The Washington Manual of Oncology, 3 Ed.

Neuro-oncology

Andrew Lin • Jian Campian • Michael R. Chicoine • Jiayi Huang • David D. Tran

 I. GENERAL APPROACH TO EVALUATING AN INTRACRANIAL MASS LESION

1. Presentation. Intracranial mass lesions can be found during an evaluation for headache, seizure, or a focal neurological deficit; occasionally, they are also found incidentally. Brain tumors may cause an obstructive hydrocephalus or increased intracranial pressure through mass effect, resulting in headache, nausea, and vomiting. If they cause hydrocephalus, depending on the severity, brain tumors can cause global neurologic dysfunction. More typically, brain tumors give rise to focal deficits or changes in behavior that are slowly evolving or occasional, sudden in onset, particularly in the setting of a seizure.
2. Evaluation. Intracranial mass lesions have a wide spectrum of differential diagnoses, and it can be difficult to distinguish among the possible etiologies by imaging characteristics. Lesions due to a primary or secondary brain tumor can be difficult to differentiate from one another and from lesions of other etiologies such as infection (e.g., an abscess), areas of demyelination, and even subacute stroke. Therefore, definitive management of an intracranial mass lesion often requires a tissue diagnosis.

 Common primary brain tumors and their relative frequencies can be found in Table 10-1.

1. Treatment. Prior to tissue diagnosis, two important management considerations are the treatment of seizures and increased intracranial pressure.
2. Seizures. Seizures are a common complication of supratentorial tumors, and treatment should be initiated after the first seizure. In patients with a tumor who have never had a seizure, there is data supporting the use of short-term perioperative seizure prophylaxis, but no definitive data supporting the use of long-term seizure prophylaxis. Levetiracetam and lacosamide are the antiepileptic drugs of choice as they do not have significant drug–drug interactions and are unlikely to interfere with chemotherapy unlike older antiepileptic drugs.

TABLE 10-1

Primary Brain Tumors and Their Frequency

2. Increased intracranial pressure. Another common neurologic complication of brain tumors is mass effect and vasogenic edema. Tumor-induced edema is commonly treated with corticosteroids such as dexamethasone. However, if there is clinical or radiological suspicion for CNS lymphoma, corticosteroid treatment should be withheld if possible until after the tissue biopsy, as corticosteroids may severely hamper diagnostic yield. Once symptoms improve, attempts should be made to wean patients off or to a lower dose of dexamethasone as soon as clinically safe to avoid the potentially debilitating, long-term side effects of chronic corticosteroid treatment. In recent years, bevacizumab, an anti-VEGFA monoclonal antibody, has increasingly been used to decrease symptoms from mass effect, that is, as a steroid-sparing agent.
3. GLIOMAS
4. Introduction. Gliomas account for 30% of all primary CNS tumors, but cause a disproportionate amount of morbidity and mortality as they comprise 80% of all malignant primary brain tumors.

The World Health Organization (WHO) grades gliomas on a scale of I to IV and then subclassifies gliomas by histology (Table 10-1). In this classification scheme, gliomas are classified by the cell type(s) that the predominant tumor cell population resembles. Historically, gliomas were thought to arise following the transformation of fully differentiated glia: that is, astrocytomas arise from astrocytes and oligodendrogliomas arise from oligodendrocytes. It is now hypothesized that these tumors result from the transformation of neural stem cells (N Engl J Med 2005;353:811) and that the phenotype is a function of their molecular makeup. An early mutation that gives rise to slow-growing, indolent gliomas is the IDH1 mutation. Greater than 90% of IDH1 mutations occur at R132H; this mutation can be identified by immunohistochemistry and is an important pathologic finding as it has prognostic, and likely predictive, significance.

1. WHO grade IV (Glioblastoma Multiforme)
2. Epidemiology. Glioblastoma multiforme (GBM) is the most common subtype of gliomas, accounting for approximately 50% with an incidence of 2 to 3 per 100,000 people. These tumors can arise de novo as grade IV astrocytomas (primary GBM) or less frequently, following transformation of lower grade gliomas (secondary GBM). Primary GBMs occur most commonly in older patients with a median age of 55 years, whereas secondary GBMs typically occur in younger patients with a median age of 39 years. Despite maximal medical management and an improved understanding of their genetic compositions, prognosis remains poor.
3. Imaging. On magnetic resonance imaging (MRI), GBMs typically demonstrate a prominent enhancement pattern that can be peripheral or solid. The tumor is T2 hyperintense with surrounding vasogenic edema, T1 hypointense, and frequently crosses to the contralateral hemisphere. Because these tumors are highly cellular, they often restrict diffusion weakly in comparison with bacterial brain abscesses, which typically have prominent area of restricted diffusion.
4. Pathology. When GBMs arise de novo, GBMs are almost exclusively IDH1 mutation–negative. In these tumors, the methylation status of the MGMT promoter is the marker of prognostic and predictive significance. MGMTencodes a DNA repair enzyme. When the expression of the MGMT gene is silenced via methylation of CpG islands in the promoter, GBMs are less aggressive and more sensitive to alkylating agents like temozolomide (N Engl J Med 352:997). The median survival of patients with GBM possessing a methylated MGMT promoter and treated with concurrent chemoradiotherapy is 21.7 months—in contrast to a median survival of 12.7 months in similarly treated tumors with an unmethylated promoter.
5. Treatment. When a lesion suspicious for GBM is in an eloquent location within the brain and is unresectable, a biopsy is indicated. When the lesion is amenable to surgery, a gross total resection or maximal debulking is preferred. In fact, there is limited class I evidence that demonstrates a survival advantage when the grossly abnormal brain tissue is completely resected. Unfortunately, GBMs are diffusely infiltrative, and therefore surgery is not curative. To further reduce the tumor burden regardless of the extent of resection, standard of care in the treatment of newly diagnosed GBM includes concurrent conformal fractionated radiation and temozolomide chemotherapy, as protocoled by EORTC 22981 (N Engl J Med 2005;352:987). In this trial, 18- to 70-year-old patients with newly diagnosed, resected GBM were randomized to radiotherapy alone or concurrent radiotherapy and temozolomide chemotherapy. The median survival was extended by 2.5 months with the addition of temozolomide to radiation—12.1 to 14.6 months, and the 2-year survival rate increased from 10.4% to 26.5% in the combined modality arm. Notably, survival in GBM favors young persons with a better performance status.

