High-grade gliomas (HGGs) are malignant tumors and typically include glioblastoma multiforme and anaplastic astrocytoma subtypes. Brainstem gliomas and ependymomas are separate entities with respect to clinical presentation, treatment, prognosis, and outcome in comparison with supratentorial HGGs. In children, these tumors account for 3% to 7% of newly diagnosed brain tumors and 20% of all diagnoses of pediatric supratentorial brain tumors. These neoplasms are highly proliferative and mitotically active and of glial origin. This article reviews clinical, diagnostic, and pathologic features of HGG and current treatments and potential future therapies specific to pediatric patients with HGGs.
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High-grade gliomas include anaplastic astrocytomas and glioblastomas. They account for 3% to 7% of primary brain tumors in children and peak in incidence during adolescence.
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Molecular mutations seen in pediatric glioblastoma multiforme and AAs include p53, PTEN, and LOH at 10q23. p53 and PTEN are associated with a poor prognosis.
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The goals of surgery include pathologic diagnosis and/or gross total resection. Longer progression-free survival is associated with a greater extent of resection.
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In children older than 3 years, chemotherapy plus radiation after surgery is the standard of care. In children younger than 3 years, radiation is associated with significant neurologic morbidity and should be used only when necessary.
Introduction
Gliomas are primary brain tumors derived from astrocytes and oligodendroglia and are historically separated into low- or high-grade categories according to the World Health Organization (WHO) classification system. Low-grade astrocytomas (WHO grade I and II) are approximately 40% of primary supratentorial tumors of childhood and are more common than high-grade astrocytomas (WHO grade III and IV). Supratentorial high-grade gliomas (HGGs) are further divided into anaplastic astrocytomas (AAs, WHO grade III), anaplastic oligodendrogliomas (WHO grade III), mixed astrocytic tumors, and glioblastoma multiforme (GBM, WHO grade IV). As expected, survival rates are poor and mortality is highest in patients with malignant astrocytomas.
Epidemiology
HGGs account for between 3% and 7% of newly diagnosed primary brain tumors in children. GBM is the most common primary brain tumor in the adult population, but GBMs along with AAs account for only about 20% of pediatric supratentorial brain tumors. In the pediatric population, malignant astrocytomas seem to affect boys and girls equally. The incidence peaks during adolescence, although very young children can also develop malignant astrocytomas.
At present, the only known risk factor associated with developing an HGG is prior radiation therapy. Other rare risk factors include genetic syndromes such as Li-Fraumeni syndrome. This syndrome is characterized by 1 or more cancer occurrences in children, including HGGs. Mutations of the p53 tumor suppressor gene play a key role in tumorigenesis in these patients. Neurofibromatosis type 1 is an autosomal dominant genetic disorder caused by mutations of the neurofibromin gene. The clinical manifestations include cutaneous café au lait spots, neurofibromas in any organ system, optic gliomas, and intracranial HGGs. Turcot syndrome, a disease of DNA mismatch repair characterized by adenomatous colorectal polyps and malignant neuroepithelial tumors, has been associated with HGGs in children. Other diseases of constitutional mismatch repair deficiency, specifically expression of the MSH6 mismatch repair gene mutation has been linked to HGG development in children. In addition, there have been case reports of GBM occurring in patients with Ollier disease and Maffucci syndrome, both diseases of cartilaginous dysplasia. However, the significance of the occurrence of these malignancies in these syndromes is unknown.
Epidemiology
HGGs account for between 3% and 7% of newly diagnosed primary brain tumors in children. GBM is the most common primary brain tumor in the adult population, but GBMs along with AAs account for only about 20% of pediatric supratentorial brain tumors. In the pediatric population, malignant astrocytomas seem to affect boys and girls equally. The incidence peaks during adolescence, although very young children can also develop malignant astrocytomas.
