Diffuse midline glioma (DMG) H3 K27M-mutant is a rare, grade IV glial neoplasm recently added to 2016 World Health Organization (WHO) classification. DMGs are mainly seen in pediatric patients with 80% of diffuse intrinsic pontine gliomas (DIPG) having H3F3A p.Lys28Met mutations, but are very rare in adults.

430 patients enrolled in our natural history study were reviewed, and cases with histone-mutations were analyzed for this study.

We found nine histone-mutated gliomas. Average age was 46 years, six patients were males. Tumors were localized in the brainstem in five patients, one thalamus, one cervical cord, and two hemispheric non-midline tumors. None of the tumors had a DIPG-like MRI appearance. The two hemispheric tumors were cystic and ring enhancing. Three tumors were relatively circumscribed and the other tumors had an infiltrative MRI appearance. Five of nine tumors had contrast enhancement at diagnosis. By histologic features alone, two cases were WHO Grade II, four were Grade III, and three Grade IV glial neoplasms. All nine cases had mutational profiling performed. All tumors were isocitrate dehydrogenase (IDH1/2) wild-type. Eight patients had H3F3A p.Lys28Met mutation, one hemispheric tumor had an H3F3A p.Gly35Val mutation. Co-occurring mutations included ATRX (n=4), TP53 (n=3), FGFR1 (n=2), and single cases with mutations in PPM1D and KRAS. The integrated pathologic evaluation changed the initial diagnosis in three cases.

In our series, most adult histone-mutated gliomas are midline and may have a unique circumscribed appearance by imaging. However, histone mutations, predominantly H3F3A p.Gly35Val, can occur in IDH wildtype hemispheric high-grade gliomas (HGGs), as previously reported in pediatric hemispheric HGGs, underscoring the importance of testing non-midline tumors for histone mutations and highlighting the need for additional studies of the clinical, radiographic, and molecular features of these rare cancers.