 3-D conformal radiotherapy to the volume of the tumor and a surrounding margin is administered in daily fractions of 2 Gy given 5 days per week for 6 weeks for a total dose of 60 Gy. Temozolomide is administered concurrently with radiation at 75 mg/m² orally daily during the entire 6-week period of radiation. After a 4- to 6-week break, maintenance temozolomide is given at 150 to 200 mg/m² orally daily for five consecutive days every 28 days for a minimum of six cycles. Throughout the treatment course, frequent laboratory testing, in particular complete blood counts and complete metabolic panel, is recommended. Thrombocytopenia, neutropenia, and severe lymphopenia are common reasons for the discontinuation and/or dose modifications of temozolomide. In patients who become severely immunosuppressed with CD4 counts less than 200 cells/mm³, trimethoprim-sulfamethoxazole is often used as prophylaxis against Pneumocystis jirovecii (PCP) pneumonia.

 In 2009, bevacizumab, a humanized monoclonal antibody that targets VEGF, was granted accelerated approval by the U.S. Food and Drug Administration (FDA) as a single agent in recurrent GBM. The approval was based on demonstration of durable objective response rates observed in two prospective single-arm phase II studies (J Clin Oncol 2009;27:4733; J Clin Oncol 2009;27:740). However, two recent Phase III randomized, placebo-controlled, double-blinded trials using bevacizumab in combination with standard conformal radiation and concurrent temozolomide in newly diagnosed GBM have shown an improvement in progression-free survival of 3 to 4 months, but failed to show an improvement in overall survival. The AVAglio trial conducted in Europe reported an improvement in patients’ quality of life with the addition of bevacizumab. In contrast, the RTOG 0825 study in North America registered a negative impact on neurocognitive function in the bevacizumab arm. As a result, the ultimate utility of antiangiogenic therapy in the management of newly diagnosed GBM remains unclear.

5. Monitoring. Radiologic surveillance by MRI is routine practice. During the first 3 months after chemoradiotherapy, patients can develop worsening contrast enhancement that is indistinguishable from true tumor progression. This is due to breakdown of the blood–brain barrier from robust peritumoral inflammation induced by therapy. This phenomenon is known as pseudoprogression. Late pseudoprogression, often referred to as radiation necrosis, can also occur months, and rarely years, after radiotherapy has been completed and is thought to be related to delayed ischemic changes caused by radiation damage. Pseudoprogression and radiation necrosis are not only a radiologic phenomenon, but also can precipitate significant neurologic complications when they are associated with significant vasogenic edema and mass effect. Distinguishing between pseudoprogression/radiation necrosis and true tumor progression is difficult. Radiologic techniques such as 18-Fluoro-deoxyglucose positron emission tomography (FDG-PET) and MRI perfusion may be helpful in distinguishing between the two processes, but their use has not been validated prospectively. The only definitive way to differentiate the two is by obtaining additional tissue or by serially imaging the lesion in question and monitoring for regression or stability—which is evidence of pseudoprogression—or enlargement of the contrast enhancement, which is evidence of progression.
6. WHO grade III
7. Epidemiology. Approximately 10% of gliomas that are diagnosed each year are anaplastic (WHO grade III) astrocytomas, and another 5% to 10% are anaplastic oligodendrogliomas and mixed oligoastrocytomas.
8. Imaging. Anaplastic astrocytomas have poorly defined borders with heterogeneous signal intensity on T1 and T2, and these tumors frequently contrast enhance, although not as intensely as GBM. Anaplastic oligodendrogliomas are frequently T2 hyperintense and T1 hypointense, and are frequently calcified, which can be seen on susceptibility-weighted imaging. Contrast enhancement occurs less frequently in oligodendrogliomas, and when it occurs, the enhancement is typically faint.
9. Pathology. WHO grade III gliomas can be histologically classified as astrocytomas, oligodendrogliomas, or mixed oligoastrocytomas. These tumors are frequently IDH1 mutated and are predicted to follow a more indolent growth pattern. In oligodendrogliomas and rarely mixed oligoastrocytomas, a recurrent cytogenetic abnormality of prognostic and predictive importance is loss of heterozygosity at chromosomes 1p and 19q. In one large series, 89% of oligodendrogliomas, 19% of mixed oligoastrocytomas, and 0% of pure astrocytomas harbor the 1p and 19q codeletions (J Clin Oncol 2006;24:5419). Therefore, oligodendrogliomas typically carry the best prognosis, followed by mixed oligoastrocytomas and then astrocytomas.
10. Treatment. Like GBM, WHO grade III gliomas are considered high-grade, malignant gliomas and are often managed similarly to GBM, with maximal resection followed by radiotherapy and temozolomide. The exception is anaplastic oligodendrogliomas and mixed oligoastrocytomas with 1p and 19q codeletions, in which activity of an older chemotherapy regimen, PCV (procarbazine, CCNU, and vincristine), and not temozolomide, has been clearly demonstrated in the randomized, controlled RTOG 9402 trial. Overall survival was extended with the addition of PCV to radiation in patients with 1p and 19q codeletions from a median of 7.3 years to a median of 14.7 years. Patients without 1p, 19q codeletions derived no appreciable survival benefit with the addition of PCV. Randomized studies are currently ongoing to prospectively examine the benefit of temozolomide for grade III gliomas and to compare it with PCV chemotherapy.
11. Monitoring. The natural history of these tumors is that they tend to progress to grade IV. Therefore, routine MRI surveillance is required. Like GBM, pseudoprogression and radiation necrosis are frequent imitators of true progression following chemoradiotherapy.
12. WHO grade II
13. Epidemiology. Low-grade gliomas (WHO grade II) are also astrocytomas, oligodendrogliomas, or mixed oligoastrocytomas and account for about 20% of all gliomas.
14. Imaging. Typically, these tumors do not contrast enhance and are more homogeneously T1 hypointense and T2 hyperintense.
15. Pathology. Again, these tumors are frequently IDH1 mutated. In low-grade gliomas with an oligodendroglial component, the presence or absence of 1p and 19q codeletions is again of prognostic, and perhaps predictive, significance.
16. Treatment. Patients with low-grade gliomas also undergo resection if the tumor is surgically amenable. Once the diagnosis is made, they are often watched expectantly, unless the patient and tumor carry markers of poor prognosis (such as age >40 years, a high proliferative index, a substantial amount of residual disease, and significant neurological symptoms), as upfront radiation therapy has been shown to improve progression-free survival, but failed to enhance overall survival compared with patients who were followed expectantly and treated at the time of disease recurrence of progression (Lancet 2005;366(9490):985). The rationale behind postponing radiotherapy is to delay the neurocognitive side effects of treatment, especially in younger patients.
17. Monitoring. Again routine surveillance with MRI is required as the natural history of these low-grade tumors is their tendency to transform into higher grade tumors. When treatment is deferred, it is important that the patient is closely monitored for radiographic evidence of transformation to a higher grade tumor.
18. Pilocytic astrocytomas (WHO grade I)
19. Epidemiology. Pilocytic astrocytomas are the most common WHO grade I gliomas. These tumors are slow-growing, circumscribed, often cystic lesions that occur more frequently in children and young adults.
20. Presentation. They often occur in the cerebellum, anterior optic pathways, and brain stem, and present with chronic signs of neurologic dysfunction related to location, such as obstruction of cerebrospinal fluid (CSF) pathways causing hydrocephalus, focal neurologic deficits, and, rarely, seizures.
21. Imaging. These tumors are circumscribed and often have a cystic component and a nodule that is intensely contrast enhancing.
22. Pathology. A significant proportion of pilocytic astrocytomas occur in the setting of the neurofibromatosis type 1 (NF1) tumor predisposition syndrome, caused by a germline mutation in the tumor suppressor, NF1. Owing to a less aggressive phenotype, NF1-associated pilocytic astrocytomas are managed more conservatively than the sporadic variety. Sporadic pilocytic astrocytomas do not harbor mutations in NF1, but are frequently associated with molecular changes in the BRAF serine/threonine kinase gene (in 50% to 65% of tumors of all locations and 80% of cerebellar tumors) and are associated with a less aggressive clinical phenotype.
23. Treatment. In sporadic (non-NF1–associated) pilocytic astrocytomas, complete surgical excision is the preferred treatment when the tumor is surgically amenable as this approach is potentially curative (10-year survival rate is >80%). For unresectable tumors, radiation was for many years the primary treatment modality. However, in recent years, chemotherapy and debulking surgeries have been used as the primary treatment to delay radiation and the cognitive side effects that occur with radiation.
24. Monitoring. Long-term follow-up with serial imaging is warranted even when total resection has been performed, as these tumors may recur after resection.
25. Ependymoma (WHO grade II and III)
26. Epidemiology. This subset of tumors comprises 5% to 8% of gliomas and occurs in all age groups but is more common in children.
27. Presentation. These tumors typically occur along the ventricular system at the 4th ventricle, the lateral ventricles, the cerebral aqueduct, or within the spinal cord. Presenting symptoms are variable and depend on the location of the tumor.
28. Imaging/Diagnostic testing. On MRI, these tumors are hyperintense on T2, hypo- to isointense on T1, and the majority of tumors are contrast enhancing.

