Semiquantitative Assessment of Intratumoral Susceptibility Signals Using Non-Contrast-Enhanced High-Field High-Resolution Susceptibility-Weighted Imaging in Patients with Gliomas: Comparison with MR Perfusion Imaging

Materials and Methods

Image Analysis

For qualitative image analysis, conventional MR images and HR-SWIs were assessed by 2 experienced radiologists. Intratumoral calcifications or macrohemorrhages, which could cause susceptibility signals on HR-SWI, were excluded on the basis of low signals in conventional MR imaging, including gradient-echo images, and susceptibility artifacts detected on diffusion-weighted images (DWIs) and DSC images. We detected several microbleeds that were not related to tumor, in the bilateral basal ganglia and thalami, associated with small vessel disease in 2 patients. However, we did not detect any lobar microbleeds, small cavernoma, or incidental calcification on HR-SWI, conventional gradient-echo, DWI, and DSC images.

ITSS was defined as low signal intensity and a fine linear or dotlike structure, with or without conglomeration, seen within the tumor on HR-SWI. We assessed the presence or absence of ITSS in each tumor and compared the incidence of ITSS between high- and low-grade gliomas. We also determined the specific morphology of the ITSS and reached a consensus as to which type was predominantly seen in each high- or low-grade glioma. The morphology of the ITSS was classified into 3 categories: conglomerated dots, conglomerated fine linear structures, and dots mixed with fine linear structures (Fig 1).

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Fig 1.

The morphology of ITSS. A, Conglomerated fine linear (arrows) ITSSs. B, Mixed dots (arrows) and fine linear (arrowheads) ITSSs.

For the quantitative or semiquantitative analysis, the degree of ITSS was divided into 4 grades: grade 0, no ITSS; grade one, 1–5 dotlike or fine linear ITSSs; grade two, 6–10 dotlike or fine linear ITSSs; and grade 3, ≥11 dotlike or fine linear ITSSs in the continuous area within a tumor. Normalized rCBV maps were calculated on a pixel-by-pixel basis by dividing pixel rCBV values by the mean rCBV value of the contralateral normal-appearing white matter of the centrum semiovale. The size of the region of interest in the contralateral normal white matter was kept constant (diameter, 3 mm). Coregistration between the HR-SWIs and the normalized rCBV maps was performed on the basis of geometric information stored in the respective datasets. The normalized rCBV maps were displayed as color overlays on the HR-SWIs. Four separate regions of interest were designated in the region of maximum abnormalities within the same tumor segments, including maximum degree of ITSSs as determined visually on the coregistered HR-SWI and rCBV map. The size of the region of interest was kept constant (diameter, 1.5 mm), and the rCBVmax value among the 4 regions of interest was recorded. This maximum value of the region of interest analysis has been reported to provide the highest intraobserver and interobserver reproducibility in MR perfusion measurements.¹⁶

We assessed the level of interobserver variability for the degree of ITSS and rCBVmax measurements and calculated the correlation coefficient between the degree of ITSS and the rCBVmax obtained from DSC. The degree of ITSS and rCBVmax was compared among WHO grades II, III, and IV, and the correlation coefficients between the ITSS degree or rCBVmax and glioma grade were determined. Finally, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of HR-SWI were calculated for the correct identification of high-grade (WHO grades III and IV) and low-grade (WHO grade II) gliomas. The sensitivity and specificity were estimated by using standard statistical formulas and were based on the consensus data from the quantitative measures.

Results

Of the 41 tumors, 12 were low-grade astrocytomas (WHO grade II), 7 were anaplastic astrocytomas (WHO grade III), and 22 were glioblastoma multiformes (WHO grade IV).

In the qualitative analysis, the ITSSs were seen in 22 (100%) of 22 glioblastoma multiformes (WHO grade IV) and in 3 (43%) of 7 anaplastic astrocytomas (WHO grade III). There was no evidence of ITSS in low-grade astrocytomas (WHO grade II). On HR-SWI, these ITSSs were usually located in the inner portion of the contrast-enhancing rim on contrast-enhanced T1-weighted images. Regarding the morphology of the ITSSs, conglomerated mixed fine linear and dotlike ITSSs were most frequent in glioblastomas, and the fine linear ITSSs were seen in all anaplastic astrocytomas. The fine linear or dotlike ITSSs partly corresponded with the regions of visual rCBVmax on coregistered images of HR-SWI and normalized rCBV maps. However, densely prominent ITSSs did not correspond with the regions of visual rCBVmax.

