Utility of Percentage Signal Recovery and Baseline Signal in DSC-MRI Optimized for Relative CBV Measurement for Differentiating Glioblastoma, Lymphoma, Metastasis, and Meningioma

BACKGROUND AND PURPOSE: The percentage signal recovery in non-leakage-corrected (no preload, high flip angle, intermediate TE) DSC-MR imaging is known to differ significantly for glioblastoma, metastasis, and primary CNS lymphoma. Because the percentage signal recovery is influenced by preload and pulse sequence parameters, we investigated whether the percentage signal recovery can still differentiate these common contrast-enhancing neoplasms using a DSC-MR imaging protocol designed for relative CBV accuracy (preload, intermediate flip angle, low TE). MATERIALS AND METHODS: We retrospectively analyzed DSC-MR imaging of treatment-naïve, pathology-proved glioblastomas (n = 14), primary central nervous system lymphomas (n = 7), metastases (n = 20), and meningiomas (n = 13) using a protocol designed for relative CBV accuracy (a one-quarter-dose preload and single-dose bolus of gadobutrol, TR/TE = 1290/40 ms, flip angle = 60° at 1.5T). Mean percentage signal recovery, relative CBV, and normalized baseline signal intensity were compared within contrast-enhancing lesion volumes. Classification accuracy was determined by receiver operating characteristic analysis. RESULTS: Relative CBV best differentiated meningioma from glioblastoma and from metastasis with areas under the curve of 0.84 and 0.82, respectively. The percentage signal recovery best differentiated primary central nervous system lymphoma from metastasis with an area under the curve of 0.81. Relative CBV and percentage signal recovery were similar in differentiating primary central nervous system lymphoma from glioblastoma and from meningioma. Although neither relative CBV nor percentage signal recovery differentiated glioblastoma from metastasis, mean normalized baseline signal intensity achieved 86% sensitivity and 50% specificity. CONCLUSIONS: Similar to results for non-preload-based DSC-MR imaging, percentage signal recovery for one-quarter-dose preload-based, intermediate flip angle DSC-MR imaging differentiates most pair-wise comparisons of glioblastoma, metastasis, primary central nervous system lymphoma, and meningioma, except for glioblastoma versus metastasis. Differences in normalized post-preload baseline signal for glioblastoma and metastasis, reflecting a snapshot of dynamic contrast enhancement, may motivate the use of single-dose multiecho protocols permitting simultaneous quantification of DSC-MR imaging and dynamic contrast-enhanced MR imaging parameters.

C onventional MR imaging cannot always differentiate contrast-enhancing malignant brain tumors, including glioblastoma, primary central nervous system lymphoma (PCNSL), and cerebral metastasis. 1 Meningioma and dural-based metastasis may also appear similar on conventional MR imaging. Because management differs for these tumors, timely and accurate identification is imperative. Perfusion-weighted MR imaging can help characterize brain tumors, and DSC-MR imaging is the most popular method for measuring brain perfusion with MR imaging. 2 By tracking T2*-weighted signal changes during the first passage of a gadolinium-based contrast agent bolus, relative cerebral blood volume (rCBV) compared with normal-appearing white matter (NAWM) and percentage signal recovery (PSR) compared with baseline can be calculated. 3 rCBV reflects tumor neoangiogenesis and correlates with glioma grade. 4 The PSR reflects a complex interplay of capillary permeability related to blood-brain barrier integrity and contrast agent extravasation from tumor capillaries, as well as tumor cell size and cell density. 5 Because glioblastoma and lymphoma have a disrupted BBB, which is absent in metastases and meningiomas, gadoliniumbased contrast agent extravasates in these tumors, inducing T1 and T2* shortening that obfuscates rCBV measurements. Preload contrast agent administration helps mitigate these leakage effects, rendering rCBV measurements more accurate. 