 In children, ependymomas typically develop in the posterior fossa. In adults, and patients with NF2, the majority of ependymomas occur along the spinal cord. Ependymomas infrequently develop supratentorially—when this occurs they can be intraparenchymal or intraventricular.

 Ependymomas often track along CSF pathways into the cisterns; hence, at the time of diagnosis, 10% to 30% have disseminated disease and have seeded the spinal column with “drop metastases.” Because of the high incidence of CSF dissemination, all patients with ependymomas should have imaging of the entire neuroaxis. Of note, the role of CSF cytology is not completely defined, as it is unclear whether CSF cytology can detect microscopic dissemination that cannot be appreciated on imaging.

4. Treatment. In all patients with ependymoma, extent of surgical resection is an important prognostic factor in that complete surgical removal will cure a small percentage of cases. As these tumors frequently recur even in patients with a complete resection, focal radiation to the tumor bed is recommended and has been shown to result in a survival advantage. In the case of CSF dissemination, radiation to the entire neuroaxis may provide some benefit.

 Overall, children have a poorer prognosis than adults, possibly related to the infratentorial predominance. Subtotal resection, age younger than 3 years, and anaplastic features are all associated with a poorer prognosis.

 Tumor recurrence often occurs at the original tumor site, and the recurrent tumor usually remains a similar grade, although progression can occur. Overall, 5-year survival ranges are 30% to 40% in children and 40% to 50% in adults.

 III. METASTASES TO THE CNS

1. Brain metastases
2. Epidemiology. Secondary brain tumors that arise from a primary tumor outside the CNS are overwhelmingly the most common malignant intracranial masses found in adults. Autopsy studies have revealed the presence of intracranial metastasis in ~25% of cancer patients. The majority of brain metastases in adults result from primary malignancies arising from lung, breast, and melanoma.
3. Presentation. The presenting signs and symptoms of intracranial metastases are similar to those of most primary brain neoplasms (i.e., focal neurologic deficit, headaches, and seizures). Close to 10% of brain metastases present as foci of intraparenchymal hemorrhage. The intraparenchymal hemorrhage can conceal the tumor at the time of initial presentation, resulting in a delay in diagnosis. In particular, melanoma, choriocarcinoma, thyroid carcinoma, and renal cell carcinoma are commonly associated with symptomatic hemorrhage. Other cancers, such as lung cancer, hemorrhage less frequently, but owing to the sheer numbers of metastatic cases, account for a significant proportion of hemorrhages associated with brain metastases.
4. Imaging. Brain metastases may be single or multiple, and tend to be located at the gray–white junction. They are usually well circumscribed, demonstrate peripheral enhancement on computed tomography (CT) or MRI, and often cause significant vasogenic edema. The finding of multiple synchronous lesions in an immunocompetent individual strongly supports the diagnosis of brain metastasis and is helpful in differentiating them from primary brain tumors or other mass lesions. In a patient who is found to have a brain mass that looks like it could be a metastasis but no primary is known, the evaluation should focus on the lungs, as 66% of these patients will have a lesion on chest radiography that represents primary lung cancer or pulmonary metastasis from other sites.
5. Treatment. The mainstays of treatment for metastatic disease are corticosteroids and, where appropriate, surgery and/or radiotherapy. Prognosis with treatment is related to age, Karnofsky performance score (KPS), number of metastases, response to therapy, and status of systemic disease.

