NCI/PDQ<sup>®</sup> Health professionals: Adult Brain Tumors Treatment (PDQ®)

General Information

Note: Information on brain tumors in children is available in the PDQ® summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.

Note: Estimated new cases and deaths from brain and other nervous system tumors in the United States in 2010: 1

New cases: 22,020.
Deaths: 13,140.

Brain tumors account for 85% to 90% of all primary central nervous system (CNS) tumors. 2 Available registry data from the Surveillance, Epidemiology, and End Results (SEER) database for 1996 to 2000 indicate that the combined incidence of primary invasive CNS tumors in the United States is 6.6 per 100,000 persons per year with an estimated mortality of 4.7 per 100,000 persons per year. 3 Worldwide, approximately 176,000 new cases of brain and other CNS tumors were diagnosed in the year 2000, with an estimated mortality of 128,000. 4 In general, the incidence of primary brain tumors is higher in whites than in blacks, and mortality is higher in males than in females. 2

Anaplastic astrocytoma and glioblastoma account for approximately 38% of primary brain tumors; meningiomas and other mesenchymal tumors account for approximately 27%. 2 Other less common primary brain tumors include pituitary tumors, schwannomas, CNS lymphomas, oligodendrogliomas, ependymomas, low-grade astrocytomas, and medulloblastomas, in decreasing order of frequency. Schwannomas, meningiomas, and ependymomas account for as much as 79% of primary spinal tumors. 5 Other less common primary spinal tumors include sarcomas, astrocytomas, vascular tumors, and chordomas, in decreasing order of frequency. The familial tumor syndromes (and respective chromosomal abnormalities that are associated with CNS neoplasms) include neurofibromatosis type I (17q11), neurofibromatosis type II (22q12), von Hippel-Lindau disease (3p25-26), tuberous sclerosis (9q34, 16p13), Li-Fraumeni syndrome (17p13), Turcot syndrome type 1 (3p21, 7p22), Turcot syndrome type 2 (5q21), and nevoid basal cell carcinoma syndrome (9q22.3). 6 7

Few definitive observations on environmental or occupational causes of primary CNS tumors have been made. 2 Exposure to vinyl chloride may predispose to the development of glioma. 8 Epstein-Barr virus infection has been implicated in the etiology of primary CNS lymphoma. 9 Transplant recipients and patients with the acquired immunodeficiency syndrome have substantially increased risks for primary CNS lymphoma. 2 10 (Refer to the PDQ® summary on Primary CNS Lymphoma Treatment for more information.)

The clinical presentation of various brain tumors is best appreciated by considering the relationship of signs and symptoms to anatomy. 2 General signs and symptoms include headaches; gastrointestinal symptoms such as nausea, loss of appetite, and vomiting; and changes in personality, mood, mental capacity, and concentration. Whether primary, metastatic, malignant, or benign, brain tumors must be differentiated from other space-occupying lesions such as abscesses, arteriovenous malformations, and infarction, which can have a similar clinical presentation. 11 Other clinical presentations of brain tumors include focal cerebral syndromes such as seizures. 2 Seizures are a presenting symptom in approximately 20% of patients with supratentorial brain tumors and may antedate the clinical diagnosis by months to years in patients with slow-growing tumors. Of all patients with brain tumors, 70% with primary parenchymal tumors and 40% with metastatic brain tumors develop seizures at some time during the clinical course. 12

Computed tomography (CT) and magnetic resonance imaging (MRI) have complementary roles in the diagnosis of CNS neoplasms. 11 13 The speed of CT is desirable for evaluating clinically unstable patients; it is superior for detecting calcification, skull lesions, and hyperacute hemorrhage (bleeding less than 24 hours old) and helps direct differential diagnosis as well as immediate management. MRI has superior soft-tissue resolution; it can better detect isodense lesions, tumor enhancement, and associated findings such as edema, all phases of hemorrhagic states (except hyperacute), and infarction. High-quality MRI is the diagnostic study of choice in the evaluation of intramedullary and extramedullary spinal cord lesions. 2 In posttherapy imaging, single-photon emission computed tomography (SPECT) and positron emission tomography (PET) may be useful in differentiating tumor recurrence from radiation necrosis. 11

Specific genetic or chromosomal abnormalities involving deletions of 1p and 19q have been identified for a subset of oligodendroglial tumors, which have a high response rate to lomustine, procarbazine, and vincristine (PCV) therapy. 7 14 15 16 17 18 Other CNS tumors are associated with characteristic patterns of altered oncogenes, altered tumor-suppressor genes, and chromosomal abnormalities. As noted above, familial tumor syndromes with defined chromosomal abnormalities are associated with gliomas. (Refer to the Classification section of this summary for more information.)

