Other Glial Neoplasms

Brief Historical Overview

In 2005, two groups simultaneously described series of low-grade brain tumors in children and young adults that were associated with seizures and had the histologic features of angiocentric glioma, referring to them as “monomorphous angiocentric glioma” and “angiocentric neuroepithelial tumor.” The unique clinical, radiologic, and pathologic features led to the acceptance of this entity as angiocentric glioma by the World Health Organization (WHO) in 2007.

Definitions and Synonyms

Angiocentric glioma is a low-grade (WHO grade I), slowly growing or stable supratentorial tumor of childhood and young adulthood that is strongly associated with seizures. It is composed of cytologically bland, spindled, and monomorphic glioma cells surrounding cortical and subcortical blood vessels, as well as aggregating under the pia. Despite some ependymal features immunohistochemically and ultrastructurally, these tumors show an infiltrative growth pattern and distinctive genetic alterations, suggesting that they are distinct from classic ependymomas.

Incidence and Demographics

This tumor is rare, with approximately 90 cases reported to date. It occurs most frequently in children and young adults (mean age, 16 years), with over half presenting in the first 10 years of life. There does not appear to be a gender predilection.

Clinical Manifestations and Localization

Angiocentric glioma presents as a slowly growing, cerebral hemispheric mass lesion, most often involving the temporal, frontal, or parietal lobes. Nearly all patients have a long-standing history of epilepsy that is refractory to medical treatment. Other less common symptoms include headache and visual disturbance.

Radiologic Features and Gross Pathology

Tumors are typically centered in the cortex, but often extend into subcortical regions of the frontal, temporal, or parietal lobes. On magnetic resonance (MR) imaging, these lesions expand the involved cortex and are T2- or fluid-attenuated inversion recovery (FLAIR) hyperintense but generally lack contrast enhancement ( Fig. 9.1A ), except in very rare examples that have undergone malignant transformation to anaplastic ependymoma ( Fig. 9.2D ). T1-weighted imaging is variable, and a “rim-like” hyperintensity surrounding the lesion has been described. There is often only minimal mass effect. A stalk-like extension toward the ventricular system has been reported, as have calcifications.

Histopathology

The defining histologic feature of angiocentric glioma is the presence of monomorphous, bipolar tumor cells intimately associated with blood vessels of the involved cortex and white matter ( Fig. 9.1B–E ). Tumor cells are uniform, spindle-shaped with oval or elongated nuclei and have speckled chromatin as well as pink, tapering cytoplasm. Some tumors will contain cells that are more epithelioid, with prominent cytoplasm and recognizable cell borders. The predominant tissue pattern arises from elongate, slender tumor cells oriented parallel to blood vessels, sometimes expanding perivascular spaces with streaming arrays of either single or multilayered cells. In some examples, tumor cells are radially oriented to vessels in a pattern, highly reminiscent of ependymal pseudorosettes. There is also a tendency of tumor cells to orient perpendicularly to the pia mater, giving a palisading appearance at the brain surface or in parallel fashion ( Fig. 9.1E ). In addition to the perivascular and subpial distribution, scattered single cells or cell clusters are present at variable density within the cortical and subcortical parenchyma. Normal brain elements, including cortical neurons and neuropil, are present within the substance of this low-grade neoplasm, consistent with an infiltrative growth pattern, but distinct from that of diffuse gliomas. Similar to other low-grade, epilepsy-associated neoplasms of childhood, coexisting cortical dysplasia can be identified adjacent to angiocentric glioma in adequately sampled resection specimens. In lesions resected from adults with long-standing histories of seizures, neurofibrillary changes in native neurons have been described. Mitoses are generally rare or absent, and necrosis and microvascular proliferation are not seen in this tumor type. Rare examples of mixed angiocentric glioma/ependymoma and/or anaplastic recurrences have been documented ( Fig. 9.2 )

Differential Diagnosis

The angiocentric pattern of these tumors, especially when cells are oriented radially around central blood vessels, resembles classic ependymoma. Indeed, immunohistochemical and ultrastructural data have supported ependymal differentiation. However, unlike classic ependymoma, angiocentric glioma does not form a discrete mass (except in rare cases mixed with conventional ependymoma), but rather infiltrates the brain in a combined diffuse and angiocentric fashion. As such, the MRI shows a T2-bright region of invaded brain, rather than a solid contrast-enhancing mass. Pilocytic astrocytoma is composed of cytologically bland, often spindled GFAP-positive cells, much like angiocentric glioma. Although pilocytic astrocytomas, and especially the pilomyxoid variant, can have a perivascular growth pattern and orient toward vessels, the degree is usually less dramatic than that of angiocentric glioma. Moreover, unlike angiocentric glioma, pilocytic astrocytomas tend to form solid components that push aside, rather than invade, adjacent brain. Diffuse astrocytoma shares the infiltrative growth pattern and elongate nuclei seen in angiocentric glioma, but it lacks the angiocentricity, typically involves larger portions of the brain, and shows greater nuclear hyperchromasia and pleomorphism.

Ancillary Diagnostic Studies

Immunoreactivity is consistently strong for GFAP, S-100, and vimentin and shows “dot-like” cytoplasmic staining for EMA —a pattern typical of ependymoma ( Fig. 9.1F and G ). Staining for other ependymoma-associated markers, such as CD99 and D2-40, is variable, but may similarly highlight dot-like positivity in some cases ( Fig. 9.1H ). The infiltrative growth pattern is also highlighted with stains for neurofilament protein, which show entrapped axons between tumor cells ( Fig. 9.1I ). Ependymal differentiation is also seen on electron microscopy, which demonstrates microlumen formation, microvilli, cilia, and complex, zipper-like intermediate junctions ( Fig. 9.1J ). The MIB-1 proliferation index is less than 1% in the majority of cases, and ranges from 1% to 5%.

Genetics

Numerous investigations have demonstrated that angiocentric gliomas do not harbor the IDH1 or IDH2 mutations that are typical of a subset of diffusely infiltrative gliomas. Similarly, BRAF mutations have not been identified in these tumors. However, recent studies indicate that angiocentric gliomas harbor genetic alterations that are highly sensitive and specific. In one study of 19 angiocentric gliomas, 100% were found to have gene fusions that involved the MYB locus, and nearly all were found to have QKI as a fusion partner ( MYB-QKI fusions); none of the other gliomas in the study contained MYB-QKI fusions. In a second investigation, MYB-QKI rearrangements were identified in 87% of the 15 angiocentric gliomas studied, but in none of the other tumors. Thus, MYB-QKI fusions appear to be a highly specific and sensitive genetic alteration in angiocentric glioma.

Comparative genomic hybridization (CGH) has also been performed on a series of eight cases, but uncovered only a single loss of chromosomal band 6q24-q25 in one tumor. A gain at chromosome 11p11.2, the site of protein tyrosine phosphatase receptor J, was found on high resolution array-CGH in a second tumor.

Treatment and Prognosis

The behavior of those angiocentric gliomas documented in the literature thus far suggests a stable clinical course and probable cure by gross total surgical resection alone. Gross total resection is also associated with seizure control in almost all cases. The majority of patients undergoing subtotal resections have shown stable, residual tumor on MR imaging, with recurrences occurring uncommonly. Seizure control following subtotal resection is more variable. In one instance, a histologically low-grade angiocentric glioma recurred as an anaplastic variant after 21 months and was fatal. A second case followed a similar pattern of anaplastic transformation, and we have encountered another such example ( Fig. 9.2D–F ). No features have been identified that are predictive of anaplastic transformation or aggressive clinical behavior in classic angiocentric glioma.