Apparent Diffusion and Fractional Anisotropy of Diffuse Intrinsic Brain Stem Gliomas

Diffusion Properties of DIBSG at Initial Presentation

ADC mapping has been shown to provide important prognostic information in malignant supratentorial astrocytoma in adults. Specifically, tumors with particularly low ADC_min values had the worst clinical courses.^14,26 This observation is likely explained by the fact that increased tumor cellularity distinguishes grade IV glioblastoma from lower grade gliomas on pathology (among other features such as high vascularity and high mitotic index). Highly cellular tumors or areas of particularly high cellularity restrict diffusion, resulting in low ADC measurements. Consistent with these findings in adults with gliomas, patients with DIBSG with lower ADC at presentation generally did worse in this study. However, all DIBSGs are relatively hypocellular lesions. For example, the mean ADC of DIBSG was significantly higher (with no overlap) than the mean ADC of high-grade (WHO IV) hypercellular medulloblastoma. The diffusion in DIBSG was also significantly less restricted than that in normal brain stem.

Also observed was a negative correlation between initial FA and survival times, indicating that patients with tumors with higher baseline anisotropic water diffusion are at higher risk for rapid disease progression. In the normal brain stem, water diffusion is highly directional due to white matter tracts, and FA in our controls with normal brain stem was approximately twice as high as that in DIBSG. Our initial hypothesis was that a reduction of FA in DIBSG would correlate with the extent of tumor infiltration and destruction of anisotropic normal tissue as previously suggested^17–19 and that lower FA would predict a poorer clinical course. However, our results clearly rejected this hypothesis. We observed a negative correlation (instead of a positive one) between initial FA and survival length, indicating that patients with tumors of higher baseline anisotropic water diffusion are at higher risk for rapid disease progression.

Changes of ADC and FA after Therapy

In adult gliomas, a posttreatment increase of ADC was a predictor of a more favorable clinical course.^{15,16,27–29} Therefore, the changes after RT hoped for by the treating clinicians—in terms of diffusion properties—are an increase of ADC (and a drop of FA). These changes would be consistent with increased extracellular space caused by cell death, which in turn might suggest a reduction of tumor volume before changes on conventional MR imaging.^{15,16,27–29} However, the opposite was observed in this study. There was a significant ≈20% reduction of ADC, whereas FA increased by ≈30% between baseline and the early posttreatment phase. With ADC and FA as surrogates for tissue status at the microscopic level, this finding would suggest that lesions after RT are apparently more cellular with less extracellular fluid accumulation. It is possible that the observed diffusion characteristics were a result of competing effects, such that cell death and increased diffusion may have been more than compensated for by the reduction of extracellular space (therefore reduced diffusion). However, in recent MR spectroscopy studies, metabolic indicators for a significant response to therapy (decreased metabolite concentrations, particularly choline, and increased lipids due to cell membrane breakdown) were generally not observed.³⁰ Therefore, the often-noted reduction of lesion volume after therapy is less likely to be caused by a loss of tumor cells. More likely is a tumor volume reduction due to reduced vasogenic edema consistent with the transient clinical improvement in DIBSG.

In this study, ADC decreased after RT in all patients with DIBSG. However, the extent of the decrease did not correlate with ΔT_EFS after therapy. Indeed, there was a tendency toward longer survival in patients in whom a more substantial drop of ADC was observed, though significance was not reached.

A significant positive correlation between Δ_FA and ΔT_EFS was observed at the caudal midbrain level. In other words, patients with the most pronounced change from isotropic toward anisotropic diffusion had the longest ΔT_EFS. All patients in our study received steroids at the time of diagnosis, with the intention of removing extracellular water and reducing peritumoral edema. Several studies have shown significant decreases in ADC in both peritumoral edema and the solid component of the tumors between 48 and 72 hours after steroid administration.^31,32 In addition, a recent study has shown significant ADC drop in gliomas treated by Avastin (bevacizumab), whose antitumoral effect is still controversial.^33,34 Therefore, our interpretation is that vasogenic edema has been met effectively with anticancer therapy and steroids, by improving the vascular structure and the leakiness of blood vessels.

ADC and FA of Individual Anatomic Regions

Our study indicates that diffusion characteristics at the caudal midbrain are most relevant in respect to prognoses. Baseline ADC and FA in the caudal midbrain showed the most significant correlation with overall survival. In addition, of all posttherapy changes, only Δ_FA at the caudal midbrain level correlated with ΔT_EFS. This observation suggests that a careful analysis of all substructures involved is of importance for optimal patient management. The reason for the significance of the caudal midbrain is unclear. It could be that microenvironmental factors (“seed and soil”) cause tumors involving caudal midbrain structures to be particularly infiltrative or to transition, with a higher likelihood, from lower grade to higher grade lesions. It has also been shown that tumors originating from different locations vary in their genetic profile,⁹ and the caudal midbrain may be associated with more malignant subtypes.

Is There an Added Value in Measuring FA?

A standard diffusion-weighted MR imaging scan is very fast and can be accomplished typically within 1 minute of total scanning time. DTI, particularly with a large number of diffusion directions, can take several minutes. This may stress young patients because of the high noise level during a longer period. However, in a previous study, it was demonstrated that FA was more sensitive than ADC in demonstrating tumor infiltration in supratentorial gliomas.³⁵ In this study, we found that only Δ_FA (in the caudal midbrain) correlated with ΔT_EFS. While the number patients enrolled in this study was small and prospective confirmation is clearly needed, this finding indicates that there might be added value in performing more complex DTI studies instead of diffusion-weighted imaging alone.

Limitations

Apart from the small number of patients enrolled, a result of the low incidence of the disease, a number of other limitations of this study need to be acknowledged. First, histologic confirmation of the tumor type was available only in 1 subject, whereas no biopsies or postmortem examinations were available for the remaining subjects. Therefore a definitive correlation of diffusion changes with tumor biology was not possible at this point.

Second, a possible confounding factor is the differences in how subjects were treated. All patients underwent standard-dose radiation therapy, but there were differences in respect to chemotherapies (type and duration) that were administered to individual patients. One might speculate that initial imaging would better correlate with outcome if patients were all treated equally. A separate analysis of the 5 patients (subjects 1,2,4,5,6) who were treated identically (not reported in detail) did not, however, indicate that the correlation would improve if a more homogeneous study group were available. Also, the impact of steroids on diffusion properties of the lesions in patients who are treated at the same time is unknown. All patients received steroids (dexamethasone) at initial diagnoses. Doses were subsequent to therapy, adjusted and leveled off to the extent possible in individual patients. With DTI performed typically every 3 months, there is the possibility of underdetected changes in ADC and FA, particularly during initial RT.

Finally, for advanced imaging such as DTI to become useful for patient management in clinical settings, methods need to be used that are both robust and reproducible. However, approaches for obtaining mean ADC, ADC_min, ADC_max, mean FA, FA_min, and FA_max are variable and sensitive to user bias. For example, in 1 study the ADC_min was obtained from 5 to ten 40- to 60-mm² regions of interest within solid components of the tumor on the ADC maps.¹⁴ Other groups obtained ADC_min by placing regions of interest in the solid tumor components on each contiguous section and selecting the lowest ADC value by visual inspection.^26,36 In our study, we outlined the solid tumor component at 5 readily recognizable anatomic levels and obtained ADC and FA values for these regions. Obtaining ADC and FA from these relatively large areas will result in an overestimation (underestimation) of ADC_max and ADC_min and FA_max and FA_min. On the other hand, this method is fast and involves only a minimum of subjectivity (avoiding cystic, necrotic, and hemorrhagic areas) and is thus robust and reproducible.