Lisa M. DeAngelis
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Malignant primary brain tumors represent 2% (17,000 cases) of all cancers and 2.5% (10,000 cases) of cancer deaths annually in the United States (Table 14.1). The male-to-female ratio is 3:2. The incidence peaks at 5 to 10 years of age and again at 50 to 55 years of age. Brain cancers are the most common solid tumors in children, and childhood brain cancers are discussed further in Chapter 18, “Brain Tumors.”
Table 14.1 Features of Common Central Nervous System Tumors
MS, median survival; CSF, cerebrospinal fluid; CNS, central nervous system; RT, radiation therapy.
B. Etiology
1. Environmental factors, such as tobacco, alcohol, and diet, have not been associated with primary central nervous system (CNS) tumors. Exposure to ionizing radiation, however, can induce the formation of meningiomas, nerve sheath tumors, sarcomas, and astrocytomas. Exposure to electromagnetic radiation, including cell phones and computer terminals, does not cause brain tumors. Occupational exposure to vinyl chlorides may be a risk factor for astrocytomas; animal studies have shown that exposure to N-nitroso compounds, aromatic hydrocarbons, triazenes, and hydrazines increases the risk for astrocytoma formation, but it is not clear whether these compounds play a role in human tumor formation. Recent data suggest that individuals with atopy or chronic asthma may be at lower risk of glioma.
2. Hereditary neurocutaneous syndromes
a. Neurofibromatosis I is a dominantly inherited condition of multiple neurofibromas, café-au-lait spots, axillary freckling, and Lisch nodules of the iris that confers an increased risk for optic glioma, intracranial astrocytoma, neurofibrosarcoma, neural crest–derived tumors (glomus tumor, pheochromocytoma), embryonal tumors, leukemia, and Wilms tumor. The gene for this disorder is on chromosome 17q11, and its product, neurofibromin, is a tumor suppressor that regulates the Ras pathway, which transmits mitogenic signals to the nucleus.
b. Neurofibromatosis II is a condition of multiple schwannomas, especially vestibular schwannomas, that is also associated with an increased risk for ependymoma and meningioma. The gene for this disorder is located on chromosome 22q12, and its product, merlin, encodes a member of the ezrin-radixin-moesin (ERM) family of membrane and cytoskeletal linker proteins thought to be important for cell motility and adhesion.
c. Tuberous sclerosis (Bourneville disease) is a dominantly transmitted disorder characterized by the development of hamartomas, including subependymal nodules and cerebral cortical tubers that have abnormal cortical architecture and can be associated with mental retardation, epilepsy, and behavioral disturbances such as autism. Hamartomatous lesions of other organ systems include facial angiofibromas, forehead plaques, shagreen patches, cardiac rhabdomyomas, and renal angiomyolipomas and cysts. This disorder is associated with the formation of subependymal giant-cell astrocytomas. Two responsible tumor-suppressor genes, TSC-1 (chromosome 9q34) and TSC-2(chromosome 16p13), have been identified.
d. Nevoid basal cell carcinoma syndrome (Gorlin syndrome) is a dominantly inherited syndrome of multiple basal cell carcinomas that may be associated with medulloblastoma, meningioma, craniopharyngioma, and some systemic tumors (ovarian tumors, cardiac fibroma, maxillary fibrosarcoma, adrenal cortical adenoma, rhabdomyosarcoma, seminoma). Other features include jaw cysts, palmar and plantar pits, and spine and rib anomalies. The loss of a tumor-suppressor gene on chromosome 9q22 is responsible for this disorder. Its gene product, PTCH, is the human homologue of the Drosophila patched gene, part of the hedgehog signaling pathway, which is important in embryonic patterning and cell fate.
e. Neurocutaneous melanosis is a developmental rather than inherited condition of large, hairy, pigmented benign nevi of the skin associated with infiltration of the meninges by melanin-containing cells. Although the pigmented lesions of the skin remain benign, the pigmented cells in the meninges often undergo malignant transformation with neural invasion, resulting in primary CNS melanoma.
3. Hereditary cancer syndromes
a. von Hippel–Lindau disease is a dominantly transmitted disorder characterized by hemangioblastomas of the retina, cerebellum, and, less commonly, spinal cord. Other associated tumors include renal carcinoma, pheochromocytoma, islet cell tumors, endolymphatic sac tumors, and benign renal, pancreatic, and epididymal cysts. The disorder is due to the loss of a tumor-suppressor gene on chromosome 3p25-26. This loss results in the overexpression of vascular endothelial growth factor (VEGF) and erythropoietin, which are normally induced by hypoxia.
b. Turcot syndrome is a rare autosomal dominant or recessive familial syndrome associated with colon cancer, glioblastoma, and medulloblastoma. It is due to a germline mutation of the APC gene on chromosome 5q21, or germline mutations of genes governing the DNA replication mechanism including the hMLH-1 or hPMS-2 genes, both of which encode proteins responsible for DNA mismatch repair.
c. Li-Fraumeni syndrome is a clinical syndrome of familial breast cancer, sarcomas, leukemia, and primary brain tumors that is associated with germ line p53 (chromosome 17) mutations.
