Diffuse intrinsic pontine glioma (DIPG) is a type of intrinsic brainstem glial tumor that occurs primarily in the pediatric population. DIPG is initially diagnosed based on clinical symptoms and the characteristic location on imaging. Histologically, these tumors are characterized by a heterogenous population of cells with multiple genetic mutations and high infiltrative capacity. The most common mutation seen in this group is a lysine to methionine point mutation seen at position 27 (K27M) within histone 3 (H3). Tumors with the H3 K27M mutation, are considered grade 4 and are now categorized within the H3 K27-altered diffuse midline glioma category by World Health Organization classification. Due to its critical location and aggressive nature, DIPG is resistant to the most eradicative treatment and is universally fatal; however, modern advances in the surgical techniques resulting in safe biopsy of the lesion have significantly improved our understanding of this disease at the molecular level. Genomic analysis has shown several mutations that play a role in the pathophysiology of the disease and can be targeted therapeutically. In this review, we will elaborate on DIPG from general aspects and the evolving molecular landscape. We will also review innovative therapeutic options that have been trialed along with new promising treatments on the horizon.

Pediatric central nervous system (CNS) tumors are the most common solid tumor in children, with the majority being glial in origin. These tumors are classified by the World Health Organization (WHO) as either being low grade (WHO grade 1 and 2) or high grade (WHO grade 3 and 4). Our knowledge of the molecular landscape of pediatric brain tumors has advanced over the last decade, which has led to newer categorizations along with an expansion of therapeutic targets and options. In this review, we will give an overview of common CNS tumors seen in children along with a focus on treatment options and future considerations.

Diffuse midline glioma (DMG), H3 K27-altered are highly aggressive, incurable central nervous system (CNS) tumors. The current standard palliative treatment is radiotherapy, with most children succumbing to the disease in less than one year from the time of diagnosis. Over the past decade, there have been significant advancements in our understanding of these heterogeneous tumors at the molecular level. As a result, most of the newer clinical trials offered utilize more targeted approaches with information derived from the tumor biopsy. In this systematic review, we used individual participant data from seven recent clinical trials published over the past five years that met our inclusion and exclusion criteria to analyze factors that influence overall survival (OS). We found that the most prominent genetic alterations H3.3 (H3F3A) and TP53 were associated with worse OS and that ACVR had a protective effect. In addition, re-irradiation was the only statistically significant treatment modality that showed any survival benefit. Our findings highlight some important characteristics of DMG, H3 K27-altered and their effects on OS along with the importance of continuing to review clinical trial data to improve our therapies for these fatal tumors.

Atypical teratoid/rhabdoid tumors (AT/RT) are malignant central nervous system (CNS) tumors. Typically, AT/RT is classified as SMARCB1 (INI-1) deficient or as SMARCA4 (BRG1) deficient. In this case, we describe a unique case of AT/RT with a novel SMARCA4 missense variant identified on next-generation sequencing but retained expression of INI-1 and BRG-1 on immunohistochemistry. Diagnosis of the tumor and discovery of the novel SMARCA4 variant was only possible after comprehensive tumor molecular testing tailored for pediatric malignancies. This case highlights the importance of molecular genetic testing as part of a workup in neoplasms concerning for possible AT/RT.