BACKGROUND: Mean diffusivity (MD) and fractional anisotropy (FA) from diffusion MRI (dMRI) have been associated with cell density and tissue anisotropy across tumors, but it is unknown whether these associations persist at the microscopic level. PURPOSE: To quantify the degree to which cell density and anisotropy, as determined from histology, account for the intra-tumor variability of MD and FA in meningioma tumors. Furthermore, to clarify whether other histological features account for additional intra-tumor variability of dMRI parameters. MATERIALS AND METHODS: We performed ex-vivo dMRI at 200 μm isotropic resolution and histological imaging of 16 excised meningioma tumor samples. Diffusion tensor imaging (DTI) was used to map MD and FA, as well as the in-plane FA (FAIP). Histology images were analyzed in terms of cell nuclei density (CD) and structure anisotropy (SA; obtained from structure tensor analysis) and were used separately in a regression analysis to predict MD and FAIP, respectively. A convolutional neural network (CNN) was also trained to predict the dMRI parameters from histology patches. The association between MRI and histology was analyzed in terms of out-of-sample (R2OS) on the intra-tumor level and within-sample R2 across tumors. Regions where the dMRI parameters were poorly predicted from histology were analyzed to identify features apart from CD and SA that could influence MD and FAIP, respectively. RESULTS: Cell density assessed by histology poorly explained intra-tumor variability of MD at the mesoscopic level (200 μm), as median R2OS = 0.04 (interquartile range 0.01-0.26). Structure anisotropy explained more of the variation in FAIP (median R2OS = 0.31, 0.20-0.42). Samples with low R2OS for FAIP exhibited low variations throughout the samples and thus low explainable variability, however, this was not the case for MD. Across tumors, CD and SA were clearly associated with MD (R2 = 0.60) and FAIP (R2 = 0.81), respectively. In 37% of the samples (6 out of 16), cell density did not explain intra-tumor variability of MD when compared to the degree explained by the CNN. Tumor vascularization, psammoma bodies, microcysts, and tissue cohesivity were associated with bias in MD prediction based solely on CD. Our results support that FAIP is high in the presence of elongated and aligned cell structures, but low otherwise. CONCLUSION: Cell density and structure anisotropy account for variability in MD and FAIP across tumors but cell density does not explain MD variations within the tumor, which means that low or high values of MD locally may not always reflect high or low tumor cell density. Features beyond cell density need to be considered when interpreting MD.

Department of Medical Imaging and Physiology Skåne University Hospital Lund University Lund Sweden

Diagnostic Radiology Clinical Sciences Lund University Lund Sweden

F M Kirby Research Center for Functional Brain Imaging Kennedy Krieger Institute Baltimore MD USA

Faculty of Information Technology Czech Technical University Prague Prague Czech Republic

Lund University Bioimaging Centre Lund University Lund Sweden

Medical Radiation Physics Clinical Sciences Lund University Lund Sweden

Neurosurgery Clinical Sciences Lund University Lund Sweden

Pathology Clinical Sciences Lund University Lund Sweden

Russell H Morgan Department of Radiology and Radiological Science Johns Hopkins University School of Medicine Baltimore MD USA

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