Recent evidence on the molecular heterogeneity of gliomas and the implications these differences have for both prognosis and response to therapy has led to a large shift in thinking about the classification of gliomas (5). Patients with an IDH1 mutation have improved prognosis over patients with a wild type IDH1 tumor of the same grade (6,7). IDH mutation may also be predictive of therapeutic outcome from specific treatments such as an increased sensitivity to radiation (8). Recent efforts have investigated noninvasive biomarkers to identify IDH1-mutant tumors in humans. MR spectroscopy is capable of detecting 2-hydroxygluterate (2HG), a metabolite produced in excess due to mutations in the enzyme IDH1. However clinical application is limited by long imaging times, complex data processing, and low spectral resolution (9). The central hypothesis of this work is that tumor stiffness can be used to distinguish between IDH1-mutant and wild-type gliomas.

Eighteen patients with previously identified gliomas scheduled for resection were recruited for this study. MR imaging was performed on 3T scanners (GE HD14 and DV24 Signa, General Electric Healthcare, Waukesha, WI). MRE images were acquired using a single-shot SE EPI MRE sequence with the following parameters: axial slices, TR/TE = 3600/62 ms, 24 cm field of view, 72 x 72 imaging matrix reconstructed to 128 x 128, 3x ASSET acceleration, 3 mm slice thickness, one 40 mT/m 16.7 ms zeroth- and first-order moment nulled motion-encoding gradient on each side of the refocusing RF pulse synchronized to the applied shear wave frequency, 6 motion-encoding directions, and 4 phase offsets. Shear waves were applied at a frequency of 60 Hz using a soft, pillow-like driver positioned beneath the head and connected to a pneumatic actuator (Figure 1) (10).

Tissue stiffness was quantified using a 3D direct inversion algorithm (10). The first temporal harmonic of the vector curl of the acquired wave field is calculated followed by a 3x3x3 Romano smoothing filter. Elastograms are then calculated from this data using a direct inversion of the Helmholtz equation. Tumor regions of interest (ROIs) were manually drawn by an experienced observer. ROIs were drawn on the contralateral hemisphere to serve as the normal brain/control for each patient. Reported stiffness values are the median value of the magnitude of the complex shear modulus for each ROI. Histological results including tumor grade and IDH mutation status were reported following surgical resection of the tumor. Statistical analysis was performed using a two-sample t-test (MATLAB) and p<0.05 was considered significant.

Eighteen patients (7 female, 40 ± 13 years) with previously diagnosed glioma underwent MRE, composed of 4 grade II, 8 grade III, and 6 grade IV (WHO glioblastoma) as determined by pathology. Twelve patients had tumors with a mutation in IDH1; 100% of grade II, 75% of grade III, and 33% of grade IV. The MRE exam was well tolerated by all patients. All gliomas were softer than unaffected brain tissue; 1.6±0.6 kPa compared to 2.5±0.6 kPa respectively (p < 0.001). Tumors with a mutation in the IDH1 gene (n = 12) were significantly stiffer than wild-type IDH1 (n = 6); 1.8±0.6 kPa compared to 1.2±0.3 kPa respectively (p = 0.018) (Figure 2). To demonstrate the large mechanical heterogeneity between IDH1+/- tumors, Figure 3 shows the MRE results from two grade III tumors. While histologically equivalent, the mechanical properties of the two tumors differed by almost 85% with stiffness values of 2.86 kPa and 1.55 kPa for the IDH1-mutated and non-mutated tumors respectively. This study demonstrates the feasibility of using MRE for the noninvasive quantification of glioma stiffness. Gliomas are softer than normal brain tissue. The results presented here are consistent with previously reported MRE results in glioblastoma (1,3). Additionally, glioma stiffness may be a biomarker of IDH mutation status, where stiffer tumors are indicative of a mutated IDH1. MRE may provide complementary information for use as a noninvasive neuro-radiological biomarker. IDH mutations in glioma are associated with improved outcome and may be associated with improved response to radiation therapy. The correlation between tumor stiffness and genomic differences may have important implications for the noninvasive assessment of IDH mutation for glioma classification and monitoring of the disease.