Characteristics of H3 K27M-mutant gliomas in adults

Abstract

Background: Diffuse H3 K27M-mutant gliomas occur primarily in children but can also be encountered in adults. The aim of this study was to describe the characteristics of H3 K27M-mutant gliomas in adults.

Methods: We analyzed the characteristics of 21 adult H3 K27M-mutant gliomas and compared them with those of 135 adult diffuse gliomas without histone H3 and without isocitrate dehydrogenase (IDH) mutation (IDH/H3 wild type).

Results: The median age at diagnosis in H3 K27M-mutant gliomas was 32 years (range: 18-82 y). All tumors had a midline location (spinal cord n = 6, thalamus n = 5, brainstem n = 5, cerebellum n = 3, hypothalamus n = 1, and pineal region n = 1) and were IDH and BRAF-V600E wild type. The identification of an H3 K27M mutation significantly impacted the diagnosis in 3 patients (14%) for whom the histological aspect initially suggested a diffuse low-grade glioma and in 7 patients (33%) for whom pathological analysis hesitated between a diffuse glioma, ganglioglioma, or pilocytic astrocytoma. Compared with IDH/H3 wild-type gliomas, H3 K27M-mutant gliomas were diagnosed at an earlier age (32 vs 64 y, P < .001), always had a midline location (21/21 vs 21/130, P < .001), less frequently had a methylated MGMT promoter (1/21 vs 52/129, P = .002), and lacked EGFR amplification (0/21 vs 26/128, P = .02). The median survival was 19.6 months in H3 K27M-mutant gliomas and 17 months in IDH/H3 wild-type gliomas (P = .3).

Conclusion: In adults, as in children, H3 K27M mutations define a distinct subgroup of IDH wild-type gliomas characterized by a constant midline location, low rate of MGMT promoter methylation, and poor prognosis.

Keywords: H3 K27M; IDH; glioma; histone.

Fig. 1

MRI characteristics of adults with H3 K27M-mutant gliomas. Top: numbers correspond to the patient numbers. For patients 1, 2, 6, 7, 10, 11, 15, 17, and 18, who had non-enhancing tumor, axial T2/fluid-attenuated inversion recovery (FLAIR) sequences are shown. For patients 3, 4, 5, 8, 9, 12, 13, 14, and 21, who had contrast-enhancing tumor, T1 post-contrast sequences are shown. Bottom: tumor growth before treatment onset in patients 1, 15, and 9. Patient 1 presented with unexplained anorexia and vomiting 32 months before diagnosis that led to an MRI that was considered normal at the time despite the presence of a hypersignal within the medulla oblongata. In patient 15, initial suspicion of grade I ganglioglioma led to an initial follow-up. In patient 9, initial follow-up resulted from the initial suspicion of a myelitis.

Fig. 2

Examples of histopathological features observed in adults with H3 K27M-mutant gliomas. Hematoxylin and eosin (H&E) × 400 (scale bar = 20 µm). (A) Histopathological features of case 9 diagnosed as spinal glioblastoma showing a highly pleomorphic infiltrating astrocytoma with microvascular proliferation. (B) Histopathological features of case 11 initially diagnosed as a thalamic low-grade astrocytoma showing a tumor of low density with astrocytic neoplastic cells and p53 staining (embedded picture). (C) Histopathological features of case 12 initially diagnosed as a spinal ganglioglioma showing a tumor of low density with neoplastic glial and ganglionic tumor cells expressing CD34 (embedded picture). (D) Histopathological features of case 1 initially diagnosed as a brainstem pilocytic astrocytoma showing a low density with compacted bipolar cells intermingled with Rosenthal fibers (shown at a higher magnification in embedded picture).

Fig. 3

Overall survival in patients with H3 K27M-mutant gliomas, IDH/H3 wild-type gliomas (irrespective of localization), and midline IDH/H3 wild-type gliomas.