Diffuse-type WHO grade II gliomas are heterogeneous tumors that generally do not enhance on postgadolinium T1-weighted MRIs. The grade II nonenhancing glioma population in this study served as the test data set for the nADC threshold for distinguishing grade II OD from grade II AS that was determined using logistic regression on a training set of patients in a previous study.19
The current study also compared the MRI diffusion parameters and microstructural tissue properties of nADC-guided biopsies collected from pink (low nADC) and blue (high nADC) regions on nADC colormaps.25
ROC analysis indicated a strong distinction between the nADC values of OD and AS in this new patient cohort, which is consistent with the high classification accuracy that was found using logistic regression on the training set of patients in our previous study. Using the previously determined threshold of 1.8 median nADC within the T2 lesion, we were able to distinguish AS from OD in this new patient cohort with high sensitivity and specificity. These results further validate the use of the median nADC within the T2 lesion to classify diffuse-type gliomas that are suspected of having grade II histology. Nonenhancing gliomas may also be of mixed histology (eg, OA) and have a biologic behavior that comprises the spectrum from AS to OD. We therefore performed a second ROC analysis of the entire patient cohort to determine whether the OA gliomas with molecular characteristics that were OD-like would be classified with the OD gliomas, based on their median nADC values. Again, there was a strong distinction between OD-like gliomas, which were defined as having an oligodendroglial component in conjunction with 1p/19q chromosomal codeletions, and AS-like gliomas, which did not have these histologic and chromosomal features. This finding was a key outcome of the study because of the more favorable prognosis for patients harboring gliomas with OD-like features. It suggests that the median nADC may be a useful prognostic marker for unresectable nonenhancing tumor.
All of the mixed OAs that had nADC values similar to OD (<1.8) had deletions in chromosomes 1p and19q, while gliomas with nADC values similar to AS (≥1.8) showed no 1p/19q codeletions. OA with intact 1p/19q also appeared similar to AS on nADC colormaps, having a large central blue region and a sharp, smooth transition to a thin pink rim (data not shown). This is similar to observations by other groups: a sharp, smooth border along with homogeneous signal intensity on T1- and T2-weighted MRI was associated with intact (nondeleted) 1p/19q chromosomes.27,28
In contrast, the typical pattern on nADC colormaps of OD and 1p/19q codeleted OA gliomas was a small central blue region surrounded by the more extensive and homogeneous pink region.
Normalized ADC values were higher in the high tumor fraction biopsies relative to the low tumor fraction biopsies. This appears to be contrary to previous papers suggesting lower nADC values in more highly cellular tumor regions.16
However, when one considers that the low tumor fraction biopsies comprised primarily normal brain, while the high tumor fraction biopsies comprised primarily tumor, the results are consistent with the higher ADC values that are typically reported for tumor versus normal brain. Indeed, 5 of the 17 low tumor fraction biopsies contained no discernible tumor cells at all (data not shown). This not only explains the lower nADC values in the low tumor fraction biopsies but also underscores the need for additional imaging methods, such as MR spectroscopy,29
to help distinguish tumors from nontumors within the hyperintense lesion on T2-weighted images. In addition to the positive association between nADC values and tumor burden, we also found a positive association between nADC values and SMI-31 scores of axonal disruption. Taken together, both an increase in the number of tumor cells and an increase in the degree of axonal disruption can result in an increase in the nADC value within a region of tumor.
There was no difference in the nFA value of low and high tumor fraction biopsies and no association between nFA and SMI-31 score. The lack of a clear relationship between nFA and the underlying tumor microstructure may be due partly to the inability to fully characterize the anisotropic water movement with the 6-direction diffusion tensor sequence that we used for this study. Of the 2 tissue properties that we measured, however, the SMI-31 score of axonal disruption appeared to have the strongest influence on the nFA.
Separating the biopsies by subtype, the association between nADC and SMI-31 score was observed in only the AS-like biopsies. This was due in part to the larger range and higher values of SMI-31 scores observed in AS-like biopsies compared with OD-like biopsies. Although both subtypes exhibited the positive association between nADC and tumor fraction, statistical significance was reached only in the OD-like biopsies. This was due in part to the more equal distribution of biopsies with high and low tumor fraction among the OD-like biopsies compared with the AS-like biopsies. These findings reflected the different patterns of infiltration of AS and OD that were observed in this study. In AS, engulfed normal structures were often disrupted, particularly in regions where there was a predominance of tumor cells. However, in OD the underlying normal structures were often maintained irrespective of the number of tumor cells in a given region.
Examination of the biopsies from the pink (high nADC) and blue (low nADC) colormap regions showed that there was a strong association between the colormap region and SMI-31 score and a weak (not statistically significant) association between the colormap region and tumor fraction. The biopsies from OD-like gliomas were overwhelmingly pink, consistent with their characteristic appearance on colormaps, which was primarily pink with a small blue region in the center of the tumor. The pink OD-like biopsies had predominantly a combination of low SMI-31 scores and low tissue fractions, while the blue OD-like biopsies all had high tissue fraction. This parallels the 2 results showing that (1) the SMI-31 score was strongly associated with colormap region, and (2) the tissue fraction was associated with nADC in OD-like gliomas. In comparison, the biopsies from the AS-like gliomas were primarily blue, consistent with their characteristic appearance on colormaps, which had a large central blue region transitioning rapidly to a thin pink rim. The blue AS-like biopsies had predominantly a combination of high SMI-31 scores and high tissue fractions, while the pink AS-like biopsies primarily had low SMI-31. Again, these results parallel the 2 findings that (1) the SMI-31 score was strongly associated with colormap region, and (2) the SMI-31 score was associated with nADC in AS-like tumors.
In conclusion, the median nADC value within the T2 lesion could be used to classify the histology of the OD and AS in a new cohort of diffuse-type grade II gliomas, validating the findings from our previous study on a training cohort. Mixed OAs harboring the favorable prognostic marker—1p/19q chromosomal codeletion—could also be classified by their median nADC values. The ADC values within tumor subregions were associated primarily with the degree of disruption of neuronal processes and less so with the fraction of tumor cells, particularly in AS and mixed OA with intact 1p/19q chromosomes. In OD and mixed OA with 1p/19q chromosomal codeletions, the ADC is less influenced by the degree of neuronal disruption and is more associated with the fraction of tumor cells in a given region. These results suggest that ADC variations in grade II gliomas are prognostically significant and are influenced by the arrangement and density of neuronal processes and tumor cells rather than by overall cell density. More studies are needed to determine whether the observed associations hold among nonenhancing gliomas of higher histologic grade and how the inclusion of additional imaging parameters can improve the noninvasive diagnosis of nonenhancing gliomsa of all histologic grades and subtypes.
Conflict of interest statement. None declared.