Abstract Purpose Glioblastoma (GBM) is one of the deadliest cancers with no cure. While conventional MRI has been widely adopted for examining GBM clinically, accurate neuroimaging assessment of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation, remains an unmet need in the clinical management of GBMs. Experimental Design We employ a novel Diffusion Histology Imaging (DHI) approach, combining diffusion basis spectrum imaging (DBSI) and machine learning, to detect, differentiate, and quantify areas of high cellularity, tumor necrosis, and tumor infiltration in GBM. Results Gd-enhanced T1W or hyper-intense FLAIR failed to reflect the morphological complexity underlying tumor in GBM patients. Contrary to the conventional wisdom that apparent diffusion coefficient (ADC) negatively correlates with increased tumor cellularity, we demonstrate disagreement between ADC and histologically confirmed tumor cellularity in glioblastoma specimens, whereas DBSI-derived restricted isotropic diffusion fraction positively correlated with tumor cellularity in the same specimens. By incorporating DBSI metrics as classifiers for a supervised machine learning algorithm, we accurately predicted high tumor cellularity, tumor necrosis, and tumor infiltration with 87.5%, 89.0% and 93.4% accuracy, respectively. Conclusion Our results suggest that DHI could serve as a favorable alternative to current neuroimaging techniques for guiding biopsy or surgery as well as monitoring therapeutic response in the treatment of glioblastoma. Translational Relevance Current clinical diagnosis, surgical planning, and assessment of treatment response for GBM patients relies heavily on gadolinium-enhanced T1-weighted MRI, which is non-specific for tumor growth and merely reflects a disrupted blood-brain barrier. The complex tumor microenvironment and spatial heterogeneity make GBM difficult to characterize using current clinical imaging modalities. In this study, we developed a novel imaging technique to characterize and accurately predict key histological features of GBM - high tumor cellularity, tumor necrosis, and tumor infiltration. While further validation in a larger cohort of patients is needed, the current proof-of-concept approach could provide a solution to resolve important clinical questions such as the identification of true tumor progression vs. pseudoprogression or radiation necrosis.

Diffusion Histology Imaging Combining Diffusion Basis Spectrum Imaging (DBSI) and Machine Learning Improves Detection and Classification of Glioblastoma Pathology