4. Immune suppression. Transplant recipients and patients with acquired immunodeficiency syndrome (AIDS) have a markedly increased risk for primary CNS lymphoma.
II. DIAGNOSIS
A. Clinical presentation depends on the location of the tumor and its rate of growth. In general, slow-growing tumors cause little in the way of focal deficits because the brain tissue is slowly compressed and compensatory mechanisms appear to occur. After they reach a certain size, the compensatory mechanisms fail or cerebrospinal fluid (CSF) pathways may be obstructed, causing increased intracranial pressure (ICP). Fast-growing tumors tend to be associated with considerable surrounding cerebral edema; the edema, in addition to the tumor mass, is more likely to cause focal deficits. Usually, the deficits caused by edema are reversible, whereas those caused by the tumor may not be reversible. Specific signs and symptoms associated with tumors of the CNS include the following:
1. Headache occurs in about 50% of brain tumor patients. They are most likely to occur in younger patients with fast-growing tumors and are typically deep, dull, and not intense or throbbing. They are characteristically worse on arising in the morning and are exacerbated by straining or lifting. Lateralization of headache occasionally facilitates tumor localization.
2. Seizures. In 20% of patients >20 years of age, the onset of seizures is caused by a neoplasm. The seizures may be generalized or partial (focal). Simple partial seizures commonly consist of transient sensory or motor phenomena of a single limb or side. Complex partial seizures, often of frontal or temporal lobe origin, consist of changes in the level of consciousness or awareness of surroundings, frequently in conjunction with abnormal olfactory or gustatory phenomena. Speech arrest may also occur. Generalized seizures result in loss of consciousness, bowel and bladder incontinence, and bilateral tonic–clonic movements. In patients with brain tumors, generalized seizures always have a focal origin even if the focal signature is not evident at seizure onset; evidence of focality is often found on postictal examination of the patient.
3. Increased ICP may result from a large mass or from obstructive hydrocephalus. Large supratentorial masses cause progressive obtundation and can lead to transtentorial herniation, which classically presents with an ipsilateral third cranial nerve palsy and contralateral hemiparesis. Hydrocephalus causes gait ataxia, nausea, vomiting, headache, and decreased alertness. If untreated, hydrocephalus can lead to central herniation, which is not heralded by a third nerve palsy. Papilledema is a sign of increased ICP, but it is rarely seen in current brain tumor patients because of the availability of modern neuroimaging, which facilitates early diagnosis. Unusual signs and symptoms of increased ICP include visual obscurations, dizziness, and false localizing signs, the most common of which is sixth cranial nerve dysfunction owing to stretching of the nerve from downward pressure caused by a large supratentorial mass.
4. Supratentorial tumors usually present with focal signs and symptoms, including hemiparesis (frontal lobe), aphasia (left frontal and posterior temporal lobes), hemineglect (parietal lobe), and hemianopsia (temporal, parietal or occipital lobes).
5. Hypothalamic tumors may be associated with disturbance of body temperature regulation, diabetes insipidus, hyperphagia, and, if the optic chiasm is involved, visual-field deficit, typically a bitemporal hemianopia.
6. Brainstem tumors, such as brainstem gliomas, present with multiple cranial nerve deficits, hemiparesis, and ataxia.
7. Nerve-sheath tumors, such as acoustic neuromas, result in deficits of the involved cranial or spinal nerve. As the tumor enlarges, surrounding neural structures may also be compressed, leading to further symptoms.
8. Cerebellar tumors are associated with dysmetria, ataxia, vertigo, nystagmus, headache, and vomiting.
9. Spinal cord tumors present with spastic paraparesis and sensory loss below the level of the tumor as well as disturbances of bowel and bladder function.
10. Meningeal involvement by primary CNS tumors is less common than with metastatic tumors (see Chapter 32) and is seen primarily with medulloblastoma, pineoblastoma, germ cell tumor, primary CNS lymphoma, and, to a lesser degree, ependymoma. The hallmark of meningeal disease is neurologic dysfunction at multiple levels of the neuraxis. Nonspecific features include seizures and changes in mentation.
