Lisa M. DeAngelis Patrick Y. Wen
Primary brain tumors are diagnosed in approximately 52,000 people each year in the United States. At least one-half of these tumors are malignant and associated with a high mortality rate. Glial tumors account for about 60% of all primary brain tumors, and 80% of those are malignant neoplasms. Meningiomas account for 25%, vestibular schwannomas 10%, and central nervous system (CNS) lymphomas about 2%. Brain metastases are three times more common than all primary brain tumors combined and are diagnosed in approximately 150,000 people each year. Metastases to the leptomeninges and epidural space of the spinal cord each occur in approximately 3–5% of patients with systemic cancer and are also a major cause of neurologic disability in this population.
APPROACH TO THE
PATIENT Primary and Metastatic Tumors of the Nervous System
CLINICAL FEATURES Brain tumors of any type can present with a variety of symptoms and signs that fall into two categories: general and focal; patients often have a combination of the two (Table 37-1). General or nonspecific symptoms include headache, cognitive difficulties, personality change, and gait disorder. Generalized symptoms arise when the enlarging tumor and its surrounding edema cause an increase in intracranial pressure or direct compression of cerebrospinal fluid (CSF) circulation leading to hydrocephalus. The classic headache associated with a brain tumor is most evident in the morning and improves during the day, but this particular pattern is actually seen in a minority of patients. Headache may be accompanied by nausea or vomiting when intracranial pressure is elevated. Headaches are often holocephalic but can be ipsilateral to the side of a tumor. Occasionally, headaches have features of a typical migraine with unilateral throbbing pain associated with visual scotoma. Personality changes may include apathy and withdrawal from social circumstances, mimicking depression. Focal or lateralizing findings include hemiparesis, aphasia, or visual field defect. Lateralizing symptoms such as hemiparesis are typically subacute and progressive. A visual field defect is often not noticed by the patient; its presence may only be revealed after it leads to an injury such as an automobile accident occurring in the blind visual field. Language difficulties may be mistaken for confusion. Seizures are a common presentation of brain tumors, occurring in about 25% of patients with brain metastases or malignant gliomas but can be the presenting symptom in up to 90% of patients with lowgrade gliomas. Most seizures have a focal signature that reflects their location in the brain and many proceed to secondary generalization. All generalized seizures that arise from a brain tumor will have a focal onset whether or not it is apparent clinically.
SYMPTOMS AND SIGNS AT PRESENTATION OF BRAIN TUMORS
NEUROIMAGING Cranial MRI is the preferred diagnostic test for any patient suspected of having a brain tumor, and should be performed with gadolinium contrast administration. CT scan should be reserved for those patients unable to undergo MRI (e.g., pacemaker). Malignant brain tumors—whether primary or metastatic—typically enhance with gadolinium and may have central areas of necrosis; they are characteristically surrounded by edema of the neighboring white matter. Low-grade gliomas typically do not enhance with gadolinium and are best appreciated on fluid-attenuated inversion recovery (FLAIR) MR images. Meningiomas have a characteristic appearance on MRI as they are dural-based with a dural tail and compress but do not invade the brain. Dural metastases or a dural lymphoma can have a similar appearance. Imaging is characteristic for many primary and metastatic tumors, but occasionally there is diagnostic uncertainty based on imaging alone. In such patients a brain biopsy may be helpful in determining a definitive diagnosis. However, when a tumor is strongly suspected, the biopsy can be obtained as an intraoperative frozen section before a definitive resection is performed.
Functional MRI is useful in presurgical planning and defining eloquent sensory, motor, and language cortex. Positron emission tomography (PET) is useful in determining the metabolic activity of the lesions seen on MRI; MR perfusion and spectroscopy can provide information on blood flow or tissue composition. These techniques may help distinguish tumor progression from necrotic tissue as a consequence of treatment with radiation and chemotherapy or identify foci of high-grade tumor in an otherwise low-grade-appearing glioma.
Neuroimaging is the only test necessary to diagnose a brain tumor. Laboratory tests are rarely useful, although patients with metastatic disease may have elevation of a tumor marker in their serum that reflects the presence of brain metastases (e.g., human chorionic gonadotropin [βhCG] from testicular cancer). Additional testing such as cerebral angiogram, electroencephalogram (EEG), or lumbar puncture is rarely indicated or helpful.