Metastatic Brain Tumors

Brain metastases outnumber primary neoplasms by at least 10 to 1, and they occur in 20% to 40% of cancer patients. 19 Because no national cancer registry documents brain metastases, the exact incidence is unknown, but it has been estimated that 98,000 to 170,000 new cases are diagnosed in the United States each year. 2 11 This number may be increasing because of the capacity of MRI to detect small metastases and because of prolonged survival resulting from improved systemic therapy. 2 19

The most common primary cancers metastasizing to the brain are lung cancer (50%), breast cancer (15%20%), unknown primary cancer (10%15%), melanoma (10%), and colon cancer (5%). 19 20 Eighty percent of brain metastases occur in the cerebral hemispheres, 15% occur in the cerebellum, and 5% occur in the brain stem. 20 Metastases to the brain are multiple in more than 70% of cases, but solitary metastases also occur. 19 Brain involvement can occur with cancers of the nasopharyngeal region by direct extension along the cranial nerves or through the foramina at the base of the skull. Dural metastases may constitute as much as 9% of total CNS metastases. 21

A lesion in the brain should not be assumed to be a metastasis just because a patient has had a previous cancer; such an assumption could result in overlooking appropriate treatment of a curable tumor. Primary brain tumors rarely spread to other areas of the body, but they can spread to other parts of the brain and to the spinal axis.

The diagnosis of brain metastases in cancer patients is based on patient history, neurological examination, and diagnostic procedures. Patients may describe headaches, weakness, seizures, sensory defects, or gait problems. Often, family members or friends may notice lethargy, emotional lability, or personality change.

A physical examination may show objective neurological findings or only minor cognitive changes. The presence of multiple lesions and a high predilection of tumor may be sufficient to make the diagnosis of metastases. In the case of a solitary lesion or a questionable relationship to the primary tumor, a brain biopsy (usually a stereotactic biopsy) may be necessary. In one study, the diagnosis of single brain metastasis was changed in 6 of 54 patients after the lesion was biopsied. The six patients had primary brain tumors or infectious and inflammatory lesions. 22 CT scans with contrast or MRIs with gadolinium are quite sensitive in diagnosing the presence of metastases. PET scanning and spectroscopic evaluation are new strategies to diagnose cerebral metastases and to differentiate the metastases from other intracranial lesions. 23

References:

American Cancer Society.: Cancer Facts and Figures 2010. Atlanta, Ga: American Cancer Society, 2010. Also available online [PUBMED Abstract]
Levin VA, Leibel SA, Gutin PH: Neoplasms of the central nervous system. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2001, pp 2100-60. [PUBMED Abstract]
Trends in SEER incidence and U.S. mortality using the joinpoint regression program 1975-2000 with up to three joinpoints by race and sex. In: Ries LAG, Eisner MP, Kosary CL, et al.: SEER Cancer Statistics Review, 1975-2000. Bethesda, Md: National Cancer Institute, 2003., Section 3: Brain and Other Nervous System Cancer (Invasive), Table III-1. Also available online. [PUBMED Abstract]
Parkin DM, Bray F, Ferlay J, et al.: Estimating the world cancer burden: Globocan 2000. Int J Cancer 94 (2): 153-6, 2001. [PUBMED Abstract]
Preston-Martin S: Descriptive epidemiology of primary tumors of the spinal cord and spinal meninges in Los Angeles County, 1972-1985. Neuroepidemiology 9 (2): 106-11, 1990. [PUBMED Abstract]
Behin A, Hoang-Xuan K, Carpentier AF, et al.: Primary brain tumours in adults. Lancet 361 (9354): 323-31, 2003. [PUBMED Abstract]
Kleihues P, Cavenee WK, eds.: Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency for Research on Cancer, 2000. [PUBMED Abstract]
Moss AR: Occupational exposure and brain tumors. J Toxicol Environ Health 16 (5): 703-11, 1985. [PUBMED Abstract]
Hochberg FH, Miller G, Schooley RT, et al.: Central-nervous-system lymphoma related to Epstein-Barr virus. N Engl J Med 309 (13): 745-8, 1983. [PUBMED Abstract]
Schabet M: Epidemiology of primary CNS lymphoma. J Neurooncol 43 (3): 199-201, 1999. [PUBMED Abstract]
Hutter A, Schwetye KE, Bierhals AJ, et al.: Brain neoplasms: epidemiology, diagnosis, and prospects for cost-effective imaging. Neuroimaging Clin N Am 13 (2): 237-50, x-xi, 2003. [PUBMED Abstract]
Cloughesy T, Selch MT, Liau L: Brain. In: Haskell CM: Cancer Treatment. 5th ed. Philadelphia, Pa: WB Saunders Co, 2001, pp 1106-42. [PUBMED Abstract]
Ricci PE: Imaging of adult brain tumors. Neuroimaging Clin N Am 9 (4): 651-69, 1999. [PUBMED Abstract]
Buckner JC: Factors influencing survival in high-grade gliomas. Semin Oncol 30 (6 Suppl 19): 10-4, 2003. [PUBMED Abstract]
Louis DN, Cavenee WK: Neoplasms of the central nervous system. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2001, pp 2091-100. [PUBMED Abstract]
DeAngelis LM: Brain tumors. N Engl J Med 344 (2): 114-23, 2001. [PUBMED Abstract]
Ueki K, Nishikawa R, Nakazato Y, et al.: Correlation of histology and molecular genetic analysis of 1p, 19q, 10q, TP53, EGFR, CDK4, and CDKN2A in 91 astrocytic and oligodendroglial tumors. Clin Cancer Res 8 (1): 196-201, 2002. [PUBMED Abstract]
Giordana MT, Ghimenti C, Leonardo E, et al.: Molecular genetic study of a metastatic oligodendroglioma. J Neurooncol 66 (3): 265-71, 2004. [PUBMED Abstract]
Patchell RA: The management of brain metastases. Cancer Treat Rev 29 (6): 533-40, 2003. [PUBMED Abstract]
Wen PY, Black PM, Loeffler JS: Treatment of metastatic cancer. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2001, pp 2655-70. [PUBMED Abstract]
Posner JB, Chernik NL: Intracranial metastases from systemic cancer. Adv Neurol 19: 579-92, 1978. [PUBMED Abstract]
Noordijk EM, Vecht CJ, Haaxma-Reiche H, et al.: The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 29 (4): 711-7, 1994. [PUBMED Abstract]
Schaefer PW, Budzik RF Jr, Gonzalez RG: Imaging of cerebral metastases. Neurosurg Clin N Am 7 (3): 393-423, 1996. [PUBMED Abstract]

