Neurooncology
Patrick Y. Wen
Santosh Kesari
PRIMARY BRAIN TUMORSBackground
Primary brain tumors (PBTs) are a heterogeneous group of neoplasms with varied outcomes and management strategies.
Epidemiology
1. Approximately 52,000 PBTs are diagnosed annually in the United States; 21,000 are malignant and result in 13,000 deaths each year.
2. There has been a steady rise in incidence of PBTs during the last two decades, in part due to increased sensitivity of imaging modalities.
3. Incidence of PBTs is 11 to 19/100,000 persons per year. There is an early peak between ages 0 and 4 years (incidence of 3.1/100,000), a trough between 15 and 24 years (1.8/100,000), and then a gradual rise in incidence to reach a plateau between 65 and 79 years (18/100,000).
4. Central nervous system (CNS) tumors account for 1.5% of all new cancers and 2.4% of all cancer deaths annually.
5. PBTs are the most common type of solid tumor in children, the second leading cause of cancer death under the age of 15 years, and the third leading cause of death under age 30.
6. In adults, the most common tumor types (in decreasing order of frequency) are meningioma, glioblastoma (GBM), pituitary adenoma, astrocytoma, vestibular schwannoma, oligodendroglioma, lymphoma, ependymoma, and medulloblastoma.
7. In children, the most common tumor types in decreasing frequency are astrocytoma, medulloblastoma, ependymoma, craniopharyngioma, GBM, and germ cell tumors.
Genetic Factors
One percent to 5% of patients with brain tumors have an underlying genetic syndrome that increases their risk of developing a brain tumor (Table 6-1).
Environmental Factors
There are only two unequivocal risk factors for PBTs:
1. Cranial irradiation is associated with an increased risk for meningiomas (tenfold risk) and gliomas (three- to sevenfold risk) with a latency period of 10 to 20 years after exposure.
2. Immunosuppression is associated with an increased risk for CNS lymphoma.
3. Recent epidemiological studies suggest that analog cell phones used for more than 10 years may increase the risk of ipsilateral vestibular schwannoma and glioma.
Pathophysiology
1. Most PBTs arise from cells of glial origin.
2. Cell of origin of astrocytomas is uncertain, but there is increasing evidence that gliomas arise from neural stem cells or progenitor cells.
3. Angiogenesis plays a major role in tumor growth and survival.
TABLE 6-1 Genetic Syndromes Associated with Brain Tumors | ||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||
Molecular Genetics
1. Familial syndromes account for less than 5% of CNS tumors. The genetic syndromes associated with brain tumors are listed in Table 6-1.
2. Brain tumors result from a multistep process driven by the sequential acquisition of genetic alterations. These include loss of tumor suppressor genes (e.g., p53 and PTEN) and amplification and overexpression of protooncogenes such as the epidermal growth factor receptor (EGFR) and the platelet-derived growth factors (PDGF) and their receptors (PDGFR). The accumulation of these genetic abnormalities results in uncontrolled cell growth and tumor formation.
3. Glioma: The molecular genetics of GBMs evolving from low-grade astrocytomas (secondary GBMs) are different from that of de novo GBMs (primary GBMs). This may have implications in the selection of targeted molecular therapies for these tumors.
a. Genetic changes in secondary GBMs
1) Low-grade astrocytoma
a) p53 mutations (more than 65%)
b) PDGF-A, PDGFR-α overexpression (60%)
c) Isocitrate dehydrogenase I and 2 mutations (70%)
2) Anaplastic astrocytoma (AA)
a) Loss of heterozygosity (LOH) 19q (50%)
b) Retinoblastoma gene (Rb) alteration (25%)
3) Secondary GBMs
a) LOH 10q (DMBT1 deletion)
b) PTEN mutations (5%)
c) PDGFR-α amplification (less than 10%)
d) Deleted colon cancer (DCC) loss of expression (50%)
b. Genetic changes in primary (de novo) GBMs
1) EGFR amplification or overexpression (40% to 60%)
2) PTEN mutation (30% to 40%)
3) MDM2 amplification or overexpression (50%)
4) P16 deletion (30% to 40%)
5) LOH 10p and 10q
6) Rb alteration
4. Oligodendroglioma: Loss of chromosomes 1p and 19q, EGFR and PDGF/PDGFR overexpression.
5. Medulloblastoma:Amplification of myc, LOH 17p, 10q, 9 (sonic hedgehog/patched signaling pathway).
Prognosis
1. The prognosis of brain tumors is determined by tumor type, grade, and location and by patient’s age and functional status (Karnofsky performance status [KPS]).
2. As a result of this marked heterogeneity, the prognostic features and treatment options must be carefully reviewed for each patient.
3. The feasibility of resection is a key determinant of prognosis and depends on the location and the invasiveness of the neoplasm.
4. Histologic grade of the tumor is important and clearly dictates the survival, but care must be taken as sampling errors may underestimate the grade. Furthermore low-grade neoplasms can transform to higher grade neoplasms.
5. Advances in surgery, radiation therapy (RT), and chemotherapy have led to improvement in prognosis for some low-grade gliomas, anaplastic oligodendrogliomas (AOs) and GBMs.
Diagnosis
Location
1. The frequency of tumors at a location depends on age and type of tumor.
2. In adults, 70% of tumors occur in cerebral hemispheres; and in children, 70% of tumors occur in posterior fossa.
Clinical Presentation
1. Symptoms are due to variety of effects caused by brain tumors including pressure against adjacent structures, elevated intracranial pressure (ICP), and seizures.
2. Symptoms can be acute or subacute but generally are progressive and depend on the size, location, and growth rate of tumor and peritumor edema.
3. Acute symptoms can result from seizures, intratumoral hemorrhage, or rapid growth or edema in eloquent areas.
4. Among patients with new-onset seizures, 5% are found to have a brain tumor.
5. Generalized and focal seizures occur in 15% to 95% of patients with supratentorial tumors and are more common in low-grade tumors and meningiomas.
6. Can present with generalized or focal signs.
7. Increased ICP symptoms include change in mental status, headache, nausea, vomiting, drowsiness, and papilledema.
8. Headache is the presenting feature in 35% of patients and develops in up to 70% during the course of the disease. They are often indistinguishable from tension
headaches or migraines. It should be borne in mind that the vast majority of headaches seen in unselected populations are benign. As headache is a nearly universal phenomenon, its actual relationship to tumor is often tenuous. They are usually bilateral, diffuse, and typically worsened with Valsalva maneuvers and lying down.
