Complementary but distinct roles for MRI and 18F-fluoromisonidazole PET in the assessment of human glioblastomas

Abstract

Glioblastoma multiforme is a primary brain tumor known for its rapid proliferation, diffuse invasion, and prominent neovasculature and necrosis. This study explores the in vivo link between these characteristics and hypoxia by comparing the relative spatial geometry of developing vasculature inferred from gadolinium-enhanced T1-weighted MRI (T1Gd), edematous tumor extent revealed on T2-weighted MRI (T2), and hypoxia assessed by 18F-fluoromisonidazole PET (18F-FMISO). Given the role of hypoxia in upregulating angiogenic factors, we hypothesized that the distribution of hypoxia seen on 18F-FMISO is correlated spatially and quantitatively with the amount of leaky neovasculature seen on T1Gd.

Methods: A total of 24 patients with glioblastoma underwent T1Gd, T2, and 18F-FMISO-11 studies preceded surgical resection or biopsy, 7 followed surgery and preceded radiation therapy, and 11 followed radiation therapy. Abnormal regions seen on the MRI scan were segmented, including the necrotic center (T0), the region of abnormal blood-brain barrier associated with disrupted vasculature (T1Gd), and infiltrating tumor cells and edema (T2). The 18F-FMISO images were scaled to the blood 18F-FMISO activity to create tumor-to-blood ratio (T/B) images. The hypoxic volume (HV) was defined as the region with T/Bs greater than 1.2, and the maximum T/B (T/Bmax) was determined by the voxel with the greatest T/B value.

Results: The HV generally occupied a region straddling the outer edge of the T1Gd abnormality and into the T2. A significant correlation between HV and the volume of the T1Gd abnormality that relied on the existence of a large outlier was observed. However, there was consistent correlation between surface areas of all MRI-defined regions and the surface area of the HV. The T/Bmax, typically located within the T1Gd region, was independent of the MRI-defined tumor size. Univariate survival analysis found the most significant predictors of survival to be HV, surface area of HV, surface area of T1Gd, and T/Bmax.

Conclusion: Hypoxia may drive the peripheral growth of glioblastomas. This conclusion supports the spatial link between the volumes and surface areas of the hypoxic and MRI regions; the magnitude of hypoxia, T/Bmax, remains independent of size.

FIGURE 1

Schematic of tumor regions visible on T1Gd and T2. Table lists associations between MRI scans and schematic. T2buf = T2 buffer region.

FIGURE 2

Results of applying image segmentation to coregistered images of right temporal glioblastoma multiforme (A–C) to generate tumor regions related to each image (D–H). Overlap of HV (F) and T1Gd (G) is shown in I.

FIGURE 3

Concordance and discordance seen between T1Gd abnormalities and ¹⁸F-FMISO (overlaid in white) in right insular glioblastoma multiforme (A) and left temporal-parietal glioblastoma multiforme (B).

FIGURE 4

¹⁸F-FMISO concordance, or percentage of HV that is within each MRI-defined region, as function of timing of imaging. Box plots show median, 25th percentile, and 75th percentile of data, with minimum and maximum represented by whiskers.

FIGURE 5

Volume (A) and surface area (B) of MRI-defined tumor regions and hypoxic regions according to timing of imaging before operation, after resection and before radiation therapy, and after both operation and radiation therapy.

FIGURE 6

Scatter plots of HVsa vs. MRI-defined tumor surface areas (A) and of HV vs. MRI-defined tumor volumes (B) for PreOp patients only.

FIGURE 7

(A) Location of T/Bmax voxel within MRI-defined regions. (B) Value of T/Bmax as function of timing of imaging. Asterisks indicate significant difference between groups as tested by Mann–Whitney U test (P < 0.002 between PreOp and PostOp and P = 0.0004 between PreOp and PostXRT studies).