Classification

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Note: Some citations in the text of this section are followed by a level of evidence. The PDQ® editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ® summary on Levels of Evidence for more information.)

This classification is based on the World Health Organization (WHO) classification of nervous system tumors. 1 The WHO approach incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunologic markers in an attempt to construct a cellular classification that is universally applicable and prognostically valid. Earlier attempts to develop a TNM-based classification were dropped: tumor size (T) is less relevant than tumor histology and location, nodal status (N) does not apply because the brain and spinal cord have no lymphatics, and metastatic spread (M) rarely applies because most patients with central nervous system (CNS) neoplasms do not live long enough to develop metastatic disease. 2

The WHO grading of CNS tumors establishes a malignancy scale based on histologic features of the tumor. 3 The histologic grades are as follows:

WHO grade I includes lesions with low proliferative potential, a frequently discrete nature, and the possibility of cure following surgical resection alone.

WHO grade II includes lesions that are generally infiltrating and low in mitotic activity but recur. Some tumor types tend to progress to higher grades of malignancy.

WHO grade III includes lesions with histologic evidence of malignancy, generally in the form of mitotic activity, clearly expressed infiltrative capabilities, and anaplasia.

WHO grade IV includes lesions that are mitotically active, necrosis-prone, and generally associated with a rapid preoperative and postoperative evolution of disease.

The following outline has been adapted from the WHO classification. Tumors of glial origin are grouped under a common heading, and tumors limited to the peripheral nervous system have been excluded. Some rare or exclusively pediatric tumors are listed below for purposes of classification, but they are not discussed in the text that follows.

Neuroepithelial tumors.
1. Glial tumors.
  1. Astrocytic tumors.
    1. Pilocytic astrocytoma.
    2. Diffuse astrocytoma (including fibrillary, protoplasmic, and gemistocytic).
    3. Anaplastic astrocytoma.
    4. Glioblastoma (including giant cell glioblastoma, and gliosarcoma).
    5. Pleomorphic xanthoastrocytoma.
    6. Subependymal giant cell astrocytoma.
  2. Oligodendroglial tumors.
    1. Oligodendroglioma.
    2. Anaplastic oligodendroglioma.
  3. Mixed gliomas.
    1. Oligoastrocytoma.
    2. Anaplastic oligoastrocytoma.
  4. Ependymal tumors.
    1. Myxopapillary ependymoma.
    2. Subependymoma.
    3. Ependymoma (including cellular, papillary, clear cell, and tanycytic).
    4. Anaplastic ependymoma.
  5. Neuroepithelial tumors of uncertain origin.
2. Neuronal and mixed neuronal-glial tumors (some glial component may be present).
3. Nonglial tumors.
Meningeal tumors.
Germ cell tumors.
1. Germinoma.
2. Embryonal carcinoma.
3. Yolk-sac tumor (endodermal-sinus tumor).
4. Choriocarcinoma.
5. Teratoma.
6. Mixed germ cell tumor.
Tumors of the sellar region.
1. Pituitary adenoma. (Refer to the PDQ® summary on Pituitary Tumor Treatment for more information.)
2. Pituitary carcinoma.
3. Craniopharyngioma.
Tumors of uncertain histogenesis.
1. Capillary hemangioblastoma.
Primary CNS lymphoma. (Refer to the PDQ® summary on Primary CNS Lymphoma Treatment for more information.)
Tumors of peripheral nerves that affect the CNS.
1. Schwannoma.
Metastatic tumors.