9. Focal signs include hemiparesis, sensory loss, ataxia, aphasia, memory loss, neglect, and visual loss.
Diagnostic Tests
1. Magnetic resonance imaging (MRI) enhanced with gadolinium is the test of choice for diagnosis of brain tumors.
2. Sometimes, computed tomography (CT) with contrast is the only choice in patients with pacemakers or metallic implants.
3. Tumor cells have been found in the peritumoral edema, which corresponds to the T2-weighted MRI abnormalities.
4. Other modalities such as magnetic resonance spectroscopy (MRS), perfusion and permeability imaging, positron emission tomography (PET), and single photon emission tomography (SPECT) are helpful in distinguishing tumor from radiation necrosis or inflammation.
5. Functional MRI can be used to define eloquent areas to assess risk of surgery.
6. The presence of multiple lesions on a contrast-enhanced study favors a metastatic process, but metastases can present as a solitary lesion in up to 30% of patients.
7. Lumbar puncture (LP) for routine cerebrospinal fluid (CSF) studies, cytology, and flow cytometry is useful to rule out leptomeningeal involvement of tumors, especially in the case of lymphoma, medulloblastoma, pineal tumors, and germ cell tumors. LP is generally contraindicated if elevated ICP is suspected or if there are large mass lesions.
8. In cases of suspected metastatic disease, a full workup to search for a primary tumor should be undertaken and includes ocular, testicular, breast (mammogram in females), and prostate examinations (males) and urinalysis, complete blood count, peripheral smear, stool guaiac testing, body CT, bone scan, and, increasingly, PET scan.
9. Stereotactic biopsy or preferably craniotomy with resection of the mass allows histologic diagnosis and should be performed in most patients.
Pathology
1. The classification, prognosis, and treatment of brain tumors are ultimately dependent on the histopathologic features of the surgical specimen and the clinical context.
2. Classification of tumor is based on presumed cell of origin: Of primary CNS tumors, 50% arise from glial cells (astrocytes, oligodendroglial cells, and ependymal cells); 30% from the meninges; and 20% from neurons, Schwann cells, lymphocytes, and cells of the pituitary gland.
3. Glial tumors are graded on the basis of cellularity, nuclear atypia, mitoses, microvascular proliferation, and necrosis according to the World Health Organization (WHO) system.
4. Errors can occur when a small sample is taken for biopsy in a heterogeneous tumor and does not reflect the biology of the entire tumor.
5. Grading for astrocytomas
a. WHO grade I (pilocytic astrocytoma) is very slow growing.
b. WHO grade II (low-grade astrocytoma) shows relatively homogenous appearance, hypercellularity, nuclear atypia, and ill-defined tumor margins. Pleomorphic xanthoastrocytoma is a more benign variant.
c. WHO grade III astrocytoma (AA) shows high cellularity, mitosis, and pleomorphism.
d. WHO grade IV (GBM) not only shows features of grade III, but also has necrosis and endothelial proliferation.
6. As genotyping of tumors becomes increasingly more common and shown to be of prognostic value, the classification of tumors will evolve.
Differential Diagnosis
1. A wide differential diagnosis must be kept in mind during the initial evaluation of a brain mass as many treatable conditions can mimic brain tumors.
2. The differential includes other PBTs, metastases, lymphoma, abscesses, viral infections, encephalomyelitis, demyelination, stroke, vascular anomaly, vasculitis, and granulomatous and inflammatory disease.
Treatment
Treatment of patients with brain tumors requires close cooperation of a multidisciplinary team of physicians including neurologists, neurosurgeons, radiation therapists, oncologists, neuroradiologists, neuropathologists, and psychiatrists.
Supportive Care
1. Corticosteroids
a. Used to reduce symptomatic vasogenic edema surrounding tumors, which lowers ICP and mass effect. Clinically, improvement begins within 12 to 48 hours with maximum improvement by fifth day.
b. Response is independent of type of corticosteroid used (dexamethasone, methylprednisolone, prednisone, hydrocortisone) in equivalent doses.
c. Dexamethasone is used widely due to low mineralocorticoid (salt-retaining) side effects.
d. Dexamethasone usually given as bolus of 10 mg and then 16 mg/d by mouth (p.o.) or intravenous (IV) in four divided doses.
1) Oral absorption is excellent.
2) Half-life is long enough for it to be given twice daily.
e. Higher doses (up to 40 mg) can be given to critically ill patients until definitive treatment (surgery, radiation) is undertaken.
f. Side effects include glucose intolerance, oral candidiasis, opportunistic infections including Pneumocystis jerovecii pneumonitis (PJP), gastric irritation, adrenal suppression, steroid myopathy, osteoporosis, and psychiatric problems.
g. Patients may need glucose monitoring and H2 blockers or proton pump inhibitors to reduce gastric irritation.
h. Patients who are likely to remain on steroids for prolonged periods should have Pneumocystis carinii (PCP) prophylaxis (e.g., 160 mg of trimethoprim plus 800 mg of sulfamethoxazole [Bactrim DS] daily or 3 d/wk) and prophylactic therapy for osteoporosis (calcium and vitamin D supplements and bisphosphonates).
i. Steroids should be tapered to the lowest dose possible to avoid complications.
j. Patients who are on steroids for prolonged periods may need adjustments to control edema perioperatively and during chemotherapy and radiation treatments.
2. Anticonvulsants
a. Prophylactic antiepileptic drugs (AEDs) are not recommended for patients unless they have history of seizures. There is no evidence that patients with brain tumors who have never had a seizure benefit from prophylactic anticonvulsants.
b. Prophylactic AEDs should be given to patients undergoing craniotomies, but can be tapered off 1 to 2 weeks after the procedure.
c. Cytochrome P450 enzyme-inducing antiepileptic drugs (EIAEDs), such as phenytoin and carbamazepine, increase the metabolism of many chemotherapeutic agents and reduce their efficacy.
d. More than 20% of brain tumor patients receiving phenytoin or carbamazepine develop drug rashes.
e. The newer AEDs, such as levetiracetam, that do not induce cytochrome P450 enzymes have less drug interactions and are better tolerated.