TREATMENT Brain Tumors
Therapy of any intracranial malignancy requires both symptomatic and definitive treatments. Definitive treatment is based upon the specific tumor type and includes surgery, radiotherapy (RT), and chemotherapy. However, symptomatic treatments apply to brain tumors of any type. Most high-grade malignancies are accompanied by substantial surrounding edema, which contributes to neurologic disability and raised intracranial pressure. Glucocorticoids are highly effective at reducing perilesional edema and improving neurologic function, often within hours of administration. Dexamethasone has been the glucocorticoid of choice because of its relatively low mineralocorticoid activity. Initial doses are typically 12 mg to 16 mg a day in divided doses given orally or IV (both are equivalent). While glucocorticoids rapidly ameliorate symptoms and signs, their long-term use causes substantial toxicity including insomnia, weight gain, diabetes mellitus, steroid myopathy, and personality changes. Consequently, a taper is indicated as definitive treatment is administered and the patient improves.
Patients with brain tumors who present with seizures, require anticonvulsant drug therapy. There is no role for prophylactic anticonvulsant drugs in patients who have not had a seizure, thus their use should be restricted to those who have had a convincing ictal event. The agents of choice are those drugs that do not induce the hepatic microsomal enzyme system. These include levetiracetam, topiramate, lamotrigine, valproic acid, or lacos-amide (Chap. 26). Other drugs such as phenytoin and carbamazepine are used less frequently because they are potent enzyme inducers that can interfere with both glucocorticoid metabolism and the metabolism of chemotherapeutic agents needed to treat the underlying systemic malignancy or the primary brain tumor.
Venous thromboembolic disease occurs in 20–30% of patients with high-grade gliomas and brain metastases. Therefore, anticoagulants should be used prophylactically during hospitalization and in patients who are nonambulatory. Those who have had either a deep vein thrombosis or pulmonary embolus can receive therapeutic doses of anticoagulation safely and without increasing the risk for hemorrhage into the tumor. Inferior vena cava filters are reserved for patients with absolute contraindications to anticoagulation such as recent craniotomy.
PRIMARY BRAIN TUMORS
No underlying cause has been identified for the majority of primary brain tumors. The only established risk factors are exposure to ionizing radiation (meningiomas, gliomas, and schwannomas) and immunosuppression (primary CNS lymphoma). Evidence for an association with exposure to electromagnetic fields including cellular telephones, head injury, foods containing N-nitroso compounds, or occupational risk factors, are unproven. A small minority of patients have a family history of brain tumors. Some of these familial cases are associated with genetic syndromes (Table 37-2).
GENETIC SYNDROMES ASSOCIATED WITH PRIMARY BRAIN TUMORS
As with other neoplasms, brain tumors arise as a result of a multistep process driven by the sequential acquisition of genetic alterations. These include loss of tumor suppressor genes (e.g., p53 and phosphatase and tensin homolog on chromosome 10 [PTEN]) and amplification and overexpression of protooncogenes such as the epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptors (PDGFR). The accumulation of these genetic abnormalities results in uncontrolled cell growth and tumor formation.
Important progress has been made in understanding the molecular pathogenesis of several types of brain tumors, including glioblastomas and medulloblastomas. Glioblastomas can be separated into two main subtypes based on genetic and biologic differences (Fig. 37-1). The majority are primary glioblastomas. These arise de novo and are characterized by EGFR amplification and mutations, and deletion or mutation of PTEN. Secondary glioblastomas arise in younger patients as lower-grade tumors and transform over a period of several years into glioblastomas. These tumors have inactivation of the p53 tumor suppressor gene, overexpression of PDGFR, and mutations of the isocitrate dehydrogenase 1 and 2 genes. Despite their genetic differences, primary and secondary glioblastomas are morphologically indistinguishable, although they are likely to respond differently to molecular therapies. The molecular subtypes of medulloblastomas are also being elucidated. Approximately 25% of medulloblastomas have activating mutations of the sonic hedgehog signaling pathway, raising the possibility that inhibitors of this pathway may have therapeutic potential.
Genetic and chromosomal alterations involved in the development of primary and secondary glioblastomas. A slash indicates one or the other or both. DCC, deleted in colorectal carcinoma; EGFR, epidermal growth factor receptor; IDH, isocitrate dehydrogenase; LOH, loss of heterozygosity; MDM2, murine double minute 2; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; PIK3CA, phosphatidylinositol 3-kinase, catalytic; PTEN, phosphatase and tensin homologue; RB, retinoblastoma; WHO, World Health Organization.
The adult nervous system contains neural stem cells that are capable of self-renewal, proliferation, and differentiation into distinctive mature cell types. There is increasing evidence that neural stem cells, or related progenitor cells, can be transformed into tumor stem cells and give rise to primary brain tumors, including gliomas and medulloblastomas. These stem cells appear to be more resistant to standard therapies than the tumor cells themselves and contribute to the difficulty in eradicating these tumors. There is intense interest in developing therapeutic strategies that effectively target tumor stem cells.
INTRINSIC “MALIGNANT” TUMORS
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, and grades III and IV high-grade, astrocytomas.
These tumors occur predominantly in children and young adults.
