The present study could not detect any significant difference between the supratentorial nonenhancing LGG and HGG with regard to age, sex, tumor size, maximal rCBV ratio, mean ADC, or minimal ADC. The values of mean FA and maximal FA, however, were significantly higher in HGG than in LGG, with a higher sensitivity and specificity in the grading of nonenhancing gliomas than the other imaging parameters.
The mean ADC and minimal ADC values have been reported to correlate with tumor cell density and have been used to grade astrocytomas.14–18
The present study showed no significant difference for these two parameters, which is consistent with the study by Fan et al.2
This may relate to the larger population in our study, which included not only astrocytomas, but also oligodendrogliomas and oligoastrocytomas.
FA has been used to grade gliomas, with consensus in a majority of studies showing a trend toward higher FA values in HGG relative to LGG.19–20,22,24,25
Comparison of mean FA values in the nonenhancing part of gliomas also revealed a higher FA value in high-grade gliomas (0.220 ± 0.087) compared with low-grade gliomas (0.169 ± 0.085).20
Stadlbauer et al.,26
however, found that the mean FA value in grade III gliomas (0.170 ± 0.051) was lower than that of grade II gliomas (0.196 ± 0.032). This apparent contradiction in theories was hypothesized to be due to a difference in placement of ROIs for measurement of FA.25
ROIs were placed not only within the center of the tumor but also at the junction of the tumor with adjacent white matter in the study by Stadlbauer et al.26
The relatively less destroyed adjacent white matter fibers in grade II gliomas may have contributed to the higher FA values in the low-grade gliomas in that study.25
Mean and maximal FA values within nonenhancing gliomas of our study were also significantly higher in HGG when compared with LGG. These findings are consistent with the results in studies by Inoue et al., Beppu et al., and Kinoshita et al.21–25
The mechanisms underlying the higher FA values in HGG are complex but can be attributed to the following factors as hypothesized by various authors:
- Higher tumor cellularity in HGG may positively correlate with higher FA values.21–25,32
- Increase in the degree of directionality of water diffusion due to decrease in extracellular volume (increased cellularity) may also induce increased FA values.32
- The pseudopalisading structure in glioblastomas may contribute to the higher FA values similar to the high FA values in meningiomas.33,34
There was no maximal FA value in the nonenhancing HGG lower than 0.215, but there were 3 cases in the LGG group whose maximal FA values were higher (0.244, 0.337, and 0.363). The first case was an astrocytoma with a Ki-67 index of 5% and increased tumor cellularity; the second case was a diffuse astrocytoma with a Ki-67 index of 8%, a focal oligodendroglial component, and features suggestive of early anaplasia; and the third case was a diffuse astrocytoma with infiltration of the corpus callosum. The first two cases may suggest a positive correlation between FA value and increased tumor cellularity. The high FA value of the third case may be due to a measurement contamination with residual fibers in the corpus callosum.25
This may limit the utility of maximal FA in grading nonenhancing gliomas, when the tumors infiltrate predominantly large fiber structures with high FA values, such as corpus callosum. In those instances, careful interpretation should be performed comprehensively with other advanced imaging modalities, including PWI and MR spectroscopy.25
Accurate preoperative grading of supratentorial nonenhancing gliomas may require more than conventional MR imaging, a technique that cannot always distinguish nonenhancing HGG from LGG. Such misdiagnosis could lead to conservative treatment of an aggressive neoplasm.10,35
Our preliminary study not only indicated that the mean FA and maximal FA could differentiate grade in nonenhancing gliomas, but also provided the maximal FA color overlay map, which could easily visualize the tumor content with high FA value. This might be useful in guiding stereotactic biopsy of nonenhancing gliomas (Fig. ) in future prospective studies.
Fig. 7. A case with large mass involving the left insular, temporal, and frontal lobes. (7A) is a postcontrast T1-weighted image, which shows the nonenhancing lesion. (7B) The color maximal rCBV image overlaid on the T2*-weighted image (transverse gradient-echo (more ...)