Prevention of Venous Thromboembolism
Patients with brain tumors have an increased risk of developing venous thromboembolism (VTE) (30% lifetime risk in patients with GBM). Extra care must be taken to
prevent VTE in the perioperative period. When a patient develops VTE, anticoagulation is usually safe after the perioperative period and is more effective than inferior vena cava filtration devices. Low-molecular-weight heparin may be safer and slightly more effective than warfarin.
prevent VTE in the perioperative period. When a patient develops VTE, anticoagulation is usually safe after the perioperative period and is more effective than inferior vena cava filtration devices. Low-molecular-weight heparin may be safer and slightly more effective than warfarin.
Supportive Care
Many patients with brain tumors benefit from physical and occupational therapy, psychiatric consultation, visiting nurses, social services, patient support groups, and brain tumor organizations (American Brain Tumor Association [2720 River Rd, Des Plaines, IL 60018, Phone: (847) 827-9910 or patient line: (800) 886-2282, e-mail: info@abta.org;www.abta.org]; the National Brain Tumor Society [East Coast Office: 124 Watertown Street, Suite 2D, Watertown, MA 02472, Phone: (617) 924-9997; West Coast Office: 22 Battery Street, Suite 612, San Francisco, CA 94111-5520, Phone: (415) 834-9970, e-mail: info@braintumor.org, www.braintumor.org]).
Definitive Therapy
Surgery
1. Decisions regarding aggressiveness of surgery for a PBT are complex and depend on the age and performance status of the patient; the feasibility of decreasing the mass effect with aggressive surgery; the resectability of the tumor (including the number and location of lesions), and, in patients with recurrent disease, the time since the last surgery.
2. Biopsy or surgical resection is performed on most patients to obtain histologic confirmation of the type and grade of tumor and provides information on prognosis and treatment.
3. Biopsy is performed using stereotactic devices or intraoperative MRI. Biopsies are performed for tumors that are deep or in eloquent areas where surgical resection is contraindicated.
4. Due to heterogeneity in the tumor, a small biopsy sample may be nondiagnostic or not representative of the whole tumor.
5. Appropriate localization of biopsy to obtain the highest grade area is important.
6. Extensive tumor resection is the surgical procedure of choice for most tumors and improves neurologic function and survival. This can be achieved for many extra-axial tumors, but very few intra-axial tumors can be resected completely.
7. Partial resection can be palliative by improving neurologic function and improving survival when total resection is not possible.
8. Repeated partial resections may be beneficial, especially for benign tumors.
9. Patients who develop hydrocephalus (usually due to tumors that obstruct the third or fourth ventricles) require a ventriculoperitoneal (VP) shunt to reduce ICP.
10. Some tumors such as brainstem gliomas have characteristic imaging features. Biopsy is usually not done due to high risk of neurologic deficits. Patients are treated without tissue diagnosis.
11. Intraoperative MRI can help in clarifying normal and abnormal tissue, thereby allowing for more complete resection.
12. A postoperative MRI, with and without contrast, should be performed within 24 to 48 hours after surgery to document the extent of disease following surgical intervention.
Complications of Surgery
1. The standard risks of anesthesia and neurosurgery include hemorrhage, stroke, increased edema, direct injury to normal brain, infection, and VTE.
2. Postoperative cerebral hemorrhage may require evacuation if producing focal deficits.
3. Cerebral edema is usually present preoperatively and may be exacerbated during surgery by mechanical retraction, venous compression, brain manipulation, and overhydration. Generally, steroids are given for several days prior to craniotomy.
4. Risk of cranial infection is increased with length of operation and introduction of foreign materials (shunt tubing, clips, chemotherapy polymers) and most infections are due to cutaneous and airborne pathogens. Most patients are given perioperative prophylactic antibiotics.
5. Communicating hydrocephalus can occur transiently postoperatively.
6. Neuroendocrine disturbances such as syndrome of inappropriate secretion of antidiuretic hormone (SIADH) can occur after surgery, and electrolytes and fluid balance should be carefully monitored to prevent hyponatremia and cerebral edema.
7. Surgery of the hypothalamic-pituitary axis can result in various degrees of panhypopituitarism and diabetes insipidus (DI).
Radiation Therapy
1. RT for patients with PBTs usually involves a limited field encompassing the tumor volume (commonly defined as the region showing T2-weighted abnormalities on an MRI scan plus a 1- to 2-cm margin).
2. Usual dose is 6,000 cGy for high-grade PBT; 5,400 cGy for low-grade PBT; and 3,600 cGy for spinal tumors in 180- to 200-cGy fractions over approximately 6 weeks. The dose is 3,000 cGy in 10 fractions for brain metastases (BMs).
3. Several different treatment approaches are used including conformal external beam (most common), stereotactic brachytherapy, stereotactic radiosurgery (SRS), and stereotactic radiotherapy (SRT).
4. Increasingly sophisticated techniques are available to administer conformational irradiation, including intensity-modulated radiation therapy (IMRT), which allows variation of radiation dose in different parts of the radiation field.
5. Brachytherapy, which involves surgical implantation of radioactive isotopes, is now rarely performed. It has been replaced by SRS, which is noninvasive.
6. SRS involves the treatment of small intracranial targets using a large, single fraction of ionizing radiation in stereotactically directed narrow beams. It allows a high dose of radiation to be delivered to the tumor while relatively sparing surrounding brain. SRS can be administered using x-rays from stereotactic linear accelerators, γ-irradiation from cobalt sources in gamma knives, and protons from cyclotrons (proton beam therapy). Radiation necrosis is relatively common. Risk increases with dose and volume treated; 5% to 10% of patients require surgical resection of necrotic area for symptomatic relief.
7. SRT is stereotactic radiation administered in multiple fractions to reduce risk of radiation injury to surrounding structures. It tends to be used for larger tumors.
Chemotherapy
1. The blood-brain barrier (BBB) provides the CNS with a privileged environment and consists of the cerebrovascular-capillary endothelium. Only physiologically small, lipid-soluble drugs or actively transported drugs can cross the BBB.