Neuroepithelial tumors

Astrocytic tumors

An increased risk of astrocytic tumors has been observed in patients who receive therapeutic radiation therapy for pituitary adenomas, craniopharyngioma, pineal parenchymal tumors, germinoma, and tinea capitis. In addition, children who receive prophylactic radiation therapy of the CNS for acute lymphoblastic leukemia have an increased risk of developing astrocytomas. Recurrent lesions often signal histologic progression to a higher grade; this malignant progression is associated with a cumulative acquisition of multiple genetic alterations. 4

Pilocytic astrocytoma (WHO grade I) is a grossly circumscribed, slow-growing, often cystic tumor that occurs primarily in children and young adults. 5 Histologically, pilocytic astrocytomas are composed of varying proportions of compacted bipolar cells with Rosenthal fibers and loose-textured multipolar cells with microcysts and granular bodies. This tumor is the most common glioma in children and represents 10% of cerebral and 85% of cerebellar astrocytic tumors. Occurring throughout the neuraxis, the preferred sites include the optic nerve, optic chiasm/hypothalamus, thalamus and basal ganglia, cerebral hemispheres, cerebellum, and brain stem. Pilocytic astrocytoma is the principal CNS tumor associated with neurofibromatosis type 1 (NF1). No specific cytogenetics or molecular genetics exist with this tumor. This tumor is infrequently fatal.

(Refer to the Pilocytic Astrocytomas section of this summary for treatment information.)

Diffuse astrocytoma (WHO grade II), also known as low-grade diffuse astrocytoma, is characterized by slow growth and infiltration of neighboring brain structures. 6 Histologically, diffuse astrocytomas are composed of well-differentiated fibrillary or gemistocytic neoplastic astrocytes. This type of tumor typically affects young adults and has a tendency for malignant progression to anaplastic astrocytoma and, ultimately, glioblastoma. Diffuse astrocytomas represent 35% of all astrocytic brain tumors. 7 They may be located in any region of the CNS but most commonly develop in the cerebrum. Three histologic variants include: fibrillary astrocytoma, gemistocytic astrocytoma, and protoplasmic astrocytoma. These types of tumors may occur in patients with inherited TP53 germline mutations (Li-Fraumeni syndrome). TP53 (also known as p53) mutations have been reported in more than 60% of the cases. The most common chromosomal alteration seen in diffuse astrocytoma is the deletion of chromosome band 17p13.1. 7 The mean survival time after surgical intervention is in the range of 6 to 8 years, with considerable individual variation.

(Refer to the Diffuse Astrocytomas section of this summary for treatment information.)

Anaplastic astrocytoma (WHO grade III), also known as malignant astrocytoma and high-grade astrocytoma, may arise from a diffuse astrocytoma or may arise de novo without indication of a less malignant precursor. 8 Histologically, this tumor shows increased cellularity, distinct nuclear atypia, and marked mitotic activity when compared with a diffuse astrocytoma. Anaplastic astrocytomas possess an intrinsic tendency to progress to glioblastoma. The mean age at biopsy is approximately 41 years. This tumor primarily affects the cerebral hemispheres. It has a high frequency of TP53 mutations, which is similar to that of diffuse astrocytoma. Chromosomal abnormalities are nonspecific. Many of the genetic alterations seen in anaplastic astrocytomas involve genes that regulate cell cycle progression. 7 The mean time to progression is 2 years. Positive predictive factors include young age, high performance status, and gross total tumor resection.

(Refer to the Anaplastic Astrocytomas section of this summary for treatment information.)

Glioblastoma (WHO grade IV), also known as glioblastoma multiforme, may develop from a diffuse astrocytoma or an anaplastic astrocytoma but more commonly presents de novo without evidence of a less malignant precursor. 9 Histologically, this tumor is an anaplastic, cellular glioma composed of poorly differentiated, often pleomorphic astrocytic tumor cells with marked nuclear atypia and brisk mitotic activity. Secondary glioblastoma is the term used to describe a glioblastoma developed from a diffuse astrocytoma or an anaplastic astrocytoma. Glioblastoma is the most frequent brain tumor and accounts for approximately 12% to 15% of all brain tumors and 50% to 60% of all astrocytic tumors. The peak incidence occurs between the ages of 45 and 70 years. Glioblastoma primarily affects the cerebral hemispheres. Two histologic variants include: giant cell glioblastoma and gliosarcoma. Glioblastoma has been associated with more specific genetic abnormalities than any other astrocytic neoplasm, but none are specific to it. Amplification of the epidermal growth factor receptor locus is found in approximately 40% of primary glioblastomas but is rarely found in secondary glioblastomas; mutations of the PTEN gene are observed in 45% of primary glioblastomas and are seen more frequently in primary glioblastomas than in secondary glioblastomas. 7 Loss of heterozygosity (LOH) of chromosome 10 and loss of an entire copy of chromosome 10 are the most frequently observed chromosomal alterations. Glioblastomas are seen in mismatch repair-associated Turcot syndrome type 1. Glioblastomas are among the most aggressively malignant human neoplasms, with a mean total length of disease in patients with primary glioblastoma of less than 1 year. Mutation of the PTEN gene is associated with a poor prognosis in a subset of patients with gliomas. 7

(Refer to the Glioblastoma section of this summary for treatment information.)

