Cerebral hemispheric glioblastoma with PNET-like morphology and histone H3.3 G34 mutation in younger patients: Report of three rare cases and diagnostic pitfalls.

Recurrent mutations in H3F3A that encodes the histone 3 variant H3.3, lead to amino acid substitutions including K27M and G34R/V-which are observed in high-grade gliomas (HGGs) of children and young adults. Previous studies have focused on gliomas with K27M mutation, whereas gliomas with G34R/V mutation have received little attention. Herein, we report three rare cases of glioblastoma (GBM) with H3.3 G34 mutation arising from a cerebral hemisphere in two children and one young adult. All three cases showed microscopic characteristics of central nervous system primitive neuroectodermal tumor (CNS-PNET, called CNS embryonal tumors in WHO 2016 Revised 4 Edition) and presented H3.3 G34 mutation. H3.3 G34-mutant brain tumors were formerly a group of histopathologically distinct neoplasms, involved in GBM, CNS-PNET, and astroblastoma. However, recent studies have demonstrated that different CNS tumors with H3.3 G34 mutation display coherent epigenetic signatures, implying a single biological origin. Correspondingly, our three cases showed high consistency in tumor location, histological morphology, and molecular phenotype. Their immunophenotypes are similar to astrocytoma, with ATRX loss and TP53 mutation. Therefore it suggests that these H3.3 G34-mutant brain tumors may be a rare entity of HGG.