Pediatric low-grade glioma in the era of molecular diagnostics

Abstract

Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which are currently assigned World Health Organisation grades I and II. They differ substantially from their adult counterparts in both their underlying genetic alterations and in the infrequency with which they transform to higher grade tumors. Nonetheless, children with low grade glioma are a therapeutic challenge due to the heterogeneity in their clinical behavior - in particular, those with incomplete surgical resection often suffer repeat progressions with resultant morbidity and, in some cases, mortality. The identification of up-regulation of the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway as a near universal feature of these tumors has led to the development of targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help to further define the entities which fall under the umbrella of pediatric-type low-grade glioma. In doing so we discuss the specific molecular drivers of pediatric low grade glioma and how to effectively test for them, review the newest therapeutic agents and their utility in treating this disease, and propose a risk-based stratification system that considers both clinical and molecular parameters to aid clinicians in making treatment decisions.

Keywords: Pediatric low-grade glioma; RAS/MAPK pathway; brain tumor; clinical trial; glioma; molecular diagnostics; neuro-oncology; neurofibromatosis type I; pediatric; risk stratification; targeted therapy.

Fig. 1.

Magnetic resonance imaging (MRI) depicting pediatric low-grade glioma arising in the a. Cerebellum, b. Thalamus, and c. Occipital Lobe. Hematoxylin and eosin (H&E) staining highlighting the hallmark histologic features of d. Pilocytic astrocytoma, e. Diffuse astrocytoma, f. Pleomorphic xanthoastrocytoma, g. Ganglioglioma, h. Dysembryoplastic neuroepithelial tumour, i. Oligodendroglioma, and j. Angiocentric glioma

Fig. 2.

a. Schematic of the RAS/MAPK alterations identified across pediatric low-grade glioma. b. Average frequencies of RAS/MAPK alterations identified in pediatric low-grade glioma at the population level. c. Alteration types identified in pediatric low-grade glioma

Fig. 3.

Distribution of molecular alterations as it pertains to a. tumor location and b. tumor histology. Plots were created using https://rawgraphs.io Accessed December, 2019

Fig. 4.

Molecular testing decision tree for pediatric low-grade glioma. *The frequency with which tumors harbor an FGFR1 mutation and additional mutations justifies continued testing regardless of status. AG: angiocentric glioma, DNET: dysembryoplastic neuroepithelial tumour, GNT: glioneuronal tumor, ODG: oligodendroglioma, PA: pilocytic astrocytoma, GG: ganglioglioma, PXA: pleomorphic xanthoastrocytoma, DA: diffuse astrocytoma

Fig. 5.

Risk association for clinical and molecular features of pediatric low-grade glioma. Associated points are to be totaled for tumor location, histology, age at diagnosis and molecular driver. Point totals denote a risk association accompanied with clinical suggestions for proper tumor management. AG: angiocentric glioma, DNET: dysembryoplastic neuroepithelial tumour, GNT: glioneuronal tumor, ODG: oligodendroglioma, PA: pilocytic astrocytoma, GG: ganglioglioma, PXA: pleomorphic xanthoastrocytoma, DA: diffuse astrocytoma, DIA/DIG: Desmoplastic infantile astrocytoma/ganglioglioma, LGG, NOS: low-grade glioma, not otherwise specified