These are infiltrative tumors with a presumptive glial cell of origin. The World Health Organization (WHO) classifies astrocytomas into four prognostic grades based on histologic features: grade I (pilocytic astrocytoma, subependymal giant cell astrocytoma); grade II (diffuse astrocytoma); grade III (anaplastic astrocytoma); and grade IV (glioblastoma). Grades I and II are considered low-grade astrocytomas, and grades III and IV are considered high-grade astrocytomas.
These tumors occur predominantly in children and young adults.
Pilocytic astrocytomas (WHO grade I) are the most common tumor of childhood. They occur typically in the cerebellum but may also be found elsewhere in the neuraxis, including the optic nerves and brainstem. Frequently they appear as cystic lesions with an enhancing mural nodule. These are well-demarcated lesions that are potentially curable if they can be resected completely. Giant-cell subependymal astrocytomas are usually found in the ventricular wall of patients with tuberous sclerosis. They often do not require intervention but can be treated surgically or with inhibitors of the mammalian target of rapamycin (mTOR).
These are infiltrative tumors that usually present with seizures in young adults. They appear as nonenhancing tumors with increased T2/FLAIR signal (Fig. 48-1). If feasible, patients should undergo maximal surgical resection, although complete resection is rarely possible because of the invasive nature of the tumor. Radiation therapy (RT) is helpful, but there is no difference in overall survival between RT administered postoperatively or delayed until the time of tumor progression. There is increasing evidence that chemotherapeutic agents such as temozolomide, an oral alkylating agent, can be helpful in some patients. The tumor transforms to a malignant astrocytoma in the majority of patients, leading to variable survival with a median of about 5 years.
Fluid-attenuated inversion recovery (FLAIR) MRI of a left frontal low-grade astrocytoma. This lesion did not enhance.
Grade III (anaplastic) astrocytoma
These account for approximately 15–20% of high-grade astrocytomas. They generally present in the fourth and fifth decades of life as variably enhancing tumors. Treatment is the same as for glioblastoma, consisting of maximal safe surgical resection followed by RT with concurrent and adjuvant temozolomide or by RT and adjuvant temozolomide alone.
Grade iv astrocytoma (glioblastoma)
Glioblastoma accounts for the majority of high-grade astrocytomas. They are the most common malignant primary brain tumor, with over 10,000 cases diagnosed each year in the United States. Patients usually present in the sixth and seventh decades of life with headache, seizures, or focal neurologic deficits. The tumors appear as ring-enhancing masses with central necrosis and surrounding edema (Fig. 48-2). These are highly infiltrative tumors, and the areas of increased T2/FLAIR signal surrounding the main tumor mass contain invading tumor cells. Treatment involves maximal surgical resection followed by partial-field external-beam RT (6000 cGy in thirty 200-cGy fractions) with concomitant temozolomide, followed by 6–12 months of adjuvant temozolomide. With this regimen, median survival is increased to 14.6 months compared to only 12 months with RT alone, and 2-year survival is increased to 27%, compared to 10% with RT alone. Patients whose tumor contains the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) are relatively resistant to temozolomide and have a worse prognosis compared to those whose tumors contain low levels of MGMT as a result of silencing of the MGMT gene by promoter hypermethylation. Implantation of biodegradable polymers containing the chemotherapeutic agent carmustine into the tumor bed after resection of the tumor also produces a modest improvement in survival.
Postgadolinium T1 MRI of a large cystic left frontal glioblastoma.
Despite optimal therapy, glioblastomas invariably recur. Treatment options for recurrent disease may include reoperation, carmustine wafers, and alternate chemotherapeutic regimens. Reirradiation is rarely helpful. Bevacizumab, a humanized vascular endothelial growth factor (VEGF) monoclonal antibody, has activity in recurrent glioblastoma, increasing progression-free survival and reducing peritumoral edema and glucocorticoid use (Fig. 48-3). Treatment decisions for patients with recurrent glioblastoma must be made on an individual basis, taking into consideration such factors as previous therapy, time to relapse, performance status, and quality of life. Whenever feasible, patients with recurrent disease should be enrolled in clinical trials. Novel therapies undergoing evaluation in patients with glioblastoma include targeted molecular agents directed at receptor tyrosine kinases and signal transduction pathways; antiangiogenic agents, especially those directed at the VEGF receptors; chemotherapeutic agents that cross the blood-brain barrier more effectively than currently available drugs; gene therapy; immunotherapy; and infusion of radiolabeled drugs and targeted toxins into the tumor and surrounding brain by means of convection-enhanced delivery.
