)(echo time), where S represents signal intensity and S0 the baseline value. The value of DR2 has been shown to be approximately linearly proportional to the concentration of contrast material in tissue (28). By convention, maps were constructed using a standard mathematical ‘‘correction’’ algorithm to compensate for the confounding effects of high-permeability, ‘‘leaky’’ regions of severe BBB breakdown, regions frequently present in necrotic tumor and irradiated tumor beds (28,29). An additional strategy to correct for ‘‘leakiness,’’ also used in this study, has been the administration of a small (4–6 mL) dose of intravenous contrast material just prior to primary data acquisition (28,30–32). Theoretically, this should ‘‘presaturate’’ the peritumoral interstitium in regions of severe BBB breakdown, reducing the distorting effects of subsequent gadolinium ‘‘leakage’’ relative to the baseline T2 signal intensity of such regions (28). Data Analysis
Analyses of magnetic resonance images and the PET results were performed by consensus interpretation by two boardcertified neuroradiologists who were blinded to the tissue diagnosis but unblinded to the earlier conventional prior MRI examinations. DSCE-CBV and ASL images were first rated individually and independently according to the presence or absence of high-grade tumor components, then a consensus was reached for qualitative assessment. ASL and DSCE-CBV images were scored on a three-point scale (0 = definitely no increased perfusion compared to the corresponding contralateral ‘‘normal’’ gray or white matter, 1 = equivocal increased perfusion, 2 = definitely increased perfusion). The quality of ASL images was also rated compared to DSCE-CBV images as inferior, equivalent, or superior with regard to visual conspicuity and lesion boundaries or extent. The technique was defined as superior if better delineation or better coverage of tumor was present or greater sensitivity for small lesions (<3 mm) was found. If the patient had poor contrast in a leaky region or if suboptimal level selection was detected for ASL imaging, the technique was interpreted as inferior. Each modality was independently evaluated in a separate blinded session $2 weeks apart to reduce the potential for bias. Thus qualitative (including conventional MRI) and quantitative interpretations of ASL, DSCE-CBV, and PET imaging were not performed together in the same readout session. For quantitative analyses of the ASL and DSCE-CBV maps, representative 4 4 pixel regions of interest (ROIs) with the lowest possible standard deviation between adjacent pixels were chosen from regions with the highest obtainable signal intensity. This was achieved by manually and repeatedly moving a 4 4 pixel ROI until a region was found that
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had the least standard deviation and minimal partial volume effect between neighboring gray and white matter. Visually definable veins, surgical or presumably necrotic cavities, regions with hemorrhage, and the choroid plexus were specifically avoided. Manually obtained ROIs were normalized by dividing the mean signal intensity of tumor by that of contralateral ‘‘normal’’-appearing brain in a comparable anatomic location. Results were correlated with both the conventional MRI findings and with the clinical-pathologic standard. Specifically, to address the effect of perfusion maps in more ‘‘leaky’’ lesions, patients with mixed high-grade tumor and radiation necrosis, which presumably contain more leaky regions, were separately analyzed. Statistical Analysis
Statistical analyses were performed using a personal computer–based software package (SPSS; SPSS, Inc, Chicago, IL). To compare qualitative data of the nonrecurrence versus recurrence tumor groups, the c2 test was performed for nonparametric analyses. Two-tailed Student’s t tests, assuming unequal variance, were conducted using Microsoft Excel 2000 (Microsoft Corporation, Redmond, WA). P values <.05 were defined as statistically significant. Consistency tests, correlation tests, and Friedman’s tests based on the qualitative analyses (on the three-point scale) were performed for the comparison of ASL, DSCE-CBV MRI, and PET imaging. Binormal receiver-operating characteristic curves were constructed using various cutoff values to define the optimal cutoff values to differentiate radiation necrosis from tumor recurrence.
