Definition
- Essential:
- A diffuse glioma AND
- Loss of H3 p.K28me3 (K27me3) (immunohistochemistry) AND
- Midline location AND
- Presence of an НЗ p.K28M (K27M) or p.K28l (K27I) mutation (for НЗ K27-mutant subtypes) OR
- Presence of a pathogenic mutation or amplification of EGFR (for the EGFR mutant subtype) OR
- Overexpression of EZHIP (for the H3-wildtype with EZHIP overexpression subtype) OR
- Methylation profile of one of the subtypes of diffuse midline glioma
- Desirable:
- Results from molecular analyses that enable discrimination of the H3.1 or H3.2
- p.K28 (K27)-mutant subtype from the H3.3 p.K28 (K27)-mutant subtype
Nomenclature
- Old name:
- Diffuse midline glioma H3 K27M-mutant
- Brain stem glioma
- Diffuse intrinsic pontine glioma (DIPG)
- Because in order to recognize alternative mechanisms by which the pathogenic pathway can be altered in these tumours
- Other changes
- EZH inhibitory protein (EZHIP) overexpression
- H3 K27 mutations
CNS WHO grading
- CNS WHO grade 4
Numbers
- 0.54 cases per 1 million person-years overall
- 2.32 cases per 1 million person-years in people aged < 20 year
- No sex predilection
- Represents
- 10-15% of all paediatric brain tumours
- 75% of all paediatric brainstem tumours.
- Predominates in children but also occurs in adults
- Median patient age at diagnosis is 5 - 11 years
- Pontine tumours younger age (7 years)
- Thalamic tumours older age (11 years)
- Thalamic DMGs are rarer,
- Representing 1-5% of paediatric brain tumours
- 25% of thalamic tumours
- Spinal DMGs represent about 40% of spinal astrocytomas in paediatric and adult series
- EGFA-mutant DMGs
- Most often occur during childhood
- Median patient age of 7-8 years
- In the paediatric population, the occurrence of H3.3 p.K28M (K27M)-mutant DMGs and H3-wildtype DMGs with EZHIP overexpression peaks at about 7-8 years,
- H3.1 or H3.2 p.K28M (K27M)-mutant DMGs occur in younger patients (median patient age: ~5 years)
Location
- Arises in the midline
- Except in pineal region, cerebellum, hypothalamus
- Most common location
- Paeds
- Brainstem
- Have their epicentre in the pons and typically involve > 50% of its surface, often asymmetrically, with frequent encasement of the basilar artery
- Prognosis
- Best prognosis: Midbrain
- Worst prognosis: Pons
- Hence the term diffuse intrinsic pontine glioma [DIPG]
- Intermediate prognosis: Medulla
- Bithalamic
- Bilateral thalamic more frequent in the EGFR-mutant subtype
- There may be an exophytic component and/or infiltration into the midbrain, the cerebellar peduncles, and the cerebellar hemispheres.
- Dismal prognosis with median survival times between 10 and 14 months
- Adolescents/adults
- Unilaterally in the thalamus
- There may be an exophytic component and/or infiltration into the midbrain, the cerebellar peduncles, and the cerebellar hemispheres.
- Spinal cord
Pathology
- High grade features such as mitotic activity, microvascular proliferation and necrosis may be seen but are not necessary for the diagnosis
- Diffusely infiltrative of both adjacent and distant brain structures
- In EGFR-mutant DMGs, mitotic activity Is often present, but necrosis or microvascular proliferation is rare
- Immunophenotype
- Express OLIG2, MAP2, and S100, whereas immunoreactivity for GFAP is variable apart from in the EGEF?-mutant subtype, which is typically GFAP-positive but may lack OLIG2 and SOX10.
A, A pontine glioma showing infiltrative neoplastic cells in an oedematous background, with some residual neurons.
B, The neurofilament stain highlights the diffusely infiltrative growth.
C, Intense nuclear staining for H3 p.K28 (K27)-mutant protein, with internal negative controls in endothelial cells and neurons.
D, Immunohistochemical staining for H3 p.K28me3 (K27me3) shows loss of expression in tumour cells, with retention in endothelial cells and residual neurons.
E, Negativity for EZHIP immunostaining.
