Diffuse midline glioma H3 K27M–mutant
Diffuse midline glioma H3 K27M–mutant is a specific entity added to the 2016 update of the WHO classification of CNS tumors, that represents the majority of diffuse intrinsic pontine gliomas, although identical tumors are also found elsewhere in the midline (e.g. brainstem, spinal cord and thalamus) . They are aggressive tumors with poor prognosis and are considered WHO grade IV tumors regardless of histological features .
Epidemiology
The majority of these tumors are found in young children and are located in the pons . They are also seen elsewhere in the midline. In such cases, they tend to be encountered in children and young adults. This is particularly the case with spinal cord tumors that are seen primarily in young adults .
Clinical presentation
The clinical presentation will clearly depend upon the location of the tumor. Typically patients with brainstem tumors 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.
Pathology
Location
Diffuse midline glioma H3 K27M–mutant can be found throughout the midline structures of the central nervous system:
- thalamus
- brainstem
- mesencephalic
- pontine: most common
- medullary
- spinal cord
Microscopic appearance
H3 K27M–mutant diffuse midline gliomas usually appear histologically as astrocytic tumors. In a minority of cases they appear histologically low-grade (without mitotic figures, microvascular proliferation or necrosis), however, even then they are considered WHO grade IV tumors .
Immunophenotype
- S100: positive
- NCAM1: positive
- OLIG2: positive
- H3F3A K27M mutation: usually positive, although other mutations are also recognized (see below)
- p53 protein: positive in 50%
- GFAP: variable
- chromogranin-A: negative
- NeuN: negative
Genetics
Recent genomic work has uncovered distinct mutations found in the majority of diffuse midline gliomas resulting in the inclusion of diffuse midline glioma H3 K27M–mutant as a distinct entity and the removal of diffuse intrinsic pontine gliomas from the current WHO classification of CNS tumors .
These mutations are in the histone H3F3A gene (K27M mutations) or less frequently HIST1H3B and HIST2H3C genes .
A number of other distinct but related histone gene mutations have also been identified in similar tumors .
Radiographic features
In tumors located within the pons, 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 4 ventricle.
Usually the tumor 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/ADC: usually normal, occasionally mildly restricted
Extensive spread is relatively frequent, both craniocaudally to involve the cerebral hemispheres and spinal cord, as well as leptomeningeal spread .
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 (K27M mutations in the histone H3 gene H3F3A and related HIST1H3B genes) stereotactic biopsy is being performed in some centers, and may become routine when therapies specifically targeted to these mutations become available .
Prognosis remains poor, with a 2-year survival of less than 10% .
