Imaging of intratumoral heterogeneity in high-grade glioma

Abstract

High-grade glioma (HGG), and particularly Glioblastoma (GBM), can exhibit pronounced intratumoral heterogeneity that confounds clinical diagnosis and management. While conventional contrast-enhanced MRI lacks the capability to resolve this heterogeneity, advanced MRI techniques and PET imaging offer a spectrum of physiologic and biophysical image features to improve the specificity of imaging diagnoses. Published studies have shown how integrating these advanced techniques can help better define histologically distinct targets for surgical and radiation treatment planning, and help evaluate the regional heterogeneity of tumor recurrence and response assessment following standard adjuvant therapy. Application of texture analysis and machine learning (ML) algorithms has also enabled the emerging field of radiogenomics, which can spatially resolve the regional and genetically distinct subpopulations that coexist within a single GBM tumor. This review focuses on the latest advances in neuro-oncologic imaging and their clinical applications for the assessment of intratumoral heterogeneity.

Keywords: Advanced; Glioblastoma; Glioma; Heterogeneity; Histologic; Imaging; Intratumoral; MRI; Radiogenomics.

Figure 1:. Two separate treatment naive GBM patients undergoing image-guided biopsy within the non-enhancing vasogenic edema.

The location of biopsy A (top row, green dot) in patient A is shown to originate from within the T2 hyperintense region outside of the T1+C enhancing volume. This biopsy revealed 80% tumor burden at the time of histologic analysis. The location of biopsy B (bottom row, green dot) in patient B is also seen to originate from within the T2 hyperintense region outside of T1+C enhancement. While the imaging appearance appears identical to the previous patient case, biopsy B showed predominance of non-tumoral edematous brain, with a minimal amount (<10%) of tumor. The location of biopsy B (bottom row, green dot) in patient B is also seen to originate from within the T2 hyperintense region outside of T1+C enhancement. While the imaging appearance appears identical to the previous patient case, biopsy B showed predominance of non-tumoral edematous brain, with a minimal amount (<10%) of tumor.

Figure 2:. 40 y/o male with 2 separate biopsies for a mass suspicious for low-grade glioma.

The suspected low-grade glioma appears as a (A) T2W hyperintense, expansile mass in the left insular region with (B) no appreciable enhancing focus,. (C, D) On DSC-MRI rCBV maps that have been thresholded and color-coded, pink regions indicate high rCBV above 2.5. Green indicates low rCBV below 1.0, and Blue indicates moderate rCBV between 1 to 2.5. Two separate biopsies were taken from the patient’s tumor. Biopsy #1 within the lesion (C) was taken from a moderate rCBV region (blue) and yielded low grade (Grade 2) Oligodendroglioma on histopathology. Biopsy #2, from a high rCBV region (pink), revealed a high-grade (Grade 3) component with MIB-1 of 19%, consistent with elevated proliferative indices. The rCBV threshold of 2.5 remains consistent with the study by Maia et al. (reference #15) to separate high- vs. low-grade oligodendrogliomas.

Figure 3:. Two separate GBM patients status post standard adjuvant chemo-radiation therapy undergoing surgical biopsy for suspected recurrence.

In patient 1, (1A) T1+C images demonstrate a large heterogeneously enhancing mass concerning for tumor recurrence. The green dot depicts the stereotactic location of the biopsy specimen. (1B) On the coregistered FTB map, which is superimposed on the T1+C image, blue voxels correspond to predicted PTRE regions with low rCBV ≤ 1.0. The yellow (1.75 ≥ rCBV > 1.0) and red (rCBV > 1.75) voxels correspond to predicted tumor regions. The FTB metric is defined as the percentage of both yellow and red voxels relative to all voxels within the green ROI (green box) around the biopsy location (green dot). The FTB for the biopsy measured 0.96 (i.e., 96% of the voxels were predicted as tumor), which correlated with histologic quantification of 95% tumor from the spatially matched biopsy specimen. In patient 2, (2A) the T1+C image again demonstrates a large heterogeneous mass concerning for tumor recurrence. However, (2B) the FTB map shows an abundance of blue voxels consistent with predominant PTRE, with an FTB measurement of 0 (i.e., 0% of the voxels were predicted as tumor) within the ROI (green box) around the biopsy location (green dot). This correlated with the histologic findings of post-treatment effect, with no visible tumor within the spatially matched biopsy specimen.

Figure 4:. Radiogenomics map demarcating regions of amplification (amp) for Epidermal Growth Factor Receptor (EGFR) in a 63 y/o Male with primary GBM.

(A) The lesion is shown on the T2W image, with the margins demarcated by the bright green outline. The location of the biopsy (which was subsequently genetically profiled) is shown by the yellow arrow and yellow circle. (B) The central enhancing component is outlined by the dark green line on the T1+C image. The biopsy location (yellow arrow, yellow circle) is again shown, originating from the peripheral T2W non-enhancing component of tumor. (C) The radiogenomics map shows predicted regions of EGFR amplification (red) and non-amplified EGFR wildtype (wt) (blue), within the T2W region of interest (bright green outline) around the tumor. The radiogenomics map prediction of EGFR amplification (red) for the biopsy location corresponds with the elevated copy number variant (CNV) of 17.79, confirming EGFR amplification.

Figure 5:. Radiogenomics map demarcating regions of amplification (amp) for Epidermal Growth Factor Receptor (EGFR) in a 67 y/o Male with primary GBM.

(A) The lesion is shown on the T2W image, with the margins demarcated by the bright green outline. The location of the biopsy (which was subsequently genetically profiled) is shown by the yellow arrow and yellow circle. (B) The central enhancing component is outlined by the dark green line on the T1+C image. The biopsy location (yellow arrow, yellow circle) is again shown, originating from the T1+C enhancing component of tumor. (C) The radiogenomics map shows predicted regions of EGFR amplification (red) and non-amplified wildtype (wt) (blue), throughout the entire T2W region of interest (bright green outline). The radiogenomics map prediction of EGFR wildtype (blue) for the biopsy location corresponds with the low copy number variant (CNV) of 2.89 for EGFR, consistent with absence of amplification.