We searched PubMed between 1990 and February, 2012, for relevant articles published in English. We generated search terms by use of each histological entity of interest (“pilocytic astrocytoma”, “pleomorphic xanthoastrocytoma”, “ganglioglioma”, “oligodendroglioma”, “oligoastrocytoma”, “glioblastoma”, and “diffuse intrinsic pontine glioma”) in combination with the terms “pediatric” AND “molecular”. We also included reports on associated topics.
ReviewMolecular diagnostics in paediatric glial tumours
Introduction
A growing understanding of paediatric CNS tumours through molecular characterisation has enabled the development of specialised molecularly targeted therapies to augment, or in some cases, supersede conventional treatment methods. However, the extent to which molecular phenotypes of paediatric brain tumours resemble their adult counterparts is uncertain. The prognosis of children with brain tumours depends on several clinical factors, such as age at diagnosis, histology, location of tumour, extent of surgical resection, and type of adjuvant treatment, but the molecular phenotype of the tumour in question undoubtedly provides additional clinically relevant insights. Even within the paediatric population, substantial molecular heterogeneity exists, resulting in variable biological behaviour in tumours with identical histological diagnoses. Furthermore, no reliable measure of classification exists for an important group of paediatric low-grade gliomas that cannot be differentiated by histology alone and are generally labelled as diffuse or low-grade astrocytomas. Most importantly, WHO classification is well established in clinical practice, but histopathological grading of paediatric glial tumours is a substantial challenge to researchers and clinicians in the interpretation of published work, partly because of the descriptive nature of histological criteria and therefore the inconsistency in histological diagnosis. Thus, molecular profiling of paediatric glial tumours has become an increasingly essential method for accurate diagnostic and prognostic assessment. In view of these challenges, in this Review we present the molecular features of paediatric glial tumours by histological entity, and discuss their significance within the clinical context of diagnosis, treatment, and prognosis, with a shift from histopathology to molecular diagnostics.
Section snippets
Ganglioglioma
Ganglioglioma is a rare intra-axial CNS tumour, which is diagnosed most frequently in children and young adults and often presents in structurally epileptogenic regions of the temporal lobe. Ganglioglioma is a mixed neoplasm, consisting of both neuronal and glial components. Its histological features overlap with those of other low-grade neuroepithelial tumours, such as desmoplastic infantile astrocytoma, desmoplastic infantile ganglioglioma, dysembryoplastic neuroepithelial tumour, pleomorphic
Pleomorphic xanthoastrocytoma
Pleomorphic xanthoastrocytoma is an epileptogenic tumour of neuroepithelial or mesenchymal origin, which typically occurs in children and young adults. It generally behaves as an indolent tumour, but can occasionally undergo malignant evolution. Comparative genomic hybridisation analysis identified loss of chromosome 9 as the most common chromosomal change in pleomorphic xanthoastrocytoma, many of these tumours having homozygous deletions in the CDKN2A/p14ARF and CDKN2B tumour-suppressor gene
Pilocytic astrocytoma
Pilocytic astrocytoma is an indolent, generally well circumscribed glial tumour that occurs mainly in children, representing 11–18% of primary CNS tumours in this population.16 The tumour typically shows a normal karyotype, although a few cytogenetic abnormalities have been described that do not seem to correlate with outcome.17, 18 A high percentage of pilocytic astrocytomas harbour 7q34 duplication, resulting in gene fusions between BRAF and KIAA1549.4, 19, 20, 21, 22, 23 Conversely, BRAF
Oligodendroglioma
Loss of chromosome 1p and 19q from translocation t(1;19)(q10;p10) is the molecular signature of oligodendroglial neoplasms, and is present in about 80% of low-grade oligodendrogliomas and 50–70% of anaplastic oligodendrogliomas.32, 33 This chromosomal marker predicts a less aggressive clinical course, favourable response to adjuvant therapy, and prolonged survival in patients with anaplastic oligodendroglioma.14, 33 However, studies so far have focused mainly on adults, and less is known about
Oligoastrocytoma
Oligoastrocytoma has a mixed histological phenotype, since it harbours both astrocytic and oligodendroglial elements. The association of oligoastrocytomas with both astrocytic and oligodendroglial lineages is also evident in its range of molecular abnormalities, the frequency of which nominally falls between those reported for oligodendroglioma and astrocytoma.41 In adults, TP53 mutation, 1p/19q co-deletion, MGMT promoter methylation, and IDH1 mutation have been described in low-grade
Paediatric glioblastoma
Although histologically indistinguishable from adult glioblastoma, paediatric glioblastoma has distinct molecular features and accounts for about 3% of all primary CNS tumours in childhood.16 Unlike in adults, EGFR amplification and PTEN deletion are rarely reported in paediatric glioblastoma.45, 46, 47 When present, PTEN mutation and loss of PTEN expression are associated with poor prognosis in children.48, 49 In glioblastoma cells, increased activity in the oncogenic AKT pathway is a result
Diffuse pontine intrinsic glioma
Diffuse intrinsic pontine glioma is found almost exclusively in children, and represents 10–15% of paediatric CNS tumours. Molecular studies of this tumour entity have been limited by tissue availability, because diagnostic biopsy is not done routinely. However, several lines of evidence from studies show that diffuse intrinsic pontine glioma is molecularly distinct from adult high-grade glioma and paediatric non-brainstem high-grade glioma. Barrow and colleagues64 did comparative genomic
Conclusions
Molecular and genomic analyses provide a unique opportunity to understand better paediatric brain tumours, especially in comparison with their histological counterparts in adults. Molecular profiling of tumours provides novel diagnostic, therapeutic, and prognostic insights that cannot be entirely appreciated from conventional histopathological methods (table 3). As tumour genotyping methods become more readily available and accessible, individualised cancer therapy in children can be fully
Search strategy and selection criteria
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