Historical Context

Gliomas account for the majority of supratentorial tumors in childhood.1 In contrast to the situation in adults, low-grade gliomas are substantially more common in children than are malignant lesions. Most low-grade gliomas are grade I or II astrocytomas, which are the focus of this chapter, and the remainder are oligodendrogliomas, gangliogliomas, and a host of less common lesions, such as pleomorphic xanthoastrocytomas, dysembryoplastic neuroepithelial tumors, and desmoplastic infantile gangliogliomas, which occur most commonly in the pediatric age group1,2 and are discussed elsewhere in this text. The management of these lesions is strongly influenced by histology and tumor resectability. Low-grade astrocytomas have historically been treated with surgery alone, and the use of adjuvant therapy for incompletely resected lesions has been an area of long-standing controversy. In contrast, malignant lesions have typically been managed using multimodality approaches, incorporating postoperative irradiation and, in more recent years, chemotherapy. Whereas the prognosis is excellent for completely resected cortically based low-grade gliomas, and surgery is often curative, the survival rates have been suboptimal for patients with malignant gliomas, and these tumors remain a subject of intense interest from both a research and therapeutic perspective.

Epidemiology

Although no genetic or environmental cause is apparent for most supratentorial astrocytomas in children, a small subset of patients harbors an underlying syndrome that predisposes to tumor development. Neurofibromatosis type 1 (NF-1) is the most common syndromic cause of gliomas, and it results from mutations in the neurofibromin gene (17q), which promotes G-protein–mediated signaling.3 The most common location for tumors in such patients is the optic pathways, although glial neoplasms, both low grade and high grade, can also arise in the cerebral cortex4 ( Table 16.1 ).

Patients with tuberous sclerosis also have an increased incidence of supratentorial tumors, most characteristically subependymal giant cell astrocytomas (SEGAs) arising in the region of the foramen of Monro. This syndrome results from mutations in the TSC1 or TSC2 genes, which lead to dysregulated signaling via the mTOR pathway.5 Affected patients commonly have seizures, mental retardation, and adenoma sebaceum in addition to cortical and subependymal hamartomas (tubers), angioleiomyomas of the kidney, and rhabdomyomas of the heart.

Two other less common syndromes associated with an increased incidence of gliomas are Turcot and Li-Fraumeni. The former is associated with mutations in the mismatch repair or adenomatous polyposis genes, whereas the latter is associated with mutations in the TP53 gene.6–8

Pathological Classification

Low-grade astrocytomas are subdivided into several groups, based on their histological appearance,2 including pilocytic astrocytomas and subependymal giant cell astrocytomas, which are typically grade I lesions, and fibrillary and pilomyxoid astrocytomas, which are considered grade II lesions. Malignant gliomas are subdivided into anaplastic (grade III) astrocytomas and glioblastomas (grade IV) ( Table 16.2 ).

Pilocytic astrocytomas are characterized by having regions with compact bipolar astrocytes interspersed with loosely packed areas containing microcysts. Macrocysts are also common. Eosinophilic granular bodies and Rosenthal fibers are characteristically seen. Occasional mitotic figures, leptomeningeal infiltration, and vascular proliferation may be noted but do not appear to adversely affect prognosis, in contrast to the situation with nonpilocytic astrocytomas ( Table 16.3 ).

Pleomorphic xanthoastrocytomas are generally classified as grade II gliomas, most typically originate in the temporal or parietal lobes, and often have an associated cyst. These lesions are characterized by pronounced nuclear atypia with pleomorphism and multinucleation. Abundant lipid-rich cells and pronounced reticulin reactivity are also typical. Approximately 20% of these lesions appear to undergo malignant transformation with pronounced mitosis, necrosis, and endothelial proliferation ( Table 16.4 ).

Subependymal giant cell astrocytomas arise most commonly in the setting of tuberous sclerosis in the vicinity of the foramen of Monro, and are composed of large cells resembling astrocytes. Perivascular pseudopalisading is often seen, but mitoses are rare. Immunoreactivity for both glial and neuronal markers may be noted ( Table 16.5 ).

Nonpilocytic fibrillary astrocytomas are characterized by an overabundance of astrocytes with nuclear atypia, lacking the characteristic features of pilocytic lesions. Grade III lesions characteristically have increased mitotic indices and pleomorphism, whereas grade IV lesions also have a combination of endothelial proliferation and necrosis.

Molecular Pathogenesis

Until recently, pilocytic astrocytomas were thought to be largely devoid of consistent genetic aberrations. However, a series of studies have demonstrated that these tumors characteristically exhibit alterations in the BRAF gene, most commonly involving translocations between BRAF and KIAA, or activating BRAF mutations, such as BRAF^v600E , leading to constitutive activation of downstream signaling elements in the MEK/MAPK pathway.9–11 As with the TSC mutations noted in patients with SEGAs, this recurring abnormality has provided insights regarding strategies for molecularly targeted therapies.