B. Evaluation. Imaging studies must be performed to evaluate patients suspected of having CNS mass lesions.
1. Computed tomography (CT) and magnetic resonance imaging (MRI) are the primary imaging modalities for evaluating presumed CNS tumors. MRI is preferable because of its greater sensitivity, especially for lesions in the brainstem, posterior fossa, medial temporal lobes, and spinal cord. Contrast studies should always be performed because many tumors show contrast enhancement. CT should only be used for those patients unable to undergo MRI (e.g., pacemaker).
2. Lumbar puncture is almost never a part of the initial evaluation of a suspected CNS tumor and in fact is often contraindicated in this setting. It is used primarily to stage tumors known to disseminate along the neuraxis or to evaluate patients with clinical or radiographic evidence of meningeal dissemination (see Section II.A.10). A notable exception is primary CNS lymphoma, which can be diagnosed in about 15% of patients by examination of CSF in lieu of biopsy.
3. Angiography is never required in the evaluation of suspected CNS tumors. It is useful in the preoperative evaluation of highly vascular tumors that require embolization to reduce the blood supply before surgical resection is performed. The need for embolization is determined by the neurosurgical consultant.
4. Systemic evaluation. After a mass lesion is demonstrated on CT or MRI scan, its specific etiology must be determined. The differential diagnosis includes a primary tumor of the nervous system, metastasis, stroke, and inflammatory or infectious process (e.g., multiple sclerosis, cerebral abscess). Radiographic features can help differentiate among these diagnoses; combined with the patient’s history and physical examination, they can lead to a presumptive diagnosis with reasonable certainty in most patients.
A systemic evaluation is not necessary in the initial evaluation of a patient with a single lesion seen on MRI. Doing a comprehensive evaluation usually delays the diagnosis and is rarely informative. Such patients should immediately undergo surgical resection and any subsequent testing based on the pathology. If a primary brain tumor is found, no systemic evaluation is necessary. If a metastasis is identified, a systemic workup can proceed accordingly and be completed with a body positron emission tomography (PET) scan. This is a reasonable approach because resection is the optimal treatment for either a primary brain tumor or a single brain metastasis. If multiple lesions are identified on the initial MRI, a systemic evaluation is in order; body PET in concert with body CT is the preferred approach.
5. Surgery is required for definitive diagnosis in most cases of suspected primary nervous system tumors and is usually a cornerstone of treatment as well. Exceptions include tumors not requiring surgical extirpation as a component of therapy and that can be diagnosed by characteristic imaging features (e.g., neurofibroma, optic nerve glioma, brainstem glioma). In addition, when nonneoplastic processes (e.g., stroke, multiple sclerosis) are a consideration, clinical and radiographic observation may be appropriate.
III. ASTROCYTOMA AND GLIOBLASTOMA
A. Pathology. Astrocytomas are highly infiltrative tumors that are graded by their degree of anaplasia according to World Health Organization (WHO) criteria. Low-grade tumors are classified as astrocytoma (WHO grade II), those with more evidence of cytologic atypia and increased cellularity as anaplastic astrocytoma (WHO grade III), and those with highly malignant features as glioblastoma (GBM; WHO grade IV). GBMs with sarcomatous features are gliosarcomas and behave in a fashion identical to GBMs. The very low grade pilocytic astrocytoma constitutes WHO grade I; it is almost exclusively seen in children. WHO grade III and IV tumors are malignant astrocytomas.
The incidence of astrocytoma increases with age, and as the age of the patient increases, the astrocytoma is more likely to be of higher grade. Astrocytomas are most commonly supratentorial but may occur in the cerebellum, brainstem, and spinal cord.
Immunohistochemical properties of neurologic malignancies are shown in Appendix C4.V.
B. Radiology. On CT or MRI scans, astrocytomas are usually solitary lesions primarily in the white matter. Grade II astrocytoma appears as a nonenhancing infiltrative mass best seen on T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI sequences. The high-grade astrocytomas (grades III and IV) usually enhance after administration of contrast material and are surrounded by focal edema; occasionally, anaplastic gliomas do not enhance on MRI. GBMs often have central necrosis and may appear as ring-enhancing lesions. Uncommonly, cystic components may be associated with low- or high-grade astrocytomas.
C. Treatment
1. Dexamethasone reduces the cerebral edema associated with malignant brain tumors by decreasing vascular permeability through its action on endothelial junctions. It is occasionally useful in patients with low-grade gliomas. Neurologic dysfunction from brain tumors is often due to the surrounding edema rather than to the tumor itself. Therefore, treatment with steroids usually results in considerable clinical improvement. Dosing schedules vary, but the typical starting dose is 8 mg PO or IV twice a day. Doses should be reduced once definitive treatment has been undertaken (usually postoperatively or during radiation therapy (RT)), and most patients can be tapered off completely. Common steroid-related side effects in brain tumor patients include insomnia, weight gain, hyperglycemia, steroid myopathy, and affective disturbance.
