Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults

Abstract

Background: Diffuse hemispheric gliomas, H3 G34-mutant (DHG H3G34-mutant) constitute a distinct type of aggressive brain tumors. Although initially described in children, they can also affect adults. The aims of this study were to describe the characteristics of DHG H3G34-mutant in adults and to compare them to those of established types of adult WHO grade IV gliomas.

Methods: The characteristics of 17 adult DHG H3G34-mutant, 32 H3.3 K27M-mutant diffuse midline gliomas (DMG), 100 IDH-wildtype, and 36 IDH-mutant glioblastomas were retrospectively analyzed.

Results: Median age at diagnosis in adult DHG H3G34-mutant was 25 years (range: 19-33). All tumors were hemispheric. For 9 patients (56%), absent or faint contrast enhancement initially suggested another diagnosis than a high-grade glioma, and diffusion-weighted imaging seemed retrospectively more helpful to suspect an aggressive tumor than MR-spectroscopy and perfusion MRI. All cases were IDH-wildtype. Most cases were immunonegative for ATRX (93%) and Olig2 (100%) and exhibited MGMT promoter methylation (82%). The clinical and radiological presentations of adult DHG H3G34-mutant were different from those of established types of adult grade IV gliomas. Median overall survival of adult DHG H3G34-mutant was 12.4 months compared to 19.6 months (P = .56), 11.7 months (P = .45), and 50.5 months (P = .006) in H3.3 K27M-mutant DMG, IDH-wildtype, and IDH-mutant glioblastomas, respectively.

Conclusions: Adult DHG H3G34-mutant are associated with distinct characteristics compared to those of established types of adult WHO grade IV gliomas. This study supports considering these tumors as a new type of WHO grade IV glioma in future classifications.

Keywords: H3.3 G34R/V mutation; H3.3 K27M mutation; PNET; diffuse hemispheric glioma; survival.

Figure 1.

Histological characteristics of adult diffuse hemispheric gliomas, H3 G34-mutant (Scale bar = 100 µm). (A) PNET-like morphology, characterized by small round cells, with anaplastic features including endothelial cell proliferation, negative Olig2 immunostaining, positive TP53 staining and ATRX loss. (B) Undifferenciated glial morphology, characterized by irregularly shaped nuclei and poorly delimited cytoplasms with anaplastic features including endothelial cell proliferation, positive Olig2 (reactive glial cells), ATRX, and TP53 stainings. (C) Monstrocellular morphology, characterized by multinucleated cells, with anaplastic features including endothelial cell proliferation, necrosis, negative Olig2 immunostaining, positive TP53 staining, and ATRX loss. (D) Oligoid morphology, characterized by small cells with a clear peri-nuclear halo, with anaplastic features including endothelial cell proliferation and 2 mitoses, positive Olig2 (reactive glial cells) and TP53 immunostaining and ATRX loss.

Figure 2.

Radiological characteristics of adult diffuse hemispheric gliomas, H3 G34-mutant For each case, T1-weighted contrast-enhanced MRI (left), T2-weighted FLAIR MRI (middle) and ADC map (right) are shown. (A) Frontal cortico-subcortical, poorly delimited, diffuse hemispheric glioma, H3 G34-mutant without contrast enhancement, displaying focal ADC restriction and a metabolic profile on MR spectroscopy demonstrating no Choline/Creatinine ratio increase but an elevated Choline/N-Acetyl-Aspartate ratio (2.35) and a lipid peak (patient 10). In this patient, a low-grade glioma was initially suspected. (B–D) Three other cases of diffuse hemispheric gliomas, H3 G34-mutant with a misleading presentation, including absent or faint contrast enhancement and a focal ADC restriction. These characteristics led to suspect at first diagnosis multiple sclerosis (B—Patient 5, D—Patient 3), limbic encephalitis (C—Patient 4) or low-grade glioma (D—Patient 3). (E) Fronto-callosal diffuse hemispheric glioma, H3 G34-mutant with a presentation suggestive of high-grade glioma, including necrosis area and an evident contrast enhancement (patient 6). Three years earlier, this patient underwent an MRI which was normal.

Figure 3.

Kaplan–Meier survival analysis of diffuse hemispheric gliomas, H3 G34-mutant, H3.3 K27M-mutant diffuse midline gliomas, IDH-mutant glioblastomas, and IDH-wildtype glioblastomas patients. Patients at risk are indicated below.