RESULTS Thirty patients who underwent 35 separate evaluations for predominant radiation necrosis versus predominant recurrent brain tumor were enrolled. Primary diagnoses before PBT were World Health Organization grade II in seven patients, grade III in nine patients, and grade IV in 19 patients. Six of the grade II and three of the grade III gliomas were mixed astrocytoma and oligodendroglioma. The age range was 20 to 69 years (mean, 42 11 years); there were eight women and 22 men. For all 35 evaluations after PBT, histopathology revealed seven predominantly radiation necrosis, five predominant low-grade tumors, and 23 predominant high-grade tumors. The time interval between perfusion MRI and biopsy ranged from <1 day to 4 weeks (mean, 6 8 days). For all but three time points, diagnoses were established by surgical pathology. In the three patients for which biopsies were not available, final diagnoses were established by a minimum of 12 months of stable follow-up without clinical signs of high-grade tumor recurrence or progression. A total of 26 PET, 33 ASL, and 32 DSCE-CBVexams were included for qualitative interpretation. Of these, three
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patients had undergone two ASL examinations, and two patients had undergone two DSCE-CBV examinations. For all modalities, the visual (qualitative) distinction between patients with predominant radiation necrosis or low-grade tumor versus those with predominant high-grade tumor recurrence or progression, as measured by the three-point ranking scale, were statistically significant (c2 test, P < .01). Mean ranking scores for each imaging methods are shown in Table 1. Patients with relative increased perfusion (ranking scores of 3 or 4) in treated tumor beds were diagnosed as having local tumor recurrence or progression (Figs 1 and 2). The sensitivity and specificity of PET, ASL, and DSCE-CBV imaging in detecting predominantly high-grade tumor, based on this visual inspection, are shown in Table 1. The quality of DSCE-CBV versus ASL images was rated as superior in 17, inferior in seven, and equivalent in the remaining eight patients. Reasons for the superiority of DSCE-CBV imaging included better delineation of tumor extent, greater sensitivity for the detection of small lesions, and imaging through the ‘‘suboptimal’’ level with the ASL technique. Reasons for the inferiority of DSCE-CBV imaging included noise from cortical vessels, poor contrast in ‘‘leaky’’ areas of severe BBB breakdown, and technical errors during scanning. DSCE-CBV imaging was judged superior to ASL imaging in both anatomic resolution and coverage in two patients. ASL images were better correlated with PET results compared to DSCE-CBV images. Consistency tests, based on the threepoint qualitative scale, showed good correlation between ASL and PET imaging (k = 0.75), whereas comparisons between ASL and DSCE-CBV imaging (k = 0.47) and also between DSCE-CBV and PET imaging (k = 0.56) did not show good correlations. Quantitative analyses were possible in 23 examinations for ASL imaging and in 19 examinations for DSCE-CBV imaging. ROI measurements could not be obtained in the remainder of the patients, because the original source image digital data were unavailable for analysis. On the basis of the quantitative analysis, binormal receiver-operating characteristic curves were constructed to define the optimal cutoff value; a cutoff value of 1.3 provided the optimal sensitivity and specificity values for the detection of high-grade tumor recurrence for both DSCE-CBV and ASL imaging (Fig 3, Table 2). Because DSCE-CBV imaging might underestimate true blood volume because of leakage artifacts, patients with histologic high-grade tumors with radiation necrosis (mixed histology) were subcategorized. When patients with mixed histology were excluded, sensitivity and specificity values were improved (Table 2). Seventeen of 23 ASL measurements and 15 of 19 DSCE-CBV measurements resulted in the correct categorization of predominant high-grade tumor recurrence, using the cutoff value of 1.3. Mean normalized ROI values and their scatterplot representation, stratified according to final diagnoses for each ASL and DSCE-CBV examination, are summarized in Table 3. Differences between the nonrecurrence and high-grade recurrence groups were 285
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TABLE 1. Distribution of Sensitivity and Specificity Values of Predominantly Recurrent or Progressive Versus Nonrecurrent Highgrade Tumor Modality ASL imaging DSCE-CBV imaging PET imaging Histopathology
Total
Nonrecurrence
Recurrence
Sensitivity
Specificity
33 32 26 35
12 (36%) 10 (33%) 12 (46%) 12 (34%)
21 (64%) 22 (67%) 14 (54%) 23 (66%)
88% 86% 81%
89% 70% 90%
ASL, arterial spin-labeled; DSCE-CBV, dynamic susceptibility contrast-enhanced cerebral blood volume; PET, positron emission tomographic. The findings are based on grading scores on three-point scale for ASL, DSCE-CBV, and PET imaging in patients treated with proton-beam therapy (Friedman’s test, P < .01 for all three comparisons). Consensus rating scores of 0 and 1 indicated nonrecurrence, whereas a score of 2 indicated high-grade recurrence.
