Decoding Diffuse Midline Gliomas: A Comprehensive Review of Pathogenesis, Diagnosis and Treatment

Abstract

Diffuse midline gliomas (DMGs) are a group of aggressive CNS tumors, primarily affecting children and young adults, which have historically been associated with dismal outcomes. As the name implies, they arise in midline structures in the CNS, primarily in the thalamus, brainstem, and spinal cord. In more recent years, significant advances have been made in our understanding of DMGs, including molecular features, with the identification of potential therapeutic targets. We aim to provide an overview of the most recent updates in the field of DMGs, including classification, molecular subtypes, diagnostic techniques, and emerging therapeutic strategies including a review of the ongoing clinical trials, thus providing the treating multidisciplinary team with a comprehensive understanding of the current landscape and potential therapeutic strategies for this devastating group of tumors.

Keywords: H3 K27M; H3 K27me3; brainstem; diffuse midline glioma; prognosis; spinal cord; thalamus.

Figure 1

Schematic summary of the genes implicated in the pathogenesis of DMG (Adopted with modifications from reference [5]).

Figure 2

(A) Axial T1-weighted post IV contrast sequence. (B) Axial T1-weighted pre-IV contrast sequence. (C) Axial FLAIR sequence. (D) Axial T2-weighted sequence. (E) Dynamic susceptibility contrast (DSC) MR perfusion images, cerebral blood volume (CBV). (F) Diffusion weighted images (DWI), b 1000. (G) Coronal T1-weighted post IV contrast sequence. (H) Apparent diffusion coefficient (ADC) map.

Figure 3

(A) Axial T1-weighted post IV contrast fat saturated sequence. (B) Axial T1-weighted pre-IV contrast sequence. (C) Axial FLAIR sequence post IV contrast. (D) Axial T2 TSE sequence. (E) Sagittal T1-weighted post IV contrast sequence. (F) Sagittal T1-weighted pre-IV contrast sequence. (G) Coronal T1-weighted post IV contrast sequence. (H) Sagittal T2 TSE sequence. FLAIR (fluid attenuation inversion recovery). TSE (turbo spin echo).

Figure 4

(A) Sagittal T1-weighted pre-IV contrast sequence of the dorsal spine. (B) Sagittal T1-weighted post IV contrast sequence of the dorsal spine. (C) Sagittal STIR sequence of the dorsal spine. (D) SagittalT2-weighted sequence of the dorsal spine.

Figure 5

A 52-year-old woman presented with disorientation, right ear pain, and mood changes of 2 months duration. The overall appearance for the radiologist was suggestive of low-grade glioma with a possibility of high-grade cystic component. Accordingly, a stereotactic biopsy of the left thalamic lesion was performed. (A) A moderately cellular tumor with pleomorphic cells and scattered mitotic figures (H&E, X20). (B) ATRX immunostain showed retained nuclear stain. (C) H3 K27M showed positive nuclear staining. (D) H3 K27me3 showed loss of nuclear stain of the infiltrating tumor cells. The final diagnosis was DMG, H3 K27-altered, CNS WHO grade-4.

Figure 6

A 7-year-old female patient with a midbrain mass invading the pons and the thalamus. (A) High power from the abnormal area with mild increase in cellularity as well as scattered atypical cells. No mitotic figures, microvascular proliferation or necrosis could be appreciated. The case was diagnosed in 2014 as grade-2 fibrillary astrocytoma. Recently, further immunostains were performed. (B) The atypical tumor cells are positive for H3 K27M immunostain (normal cells serve as the negative internal control). (C) Immunostain for H3 K27me3 showed loss of nuclear stain in the infiltrating atypical tumor cells (normal cells serve as the internal positive control). The new findings supported reclassification of the tumor as DMG, H3 K27-altered, CNS WHO grade 4.

Figure 7

A spinal cord tumor in a 14-year-old male patient. (A) On H&E, there was aggregation of small cells in a fibrillary background, with calcifications. (B) In other areas, the tumor was composed of compact proliferation of small cell. (C) GFAP immunostain was negative in the tumor cells. (D) Synaptophysin was positive. (E) The H3 K27M immunostain showed no nuclear stain, while (F), H3 K27me3, showed loss of nuclear stain (endothelium serves as positive internal control). The final diagnosis was DMG, H3 K27-altered, CNS WHO grade-4.