Abstract
Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumour-related death in children. In the majority of cases diagnosis is based on clinical and MRI findings, resulting in the scarcity of pre-treatment specimens available to study. Our group has developed an autopsy-based protocol to investigate the histologic and biologic spectrum of DIPG. This has also allowed us to investigate the terminal pattern of disease and gain a better understanding of what challenges we are facing in treating DIPG. Here, we review 72 DIPG cases with well documented clinical history and molecular data and describe the pathological features of this disease in relation to clinical and genetic features. Fifty-three of the samples were autopsy material (7 pre-treatment) and 19 were pre-treatment biopsy/surgical specimens. Upon histological review, 62 patients had high-grade astrocytomas (18 WHO grade III and 44 WHO grade IV patients), 8 had WHO grade II astrocytomas, and 2 had features of primitive neuroectodermal tumour (PNET). K27M-H3 mutations were exclusively found in tumours with WHO grade II–IV astrocytoma histology. K27M-H3.1 and ACVR1 mutations as well as ALT phenotype were only found in WHO grade III–IV astrocytomas, while PIK3CA mutations and PDGFRA gains/amplifications were found in WHO grade II–IV astrocytomas. Approximately 1/3 of DIPG patients had leptomeningeal spread of their tumour. Further, diffuse invasion of the brainstem, spinal cord and thalamus was common with some cases showing spread as distant as the frontal lobes. These findings suggest that focal radiation may be inadequate for some of these patients. Importantly, we show that clinically classic DIPGs represent a diverse histologic spectrum, including multiple cases which would fit WHO criteria of grade II astrocytoma which nevertheless behave clinically as high-grade astrocytomas and harbour the histone K27M-H3.3 mutation. This suggests that the current WHO astrocytoma grading scheme may not appropriately predict outcome for paediatric brainstem gliomas.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 573-581 |
| Number of pages | 9 |
| Journal | Acta Neuropathologica |
| Volume | 128 |
| Issue number | 4 |
| DOIs | |
| State | Published - Oct 2014 |
Funding
Acknowledgments We would like to thank Dr. Anne Bendel (Children\u2019s Hospital Minneapolis), Drs. Jennifer Chang and lucie lafay-Cousin (University of Calgary), Drs. Sandra Dunn, Juliette Hukin and Chris Dunham (BC Children\u2019s Hospital), Dr. Katrin Scheine-mann (McMaster Children\u2019s Hospital), Dr. Jean Mchaud (Children\u2019s Hospital of eastern Ontario), Drs. Shayna Zelcer and David ramsay (london Health Sciences Centre), Dr. Javad Nazarian (george Washington University), Dr. Jason Fangusaro (Children\u2019s Hospital of Chicago), Dr. Matthias Karajannis (NYU langone Medical Center), Dr. Nicholas Foreman (University of Colorado), Drs. Julia Hegert and Amy Smith (Arnold Palmer Hospital for Children), Dr. Mark Souwei-dane (Weill Cornell Medical College) and Dr. Jason Cain (Monash Institute of Cancer research) for providing us with DIPg biological material for this study. This work was supported by an operating grant from the National Brain Tumor Society and the Canadian Institutes of Health research [MOP 115004]. Pawel Buczkowicz is a recipient of CIHr Doctoral Frederick Banting and Charles Best Canada graduate Scholarships award.
Keywords
- ACVR1
- Astrocytoma
- DIPG
- Glioma
- H3.3
- H3F3A
- K27M
- Paediatric
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Clinical Neurology
- Cellular and Molecular Neuroscience