6,7 However, the introduction of a preload dose impacts PSR measurements, because Bell et al 8 demonstrated that PSR in high-grade gliomas decreases with increasing preload dose. Likewise, Boxerman et al 9 demonstrated that while T1-sensitive DSC-MR imaging acquisitions with a high flip angle (FA) and short-TE yield increased PSR in high-grade gliomas, preload administration diminishes the variation in PSR measured with different protocols. Therefore, a trade-off exists for DSC-MR imaging acquisition parameters between PSR sensitivity and rCBV accuracy. PSR has been shown to significantly differ among glioblastoma, PCNSL, and metastasis when using a non-leakage-corrected protocol optimized for PSR sensitivity with a high FA, intermediate TE, and without preload at 1.5T. 10 However, DSC-MR imaging performed for rCBV measurement often includes a preload dose of contrast to minimize contrast agent leakage effects. 7 This study aimed to determine whether the PSR can still differentiate these common contrastenhancing brain tumors using a preload-based, intermediate-FA, low-TE DSC-MR imaging protocol designed for rCBV accuracy. 2,6

Image Postprocessing
A neuroradiologist with 15 years' post-Certificate of Added Qualification experience semiautomatically segmented contrast-enhancing lesion volumes on postcontrast T1-weighted images using the IB Delta Suite plug-in (Imaging Biometrics, Elm Grove, Wisconsin) for OsiriX-MD (http://www.osirix-viewer.com), avoiding necrosis and susceptibility artifacts. For normalization, a 70-to 80-mm 2 elliptic ROI was placed in the contralateral NAWM. We computed rCBV maps using commercial software (OsiriX Pro Version 2.04 and IB Neuro Version 1.1, Imaging Biometrics) that incorporates a postprocessing leakage-correction algorithm and normalized CBV to mean CBV in NAWM (rCBV). 4,11 Voxels with subzero rCBV were excluded from the final analysis. PSR was calculated for each voxel using the following formula: PSR ϭ (S 1 Ϫ S min )/(S 0 Ϫ S min ), where S 0 is the baseline signal intensity (SI) averaged over the first 10 time points, S 1 is the tail averaged over the last 10 time points, and S min is the minimum SI in the dynamic series. PSR maps were generated without postprocessing leakage correction using Matlab and Statistics Toolbox Release 2017b (MathWorks, Natick, Massachusetts). In addition to rCBV and PSR, we also computed the normalized baseline DSC-MR imaging signal as S 0,tumor /S 0,NAWM . To qualitatively compare signal-time curves for the different tumor types, we computed the population-average relative signal-time curves as S tumor (t)/S 0,tumor for each of the 4 tumor types.

Statistical Analysis
All modeling was performed using SAS Software, Version 9.4 (SAS Institute, Cary, North Carolina) with the LOGISTIC and GLIMMIX procedures. Mean and interval estimates were calculated for rCBV, PSR, and normalized baseline signal S 0 by tumor pathology using generalized linear modeling, assuming a log-normal distribution. Receiver operating characteristic analysis was performed for each parameter and each pair-wise comparison to calculate the area under the curve (AUC). The Youden Index was used to examine the diagnostic performance of different thresholds, though empiric thresholds should be interpreted with caution. 12 Somers D, a measure of the correlation between variables that are not both continuous (ranging between Ϫ1.0 and 1.0 like the Pearson r), was calculated to estimate the correlation between measured parameters (rCBV, PSR, S 0 ) and tumor type. All interval estimates were calculated for 95% confidence.

DISCUSSION
This study evaluated the utility of PSR for differentiating common contrast-enhancing brain tumors using a DSC-MR imaging protocol designed for rCBV accuracy (preload contrast administration, intermediate FA, low TE). 3 Because treatment of glioblastoma multiforme, brain metastasis, and PCNSL differs substantially, a definitive diagnosis at initial imaging may impact shortterm patient management, including subsequent diagnostic tests. Similar to results obtained by Mangla et al 10 for PSR-optimized acquisitions (no preload, high FA, intermediate TE), rCBVoptimized PSR differentiates most pair-wise comparisons of glioblastoma, metastasis, PCNSL, and meningioma. However, our results failed to confirm that PSR is strictly better than rCBV in differentiating tumors. Moreover, neither rCBV nor PSR differentiated glioblastoma and metastasis, which is arguably the most difficult distinction in clinical practice. Thus, our results indicate that rCBV-optimized protocols using preload and parameters with reduced T1 sensitivity may suppress the PSR differences previously demonstrated by PSR-optimized protocols without preload.
