Revisiting pediatric HGGs and PNETs according to the WHO CNS5 criteria: A clinical and genomic retrospective analysis

Abstract Background The 2021 WHO Classification of Tumors of the Central Nervous System, 5th edition (WHO CNS5), introduced revised diagnostic criteria for pediatric brain tumors (BTs), redefining pediatric-type diffuse high-grade gliomas (pHGGs) into 4 subtypes: diffuse midline glioma, H3 K27-altered (DMG-H3K27), diffuse hemispheric glioma, H3 G34-mutant (DHG-H3G34), diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (DpHGG-H3wt/IDHwt), and infant-type hemispheric glioma (IHG). This study revisits prior diagnoses of HGGs and primitive neuroectodermal tumors (PNETs) in children and incorporates next-generation sequencing (NGS) to classify tumors according to the revised criteria and analyze their clinicogenomic characteristics and outcomes. Methods A retrospective review of pediatric patients diagnosed with glioblastoma (GBM), anaplastic astrocytoma, anaplastic oligoastrocytoma (AOA), gliomatosis cerebri, or PNET between 1997 and 2023 was conducted. Cases underwent pathology review, immunohistochemistry (IHC), and BT-targeted NGS for reclassification per WHO CNS5. An additional 20 patients diagnosed with pHGG via genetics-integrated diagnosis since 2020 were included. Clinical characteristics, genomic alterations, and outcomes were analyzed. Results Among the 78 reviewed cases, 41 were reclassified as pHGGs. TP53 mutations were the most prevalent, particularly in DpHGG-H3wt/IDHwt, which showed associations with cancer predisposition syndrome (CPS). Two patients with Li-Fraumeni syndrome (LFS) developed DpHGG-H3wt/IDHwt adjacent to prior radiation fields. The 2-year overall survival (OS) rates were lowest in DpHGG-H3wt/IDHwt (23.2%) and highest in IHG (92.3%). Long-term survival was observed in IHG patients, with a 5-year OS rate of 73.8%, indicating the need for different adjuvant treatment strategies compared to other pHGGs. Conclusions BT-targeted NGS facilitates the reclassification of pHGGs, revealing associations with CPS. Routine germline sequencing is warranted, and accurate molecular diagnosis enables a shift in treatment strategies tailored to specific pHGG subtypes.