The molecular basis for childhood fibrillary low-grade astrocytomas remains less well defined. Although in adults such tumors are felt to be an initial step in a pathway of gliomagenesis that ultimately culminates in higher grade lesions,12,13 such a phenotype is less commonly observed in childhood lesions, which highlights the potential differences between similar-appearing tumors in these two age groups. In this regard, our previous studies have noted TP53 mutations in 40 to 50% of pediatric malignant gliomas, comparable to the frequency in adult malignant astrocytomas that progress secondarily from low-grade gliomas.12,14 However, adult grade II fibrillary astrocytomas and secondary malignant gliomas also commonly exhibit mutations in the IDH1 or IDH2 genes,12,15 and such mutations are uncommon in childhood lesions, which suggests that despite their similarities in terms of TP53 alterations, childhood high-grade gliomas arise by a distinct mechanism from adult secondary malignant gliomas.16 Childhood lesions are also biologically distinct from so-called primary adult malignant gliomas, which arise de novo as grade IV lesions, because adult lesions characteristically exhibit deletions or mutations of the PTEN gene, in association with amplification or rearrangement of the EGFR gene,12,13 whereas these alterations are observed in only approximately 10% of pediatric malignant gliomas.17 In view of recent reports that highlight the existence of multiple pathways of tumorigenesis in adults,18 it is likely that pediatric lesions are not only genetically distinct from many adult lesions, but may themselves encompass several parallel pathways of tumorigenesis.

Despite the above differences between childhood and adult malignant gliomas, these lesions share a therapeutically relevant similarity in the association between response to alkylating agents, such as temozolomide and nitrosoureas, and expression levels of the DNA repair protein methylguanine DNA-methyltransferase (MGMT).19–21 MGMT promotes alkylator resistance by removing drug-induced alkyl groups, and methylation of the MGMT promoter, which is a marker for silencing of MGMT gene expression, has been associated with an improved prognosis in adults treated with nitrosoureas and temozolomide.21 Similarly, children treated with CCNU-based or temozolomide-based regimens whose tumors have low levels of MGMT expression have been noted to have a significantly better prognosis than those with MGMT overexpression.19,20

Symptoms and Signs

The mode of presentation of a supratentorial astrocytoma is influenced by the age of the child and the histology and location of the tumor. Brain tumors in infants often produce nonlocalizing symptoms, such as irritability, failure to thrive, and macrocephaly. In older children, tumors often present with seizures or focal neurological deficits, such as hemiparesis or hemisensory deficits. Symptom progression tends to be more rapid in tumors that are histologically malignant, and such lesions are more likely to present with manifestations of increased intracranial pressure, such as headache and vomiting, whereas lower grade lesions most commonly reach clinical attention as a result of seizures.

Diagnostic Evaluation

Either computed tomography (CT) or magnetic resonance imaging (MRI) may be employed to establish the diagnosis of a brain tumor, although MRI, with and without intravenous contrast, is the preferred modality for defining the size and growth characteristics of the tumor and for preoperative planning. Low-grade astrocytomas are typically hypodense on CT and hypointense on T1-weighted MRI in comparison to the surrounding brain. Pilocytic tumors often exhibit well-defined borders with enhancement in the form of a mural nodule or a uniform or ring-like pattern. Pleomorphic xanthoastrocytomas characteristically arise at or close to the cortical surface in association with an underlying cyst. Enhancement of the solid tumor component is typically seen. Subependymal giant cell astrocytomas appear as well-circumscribed, partially calcified, homogeneously enhancing lesions located adjacent to the foramen of Monro and are often associated with obstructive hydrocephalus ( Table 16.6 ).

Low-grade fibrillary astrocytomas generally have ill-defined margins on CT or T1-weighted MRI and may appear as a poorly circumscribed area of increased signal on T2-weighted images with minimal enhancement on contrasted images. In contrast, malignant gliomas typically exhibit irregular or ring-like enhancement on CT and MRI with a surrounding area of low density on CT, low intensity on T1-weighted MRI, and high intensity on T2-weighted MRI that represents infiltrating tumor and edema. Because these lesions grow more rapidly than low-grade gliomas, they often produce substantially greater local mass effect.

Although in selected cases, such as optic pathway gliomas in patients with NF-14 or SEGAs in patients with tuberous sclerosis, the MRI appearance is sufficiently clear-cut to establish the diagnosis without the need for surgical biopsy, in most supratentorial astrocytomas, surgery is performed both to definitively establish the histological diagnosis and to achieve tumor resection.