Postgadolinium T1 MRI of a recurrent glioblastoma before A and after B administration of bevacizumab. Note the decreased enhancement and mass effect.
The most important adverse prognostic factors in patients with high-grade astrocytomas are older age, histologic features of glioblastoma, poor Karnofsky performance status, and unresectable tumor. Patients whose tumor contains an unmethylated MGMT promoter resulting in the presence of the repair enzyme in tumor cells and resistance to temozolomide also have a worse prognosis.
Rarely, patients may present with a highly infiltrating, nonenhancing tumor of variable histologic grade involving more than two lobes of the brain. These tumors may be indolent initially, but will eventually behave aggressively and have a poor outcome. Treatment involves RT and temozolomide chemotherapy.
Oligodendrogliomas account for approximately 15–20% of gliomas. They are classified by the WHO into well-differentiated oligodendrogliomas (grade II) or anaplastic oligodendrogliomas (AOs) (grade III). Tumors with oligodendroglial components have distinctive pathologic features such as perinuclear clearing—giving rise to a “fried-egg” appearance—and a reticular pattern of blood vessel growth. Some tumors have both an oligodendroglial as well as an astrocytic component. These mixed tumors, or oligoastrocytomas (OAs), are also classified into well-differentiated OA (grade II) or anaplastic oligoastrocytomas (AOAs) (grade III).
Grade II oligodendrogliomas and OAs are generally more responsive to therapy and have a better prognosis than pure astrocytic tumors. These tumors present similarly to grade II astrocytomas in young adults. The tumors are nonenhancing and often partially calcified. They should be treated with surgery and, if necessary, RT and chemotherapy. Patients with oligodendrogliomas have a median survival in excess of 10 years.
AOs and AOAs present in the fourth and fifth decades as variably enhancing tumors. They are more responsive to therapy than grade III astrocytomas. Co-deletion of chromosomes 1p and 19q, mediated by an unbalanced translocation of 19p to 1q, occurs in 61–89% of patients with AO and 14–20% of patients with AOA. Tumors with the 1p and 19q co-deletion are particularly sensitive to chemotherapy with procarbazine, lomustine (cyclohexylchloroethylnitrosourea [CCNU]), and vincristine (PCV) or temozolomide, as well as to RT. Median survival of patients with AO or AOA is approximately 3–6 years, but those with co-deleted tumors can have a median survival of 10–14 years if treated with RT and chemotherapy.
Ependymomas are tumors derived from ependymal cells that line the ventricular surface. They account for approximately 5% of childhood tumors and frequently arise from the wall of the fourth ventricle in the posterior fossa. Although adults can have intracranial ependymomas, they occur more commonly in the spine, especially in the filum terminale of the spinal cord where they have a myxopapillary histology. Ependymomas that can be completely resected are potentially curable. Partially resected ependymomas will recur and require irradiation. The less common anaplastic ependymoma is more aggressive and is treated with resection and RT; chemotherapy has limited efficacy. Subependymomas are slow-growing benign lesions arising in the wall of ventricles that often do not require treatment.
OTHER LESS COMMON GLIOMAS
Gangliogliomas and pleomorphic xanthoastrocytomas occur in young adults. They behave as more indolent forms of grade II gliomas and are treated in the same way. Brainstem gliomas usually occur in children or young adults. Despite treatment with RT and chemotherapy, the prognosis is poor, with a median survival of only 1 year. Gliosarcomas contain both an astrocytic as well as a sarcomatous component and are treated in the same way as glioblastomas.
PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Primary central nervous system lymphoma (PCNSL) is a rare non-Hodgkin lymphoma accounting for less than 3% of primary brain tumors. For unclear reasons, its incidence is increasing, particularly in immunocompetent individuals.
PCNSL in immunocompetent patients usually consists of a diffuse large B cell lymphoma. PCNSL may also occur in immunocompromised patients, usually those infected with the human immunodeficiency virus (HIV) or organ transplant recipients on immunosuppressive therapy. PCNSL in immunocompromised patients is typically large cell with immunoblastic and more aggressive features. These patients are usually severely immunocompromised, with CD4 counts of less than 50/mL. The Epstein-Barr virus (EBV) frequently plays an important role in the pathogenesis of HIV-related PCNSL.
Immunocompetent patients with PCNSL are older (median 60 years) compared to patients with HIV-related PCNSL (median 31 years). PCNSL usually presents as a mass lesion, with neuropsychiatric symptoms, symptoms of increased intracranial pressure, lateralizing signs, or seizures.