Pleomorphic xanthoastrocytoma (WHO grade II) is a rare astrocytic tumor composed of pleomorphic and lipidized cells expressing glial fibrillary acidic protein (GFAP). 10 This tumor accounts for fewer than 1% of all astrocytic neoplasms, typically develops in children and young adults, and commonly involves the cerebrum and meninges. This tumor has a relatively favorable prognosis; recurrence-free survival rates of 72% at 5 years and 61% at 10 years have been reported. No specific cytogenetics or molecular genetics exist with this tumor.

Subependymal giant cell astrocytoma (SEGA) (WHO grade I) is a benign, slow-growing tumor typically arising in the wall of the lateral ventricles and composed of large ganglioid astrocytes. 11 SEGA occurs almost exclusively in patients with tuberous sclerosis complex (TSC); its incidence ranges from approximately 6% to 16% of patients with TSC. SEGA typically occurs during the first 2 decades of life. Genetic linkage studies indicate two distinct TSC loci on chromosome 9q (TSC1) and on chromosome 16p (TSC2). Its relationship with astroglial tumors remains unclear. 1

Refer to the PDQ® summaries on Childhood Astrocytomas Treatment and Childhood Brain Stem Glioma Treatment for more information.

Oligodendroglial tumors

The most common genetic alteration in oligodendroglial tumors is LOH on the long arm of chromosome 19q, the incidence of which ranges from 50% to more than 80%. 12 The second most common genetic alteration in oligodendroglial tumors is LOH on the short arm of chromosome 1p. Specific chromosomal abnormalities involving deletions of both 1p and 19q have been identified for a subset of oligodendroglial tumors, which have a good response to lomustine, procarbazine, and vincristine (PCV) therapy. 13 14 Median postoperative survival times have been reported to range from 3 to 10 years for all histologic grades of oligodendroglial tumors. 15

Oligodendroglioma (WHO grade II) is a well-differentiated tumor, composed predominantly of cells morphologically resembling oligodendroglia, which grows diffusely in the cortex and white matter. 12 This tumor accounts for approximately 50% of oligodendroglial tumors and between 5% and 18% of all gliomas. 7 Most oligodendrogliomas occur in adults, with a peak incidence in the fifth and sixth decades of life. Compared to patients with astrocytoma, patients with oligodendroglioma respond better to radiation therapy and chemotherapy. 15 Temozolomide appears to have activity in low-grade oligodendrogliomas and oligoastrocytomas combined with a 1p allelic loss. Clinical improvement was noted in 51% of patients, and the radiologic response rate was 31%. 16[Level of evidence: 3iiiDiv]

Anaplastic oligodendroglioma (WHO grade III) is an oligodendroglial tumor with focal or diffuse histologic features of malignancy and a less favorable prognosis than grade II oligodendroglioma. 17 Approximately 50% of oligodendroglial tumors are anaplastic oligodendrogliomas. 7 These types of tumors manifest mainly in adults and occur primarily in the frontal lobe and secondarily in the temporal lobe. In a study of 39 patients, chemotherapy was effective in tumors with a chromosomal abnormality (i.e., an allelic loss at 1p and 19q, which is present in 65% of tumors) with a response rate to combination therapy with procarbazine, lomustine, and vincristine (PCV) approaching 100%. The 5-year survival rate in this group was 95%. 18 19[Level of evidence: 3iiiDiv]

(Refer to the Oligodendroglial Tumors section of this summary for treatment information.)

Mixed gliomas

Oligoastrocytoma (WHO grade II) is composed of two distinct neoplastic cell types that morphologically resemble tumor cells in oligodendroglioma and diffuse astrocytoma. 20 Estimates of incidence vary greatly. In one large U.S. study, only 1.8% of gliomas were classified as mixed gliomas. The median age of patients is reported to range from 35 years to 45 years. This tumor has a predilection for the cerebral hemispheres; the frontal lobes are most commonly affected, followed by the temporal lobes. These types of tumors contain no specific genetic alterations or chromosomal abnormalities; however, about 30% of oligoastrocytomas have genetic aberrations commonly found in astrocytic tumors. One study reported a median survival time of 6.3 years. Temozolomide appears to have activity in low-grade oligoastrocytomas and oligodendrogliomas combined with a 1p allelic loss. Clinical improvement was noted in 51% of patients, and the radiologic response rate was 31%. 16[Level of evidence: 3iiiDiv]

Anaplastic oligoastrocytoma (WHO grade III) is a more poorly differentiated tumor than oligoastrocytoma. 21 These types of tumors accounted for 4% of tumors in a large series of supratentorial anaplastic gliomas in adults. The mean age of patients has been reported to be 45 years. Anaplastic oligoastrocytomas are predominantly hemispheric tumors, and the frontal lobes are more commonly involved than the temporal lobes. These tumors share many genetic alterations that are also implicated in the progression of astrocytomas and oligodendrogliomas. The prognosis of patients with anaplastic oligoastrocytomas is relatively poor though considerably better than for patients with glioblastoma.

