Unusual Gliomas

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CHAPTER 123 Unusual Gliomas

Unusual gliomas of the central nervous system deserve special consideration. Although these tumors are rare and our knowledge of their ontogeny, pathology, and nosology is incomplete, it is important to distinguish them from the more common gliomas. Many of these tumors have indolent growth (World Health Organization [WHO] grades I and II), and they commonly reach medical attention because of epilepsy. There are insufficient data to predict outcome and direct treatment in the more recently identified tumor types. Consequently, it is important to identify these lesions accurately to further improve our knowledge of optimal treatment. The routine use of immunohistochemistry and, in some cases, molecular and genetic assays may be essential for the diagnosis of some of these rare tumors. One of the common findings that help identify unusual gliomas is the presence of cells within the lesion that are distinct in their morphology, express neuronal antigens, or present a cytoarchitecture that separates them from the more well-known glioma types. It is well recognized that variability in cell morphology is common in gliomas. Therefore, cytologic variability is not sufficient to merit a new diagnostic class. However, newer types of gliomas demonstrate clinical, radiologic, and morphologic patterns that merit consideration as a novel diagnostic group. We will address some of the traditional as well as more recently identified unusual gliomas and provide references that may help with management and identification for surgeons and neurologists who may not be familiar with some of these entities.

Subependymal Giant Cell Astrocytoma

World Health Organization Grade I

Clinical Presentation and History

Subependymal giant cell astrocytomas generally occur only in patients with tuberous sclerosis.1 They are typically intraventricular lesions that rarely cause symptoms unless they obstruct ventricular outflow through the foramen of Monro. Tuberous sclerosis is an autosomal dominant phakomatosis associated with mental retardation, seizures, and adenoma sebaceum. Other findings include altered skin pigmentation, retinal tumors, subungual fibromas, and tumors of the spleen and pancreas. The natural history of subependymal giant cell astrocytoma is slow growth with little risk for transformation to a high-grade glioma. Consequently, treatment is not indicated unless the size and location of the tumor result in neurological findings (e.g., ventricular obstruction).1

Imaging

Subependymal giant cell astrocytomas have a characteristic appearance on magnetic resonance imaging (MRI) (Fig. 123-1). The classic finding is an intraventricular tumor in a patient with known tuberous sclerosis. These lesions are generally isointense on T1-weighted images and hyperintense on T2-weighted images. There is modest signal change in the surrounding white matter. Hypointense portions of the tumor represent calcifications, which are common. After contrast administration, the tumors commonly enhance strongly.2 Computed tomography (CT) can demonstrate calcifications as well as contrast enhancement. In infants, transcranial ultrasonography can be useful for following ventricular size and for detecting an increase in tumor size.

Pathology

The diagnosis of a subependymal giant cell astrocytoma is rarely difficult unless the patient has minimal evidence of tuberous sclerosis and an intraventricular tumor is found during a work-up for neurological symptoms. These tumors receive their name from their common location (periventricular) and typical pathologic appearance (giant cells mixed with astrocyte lineage cells). They are often well-demarcated tumors that show modest infiltration into the surrounding white matter but expand into the ventricular cavity. Routine histologic examination reveals not only giant cells with abundant eosinophilic cytoplasm but also spindle-shaped cells with eccentric nuclei.1,3 The presence of large eosinophilic cytoplasm can mimic gemistocytic astrocytomas; however, the location of the tumor is not consistent with that diagnosis because gemistocytic astrocytomas are found in brain parenchyma and have a high rate of malignant transformation (Fig. 123-2). Mitoses, necrosis, endothelial proliferation, and nuclear atypia may be present; however, these findings do not correlate with aggressive behavior. Anaplastic transformation is uncommon.

Immunohistochemistry reveals tumor cells that are positive for glial fibrillary acidic protein (GFAP) and S-100. One report suggests that subependymal giant cell astrocytomas associated with tuberous sclerosis do not stain for GFAP and may represent a lack of differentiation of cells along the astrocyte lineage in this condition.