Figure 1. A 45-year-old man with a history of attempted resection of grade IV glioma, chemotherapy, proton-beam therapy, and subsequent new abnormal enhancing lesion on follow-up magnetic resonance imaging. Positron emission tomographic image (a) shows ring-shaped hypermetabolism in the right frontal lobe (arrow). Contrast-enhanced T1-weighted axial image (b) illustrates a heterogeneously ring-enhancing lesion at the site of lesion. Both axial arterial spin-labeled (c) and dynamic susceptibility contrast-enhanced cerebral blood volume (d) maps show ring-shaped hyperperfusion in the contrast-enhancing lesion, suggesting predominant high-grade tumor recurrence, which was confirmed on histopathology.
Figure 2. A 47-year-old man with a history of attempted resection of grade IV glioma and proton-beam therapy with new abnormal enhancing lesion on follow-up. Positron emission tomographic imaging (a) shows hypermetabolism at the site of the lesion on contrast-enhanced T1 axial imaging (b). Arterial spin-labeled (ASL) (c) and dynamic susceptibility contrast-enhanced cerebral blood volume (DSCE-CBV) (d) images show hyperperfusion that correlates with the axial postcontrast T1-weighted image. Note that the lesion is more conspicuous on ASL than on DSCECBV imaging. Subsequent surgical resection confirmed predominantly tumor recurrence.
not statistically significant. On the basis of a previously published (20) normalized cutoff value of 1.5 for detection of native, untreated high-grade tumors, sensitivity was found to be 83% for ASL imaging and 80% for DSCE-CBV imaging. When patients with mixed predominantly high286
grade tumors and radiation necrosis were excluded, the sensitivity of DSCE-CBV imaging for predominant tumor improved to 92%, but the sensitivity of ASL imaging did not significantly change. Using quantitative analyses and a cutoff of 1.5, ASL and DSCE-CBV imaging had two
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Figure 3. Receiver-operating characteristic curves for arterial spin-labeled (ASL) and dynamic susceptibility contrast-enhanced cerebral blood volume (DSCE-CBV) images obtained using mean region-of-interest measurement (95% confidence interval for ASL imaging, 0.42–0.97; 95% confidence interval for DSCE-CBV imaging, 0.34–0.97).
TABLE 2. Test Characteristics for the Detection of Predominant Recurrent or Progressive High-Grade Glioma in PBT-treated Patients, Based on Quantitative ROI Analyses, Applying a Cutoff Ratio of 1.3 ASL Imaging
Variable Sensitivity Specificity PPV NPV
DSCE-CBV Imaging
With Mixed Histology
Without Mixed Histology
With Mixed Histology
Without Mixed Histology
(n = 23)
(n = 18)
(n = 19)
(n = 15)
94% 50% 88% 12%
92% 50% 85% 15%
71% 40% 77% 15%
90% 40% 75% 16%
ASL, arterial spin-labeled; DSCE-CBV, dynamic susceptibility contrast-enhanced cerebral blood volume, NPV, negative predictive value; PBT, proton-beam therapy; PPV, positive predictive value; ROI, region of interest. The second and fourth columns represent patients excluding mixed high-grade tumor and radiation necrosis.
TABLE 3. Mean Normalized ROI Values Based on Quantitative ROI Analyses of the Perfusion Map Values, Stratified According to Clinical-pathologic Diagnoses Normalized ROI
Histopathology
ASL Imaging
DSCE-CBV Imaging
(n = 23)
(n = 19)
Predominant radiation 2.0 1.4 (n = 5) 2 1.5 (n = 5) necrosis/low-grade tumor Predominant high-grade 3.9 5 (n = 13) 2.6 1.8 (n = 10) tumor recurrence Radiation necrosis with 4.3 1.6 (n = 5) 1.2 0.3 (n = 4) mixed high-grade tumor The differences between the nonrecurrence and predominantly highgrade recurrence for histopathologic subgroups were not statistically significant (Student’s t test).
false-positive diagnoses of high-grade recurrence, for what were histologically proven to be oligodendrogliomas. In one case of predominant radiation necrosis, ASL measurement was truly negative for high-grade recurrence (0.7), whereas the DSCE-CBV measurement was falsely positive (1.5) (Fig 4).