Grade I astrocytomas
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. They are potentially curable if they can be completely resected. 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).
Grade II astrocytomas
These are infiltrative tumors that usually present with seizures in young adults. They appear as nonenhancing tumors with increased T2/FLAIR signal (Fig. 37-2). If feasible, patients should undergo maximal surgical resection, although complete resection is rarely possible because of the invasive nature of the tumor. Radiotherapy is helpful, but there is no difference in overall survival between radiotherapy 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.
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 highgrade 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 radiotherapy with concurrent and adjuvant temozolomide, or with radiotherapy and adjuvant temozolomide alone.
Grade IV astrocytoma (glioblastoma)
Glioblastoma accounts for the majority of high-grade astrocytomas. They are the most common cause of malignant primary brain tumors, 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. 37-3). 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 radiotherapy (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 radiotherapy alone, and 2-year survival is increased to 27%, compared to 10% with radiotherapy 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. 37-4). 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 with 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 involving more than two lobes. These tumors do not qualify for the histologic diagnosis of glioblastoma but behave aggressively and have a similarly poor outcome. Treatment involves radiotherapy 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 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, radiotherapy and chemotherapy. Patients with oligodendrogliomas have a median survival in excess of 10 years.
Anaplastic oligodendrogliomas 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 to 89% of patients with AO and 14 to 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 radiotherapy. Median survival of patients with AO or AOA is approximately 3–6 years.
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 ependymomas are more aggressive but can be treated in the same way as ependymomas. 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 radiotherapy and chemotherapy, the prognosis is poor with 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’s 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 diffuse large B-cell lymphomas. 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 are older (median 60 years) compared to 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. 37-5). Immuno-competent 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, since 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 assessed by performing positron emission tomography (PET) or computerized tomography (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
Unlike other primary brain tumors, PCNSL is relatively sensitive to glucocorticoids, chemotherapy, and radiotherapy. 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 to 80% and median survival up to 50 months. Combination of methotrexate with other chemotherapeutic agents such as cytarabine, as well as whole-brain radiotherapy, increases the response rate to 70–100%. However, radiotherapy is associated with delayed neurotoxicity, especially in patients over the age of 60 years. As a result radiotherapy is frequently omitted in older patients with PCNSL. There is emerging evidence that the anti-CD20 monoclonal antibody rituximab may have activity in PCNSL, although there remain concerns about its ability to pass through the blood-brain barrier as it becomes reconstituted with therapy. For some patients, highdose 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 radiotherapy 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 cerebrospinal fluid 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 radiotherapy, 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. The 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’s 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 appear as 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.
PINEAL REGION TUMORS
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’s 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, while pineoblastomas and malignant germ cell tumors require craniospinal radiation and chemotherapy.
EXTRINSIC “BENIGN” TUMORS
Meningiomas are diagnosed with increasing frequency as more people undergo neuroimaging studies for various indications. They are now the most common primary brain tumor, accounting for approximately 32% of the total. Their incidence increases with age. They tend to be more common in women and in patients with neurofibromatosis type 2. They also occur more commonly in patients with a past history of cranial irradiation.
Meningiomas arise from the dura mater and are composed of neoplastic meningothelial (arachnoidal cap) cells. They are most commonly located over the cerebral convexities, especially adjacent to the sagittal sinus, but can also occur in the skull base and along the dorsum of the spinal cord. Meningiomas are classified by the WHO into three histologic grades of increasing aggressiveness: grade I (benign meningiomas), grade II (atypical meningiomas), and grade III (malignant meningiomas).
Many meningiomas are found incidentally following neuroimaging for unrelated reasons. They can also present with headaches, seizures, or focal neurologic deficits. On imaging studies they have a characteristic appearance usually consisting of a partially calcified, densely enhancing extraaxial tumor arising from the dura (Fig. 37-6). Occasionally they may have a dural tail, consisting of thickened, enhanced dura extending like a tail from the mass. The main differential diagnosis of meningioma is a dural metastasis.
Postgadolinium T1 MRI demonstrating multiple meningiomas along the falx and left parietal cortex.
If the meningioma is small and asymptomatic, no intervention is necessary and the lesion can be observed with serial MRI studies. Larger, symptomatic lesions should be resected surgically. If complete resection is achieved, the patient is cured. Incompletely resected tumors tend to recur, although the rate of recurrence can be very slow with grade I tumors. Tumors that cannot be resected, or can only be partially removed, may benefit from treatment with external beam radiotherapy or stereotactic radiosurgery (SRS). These treatments may also be helpful in patients whose tumor has recurred after surgery. Hormonal therapy and chemotherapy are currently unproven.
Rarer tumors that resemble meningiomas include hemangiopericytomas and solitary fibrous tumors. These are treated with surgery and radiotherapy but have a higher propensity to recur.