2. Chemotherapy is useful for primary central nervous system lymphoma (PCNSL), AOs, oligodendrogliomas, AAs, and medulloblastoma. Temozolomide has modest efficacy in GBM.
NEUROEPITHELIAL TUMORSPilocytic Astrocytoma
Background
1. The most common noninfiltrative, focal astrocytoma in childhood.
2. Mainly in children and adolescents but 25% in patients older than 18.
3. Also seen in individuals with neurofibromatosis type I (NF1).
Pathophysiology
Mostly sporadic, but deletions of 17q (NF1) associated with 15% of optic gliomas in patients with NF1.
Prognosis
1. Indolent course, often surgically resectable, and rarely transforms to malignant tumor.
2. Greater than 90% 10-year survival for supratentorial lesions after total resection.
3. A 95% 25-year disease-free survival for cerebellar astrocytoma after total resection.
4. A 74% to 84% 10-year survival for subtotal resection.
5. In children, 75% stable at 4-year follow-up after surgery and chemotherapy (vincristine and actinomycin D) when too young to receive radiation.
Diagnosis
Location
1. In children, it occurs in the cerebellum, optic pathway, and hypothalamus.
2. In young adults, it arises in cerebrum, brainstem, optic nerve, thalamus, and hypothalamus.
Clinical Presentation
Clinical features depend on location. Cerebellar lesions produce symptoms secondary to obstruction of CSF flow or pressure on cerebellum leading to headaches and ataxia.
Diagnostic Tests
MRI shows a cyst with mural nodule that enhances or a nodule alone.
Pathology
1. WHO grade I, grossly well-circumscribed, and gelatinous appearance.
2. Two microscopic patterns: A tightly packed parallel array of well-differentiated astrocytes with Rosenthal fibers (globular, refractile, homogenous, eosinophilic bodies) and a loose matrix of astrocytes, long slender piloid “hairlike” cells, and amphophilic granular bodies.
Differential Diagnosis
Low-grade diffuse astrocytoma, dysembryoplastic neuroepithelioma, ependymoma, and ganglioglioma.
Treatment
1. Some tumors in surgically inaccessible areas (e.g., optic nerve glioma) grow very slowly and may be observed for many years before definitive therapy is required.
2. Surgically curable if complete resection is possible.
3. Conformal radiation or SRT is helpful if resection is not possible or for recurrent tumor.
4. Chemotherapy with agents such as carboplatin and vincristine is useful in young children.
Low-grade Diffuse Astrocytoma Background
1. Low-grade diffuse astrocytomas are slow-growing tumors.
2. Although referred to as “low-grade,” these tumors grow and gradually evolve to higher grade astrocytomas, ultimately causing morbidity and reduced survival.
3. Early diagnosis is difficult due to nonfocal findings with these tumors.
Epidemiology
1. Low-grade astrocytomas comprise 10% of all adult PBTs and 25% to 30% of all cerebral gliomas; 1,500 new cases are diagnosed in the United States each year.
2. Incidence is 1.3 to 2.2/100,000 and peaks in the third and fourth decades.
3. In adults, most arise in the cerebral hemispheres and in children most arise in the posterior fossa.
Pathophysiology
Most tumors have acquired p53 mutations and overexpression of PDGF.
Prognosis
1. Highly variable and depends on age and amount of residual tumor after surgery.
2. Positive prognostic factors include long duration of symptoms, excellent postoperative neurologic status, and low MIB-1 proliferation index (<3% to 5%).
3. Low-grade glioma has median survival of 5 to 8 years with gross total resection, 35% at 5 years with biopsy or subtotal resection, and 46% at 5 years with subtotal resection and radiation.
Diagnosis
Clinical Presentation
Usually present with new-onset seizures (50% to 70%). Less commonly they present with headaches, focal deficits, or subtle neurobehavioral changes.
Diagnostic Tests
1. CT shows a low-density mass or occasionally a partially calcified mass that does not show enhancement.
2. MRI typically shows a nonenhancing white matter mass, hypointense T1, hyperintense T2, and fluid-enhanced inversion recovery (FLAIR) with ill-defined borders and little or no edema.
3. FDG-PET shows glucose hypometabolism.
Pathology
1. WHO grade II, low-grade tumor.
2. Hypercellular, well-differentiated astrocytes; may be cystic, infiltrative.
3. Diffuse variants include fibrillary, protoplasmic, and gemistocytic.
4. Biopsy results can be misleading, as gliomas often have varying degrees of cellularity, mitoses, or necrosis from one region to another.
Differential Diagnosis
Includes high-grade tumor, oligodendroglioma, ganglioglioma, dysembryoplastic neuroepithelioma (DNT), infarction, demyelination, progressive multifocal leukoencephalopathy (PML), and vasculitis.
Treatment
1. Maximal resection associated with improved survival. Advances in neurosurgery, including intraoperative mapping and intraoperative MRI, have allowed more aggressive resection of these tumors with preservation of neurologic function.
2. Standard radiation dose for low-grade astrocytomas is 4,500 to 5,400 cGy, given at a rate of 180 to 200 cGy/d.
3. Radiation usually administered to T2-weighted MRI abnormality together with a 1- to 2-cm margin. Increasingly more conformal therapy with SRT and IMRT is utilized. Whole-brain irradiation is associated with increased neurotoxicity and no longer used.
4. Adjuvant irradiation (following surgery) prolongs survival in patients who have only subtotal resection.
5. Timing of irradiation is controversial. Adjuvant irradiation delays recurrence, but overall survival similar to patients who do not receive irradiation until there is evidence of recurrent disease.
6. Chemotherapy with agents such as temozolomide or procarbazine, CCNU (lomustine), vincristine (PCV) has activity in patients with diffuse infiltrating tumors.
Pleomorphic Xanthoastrocytoma
Background
1. Rare focal astrocytoma with characteristic clinical, imaging, and pathologic features.
2. Most common in second and third decade of life.
Pathophysiology
1. Believed to originate from subpial astrocytes due to its superficial location with attachment to the leptomeninges.
2. p53 mutations found in a small portion of patients.
Prognosis
1. Indolent lesions.
2. Good with resection, 76% 10-year survival.
3. Rare anaplasia associated with poor prognosis.
Diagnosis
Location
Predilection for superficial temporal and parietal lobes involving the leptomeninges and, rarely, the dura.