2. Surgical resection should be performed whenever technically feasible. Not only is surgery necessary for adequate tissue sampling for pathologic diagnosis, but it can also lead to neurologic improvement from reduction of mass effect. The degree of surgical resection has been shown to correlate with survival, especially for higher-grade lesions. The term gross total resection refers to removal of all or nearly all tumor visualized radiographically. Based on the infiltrative nature of all grades of astrocytoma, however, residual tumor always remains. Postoperative MRI scans should be performed within 3 to 4 days of surgery to determine the extent of surgical resection. If resection is not possible, biopsy should be performed for histologic diagnosis.
3. Radiation therapy (RT) substantially improves survival, and a dose–response relationship has been documented for high-grade tumors. Low-grade astrocytomas are treated with 5,000 to 5,400 cGy and anaplastic astrocytomas and GBMs with 6,000 cGy of RT to the tumor and surrounding margins. RT may be deferred in some patients with low-grade astrocytomas who have seizures controlled by antiepileptic drugs and no other neurologic symptoms. Radiation sensitizers are not beneficial in the treatment of astrocytomas. Adjuvant (boost) RT, such as interstitial brachytherapy or radiosurgery, does not offer a survival advantage to patients with malignant gliomas; complications of such therapies include steroid dependence and the need for further surgical debulking in one-half of patients for control of radionecrosis.
4. Chemotherapy with temozolomide has become the standard of care for patients with GBM. It is given concurrently during RT at 75 mg/m2/d continuously, and for at least six cycles as adjuvant therapy at a dose of 150 to 200 mg/m2 for 5 consecutive days every 4 weeks. Many continue the drug until progression or 24 cycles have been completed. Treatment is usually well tolerated. Although efficacy has not been established for patients with anaplastic astrocytoma, many have adopted this regimen for all patients with malignant gliomas.
5. Treatment at recurrence. Astrocytomas, including GBM, may respond to treatment at recurrence, and treatment strategies usually parallel those given at diagnosis. The decision to treat at recurrence and the type of treatment to be administered depends on patient characteristics, such as age and performance status, and on tumor features, such as histologic grade and surgical accessibility. Dexamethasone may be reinstituted to control neurologic symptoms. Further surgical debulking may be an option and can improve neurologic function if the patient has a large enhancing mass with extensive edema. Postoperatively, or in the absence of surgery, chemotherapy should be employed. The antiangiogenic drug bevacizumab (Avastin) has become the standard at recurrence. It is usually combined with a chemotherapeutic drug such as a nitrosourea, carboplatin, or irinotecan. Optimally, patients should be offered participation in a clinical trial if available. Further irradiation, such as stereotactic radiosurgery, rarely has a role in the treatment of these highly infiltrative neoplasms.
6. Patient follow-up. Patients with an astrocytoma require lifelong follow-up. Low-grade astrocytomas can recur, often as higher-grade lesions, as long as 20 years after treatment. Tumor recurrence is usually at the primary site, but occasionally astrocytomas can become multifocal or recur at distal sites within the neuraxis. Metastasis to systemic tissues is exceedingly rare. Monitoring for tumor recurrence can be achieved best with serial neurologic examination and MRI scan. The rate of monitoring is individualized and depends on the grade of the tumor, the performance status of the patient, and the intention for further therapy.
D. Survival. Median survival is about 5 years for astrocytoma, 3 years for anaplastic astrocytoma, and 18 months for GBM. About 5% of patients with GBM survive for 5 years or longer.
IV. OTHER GLIAL NEOPLASMS
A. Oligodendroglioma
1. Pathology. Oligodendrogliomas arise from the oligodendrocytes or myelin-producing cells of the CNS and may occur in conjunction with astrocytomas as a mixed tumor or in a pure form. Most are lower-grade lesions, but anaplastic tumors also occur. Oligodendrogliomas are characterized by loss of heterozygosity of chromosomes 1p and 19q, which correlates with chemosensitivity and improved prognosis.
2. Clinical features. Compared with astrocytoma, oligodendroglioma is more likely to cause seizures and have a higher tendency to calcify and hemorrhage (about 10% of patients). Oligodendrogliomas are most common in the frontal and temporal lobes, particularly in the insular cortex. Intratumoral calcifications are a radiographic feature best appreciated on CT scan.
3. Treatment is similar to that for astrocytoma and includes dexamethasone for control of symptoms and aggressive surgical resection. Low-grade oligodendroglioma may be followed, and many do not require immediate treatment. When therapy is required, oligodendrogliomas are chemosensitive and may be treated with temozolomide deferring RT until necessary. High-grade oligodendrogliomas all require therapy at diagnosis. Adding chemotherapy to RT at diagnosis significantly prolongs progression-free survival but has no effect on overall survival, suggesting that it may be administered at diagnosis or held until recurrence. Median survival of low-grade oligodendroglioma exceeds 15 years and is about 5 years for the anaplastic oligodendroglioma.