(Refer to the Mixed Gliomas section of this summary for treatment information.)

Ependymal tumors

Myxopapillary ependymoma (WHO grade I) is a slow-growing astrocytic tumor, histologically characterized by tumor cells arranged in a papillary pattern around vascularized mucoid stromal cores. 22 In a large series of cases of ependymal tumors, 13% were found to be of the myxopapillary type. The average age at presentation is approximately 36 years. This tumor almost exclusively occurs in the conus-cauda-filum terminate region of the spinal cord. No specific cytogenetics or molecular genetics exist with this tumor. The prognosis for patients with myxopapillary ependymoma is good with the possibility of more than 10 years of survival after total or partial resection.

Subependymoma (WHO grade I) is a slow-growing glial neoplasm that is typically attached to the ventricular wall. 23 In a large series of cases, this histologic type accounted for 8.3% of ependymal tumors. This tumor occurs most frequently in middle-aged and elderly males. Consistent cytogenetic abnormalities have not been found. Subependymoma carries a good prognosis; surgical removal is usually curative.

Ependymoma (WHO grade II) is a slow-growing tumor of children and young adults that originates from the wall of the cerebral ventricles or from the spinal canal and is composed of neoplastic ependymal cells. 11 These types of tumors account for 3% to 5% of all neuroepithelial tumors and for 30% of those in children younger than 3 years. Ependymomas are the most common neuroepithelial neoplasms in the spinal cord and comprise 50% to 60% of spinal gliomas. These tumors occur at any site in the ventricular system and in the spinal canal; they develop most commonly in the posterior fossa and in the spinal cord, followed by the lateral ventricles and the third ventricle. Histologic variants include cellular ependymoma, papillary ependymoma, clear cell ependymoma, and tanycytic ependymoma. Almost 33% of ependymomas involve aberrations of chromosome 22. These types of tumors contain no specific genetic alterations. Spinal ependymomas are a primary manifestation of neurofibromatosis type 2 (NF2), which indicates a possible role for the NF2 gene in these neoplasms. In a series of adult patients with ependymoma, survival rates at 5 and 10 years were approximately 57% and 45%, respectively.

Anaplastic ependymoma (WHO grade III) is a malignant glioma of ependymal origin with accelerated growth and an unfavorable outcome, particularly in children. 24 Incidence data vary considerably. No specific genetic alterations for this tumor are known. Prognostic correlations between histology and clinical outcome have been inconsistent. In a large series, no correlation between survival times and classic histopathological findings of malignancy were observed.

(Refer to the Ependymal Tumors section of this summary for treatment information. Refer to the PDQ® summaries on Childhood Ependymoma Treatment and Childhood Central Nervous System Embryonal Tumors Treatment for more information.)

Neuroepithelial tumors of uncertain origin

Astroblastoma (no WHO grade) is a rare glial tumor with preferential manifestation in young adults. Histologically, it is characterized by a perivascular pattern of GFAP-positive astrocytic cells with broad, nontapering processes radiating toward a central blood vessel. 25 This is a rare tumor for which no reliable epidemiological data exist. Insufficient clinical-pathologic data are available to establish a WHO grade. The cerebral hemispheres are most affected; tumors may also develop in the corpus callosum, cerebellum, optic nerves, brain stem, and cauda equine. Low-grade astroblastomas appear to have a better prognosis than those with high-grade histological features.

Chordoid glioma of the third ventricle (provisional WHO grade II) is a rare, slow-growing glial tumor located in the third ventricle of adults. It is histologically characterized by clusters and cords of epithelioid, GFAP-expressing tumor cells within a variably mucinous stroma typically containing a lymphoplasmacytic infiltrate. 26 The mean age of patients is 46 years. The location of chordoid gliomas within the third ventricle and their attachment to hypothalamic and suprasellar structures often preclude complete resection. Postoperative tumor enlargement has been observed in 50% of the patients undergoing subtotal resections.

Gliomatosis cerebri (WHO grade III) is a rare, diffuse glial tumor that infiltrates the brain extensively, involves more than two lobes, is frequently bilateral, and often extends to the infratentorial structures and spinal cord. 27 In a large retrospective series, the peak incidence occurred in patients between the ages of 40 and 50 years. This tumor contains no specific chromosomal abnormalities or genetic alterations; however, the chromosomal changes, in general, are not similar to those seen in astrocytomas, which suggests that this tumor belongs to a separate genetic category. The prognosis is typically poor. A survival analysis that involved 124 patients revealed that 53% died within 12 months after onset of symptoms, 63% by 24 months, and 73% by 36 months.