Clinical Presentation
Usually have a long history of seizures before diagnosis. Occasionally causes headaches and focal deficits.
Diagnostic Tests
MRI shows a heterogenous, superficial meningocerebral nodule, often associated with a cyst, iso- to hypointense on T1-weighted images and enhancing.
Pathology
WHO grade II; enlarged, lipid-laden astrocytes; inflammation; extreme pleomorphism; cellular atypia; and spindle and multinucleated giant cells. No necrosis or vascular hyperplasia.
Differential Diagnosis
Can be mistaken histologically for fibrous histiocytoma of the meninges, giant cell astrocytoma with histiocytic infiltration, and lipidized giant cell GBM multiforme. Must also be differentiated from other forms of gliomas and DNT.
Treatment
1. Surgical resection.
2. RT and chemotherapy for recurrent tumor.
Subependymal Giant Cell Astrocytoma
Background
1. Subependymal giant cell astrocytoma (SEGA) is a slow-growing focal astrocytoma.
2. Found in children and young adults.
3. Mostly associated with tuberous sclerosis (TS) and present in 15% of patients with TS.
Pathophysiology
1. Associated with neurocutaneous disorders such as TS and nevus sebaceous syndrome.
2. Partial loss of chromosome 22q.
Prognosis
1. Slow growing and benign.
2. Rarely malignant degeneration.
Diagnosis
Location
Arises in the wall of the lateral ventricle, attached to caudate head.
Clinical Presentation
May obstruct CSF flow at the foramen of Monro and cause obstructive hydrocephalus producing headache and visual disturbance.
Diagnostic Tests
MRI shows an intraventricular enhancing mass.
Pathology
1. WHO grade I, giant astrocytes with glassy, eosinophilic cytoplasm, without significant anaplasia. May express neuronal markers.
2. Lesion represents neoplastic transformation of “candle guttering” subependymal nodules in TS.
Differential Diagnosis
Choroid plexus tumors, ependymoma, subependymoma, and astrocytoma.
Treatment
1. Surgical debulking for obstructive symptoms.
2. Occasional role for SRS or SRT.
3. No role for chemotherapy.
High-grade Astrocytomas
Background
1. In adults, high-grade astrocytomas (HGAs) are the most common malignant PBT (60% to 70%) and include AA, anaplastic mixed oligoastrocytoma (AOA), and GBM.
2. Approximately 14,000 new cases of HGA are diagnosed each year and account for 2.3% of all cancer-related deaths. Incidence of GBM is 3 to 4/100,000.
3. AA has a bimodal peak in the first and third decades (peak age, 35 to 50 years).
4. GBM peak age 60 years.
5. Male-to-female ratio is 3:2.
Pathophysiology
1. Usually sporadic. A minority of HGA arise from low-grade astrocytomas.
2. Difficult to treat because they diffusely infiltrate surrounding tissues and frequently cross the midline to involve the contralateral brain.
3. Associated with EGFR and PDGF overexpression, and p16, PTEN, and p53 mutations (see Primary Brain Tumors, Pathophysiology, Molecular Genetics, above).
Prognosis
1. Uniformly fatal despite aggressive therapy. Occasional long-term survivors.
2. Factors that portend a poor prognosis: Age older than 50, subtotal resection, poor functional status (KPS < 70), abnormal mental status.
3. For GBM, the median survival is 15 months despite maximal therapy.
4. For AA, the median survival is 2 to 3 years with maximal therapy.
5. For AOA, the median survival is 3 to 5 years with maximal therapy.
Diagnosis
Location
Cerebral hemispheres, especially frontal (40%) and temporal (30%) lobes, and rarely in adults’ brainstem, cerebellum, and spinal cord.
Clinical Presentation
1. Patients often present with symptoms of increased ICP (headache, nausea, vomiting), seizures, or focal neurologic findings related to the size and location of the tumor and associated peritumoral edema.
2. Can have symptoms up to 2 years before diagnosis in AA and for several months with GBM.
Diagnostic Tests
1. Both AA and GBM on CT and MRI can show heterogeneous enhancing lesions with vasogenic edema, mass effect, and frequently, tracks along white matter paths including the corpus callosum (butterfly glioma). Occasionally have associated
hemorrhage or calcification. GBM usually also has ring enhancement and central necrosis.
2. MRS shows elevated choline peaks (reflecting active membrane synthesis) and decreased N-acetyl aspartate peaks (reflecting neuronal loss).
3. In recurrent glioma, PET, thallium/technetium SPECT, or MRS can help distinguish radiation necrosis (hypometabolic) from tumor (hypermetabolic).
4. Histologic diagnosis ultimately depends on obtaining tissue via biopsy or craniotomy.
Pathology
1. AA (WHO grade III): Mitoses, nuclear atypia, hyperchromatic nuclei.
2. GBM (WHO grade IV): Pseudopalisading areas of necrosis, endothelial vascular proliferation, pleomorphism, and mitosis. Variants include giant cell GBM (large bizarre cells), small cell GBM, GBM with oligodendroglial features and gliosarcoma (spindle cell component).
Differential Diagnosis
Includes other PBTs, metastases, lymphoma, and abscess.
Treatment
Surgery
1. Craniotomy with maximal safe resection of tumor improves neurologic deficits and quality of life and results in modest prolongation of survival.
2. The extent of tumor debulking should be documented with an immediate postoperative MRI scan performed with and without contrast.
3. If resection is not possible because the tumor is in eloquent area, it should be biopsied to obtain histologic diagnosis. Every effort should be made to obtain tissue from area of actively growing tumor (usually enhancing area). PET and perfusion MRI may help direct biopsy.
Radiation Therapy
1. RT is standard treatment. Ameliorates symptoms and improves survival by 50% to 100%.
2. Usually 6,000 cGy in thirty to thirty-two 180- to 200-cGy fractions given to localized field surrounding the area of the tumor (T2 abnormality plus 2-cm margin) plus cone-down radiation to the tumor bed.
3. Patients should be followed up closely with serial MRI scans after the completion of RT.
4. Because RT can produce additional BBB dysfunction, corticosteroid requirements may increase and scans may look worse during the first 1 to 2 months after completion of RT, even though there is no actual tumor progression (pseudoprogression).