B. Juvenile pilocytic astrocytoma (JPA)
1. Pathology. Pilocytic astrocytomas (grade I) differ in histology and clinical behavior from the astrocytomas discussed in Section III. They are less invasive, more circumscribed, and much less likely to progress to a more anaplastic state.
2. Clinical features. Pilocytic astrocytoma tends to occur in children and young adults and have a predilection for the cerebellum, hypothalamus, optic chiasm, and thalamus. Radiographically, they are well-demarcated masses that enhance densely and homogeneously and may have cystic components.
3. Treatment. JPAs are not infiltrative or histologically progressive and, therefore, can be cured by surgical excision. Subtotally resected tumors may be observed or rarely require immediate focal irradiation. Nonresectable tumors (e.g., optic gliomas) may also be followed or can be treated with RT (5,400 cGy, focal fields) or, in very young patients, with chemotherapy if symptoms dictate the need for immediate treatment. JPAs respond to nitrosoureas, procarbazine, cyclophosphamide, vincristine, platinum compounds, and etoposide.
4. Survival depends on tumor location and extent of resection. The overall survival rate is 80% at 10 years and 70% at 20 years.
C. Ependymoma
1. Pathology. Ependymomas arise from ependymal cells. Therefore, these tumors localize to the ventricular system and spinal canal, most often in the fourth ventricle and in the region of the cauda equina. They are more frequent in children but occur in adults as well. Most are histologically benign, but some, including the anaplastic ependymoma, ependymoblastoma, and myxopapillary ependymoma, can disseminate through the spinal fluid.
2. Treatment. Ependymomas can be cured by total resection, particularly the filum terminale myxopapillary ependymoma. Unfortunately, their location often prevents complete excision, and RT must often be administered postoperatively. Radiation is usually given to a focal field to a dose of 5,400 cGy. Chemotherapy plays less of a role in the treatment of ependymomas, but when used, platinum compounds are considered most effective. Temozolomide and bevacizumab also have some activity.
D. Brainstem glioma.
1. Pathology. Brainstem gliomas are astrocytomas that arise in the brainstem, usually the pons, and are more common in children than adults. They can be any grade of astrocytoma, but their outcome is primarily determined by their location, so they are classified separately from the other astrocytomas. Patients present with multiple cranial nerve palsies and ataxia.
2. Treatment. Surgical resection is not possible because of the tumor location, and diagnosis is usually based on the typical radiographic and clinical findings. Biopsy is occasionally pursued, and only when an exophytic component is apparent on MRI. Treatment consists of focal RT, usually to 6,000 cGy. Chemotherapy is largely ineffective for brainstem gliomas. Median survival for patients with diffuse pontine gliomas is about 1 year. Patients with more localized, discrete tumors, particularly those in the midbrain or medulla, have a longer survival of several years.
V. PRIMARY CNS LYMPHOMA. Primary CNS lymphoma (PCNSL) is discussed in Chapter 21, Non-Hodgkin Lymphoma, Section VIII.C and Chapter 36, Section II.G. Compared with gliomas, PCNSLs are more likely to cause cognitive and behavioral abnormalities and are less likely to cause seizures. These clinical features reflect the tendency of PCNSLs to occur in deep, periventricular structures and to be multiple in about 40% of patients. In addition, the eye is involved in about 25% of PCNSL patients at diagnosis often producing visual symptoms, such as floaters, suggestive of vitreitis. Radiographically, these tumors usually enhance homogeneously; rarely, they are nonenhancing lesions seen on FLAIR or T2 MRI. Diagnosis is usually by stereotactic biopsy because resection does not improve survival. Chemotherapy with high-dose methotrexate-based regimens should be the first-line treatment in all patients.
VI. MEDULLOBLASTOMA
A. Pathology. Medulloblastomas are embryonal tumors arising from primitive germinal cells in the cerebellum; they most commonly localize to the vermis and fourth ventricle. They are more common in childhood but occur in young adults as well. Medulloblastoma is associated with isochromosome 17q and a unique microarray gene expression that is distinct from other CNS tumors. Aberrant activation of the hedgehog signaling pathway is evident in about 30% of medulloblastomas. Approximately 15% of medulloblastomas harbor p53 mutations which are associated with treatment resistance and poor survival.
B. Clinical features. Medulloblastomas often cause obstructive hydrocephalus from compression of the fourth ventricle. Therefore, patients may present with signs of increased ICP (e.g., gait ataxia, headache, nausea, and vomiting) rather than with signs localizing to the site of their tumor.