At present, the only known risk factor associated with developing an HGG is prior radiation therapy. Other rare risk factors include genetic syndromes such as Li-Fraumeni syndrome. This syndrome is characterized by 1 or more cancer occurrences in children, including HGGs. Mutations of the p53 tumor suppressor gene play a key role in tumorigenesis in these patients. Neurofibromatosis type 1 is an autosomal dominant genetic disorder caused by mutations of the neurofibromin gene. The clinical manifestations include cutaneous café au lait spots, neurofibromas in any organ system, optic gliomas, and intracranial HGGs. Turcot syndrome, a disease of DNA mismatch repair characterized by adenomatous colorectal polyps and malignant neuroepithelial tumors, has been associated with HGGs in children. Other diseases of constitutional mismatch repair deficiency, specifically expression of the MSH6 mismatch repair gene mutation has been linked to HGG development in children. In addition, there have been case reports of GBM occurring in patients with Ollier disease and Maffucci syndrome, both diseases of cartilaginous dysplasia. However, the significance of the occurrence of these malignancies in these syndromes is unknown.
Pathology
Histopathology
AAs are highly proliferative mitotically active tumors of glial origin with increased cellularity and cellular atypia. GBMs consist of active poorly differentiated astrocytes with high mitotic activity. These neoplasms are typically heterogeneous with areas of hypervascularity and necrosis. Often the necrotic areas are toward the center of the lesion and surrounded by dense hypervascular tissue. The peripheral zones of both AA and GBM are composed of less dense cellular layers that invade and infiltrate the surrounding brain tissue. Typically this invasion is along white matter tracts, including the anterior and posterior commissures, corpus callosum, fornix, and internal capsule. Infiltrating tumor cells are commonly found many centimeters from the original tumor location.
Molecular Features
The molecular profiles of pediatric and adult HGGs are distinct. Mutations in the p53 tumor suppressor gene are characteristic features of pediatric GBMs and are associated with a poor prognosis. In a multi-institutional trial, the Children’s Cancer Group (CCG) identified p53 mutations in 40.5% of pediatric HGGs. This same p53 mutation is only seen in secondary adult GBMs. Secondary GBM refers to HGGs that have arisen from the progression of lower-grade gliomas. p53 overexpression in children is associated with a 5-year progression-free survival (PFS) rate of 17% in comparison with a PFS rate of 44% in patients with low p53 expression.
Epidermal growth factor receptor (EGFR), PTEN, and the Ras pathway are activated in most adult GBMs, although these alterations are only present in a subset of pediatric patients. EGFR amplification is rare (<10%) in children with GBMs than in adults with GBMs, although positive and elevated EGFR immunoreactivity is seen in 80% of pediatric tumors. The CCG trial reported that 24% of pediatric GBMs and AAs had PTEN deletions. Although mutations in PTEN are rare in pediatric GBM than in GBM in adults, if present, a poorer prognosis can be expected. LOH at 10q23 is a common abnormality found in 80% of pediatric GBMs.
There are at least 2 molecular subtypes of pediatric GBM. One has activation of the Ras/Akt and MAPK pathways and is associated with a poor clinical prognosis. The other subtype does not have Ras/Akt or MAPK pathway activation and has a much more favorable prognosis. In most adult GBMs, the Ras pathway is activated. In children with GBMs with Ras activation, high expression of CD133, nestin, dlx2, and MELK is also seen.
YB1, a protein involved in brain embryogenesis, is upregulated in 72% of pediatric GBMs. This protein is unique to pediatric GBMs and, when localized to the nucleus, is associated with a poor prognosis. When expressed in the cytoplasm of Ras/Akt-negative GBMs, it was associated with a better outcome. A strong positive association between MIB-1 labeling, patient outcome, and histology has also been found. Mean labeling indices were 19.4 ± 2.66 for tumors classified as AA versus 32.1 ± 3.08 for those classified as GBM ( P = .0024). The 5-year PFS was 33% ± 7% in 43 patients whose tumors had MIB-1 indices of less than 18%, 22% ± 8% in 27 patients whose tumors had indices between 18% and 36%, and 11% ± 6% in 28 patients whose tumors had indices greater than 36% ( P = .003), reflecting a significant inverse correlation between proliferative indices and PFS.
Pediatric AAs are associated with both loss and gain of DNA copy number. The most common gains are on chromosome 5q (40%) and 1q (30%), whereas the most common losses are chromosomes 22q (50%) and 6q, 9q (40%). Losses on 17p have also been reported. A shorter survival time is associated with a gain on the 1q arm. PTEN mutation is rare (8%) in pediatric AA, but if present is associated with poor prognosis. In addition, p53 mutations are present in 95% of pediatric AAs.
