A comprehensive analysis of infantile central nervous system tumors to improve distinctive criteria for infant-type hemispheric glioma versus desmoplastic infantile ganglioglioma/astrocytoma

Brain Pathol. 2023 Sep;33(5):e13182. doi: 10.1111/bpa.13182. Epub 2023 Jun 22.


Recent epigenomic analyses have revealed the existence of a new DNA methylation class (MC) of infant-type hemispheric glioma (IHG). Like desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA), these tumors mainly affect infants and are supratentorial. While DIG/DIA is characterized by BRAF or RAF1 alterations, IHG has been shown to have receptor tyrosine kinase (RTK) gene fusions (ALK, ROS1, NTRK1/2/3, and MET). However, in this rapidly evolving field, a more comprehensive analysis of infantile glial/glioneuronal tumors including clinical, radiological, histopathological, and molecular data is needed. Here, we retrospectively investigated data from 30 infantile glial/glioneuronal tumors, consecutively compiled from our center. They were analyzed by two experienced pediatric neuroradiologists in consensus, without former knowledge of the molecular data. We also performed a comprehensive clinical, and histopathological examination (including molecular evaluation by next-generation sequencing, RNA sequencing, and fluorescence in situ hybridization [FISH] analyses), as well as DNA methylation profiling for the samples having sufficient material available. The integrative histopathological, genetic, and epigenetic analyses, including t-distributed stochastic neighbor embedding (t-SNE) analyses segregated tumors into 10 DIG/DIA (33.3%), six IHG (20.0%), three gangliogliomas (10.0%), two pleomorphic xanthoastrocytomas (6.7%), two pilocytic astrocytomas (6.7%), two supratentorial ependymomas, ZFTA fusion-positive (6.7%), two supratentorial ependymomas, YAP1 fusion-positive (6.7%), two embryonal tumors with PLAGL2-family amplification (6.7%), and one diffuse low-grade glioma, MAPK-pathway altered. This study highlights the significant differential features, in terms of histopathology (leptomeningeal infiltration, intense desmoplasia and ganglion cells in DIG/DIA and necrosis, microvascular proliferation, and siderophages in IHG), and radiology between DIG/DIA and IHG. Moreover, these results are consistent with the literature data concerning the molecular dichotomy (BRAF/RAF1 alterations vs. RTK genes' fusions) between DIG/DIA and IHG. This study characterized histopathologically and radiologically two additional cases of the novel embryonal tumor characterized by PLAGL2 gene amplification.

Keywords: DNA-methylation; desmoplastic infantile ganglioglioma/astrocytoma; infant-type hemispheric glioma; infantile.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Astrocytoma* / genetics
  • Astrocytoma* / pathology
  • Brain Neoplasms* / pathology
  • Central Nervous System Neoplasms*
  • DNA-Binding Proteins / genetics
  • Ependymoma*
  • Ganglioglioma* / genetics
  • Ganglioglioma* / pathology
  • Humans
  • In Situ Hybridization, Fluorescence
  • Neoplasms, Neuroepithelial*
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins B-raf / genetics
  • RNA-Binding Proteins
  • Retrospective Studies
  • Transcription Factors / genetics


  • Proto-Oncogene Proteins B-raf
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins
  • PLAGL2 protein, human
  • DNA-Binding Proteins
  • Transcription Factors
  • RNA-Binding Proteins