Diffusion tensor imaging reveals early dissemination of pediatric diffuse intrinsic pontine gliomas Matthias W. Wagner¹, Joyce Mhlanga¹, Thangamadhan Bosemani¹, Kathryn A. Carson 2,3, Kenneth J. Cohen⁴, Andrea Poretti¹, Thierry A. G. M. Huisman¹ ¹ Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 2 Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, ³ Division of General Internal Medicine, Department of Medicine, and ⁴ Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD, USA EP-131 ASNR 53 rd Annual Meeting, Chicago, April 25-30, 2015

Disclosure  K.A. Carson is supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (Grant Number 1UL1TR001079)

Diffuse intrinsic pontine glioma (DIPG)  10% of all brain tumors in children  Tumor dissemination in 26% within the first 7 months after initial presentation  Role of neuroimaging: 1.DIPG typically diagnosed by imaging characteristics 2.Tumor involves >50-70% of the pons 3.T1w hypo, T2w hyper T2w T1w

Diffusion Tensor Imaging (DTI)  Advanced MR technique for in vivo evaluation of the microstructure and integrity of white matter tracts  DTI Scalars: Fractional anisotropy (FA) Mean diffusivity (MD) Axial diffusivity (AD) Radial diffusivity (RD) λ1λ1 λ2λ2 λ3λ3

Purpose  Comparison of the microstructural integrity of supratentorial WM tracts at initial presentation using DTI  Hypotheses: 1.DIPG: Tumor dissemination along the corticospinal tract (CST) 2.Low-grade brain stem glioma (LGBG): No tumor dissemination 3.Controls: No tumor dissemination Changes in DTI scalars No changes in DTI scalars

Inclusion criteria A.Diagnosis of DIPG or LGBG based on neuroimaging and/or histology B.Absence of macroscopic tumor dissemination at diagnosis as assessed by conventional MRI C.Availability of pre-treatment DTI data D.Age at MRI <18 years E.Controls with normal brain anatomy + absence of neurological disorders

Methods: DTI analysis  ROI based analysis of DIPG, LGBG, controls  FA+MD+AD+RD Bilateral posterior centrum semiovale (PCSO, A) Bilateral posterior limb of internal capsule (PLIC, B)

Statistical analysis / Histology  Two-sample t-tests: age difference DIPG ↔ controls, LGBG ↔ controls, DIPG ↔ LGBG  Wilcoxon rank sum tests: DTI scalars DIPG ↔ controls, LGBG ↔ controls  Linear regression model: DTI scalars DIPG ↔ LGBG  All tests: 2-sided, significance if p<0.05, no adjustment for multiple comparisons  Histology available for bilateral PLIC and PCSO in one DIPG patient

Results: Patients / Controls  DIPG: n = 8 (5 males), mean age at MRI = 5.74 ± age-matched controls (p>0.99)  LGBG: n = 8 (3 males), mean age at MRI = 8.82 ± 3.23 years 25 age-matched controls (p>0.99)

Results: DTI DIPG ↔ controls * indicates significance, p<0.05

No significant differences Results: DTI LGBG ↔ controls

Results: DTI DIPG ↔ LGBG * indicates significance, p<0.05

Results: Histology A, B: Sections from main tumor bulk in the pons show hypercellularity with diffuse infiltration of hyperchromatic, atypical astrocytes (arrow) C, D: Sections of the left PLIC showed infiltrating astrocytoma and increased mitotic activity (arrow) E, F: Infiltrating tumor not observed in the right PLIC

Conclusion 1.Conventional MRI fails to demonstrate early tumor dissemination/migration in pediatric DIPG 2.Quantitative DTI analysis may detect early dissemination/migration of tumor cells along the CST in DIPG 3.In pediatric DIPG, DTI may help to: I.Understand tumor biology II.Monitor disease progression III.Guide treatment options