Multimodal imaging-defined subregions in newly diagnosed glioblastoma: impact on overall survival

Abstract

Background: Although glioblastomas are heterogeneous brain-infiltrating tumors, their treatment is mostly focused on the contrast-enhancing tumor mass. In this study, we combined conventional MRI, diffusion-weighted imaging (DWI), and amino acid PET to explore imaging-defined glioblastoma subregions and evaluate their potential prognostic value.

Methods: Contrast-enhanced T1, T2/fluid attenuated inversion recovery (FLAIR) MR images, apparent diffusion coefficient (ADC) maps from DWI, and alpha-[11C]-methyl-L-tryptophan (AMT)-PET images were analyzed in 30 patients with newly diagnosed glioblastoma. Five tumor subregions were identified based on a combination of MRI contrast enhancement, T2/FLAIR signal abnormalities, and AMT uptake on PET. ADC and AMT uptake tumor/contralateral normal cortex (T/N) ratios in these tumor subregions were correlated, and their prognostic value was determined.

Results: A total of 115 MRI/PET-defined subregions were analyzed. Most tumors showed not only a high-AMT uptake (T/N ratio > 1.65, N = 27) but also a low-uptake subregion (N = 21) within the contrast-enhancing tumor mass. High AMT uptake extending beyond contrast enhancement was also common (N = 25) and was associated with low ADC (r = -0.40, P = 0.05). Higher AMT uptake in the contrast-enhancing tumor subregions was strongly prognostic for overall survival (hazard ratio: 7.83; 95% CI: 1.98-31.02, P = 0.003), independent of clinical and molecular genetic prognostic variables. Nonresected high-AMT uptake subregions predicted the sites of tumor progression on posttreatment PET performed in 10 patients.

Conclusions: Glioblastomas show heterogeneous amino acid uptake with high-uptake regions often extending into non-enhancing brain with high cellularity; nonresection of these predict the site of posttreatment progression. High tryptophan uptake values in MRI contrast-enhancing tumor subregions are a strong, independent imaging marker for longer overall survival.

Keywords: amino acid; diffusion-weighted imaging; glioblastoma; positron emission tomography; survival.

© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Fig. 1

Five glioblastoma subregions defined by combined MRI and PET features demonstrated on 3 glioblastomas. Post-contrast MRIs with (upper and middle panels) and without (lower panels) PET fusion of glioblastomas; the lower 2 panels show enlarged regions outlined on the upper images. PET images are thresholded so that red areas are consistent with >65% increase, as compared with normal contralateral cortex. (A) 1: Gadolinium (Gad) enhancement with high alpha-[11C]-methyl-L-tryptophan (AMT) uptake, consistent with metabolically active tumor mass. (B) 2: Gad-enhancing mass with low-AMT uptake, suggesting blood–brain barrier damage with low tumor burden. 3: No enhancement outside the MRI-defined tumor mass, with high-AMT uptake, suggesting tumor-infiltrated brain. (C) 4: No enhancement, low-AMT uptake in the tumor core, consistent with central necrosis. 5: Non-enhancing, hyperintense T2/FLAIR, low-AMT subregion, consistent with vasogenic edema. Red dashed lines indicate the outline of the high PET uptake areas (1 and 3) on MRI with or without fused PET images (A and B).

Fig. 2

Examples showing a mismatch between MRI abnormalities and high alpha-[11C]-methyl-L-tryptophan (AMT) uptake on PET in 2 glioblastomas. (A) Heterogeneous AMT uptake in a Gad-positive glioblastoma, with both high- and low-AMT uptake subregions. (B) Increased AMT uptake localized outside the cystic, contrast-enhancing low-AMT uptake tumor mass. On the middle and lower panels, the tumor region is enlarged, and red dashed lines indicate the outline of high-AMT uptake areas (red on the upper panels, based on a 1.65 tumor/normal cortex ratio) on both T1-Gad (middle) and T2 (lower) MR images.

Fig. 3

Correlation between alpha-[11C]-methyl-L-tryptophan (AMT) uptake and apparent diffusion coefficient (ADC) tumor/normal (T/N) ratios. (A) Negative correlation in the whole set of tumor subregions (N = 115; Spearman’s rho [r] = −0.52, P < 0.0001). (B) A similar trend was detected in Gad-negative/high-AMT subregions, consistent with tumor-infiltrated brain (N = 25, r = −0.40, P = 0.05).

Fig. 4

Kaplan–Meier survival curves for alpha-[11C]-methyl-L-tryptophan (AMT) uptake tumor/normal (T/N) ratios in the gadolinium-positive/high-AMT subregions. Patients with high AMT T/N ratios (based on a cutoff threshold of 2.38; solid line) had a substantially longer cumulative survival than those with low-AMT uptake (dashed line) (HR: 7.8, 95% CI: 2.0–31.0, P = 0.003).