DISCUSSION Our pilot data confirm previous literature that has suggested that both susceptibility-based DSCE-CBV and ASL MRI techniques may be of value in assessing tumor grade on the basis of neovascularity. These methods provide high sensitivity for distinguishing predominant recurrent malignant glioma from predominant radiation necrosis, with values comparable to or surpassing those of PET imaging (1,20,29,33–38). Our data extend the literature by documenting that the ASL technique may provide higher sensitivity and specificity values than DSCE-CBV imaging in some patients. Comparison of ASL technique to DSCE-CBV and PET imaging in patients with irradiated primary brain tumors has not previously been emphasized in the literature. In our study, qualitative analyses of ASL images provided higher sensitivity (88%) and specificity (89%) compared to both DSCE-CBVand PET imaging in detecting predominant tumor recurrence in patients after treatment with PBT. When quantitative analyses were performed, the sensitivity values were increased. The low sensitivity of DSCE-CBV findings likely arose from vascular leakage, probably caused by radiation necrosis (Fig 4). Radiation therapy has been shown to induce breakdown of the BBB and vascular leakage (6). In instances of approximately equally mixed combined 287
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Figure 4. A 58-year-old man with grade IV glioma and a history of attempted resection, proton-beam therapy, and with a new enhancing lesion on follow-up magnetic resonance imaging. Positron emission tomographic imaging (not shown) shows hypometabolism at the site of the abnormally enhancing left parieto-occipital lesion on contrast-enhanced T1-weighted axial image (a). Whereas the arterial spin-labeled (ASL) image (b) shows hypoperfusion, the dynamic susceptibility contrast-enhanced cerebral blood volume (DSCE-CBV) image (c) shows hyperperfusion of the enhancing lesion that is surrounded with hypoperfused region due to vasogenic edema. Histopathology of this lesion confirmed radiation necrosis. This case therefore demonstrates ‘‘true-negative’’ ASL and ‘‘false-positive’’ DSCE-CBV findings.
malignant tumor recurrence superimposed on radiation necrosis, vascular leakage may be exaggerated, and this may not be fully compensated for during CBV map construction by our standard mathematical correction algorithms. Quantitative analyses of astrocytomas have also documented that tumor DSCE-CBV is reduced after radiotherapy compared to pretreatment levels and that this reduction is dose dependent (19). Other possible reasons for falsely low DSCECBV sensitivity are intratumoral susceptibility artifacts due to recent hemorrhage (deoxyhemoglobin) or chronic hemosiderin deposition (39–41). Mixed primary brain tumor with radiation necrosis after surgery, chemotherapy, and radiation therapy is relatively common. In one study, an even mix of tumor recurrence and radiation necrosis was found in 33% of patients with gliomas who received external-beam radiotherapy and subsequently underwent biopsy to distinguish tumor recurrence from radiation necrosis (42). ASL imaging may be of benefit for high-grade tumor detection in these instances because it is theoretically less likely to be affected by the BBB breakdown, which is exceedingly common within these patients (20); the correlation (k = 0.75) between ASL and PET imaging may support this hypothesis. We did not report the individual specificity values for the visual interpretation of the ASL, DSCECBV, and PET maps because visual interpretation of these functional maps was of necessity performed in conjunction with that of conventional MRI findings, and thus we felt that it could not be interpreted separately from these data. Quantitative analyses of ASL provided the highest sensitivity (94%) for differentiating nonrecurrence from malignant recurrence using a cutoff value of 1.3. Using the same normalized threshold value of 1.3, ASL showed only one false-negative result. A DSCE-CBV cutoff value of 1.5 has provided 288
