Childhood brain tumors: current management, biological insights, and future directions

Abstract

Brain tumors are the most common solid tumors in children, and, unfortunately, many subtypes continue to have a suboptimal long-term outcome. During the last several years, however, remarkable advances in our understanding of the molecular underpinnings of these tumors have occurred as a result of high-resolution genomic, epigenetic, and transcriptomic profiling, which have provided insights for improved tumor categorization and molecularly directed therapies. While tumors such as medulloblastomas have been historically grouped into standard- and high-risk categories, it is now recognized that these tumors encompass four or more molecular subsets with distinct clinical and molecular characteristics. Likewise, high-grade glioma, which for decades was considered a single high-risk entity, is now known to comprise multiple subsets of tumors that differ in terms of patient age, tumor location, and prognosis. The situation is even more complex for ependymoma, for which at least nine subsets of tumors have been described. Conversely, the majority of pilocytic astrocytomas appear to result from genetic changes that alter a single, therapeutically targetable molecular pathway. Accordingly, the present era is one in which treatment is evolving from the historical standard of radiation and conventional chemotherapy to a more nuanced approach in which these modalities are applied in a risk-adapted framework and molecularly targeted therapies are implemented to augment or, in some cases, replace conventional therapy. Herein, the authors review advances in the categorization and treatment of several of the more common pediatric brain tumors and discuss current and future directions in tumor management that hold significant promise for patients with these challenging tumors.

Keywords: COG = Children’s Oncology Group; DIPG = diffuse intrinsic pontine glioma; GTR = gross-total resection; HGG = high-grade glioma; LGG = low-grade glioma; MAPK = mitogen-activated protein kinase; NF1 = neurofibromatosis type 1; NTR = near-total resection; PBTC = Pediatric Brain Tumor Consortium; PFS = progression-free survival; RT = radiation therapy; SHH = Sonic Hedgehog; SIOP = International Society of Paediatric Oncology; WHO = World Health Organization; WNT = Wingless/Integrated; astrocytoma; brain tumor; ependymoma; genomics; medulloblastoma; oncology; targeted therapy.

FIG. 1.

A: Schematic of the frequency of MAPK pathway alterations detected by biopsy of pilocytic astrocytomas. This underestimates the frequency of NF1 mutations among children with LGGs because the tumors in patients affected by NF1 often do not undergo biopsy. Although BRAF fusions (BRAF Fus) constitute the majority of alterations in pilocytic astrocytoma, BRAF mutations are more commonly observed in pleomorphic xanthoastrocytomas and gangliogliomas. B: Frequency of the different BRAF abnormalities as a function of tumor location and histological diagnosis.

FIG. 2.

Schematic (upper) depicting the four WHO-recognized subgroups of medulloblastoma, as well as the additional subtypes noted more recently and their distinguishing characteristics in terms of amplifications (amp) and duplications (dup). The figure (lower) also depicts the histological diversity of medulloblastomas: WNT tumors most commonly have a classic histology, whereas SHH tumors have desmoplastic histology with varying degrees of nodularity. Large cell/anaplastic (LCA) histology is most commonly seen in group 3 and less commonly in group 4 tumors.

FIG. 3.

A: Illustration of the nine recognized subsets of ependymomas. Only four of these subsets (ST-EPN-YAP1, ST-EPN-RELA, PF-EPN-A, and PF-EPN-B) typically occur during the childhood years and thus are the focus of this paper. The subependymoma (SE) groups typically affect middle-aged or older adults, and the spinal lesions, although occasionally encountered in children, are largely seen in adults. B: Estimate of the overall frequency of the different subtypes of ependymomas.

FIG. 4.

Schematic illustrating the multiple subgroups of HGGs that differ based on lesion location, age at onset, and prognosis. In addition to the subgroup-defining alterations, such as BRAF^V600E and histone K27M mutations, tumors commonly harbor associated mutations (mut), amplifications (amp), deletions (del), and loss of heterozygosity (LOH) in a host of other genes.