Operative Management

The timing of operative intervention is largely determined by the condition of the child. Patients who present with a large symptomatic mass undergo resection on an urgent or semi-urgent basis, whereas smaller lesions that present with seizures and minimal mass effect are treated more electively. Corticosteroids (e.g., Decadron, 0.1 mg/kg q6h) are generally begun on admission in children with large tumors, or administered preoperatively, continued intraoperatively, and then tapered after surgery if significant tumor debulking has been achieved. Because children with hemispheric tumors may be at risk for seizures during the perioperative period, anticonvulsants are often begun preoperatively, even if the child has not previously had a seizure. In those children who have long-standing intractable seizures as the presenting symptom of their tumor, a formal preoperative epilepsy evaluation may be warranted, along with extra- or intraoperative functional and seizure mapping to optimize the chances for long-term seizure control.

The goals of the operation (e.g., biopsy, reduction of mass effect, gross total resection) are influenced by the growth characteristics of the tumor as depicted by preoperative imaging. For well-circumscribed superficial lesions, a gross total resection is often the operative goal, if this can be achieved without inordinate risk. This is feasible for most superficial pilocytic astrocytomas, many superficial nonpilocytic astrocytomas, and some superficial high-grade gliomas, and in these tumors there appears to be a major prognostic advantage to obtaining a gross total or near total resection. Conversely, for some infiltrative, poorly circumscribed high-grade gliomas and nonpilocytic low-grade gliomas that cross the midline or extensively invade the deep nuclei and other critical brain regions, extensive resection may not be feasible without unacceptable morbidity. In small or highly diffuse lesions, image-guided stereotactic biopsy may be preferable to an extensive open operation with limited tumor removal as a means for safely establishing a histological diagnosis in preparation for adjuvant therapy. For some large lesions with extensive mass effect but poorly circumscribed borders, an open biopsy combined with a subtotal resection may be of value in stabilizing the patient in preparation for further treatment.

Several adjuncts have become available during the last several years that have facilitated radical removal of lesions previously thought to be unresectable, or resectable only with substantial morbidity. Stereotactic guidance systems have allowed preoperative and intraoperative localization of the tumor, which permits the surgeon to choose an operative approach that minimizes manipulation of functionally critical brain and maximizes the extent of resection that can be achieved. Ultrasound has also been used by some surgeons to provide “real-time” feedback on the location of the lesion, and more recently, intraoperative MRI has been used in several centers to maximize tumor resections.

For superficial cortical tumors and subcortical lesions that are not immediately beneath functionally essential cortex, the most direct trajectory to the lesion is usually selected. However, for lesions adjacent to or involving critical brain regions, stereotactic and functional mapping techniques are useful for selecting the safest approach to the tumor. In this regard, a variety of techniques have been developed for functional localization of critical brain areas in the vicinity of a superficial tumor or over-lying a deep-seated lesion to help in choosing a safe surgical trajectory to the tumor. These include functional MRI, diffusion tensor imaging, cortical stimulation techniques, and sensorimotor and speech mapping. The approach to deep lesions is also influenced by the predominant direction of tumor growth. Lesions that grow medially and encroach on or expand within the lateral ventricle can be approached transcallosally or transfrontally, whereas tumors that extend laterally in the nondominant hemisphere may be approached through the insula after the sylvian fissure has been opened. Laterally extending lesions within the dominant hemisphere and tumors that arise more posteriorly within the thalamus may be reached using a posterior parietal approach situated behind the sensorimotor cortex and above the angular gyrus. Selected lesions can also be reached via an occipital trajectory. Finally, tumors that project anterolaterally can be reached from a paramedian frontal trajectory, provided that care is taken to avoid injury to the motor pathways, whereas inferolaterally projecting deep lesions can be approached via the middle or inferior temporal gyrus or sulcus.

The tumor resection is usually initiated using ultrasonic aspiration to debulk the center of the lesion after an adequate biopsy specimen has been obtained. Some low-grade gliomas, particularly pilocytic tumors, have a well-delineated peritumoral plane, although for most nonpilocytic and high-grade gliomas, no such plane is observed, and the resection must proceed from the inside outward until a boundary between tumor and normal brain is reached. For cystic benign astrocytomas with a well-defined nodule in which the cyst lining is nonenhancing and translucent, resection of the wall is unnecessary, whereas in tumors with walls that are thick and enhancing, removal of this component of the tumor is warranted, if feasible, to optimize the chances for disease control. Postoperative imaging during the first 48 hours is generally warranted to determine the extent of tumor resection, given that the extent of residual disease is a major predictor of outcome.