 After the diagnosis of brain metastasis, corticosteroids are typically started, then either tapered off or down to the lowest tolerated dose following cytoreduction of the tumor. Antiepileptic drugs are indicated in patients that have had a seizure and may be used prophylactically in patients following surgery, but again, there is no data supporting the use of long-term seizure prophylaxis in patients who have not had a seizure.

1. Whole brain radiation. Without treatment, patients with metastases to the brain have a life expectancy of about 1 month, though there is wide variability. With the addition of corticosteroids, median survival is extended to approximately 2 months. The first major advance in the treatment of brain metastases was whole brain radiation, which provides symptomatic improvement in most patients and extends survival to approximately 4 months. It is still widely used in patients with brain metastases that are too numerous to be treated with surgery or stereotactic radiosurgery. It is also used in patients in whom the primary goal is palliation due to their poor prognosis.

 In patients that have received surgery or stereotactic radiosurgery, whole brain radiation has not been shown to improve overall survival, though it may improve control of intracranial tumor burden over a period of months. Since whole brain radiotherapy has significant potential neurocognitive effects, it may be reasonable to withhold in this setting until the time of recurrence. A recent randomized study has shown that memantine (an NMDA receptor antagonist) when given concurrently with (and for at least 6 months after) whole brain radiotherapy appears to reduce the decline in delayed recall and cognitive function (Neuro-Oncology2013;15:1429).

1. Surgery versus stereotactic radiosurgery. Surgery is the current treatment of choice for solitary brain metastases in patients with fair control of systemic disease, and in whom the lesion is in a surgically amenable location. Surgical excision not only appears to improve survival, it provides a tissue diagnosis and results in rapid decompression in patients with a large tumor with significant mass effect and vasogenic edema, and provides relief in patients with hydrocephalus from a posterior fossa tumor.

 Alternatively, patients may be treated with stereotactic radiosurgery if the lesion is 3 to 4 cm or smaller. Several retrospective studies of radiosurgery have demonstrated a survival benefit that is comparable to surgery. The downside of radiosurgery is that it does not provide a tissue diagnosis. Nevertheless, it is a viable treatment option, especially for metastases that are surgically inaccessible and occur in the setting of poorly controlled systemic disease. It is often used when there are multiple but limited lesions, such as less than 4 to 5.

 In patients that undergo surgery in whom whole brain radiation is withheld, adjuvant radiosurgery to the resection site is an alternative to reduce the risk of local recurrence.

 Chemotherapy has an increasing, although still emerging, role in the treatment of brain metastases. The blood–brain barrier is a limiting factor in the use of chemotherapy for brain metastases in that it prevents the efficient passage of many therapeutic agents. For the vast majority of brain metastases, chemotherapy has an ancillary role. That said, early successes have been reported with antibody-based therapies and small molecule targeted therapies that may have better blood–brain barrier penetration, such as sorafenib in renal cell carcinoma that is metastatic to the brain or BRAF inhibitors in melanomatous brain metastases. The only tumors where chemotherapy is used as first-line treatment is in exquisitely chemosensitive tumors such as metastatic germ cell tumors, choriocarcinoma, and lymphoma.

1. Leptomeningeal metastasis
2. Overview. Leptomeningeal metastasis is also known as carcinomatous meningitis or leptomeningeal carcinomatosis and is the metastatic spread of a malignancy to the leptomeninges (pia and arachnoid mater, which make up the subarachnoid space).
3. Epidemiology. Autopsy studies have shown that leptomeningeal metastasis is present in 1% to 8% of cancer patients. The same solid tumors that frequently metastasize to the brain parenchyma, such as lung, breast, and melanoma, also metastasize to the leptomeninges. Additionally, in leptomeningeal carcinomatosis, leukemia and systemic lymphoma are also frequent perpetrators.
4. Presentation. The presenting signs and symptoms of leptomeningeal metastasis are widely variable and include diffuse neurologic dysfunction. These patients may have signs of hydrocephalus and increased intracranial pressure, headache, nausea and vomiting, focal neurologic deficits, seizures, cranial neuropathies, meningismus, cerebellar symptoms, or myelopathy.
5. Imaging/Diagnostic tests. Patients with suspected leptomeningeal metastasis should receive an MRI of the brain and entire spinal cord. MRI is fairly sensitive in evaluating for leptomeningeal involvement of solid tumors, but is significantly less sensitive in detecting leptomeningeal spread in hematopoietic malignancies.

 CSF cytology may provide a definitive diagnosis. The sensitivity of CSF cytology increases with repeated sampling from 71% after the first lumbar puncture to 86% after two and 90% after three lumbar punctures. The diagnostic yield of CSF sampling can also be increased by performing flow cytometry for hematopoietic malignancies and by testing for tumor markers for solid tumors.

