Pediatric-Type Diffuse Low-Grade Gliomas
Main Text
Preamble
The 5th edition WHO classification of CNS tumors groups many neoplasms into tumor “families.” By far, the largest, most varied tumor family is gliomas, glioneuronal tumors, and neuronal tumors. This tumor “family” is subdivided by age and tumor grade into adult-type diffuse gliomas (the largest single group), pediatric-type diffuse low-grade gliomas, pediatric-type high-grade gliomas, and circumscribed astrocytic gliomas.
This chapter focuses on the relatively small but important group of pediatric-type diffuse low-grade gliomas (LGGs).
Pediatric-Type Diffuse Low-Grade Gliomas
Preamble
There are just four recognized neoplasms in this group of pediatric-type diffuse LGGs: Diffuse astrocytoma, MYB– or MYBL1-altered; angiocentric glioma (AG); polymorphous low-grade neuroepithelial tumor of the young (PLNTY); and diffuse LGG, MAPK pathway-altered. While these neoplasms are designated as “pediatric-type” tumors, they also occur in adults.
Together with glioneuronal tumors, pediatric-type diffuse LGGs represent nearly 1/3 of pediatric CNS neoplasms. Pediatric-type LGGs are a clinically and biologically distinct group of tumors with a generally favorable outcome. Most are epileptogenic and are often characterized clinically by pharmacologically resistant seizures.
Diffuse Astrocytoma, MYB– or MYBL1-Altered
Terminology
Diffuse astrocytoma, MYB- or MYBL1-altered, is a diffusely infiltrative glial neoplasm composed of monomorphic cells with genetic alterations in MYB or MYBL1.
Pathology
Tumors are unencapsulated, soft, gray-white, cortical and subcortical supratentorial masses with monomorphic glial cells in a fibrillar matrix. Histologic features of anaplasia, such as necrosis and microvascular proliferation, are absent, as are IDH, BRAF V600E, and H3 mutations. Mitotic activity is absent or low.
MYB-altered diffuse astrocytomas are CNS WHO grade 1 neoplasms and account for ~ 2% of pediatric LGGs.
Clinical Issues
Median age at diagnosis is 29 years, but patients typically have had seizures—often pharmacoresistant—since childhood. Reported cases range from 4-50 years with a 3:1 M:F ratio.
Prognosis is favorable. Most patients become seizure free after complete resection, and malignant progression has not been reported.
Imaging
CT may show an ill-defined, hypodense, nonenhancing, cortical/subcortical cerebral hemispheric mass.
MYB– or MYBL1-altered gliomas are typically hypointense on T1WI and heterogeneously hyperintense on T2/FLAIR sequences (some cases report a T2/FLAIR mismatch sign). These tumors do not demonstrate hemorrhage on T2* GRE or SWI and do not enhance following contrast administration (18-1). Restricted diffusion is absent, and pMR shows low rCBV.
Differential Diagnosis
The major imaging and histopathologic differential diagnosis is AG. MYB– or MYB1-altered diffuse astrocytomas have overlapping histopathologic and imaging features. Almost all AGs have MYB rearrangements, most commonly MYB:: QKI fusions. Both are pediatric-type LGGs, both are CNS WHO grade 1 lesions, and both often present with pharmacoresistant epilepsy. Diffuse astrocytomas, MYB– or MYBL1-altered, form a distinct methylation cluster on whole-genome methylation profiling.
MYB- or MYBL1-altered diffuse astrocytomas are relatively indolent tumors and must be distinguished from adult-type IDH-mutant and IDH-wildtype diffuse astrocytic gliomas.
Angiocentric Glioma
Terminology
AG is a diffuse glioma with diffuse growth architecture in a focal angiocentric pattern.
Pathology
More than 85% of AGs are supratentorial, superficially located, diffuse, expansile neoplasms with angiocentric growth, infiltrative borders, and ependymal differentiation. Involvement of both cortical and subcortical regions is typical. Most AGs are located in the temporal or frontal lobes. Approximately 15% are located in the brainstem.
Almost all AGs have a MYB:: QKI gene fusion/rearrangement as the driver event in their development. AGs are characterized histopathologically by elongated bipolar spindle cells with a striking angiocentric orientation. Adjacent focal cortical dysplasia (FCD) is common.
Mitoses are sparse or absent; MIB-1 is generally < 1%. Necrosis and microvascular proliferation are absent.
AGs are CNS WHO grade 1 neoplasms.
Clinical Issues
AGs are typically tumors of children and young adults. Median age at diagnosis is 13 years, although 20-25% of cases are > 20 years of age. There is a 2:1 M:F predominance. More than 90% present with seizures and often have a long history of pharmacoresistant epilepsy.
The majority of AGs are curable with complete surgical resection. If the AG is associated with FCD, fMRI-guided extensive resection may be required for a seizure-free result.
Imaging
NECT shows a solid, cortically based tumor with variable attenuation. Dystrophic calcification is present in some cases.
Cystoid components are present in ~ 1/2 of all cases (18-2). A rim-like or intratumoral high intensity on T1WI is common. “Blurring” of the gray matter-white matter junction is typical (18-3).
In 20% of cases, T2 and FLAIR demonstrate a stalk-like high-intensity lesion extending through the white matter towards the ventricle (18-4). Focal atrophy of the brain parenchyma near the tumor is common. Heterogeneous, nodular, or rim enhancement occurs in 5-25% of cases. FCD is present in some cases.
