Epidemiology, Diagnostic Strategies, and Therapeutic Advances in Diffuse Midline Glioma

Abstract

Object: Diffuse midline glioma (DMG) is a highly aggressive and lethal brain tumor predominantly affecting children and young adults. Previously known as diffuse intrinsic pontine glioma (DIPG) or grade IV brain stem glioma, DMG has recently been reclassified as "diffuse midline glioma" according to the WHO CNS5 nomenclature, expanding the DMG demographic. Limited therapeutic options result in a poor prognosis, despite advances in diagnosis and treatment. Radiotherapy has historically been the primary treatment modality to improve patient survival. Methods: This systematic literature review aims to comprehensively compile information on the diagnosis and treatment of DMG from 1 January 2012 to 31 July 2023. The review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement and utilized databases such as PubMed, Cochrane Library, and SciELO. Results: Currently, molecular classification of DMG plays an increasingly vital role in determining prognosis and treatment options. Emerging therapeutic avenues, including immunomodulatory agents, anti-GD2 CAR T-cell and anti-GD2 CAR-NK therapies, techniques to increase blood-brain barrier permeability, isocitrate dehydrogenase inhibitors, oncolytic and peptide vaccines, are being explored based on the tumor's molecular composition. However, more clinical trials are required to establish solid guidelines for toxicity, dosage, and efficacy. Conclusions: The identification of the H3K27 genetic mutation has led to the reclassification of certain midline tumors, expanding the DMG demographic. The field of DMG research continues to evolve, with encouraging findings that underscore the importance of highly specific and tailored therapeutic strategies to achieve therapeutic success.

Keywords: DIPG; DMG; clinical trials; diagnosis; histone 3; molecular classification; treatment.

Figure 3

Representative histology of pediatric DMG. Histologic geographic variability of DMG. ×4 (A,C) and ×20 (B,D). Hematoxylin and eosin stains from different sections of a single tumor showing low-grade (A,B) and high-grade (C,D) areas. (E) Immunohistochemical staining of the same sample using antibody directed to the H3K27M epitope. The sample is strongly positive. (F) Immunohistochemical staining of mutant p53, a common co-occurring mutation in DMG. (A–D) Reprinted with permission and adapted from Warren et al. (2012) [15] and (E,F) reprinted with permission and adapted from Srikanthan et al. (2021) [35].

Figure 1

PRISMA flow diagram.

Figure 2

MRI imaging of DMG tumors. Patient 1: (A) DMG lesion on T1-weighted without contrast sagittal image, (B) DMG lesion on T1-weighted post-contrast sagittal image, (C) DMG lesion on T2-weighted coronal image. Patient 2: (D) DMG lesion on T2-weighted coronal image. (E) DMG lesion on T1-weighted without contrast sagittal image, (F) DMG lesion on FLAIR axial image.

Figure 4

DMG treatment. Current and investigational therapies for diffuse midline glioma. The combination of chemoradiotherapy remains the standard of care with low overall survival rates.