Management and Outcome

In general, subependymal giant cell astrocytomas do not require intervention unless they obstruct the foramen of Monro. The primary treatment is surgical, with total resection being the goal.4 When total resection proves to be too hazardous, subtotal resection may be adequate because these tumors often grow slowly and rarely become aggressive. There are few data regarding the role of radiation and chemotherapy in these lesions. Surgical planning is beyond the scope of this chapter, but careful planning is required to provide adequate access to the lesion; this can most often be achieved through a transcortical or transcallosal approach. In addition, tuberous sclerosis is associated with cardiac abnormalities, and a cardiac assessment is an important part of preoperative planning, particularly in children. If surgery is not possible or if hydrocephalus persists following tumor resection, shunting can relieve both ventricular obstruction and intracranial hypertension. It is appropriate to continue surveillance of these patients because recurrence is possible. An attempt to use chemotherapy in the treatment of these tumors has shown some modest early success.5

Angiocentric Glioma

World Health Organization Grade I

Clinical Presentation and History

Described in 2005,6 angiocentric glioma (AG) was recently codified by the WHO and grouped with astroblastoma and chordoid glioma.7 AG can occur at any age; however, it is most commonly seen in young adults, with a mean age of onset of 17 years. Patients typically present with a long-standing history of intractable seizures.

Imaging

MRI of these lesions typically demonstrates a cortical lesion with expansion of a gyrus (Fig. 123-3). A stalk often extends to the ventricular surface, and this is thought to be nearly pathognomonic for AG.6 Lesions are hyperintense on T2- and fluid-attenuated inversion recovery (FLAIR)-weighted images. Contrast enhancement is either sparse or absent.

Pathology

Microscopically, tumors demonstrate monomorphous, bipolar cells associated with the normal vessels of the cortex and white matter.8 Tumor cells are arranged radially akin to ependymal rosettes (Fig. 123-4). Tumor cells are uniform and spindle shaped. Mitoses are rare, with a proliferative index of less than 5%. Immunohistochemically, these tumors are positive for S-100, GFAP, and vimentin. Some cells are epithelial membrane antigen (EMA) positive as well. Cytogenetics and molecular studies are noninformative and yet to be confirmed.

Management and Outcome

AGs tend to follow an indolent course with rare progression.6,7 Surgical cure is obtained by total resection, and after subtotal resections, progression is not encountered at 2.5 and 4 years follow-up without adjuvant therapy.68 More aggressive forms are exceedingly rare and controversial.

Astroblastoma

World Health Organization Grade I

Clinical Presentation and History

Astroblastomas are extremely rare tumors that have received little attention since their initial description by Bailey and Bucy in 1930.9 The acceptance of astroblastoma as a distinct and separate entity has been an issue of some debate because astroblastic features can be found in other neoplastic entities such as anaplastic astrocytomas, glioblastomas, and gemistocytic astrocytomas.9,10 Most astroblastomas are found in the first three decades of life; astroblastomas found later in life have been the highly malignant form. A striking female preponderance (11 : 1) has been reported in larger series.11 Astroblastomas affect the cerebral hemispheres, usually involving the cortex and the subcortical regions or the periventricular regions. No astroblastomas have been reported outside the supratentorial compartment. Patients usually present with symptoms and signs related to cortical dysfunction or from related mass effect, such as hemiparesis, seizures, or personality changes.

Great variability in the natural history of astroblastomas has been reported through case reports; these tumors can have a slow evolution with a relatively favorable outcome, or they can exhibit a rapidly progressive nature leading to fatality. In Bailey and Bucy’s9 series of 25 patients, 1 patient was alive and well 7 years after surgical resection. The relative malignancy of the remaining cases may have been related to anaplastic features. Bonnin and Rubinstein10 attempted to establish clinicopathologic correlations, reinforcing the idea that astroblastomas with malignant features indicative of anaplasia are susceptible to progression to glioblastoma. In their series, those cases that displayed benign histologic features had a benign clinical course, with no postsurgical recurrences after 12 and 20 years. The specimens that displayed malignant features appeared to correlate with a rapidly fatal clinical course, with one death 10 months and the other 16 months after surgery, with pathologic evidence of tumor progression to glioblastoma and gliosarcoma.

Imaging

Studies of imaging characteristics of astroblastomas have been limited (Fig. 123-5). The appearance of astroblastomas on CT has ranged from a poorly defined, hypodense tumor with an irregular enhancement pattern to a well-defined tumor with intense enhancement. One case series has attempted to describe the imaging characteristics of these lesions.11 Tumors are generally hypointense to white matter on T1-weighted imaging and hyperintense on T2-weighted and FLAIR images. Frequent rim enhancement is seen around a cystic center. Calcifications can be present, and vasogenic edema is often minimal. Frequently, multiple intratumoral cysts are seen, giving the “bubbly” appearance.