5. Despite RT, 80% of tumor recur within primary site of disease.
6. Other radiotherapy methods such as brachytherapy, hyperfractionation, radiosurgery, and radiosensitizers have not significantly improved survival.
Chemotherapy
1. Adjuvant chemotherapy is marginally beneficial in prolonging survival and improving quality of life. Overall, it produces an approximately 2.5 months increase in median survival and a small increase in long-term survivors. Benefit greater for young patients, those with AA and AOA and patients with methylation of the methylaguanine DNA methytransferase (MGMT) gene promoter.
2. Alkylating agents are the most active chemotherapeutic agents for HGA.
3. Temozolomide is more effective than carmustine (BCNU) or PCV (procarbazine, lomustine [CCNU], and vincristine).
4. BCNU is administered IV in doses of 200 mg/m2 as a single dose or 80 mg/m2 for 3 days every 6 to 8 weeks. Usually six cycles administered. Dose-limiting toxicities include marrow suppression, pulmonary and hepatic toxicity, and nausea.
5. PCV (procarbazine [60 mg/m2] p.o. on days 8 to 21 every 6 weeks), lomustine (CCNU) (110 mg/m2 p.o. every 6 weeks), vincristine (1.4 mg/m2 [maximum,
2 mg] on days 8 and 29) every 6 weeks for six cycles. Toxicity is similar to that of carmustine. Vincristine may produce neuropathy. Lomustine alone increasingly used instead of PCV.
6. Temozolomide is given with RT (75 mg/m2 p.o. daily for 6 weeks with RT), followed by 4 weeks off treatment, and then 150 to 200 mg/m2 p.o. days 1 through 5 every 28 days for 6 to 12 months. Toxicities include nausea, fatigue, and marrow suppression. Use of prolonged low-dose temozolomide increases risk of PCP. Patients receiving this regimen require PCP prophylaxis.
7. Carboplatin, irinotecan, etoposide, tamoxifen, and cis-retinoic acid have minimal activity.
8. Slow-release polymer wafers impregnated with BCNU (Gliadel wafers) placed in the wall of the surgical cavity at time of debulking improves survival in newly diagnosed and recurrent GBM by approximately 2 months.
9. Increasing evidence suggesting that bevacizumab, a humanized monoclonal antibody that binds vascular endothelial growth factor (VEGF), has antitumor activity and helps reduce peritumoral edema and corticosteroid use.
Experimental Therapies
Targeted molecular therapy (e.g., inhibitors of EGFR and PDFGR receptors and various signal transduction molecules), inhibitors of angiogenesis (e.g., bevaizumab, VEGFR inhibitors), viral gene therapy, tumor vaccines (dendritic and peptide), immunotoxins, monoclonal antibodies, and inhibitors of tumor invasion are being evaluated in clinical trials.
Gliomatosis Cerebri
Background
1. Gliomatosis cerebri is characterized by widespread dissemination of neoplastic astrocytes, often involving an entire cerebral hemisphere with or without discrete mass lesions.
2. These tumors are rare. Peak incidence is 40 to 50 years of age.
Pathophysiology
Molecular genetic alterations in gliomatosis cerebri resemble those in diffuse astrocytomas.
Prognosis
Prognosis is variable but often similar to GBM.
Diagnosis
Location
Diffuse infiltration without discrete tumor masses, usually deep in thalamus and basal ganglia.
Clinical Presentation
Cognitive/neurobehavioral changes, headaches, seizures, and papilledema.
Diagnostic Tests
MRI shows homogenous hypodense areas, loss of gray-white junction, swollen hemispheres, diffuse increase in T2 and FLAIR signal, and minimal to no enhancement.
Pathology
1. Grossly diffuse enlarged brain, microscopically extensive gray-white matter infiltration of tumor cells.
2. Graded from low grade to high grade (WHO grades II to III).
3. Rarely an oligodendroglioma.
Differential Diagnosis
Inflammatory, infectious, or demyelinating process in the appropriate clinical context.
Treatment
1. Stereotactic biopsy needed for diagnosis; usually not resectable.
2. Some patients respond temporarily to radiotherapy.
3. Occasional response to temozolomide and nitrosoureas (lomustine and carmustine).
Brainstem Glioma
Background
1. In children, brainstem gliomas account for 15% of PBTs and include diffuse pontine glioma (80%), cervicomedullary glioma, dorsally exophytic glioma, tectal glioma, and focal glioma.
2. In adults, brainstem gliomas are uncommon and account for less than 3% of gliomas.
Pathophysiology
Usually astrocytic in origin. Its prognosis is generally worse than the pathology would suggest because of its location.
Prognosis
Diffuse pontine glioma has a poor prognosis with a median survival of only 1 year despite aggressive therapy. Intrinsic focal low-grade brainstem gliomas have a better prognosis: 80% 5-year survival.
Diagnosis
Clinical Presentation
Brainstem gliomas present with cranial nerve (CN) palsies, ataxia, weakness, and numbness.
Pathology
Diffuse brainstem gliomas are not usually biopsied. Diagnosis is based on characteristic imaging findings. Focal lesions, especially if they are exophytic, sometimes can be biopsied.
Differential Diagnosis
Includes ependymoma, medulloblastoma, vascular malformation, cysticercosis, encephalitis, tuberculoma, multiple sclerosis, postinfectious encephalomyelitis, or gliosis.
Treatment
1. Surgery may be indicated for cervicomedullary, focal, cystic, or exophytic tumors.
2. Biopsy (open or CT-guided stereotactic) is indicated when the diagnosis of brainstem glioma is in doubt.
3. Treatment for diffuse brainstem glioma is RT (54 to 56 Gy in daily fractions of 1.8 to 2.0 Gy).
4. VP shunt may be necessary for obstructive hydrocephalus.
5. Chemotherapy with temozolomide, PCV, carboplatin of limited benefit.
Oligodendroglioma
Background
1. Comprise up to 20% to 30% of gliomas (increasingly diagnosed as criteria expanded).
2. Most occur at ages 30 to 50, men more often than women.
3. Most common primary tumor to hemorrhage.
Pathophysiology
1. Arise from oligodendrocytes or glial precursor cells.
2. Mixed oligoastrocytomas probably develop from a common glial stem cell.
3. Many have deletions in chromosome 1p and 19q (due to an unbalanced translocation) and PDGF overexpression.
4. (AOs) also have deletions in chromosomes 9p and 10q and overexpression of CDK4.