Diagnosing PCNSL is important because the first-line treatment for PCNSL is chemotherapy, not surgical resection. 13 We found that, consistent with prior studies, 10,14 PCNSL has lower  rCBV and higher PSR than glioblastoma and metastases; however, we found that the PSR is not strictly better than rCBV at differentiating PCNSL from other types of tumors. While PSR differentiated PCNSL from metastasis better than rCBV, both parameters achieved similar diagnostic performance when differentiating PCNSL from glioblastoma or meningioma. Even with onequarter-dose preload, PCNSL signal recovery consistently exceeded baseline, similar to studies without preload. PSR Ͼ 1 in the setting of elevated rCBV appears to be a particularly simple and effective way to render a prospective, preliminary diagnosis of PCNSL versus other common intra-axial tumors and non-neoplastic pathologies like tumefactive infectious or inflammatory lesions. High PSR exceeding unity is characteristic of PCNSL and reflects the dominance of T1 over T2* effects during the "tail" of the signal-time curve. Although the mechanisms dictating the competition between T1 and T2* effects are complex, tumor vascularity, permeability, cellular features, contrast agent kinetics, pulse sequence parameters, and preload dose all appear to play a role. The unique histologic and physiologic features of PCNSL, such as dense cellularity, small cell size, angiocentric growth pattern, and absence of neoangiogenesis, likely contribute to the characteristically high PSR. 15 By comparison, glioblastoma exhibits greater neoangiogenesis, capillary heterogeneity, and microvascular density. 16 Higher doses of preload may diminish the high PSR of PCNSL, but no studies have evaluated the effect of preload dosing in PCNSL. We included meningiomas because they can closely resemble dural-based metastases on conventional imaging, and differentiation using DSC-MR imaging would have clinical value. We found that meningiomas have significantly higher rCBV than the other tumors, consistent with a prior case series, 17 primarily owing to the tendency for the meningioma signal-time curve to drop and remain below baseline, resulting in a low PSR. Extra-axial tumors lack a BBB and therefore are expected to have greater contrast extravasation than intra-axial tumors. Contrast-enhancing lesions with an appropriate combination of cell size and density in the absence of a BBB may have postbolus signal-time curves that stay suppressed below the baseline signal, consequently producing artifactually higher rCBV measurements on integration of ⌬R2*(t). Therefore, it is possible that the reportedly high rCBV for meningioma may reflect low PSR more so than exceptionally high vascular density.
Our study included only intra-axial metastases, and it is unclear whether the rCBV, PSR, and baseline signals of intra-axial metastases are generalizable to dural-based metastases. Extra-axial tumors, for instance, likely have different first-pass kinetics than intra-axial tumors owing to complete absence of the BBB, consequent substantial contrast extravasation and blood pool phase, variable vascularity, and the potential presence of intralesion mineralization. First-pass enhancement may also be more difficult to differentiate from recirculation enhancement in extraaxial tumors. Our results are consistent with 1 study that found significantly higher CBV in 16 meningiomas compared with 6 dural-based metastases, 18 but another study of 12 meningiomas and 8 dural-based metastases found no significant difference in rCBV. 19 Although it is unclear whether preload administration has a substantial impact on CBV estimation in extra-axial lesions given the substantial degree of contrast agent extravasation, neither of these studies used a preload. Whereas the former used a TE (28 ms) and FA (45°) close to currently accepted optimal values for CBV accuracy, 20 the latter did not (8 ms, 7°); this difference could impact CBV estimation. The conclusions of these studies may also differ because of small sample sizes, varying primary tumor types for metastases, 21 and varying grades for meningiomas. 22 We achieved only modest discrimination of metastasis and meningioma using PSR, which was lower for meningiomas than metastases. In light of BBB differences, it is probably best to conclude that if the PSR and CBV of dural-based lesions differ appreciably from those that we found for meningiomas, the lesion is more likely to be a dural-based metastasis. As the signal-time curve becomes more similar to that for meningiomas, with lower PSR and CBV, then the diagnosis is less certain.
Of all pair-wise comparisons, distinguishing a solitary cerebral metastasis from glioblastoma is the most vexing clinical scenario in our experience. We did not observe a significant difference in the rCBV or PSR between glioblastoma and metastasis. These results are consistent with 1 recent study 23 (TE ϭ 80 ms, no preload) but contradict prior no-preload studies (TE ϭ 50 ms, FA ϭ 80°; TE ϭ 54 ms, FA ϭ 35°) that found significantly higher rCBV and PSR in glioblastomas than in metastases. 10,24 Our use of preload and pulse sequence parameters with greater T2* sensitivity appears to have eliminated these PSR differences. While other studies have found that rCBV in peritumoral nonenhancing FLAIR hyperintensity is significantly greater for glioblastoma than metastasis, we restricted our analysis to contrast-enhancing voxels. 10,23 Although rCBV and PSR could not differentiate glioblastoma from metastasis, we found that glioblastoma exhibits significantly higher normalized baseline signal than metastasis. No previous DSC-MR imaging studies have reported differences in baseline signal after preload administration, to our knowledge. Because baseline signal was measured after preload administration, it provides a snapshot of dynamic contrast-enhanced (DCE)-MR imaging and may serve as a proxy for extravascular extracellular volume (V e ) and/or volume transfer constant (k trans ). Because metastatic capillaries lack a BBB, greater contrast agent extravasation is expected than in glioblastoma, which possesses a BBB, albeit a heterogeneous, disrupted one. 25,26 Greater leakage of contrast agent within metastases should increase its distribution within the extravascular extracellular space, which is more restricted in glioblastomas by densely packed capillary buds composing the microvasculature. 27 Our imaging protocol appears to uncover these differences in contrast agent extravasation after preload administration, though DSC-MR images were not acquired before preload administration, precluding a comparison of baseline signal before any contrast agent administration. Our results are consistent with a prior DCE-MR imaging study reporting higher k trans in glioblastoma versus metastasis 28 and PSR-optimized DSC-MR imaging studies reporting higher PSR in glioblastoma versus metastasis. 10,24,29 Differences in contrast agent leakage are also supported by a DCE-MR imaging study finding that the SI of glioblastoma and melanoma/hypervascular metastasis remained high after contrast agent administration, whereas the signal of nonmelanoma/hypovascular metastasis decreased. 30 Our results support the pursuit of DCE-MR imaging to differentiate glioblastoma and metastasis. DSC-MR imaging paradigms that perform DCE-MR imaging during the administration of the preload dose 31 or multiecho pulse sequences that acquire DCE-MR imaging data in conjunction with CBV-optimized DSC-MR imaging using a single contrast agent dose 32 may provide the opportunity for comprehensive brain tumor analysis with better differentiation of glioblastoma and metastasis.