C. Staging and treatment. Patients require full staging of the neuraxis, including contrast-enhanced MRI of the head and full spine and cytologic examination of CSF, because medulloblastoma disseminates in the CSF. Spinal imaging can often be performed preoperatively. CSF should be obtained intraoperatively or not until 2 weeks after surgery to avoid false-positive results.
1. Surgery. The extent of surgical resection correlates with survival in patients with medulloblastoma, and gross total resection should be the goal. Patients with persistent hydrocephalus may require placement of a ventriculoperitoneal shunt. Dexamethasone is used to control cerebral edema, especially in the perioperative period.
2. Radiation therapy, consisting of craniospinal irradiation, is required for all patients, including those with negative staging studies. The standard dose ranges from 3,000 to 3,600 cGy to the whole brain and spine with an additional boost to the tumor of 5,500 to 6,000 cGy. Recent data suggest that the craniospinal dose can be reduced to 2,400 cGy when adjuvant chemotherapy, which is now the standard of care, is used.
3. Chemotherapy. Chemotherapy as part of initial treatment used to be reserved for patients with disseminated disease. However, increasingly it is being incorporated into the regimen of all patients because it allows for reduction of the dose of craniospinal irradiation and consequently a reduction in the long-term sequelae of treatment.
A standard regimen incorporates lomustine, vincristine, and cisplatin or cyclophosphamide, vincristine, and cisplatin. In both regimens, weekly vincristine is given during radiotherapy at a dose of 1.5 mg/m2 (to a maximum dose of 2 mg). After completion of RT, either lomustine at 75 mg/m2 PO or cyclophosphamide at 1,000 mg/m2 IV plus cisplatin at 75 mg/m2 IV are given every 6 weeks; vincristine is given at 1.5 mg/m2 for 3 weeks of each cycle. Eight 6-week cycles of chemotherapy are administered.
Relapsed medulloblastoma may be treated with high-dose chemotherapy and autologous stem cell rescue. In addition, an inhibitor of the hedgehog pathway was shown to cause marked but transient tumor regression in a patient whose tumor had activation of the hedgehog pathway.
D. Prognosis. Patients with medulloblastomas who have had a gross total resection and show no evidence of tumor dissemination (standard risk) have a 5-year survival rate of 70% to 80%. In patients with disseminated tumor (poor risk), the median survival is about 5 years.
VII. GERM CELL TUMORS
A. Pathology. Germ cell tumors arising in the nervous system are usually located in the pineal and suprasellar regions. They are of two basic types: germinomas and nongerminomatous germ cell tumors. The former are highly sensitive to radiation and are analogous to systemic seminomas and dysgerminomas. The latter include teratomas, choriocarcinomas, endodermal sinus tumors, and some tumors of mixed histology, and are relatively resistant to radiation. All germ cell tumors, except mature teratomas, are malignant. They are more common in males and in those of Asian ancestry. They occur mostly in the first three decades of life.
B. Evaluation. Because germ cell tumors can readily disseminate in the neuraxis, all patients require complete staging, including contrast MRI of the brain and complete spine, CSF cytologic examination, and determination of serum and CSF α-fetoprotein and β-human chorionic gonadotropin levels; CSF placental alkaline phosphatase may also be helpful.
C. Treatment. Surgical resection should be performed first with a goal of achieving a complete excision. If resection is not feasible, biopsy is necessary for histologic diagnosis. Resection constitutes complete therapy for the rare mature teratomas. Germinomas without evidence of neuraxis dissemination are treated with irradiation of the tumor and surrounding ventricular system; even those with positive markers can be treated with radiotherapy alone. Nongerminomatous germ cell tumors and tumors with evidence of neuraxis dissemination are treated with craniospinal irradiation and chemotherapy. Regimens are similar to those used for systemic germ cell tumors. The 5-year survival rate is 90% for germinomas and may approach 50% for nongerminomas that are more resistant to therapy.
VIII. BENIGN NERVOUS SYSTEM TUMORS
A. Meningiomas are tumors arising from arachnoidal cells. Their incidence increases with age, and they are more common in women. Meningiomas may occur over the convexities, parasagittal along the falx, along the sphenoid wing, retroclival, or along the thoracic spine. Although most of these tumors are benign, some are histologically atypical or malignant. The tumors are recognized radiographically by their extra-axial location and their dense, homogeneous pattern of contrast enhancement. Patients with small asymptomatic meningiomas can be followed.
Treatment is surgical resection which is often curative. Recurrent tumors may be treated with RT or stereotactic radiosurgery. These tumors are not responsive to chemotherapy. Receptors for estrogen, androgens, and especially progesterone have been demonstrated in meningiomas, but the tumors rarely respond to hormonal manipulation.