5. Treatment. Treatment options include radiation and systemic or intrathecal chemotherapy. The main role of surgery is palliation of hydrocephalus via shunting.
6. Symptomatic therapy. In patients with headache, intracranial pressure should be evaluated by lumbar puncture. In the setting of increased intracranial pressure, corticosteroids can be used to treat edema, and even in the absence of hydrocephalus, shunting can be considered.
7. Radiation. With the exception of hematologic malignancies, in which radiation to the brain and the entire spinal cord is fairly common, radiation is primarily used for directed palliation of symptoms and bulky disease seen on imaging, as radiation of the entire neuroaxis is often poorly tolerated. With radiation, noncommunicating hydrocephalus from leptomeningeal carcinomatosis can frequently be treated without shunting.
8. Chemotherapy. For leptomeningeal carcinomatosis, chemotherapy can be delivered intrathecally or systemically. Intrathecal chemotherapy is the delivery of chemotherapy through an Ommaya reservoir or a lumbar puncture catheter. The typical agents used for intrathecal treatment are methotrexate, thiotepa, and cytarabine. Intrathecal administration of chemotherapy bypasses the blood–brain barrier—the main barrier in treating patients with systemic chemotherapy. Because of the blood–brain barrier, only certain drugs can achieve therapeutic levels in the CNS when administered systemically. The benefit of systemic chemotherapy compared with intrathecal chemotherapy is that it treats both CNS and non-CNS disease.
9. Prognosis. The prognosis of leptomeningeal metastasis is poor with the median survival between 2 and 3 months for solid tumors and closer to 5 months for hematological malignancies.

 IV. MENINGIOMAS

1. Epidemiology. Meningiomas are benign, slow-growing, extra-axial tumors that are attached to the dura mater and arise from arachnoidal cap cells. They represent 30% of primary intracranial tumors and are a common incidental finding at autopsy. Advances in cranial imaging have increased the number of incidentally discovered asymptomatic lesions.

The peak age for meningiomas is 45 years of age, and there is a female predominance of almost 3:1, which increases to almost 10:1 for spinal meningiomas. These tumors are rare in children, except in association with neurofibromatosis type 2 in whom multiple meningiomas can develop at a younger age.

1. Presentation. Most meningiomas are present for many years prior to diagnosis, but are asymptomatic until they slowly reach a size where they begin to compress adjacent structures. Neurologic deficits that can occur include vision loss, cranial nerve palsies, hearing loss, mental status changes, motor weakness, and deficits arising from obstructive hydrocephalus. These tumors may also come to attention during the evaluation of seizures or headaches.
2. Imaging. These tumors may occur in almost any location but favor the falx cerebri, the cerebral convexity, the skull base (at the sphenoid bone, olfactory groove, parasellar region, the posterior fossa), the tentorium cerebelli, the ventricles, and the spinal canal.

Meningiomas frequently demonstrate calcifications and typically have an extra-axial location. On MRI, these tumors are typically isointense on T1 sequences without contrast, and homogeneously enhancing on T1 sequences with intravenous gadolinium administration. An attachment to adjacent dura may be visualized on the MRI (a “dural tail”), and significant edema in the surrounding brain parenchyma may be seen.

Imaging is problematic in differentiating atypical (grade II) and malignant (grade III) meningiomas from benign (grade I) meningiomas. Nevertheless, peritumoral vasogenic edema, intratumoral cystic change, boney destruction, arterial encasement, hyperostosis of adjacent bone, and extension through the skull base might suggest a higher grade, but not reliably.

1. Pathology. Many histologic variants have been described and are not useful for predicting clinical behavior, except in determining grade. The majority of meningiomas are WHO grade I, although up to 35% of meningiomas are grade II. Only a small minority of the tumors are malignant, WHO grade III tumors.

The grade of the meningioma is of prognostic significance. Grade I tumors often remain stable in size or grow very slowly and are frequently observed. In contrast, grade II tumors recur locally after treatment in 30% to 40% of cases, and the median survival in one reported series was around 12 years. Malignant grade III tumors have a higher recurrence rate of ~80% and have a reduced median survival of about 3 years.

Meningiomas occur in 45% to 60% of persons with neurofibromatosis type 2, which is caused by a germline mutation in the NF2 tumor suppressor. As it turns out, 50% of sporadic meningiomas also harbor NF2mutations; however, in these sporadic meningiomas, mutations in oncogenes like Smoothened (SMO) and PI3K/AKT and in tumor suppressors, other than NF2, have also been identified.

1. Treatment. The decision about whether to treat an asymptomatic meningioma is often difficult and requires consideration of multiple factors including patient age, general medical condition, operative morbidity, as well as tumor size, grade, and location.

Expectant management with serial imaging is often reasonable for incidentally discovered asymptomatic lesions that do not appear to be expanding, infiltrating, or causing significant edema. Surgical removal offers the greatest chance of cure and is usually feasible, depending on the location.

Recent advances in radiotherapy techniques including stereotactic radiosurgery make it an option for treatment including the use of fractionated and stereotactic radiosurgical modalities. Radiotherapy is used in nonoperative cases, as it can result in regression of the tumor after 2 or 3 years; it is also used as adjuvant therapy, when a meningioma is incompletely resected and in grade II and III tumors—even when the tumor is completely resected—since these meningiomas have a high rate of recurrence without additional therapy. Prospective trials are underway that will clarify the indications for radiotherapy in grade II and III meningiomas.

1. PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
2. Overview. Primary central nervous system lymphoma (PCNSL) is an uncommon, typically aggressive form of non-Hodgkin’s lymphoma that does not represent spread from systemic disease. PCNSL can occur in immunocompetent individuals but occurs most commonly in people who are immunosuppressed from HIV infection, immunosuppressive medications, or an inherited immunodeficiency.
3. Epidemiology. The median age at diagnosis is 52 years in an immunocompetent individual and 34 years in an immunosuppressed person, and accounts for 4% of primary CNS tumors.
4. Presentation. Patients with PCNSL come to medical attention because of a focal neurologic deficit, a personality change, or symptoms related to increased intracranial pressure, such as headache, nausea, and vomiting. Seizures and vision changes are less common presentations.
5. Imaging/Diagnostic tests. PCNSL typically causes parenchymal lesion(s) that can be found anywhere, though the most common sites are periventricular and superficial regions of the brain that are adjacent to the ventricle or the meninges. On MRI, noncontrast T1-weighted images are generally hypo/isointense, whereas T2 weighted images are generally iso/hyperintense. Lesions due to PCNSL have moderate-to-marked contrast enhancement and tend to show restricted diffusion due to their high cellularity, even more so than high-grade gliomas and metastases.