Differential Diagnosis
The major differential diagnoses for AG are other low-grade epileptogenic gliomas, such as PLNTY and FCD type IIA (FCD IIA). All three can exhibit stalk-like T2/FLAIR hyperintensity extending through the white matter towards the lateral ventricle, and FCD can coexist with AGs.
Polymorphous Low-Grade Neuroepithelial Tumor of the Young
Terminology
Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is classified by the WHO as one of the pediatric-type diffuse LGGs.
Etiology
PLNTYs are characterized by aberrant CD34 expression and activating alterations in the MAPK pathway. BRAF p. V600E mutations, FGFR2 or FGFR3 fusions, and other MAPK pathway-driving genetic abnormalities may be present.
Pathology
PLNTYs are supratentorial, cortical/subcortical masses. 2/3 are found in the temporal lobe.
PLNTYs are characterized by CD34 immunopositive oligodendroglioma-like tumor cells showing a mixed compact and infiltrating growth pattern. Oligodendroglioma-like features, including small round nuclei, “fried egg” perinuclear halos, and branching capillaries, are common, but IDH mutations and 1p/19q codeletion are absent.
Consistent with their name, PLNTYs also often harbor patently astrocytic or histologically ambiguous features in addition to their oligodendroglioma-like appearance. Overtly neoplastic neuronal components are usually absent, although some dysmorphic neurons may be present. Coexistence of FCD is common.
Calcifications are common and range from discrete calcospherules to confluent calcific masses exhibiting osseous metaplasia. Mitoses are few or absent. Necrosis and microvascular proliferation are absent.
PLNTYs are IDH-wildtype, CNS WHO grade 1 lesions. Malignant transformation is exceptionally rare. A single case with FGFR3:: TACC3 fusion with GBM-like disseminated disease has been reported.
Clinical Issues
PLNTYs are rare. While age at diagnosis ranges from 4-57 years, mean age at presentation is 22 years. The most common presentation is refractory epilepsy. There is a slight female predominance.
Despite its name, PLNTY also occurs in older adults who may present with new-onset headaches and psychiatric symptoms.
Most patients are seizure free after gross total tumor resection.
Imaging
PLNTYs have wide radiologic variability. They can be well-circumscribed, cystic, or (less commonly) infiltrative lesions. The majority of PLNTYs are well-defined cortical/subcortical masses that are hyperdense on NECT. Between 80-85% are calcified (18-5A). 2/3 of cases are mixed solid and cystic lesions.
Most PLNTYs are iso- to hypointense on T1WI and iso- to hyperintense on T2/FLAIR sequences. A tapered, hyperintense transmantle or stalk-like sign may extend through the white matter towards the lateral ventricles in PLNTYs associated with FCD (18-6). About 1/3 of all reported cases enhance on T1 C+(18-5). Restricted diffusion is absent, and most PLNTYs show decreased rCBF on dynamic susceptibility pMR.
Differential Diagnosis
The major imaging and histopathologic differential diagnostic consideration is oligodendroglioma. Other low-grade, pediatric-type gliomas and glioneuronal tumors, such as ganglioglioma, AG, and dysembryoplastic neuroepithelial tumor (DNET), are common temporal lobe lesions in young patients with refractory epilepsy.
Diffuse Low-Grade Glioma, MAPK Pathway-Altered
Terminology
Diffuse LGG, MAPK pathway-altered, is a diffuse astrocytic or oligodendroglial-like tumor of childhood.
Pathology
MAPK pathway-altered pediatric diffuse LGGs are LGGs with diffuse astrocytic, oligodendroglial, or mixed morphology.
MAPK pathway-altered pediatric diffuse LGGs have mutations in the tyrosine kinase domain (TDK) of FGFR1 or a BRAF p. V600E mutation. These tumors are IDH-wildtype and H3-wildtype. CDKN2A homozygous deletions are absent. Cellular atypia is minimal, and mitotic activity is either absent or minimal. Microvascular proliferation and necrosis are absent.
DNA methylation profiling has not demonstrated a single cluster for MAPK pathway-altered pediatric diffuse LGGs. No WHO grade has been formally established.
These tumors occur throughout the neuraxis but are more commonly found in the cerebral hemispheres.
Clinical Issues
These are rare tumors. Most patients are under 19 years of age and many present with epilepsy. The availability of novel targeted therapies, such as BRAF inhibitors, for MAPK pathway-altered gliomas may significantly alter their disease course.
Imaging
Imaging findings are nonspecific; diffusely-infiltrating, T2/FLAIR hyperintensity is typical. Enhancement on T1 C+ is variable; nonenhancing infiltrating areas of tumor extension are common (18-7).
Differential Diagnosis
The main differential diagnoses include pediatric-type diffuse LGGs, such as MYB– or MYBL1–altered diffuse astrocytoma, and circumscribed astrocytic gliomas, such as pilocytic astrocytoma and high-grade astrocytoma with piloid features.
The imaging differential diagnosis also includes pediatric-type diffuse high-grade gliomas, such as diffuse hemispheric glioma, H3 G34-mutant, diffuse pediatric-type high-grade glioma, H3- and IDH-wildtype, and diffuse midline glioma, H3 K27-altered.
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