Pediatric-Type Diffuse High-Grade Gliomas
Main Text
Preamble
In recent years, with the advent of molecular diagnosis, our classification of pediatric high-grade gliomas has moved from a histology-based (e.g., “glioblastoma”) and location-based (e.g., diffuse intrinsic pontine glioma) scheme to one focused almost exclusively on the genetic and molecular profile of tumors.
Two tumors that were recently considered distinct based upon their location—diffuse intrinsic pontine gliomas (DIPGs) and thalamic gliomas—are now understood to be biologically similar tumors and are now classified as diffuse midline gliomas (DMGs), most of which harbor an H3K27M mutation.
What would have previously been designated “pediatric glioblastomas” are now classified based upon their molecular profile, including diffuse hemispheric glioma, H3 G34-mutant; diffuse pediatric-type high-grade glioma, H3-wildtype or IDH-wildtype; and infant-type hemispheric glioma.
Pediatric-Type Diffuse High-Grade Gliomas
Diffuse Midline Glioma, H3 K27-Altered
Terminology
DMG is an infiltrative glioma located in a midline location with loss of H3 p.K28me3 (K27me3).
The term DIPG remains an acceptable term to describe these tumors when they arise in the pons.
Etiology
Most tumors are due to spontaneous mutations, but some tumor predisposition syndromes (e.g., Li Fraumeni and mismatch repair deficiency) are associated with a small proportion of these tumors.
Pathology
DMGs infiltrate adjacent parenchyma in a diffuse fashion. Tumor cells are small and monomorphic and may show astrocytic, piloid, oligodendroglial, giant cell, undifferentiated, or epithelioid cytology. All DMGs are considered CNS WHO grade 4.
Molecular subtypes include DMG, H3.3 K27-mutant; DMG, H3.1 or H3.2 K27-mutant; DMG, H3-wildtype with EZHIP overexpression; and DMG, EGFR-mutant.
Clinical Issues
DIPG represents 10-15% of pediatric brain tumors and 75% of all pediatric brainstem tumors. Thalamic DMGs represent 1-5% of pediatric brain tumors and 25% of thalamic tumors. Spinal DMGs represent ~ 40% of spinal astrocytomas.
Most patients with DIPG present with a short clinical history of cranial nerve palsy, pyramidal tract impairment, and ataxia. Thalamic DMGs usually present with intracranial hypertension and motor/sensory deficits.
The prognosis of DMG is poor with a two-year survival of < 10%. Due to their midline location, surgical options are limited.
Historically, DIPG was often treated based upon imaging alone without biopsy, but biopsy is now universal in the age of molecular diagnostics. Radiation therapy remains the mainstay for treatment of DMG.
Imaging
General Features
DIPG typically shows a poorly defined, T2-hyperintense, and expansile lesion centered in the pons. Large tumors often partially or completely surround the basilar artery without narrowing (19-1) (19-2). DMGs in the thalamus and spinal cord have similar imaging features and may be unilateral (19-3)or bithalamic (19-4). Metastatic disease may be present at diagnosis but is less common. Despite the fact that DMG has an imaging appearance of a hypocellular tumor (CT hypodensity and bright ADC), these tumors are WHO grade 4 tumors with a very poor prognosis.
CT Findings
DMGs typically show expansile and mass-like low attenuation with poorly defined borders. When located in the pons (DIPG), it can be difficult to distinguish pathologic low attenuation from skull base attenuation artifact—look for effacement of the fourth ventricle and prepontine cisterns.
MR Findings
DMGs appear as poorly marginated and expansile masses on MR, often infiltrating adjacent white matter tracts.
T1: Usually fairly homogeneous hypointensity with poorly defined margins.
T2/FLAIR: Typically ill-defined homogeneous hyperintensity with mass effect. Cysts are rare.
DWI: The majority of tumors show facilitated diffusion with ADC greater than adjacent brain. Patchy areas of diffusion restriction at the time of diagnosis may suggest a more aggressive course.
T1 C+: Typically absent or minimal enhancement at diagnosis. Contrast enhancement is more common following therapy or in later stages of the disease.
GRE/SWI: Calcifications and hemorrhage are rare.
PWI: Increased rCBV and CBF are common.