Neuronal and mixed neuronal-glial tumors

These types of tumors are relatively uncommon and generally have a favorable prognosis. 28

Gangliocytoma (WHO grade I) and ganglioglioma (WHO grade I or II) are well-differentiated, slow-growing neuroepithelial tumors comprised of neoplastic, matureganglion cells, either alone (gangliocytoma) or in combination with neoplastic glial cells (ganglioglioma). 28 Anaplastic gangliogliomas (WHO grade III), i.e., gangliogliomas that show anaplastic features in their glial component, are sometimes seen; rare cases exhibit WHO grade IV (glioblastoma) changes in the glial component. These types of tumors account for 0.4% of all CNS tumors and 1.3% of all brain tumors, and can occur at any age. These types of tumors may occur throughout the CNS; most are supratentorial and involve the temporal lobe. Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease) occurs in the setting of Cowden disease, which is associated with a germline mutation of the gene PTEN/MMAC1 (located on 10q23). No specific chromosomal abnormalities or molecular genetics are associated with sporadic cases. The correlation of anaplasia with clinical outcome is inconsistent.

Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) (WHO grade I) are large cystic tumors of infants that involve the superficial cerebral cortex and leptomeninges, often attached to dura. 29 DIG contains a variable neuronal component in addition to neoplastic astrocytes. These are rare neoplasms that typically occur within the first 2 years of life. No specific cytogenetics or molecular genetics exist with these types of tumors. Follow-up studies indicate that gross total resection results in long-term survival in patients with DIA and DIG.

Dysembryoplastic neuroepithelial tumor (WHO grade I) is a benign, usually supratentorial, neuronal-glial neoplasm that occurs primarily in children and young adults with a long-standing history of partial seizures. 30 In one study, almost 90% of lesions associated with drug-resistant seizures were found to be dysembryoplastic neuroepithelial tumors. This tumor may develop in any part of the supratentorial cortex, but it has a predilection for the temporal lobe. These types of tumors may occasionally occur in patients with NF1. This tumor carries a good prognosis.

Central neurocytoma (WHO grade II) is composed of round cells with neuronal differentiation. 31 In a large surgical series, incidence ranged from 0.25% to 0.5% of all brain tumors. Almost 75% of these types of tumors are diagnosed between the ages of 20 and 40 years. No specific cytogenetic abnormalities or molecular genetics exist with this tumor. The clinical course of central neurocytoma is benign; the treatment of choice is complete surgical resection. Salvage radiation therapy has been used in patients whose tumors were incompletely resected. 32

Cerebellar liponeurocytoma (WHO grade I or II), previously called lipomatous medulloblastoma, is a rare cerebellar neoplasm with advanced neuronal/neurocytic and focal lipomatous differentiation. 33 Patients typically present with this tumor during their fifth or sixth decade of life. Cerebellar liponeurocytoma is associated with a favorable clinical outcome.

Paraganglioma (WHO grade I) is a neuroendocrine neoplasm, usually encapsulated and benign, that arises in specialized neural crest cells associated with segmental or collateral autonomic ganglia (paraganglia) throughout the body. 34 Depending on the anatomic location, this tumor is also known as carotid body paraganglioma (chemodectoma) and jugulotympanic paraganglioma (glomus jugulare tumor). An uncommon tumor, paraganglioma typically presents as a spinal intradural tumor in the cauda equina region. Tumors of the carotid body may show familial clustering. No specific cytogenetic abnormalities or molecular genetics exist with this tumor. Tumor location is more relevant than histology in assessing a prognosis; the metastatic rate of para-aortic paraganglioma is high (28%42%) compared with that of carotid body tumors (2%9%). Almost 50% of glomus jugulare tumors recur locally; only 5% metastasize.

Embryonal tumors

Ependymoblastoma (WHO grade IV) is a rare, malignant, embryonal brain tumor that occurs in neonates and young children. 35 Ependymoblastomas are often large and supratentorial and generally relate to the ventricles, though they do occur at other sites. These types of tumors grow rapidly, with craniospinal dissemination, and have a fatal outcome within 6 to 12 months of diagnosis.

Medulloblastoma (WHO grade IV) is a malignant, invasive embryonal tumor of the cerebellum that occurs primarily in children, has a predominantly neuronal differentiation, and has a tendency to metastasize via CSF pathways. 36 The annual incidence is 0.5 per 100,000 children younger than 15 years. In adulthood, 80% of medulloblastomas occur in people aged 21 to 40 years. These types of tumors rarely occur beyond the fifth decade of life. Medulloblastomas have been diagnosed in several familial cancer syndromes, including TP53 germline mutations, the nevoid basal cell carcinoma syndrome (NBCCS), and Turcot syndrome type 2. The most common specific cytogenetic abnormality in medulloblastomas is isochromosome 17q [i(17q)], which is present in approximately 50% of cases. A number of genetic alterations in this tumor have been described, but none appear to be specific for this tumor. The 5-year survival rate has been estimated to be 50% to 70%. The incidence in adults is 0.05 per 100,000. Medulloblastoma responds to surgery, radiation therapy, and chemotherapy. 37

Supratentorial primitive neuroectodermal tumor (PNET) (WHO grade IV) is an embryonal tumor in the cerebrum or suprasellar region that is composed of undifferentiated or poorly differentiated neuroepithelial cells, which have the capacity for differentiation along neuronal, astrocytic, ependymal, muscular, or melanocytic lines. 38 Synonyms include cerebral medulloblastoma, cerebral neuroblastoma, cerebral ganglioneuroblastoma, blue tumor, and primitive neuroectodermal tumor. This is a rare tumor that occurs in children (mean age, 5.5 years); a precise incidence has not been determined. No specific cytogenetic abnormalities or molecular genetics exist with this tumor. The overall 5-year survival rate has been reported to be 34%.