In the quantitative analysis, interobserver agreement for the degree of ITSS and rCBVmax was excellent for determining the degree of ITSS (ICC = 0.93) and for measuring rCBVmax (ICC = 0.82). The degree of ITSS showed a significant correlation with the value of rCBVmax in the same tumor segments (r = 0.72, P < .0001; Figs 2⇓⇓–5). The Kruskal-Wallis test showed that the degree of ITSS was significantly different among all 3 grades (P < .005). Tables 1 and 2 list the sensitivity, specificity, PPV, and NPV of ITSS degree and rCBVmax for differentiating among the 3 groups with various histopathologic grades. The Spearman correlation coefficient between the degree of ITSS and the glioma grade was 0.88 (95% [CI], 0.79–0.94). In the ROC curve analysis with histopathologic correlation, optimal sensitivity, specificity, PPV, and NPV to determine a high-grade glioma by using the ITSS degree and rCBVmax were 85.2%, 92.9%, 95.8%, and 76.5%, respectively, listed in Table 3, and 92.6%, 85.7%, 92.6%, and 85.7%, respectively, listed in Table 4, (Fig 6).

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Fig 2.

MR images of a 39-year-old woman with left frontal low-grade astrocytoma (WHO grade II). A, The axial T2-weighted image shows an ill-defined mass with high signal intensity in the left frontal lobe. B, HR-SWI demonstrates no evidence of the ITSS. C, Corresponding rCBV map shows relatively low rCBVmax values of 1.31.

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Fig 3.

MR images of a 53-year-old man with a right frontal anaplastic astrocytoma. A, The contrast-enhanced axial T1-weighted image shows an ill-defined mass with minimal contrast enhancement. B, HR-SWI demonstrates a few fine linear and dotlike ITSSs (white circle) in the peripheral area. C, Corresponding rCBV map shows a high rCBVmax value of 2.53 in the tumor segment, including maximum degree of ITSS.

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Fig 4.

MR images of a 55-year-old man with a glioblastoma multiforme. A, The contrast-enhanced axial T1-weighted image shows a mass with irregular peripheral rim enhancement in the right parietal lobe. B, HR-SWI reveals conglomerated fine linear ITSSs just in the inner portion of the enhancing rim on the contrast-enhanced T1-weighted image. C, Corresponding rCBV map shows high rCBVmax values (4.71) in the tumor segment, including a maximum degree of ITSS. D, Coregistered image of HR-SWI and rCBV shows that the area of attenuated prominent ITSSs (arrows) does not correspond with the area of visual rCBVmax, and the area of fine linear ITSSs partly corresponds with the area of visual rCBVmax. E, Corresponding histopathologic specimen (CD34 vessel staining, original magnification ×10) demonstrates pseudopalisading necrosis (black arrows) and tumor vessels (white arrows).

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Fig 5.

Scatterplot shows the correlation between the degree of ITSS and rCBVmax within the same tumor segment (r = 0.72; 95% CI, 0.53–0.84).

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Fig 6.

The comparison of ROC curve analysis between the degree of ITSS and rCBVmax for correctly identifying a high-grade glioma (WHO grades III and IV). The AUC for the degree of ITSS is 0.919 (95% CI, 0.790–0.980) and that for the rCBVmax is 0.947 (95% CI, 0.828–0.991). The P value for the difference between the 2 AUCs is .54.

Discussion

The main finding of this study was that the degree of ITSS showed a significant correlation with the value of rCBVmax in the same tumor segments. On the other hand, the direct correspondence between the areas of ITSS and rCBVmax was variable. The specific morphologic patterns (fine linear and dotlike) of ITSS partly corresponded with the areas of visual rCBVmax. However, the areas of densely prominent ITSSs did not accurately correspond with the areas of visual rCBVmax. HR-SWI demonstrated the highest degree of ITSS in glioblastoma multiformes, suggesting that ITSSs can be a potentially helpful sign for a correct diagnosis of high-grade gliomas. The ITSSs were seen in all glioblastomas, though the degree was somewhat different in each tumor and was never seen in low-grade gliomas (grade II). In anaplastic astrocytomas, the degree of ITSS was variable. We also found that the diagnostic performance of HR-SWI for grading gliomas was comparable with that of DSC. In the ROC curve analysis, the diagnostic accuracy of HR-SWI for determining high-grade glioma was relatively high. The specificity and PPV of the high degree (grade II or more) of ITSS for determining high-grade gliomas were high.