B. Craniopharyngiomas are congenital, cystic suprasellar tumors thought to arise from epithelial remnants of Rathke pouch. They present with dysfunction of the optic chiasm or hypothalamic–pituitary axis as a result of tumor compression. The tumor may contain calcifications and an oily cellular debris that causes a severe chemical meningitis if a cyst ruptures into the spinal fluid. The tumor is histologically benign and can be cured by total resection. Unfortunately, this is often not possible, and RT may be required for tumor control.
C. Pituitary adenoma. Adenomas of the pituitary gland can be either secreting or nonsecreting tumors. Secretory tumors can cause acromegaly (growth hormone), infertility and galactorrhea (prolactin), or Cushing disease (adrenocorticotropic hormone, ACTH). These tumors are often microadenomas (<1 cm), but are usually visualized on MRI. Nonsecretory tumors are typically macroadenomas (>1 cm) and cause bitemporal hemianopsia because of optic chiasm compression, pituitary apoplexy resulting from hemorrhage into the tumor, or hypopituitarism. Treatment of either micro- or macroadenomas may consist of surgical resection, usually by the transsphenoidal route. However, secretory tumors may be treated pharmacologically: prolactinomas with cabergoline and growth hormone–secreting tumors with somatostatin or an analog such as octreotide. Recurrent tumors may require RT.
D. Vestibular schwannoma (acoustic neuroma). Vestibular schwannomas arise from the vestibular branch of the eighth cranial nerve. Initial symptoms are sensorineural hearing loss, tinnitus, and vertigo. Involvement of adjacent neural structures can cause facial weakness, facial numbness, dysphagia, and ataxia. On contrast-enhanced MRI scans, these tumors are seen as a homogeneous, densely enhancing mass that follows the eighth cranial nerve into the internal auditory canal; the diagnosis is usually clear on MRI. Management depends on the extent of hearing loss and whether bilateral tumors are present, but therapeutic options include surgical resection and stereotactic radiosurgery. Bilateral acoustic neuromas constitute a diagnosis of neurofibromatosis II. Spinal schwannomas cause a radiculomyelopathy and can be cured by total resection. Rarely, these tumors can have sarcomatous degeneration.
IX. SPECIAL CLINICAL PROBLEMS
A. Seizures. Seizures occur in about 25% to 30% of all brain tumor patients. Once a patient has had a seizure, they are maintained on anticonvulsants. The choice of agent usually depends on the common side effect profile and potential for drug interactions. Anticonvulsants that induce hepatic enzymes (e.g., phenytoin, carbamazepine) can enhance chemotherapy metabolism, resulting in subtherapeutic serum levels. These drugs also tend to be associated with greater sedation and a worse toxicity profile. Therefore, newer agents are used more commonly. Although frequently administered, prophylactic anticonvulsants are ineffective in the prevention of seizures in brain tumor patients who have not had a seizure. They should be avoided.
1. Levetiracetam (Keppra) is the first-line choice of antiepileptic agents in brain tumor patients because of its efficacy, favorable toxicity profile, and lack of hepatic microsomal enzyme induction. The starting dose is usually 500 mg bid and can be increased to 1,500 mg bid titrated to seizure control. Serum levels are available but do not correlate well with seizure control. Side effects include personality change, depression, and sedation.
2. Lamotrigine (Lamictal) is a highly effective antiepileptic for patients with brain tumors. It needs to be titrated slowly and can interact with valproic acid. The dose is usually 225 to 375 mg/d in two divided doses when used as an adjunct or monotherapy in patients not receiving valproate or other enzyme-inducing antiepileptics. Patients taking concurrent valproic acid usually require less and those taking concurrent enzyme inducing antiepileptic agents may need more lamotrigine.
3. Carbamazepine (Tegretol) is often a second-line agent in the treatment of seizures. It is available only in an oral form, and doses must be slowly increased to maintenance levels because rapid loading is not tolerated. Doses range from 7 to 15 mg/kg per day, divided into twice-daily or thrice-daily fractions, typically 600 to 1,000 mg/d for an adult. Therapeutic serum levels range from 6 to 12 μg/mL. Side effects include granulocytopenia, diplopia, nystagmus, fatigue, hepatic dysfunction, and allergic dermatitis. Monitoring of blood counts is required.
4. Valproate (Depakote) is administered orally at a dose of 15 mg/kg per day divided into thrice-daily doses and elevated by 5 mg/kg/day as needed to control seizures; the therapeutic level is 50 to 100 μg/mL. Valproate is available as an IV preparation and is usually the second choice after phenytoin for a patient unable to take oral medication. Side effects include hepatic and pancreatic toxicity, thrombocytopenia, nausea, tremor, and alopecia. Monitoring of LFTs is required.
