Pediatric low-grade gliomas: next biologically driven steps

Abstract

Despite the fact that they are not typically life-threatening, low-grade gliomas (LGGs) remain a significant clinical challenge in pediatric neuro-oncology due to comorbidities associated with these tumors and/or their treatments, and their propensity to multiply recurs. LGGs, in total the most common brain tumors arising in childhood, can often become a chronic problem requiring decades of management. The Second International Consensus Conference on Pediatric Low-Grade Gliomas held in Padua, Italy in 2016 was convened in an attempt to advance the pace of translating biological discoveries on LGGs into meaningful clinical benefit. Topics discussed included: the implications of our growing biological understanding of the genomics underlying these tumors; the assessment of the model systems available; the implications of the molecular and histopathologic differences between adult and pediatric diffuse gliomas; and steps needed to expedite targeted therapy into late-stage clinical trials for newly diagnosed cases. Methods for the diagnostic assessment of alterations in the Ras/mitogen-activated protein kinase pathway, typical for these tumors, were also considered. While the overall tone was positive, with a consensus that progress is being and will continue to be made, the scale of the challenge presented by this complex group of tumors was also acknowledged. The conclusions and recommendations of the meeting panel are provided here as an outline of current thinking and a basis for further discussion.

Keywords: MAPK pathway; low-grade glioma; molecular diagnostics; neurooncology; pediatric brain tumor; targeted therapy.

Fig. 1

Possible order of investigation for rationally targeted molecular testing based on tumor location and histology. Upfront next-generation sequencing (DNA + RNA) can also be used to supersede this order and give the most comprehensive overview. PA, pilocytic astrocytoma; (A)GG, (anaplastic) ganglioglioma; PXA, pleomorphic xanthoastrocytoma; DNET, dysembryoplastic neuroepithelial tumor; O, oligodendroglioma; OA, oligoastrocytoma; RGNT, rosette-forming glioneuronal tumor; AG, angiocentric glioma; DA (pediatric-type) diffuse glioma; mut, mutation; dup, tyrosine kinase internal tandem duplication; fus, fusion.

Fig. 2

Example of a possible framework for an integrated molecular-histological stratification of pediatric LGG. LGNET, low-grade neuroepithelial tumor; PA, pilocytic astrocytoma; GG, ganglioglioma; DLGNT, diffuse leptomeningeal glioneuronal tumor; DG, diffuse glioma (pediatric type); DIA/DIG, desmoplastic infantile astrocytoma/ganglioglioma; NOS, not otherwise specified.