Genetic
- Common genetic and epigenetic characteristics of midline gliomas are suggestive of a distinct developmental origin
- Nestin- / Olig2- expressing neural precursor-like cell has been suggested as the possible cell of origin in one study
Cell origin
- Unknown
- Can possibly arise from a variety of neural stem cells
Presentation
- Short medical history (< 2 months)
- Classic triad:
- Cranial nerve palsy (82%)
- Long tract signs such as pyramidal tract impairment (51%)
- Ataxia (62%)
- Common initial symptoms of thalamic DMGs include
- Intracranial hypertension
- Motor or sensory deficit
- Tumors arising in the thalamus are often associated with motor weakness and gait disturbance
Radiological
- T1
- Hypointensity or iso-intensity
- T1+ C
- Most do not show enhancement
- T2
- Hyperintensity
- FLAIR
- Can vary considerably
- DWI:
- ADC values can be used to non-invasively predict the H3 K27M mutational status
- Specifically, minimal ADC and peri-tumoral ADC values were significantly lower in H3 K27M-mutant gliomas compared with H3 K27Mwildtype gliomas
- Presence of restricted diffusion at non-enhancing DMG is called DWI-Gd mismatch sign
Molecular testing: H3 K27me3-retained staining in some cells, Homozygous loss of CDKN2A/B, EGFR mutation.
T2w (A, B), DWI (C), and T1w-CE (D) show an expansile, mildly T2w hyperintense, bithalamic tumour extending into the brainstem.
There is associated hydrocephalus. The mass only showed small foci of faint enhancement (arrow)
Treatment
- They are diagnosed radiologically and when typical, do not require biopsy.
- Radiological + Clinical diagnosis
- T1 hypointensity/T2 hyperintensity on MRI
- Long tract signs
- Cerebellar signs and/or
- Palsies of CN IV, VI, and VII
- Radiotherapy
- Dose 54Gy
- Symptoms generally resolve with RT for 6 months before recuring.
- Surgical options are limited due to tumour location, only done in research settings
flowchart TD A["MRI brain"] A --> B["Diffuse lesion<br />(Usually pontine, high grade, clinically aggressive)"] A --> C["Lesion not diffuse on MRI"] B --> D["No need of biopsy<br />Steroids, CSF diversion if needed"] D --> E["DIRECT RT+CT"] C --> F["Regardless of location,<br />have a significant probability<br />of being <b>low grade</b>."]
Prognosis
- Poor prognosis with 2 year survival rate of < 10%
- Spread
- Leptomeningeal involvement in 40% of cases
- Diffuse spread to involve the thalamus, cervical cord, and even the frontal lobe
- Good prognostic indicators
- Age (< 3 or > 10 years)
- Longer symptom latency (> 24 weeks),
- Systemic therapy at diagnosis
- Patients with DMGs harbouring either an H3.1 or H3.2 p.K28M (K27M) mutation or showing EZHIP overexpression have slightly longer overall survival (16 months) than do patients with DMGs that bear an НЗ.З p.K28M (K27M) mutation (11 months)
- The median survival for children with bithalamic gliomas with confirmed EGFR mutation was 10-14 months,
- Most children succumbing to their disease within 2 years
Differential diagnosis
- Brainstem tumours (importance of biopsy)
- Low-grade primary CNS tumours
- Pilocytic astrocytoma
- Ganglioglioma
- MYB- or MYBL1-altered diffuse astrocytoma
- High-grade tumours comprising
- H3 K27-altered DMG
- H3-wildtype tumours
- Diffuse paediatric-type high-grade glioma MYCN subtype,
- Atypical teratoid/rhabdoid tumour
- Embryonal tumour with multilayered rosettes)
- Focal vs diffuse brainstem gliomas
ㅤ | DIPG (75-80%) | Focal |
Age | 5-10yo | Older age |
MRI | Homogeneous, diffuse tumour at pons contrast+ highly variable | Medulla/cervicomedullary tectal glioma dorsal exophytic growth |
Pathology | High grade glioma (WHO 3 or 4) molecular: TP53, H3K27M-mutant | Pilocytic astrocytoma Ganglioglioma |
Treatment | MRI diagnosis, NO BIOPSY shunt | Subtotal removal of dorsal exophytic lesion shunt |
Adjuvant Treatment | Direct RT + chemo Steroid RT 44-55Gy/30Fr (in 6 weeks) - 80% improve but decline rapidly afterwards +/- Temodal | Reoperation if recur (remain histologically benign) or RT |
Survival | Die in 1 yr | 5yr OS >90% |
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