For the most part, PCNSL starts intraparenchymally, and the leptomeninges are involved secondarily (in approximately 10% to 25% of patients). In contrast, systemic lymphoma that involves the CNS favors the leptomeninges, and a parenchymal lesion is found only in a third of these patients.

A CT chest/abdomen/pelvis, lumbar puncture if safe, bone marrow biopsy, and at times, testicular ultrasound (especially for men >60 years old) is indicated to evaluate for systemic disease. Many tumors have a rapid lytic response to corticosteroid treatment, so corticosteroids should be withheld until a diagnostic biopsy has been performed, unless there is severe mass effect. In the case when the biopsy is nondiagnostic in the setting of corticosteroid administration, the biopsy should be repeated after stopping the corticosteroid for 10 to 14 days. If CSF cytology is positive, spine MRI should also be acquired.

Patients with suspected PCNSL should be checked for HIV infection and should undergo a detailed ophthalmological evaluation for intraocular involvement, as ocular involvement is present in as many as 20% of all cases and is a more accessible site for biopsy. The diagnosis can be made minimally invasively by lumbar puncture, though the sensitivity of cytology and flow cytometry is low. Brain biopsy is often needed to make the diagnosis.

1. Treatment. 90% of immunocompetent individuals with PCNSL have an aggressive diffuse large B-cell lymphoma. There is no benefit to surgical resection, and so the only surgical indication is stereotactic biopsy for diagnosis.

Although PCNSL is quite radiosensitive, whole brain radiation for this indication is falling out of favor. Radiotherapy can cause progressive memory loss and ataxia, especially in older patients when given concurrently with high-dose methotrexate chemotherapy. Hence, most experts do not recommend its use as an initial treatment unless there is a contraindication to chemotherapy. Radiation can be given as consolidation therapy after induction chemotherapy, or (more commonly) it is reserved for progressive PCNSL that is refractory to treatment with chemotherapy.

In PCNSL, high-dose methotrexate is considered the most active single agent and is frequently used in combination with other chemotherapeutics. In addition to traditional cytotoxic agents, rituximab is used by some experts in CD20-positive non-Hodgkin’s lymphomas, though its use has not been validated by a randomized clinical trial.

1. AIDS-associated PCNSL
2. Epidemiology. PCNSL that occurs in the setting of AIDS has a particularly poor prognosis. PCNSL occurs in HIV-positive patients with a CD4 count less than 50 cells/microL and is an AIDS-defining illness.
3. Imaging/Diagnostic tests. In AIDS patients, the two most common causes of brain lesions are toxoplasmosis and PCNSL. SPECT and PET may be useful in differentiating these two entities.

 The pathogenesis of PCNSL in an immunosuppressed person is strongly tied to EBV infection, as the virus immortalizes B cells and drives their proliferation. In AIDS-associated PCNSL, the rate of EBV infection is 80% to 100%, in contrast to immunocompetent patient populations, where the EBV virus is detected in only 0 to 20% of individuals.

 CSF EBV PCR is thus highly sensitive and specific for HIV-associated PCNSL in an AIDS patient with an intracranial mass. Like PCNSL in immunocompetent individuals, CSF cytology is minimally invasive and can make a definitive diagnosis, but has a low sensitivity of around 25%. Again, the sensitivity of CSF analysis can be increased by concurrently performing flow cytometry.

3. Treatment. Many of the same principles of treatment described above apply to PCNSL in immunocompromised patients. The only difference is that in AIDS-associated PCNSL, the initiation of highly active antiretroviral therapy (HAART) is a cornerstone of treatment since spontaneous remission has been seen with initiation of HAART.

 VI. EMBRYONAL TUMORS (WHO Grade IV)

1. Overview. Embryonal tumors encompass a wide variety of clinically important, mainly pediatric tumors that do not have a universally accepted classification scheme based on histopathologic criteria. They may demonstrate many different patterns of histologic differentiation. Some tumors included in this class are medulloblastoma, ependymoblastoma, medulloepithelioma, atypical teratoid/rhabdoid tumors, and all other tumors known as supratentorial primitive neuroectodermal tumors (PNETs). As a group, they represent aggressive, malignant tumors that are all rather rare with the exception of medulloblastoma. All are WHO grade IV tumors. Medulloblastoma, in particular, accounts for almost a fourth of all pediatric brain tumors and is the most common malignant brain tumor of childhood and in young adults, and as a result, will be reviewed in detail here. Of note, supratentorial PNETs occur most frequently in young adults in their second and third decades of life, and treatment options follow a similar approach as for medulloblastoma.
2. Medulloblastoma
3. Epidemiology. Medulloblastoma occurs primarily in children: 70% of these tumors are found in children younger than age 16 with a peak incidence between ages 5 and 7 years. Less commonly, medulloblastomas develop in adults; when it does, it occurs primarily in the third or fourth decade of life.
4. Presentation. These tumors are typically found in the cerebellum and frequently compress the fourth ventricle. Hence, most patients present with signs and symptoms of hydrocephalus such as papilledema, lethargy, headache, nausea/vomiting, and diplopia; or cerebellar signs and symptoms like nystagmus, clumsiness, and incoordination.
5. Imaging/Diagnostic tests. Radiographic features are of a midline, well-demarcated, densely enhancing cerebellar mass that is often hyperdense on noncontrast CT scan. Obstructive hydrocephalus is a common feature. On MRI, medulloblastomas are iso/hypointense on T1 and heterogeneous on T2 with heterogeneous contrast enhancement.

 In one-third of patients, there is dissemination through the CSF pathways, and rarely the tumor spreads systemically, usually to bone or lung. Hence, neuroimaging of the entire neuroaxis and CSF cytology (preoperatively if it can be performed safely or 10 to 14 days following surgical decompression if the patient is at risk of herniation) are mainstays of the initial evaluation.

