Childhood Malignant Brain Tumors: Balancing the Bench and Bedside

Abstract

Brain tumors are the leading cause of childhood cancer deaths in developed countries. They also represent the most common solid tumor in this age group, accounting for approximately one-quarter of all pediatric cancers. Developments in neuro-imaging, neurosurgical techniques, adjuvant therapy and supportive care have improved survival rates for certain tumors, allowing a future focus on optimizing cure, whilst minimizing long-term adverse effects. Recent times have witnessed a rapid evolution in the molecular characterization of several of the common pediatric brain tumors, allowing unique clinical and biological patient subgroups to be identified. However, a resulting paradigm shift in both translational therapy and subsequent survival for many of these tumors remains elusive, while recurrence remains a great clinical challenge. This review will provide an insight into the key molecular developments and global co-operative trial results for the most common malignant pediatric brain tumors (medulloblastoma, high-grade gliomas and ependymoma), highlighting potential future directions for management, including novel therapeutic options, and critical challenges that remain unsolved.

Keywords: brain; ependymoma; glioma; medulloblastoma; pediatric; tumor.

Figure 1

Molecular subgroups and in-group subtypes of medulloblastoma; the four globally recognized molecular subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) are shown, together with the current subtypes within WNT and SHH subgroups, as per [13], and Groups 3 and 4, in accordance with [14,15]. Two WNT-activated subtypes are reported, alongside 4 SHH subtypes. Groups 3 and 4 are likely now best considered as a spectrum of 8 different subtypes, each with biological and clinical characteristics. Age-related cartoons depict infant, young child (2–5 years), child (5–12 years), adolescent and older (12+ years). Key: OS = overall survival, DN = desmoplastic/nodular histology, LCA = large cell anaplastic histology, MBEN = medulloblastoma with extensive nodularity, amp. = amplification, mut. = mutation, del. = deletion, and actvn. = activation.

Figure 2

Molecular subgroups of pediatric high-grade glioma. At least nine subgroups are thought to exist, with biological and clinical features highlighted in accordance with [84,90,91]. Age-related cartoons depict infant, young child (2–5 years), child (5–12 years), and adolescent/adult (12+ years). Key: amp. = amplification, mut. = mutation, del. = deletion, IDH = isocitrate dehydrogenase, and PXA, pleomorphic xanthoastrocytoma.

Figure 3

Predominant molecular subtypes of pediatric intracranial ependymoma. Posterior fossa and supratentorial childhood ependymomas are shown, further categorized into four in-group subtypes; PF-A, PF-B, ZFTA-fused and YAP1-fused. The clinical and biological characteristics of these subtypes are shown, in accordance with [59,120,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153]. Nine molecular subtypes of ependymoma are reported but the remaining subtypes occur in either the spinal cord (spinal subependymoma, spinal myxopapillary ependymoma, spinal ependymoma) or the adult brain (subependymoma: PF and ST) so are not depicted in this figure. Age-related cartoons depict infant, young child (2–5 years), child (5–12 years), adolescent/adult (12+ years). Key: WHO = World Health Organization, CIN = chromosomal instability, GTR = gross total resection, IR = incomplete resection.