Diffuse midline gliomas (DMG) H3 K27M-mutant was introduced in the 2016 WHO Classification of Tumors of the Central Nervous System, unifying diffuse intrinsic pontine gliomas (DIPG) and gliomas from the thalamus and spinal cord harboring a histone H3-K27M mutation leading to Polycomb Repressor Complex 2 (PRC2) inhibition [7]. These gliomas are relatively much more common in the pediatric than the adult population, and patients show a dismal prognosis with a median overall survival below 1 year [11].

We and others previously reported the identification of few cases of brainstem glial tumors that lacked a histone H3 mutation [3]. To address this question more precisely, we combined a retrospective cohort of patients operated for DIPG at the Necker Enfants-Malades Hospital and patients included in the BIOMEDE clinical trial (NCT02233049), both selected with strict clinical and radiological criteria [12]. Following the histopathological analysis, we identified 9 cases out of 241 brainstem gliomas (3.7%) that displayed a typical infiltrating DIPG histopathology and H3K27 trimethylation loss but that lacked K27M positivity by immunohistochemistry (IHC)(Fig. 1 a–d; Supplementary Table 1, online resource).