Diffuse brainstem glioma (historical)

Diffuse brainstem gliomas, also known as diffuse intrinsic brainstem glioma (DIBG), is a term used to describe infiltrating astrocytomas, no longer recognised as a distinct entity in the 2016 update to the WHO classification of CNS tumours. It encompassed a variety of tumours, ranging from WHO grade II to WHO grade IV tumours. Using previous classifications, they accounted for 60-75% of all brainstem gliomas. 

Terminology

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

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

The rest (i.e. diffuse tumours of the brainstem gliomas without K27M mutations) now are classified as non-location-specific tumours based on IDH mutation and 1p19q co-deletion status. 

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

Epidemiology 

These tumours typically present in childhood (3 to 10 years of age) and make up 10-15% of all paediatric brain tumours and 20-30% of paediatric posterior fossa tumours.

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

Clinical presentation 

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

Pathology

Recent 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 tumours, diffuse intrinsic brainstem glioma (DIBG) has been removed and diffuse midline glioma, H3 K27M–mutant has been added as a specific entity ⁶. 

Radiographic features

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 tumour is exophytic, either outwards into the basal cisterns or centrally in the 4^th ventricle.

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

CT

Typically hypodense with little, if any, enhancement.

MRI

• T1: decreased intensity
• T2: heterogeneously increased
• T1 C+ (Gd): usually minimal (can enhance post radiotherapy)
• DWI: usually normal, occasionally mildly restricted

Treatment and prognosis

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

Treatment usually comprisesRadiotherapy is the mainstay of chemotherapy only. In children over 3 years of age (or preferably even older) then radiotherapytreatment. Initial response may be considered. Necrosis may result from radiotherapy, however, it may also be seen as part of the natural course of the tumour.

Initial response can be dramatic and 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.

Differential diagnosis

General imaging differential considerations include:

• rhombencephalitis
• acute demyelinating encephalomyelitis (ADEM)
• neurofibromatosis type I (NF1)
• tuberous sclerosis (TS)
• osmotic demyelination
• Langerhans cell histiocytosis
• hamartoma

They should also be distinguished from other tumours:

• medulloblastoma
• ependymoma