These are generally benign tumors arising from the Schwann cells of cranial and spinal nerve roots. The most common schwannomas, termed vestibular schwannomas or acoustic neuromas, arise from the vestibular portion of the eighth cranial nerve and account for approximately 9% of primary brain tumors. Patients with neurofibromatosis type 2 have a high incidence of vestibular schwannomas that are frequently bilateral. Schwannomas arising from other cranial nerves, such as the trigeminal nerve (cranial nerve V), occur with much lower frequency. Neurofibromatosis type 1 is associated with an increased incidence of schwannomas of the spinal nerve roots.
Vestibular schwannomas may be found incidentally on neuroimaging or present with progressive unilateral hearing loss, dizziness, tinnitus, or less commonly, symptoms resulting from compression of the brainstem and cerebellum. On MRI they appear as densely enhancing lesions, enlarging the internal auditory canal and often extending into the cerebellopontine angle (Fig. 37-7). The differential diagnosis includes meningioma. Very small, asymptomatic lesions can be observed with serial MRIs. Larger lesions should be treated with surgery or stereotactic radiosurgery. The optimal treatment will depend on the size of the tumor, symptoms, and the patient’s preference. In patients with small vestibular schwannomas and relatively intact hearing, early surgical intervention increases the chance of preserving hearing.
Postgadolinium MRI of a right vestibular schwannoma. The tumor can be seen to involve the internal auditory canal.
PITUITARY TUMORS (CHAP. 38)
These account for approximately 9% of primary brain tumors. They can be divided into functioning and nonfunctioning tumors. Functioning tumors are usually microadenomas (<1 cm in diameter) that secrete hormones and produce specific endocrine syndromes (e.g., acromegaly for growth hormone–secreting tumors, Cushing’s syndrome for adrenocorticotropic hormone [ACTH]-secreting tumors, and galactorrhea, amenorrhea, and infertility for prolactin-secreting tumors]). Nonfunctioning pituitary tumors tend to be macroadenomas (>1 cm) that produce symptoms by mass effect, giving rise to headaches, visual impairment (such as bitemporal hemianopia), and hypopituitarism. Prolactin-secreting tumors respond well to dopamine agonists such as bromocriptine and cabergoline. Other pituitary tumors usually require treatment with surgery and sometimes radiotherapy or radiosurgery and hormonal therapy.
Craniopharyngiomas are rare, usually suprasellar, partially calcified, solid, or mixed solid-cystic benign tumors that arise from remnants of Rathke’s pouch. They have a bimodal distribution, occurring predominantly in children but also between the ages of 55 and 65 years. They present with headaches, visual impairment, and impaired growth in children and hypopituitarism in adults. Treatment involves surgery, radiotherapy, or the combination of the two.
OTHER BENIGN TUMORS
Dysembryoplastic neuroepithelial tumors (DNTs)
These are benign, supratentorial tumors, usually in the temporal lobes. They typically occur in children and young adults with a long-standing history of seizures. If the seizures are refractory, surgical resection is curative.
These consist of squamous epithelium surrounding a keratin-filled cyst. They are usually found in the cerebellopontine angle and the intrasellar and suprasellar regions. They may present with headaches, cranial nerve abnormalities, seizures, or hydrocephalus. Imaging studies demonstrate extraaxial lesions with characteristics that are similar to CSF but have restricted diffusion. Treatment involves surgical resection.
Like epidermoid cysts, dermoid cysts arise from epithelial cells that are retained during closure of the neural tube. They contain both epidermal and dermal structures such as hair follicles, sweat glands, and sebaceous glands. Unlike epidermoid cysts, these tumors usually have a midline location. They occur most frequently in the posterior fossa, especially the vermis, fourth ventricle, and suprasellar cistern. Radiographically, dermoid cysts resemble lipomas, demonstrating T1 hyperintensity and variable signal on T2. Symptomatic dermoid cysts can be treated with surgery.
These usually arise in the anterior third ventricle and may present with headaches, hydrocephalus, and very rarely sudden death. Surgical resection is curative or a third ventriculostomy may relieve the obstructive hydrocephalus and be sufficient therapy.
NEUROCUTANEOUS SYNDROMES (PHAKOMATOSES)
A number of genetic disorders are characterized by cutaneous lesions and an increased risk of brain tumors. Most of these disorders have an autosomal dominance inheritance with variable penetrance.