In our cohort, PCNSL has greater PSR than glioblastoma but similar baseline signal. This discrepancy may be due to histologic differences affecting the degree to which preload controls T1 leakage effects. The high PSR in PCNSL suggests that the dose of preload used in the present study did not adequately control T1leakage effects. We expect a preload concentration that fully saturates the extravascular space in PCNSL to result in a lower PSR.
Thus, it appears that preload dose-dependent decreases in PSR may differ for different types of tumors.
Further investigation is warranted for determining how to best differentiate brain tumors, especially glioblastoma and metastasis. While guidelines exist, there is no consensus on optimal DSC-MR imaging methodology for brain tumors. 2 Protocol standardization would facilitate comparisons of data among institutions. Given that preload affects PSR, DSC-MR imaging protocols that retain rCBV accuracy without preload may be useful. Such a protocol has recently been shown to provide very accurate rCBV estimates 20 but requires use of a low FA (30°) that would likely suppress PSR differences due to reduced T1-weighting. Multiparametric imaging protocols that combine DCE-MR imaging acquisition during preload administration and DSC-MR imaging offer comprehensive signal morphology analysis and may further characterize and differentiate tumors. Additionally, multiecho DSC-MR imaging protocols have been developed that combine simultaneous gradient-echo acquisitions at different TEs to eliminate T1 effects without preload for accurate rCBV estimation, with a high-FA acquisition providing PSR weighting that may help provide tumor differentiation. 2,32 Single-dose multiecho protocols also enable simultaneous quantification of DCE-MR imaging parameters. 33 While the discrepancies between the results of our study and those of Mangla et al 10 are most likely due to differences in DSC-MR imaging parameters, there are other methodologic differences that may have impacted our comparisons. Mangla et al included patients who had been treated with steroids and patients with presumed metastatic disease without biopsy. In contrast, all of our cases were treatment-naïve and biopsy-proved, so our analysis is less susceptible to treatment effects and selection bias.
There are several limitations to our study. Because this was a retrospective study, we did not control for the elapsed time between preload administration and the DSC-MR imaging acquisition. However, preload incubation time is unlikely to significantly impact our results because previous studies have shown that the enhancement of gliomas and metastases does not significantly decline during the first 25-30 minutes after contrast injection, 34 and preload incubation times of 5-10 minutes do not affect rCBV estimates in glioblastomas. 6 Our study is also limited by the sample size. Because TR, TE, FA, and field strength all affect baseline signal and PSR, we only analyzed our largest cohort of patients scanned with the same pulse sequence parameters and field strength. We also did not differentiate metastases by primary tumor type, which may be associated with PSR differences.

CONCLUSIONS
With a protocol designed for rCBV accuracy that incorporates preload and intermediate FA, PSR failed to differentiate glioblastoma from metastasis but could differentiate other pair-wise comparisons of glioblastoma, PCNSL, metastasis, and meningioma. This finding differs from those in previous studies in which PSR-optimized DSC-MR imaging (no preload, high-FA) significantly differentiated glioblastoma and metastasis. 10 However, differences in post-preload baseline signal between glioblastoma and metastasis, reflecting tissue-specific competing T1 and T2* leakage effects, motivate pursuit of DCE-MR imaging and no-preload DSC-MR imaging as tools for differentiating glioblastoma and metastasis. Future directions include assessment of tumor differentiation using PSR obtained with a rCBV-accurate DSC-MR imaging protocol without preload and single-dose multiecho protocols that permit simultaneous quantification of DSC-MR imaging and DCE-MR imaging parameters.