The maximal FA had the highest sensitivity (100%) in grading supratentorial nonenhancing gliomas. However, the bivariate(mean FA + maximal FA) on LDA method improved the diagnostic accuracy with better AUC of 0.944, specificity of 92.3%, and sensitivity of 86.7%. These indicated that a combination of univariate and bivariate(mean FA + maximal FA) on the LDA method could supply useful information for more accurate grading prediction of supratentorial nonenhancing gliomas.
Previous studies have demonstrated that the maximal rCBV ratio of HGG was significantly higher than the rCBV ratio of LGG,9,11
which was attributed to angiogenesis in the HGG. However, increased tumor vascularity can also be found in LGG, which will result in an elevated rCBV ratio. The pilocytic astrocytomas (WHO grade I), although biologically benign, have been described to exhibit histological evidence of angiogenesis and elevated rCBV ratio.27
The low-grade oligodendrogliomas have also been reported to show elevated rCBV ratio due to their inherent dense network of branching capillaries resembling a “chicken wire” pattern.9–13,36,37
Xu et al. found no significant difference in rCBV ratio between low- and high-grade oligodendrogliomas.36
Lev et al. reported that 50% of low-grade oligodendrogliomas presented elevated rCBV ratio.9
Cha et al. examined 14 low-grade oligodendrogliomas and found a range of rCBV ratio values from 1.29 to 9.24.37
In this study we could not find any significant difference in maximal rCBV ratio comparing supratentorial nonenhancing LGG and HGG. This is in conflict with the findings by Fan et al. and Maia et al.2,4
We suspect that this may be related to the higher number of oligodendroglioma cases with higher rCBV ratio in our study. On the other hand, our study revealed that low rCBV ratio values were also present in nonenhancing HGG. There were 7/19 HGGs with rCBV ratio values lower than 1.75, the lowest value being 0.87. This may indicate the changes in vascularity as gliomas’ dedifferentiation into HGG is probably a continuum and highly variable. Consequently, we cannot exclude that some HGGs may not have yet exhibited significant angiogenesis at the time of biopsy or areas of neovascularity were not biopsied.13
The ROC analysis of maximal rCBV ratio showed a sensitivity of 60% and specificity of 62.1% with a cutoff value of 1.84 in discriminating between the nonenhancing LGGs and HGGs, which may indicate that maximal rCBV ratio alone may have a limited value in this respect.
One major limitation in the present study is that there were no biopsies guided by maximal FA information. Thus, the correlation of maximal FA with histopathological change could not be assessed. Another limitation is the use of ROI measurement to detect maximal FA and minimum ADC values. Computer-aided voxel-based semi-automated segmentation techniques may reduce the subjective bias inherent in manual ROI placement. The third limitation relates to the relatively small population, with only 28 DTI examinations. Future prospective studies with larger populations will be necessary to verify our findings of optimal parameters for accurate preoperative grading of nonenhancing gliomas. Studies combing information from dynamic contrast enhancement may be useful in determining the permeability of tumor vessels in such nonenhancing gliomas to assess the extent of possible minor leakage of contrast material into the interstitium, which may not necessarily be visible on T1-weighted imaging.
In summary, our study did not demonstrate significant difference in maximal rCBV ratio between the supratentorial nonenhancing LGG and HGG. The univariate analysis showed that the mean FA and maximal FA were better imaging parameters, with regard to grading of supratentorial nonenhancing gliomas, than mean ADC, minimum ADC, and maximal rCBV ratio. The bivariate(mean FA + maximal FA) on LDA method improved the diagnostic accuracy with a specificity of 92.3%, sensitivity of 86.7%, and AUC of 0.944, which was better than any of other imaging parameters evaluated alone. The mean FA and maximal FA, used individually or combined, may be useful in preoperative grading of supratentorial nonenhancing gliomas.
Conflict of interest: None of the authors declare any conflict of interest.