High-grade glioma in very young children: a rare and particular patient population

Abstract

In the past years, pediatric high-grade gliomas (HGG) have been the focus of several research articles and reviews, given the recent discoveries on the genetic and molecular levels pointing out a clinico-biological uniqueness of the pediatric population compared to their adult counterparts with HGG. On the other hand, there are only scarce data about HGG in very young children (below 3 years of age at diagnosis) due to their relatively low incidence. However, the few available data suggest further distinction of this very rare subgroup from older children and adults at several levels including their molecular and biological characteristics, their treatment management, as well as their outcome. This review summarizes and discusses the current available knowledge on the epidemiological, neuropathological, genetic and molecular data of this subpopulation. We discuss these findings and differences compared to older patients suffering from the same histologic disease. In addition, we highlight the particular clinical and neuro-radiological findings in this specific subgroup of patients as well as their current management approaches and treatment outcomes.

Keywords: brain tumors; chemotherapy; high-grade glioma; infants; radiotherapy.

Figure 1. Age distribution, genetic abnormalities and histopathological findings of HGG

Diagrammatic illustration demonstrating the age distribution, genetic abnormalities and histopathologic findings of HGG in very young children, older children and adults. I. Age Distribution: Bar graph showing increasing incidence of high-grade glioma depending on age at diagnosis. Of notice, the age cutoff definition for HGG in very young children varies between different groups (from 2 - 5 years), but most pediatric neuro-oncology working groups define it at three years of age. Similarly, definition of age cutoff for pediatric HGG patients varies between different groups and ranges from 16 to 21 years. II. Genetics: HGG in very young children tend to display more stable genome and few identifiable mutations, with SNORD loss and NTRK fusion genes being the most common molecular abnormalities. HGG in older children are characterized by increasing frequency of copy number aberrations, like PDGFRA amplification and CDKN2A/CDKN2B deletions and/or histone 3 (K27M or G34R/V) mutations. Adult HGG frequently display copy number variations like gain of chromosome 7 and loss of chromosome 10q as well as EGFR amplification, IDH and TERT mutations. III. Histopathology: H&E stained tumor specimens of glioblastoma in a. a very young child, b. an older child and c. an adult patient. All three examples share histological high-grade features with cell-rich tumor areas, microvascular proliferation and pseudo-palisading necrosis as well as a high mitotic activity. A histology-based discrimination of these tumor samples allowing conclusion regarding the patient's age is impossible.

Figure 2

In a right frontoparietal large glioblastoma; enhancement on a T1-weighted MRI after contrast (a) is very inhomogeneous. The corresponding ADC-map (b) also shows a variability of restricted diffusion with the most restricted areas above the roof of the right lateral ventricle. On T1-weighted images before contrast (not shown) also met-hemoglobin as residue of subacute bleeding is present.

Figure 3

T2-weighted axial image (a) showing a central hemorrhagic part (with a fluid level) of a thalamic glioblastoma together with an increased T2-signal in the posterior corpus callosum, the right frontal region and the left frontobasal parts (not shown) of the brain as a result of multifocal growth. The T1-weighted image at the corresponding level after contrast (b) shows only slight enhancement surrounding the central deoxyhemoglobin core of this tumor part and very ill defined borders.