Pathology

Astroblastomas are almost always well defined macroscopically, with their cut surfaces revealing a homogeneous, soft, pink-gray substance.10 Cystic areas are frequently encountered, and central areas of necrosis can be found in larger specimens. Microscopically, these tumors are richly supplied by blood vessels. The clusters of tumor cells form pseudorosettes in cross section (Fig. 123-6). The vessel walls are highly hyalinized. The nuclei of the tumor cells are found some distance away from the vessel, but long processes extend from the tumor cell to the vessels and end as an expanded footplate. The nuclei are oval and slightly irregular and contain coarse chromatin nodes. The perikaryon is angulated, club shaped, or fusiform. Cellular atypia can be present in varying degrees. High numbers of mitotic figures may be found in the high-grade variant.

Immunohistochemically, the tumor cells usually stain positive for GFAP, although there is variability in the extent of staining. Immunopositivity for vimentin, neuron-specific enolase, S-100, and EMA has been shown. Astroblastomas are also positive for the anti-Leu-7 (HNK-1) antibody, which is a natural killer antibody specific for cells of neuroepithelial origin. Central necrosis can be encountered in some specimens. The biologic significance of necrosis is uncertain, and it may not necessarily signify an ominous prognosis.

Management and Outcome

Surgical resection is the main therapeutic modality. Astroblastomas are well circumscribed and usually located in surgically accessible regions. Gross total resection can usually be achieved without difficulty. Owing to the rarity of these tumors, the therapeutic value of radiation and chemotherapy remains uncertain. Bonnin and Rubinstein10 reported one patient who had good tumor control with a biopsy and subsequent radiotherapy. Chemotherapy was also administered in five patients in the same series, without a clear change in prognosis. In Bailey and Bucy’s9 original series, most patients died within the year following surgery, owing to tumor regrowth. Outcome is difficult to predict because these tumors can remain indolent in some patients and undergo malignant degeneration to glioblastoma in others, resulting in rapid death.

Pilomyxoid Astrocytoma

World Health Organization Grade II

Clinical Presentation and History

Pilomyxoid astrocytomas (PMAs) are a recently described entity with similarities to pilocytic astrocytomas (PAs); however, the prognosis is not as favorable.12 It is possible that up until the description of PMA, these lesions were grouped together with PA and thus account for patients with PA experiencing a shorter disease-free survival. These tumors occur throughout the neuraxis, with a mean age at diagnosis of 18 months.13 Most are found in the hypothalamic-chiasmatic region and at the midline. Patients present with symptoms associated with elevated intracranial pressure or mass effect of eloquent parenchyma. In infants, increased head circumference may be the first presenting sign.

Pathology

PMA histology consists of a myxoid matrix, with monomorphic piloid cells in a loose fibrillary and myxoid background without Rosenthal fibers or eosinophilic granules.12 Tumor cells are arranged radially around vessels similar to perivascular rosettes seen in ependymomas (Fig. 123-8). Mitotic figures are rare. This is in contrast to PAs, which demonstrate a biphasic architecture with Rosenthal fibers and eosinophilic granular bodies (EGBs). Molecular characterization of PMA has not been performed.

Pleomorphic Xanthoastrocytoma

World Health Organization Grade II

Clinical Presentation and History

First described in 1979 by Kepes and colleagues,15 these rare tumors represent less than 1% of all astrocytoma cases.15 Pleomorphic xanthoastrocytoma (PXA) can occur throughout the supratentorial compartment (most commonly in the temporal lobe), with case reports of lesions in the cerebellum16 and spinal cord.17 Patients typically present in the second to third decade of life, with a median age of 14 years, although cases have been reported from infancy to the seventh decade.18 Both sexes are affected equally. Most patients (70% to 80%) present with seizures followed by headache and focal location-related deficits, or evidence of increased intracranial pressure.18 Rarely, patients present with symptomatic hemorrhage from the tumor.19

Supratentorial tumors are most often cortically based, adjacent to the meninges. In many cases, the tumors have been associated with chronic epilepsy, indicating an indolent course. Furthermore, their early-adult onset and histologic appearance may indicate that they are developmental in nature. These features notwithstanding, a subgroup of patients with this histologic diagnosis may experience rapid demise despite surgery and, in some cases, adjuvant radiation and chemotherapy.

Imaging

PXAs are characterized on CT and MRI as a cystic structure with an enhancing mural nodule (Fig. 123-9). Both CT and Tl-weighted MRI typically reveal a focal, ill-defined mass with mixed intensity, isointensity, or hypointensity to gray matter.20,21 The cystic component is seen in up to 60% of cases.18 Well-defined contrast enhancement of the tumor mass or nodule is often seen on CT and is demonstrated uniformly on gadolinium-enhanced MRI. The tumor is usually of high to mixed intensity on T2-weighted imaging, and the cyst is typically hyperintense. Some authors have reported associated leptomeningeal enhancement or spread.22

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