high sensitivity for grading native glial tumors in the literature (20,27). In other studies that have focused on grading native tumors using perfusion imaging (12,38,43–45), relative DSCE-CBV values greater than 1.3 (46) 1.5 (45), 1.7 (35), and 1.8 (47) have also been shown to indicate high-grade tumors. Using a threshold value of 1.5 for ASL imaging, we identified three patients with false-positive results, including one with predominant radiation necrosis and two with lowgrade tumors. When the quality of ASL and DSCE-CBV images was compared, DSCE-CBV images were found to be superior. Relative CBV provided both better delineation of tumor borders and greater sensitivity for the detection of small lesions, in part related to the higher intrinsic spatial resolution of DSCE-CBV compared to ASL maps. However, the DSCE-CBV images appeared to falsely underestimate tumor extent relative to ASL specifically in leaky regions of BBB breakdown (Fig 1). The ASL technique has limitations. The single-slice method used for this study, despite a high signal-to-noise ratio, has lower spatial resolution than DSCE-CBV imaging. Other limitations of spin-labeled techniques include long imaging times (4–8 min/slice) and the inability to image following gadolinium administration. ASL imagin cannot be performed after gadolinium administration because it shortens the T1 of blood and therefore reduces the buildup of inflowing signal, causing a severe degrading of signal-to-noise ratio in the subtracted image. Another confounding factor is the ‘‘amplification’’ of flow signal proportional to the difference in T1 between blood and tissue, because incoming blood contains spins that relax more slowly than those in adjacent tissue. Different tissues such as gray and white matter are amplified differently, which distorts quantitative flow maps. Also, partial
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volume averaging of cerebrospinal fluid with brain parenchyma results in an underestimation of flow values (48). Ours is a preliminary pilot study and had limitations. The sample size was small, and multislice ASL imaging was not technically possible at the time of our study. Therefore, we obtained only one image slice, which could have introduced selection bias. New studies are needed to address our hypothesis with high-quality multislice ASL techniques that can be acquired using whole-brain or near-whole-brain coverage pulsed ASL or continuous ASL methods. The technical variations may potentially cause bias. We also had a relatively small number of nonrecurrence patients (n = 5 for both ASL and DSCE-CBV imaging), which may have introduced error into the specificity calculation. This was a retrospective study without standardization of chemotherapy, PBT, or photon radiotherapy, although our patient group likely reflects our daily clinical practice, the very common clinical issue of ‘‘patient with history of glioma, after surgery and/or radiation therapy with a new enhancing abnormality.’’ Moreover, because of the nature of gliomas, the brain tissue being imaged is likely to contain residual tumor in most, if not all, patients, even those with predominant radiation necrosis. Because wide surgical margins were not uniformly obtained, sampling error may also have occurred. Because not all patients had surgical pathologic correlation, our assumption that clinically stable patients (without imaging or clinical evidence of progression on long-term follow-up) were without significant recurrent or progressive tumor cannot be validated. Further studies using a larger group of more standardized patients with direct pathologic correlation, multilevel new ASL techniques (49), especially with higher magnetic strength enabling shorter scanning times (50), may be indicated on the basis of our pilot results.
CONCLUSION In this small and highly selected preliminary cohort of PBTtreated patients with gliomas, the ASL technique provided more conspicuous differentiation of predominant recurrent high-grade glioma from predominant radiation necrosis, compared to both DSCE-CBV MRI and PET imaging. The greater sensitivity for detection of recurrent high grade glioma compared to DSCE-CBV imaging may in large part relate to the underestimation of DSCE-CBV in regions of marked BBB breakdown (‘‘leakiness’’) with the use of the DSCE-CBV technique. Increased cerebral blood flow on ASL imaging for newly enhancing lesions within a previously irradiated field strongly suggests predominant tumor recurrence as opposed to predominant radiation necrosis. Thus, despite the limitations of our pilot study, our results support the hypothesis that ASL imaging may have advantages over conventional MRI, DSCE-CBV MRI, and FDG-PET imaging in glioma follow-up. The addition of ASL MRI to the diagnostic imaging surveillance of treated brain tumors likely warrants further study based on our pilot results.
ASL VERSUS DSCE-CBV
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