4. Pathology. Medulloblastomas have been subclassified by gene expression profiling. It has been found that tumors with activation of WNT have the best prognosis, and tumors with amplification of MYC have the worst prognosis.
5. Treatment. A combined-modality approach is necessary for optimal treatment of these tumors. The goal of surgery in these tumors is always gross total resection, as this improves survival; unfortunately, invasion of the brainstem often limits the surgeon’s ability to completely resect this tumor. Additionally, CSF diversion (temporary ventricular drainage, ventricular shunt, or third ventriculostomy) is often a necessary step in the surgical management of these patients.

 Since medulloblastomas are fairly radiosensitive, craniospinal radiation is often needed to achieve the best possible outcome. As CSF dissemination is common, patients with medulloblastoma are typically treated with radiation to the entire neuroaxis with a boost to the primary site. A notable exception is in children younger than 3 years old, in whom radiation is often withheld or minimized since the toxicity of radiation is significantly greater in this population. In these patients, chemotherapy is used to delay, avoid, or reduce the need for radiotherapy and is widely used. It is also frequently used as adjuvant therapy to reduce the risk of relapse. Chemosensitivity is variable, and a variety of protocols are used. At the time of disease recurrence or progression or in patients with high-risk genetic features and high disease burden, high-dose chemotherapy with hematopoietic stem cell rescue has demonstrated evidence of survival benefit, especially in pediatric and young adult patients.

 Unfavorable prognostic factors for these tumors include an age of presentation of less than 3 years, subtotal resection, dissemination at the time of diagnosis, MYC amplification, and large cell variance. In the last 30 years, outcomes have improved with the current 5-year survival ranging from 50% to 70%.

 VII. NEURONAL TUMORS (WHO Grade I and II)

1. Overview. These tumors are varied in location and histology but share some degree of differentiation into neuronal cell types. All of these tumors are unusual and relatively benign. All are WHO grade I or II and are almost always controlled with surgical excision.
2. Gangliogliomas and gangliocytomas are benign tumors of either ganglionic and glial cells, or ganglionic cells alone. Gangliogliomas may occur anywhere in the CNS, but have a tendency to occur in the temporal lobe, where they are a frequent cause of medically intractable epilepsy. Rarely, the glial component may demonstrate anaplastic or malignant features and designate the tumor as high grade. Surgery is usually curative.
3. Dysembryoplastic infantile astrocytomas/gangliogliomas are large, cystic tumors of the cerebral cortex, often involving the leptomeninges, which are composed of poorly differentiated cells mixed with either neoplastic astrocytes or a neuronal component. They are often large, and typically cause macrocephaly in the affected infant.
4. Dysembryoplastic neuroepithelial tumors are hamartomata-like lesions that have been described in children and young adults, and are found predominantly in males. These tumors are frequently found during resection of lesions for treatment of refractory epilepsy. They are usually supratentorial, retain a cortical topography, and may deform the overlying skull. They may also be associated with areas of cortical dysplasia.
5. Central neurocytoma is a tumor of young adults that characteristically occurs in the lateral and third ventricles in the region of the foramen of Monro. They histologically resemble ependymomas or oligodendrogliomas and are designated WHO grade II. Typically, they cause obstructive hydrocephalus and result in headache, visual changes, or lethargy. In cases in which total resection cannot be performed, postoperative radiotherapy may be considered, although experience is limited.

VIII. TUMORS OF SPECIAL LOCATION

1. Vestibular schwannomas (also known by the older term, acoustic neuroma)
2. Epidemiology. These tumors represent 5% to 7% of intracranial tumors, but 80% of tumors in the cerebellopontine angle (CPA). They are slightly more common in women and are another important tumor type in neurofibromatosis type 2 (NF2). In NF2, they are present in 95% of patients; when vestibular schwannomas occur bilaterally, it is pathognomonic for this tumor predisposition syndrome since the development of bilateral sporadic vestibular schwannomas is exceedingly unlikely.
3. Presentation. Initial symptoms include hearing loss, tinnitus, and disequilibrium, which can progress to further neurologic deficits due to brainstem compression if not treated.
4. Imaging/Diagnostic tests. MRI evaluation demonstrates a rounded, enhancing mass extending into the internal auditory canal. CT imaging of the temporal bone often shows expansion of the internal auditory meatus. Evaluation of individuals must also include audiometric testing to assess hearing quantitatively.
5. Pathology. In sporadic vestibular schwannoma, like NF2-associated cases, these tumors harbor NF2 mutations. Although they are histologically benign, they may cause significant morbidity because of its proximity to the brainstem and adherence to the cranial nerves.
6. Treatment. The decision regarding whether to proceed with treatment using either surgery and/or radiosurgery, considers the age and general medical condition of the patient, hearing status, patient symptoms, and the size of the tumor. Many vestibular schwannomas can be safely monitored with serial imaging studies and assessments of hearing and other neurological functions. Several surgical techniques exist, including middle fossa approaches, translabyrinthine approaches, and retro-sigmoid suboccipital approaches, each with inherent advantages and disadvantages. The goal of surgery is complete resection when safely possible, but may be limited because of close proximity to other cranial nerves and occasionally the brainstem. Some patients, particularly with larger vestibular schwannomas, develop hydrocephalus, which may require a diversionary CSF shunt. Radiosurgery is often an excellent and well-tolerated option, particularly for patients with smaller tumors, but can carry some risk of delayed hearing loss and cranial nerve dysfunction. Subtotal resection followed by stereotactic radiation is a reasonable treatment option as well in some situations, particularly for larger tumors in an effort to improve preservation of the function of the facial nerve and other structures.

 Management decisions are probably best made by a collaborative team including neurosurgeons, radiation oncologists, neuro-oncologists, neuro-otologists, and neuroradiologists.

 Until recently, there were no promising medical therapies for vestibular schwannomas, and so the management of these tumors entailed balancing the risks of surgery or radiosurgery with the natural history of continued observation. It has recently been found that bevacizumab (which carries its own risks) has activity in controlling this tumor and preserving hearing. Currently, a phase II clinical trial (NCT01767792) is underway, to further evaluate bevacizumab’s efficacy and safety in treating vestibular schwannoma, although it is currently being used off-label based on retrospective data.

