Molecular and Pathological Features of Paediatric High-Grade Gliomas

Abstract

Paediatric high-grade gliomas are among the most common malignancies found in children. Despite morphological similarities to their adult counterparts, there are profound biological and molecular differences. Furthermore, and thanks to molecular biology, the diagnostic pathology of paediatric high-grade gliomas has experimented a dramatic shift towards molecular classification, with important prognostic implications, as is appropriately reflected in both the current WHO Classification of Tumours of the Central Nervous System and the WHO Classification of Paediatric Tumours. Emphasis is placed on histone 3, IDH1, and IDH2 alterations, and on Receptor of Tyrosine Kinase fusions. In this review we present the current diagnostic categories from the diagnostic pathology perspective including molecular features.

Keywords: H3G34; H3K27; brain tumour; glioblastoma; glioma; histone 3; paediatric glioma.

Figure 1

Microscopic features of malignancy in gliomas. (A): Cytological atypia, in the form of hyperchromasia, cytomegalia, irregularities in the nuclear membrane, etc, are criteria supporting malignancy. The example shown in this panel has evident atypical features that can be appreciated even at low-power magnification. (B): The presence of mitotic figures (arrow), if found in sufficient quantity, may upgrade some gliomas. Although most paediatric high-grade gliomas are per definition WHO grade 4 neoplasms, the presence of mitotic figures is supportive of its malignant behaviour. (C): Necrosis, with or without pseudopalisading, is indicative of a high-grade neoplasm. Although it does not define grade in paediatric high-grade gliomas, it suggests a highly malignant neoplasm. (D): Microvascular proliferation. The presence of vessels with multilayering of endothelium (asterisks) is a feature of aggressive neoplasms. Although not required in high-grade paediatric gliomas, it is concordant with an aggressive malignant glioma.

Figure 2

Diffuse midline glioma, H3K27-altered. The following figure features a glial neoplasm located in the midline of a paediatric patient. (A): Hypercellular neoplasm concordant with a glioma. (B): Presence of entrapped neurons (arrow) is supportive of its diffuse nature. (C): IHC for H3K27M shows diffuse and intense nuclear positivity. Note that vascular endothelia are negative, serving as an internal negative control. (D): IHC for H3K27me3 shows concomitant loss of or reduction in the marker in the neoplasm, with retained nuclear staining in entrapped normal elements, like neurons or endothelia.

Figure 3

Diffuse hemispheric glioma, H3G34-altered. The following figure features a glial hemispheric neoplasm of an adolescent patient. (A,B): These two panels show a heterogeneous neoplasm, where glial features like eosinophilic cytoplasm and indistinct cellular borders (A) coexist with more embryonal/oligodendroglial features like a higher nucleus-to-cytoplasm ratio and round cell morphology (B). (C): High-grade features, like abundant mitoses, necrosis (asterisk), or microvascular proliferation are present. (D): IHC for p53 shows diffuse strong nuclear accumulation of the protein. There was also loss of ATRX and OLIG2 and concomitant lack of mutations in the IDH1 and 2 genes.

Figure 4

Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype. The following figure features a hemispheric neoplasm in a patient with constitutive mismatch repair deficiency. (A): A hypercellular glial neoplasm with features of oligodendroglioma (fried egg appearance, plexiform capillary network) is seen. (B): Pseudopalisading necrosis (asterisk) was found in some fields. (C): IHC for neurofilaments shows a fragmented network, supportive of a diffuse glial neoplasm. (D): IHC for PMS2 shows a loss of expression in the tumour and normal cells. IHC for IDH1 and H3K27M were also negative).