5. Phenytoin (Dilantin)
a. Loading dose is 18 mg/kg (usually 1 g for adults). Maintenance doses are 5 mg/kg/day (usually 300 mg/d for adults). Phenytoin given orally can be given once or twice a day because it has a half-life of about 24 hours. For intravenous administration, phenytoin is given in the form of fosphenytoin in phenytoin-equivalent (PE) doses (18 mg PE/kg loading; 5 mg PE/kg per day in divided doses maintenance) at a rate not to exceed 150 mg PE/min. Parenteral loading of phenytoin should be performed with electrocardiogram, blood pressure, and respiratory monitoring.
b. Therapeutic levels are 10 to 20 μg/mL, but this is a general guide. Many patients have well-controlled seizures with a level <10 μg/mL, and others do not experience toxicity with a level >20 μg/mL. Dose adjustments should be made gradually, because phenytoin has zero-order kinetics, and small increases in the dose can sometimes result in large increases in serum levels.
c. Side effects of phenytoin include cognitive impairment, hirsutism, megaloblastic anemia, leukopenia, and hepatic dysfunction. Allergic reactions manifesting as a rash occur in about 20% and can proceed to a Stevens-Johnson reaction. Toxicity is manifested by nystagmus, ataxia, and lethargy.
6. Newer anticonvulsants, such as gabapentin, topiramate, vigabatrin, and zonisamide can be used at the discretion of the treating physician. Most of these agents do not induce the hepatic microsomal system.
B. Hydrocephalus can result from obstruction of CSF pathways, especially with intraventricular tumors or tumors in the upper brainstem. Patients with hydrocephalus present with headache, nausea, vomiting, gait ataxia, urinary incontinence, and progressive lethargy. Large ventricles above the level of obstruction can be diagnosed with a noncontrast CT scan. Communicating hydrocephalus may also develop in patients treated for a brain tumor; one sees progressive ventricular enlargement on serial neuroimaging. Treatment of both forms of hydrocephalus consists of placement of a ventriculoperitoneal shunt.
C. Radiation necrosis can result from RT and is common after high-dose and interstitial irradiation. Clinically and radiographically, it is indistinguishable from tumor recurrence. PET or magnetic resonance spectroscopy (MRS) may be useful in distinguishing tumor recurrence from radiation necrosis, but even these techniques cannot distinguish tumor progression from radiation necrosis reliably. Radiation necrosis can be treated with dexamethasone, but surgical debulking is often required to relieve mass effect and to provide a definite tissue diagnosis.
D. Deep-vein thrombosis (DVT) occurs in about 20% of patients with high-grade gliomas and is optimally treated with anticoagulation. Although some physicians are concerned that anticoagulation poses increased risk for intracranial hemorrhage into a brain tumor, studies have not substantiated this risk. Therefore, anticoagulation is safe in this population. Inferior vena cava filters should be avoided because patients develop chronic venous stasis and edema and may develop pulmonary emboli from the filter. However, patients with DVT who are scheduled for craniotomy must be treated with a filter.
E. Herniation results from progressive mass effect in patients with large, edematous tumors. Herniation can be central in the case of midline tumors and hydrocephalus, uncal in the case of hemispheric lesions, or tonsillar in the case of posterior fossa tumors. Once recognized, herniation is an emergency that must be treated to decrease intracranial pressure. These interventions will reduce intracranial pressure, but they will only temporize until definitive treatment is initiated. The emergency methods include the following:
1. Elevation of the head of the bed
2. Hyperventilation to a Pco2 of about 30 mm Hg
3. Creation of an osmotic gradient by administration of Mannitol at 0.5 to 2 g/kg IV (usually 50 to 100 g in adults) or hypertonic saline, 300 mL 3% solution
4. Dexamethasone, up to 100 mg IV followed by 40 to 100 mg/24 hours depending on symptoms
Suggested Reading
Iwamoto FM, Abrey LE, Beal K, et al. Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology 2009;73:1200.
Khasraw M, Lassman AB. Advances in the treatment of malignant gliomas. Curr Oncol Rep 2010;12:26.
Rossetti AO, Stupp R. Epilepsy in brain tumor patients. Curr Opin Neurol 2010;23:603.
Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459.
Tabori U, Baskin B, Shago M, et al. Universal poor survival in children with medulloblastoma harboring somatic p53 mutations. J Clin Oncol 2010;28:1345.
vonHoff K, Hinkes B, Gerber NU, et al. Long-term outcome and clinical prognostic factors in children with medulloblastoma treated in the prospective randomized multicentre trial HIT’91. Eur J Cancer 2009;45:1209.
Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med 2008;359:492.