Diffuse intrinsic pontine glioma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Rithish Nimmagadda,MBBS.[2]

INTRODUCTION

The biologic nature of brainstem gliomas varies widely; these tumors might be low-grade and require minimal therapy, or they can be swiftly deadly even with vigorous therapy. The location of the tumor within the brainstem, the length of the clinical symptoms, and, increasingly, the mutational profile all affect the prognosis and course of treatment. Histologically, these tumors are often glioblastomas (WHO grade 4) or astrocytomas (WHO grade 3; anaplastic). However, the prognosis is not better for individuals whose biopsy revealed WHO grade 2 malignancies.High grade nonpontine gliomas, which are treated similarly to diffuse intrinsic pontine gliomas, make up around 10 to 20 percent of all nonpontine gliomas.

EPIDEMIOLOGY

About one-third of all pediatric high-grade gliomas and 10 to 20 percent of all pediatric central nervous system cancers are brainstem (midbrain, pons, and medulla oblongata) gliomas. Compared to adults, children are more likely to have brainstem gliomas. For instance, about 300 pediatric cases and 100 adult cases are recorded annually in the United States. Five to nine years old is the median age for diagnosis in children, with a slight female sex preponderance.

Pathophysiology

Diffuse intrinsic pontine gliomas are almost always high-grade astrocytomas when biopsied, while up to 25% may show low grade on traditional histologic characteristics. The majority of the tumors also develop quickly. Significantly, in diffuse intrinsic pontine gliomas, histopathologic grade is not correlated with prognosis; in fact, even low-grade diffuse pontine lesions behave aggressively and have a prognosis that is comparable to that of high-grade tumors.Seldom have pons glial tumors spread to distant locations at the time of diagnosis. Rather, they usually go down well-established fiber networks, particularly into the cerebellum and thalamus. Although spinal seeding is uncommon, it might be seen as the illness progresses.

MOLECULAR LEVEL-

1.Nearly 80 percent of diffuse intrinsic pontine gliomas contain mutually exclusive mutations in either HIST3H1B, one of many genes encoding histone H3.1, or H3F3A, one of two genes expressing the histone H3.3 variation. These mutations appear to be present in all tumor cells. Both mutations change the binding of mutant histone H3 to polycomb repressive complex 2 (PRC2), a crucial developmental regulator of gene expression, by substituting methionine for lysine 27 (H3 K27M).

2.Platelet-derived growth factor receptor (PDGFR) A and c-Met protein overexpression and amplification appear to be key molecular steps in the transition of cells to a malignant phenotype, more frequently observed in tumors with the H3.3 mutation. About 15% of diffuse intrinsic pontine gliomas have activating mutations in phosphatidylinositol 3-kinase (PI3K).

3.Pediatric diffuse intrinsic pontine gliomas are exceedingly unusual to have mutations in isocitrate dehydrogenase type 1 (IDH1) or type 2 (IDH2), which characterizes a significant fraction of adult grade 2 and 3 diffuse gliomas. On the other hand, up to 25% of adult brainstem gliomas may have IDH1/2 mutations, the majority of which are non-R132H variations. These mutations are linked to a better prognosis and may benefit from adjuvant chemotherapy in addition to radiation therapy.