NEUROFIBROMATOSIS TYPE 1 (NF1) (VON RECKLINGHAUSEN’S DISEASE)
NF1 is an autosomal dominant disorder with an incidence of approximately 1 in 2600–3000. Approximately half the cases are familial; the remainder are new mutations arising in patients with unaffected parents. The NF1 gene on chromosome 17q11.2 encodes a protein, neurofibromin, a guanosine triphosphatase (GTPase)-activating protein (GAP) that modulates signaling through the ras pathway. Mutations of the NF1 gene result in a large number of nervous system tumors including neurofibromas, plexiform neurofibromas, optic nerve gliomas, astrocytomas, and meningiomas. In addition to neurofibromas, which appear as multiple, soft, rubbery cutaneous tumors, other cutaneous manifestations of NF1 include café au lait spots and axillary freckling. NF1 is also associated with hamartomas of the iris termed Lisch nodules, pheochromocytomas, pseudoarthrosis of the tibia, scoliosis, epilepsy, and mental retardation.
NEUROFIBROMATOSIS TYPE 2 (NF2)
NF2 is less common than NF1, with an incidence of 1 in 25,000–40,000. It is an autosomal dominant disorder with full penetrance. As with NF1, approximately half the cases arise from new mutations. The NF2 gene on 22q encodes a cytoskeletal protein “merlin” (moesin, ezrin, radixin-like protein) that functions as a tumor suppressor. NF2 is characterized by bilateral vestibular schwannomas in over 90% of patients, multiple meningiomas, and spinal ependymomas and astrocytomas. Treatment of bilateral vestibular schwannomas can be challenging because the goal is to preserve hearing for as long as possible. These patients may also have posterior subcapsular lens opacities and retinal hamartomas.
TUBEROUS SCLEROSIS (BOURNEVILLE’S DISEASE)
This is an autosomal dominant disorder with an incidence of approximately 1 in 5000 to 10,000 live births. It is caused by mutations in either the TSC1 gene, which maps to chromosome 9q34, and encodes a protein termed hamartin, or mutations in the TSC2 gene, which maps to chromosome 16p13.3 and encodes the tuberin protein. Hamartin forms a complex with tuberin, which inhibits cellular signaling through the mammalian target of rapamycin (mTOR), and acts as a negative regulator of the cell cycle. Patients with tuberous sclerosis have seizures, mental retardation, adenoma sebaceum (facial angiofibromas), shagreen patch, hypomelanotic macules, periungual fibromas, renal angiomyolipomas, and cardiac rhabdomyomas. These patients have an increased incidence of subependymal nodules, cortical tubers, and subependymal giant cell astrocytomas (SEGA). Patients frequently require anticonvulsants for seizures. SEGAs often do not need treatment but occasionally require surgical resection. There is emerging evidence that mTOR inhibitors may have activity in SEGAs.
TUMORS METASTATIC TO THE BRAIN
Brain metastases arise from hematogenous spread and frequently arise from either a lung primary or are associated with pulmonary metastases. Most metastases develop at the gray matter–white matter junction in the watershed distribution of the brain where intravascular tumor cells lodge in terminal arterioles. The distribution of metastases in the brain approximates the proportion of blood flow such that about 85% of all metastases are supratentorial and 15% occur in the posterior fossa. The most common sources of brain metastases are lung and breast carcinomas; melanoma has the greatest propensity to metastasize to the brain, being found in 80% of patients at autopsy (Table 37-3). Other tumor types such as ovarian and esophageal carcinoma rarely metastasize to the brain. Prostate and breast cancer also have a propensity to metastasize to the dura and can mimic meningioma. Leptomeningeal metastases are common from hematologic malignancies and also breast and lung cancers. Spinal cord compression primarily arises in patients with prostate and breast cancer, tumors with a strong propensity to metastasize to the axial skeleton.
FREQUENCY OF NERVOUS SYSTEM METASTASES BY COMMON PRIMARY TUMORS
DIAGNOSIS OF METASTASES
Brain metastases are best visualized on MRI, where they usually appear as well-circumscribed lesions (Fig. 37-8). The amount of perilesional edema can be highly variable with large lesions causing minimal edema and sometimes very small lesions causing extensive edema. Enhancement may be in a ring pattern or diffuse. Occasionally, intracranial metastases will hemorrhage; although melanoma, thyroid, and kidney cancer have the greatest propensity to hemorrhage, the most common cause of a hemorrhagic metastasis is lung cancer because it accounts for the majority of brain metastases. The radiographic appearance of brain metastasis is nonspecific, and similar appearing lesions can occur with infection including brain abscesses and also with demyelinating lesions, sarcoidosis, radiation necrosis in a previously treated patient, or a primary brain tumor that may be a second malignancy in a patient with systemic cancer. However, biopsy is rarely necessary for diagnosis in most patients because imaging alone in the appropriate clinical situation usually suffices. This is straightforward for the majority of patients with brain metastases because they have a known systemic cancer. However, in approximately 10% of patients a systemic cancer may present with a brain metastasis, and if there is not an easily accessible systemic site to biopsy, then a brain lesion must be removed for diagnostic purposes.