Prognosis
1. Deletions in 1p and 19q are favorable prognostic factors as they are sensitive to chemotherapy and radiotherapy.
2. Oligodendroglioma: Median survival is 8 to 15 years.
3. Anaplastic oligodendroglioma: Median survival is 3 to 6 years. Chemosensitive and radiosensitive subset with 1p and 19q deletions have longer survival than those without these deletions.
4. Mixed oligoastrocytomas tend to have a prognosis intermediate between AO and AA.
Diagnosis
Location
Frontal and temporal lobes most common.
Clinical Presentation
Usually present with seizures; occasionally headaches, focal deficits, or personality changes.
Diagnostic Tests
CT and MRI show calcification in 50% to 90%; well demarcated, usually no enhancement; located near cortical surface, with little or no edema; cystic (20%); hemorrhage (10%). AOs usually enhance.
Pathology
1. Oligodendroglioma, WHO grade II; AO, WHO grade III.
2. Grossly soft, grayish-pink tumors frequently with calcifications, hemorrhages, cysts, delicate vessels.
3. Microscopically round nuclei with perinuclear halo (“fried-egg” appearance in paraffin), delicate branching vessels (“chicken wire” vasculature), calcification, perineuronal satellitosis (secondary structures of Scherer).
4. Mixed oligoastrocytoma contains both oligodendroglial and astrocytic components.
5. Anaplastic variant has high cellularity, increased mitotic rate, pleomorphism, microvascular proliferation, and occasional necrosis.
Differential Diagnosis
1. Oligodendroglioma must be differentiated from astrocytoma, ganglioglioma, and DNT.
2. AO can be confused with AA and GBM.
Treatment
1. Complete surgical resection preferred and improves survival.
2. RT improves symptoms and survival in patients with partial resection. Patients with 1p deletion have increased response to RT. Trend toward deferring RT because many patients have chemosensitive tumors.
3. Approximately 65% of AOs are sensitive to PCV chemotherapy and radiation. Complete responses are seen in 30% of patients. Most tumors with loss of both chromosomes 1p and 19q are sensitive to chemotherapy. Tumors with intact 1p and no p53 mutations are less likely to respond to chemotherapy.
4. Adjuvant chemotherapy with PCV improves progression-free survival but not overall survival. Temozolomide also active in AO.
5. Treatment of newly diagnosed AO is variable. Options include radiotherapy with concurrent and adjuvant temozolomide, chemotherapy first and deferring RT, or radiotherapy first and deferring chemotherapy until the time of recurrence.
6. Increasing evidence that grade II oligodendrogliomas are also sensitive to PCV and temozolomide.
Ependymal Tumors
Background
1. Ependymomas are tumors derived from ependymal cells that line the ventricular surface.
2. Subependymomas are slow-growing benign lesions that often do not require treatment.
3. Ependymoblastoma is a primitive neuroectodermal tumor (PNET) that occurs in the first 5 years of life.
Epidemiology
1. Mostly in childhood in the first decade and is the most common intraventricular tumor in children.
2. In adults, usually occurs in spinal cord.
3. Slight male preponderance.
4. Comprises 2% to 8% of all PBTs, 6% to 12% of intracranial gliomas in children (much less common in adults), and 60% of spinal cord gliomas (most common spinal cord glioma).
5. Median age of onset for posterior fossa tumor is 6.5 years. Second peak is at 30 to 40 years for spinal cord tumor.
Pathophysiology
1. NF2 gene inactivation on chromosome 22 and mutations on chromosome 11q13.
2. Amplification of mdm2 gene in 35% of cases.
3. A 50% incidence of allelic loss of 17p in pediatric cases.
Prognosis
1. Poor prognostic factors: Age younger than 2 years, incomplete resection, supratentorial location, duration of symptoms less than 1 month, and anaplastic histology.
2. The 5-year survival after complete resection and radiotherapy is 70% to 87% compared to 30% to 40% for partial resection; overall 10-year survival of 50%.
3. In children, fourth-ventricle tumors are clinically more aggressive.
4. Anaplastic ependymoma has a 12% 5-year survival.
5. Subependymoma is indolent and often does not require treatment.
6. The prognosis for ependymoblastoma is poor with death within 1 year of surgery.
Diagnosis
Location
1. Infratentorial in 60% of cases.
2. Most frequently in fourth ventricle (70%), lateral ventricles (20%), and cauda equina (10%).
3. In adults, commonly occurs in lumbosacral spinal cord and filum terminale (myxopapillary ependymoma).
4. May spread via CSF and seed other locations (12%).
5. Ependymoblastoma usually in cerebrum with frequent craniospinal metastasis.
Clinical Presentation
1. Intracranial tumors produce symptoms due to obstruction of CSF flow (headaches, nausea, vomiting, visual disturbance), ataxia, dizziness, hemiparesis, and brainstem symptoms.
2. Spinal cord tumors present as a chronic, progressive myelopathy, or cauda equina syndrome (see the section on Spinal Cord Tumor).
Diagnostic Tests
1. MRI shows a well-demarcated, heterogenous, enhancing intraventricular mass, with frequent calcifications. Obstructive hydrocephalus and hemorrhage may be present.
2. Spinal MRI should be done to rule out neuraxis dissemination.
Pathology
1. Grossly well-circumscribed, tan, and soft tissue.
2. Microscopically densely cellular with ependymal rosettes, blepharoplasts, and perivascular pseudorosettes.
3. In cauda equina, the myxopapillary form is common.
4. Anaplastic ependymomas have malignant features such as mitotic activity, pleomorphism, and necrosis.
5. Ependymoblastoma has ependymoblastic rosettes in fields of undifferentiated cells.
6. Subependymoma is a benign lesion located within ventricles. Has both ependymal and astrocytic features.
Differential Diagnosis
Subependymoma, anaplastic ependymoma, ependymoblastoma, astrocytomas, and medulloblastoma.