Clinical Features
As with many brain tumors, the clinical presentation depends on the anatomic location of the tumor, associated effects on the surrounding brain, and the age of the patient. Constitutional symptoms such as fatigue, irritability, anorexia, loss of milestones, or failure to thrive can occur but are nonspecific in nature. Signs and symptoms of increased intracranial pressure, such as worsening headaches, nausea, and vomiting, are often seen with intracranial tumors regardless of their diagnosis or grade. Neurologic abnormalities related to tumor location may include hemiparesis; dysphasia; or, less commonly, worsening seizures related to tumor progression. Infants are a special population in whom signs and symptoms may be difficult to interpret. If the cranial sutures are still open, symptoms and signs of increased intracranial pressure may not be present; instead, the head circumference will increase, making room for the growing infiltrating tumor. A rapid increase in head circumference may be the first step in the diagnosis of a brain tumor in infants. The rate of tumor progression is related to tumor grade. Patients with HGGs have a hastening of functional decline and symptoms in comparison with those with lower-grade tumors.
Diagnostic Imaging
HGGs can be identified on computed tomographic (CT) scans as an irregular isodense or hypodense lesion centered in the white matter. There may be heterogeneous enhancement of the lesion seen on postcontrast sequences. Although CT scans play an important diagnostic role in the early detection of brain tumors in children, magnetic resonance imaging (MRI) is the most sensitive imaging tool and provides far more anatomic information. At a minimum, the following MRI sequences should be obtained: T1-weighted, precontrast and postcontrast administration, T2-weighted, and fluid-attenuated inversion recovery (FLAIR). Additional specialized magnetic resonance sequences include magnetic resonance spectroscopy (MRS), perfusion, diffusion-weighted imaging, and diffusion tensor imaging (DTI). Functional MRI (fMRI) can provide functional and structural information, which is particularly helpful for surgical planning.
HGGs can have varying imaging features on MRI. They either can have an irregularly enhancing rim surrounding a necrotic core or can be poorly marginated with diffuse infiltration into white matter tracts such as the corpus callosum and anterior and posterior commissures. These tumors are usually solitary but can be multifocal. On precontrast T1-weighted sequences, these tumors are isointense or hypointense. After contrast administration, T1-weighted sequences typically show an irregular enhancing rim surrounding a nonenhancing area of central necrosis ( Fig. 1 ). Hemorrhage is sometimes present within the tumor ( Fig. 2 ). The enhancing portion typically represents mitotically active proliferating tumor cells. T2-weighted and FLAIR sequences usually show a heterogeneous mass with variable signal intensity surrounded by a broad zone of vasogenic edema. Infiltrating malignant tumor cells extend far beyond the area of enhancement. These aggressive tumors have elevated choline level, lactate level, and lipid peaks and decreased N -acetyl-aspartate peaks on MRS. Because of the high proliferative index and elevated glucose metabolism that characterizes HGGs, PET imaging reveals high fludeoxyglucose uptake in the lesion.
Gliomatosis cerebri is the most diffuse form of HGGs and is identified by tumor infiltration throughout multiple lobes and associated vasogenic edema. Imaging of the neuraxis is indicated when there is a concern for disseminated disease throughout the brain and spinal cord. The differential diagnosis based on imaging includes abscess, demyelination, or other primary malignant brain tumors of childhood, including primitive neuroectodermal tumors, ependymoma, or pleomorphic xanthoastrocytomas.
Following surgery, chemotherapy, and/or radiation therapy, patients should be monitored radiographically for tumor recurrence. Serial MRI with close clinical follow-up is required to detect early evidence of tumor progression.
Treatment
Surgery
The goals of surgery include obtaining tissue for pathologic diagnosis and achieving a gross total resection (GTR). Depending on tumor location, GTR must be balanced against the development of disabling neurologic deficits. Preoperative MRI sequences such as DTI or fMRI as well as intraoperative image guidance navigation can assist in safely achieving a greater extent of resection while preserving neurologic function for the patient. Because of the infiltrative nature and anatomic location of these tumors, GTR is often not possible. In circumstances in which the tumor is entirely deep in location with involvement of gray matter nuclei, a limited biopsy may be the only safe option ( Fig. 3 ). Once a diagnosis is obtained, adjuvant chemotherapy and/or radiation therapy can be planned.
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Clinical Trials of Small Molecule Inhibitors in High-Grade Glioma
Passive Immunotherapeutic Strategies for the Treatment of Malignant Gliomas
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