Postgadolinium T1 MRI of multiple brain metastases from non-small cell lung cancer involving the right frontal (A) and right cerebellar (B) hemispheres. Note the diffuse enhancement pattern and absence of central necrosis.
TREATMENT Tumors Metastatic to the Brain
DEFINITIVE TREATMENT The number and location of brain metastases often determine the therapeutic options. The patient’s overall condition and the current or potential control of the systemic disease are also major determinants. Brain metastases are single in approximately one-half of patients and multiple in the other half.
RADIATION THERAPY The standard treatment for brain metastases has been whole-brain radiotherapy (WBRT) usually administered to a total dose of 3000 cGy in 10 fractions. This affords rapid palliation, and approximately 80% of patients improve with glucocorticoids and radiation therapy. However, it is not curative. Median survival is only 4–6 months. More recently, stereotactic radiosurgery (SRS) delivered through a variety of techniques including the gamma knife, linear accelerator, proton beam, and CyberKnife all can deliver highly focused doses of RT, usually in a single fraction. SRS can effectively sterilize the visible lesions and afford local disease control in 80–90% of patients. In addition, there are some patients who have clearly been cured of their brain metastases using SRS, whereas this is distinctly rare with WBRT. However, SRS can be used only for lesions 3 cm or less in diameter and should be confined to patients with only 1–3 metastases. The addition of WBRT to SRS improves disease control in the nervous system but does not prolong survival.
SURGERY Randomized controlled trials have demonstrated that surgical extirpation of a single brain metastasis followed by WBRT is superior to WBRT alone. Removal of two lesions or a single symptomatic mass, particularly if compressing the ventricular system, can also be useful. This is particularly useful in patients who have highly radioresistant lesions such as renal carcinoma. Surgical resection can afford rapid symptomatic improvement and prolonged survival. RT administered after complete resection of a brain metastasis improves disease control but does not prolong survival.
CHEMOTHERAPY Chemotherapy is rarely useful for brain metastases. Metastases from certain tumor types that are highly chemosensitive, such as germ cell tumors or small cell lung cancer, may respond to chemotherapeutic regimens chosen according to the underlying malignancy. Increasingly, there are data demonstrating responsiveness of brain metastases to chemotherapy including small molecule–targeted therapy when the lesion possesses the target. This has been best illustrated in patients with lung cancer harboring EGFR mutations that sensitize them to EGFR inhibitors. Antiangiogenic agents such as bevacizumab may also prove efficacious in the treatment of CNS metastases.
Leptomeningeal metastases are also identified as carcinomatous meningitis, meningeal carcinomatosis, or in the case of specific tumors, leukemic or lymphomatous meningitis. Among the hematologic malignancies, acute leukemia is the most common to metastasize to the subarachnoid space, and in lymphomas the aggressive diffuse lymphomas can metastasize to the subarachnoid space frequently as well. Among solid tumors, breast and lung carcinomas and melanoma most frequently spread in this fashion. Tumor cells reach the subarachnoid space via the arterial circulation or occasionally through retrograde flow in venous systems that drain metastases along the bony spine or cranium. In addition, leptomeningeal metastases may develop as a direct consequence of prior brain metastases and can develop in almost 40% of patients who have a metastasis resected from the cerebellum.
Leptomeningeal metastases are characterized clinically by multilevel symptoms and signs along the neuraxis. Combinations of lumbar and cervical radiculopathies, cranial neuropathies, seizures, confusion, and encephalopathy from hydrocephalus or raised intracranial pressure can be present. Focal deficits such as hemiparesis or aphasia are rarely due to leptomeningeal metastases unless there is direct brain infiltration and are more often associated with coexisting brain lesions. New onset limb pain in patients with breast, lung cancer, or melanoma should prompt consideration of leptomeningeal spread.
LABORATORY AND IMAGING DIAGNOSIS
Leptomeningeal metastases are particularly challenging to diagnose as identification of tumor cells in the subarachnoid compartment may be elusive. MR imaging can be definitive in patients when there are clear tumor nodules adherent to the cauda equina or spinal cord, enhancing cranial nerves, or subarachnoid enhancement on brain imaging (Fig. 37-9). Imaging is diagnostic in approximately 75% of patients and is more often positive in patients with solid tumors. Demonstration of tumor cells in the CSF is definitive and often considered the gold standard. However, CSF cytologic examination is positive in only 50% of patients on the first lumbar puncture and still misses 10% after three CSF samples. CSF cytologic examination is most useful in hematologic malignancies. Accompanying CSF abnormalities include an elevated protein concentration and an elevated white count. Hypoglycorrhachia is noted in less than 25% of patients but is useful when present. Identification of tumor markers or molecular confirmation of clonal proliferation with techniques such as flow cytometry within the CSF can also be definitive when present. Tumor markers are usually specific to solid tumors, and chromosomal or molecular markers are most useful in patients with hematologic malignancies.
