Diffuse intrinsic pontine tumors: A study of primitive neuroectodermal tumors versus the more common diffuse intrinsic pontine gliomas: Laboratory investigation

Division of Neuro-Oncology, Department of Pediatrics, The Children's Hospital of Colorado, University of Colorado, Aurora, Colorado 80045, USA.
Journal of Neurosurgery Pediatrics (Impact Factor: 1.48). 06/2012; 10(2):81-8. DOI: 10.3171/2012.3.PEDS11316
Source: PubMed


The diagnosis of diffuse pontine tumors has largely been made on the basis of MRI since the early 1990 s. In cases of tumors considered "typical," as a rule, no biopsy specimen has been obtained, and the tumors have been considered diffuse intrinsic pontine gliomas (DIPGs). There have been sporadic reports that primitive neuroectodermal tumors (PNETs) of the pons may not be distinguishable from the DIPGs by radiological imaging. This study presents 2 cases of diffuse pontine PNETs with molecular evidence that these are indeed PNETs, distinct from DIPGs, thus supporting biopsy of diffuse pontine tumors as a standard of care.
Biopsy specimens were obtained from 7 diffuse pontine tumors and snap frozen. Two of these 7 tumors were identified on the basis of pathological examination as PNETs. All 7 of the diffuse pontine tumors were analyzed for gene expression using the Affymetrix HG-U133 Plus 2.0 GeneChip microarray. Gene expression was compared with that of supratentorial PNETs, medulloblastomas, and low- and high-grade gliomas outside the brainstem.
Unsupervised hierarchical clustering analysis of gene expression demonstrated that pontine PNETs are most closely related to PNETs of the supratentorial region and not with gliomas. They do not cluster with the 5 DIPGs in the study. Thirty-eight genes, including GATA3, are uniquely differentially expressed in pontine PNETs compared with other types of pediatric brain tumors, including DIPGs and other PNETs at a false discovery rate statistical significance of less than 0.05.
The cluster and individual gene expression analyses indicate that pontine PNETs are intrinsically different from DIPGs. The 2 pontine PNET cases cluster with supratentorial PNETs, rather than with DIPGs, suggesting that these tumors should be treated with a PNET regimen, not with DIPG therapy. Since diagnosis by imaging is not reliable and the biology of the tumors is disparate, a biopsy should be performed to enable accurate diagnosis and direct potentially more effective treatments.

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    • "As in our cases, they described these tumours as having poorly differentiated cells, with scant cytoplasm and round nuclei. Interestingly, on gene expression profiling, these tumours resembled supratentorial PNET [23]. Patients in our series who were found at autopsy to have PNET were diagnosed as DIPG based on standard criteria including MRI and clinical presentation. "
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    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 material The online version of this article (doi:10.1007/s00401-014-1319-6) contains supplementary material, which is available to authorized users.
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    • "Because the vast majority of samples biopsied are malignant gliomas, the primary purpose of the biopsy in patients with a typical clinical presentation and typical radiographic appearance would not necessarily be for histologic confirmation, although this would be important for those with atypical features, particularly since brainstem PNET can mimic DIPG radiographically (Sufit et al., 2012). Rather, the major question to be addressed is whether or not treatment chosen based on biopsy results can improve the outcome of these children. "
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    ABSTRACT: Diffuse intrinsic pontine gliomas (DIPGs) are amongst the most challenging tumors to treat. Surgery is not an option, the effects of radiation therapy are temporary, and no chemotherapeutic agent has demonstrated significant efficacy. Numerous clinical trials of new agents and novel therapeutic approaches have been performed over the course of several decades in efforts to improve the outcome of children with DIPG, yet without success. The diagnosis of DIPG is based on radiographic findings in the setting of a typical clinical presentation, and tissue is not routinely obtained as the standard of care. The paradigm for treating children with these tumors has been based on that for supratentorial high-grade gliomas in adults as the biology of these lesions were presumed to be similar. However, recent pivotal studies demonstrate that DIPGs appear to be their own entity. Simply identifying this fact releases a number of constraints and opens opportunities for biologic investigation of these lesions, setting the stage to move forward in identifying DIPG-specific treatments. This review will summarize the current state of knowledge of DIPG, discuss obstacles to therapy, and summarize results of recent biologic studies.
    Full-text · Article · Dec 2012 · Frontiers in Oncology
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    Preview · Article · Jun 2012 · Journal of Neurosurgery Pediatrics
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