Diffuse brainstem glioma (historical)

Last revised by Mohammad Sattouf on 15 May 2024

Diffuse brainstem gliomas or diffuse intrinsic pontine gliomas was a term used to describe infiltrating astrocytomas arising in the brainstem, usually in children. It is no longer recognized as a distinct entity, removed from the 2016 update to the WHO classification of CNS tumors replaced by a variety of entities defined on the basis of molecular characteristics. The majority of these tumors would now be classified as diffuse midline glioma, H3 K27M–mutant which, for the sake of clarity, are described separately. 

It has become apparent that a large proportion of these tumors (particularly diffuse intrinsic pontine gliomas) harbor K27M mutations in the histone H3 gene H3F3A, or, less commonly, in the related HIST1H3B genes. These mutations are shared by other midline pediatric tumors (e.g. thalamic and spinal cord tumors).

As of the 2016 update to the WHO classification of CNS tumors, these have been given a distinct and separate diagnosis: diffuse midline glioma, H3 K27M–mutant.

The rest (i.e. diffuse tumors of the brainstem gliomas without K27M mutations) now are classified as a variety of lesions including diffuse pediatric-type high-grade gliomas, H3-wildtype and IDH-wildtype.

NOTE: The remainder of this article is therefore largely of historical relevance only. 

These tumors typically present in childhood (3 to 10 years of age) and account for 10-15% of all pediatric brain tumors, 20-30% of pediatric posterior fossa tumors and 60-75% of all brainstem gliomas. 

There is an association with neurofibromatosis type I, which however carries a better prognosis with a more indolent course.

Typically patients present with multiple cranial nerve palsies, depending on the location of the tumor, and signs of raised intracranial pressure. Cerebellar signs may also be elicited including ataxia, dysarthria, nystagmus and sleep apnea.

Genomic work has uncovered distinct mutations found in the majority of diffuse midline gliomas, particularly diffuse intrinsic pontine gliomas (DIPG). These mutations are in the histone H3F3A gene (K27M mutations) or less frequently HIST1H3B and HIST2H3C genes 5,6

As of the 2016 update to the WHO classification of CNS tumors, diffuse intrinsic brainstem glioma (DIBG) has been removed and diffuse midline glioma, H3 K27M–mutant has been added as a specific entity 6

Diffuse brainstem gliomas can be found throughout the brainstem:

  • mesencephalic

  • pontine: most common accounting for 60-75% of all cases

  • medullary: least common location

In diffuse intrinsic pontine gliomas (DIPG) the pons is enlarged, with the basilar artery displaced anteriorly against the clivus and potentially engulfed. The floor of the fourth ventricle is flattened ("flat floor of fourth ventricle sign") and obstructive hydrocephalus may be present. Occasionally the tumor is exophytic, either outwards into the basal cisterns or centrally in the 4th ventricle.

Usually, the tumor is homogeneous pre-treatment, however, in a minority of patients areas of necrosis may be present.

Typically hypodense with little, if any, enhancement.

  • T1: decreased intensity

  • T2:

    • hyperintense mass

    • relative hypointense areas may indicate foci of higher cellularity or spared white matter tract 8

  • T1 C+:

    • usually non-enhancing

    • focal enhancing areas may represent areas of higher grade

    • enhancement may occur post-radiotherapy

  • DWI/ADC:

    • typically fascilliated diffusion

    • some areas of diffusion restriction may represent areas of higher-cellularity and higher-grade 8

  • T2*/SWI: areas of marked hypointensity/blooming in cases of intralesional hemorrhage8

  • DTI: disruption of the white matter tracts indicates diffuse midline glioma rather than focal brain stem gliomas 8

The presence of restricted diffusion at non-enhancing DMG is called DWI-Gd mismatch sign9, and it is found to be a very poor prognostic sign.

Due to the high rate of severe complications with biopsy treatment has historically been commenced without histological confirmation, although due to the identification of distinct mutations (see diffuse midline glioma H3 K27M–mutant) stereotactic biopsy is being performed in some centers, and is becoming more common as therapies specifically targeted to these mutations become available 5.

Radiotherapy is the mainstay of treatment. The initial response may be falsely reassuring.

In the sporadic form, the prognosis is poor with 2-year survival being only 20% (median survival less than 1 year). This is dramatically different from focal brainstem gliomas (e.g pilocytic astrocytomas and tectal gliomas), which carry a good prognosis.

General imaging differential considerations include:

They should also be distinguished from other tumors:

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