Postgadolinium MRI images of extensive leptomeningeal metastases from breast cancer. Nodules along the dorsal surface of the spinal cord (A) and cauda equina (B) are seen.
TREATMENT Leptomeningeal Metastases
The treatment of leptomeningeal metastasis is palliative as there is no curative therapy. RT to the symptomatically involved areas, such as skull base for cranial neuropathy, can relieve pain and sometimes improve function. Whole neuraxis RT has extensive toxicity with myelosuppression and gastrointestinal irritation as well as limited effectiveness. Systemic chemotherapy with agents that can penetrate the blood-CSF barrier may be helpful. Alternatively, intrathecal chemotherapy can be effective, particularly in hematologic malignancies. This is optimally delivered through an intraventricular cannula (Ommaya reservoir) rather than by lumbar puncture. Few drugs can be delivered safely into the subarachnoid space and they have a limited spectrum of antitumor activity, perhaps accounting for the relatively poor response to this approach. In addition, impaired CSF flow dynamics can compromise intrathecal drug delivery. Surgery has a limited role in the treatment of leptomeningeal metastasis, but placement of a ventriculoperitoneal shunt can relieve raised intracranial pressure. However, it compromises delivery of chemotherapy into the CSF.
Epidural metastasis occurs in 3–5% of patients with a systemic malignancy and causes neurologic compromise by compressing the spinal cord or cauda equina. The most common cancers that metastasize to the epidural space are those malignancies that spread to bone, such as breast and prostate. Lymphoma can cause bone involvement and compression but it can also invade the intervertebral foramens and cause spinal cord compression without bone destruction. The thoracic spine is affected most commonly, followed by the lumbar and then cervical spine.
Back pain is the presenting symptom of epidural metastasis in virtually all patients; the pain may precede neurologic findings by weeks or months. The pain is usually exacerbated by lying down; by contrast, arthritic pain is often relieved by recumbency. Leg weakness is seen in about 50% of patients as is sensory dysfunction. Sphincter problems are present in about 25% of patients at diagnosis.
Diagnosis is established by imaging, with MRI of the complete spine being the best test (Fig. 37-10). Contrast is not needed to identify spinal or epidural lesions. Any patient with cancer who has severe back pain should undergo an MRI. Plain films, bone scans, or even CT scans may show bone metastases, but only MRI can reliably delineate epidural tumor. For patients unable to have an MRI, CT myelography should be performed to outline the epidural space. The differential diagnosis of epidural tumor includes epidural abscess, acute or chronic hematomas, and rarely, extramedullary hematopoiesis.
Postgadolinium T1 MRI showing circumferential epidural tumor around the thoracic spinal cord from esophageal cancer.
TREATMENT Epidural Metastasis
Epidural metastasis requires immediate treatment. A randomized controlled trial demonstrated the superiority of surgical resection followed by RT compared to RT alone. However, patients must be able to tolerate surgery, and the surgical procedure of choice is a complete removal of the mass, which is typically anterior to the spinal canal, necessitating an extensive approach and resection. Otherwise, RT is the mainstay of treatment and can be used for patients with radiosensitive tumors, such as lymphoma, or for those unable to undergo surgery. Chemotherapy is rarely used for epidural metastasis unless the patient has minimal to no neurologic deficit and a highly chemosensitive tumor such as lymphoma or germinoma. Patients generally fare well if treated before there is severe neurologic deficit. Recovery after paraparesis is better after surgery than with RT alone, but survival is often short due to widespread metastatic tumor.
NEUROLOGIC TOXICITY OF THERAPY
TOXICITY FROM RADIOTHERAPY
Radiotherapy can cause a variety of toxicities in the CNS. These are usually described based on their relationship in time to the administration of RT, e.g., they can be acute (occurring within days of RT), early delayed (months), or late delayed (years). In general, the acute and early delayed syndromes resolve and do not result in persistent deficits, whereas the late delayed toxicities are usually permanent and sometimes progressive.
Acute cerebral toxicity usually occurs during RT to the brain. RT can cause a transient disruption of the blood-brain barrier, resulting in increased edema and elevated intracranial pressure. This is usually manifest as headache, lethargy, nausea and vomiting, and can be both prevented and treated with the administration of glucocorticoids. There is no acute RT toxicity that affects the spinal cord.