MR perfusion is currently one of the best imaging techniques for the evaluation of glioma grade. The rCBV and K^trans have been reported as reliable parameters in glioma grading.^7–9 Recently, HR-SWI has been described as a useful tool for noninvasive glioma grading.^11,12,17 High rCBV values on perfusion imaging in tumors go hand in hand with evidence of blood products detected within the tumor matrix on HR-SWI.¹⁰ On the other hand, probably related to the angiogenesis and increased tumor blood supply, high-grade gliomas contain a relatively large amount of deoxyhemoglobin, which generates susceptibility effects and causes signal-intensity loss.¹¹ Pinker et al¹² reported that intralesional susceptibility effects were correlated with tumor grade, as determined by PET and histopathology, and that by direct comparison of intralesional susceptibility effects with the histopathology, intratumoral susceptibility effects reflected conglomerates of tumor microvascularity. As described in previous reports,^10,11 the detection of ITSS in higher grade gliomas not only reflects tumor vascularity but also indicates considerable susceptibility in areas of macro- and micronecrosis in higher grade gliomas. In the present study, the degree of ITSS showed a significant correlation with the value of rCBVmax in the same tumor segments.¹⁰ However, the areas of the highest ITSSs did not accurately correspond with the areas of visual rCBVmax on the coregistered HR-SWI and rCBV maps because ITSS can reflect considerable susceptibility associated with tumor necrosis and microhemorrhage as well as tumor vascularity. The fine linear or dotlike ITSSs partly corresponded with the regions of visual rCBVmax on coregistered images of HR-SWI and rCBV map.

With the advent of 3T MR imaging scanners and parallel imaging techniques, the acquisition time of HR-SWI is not exhaustive, compared with conventional gradient-echo techniques. As shown previously,^4–6,17 HR-SWI can provide valuable additional information in pathologic brain disorders. Moreover, contrary to a previous report,¹⁷ HR-SWI, as included in our imaging protocol, allowed coverage of the whole brain within the acquisition time mentioned above. At our institution, we could acquire HR-SWI with reasonable spatial resolution within 4 minutes, and our routine brain MR imaging protocol now includes non-contrast-enhanced HR-SWI.

Several previous studies have proposed that HR-SWI should be performed with contrast enhancement, because the contrast agent can shorten T1-relaxation times of blood; therefore, the extra phase shift could improve signal-intensity cancellation at shorter acquisition times and thus result in a shorter scanning time.^11,12,17 Moreover, Mittal et al¹⁰ proposed that hemorrhages can be easily distinguished from veins if HR-SWI is performed both before and after administration of contrast agent. Blood vessels will change their signal intensity due to the contrast agent, but signal intensity from hemorrhage will not change.¹⁰ However, routine MR imaging protocols for brain tumors usually include contrast-enhancement studies such as contrast-enhanced T1-weighted imaging and perfusion MR imaging. Therefore, the combination of HR-SWI and contrast enhancement does not provide an added value in diagnostic accuracy or acquisition time for glioma grading. In the present study, we performed HR-SWI without contrast administration. If the diagnostic accuracy of noncontrast-enhanced HR-SWI for glioma grading was comparable with that of perfusion MR, currently the best imaging technique for glioma grading, we would expect that a non-contrast-enhanced MR imaging protocol could be performed in routine brain tumor imaging. In the present study, the diagnostic accuracy, including sensitivity and specificity, of noncontrast-enhanced HR-SWI for glioma grading was comparable with that of DSC.

Our study has several limitations. First, the T2* first-pass technique is fairly sensitive to minor susceptibility in the tissue being examined; therefore, the rCBV measurements would be unreliable in areas of considerable ITSS. In the present study, the regions of attenuated prominent ITSS that could reflect considerable susceptibility associated with tumor necrosis and microhemorrhage did not accurately correspond with the region of rCBVmax on the coregistered HR-SWI and rCBV maps. Second, of the 41 patients, 12 underwent stereotactic biopsy, which might be prone to the sampling error of not including the most representative part of the tumor. However, we decided the biopsy site on the basis of information from both contrast enhancement and foci of rCBVmax values. It has been reported that this approach may offer a more accurate way of choosing a biopsy site.¹⁸

Third, we performed a direct correlation between HR-SWI−derived ITSS and histopathologic findings in only 3 of our patients. However, the direct histopathologic correlation has previously been reported⁸; therefore, we focused on the comparison of HR-SWI with DSC. Fourth, we did not have any guidelines or references for the morphologic classification of ITSS and the quantification of the degree of ITSS; thus, our method could be subjective. However, the interobserver agreement for our measurement of the ITSS degree was excellent. Finally, an uneven distribution of tumor grades was used for our analysis. The current study included a relatively small number of anaplastic astrocytomas (WHO grade III). For practical purposes, we grouped patients with anaplastic astrocytomas and glioblastoma multiformes together in our major analysis. Further studies with larger populations are necessary to determine the usefulness of HR-SWI in differentiating these 2 tumor groups.

Conclusions

The degree of ITSS showed a significant correlation with the value of rCBVmax in the same tumor segments. However, the direct correspondence between the areas of ITSS and rCBVmax was variable, according to the morphology and degree of ITSSs. The diagnostic performance of HR-SWI for glioma grading is comparable with that of DSC. Therefore, the ITSS can be a potentially helpful sign suggesting a correct diagnosis of high-grade glioma. Our results show the possibility of a noncontrast brain tumor imaging protocol in patients who have contraindications for contrast agents or who cannot tolerate the bolus injection.