Pediatric diffuse midline glioma H3K27- altered: A complex clinical and biological landscape behind a neatly defined tumor type

Abstract

The 2021 World Health Organization Classification of Tumors of the Central Nervous System, Fifth Edition (WHO-CNS5), has strengthened the concept of tumor grade as a combination of histologic features and molecular alterations. The WHO-CNS5 tumor type "Diffuse midline glioma, H3K27-altered," classified within the family of "Pediatric-type diffuse high-grade gliomas," incarnates an ideally perfect integrated diagnosis in which location, histology, and genetics clearly define a specific tumor entity. It tries to evenly characterize a group of neoplasms that occur primarily in children and midline structures and that have a dismal prognosis. Such a well-defined pathological categorization has strongly influenced the pediatric oncology community, leading to the uniform treatment of most cases of H3K27-altered diffuse midline gliomas (DMG), based on the simplification that the mutation overrides the histological, radiological, and clinical characteristics of such tumors. Indeed, multiple studies have described pediatric H3K27-altered DMG as incurable tumors. However, in biology and clinical practice, exceptions are frequent and complexity is the rule. First of all, H3K27 mutations have also been found in non-diffuse gliomas. On the other hand, a minority of DMGs are H3K27 wild-type but have a similarly poor prognosis. Furthermore, adult-type tumors may rarely occur in children, and differences in prognosis have emerged between adult and pediatric H3K27-altered DMGs. As well, tumor location can determine differences in the outcome: patients with thalamic and spinal DMG have significantly better survival. Finally, other concomitant molecular alterations in H3K27 gliomas have been shown to influence prognosis. So, when such additional mutations are found, which one should we focus on in order to make the correct clinical decision? Our review of the current literature on pediatric diffuse midline H3K27-altered DMG tries to address such questions. Indeed, H3K27 status has become a fundamental supplement to the histological grading of pediatric gliomas; however, it might not be sufficient alone to exhaustively define the complex biological behavior of DMG in children and might not represent an indication for a unique treatment strategy across all patients, irrespective of age, additional molecular alterations, and tumor location.

Keywords: CNS tumors; H3K27; WHO CNS 5; WHO classification; brain cancer; diffuse midline glioma; pediatric; pediatric neuro-oncology.

Figure 1

Neuroimaging findings in diffuse midline gliomas H3K27-altered. Upper row: 16-year-old male. Diffuse Midline Glioma, EGFR-mutant. Brain axial Apparent Diffusion Coefficient (ADC) map, T2-weighted, Fluid Attenuated Inversion recovery (FLAIR) and Contrast-Enhanced (CE) T1-weighted images show a bi-thalamic infiltrating and expansile lesion with increased diffusivity and a lack of contrast enhancement. There is concomitant infiltration of the left striatum. Dynamic Susceptibility Contrast (DSC) Cerebral Blood Volume (CBV) perfusion-weighted imaging map fused with T1-weighted imaging shows low perfusion of the lesion. Single voxel Magnetic Resonance Spectroscopy (MRS) with an echo time of 144 ms shows a prominent increase in the Cho/NAA ratio. Lower row: 7-year-old male. Diffuse Intrinsic Pontine Glioma (H3.3 K27-mutant). Brain axial and coronal T2-weighted, sagittal FLAIR, and axial T1-weighted images show a diffusely infiltrating lesion involving the pons. The axial CE T1-weighted image shows a left paramedian focal area of ring enhancement. Single-voxel MRS with an echo time of 144 ms shows a marked increase in the Cho/NAA ratio.

Figure 2

Histopathological and molecular findings of a representative diffuse midline glioma, H3 K27-altered (WHO 2021). (A) Hematoxylin and eosin image (original magnification: 100X) showing a diffuse, infiltrative glioma with astrocytic morphology. (B) Diffuse expression of OLIG2, a glial marker, is consistent with this tumor type. (C) Loss of H3K27me3 is present and exemplifies a mandatory diagnostic feature. (D) Sanger sequencing output showing a K27M mutation (arrow), the most frequent molecular alteration observed in this tumor type.

Figure 3

Graphic representation of how pediatric DIPGs and DMGs have been classified over the last 15 years, based on the current and the past WHO Classifications of CNS tumors (2, 3, 68). In 2007, DIPG/DMG was not recognized as a distinct entity: data from autopsies and rare biopsies showed that DIPG/DMGs were histologically classifiable as glioblastomas (GBM gr. IV), or less frequently, anaplastic astrocytomas (AA gr. III), low-grade gliomas (mainly diffuse astrocytomas, LGG-DA gr. II), or other rarer histotypes (69). In 2016, the majority of cases were classified as DMG, H3K27M-mutant tumors, although some non-K27M-mutant DMG still remained unclassified. The 2021 WHO CNS Classification unified all cases of pediatric DMGs in which a H3K27 alteration was found (loss of H3 K27me3 trimethylation). Legend: GBM, glioblastoma; AA, anaplastic astrocytoma; LGG, low-grade glioma; DA; diffuse astrocytoma; IDHwt, IDH wild-type; NOS, not otherwise specified; DMG, diffuse midline glioma; DIPG, diffuse intrinsic pontine glioma.