Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1319-6) contains supplementary material, which is available to authorized users.

Pediatric Brainstem Gliomas: A Retrospective Study of 180 Patients from the SEER Database

“…However, it should be noted that there were only 2 patients with a mixed neuronal/glial tumor and thus a larger population size is needed to accurately assess the survival rates of these types of neoplasms. These results are consistent with other studies that have patients with these diffuse intrinsic brainstem gliomas experiencing poor prognosis and survival outcomes of < 10% at 2 years in some cases [29]. Pilocytic astrocytomas tend to have much better outcomes with lower recurrence rates and a less aggressive invasion of the surrounding parenchyma [15].…”

“…Neoplastic location and histological grade were not associated with any significant influence on overall survival in their cohort. Other studies have also shown dismal survival outcomes even with radiotherapy and surgery in cohorts expressing the H3 K27M mutations compared to wild-type tumors [26-29]. With treatment options for this type of histologically unique neoplasm lacking, more needs to be done to better understand their pathology and outcomes.…”

Correlation of 18F-FDG PET and MRI Apparent Diffusion Coefficient Histogram Metrics with Survival in Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium

“…Subsequent studies with more patients may provide additional insight and be helpful to assess the relative difference between baseline and follow-up 18 F-FDG PET histogram metrics in the evaluation of children with DIPG. With genomic analyses of DIPG from biopsies improving knowledge of associated mutations (such as K27M-H3.1 mutations) (36)(37)(38), ADC (39) and PET histogram analyses may be incorporated into future prospective DIPG treatment protocols.…”

Extending the Neuroanatomic Territory of Diffuse Midline Glioma, K27M Mutant: Pineal Region Origin

“…These clinically aggressive tumors are appropriately designated WHO grade IV regardless of traditional diffuse glioma histological grading criteria [2,13] . The major predictor of overall survival for patients with pontine gliomas is the histone mutation status [13] .…”

“…These clinically aggressive tumors are appropriately designated WHO grade IV regardless of traditional diffuse glioma histological grading criteria [2,13] . The major predictor of overall survival for patients with pontine gliomas is the histone mutation status [13] . Children with pontine gliomas harboring the K27M-H3.3 mutation have an average overall survival of less than 1 year [8,13,14] , and fewer than 10% of patients survive to 2 years [2] .…”