 The decision-making process is even more difficult in the patient with NF2 and bilateral vestibular schwannomas since these patients tend to be first seen at a younger age, have a higher morbidity associated with resection, and hearing is often compromised in both ears—increasing the stakes of any further hearing loss.

1. Pineal region tumors
2. Overview. Several tumor types occur in the pineal region and are therefore considered as a group under this heading, but in general are relatively uncommon tumors.
3. Germ cell tumors
4. Epidemiology. Intracranial germ cell tumors generally occur in the midline, more often in the pineal region in men or the suprasellar region in women. Over half of the tumors that occur in the pineal region are germ cell tumors, and most of these are germinomas. These tumors are predominantly pediatric tumors, are unusual after young adulthood, and are predominately found in boys. They have an increased incidence in individuals with Klinefelter (XXY) syndrome and are more common in Asia, where it makes up greater than 10% of pediatric CNS tumors in case series from Japan.
5. Presentation. These tumors, when they present as a pineal region tumor, commonly cause obstructive hydrocephalus because of their location and can cause Parinaud’s syndrome including paresis of upgaze and convergence-retraction nystagmus.
6. Imaging/Diagnostic tests. Radiologic appearance is somewhat nonspecific, but generally these tumors are T1 iso- or hypointense, T2 hyperintense, and contrastenhancing.

 The evaluation of someone with a suspected germ cell tumor includes serum and CSF markers such as human chorionic gonadotropin (HCG), alpha-fetoprotein (AFP), and placental alkaline phosphatase (PLAP). These markers are suggestive of certain histologies and are useful in determining prognosis and response to treatment. As many as 35% of germ cell tumors may show metastasis throughout the CNS at the time of discovery; therefore, it is imperative that an MRI is obtained of the entire spinal cord.

1. Pathology. Germinomas are the most common type of germ cell tumor, and 30% will consist of a mixture of cell types. Germinomas make up 60% to 70% of germ cell tumors. They typically demonstrate positivity for PLAP, although HCG may also be present, as they are known to contain elements of syncytiotrophoblastic cells. These tumors are distinct from choriocarcinoma tumors that are positive for HCG, and histologically have evidence of both cytotrophoblastic and syncytiotrophoblastic elements.

 The remainder of germ cell tumors consist of teratomas (mature and immature), embryonal carcinomas, and yolk sac tumors. Positivity for AFP helps distinguish yolk sac tumors. Embryonal carcinoma may express HCG, AFP, or PLAP, although this is inconsistent. With the exception of mature teratomas, most germ cell tumors are considered malignant neoplasms.

1. Treatment. Patients frequently present with hydrocephalus that needs to be addressed with a procedure that diverts CSF. Subsequently, tissue confirmation is typically necessary, particularly in the case of pure germinomas or mature teratomas, in which the tumor markers (HCG and AFP) are not helpful, in order to distinguish them from other types of pineal region tumors. Diagnostic tissue may be obtained by a stereotactic needle biopsy, a transventricular endoscopic technique, or an open transcranial approach, depending upon the circumstances.

 Germinomas are exceptionally radiosensitive, and radiotherapy results in high rates of long-term survival. Chemotherapy is often used to reduce the dose of radiation needed to treat patients with germinomas, and it is used in nongerminomatous germ cell tumors, which are relatively insensitive to radiation, to improve long-term overall survival.

1. Pineal parenchymal tumors. The cells that make up the pineal gland perform a diverse array of neuroendocrine functions, and when neoplasias occur, a spectrum of differentiation from primitive to relatively terminal pineocytes occurs. Tumors are classified as pineocytomas, pineoblastomas, or some intermediate forms, and make up 15% of tumors in the region of the pineal gland. They appear similar to other tumor types in this area, and no serum markers are available.

Pineocytomas tend to occur in adults, are slow growing, and may show a variety of phenotypes such as neuronal or glial lesions. Pineoblastomas are more aggressive tumors that often disseminate throughout the CNS and resemble PNETs histologically.

1. Other. The remainder of pineal region tumors consist of small numbers of miscellaneous tumor types such as meningiomas, craniopharyngiomas, and hemangiomas.
2. Treatment. Management of these lesions is multidisciplinary and somewhat controversial. The pineal region remains a difficult region to access surgically, although an aggressive approach has been advocated by centers with more experience in lesions of this region. Some tumors that are benign may be more amenable to aggressive surgical resection, such as meningioma, epidermoid, and mature teratoma. Stereotactic biopsy is generally safe, although it also carries risk for morbidity and the chance for sampling error because of the mixed nature of many lesions. Several series have demonstrated the usefulness and safety of stereotactic biopsy in initial management of pineal tumors and cysts. The role of radiotherapy including stereotactic radiosurgery and chemotherapy in these tumors is significant.

SUGGESTED READINGS

Batchelor T, Loeffler JS. Primary CNS lymphoma. J Clin Oncol 2006;24(8):1281–1288.

Brastianos PK, Horowitz PM, Santagata S, et al. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet 2013;45(3):285–289.

Caincross G, Wang M, Shaw E, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol 2013;31(3):337–343.

Friedman HS, Prados MD, Wen PY. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27:4733–4740.

Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352(10):997–1003.

Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27:740–745.

Lin AL, Gutmann DH. Advances in the treatment of neurofibromatosis-associated tumours. Nat Rev Clin Oncol 2013;10:616–624.

Lu-Emerson C, Eichler AF. Brain Metastases. Continuum 2012;18(2):295–311.

Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352(10):987–996.

van den Bent MJ, Afra D, de Witte O, et al; EORTC radiotherapy and brain tumor groups and the UK Medical Research Council. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomized trial. Lancet 2005;366(9490):985–990.

Weller M, Pfister SM, Wick W, et al. Molecular neuro-oncology in clinical practice: a new horizon. Lancet Oncology 14(9):e370–e379.