Diffuse brainstem glioma (historical)
Citation, DOI & article data
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.
Recently, 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.
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 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:
- 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: 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 the 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.
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:
- acute demyelinating encephalomyelitis (ADEM)
- neurofibromatosis type I (NF1)
- tuberous sclerosis (TS)
- osmotic demyelination
- Langerhans cell histiocytosis
They should also be distinguished from other tumors:
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- 5. Castel D, Philippe C, Calmon R et-al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol. 2015;130 (6): 815-27. doi:10.1007/s00401-015-1478-0 - Free text at pubmed - Pubmed citation
- 6. Louis DN, Perry A, Reifenberger G et-al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131 (6): 803-20. doi:10.1007/s00401-016-1545-1 - Pubmed citation
- 7. Louis DN, Ohgaki H, Wiestler OD et-al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114 (2): 97-109. Acta Neuropathol. (full text) - doi:10.1007/s00401-007-0243-4 - Free text at pubmed - Pubmed citation