Intratumoral Heterogeneity of Tumor Infiltration of Glioblastoma Revealed by Joint Histogram Analysis of Diffusion Tensor Imaging

Purpose The purpose of this study is to propose a novel interpretation method of diffusion tensor imaging (DTI) using the joint histogram analysis of DTI-p and -q. With this method we explored the heterogeneity of tumor infiltration and examined the prognostic value of tumor infiltrative patterns for patient survival. Materials and methods A total of 115 primary glioblastoma patients (mean age 59.3 years, 87 males) were prospectively recruited from July 2010 to August 2015. Patients underwent preoperative MRI scans and maximal safe resection. DTI was processed and decomposed into p and q components. The univariate and joint histograms of DTI-p and -q were constructed using the pixels of contrast-enhancing and non-enhancing regions respectively. Eight joint histogram features were obtained and correlated with tumor progression rate and patient survival using cox-regression model. Their prognostic values were compared with clinical factors using receiver operating characteristic curves. Results The subregion of increased DTI-p and decreased DTI-q accounted for the largest proportion. Additional diffusion patterns can be identified via joint histogram analysis. Particularly, higher proportion of decreased DTI-p and increased DTI-q in non-enhancing region contributed to worse progression-free survival and overall survival (both HR = 1.12, p < 0.001); its proportion showed a positive correlation (p = 0.010, r = 0.35) with tumor progression rate. Conclusion Joint histogram analysis of DTI can provide a comprehensive measure of heterogeneity in infiltration, which showed prognostic values for glioblastoma patients. The subregion of decreased DTI-p and increased DTI-q in non-enhancing region may indicate a more invasive habitat. Funding This study was funded by a National Institute for Health Research (NIHR) Clinician Scientist Fellowship (SJP, project reference NIHR/CS/009/011); CRUK core grant C14303/A17197 and A19274 (FM lab); Cambridge Trust and China Scholarship Council (CL & SW); the Chang Gung Medical Foundation and Chang Gung Memorial Hospital, Keelung, Taiwan (JLY); CRUK & EPSRC Cancer Imaging Centre in Cambridge & Manchester (FM & TT, grant C197/A16465); Royal College of Surgeons of England (RS); NIHR Cambridge Biomedical Research Centre (TM & SJP). The Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. We would like to acknowledge the support of National Institute for Health Research, the University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Conflict of Interest none Advances in knowledge Joint histogram analysis of the isotropic (p) and anisotropic (q) components of the diffusion tensor imaging can reflect the intratumoral heterogeneity of glioblastoma infiltration. Incremental prognostic values for the prediction of overall survival and progression-free survival can be achieved by the joint histogram features, when integrated with IDH-1 mutation, MGMT methylation status and other clinical factors. The non-enhancing tumor subregion in which water molecules display decreased isotropic movement and increased anisotropic movement are potentially representative of a more invasive tumor habitat. Implications for patient care This study helps us to understand how the infiltrative patterns of glioblastoma contribute to patient outcomes. The invasive subregion identified by this approach may have clinical implications for personalized surgical resection and targeted radiation therapy. Summary Statement The joint histogram analysis may help to better understand the heterogeneity of tumor infiltration. The decreased DTI-p and increased DTI-q in non-enhancing region may be able to define an invasive subregion responsible for tumor progression.