On contrast-enhanced MRI, PCNSL usually appears as a densely enhancing tumor (Fig. 48-4). Immunocompetent patients have solitary lesions more often than immunosuppressed patients. Frequently there is involvement of the basal ganglia, corpus callosum, or periventricular region. Although the imaging features are often characteristic, PCNSL can sometimes be difficult to differentiate from high-grade gliomas, infections, or demyelination. Stereotactic biopsy is necessary to obtain a histologic diagnosis. Whenever possible, glucocorticoids should be withheld until after the biopsy has been obtained because they have a cytolytic effect on lymphoma cells and may lead to nondiagnostic tissue. In addition, patients should be tested for HIV and the extent of disease should be assessed by performing PET or CT of the body, MRI of the spine, CSF analysis, and slit-lamp examination of the eye. Bone marrow biopsy and testicular ultrasound are occasionally performed.
Postgadolinium T1 MRI demonstrating a large bifrontal primary central nervous system lymphoma (PCNSL). The periventricular location and diffuse enhancement pattern are characteristic of lymphoma.
TREATMENT Primary Central Nervous System Lymphoma
PCNSL is more sensitive to glucocorticoids, chemotherapy, and RT than other primary brain tumors. Durable complete responses and long-term survival are possible with these treatments. High-dose methotrexate, a folate antagonist that interrupts DNA synthesis, produces response rates ranging from 35–80% and median survival of up to 50 months. The combination of methotrexate with other chemotherapeutic agents such as cytarabine increases the response rate to 70–100%. The addition of whole-brain RT to methotrexate-based chemotherapy prolongs progression-free survival but not overall survival. Furthermore, RT is associated with delayed neurotoxicity, especially in patients over the age of 60 years. As a result, full-dose RT is frequently omitted, but there may be a role for reduced-dose RT. The anti-CD20 monoclonal antibody rituximab has activity in PCNSL and is often incorporated into the chemotherapy regimen. For some patients, high-dose chemotherapy with autologous stem cell rescue may offer the best chance of preventing relapse. At least 50% of patients will eventually develop recurrent disease. Treatment options include RT for patients who have not had prior irradiation, re-treatment with methotrexate, as well as other agents such as temozolomide, rituximab, procarbazine, topotecan, and pemetrexed. High-dose chemotherapy with autologous stem cell rescue may have a role in selected patients with relapsed disease. PCNSL IN IMMUNOCOMPROMISED PATIENTS
PCNSL in immunocompromised patients often produces multiple ring-enhancing lesions that can be difficult to differentiate from metastases and infections such as toxoplasmosis. The diagnosis is usually established by examination of the CSF for cytology and EBV DNA, toxoplasmosis serologic testing, brain PET imaging for hypermetabolism of the lesions consistent with tumor instead of infection, and, if necessary, brain biopsy. Since the advent of highly active antiretroviral drugs, the incidence of HIV-related PCNSL has declined. These patients may be treated with whole-brain RT, high-dose methotrexate, and initiation of highly active antiretroviral therapy. In organ transplant recipients, reduction of immunosuppression may improve outcome.
Medulloblastomas are the most common malignant brain tumor of childhood, accounting for approximately 20% of all primary CNS tumors among children. They arise from granule cell progenitors or from multipotent progenitors from the ventricular zone. Approximately 5% of children have inherited disorders with germline mutations of genes that predispose to the development of medulloblastoma. Gorlin syndrome, the most common of these inherited disorders, is due to mutations in the patched-1 (PTCH-1) gene, a key component in the sonic hedgehog pathway. Turcot syndrome, caused by mutations in the adenomatous polyposis coli (APC) gene and familial adenomatous polyposis, has also been associated with an increased incidence of medulloblastoma. Histologically, medulloblastomas are highly cellular tumors with abundant dark staining, round nuclei, and rosette formation (Homer-Wright rosettes). They present with headache, ataxia, and signs of brainstem involvement. On MRI they appear as densely enhancing tumors in the posterior fossa, sometimes associated with hydrocephalus. Seeding of the CSF is common. Treatment involves maximal surgical resection, craniospinal irradiation, and chemotherapy with agents such as cisplatin, lomustine, cyclophosphamide, and vincristine. Approximately 70% of patients have long-term survival but usually at the cost of significant neurocognitive impairment. A major goal of current research is to improve survival while minimizing long-term complications.
A large number of tumors can arise in the region of the pineal gland. These typically present with headache, visual symptoms, and hydrocephalus. Patients may have Parinaud syndrome characterized by impaired upgaze and accommodation. Some pineal tumors such as pineocytomas and benign teratomas can be treated simply by surgical resection. Germinomas respond to irradiation, whereas pineoblastomas and malignant germ cell tumors require craniospinal radiation and chemotherapy.