Glioblastoma, IDH- and H3-wildtype in young adults: a rare condition with a distinct clinico-radio-histo-molecular and epigenetic landscape

Purpose. Glioblastomas, IDH- and H3-wildtype in young adults is a rare and poorly known entity. We compared newly diagnosed glioblastomas, IDH- and H3-wildtype in young adults (18–39 years) to those in adult patients (> 39 years). Methods. We performed an observational, retrospective, single-centre cohort study at a tertiary neurosurgical oncology centre between January 2006 and December 2022. Results. We included 1.139 adult patients with a newly diagnosed glioblastoma, IDH- and H3-wildtype. Young adults: 1) represent a small proportion of patients with glioblastoma, IDH- and H3-wildtype (n = 33, 2.9%); 2) have a high rate of unclassified cases according to WHO criteria and epigenetics (n = 10, 30.3%); 3) have a longer progression-free survival (p = 0.003) and overall survival (p = 0.001) and; 4) do not have higher surgically-related adverse event rates (p = 0.198). Concerning young adults, surgical resection was associated with improved progression-free and overall survival (p < 0.001 and p < 0.001, respectively). The DNA-methylation class significantly impacts the overall survival (p = 0.028), however, the MGMT methylation status is not significantly associated with either progression-free or overall survival (p = 0.320 and p = 0.639, respectively). Conclusion. Glioblastomas, IDH- and H3-wildtype is a rare histo-molecular subtype in young adults with a better prognosis than older adults. In young adults, DNA-methylation subtypes are different from their adult counterpart and had a significant impact on survival unlike MGMT status. Given the rarity of glioblastoma IDH- and H3-wildtype in young adults, a dedicated management in specialized neurosurgical oncology centres is preferred. Further histo-molecular and epigenetic analyses are required to understand the differences in prognosis compared to adult patients.