Early delayed toxicity
Early delayed toxicity is usually apparent weeks to months after completion of cranial irradiation and is likely due to focal demyelination. Clinically it may be asymptomatic or take the form of worsening or reappearance of a preexisting neurologic deficit. At times a contrast-enhancing lesion can be seen on MRI/CT that can mimic the tumor for which the patient received the RT. For patients with a malignant glioma, this has been described as “pseudoprogression” because it mimics tumor recurrence on MRI but actually represents inflammation and necrotic debris engendered by effective therapy. This is seen with increased frequency when chemotherapy, particularly temozolomide, is given concurrently with RT. Pseudoprogression can resolve on its own or, if very symptomatic, may require resection. A rare form of early delayed toxicity is the somnolence syndrome that occurs primarily in children and is characterized by marked sleepiness.
In the spinal cord, early delayed RT toxicity is manifest as a Lhermitte symptom with paresthesias of the limbs or along the spine when the patient flexes the neck. Although frightening, it is benign, resolves on its own, and does not portend more serious problems.
Late delayed toxicity
Late delayed toxicities are the most serious as they are often irreversible and cause severe neurologic deficits. In the brain, late toxicities can take several forms, the most common of which include radiation necrosis and leukoencephalopathy. Radiation necrosis is a focal mass of necrotic tissue that is contrast enhancing on CT/MRI and may be associated with significant edema. This may appear identical to pseudoprogression but is seen months to years after RT and is always symptomatic. Clinical symptoms and signs include seizure and lateralizing findings referable to the location of the necrotic mass. The necrosis is caused by the effect of RT on cerebral vasculature with resultant fibrinoid necrosis and occlusion of the blood vessels. It can mimic tumor radiographically, but unlike tumor it is typically hypometabolic on a PET scan and has reduced perfusion on perfusion MR sequences. It may require resection for diagnosis and treatment unless it can be managed with glucocorticoids. There are rare reports of improvement with hyperbaric oxygen or anticoagulation but the usefulness of these approaches is questionable.
Leukoencephalopathy is seen most commonly after WBRT as opposed to focal RT. On T2 or FLAIR MR sequences there is diffuse increased signal seen throughout the hemispheric white matter, often bilaterally and symmetrically. There tends to be a periventricular predominance that may be associated with atrophy and ventricular enlargement. Clinically, patients develop cognitive impairment, gait disorder, and later urinary incontinence, all of which can progress over time. These symptoms mimic those of normal pressure hydrocephalus, and placement of a ventriculoperitoneal shunt can improve function in some patients but does not reverse the deficits completely. Increased age is a risk factor for leukoencephalopathy but not for radiation necrosis. Necrosis appears to depend on an as yet unidentified predisposition.
Other late neurologic toxicities include endocrine dysfunction if the pituitary or hypothalamus was included in the RT port. A radiation-induced neoplasm can occur many years after therapeutic RT for either a prior CNS tumor or a head and neck cancer; accurate diagnosis requires surgical resection or biopsy. In addition, RT causes accelerated atherosclerosis, which can cause stroke either from intracranial vascular disease or carotid plaque from neck irradiation.
The peripheral nervous system is relatively resistant to RT toxicities. Peripheral nerves are rarely affected by RT, but the plexus is more vulnerable. Plexopathy develops more commonly in the brachial distribution than in the lumbosacral distribution. It must be differentiated from tumor progression in the plexus, which is usually accomplished with CT/MR imaging of the area or PET scan demonstrating tumor infiltrating the region. Clinically, tumor progression is usually painful whereas radiation-induced plexopathy is painless. Radiation plexopathy is also more commonly associated with lymphedema of the affected limb. Sensory loss and weakness are seen in both.
TOXICITY FROM CHEMOTHERAPY
Neurotoxicity is second to myelosuppression as the dose-limiting toxicity of chemotherapeutic agents (Table 37-4). Chemotherapy causes peripheral neuropathy from a number of commonly used agents, and the type of neuropathy can differ, depending upon the drug. Vincristine causes paresthesias but little sensory loss and is associated with motor dysfunction, autonomic impairment (frequently ileus), and rarely cranial nerve compromise. Cisplatin causes large fiber sensory loss resulting in sensory ataxia but little cutaneous sensory loss and no weakness. The taxanes also cause a predominately sensory neuropathy. Agents such as bortezomib and thalidomide also cause neuropathy.
NEUROLOGIC SIGNS CAUSED BY AGENTS COMMONLY USED IN PATIENTS WITH CANCER
Encephalopathy and seizures are common toxici-ties from chemotherapeutic drugs. Ifosfamide can cause a severe encephalopathy, which is reversible with discontinuation of the drug and the use of methylene blue for severely affected patients. Fludarabine also causes a severe global encephalopathy that may be permanent. Bevacizumab and other anti-VEGF agents can cause posterior reversible encephalopathy syndrome. Cisplatin can cause hearing loss and less frequently vestibular dysfunction.