Treatment
1. Surgical resection is treatment of choice but many tumors recur regardless of completeness of resection.
2. For ependymoma and anaplastic ependymoma, postoperative local radiation (4,500 to 6,000 cGy) improves survival.
3. Craniospinal radiation reserved for tumors with CSF spread.
4. Chemotherapy is used in children younger than 3 years to delay onset of RT.
5. Results of chemotherapy are generally poor.
Choroid Plexus Tumors
Background
1. Choroid plexus tumors are derived from the choroid plexus epithelium.
2. Peak incidence in the first two decades of life. It is the most common intracranial tumor in the first year of life.
3. Accounts for less than 1% of all intracranial tumors.
Pathophysiology
1. Possible role for simian virus 40 (SV40) in pathogenesis.
2. Choroid plexus papilloma (CPP) (WHO grade I) histologically resembles normal choroid plexus and probably represents local hamartomatous overgrowths.
3. Choroid plexus carcinoma (CPC) (WHO grades III to IV) account for 10% of choroid plexus tumors. They are aggressive tumors with dense cellularity, mitoses, nuclear pleomorphism, focal necrosis, loss of papillary architecture, and invasion of neural tissue. They frequently seed CSF pathways. Usually occurs in children younger than 8 years.
Prognosis
1. Good with CPP. With complete resection, 80% 5-year survival; 4.3% recurrence rate overall.
2. Poor with CPC.
Diagnosis
Location
1. In adults, common in fourth ventricle, lateral ventricle, and third ventricle.
2. In children, most common in lateral ventricles and cerebellopontine angle (CPA).
Clinical Presentation
Present with symptoms secondary to CSF obstruction or CSF overproduction, headaches, nausea, vomiting, ataxia.
Diagnostic Tests
MRI shows homogenous, enhancing mass with prominent flow voids due to rich vascularization, frequent calcification.
Differential Diagnosis
Ependymoma, astrocytoma, and metastases.
Treatment
1. Surgical resection.
2. Postoperative RT for CPC; RT at recurrence for CPP.
Neuronal and Mixed Neuronal-Glial Tumors
Background
1. Initially thought to be hamartomas, but these are ganglion cell tumors that form a continuum between those with mixed ganglion and glial cell components (gangliogliomas) and some that are relatively pure ganglion cell tumor.
2. Include ganglioglioma, gangliocytoma, DNT, neurocytoma, and dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease).
Epidemiology
1. Occur in children and young adults in the first three decades of life.
2. Account for less than 1% of glial neoplasms.
3. Neurocytomas occur in patients aged 20 to 40.
Pathophysiology
1. Uncertain.
2. Gain of chromosome 7 in neurocytomas.
3. Gangliogliomas associated with Down syndrome, callosal dysgenesis, and neuronal migration disorders.
4. Lhermitte-Duclos disease may occur as part of Cowden disease (mucosal neuromas and breast cancer), an autosomal dominant disorder caused by germline mutation of PTEN gene.
Prognosis
1. Ganglioglioma: Indolent, cured with surgery. If subtotal resection, 41% progress. Rare malignant transformation from glial component; 89% 5-year and 84% 10-year survival.
2. Neurocytoma: Good with resection, recurrence, and CSF spread are rare.
3. DNTs are indolent.
4. Lhermitte-Duclos disease: Good with resection.
Diagnosis
Location
1. Gangliogliomas have a predilection for temporal lobe but also occur in the basal ganglia, optic pathway, brainstem, pineal gland, cerebellum, and spinal cord.
2. Neurocytomas are intraventricular, usually in body of lateral ventricle, attached to septum pellucidum. Rarely in pons, cerebellum, spinal cord, or brain parenchyma.
3. DNTs involve predominantly the cerebral cortex, especially temporal lobes.
4. Lhermitte-Duclos disease occurs in cerebellum.
Clinical Presentation
1. Gangliogliomas usually present with seizures and, less often, headaches and focal deficits.
2. Neurocytomas present with symptoms of hydrocephalus.
3. DNTs usually have chronic complex partial seizures.
4. Lhermitte-Duclos disease presents with ataxia and hydrocephalus.
Diagnostic Tests
1. Ganglioglioma: MRI is nonspecific and shows a well-demarcated, superficial, nonenhancing mass with increased T2 and FLAIR signal. Can have cysts or calcification.
2. Neurocytoma: MRI shows a heterogenous mass with multiple cysts, calcification, occasional hemorrhage, variable enhancement; some have a “honeycomb” appearance on T1-weighted images.
3. DNT: MRI shows a multicystic nonenhancing mass with gyrus-like configurations, cortical dysplasia.
4. Lhermitte-Duclos disease: MRI shows increased T2 and FLAIR abnormality in cerebellum with striped “tigroid” appearance.
Pathology
1. Gangliogliomas (WHO grades I to II) have neuronal and astrocytic neoplastic cells, granular bodies, Rosenthal fibers, large irregular ganglion cells, and perivascular infiltrates.
2. Neurocytomas (WHO grade I) have small, uniform, well-differentiated neuronal cells, frequently misdiagnosed as oligodendrogliomas.
3. DNTs (WHO grade I) have a glioneuronal element, nodular component, and cortical dysplasia.
4. Gangliocytomas (WHO grade I) are well-differentiated neoplastic cells with neuronal characteristics, no malignant transformation.
5. Lhermitte-Duclos (WHO grade I) disease has a dysplastic gangliocytoma con-fined to cerebellum; Purkinje cell layer is absent.
Treatment
1. Surgical resection; complete resection is curative for all these conditions.
2. RT may have limited role for recurrent gangliogliomas.
3. Anaplastic gangliogliomas may respond to chemotherapy with temozolomide or PCV.
Pineal Parenchymal Tumor
Background
1. Rare tumors that account for fewer than 1% of all intracranial tumors; 14% to 30% of pineal region tumors.
2. Pineocytoma most common between 25 and 35 years; pineoblastoma most common in the first two decades.
Pathophysiology
Arise from pinocyte in pineal gland.
Prognosis
1. Pineocytoma is slow growing and has favorable prognosis following resection; 86% 5-year survival.
2. Pineoblastoma has poorer prognosis; less than 50% 5-year survival.
3. Pineal parenchymal tumors of intermediate differentiation (PPTIDs) have an intermediate prognosis.
Diagnosis
Location
Pineal gland; pineoblastoma has relatively frequent leptomeningeal metastases.
Clinical Presentation