Differential Diagnosis
Primary differential considerations include other pediatric-type diffuse high-grade gliomas, discussed below, circumscribed astrocytic gliomas, such as pilocytic astrocytoma, and embryonal tumors [embryonal tumor with multilayered rosettes (ETMR) and atypical teratoid/rhabdoid tumor (ATRT)]. Other pediatric-type diffuse high-grade gliomas typically are located within the cerebral hemispheres and are more likely to enhance and show diffusion restriction. Pilocytic astrocytomas are more likely to enhance, are typically sharply marginated, and are more likely to demonstrate cystic change. Embryonal tumors (ETMR and ATRT)are usually sharply marginated and show diffusion restriction of solid components, often with minimal or no enhancement. Nonneoplastic differential considerations include tumefactive demyelinating disease of the brainstem and osmotic demyelination syndrome.
DIFFUSE MIDLINE GLIOMA, H3 K27-ALTERED: OVERVIEW
Locations: Pons > thalamus > spinal cord
Pathology: Infiltrative high-grade (WHO grade 4) midline tumor
• DMG, H3.3 K27-mutant
• DMG, H3.1 or H3.2 K27-mutant
• DMG, H3-wildtype with EZHIP overexpression
• DMG, EGFR-mutant
Imaging:
• CT: Hypointense, expansile lesions; hemorrhage/calcifications rare
• MR
T2/FLAIR: Poorly defined margins; cysts are uncommon
DWI: Usually bright on ADC (in contrast to other pediatric high-grade gliomas)
T1 C+: Usually show no/minimal contrast enhancement
PWI: Most tumors show increased perfusion
Clinical:
• Cranial nerve palsies, ataxia, increased intracranial pressure
• Poor prognosis: 2-year overall survival < 10%
Differential Diagnosis
• Embryonal tumors: Occur in very young patients; well-defined margins; diffusion restriction
• Pilocytic astrocytoma: Typically well defined, cystic, with avid enhancement
• Other pediatric high-grade gliomas: Hemispheric location, necrosis, diffusion restriction
Diffuse Hemispheric Glioma, H3 G34-Mutant
Terminology
Diffuse hemispheric glioma, H3 G34-mutant, is an infiltrative glioma arising in the cerebral hemispheres with a missense mutation of the H3-3A gene.
Pathology
Infiltration of the brain parenchyma results in expansion and distortion of involved brain ± hemorrhage and necrosis.
The most common histology is a highly cellular and infiltrative astrocytic tumor with increased mitotic activity and a glioblastoma-like pattern. A less common histologic appearance is similar to CNS embryonal tumors with small, monomorphic cells and hyperchromatic nuclei with scant cytoplasm.
The diagnosis is defined by a missense mutation at p.G35 (G34) of the histone variant H3.3. Diffuse hemispheric glioma, H3 G34-mutant, is a WHO grade 4 tumor, regardless of histology.
Clinical Issues
This tumor has no known genetic susceptibility. It occurs most commonly in adolescents. Prognosis is poor with a median overall survival of 18-22 months.
Imaging
Due to the typical location within the cerebral hemispheres, many tumors do not present until they are quite large. There is almost universal leptomeningeal contact of tumors.
CT typically demonstrates a cellular lesion sometimes demonstrating hemorrhage &/or calcifications.
MR typically shows a cellular lesion (moderate diffusion restriction in solid portions) with variable contrast enhancement. Tumor margins are variable with some demonstrating ill-defined margins (19-6A)and others well demarcated (19-5). Cyst formation and heterogeneity is more likely in larger tumors. Hemorrhage and areas of necrosis are frequently encountered. Few case series suggest that most tumors show increased perfusion.
Differential Diagnosis
Primary differential considerations include other diffuse pediatric high-grade gliomas (pHGGs), for which the imaging feature overlap is broad. Circumscribed astrocytic tumors and gangliogliomas are an important consideration but typically do not show diffusion restriction or necrosis. The imaging appearance is very similar to many embryonal tumors (ETMR and ATRT), but embryonal tumors typically occur in a much younger population.
LESS COMMON PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMAS
Diffuse Hemispheric Glioma, H3 G34-Mutant
• Pathology: Infiltrative glioma with H3-3A gene mutation, WHO grade 4
• Location: Cerebral hemispheres
• Clinical: Adolescents; no known genetic susceptibility
• Imaging: Variable “glioblastoma-like” vs. “diffuse astrocytoma”
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