(Refer to the Embryonal Cell Tumors section of this summary for treatment information. Refer to the PDQ® summary on Childhood Central Nervous System Embryonal Tumors Treatment for more information.)

Choroid plexus tumors

Choroid plexus papilloma (WHO grade I) and choroid plexus carcinoma (WHO grade III) are intraventricular papillary neoplasms derived from choroid plexus epithelium. 39 These types of tumors account for 0.4% to 0.6% of all brain tumors, 2% to 4% of brain tumors in children, and 10% to 20% of brain tumors manifesting in the first year of life. Papillomas outnumber carcinomas by a 10:1 ratio. Lateral ventricle tumors occur primarily in children; fourth ventricle tumors are evenly distributed among all age groups. An association between infection with simian virus 40 (SV40) and choroid plexus tumors has been made. These types of tumors occasionally occur in patients with Li-Fraumeni syndrome. No specific cytogenetics or molecular genetics exist with these types of tumors. Choroid plexus papilloma can be cured surgically and has a 5-year survival rate of as much as 100%. Choroid plexus carcinomas have a less favorable outcome and a 5-year survival rate of 40%.

Pineal parenchymal tumors

Pineal parenchymal tumors arise from pineocytes or their precursors, and they are distinct from other pineal gland neoplasms such as astrocytic and germ cell tumors.

Pineocytoma (WHO grade II) is a slow-growing pineal parenchymal neoplasm that primarily occurs in young adults. 40 Pineocytomas account for fewer than 1% of all brain tumors and comprise approximately 45% of all pineal parenchymal tumors. Adults aged 25 to 35 years are most frequently affected. No specific cytogenetic abnormalities or molecular genetics exist with this tumor. The 5-year survival rate has been reported to be as high as 86%.

Pineoblastoma (WHO grade IV) is a highly malignant primitive embryonal tumor of the pineal gland that manifests primarily in children. 41 Pineoblastomas are rare brain tumors that comprise approximately 45% of all pineal parenchymal tumors. No specific cytogenetic abnormalities or molecular genetics exist with this tumor. Tumors similar to pineoblastomas in appearance have been observed in patients with familial (bilateral) retinoblastoma. Projected 1-, 3-, and 5-year survival rates of pineoblastoma patients treated by various modalities are 88%, 78%, and 58%, respectively.

Pineal parenchymal tumors of intermediate differentiation are monomorphous tumors exhibiting moderately high cellularity, mild nuclear atypia, occasional mitosis, and the absence of large pineocytomatous rosettes. 40 They comprise approximately 10% of all pineal parenchymal tumors and occur in all age groups. No specific cytogenetic abnormalities or molecular genetics exist with this tumor. Clinical behavior is variable.

(Refer to the Pineal Parenchymal Tumors section of this summary for treatment information. Refer to the PDQ® summary on Childhood Central Nervous System Embryonal Tumors Treatment for more information.)

Meningeal tumors

Many tumor types are found in the meninges. Most common are meningiomas, which arise from meningothelial cells. Many mesenchymal, nonmeningothelial tumors also occur, but most are rare in the meninges and more commonly found at other sites; only hemangiopericytomas are mentioned here because they are more frequent and historically confused with meningiomas. A wide spectrum of melanocytic lesions can also be found; these are rarely hemangioblastomas and are classified as of uncertain histogenesis.

Meningiomas (WHO grades IIII) are typically slow-growing, benign, WHO grade I tumors attached to the dura mater and composed of neoplastic meningothelial (arachnoidal) cells. 42 Meningiomas are estimated to comprise between 13% and 26% of primary brain tumors and have an annual incidence of approximately 6 per 100,000 persons. Meningiomas usually occur in adults, with a peak occurrence during the sixth and seventh decades of life. Women are affected more often than men, with a female to male ratio as high as 2:1. Atypical meningiomas (WHO grade II) constitute 4.7% to 7.2% of meningiomas, while anaplastic (malignant) meningiomas (WHO grade III) account for 1.0% to 2.8% of meningiomas. These higher grade meningiomas may show a conspicuous predominance in males. Most meningiomas arise within the intracranial, orbital, and intravertebral cavities. Spinal meningiomas are most common in the thoracic region; atypical and anaplastic meningiomas are more common on the falx and the lateral convexities.

Meningiomas have a wide range of histopathologic appearances. These include:

WHO grade I: meningothelial, fibrous (fibroblastic), transitional (mixed), psammomatous, angiomatous, microcystic, secretory, lymphoplasmacyte-rich, and metaplastic.
WHO grade II: atypical, chordoid, and clear cell.
WHO grade III: anaplastic (malignant), rhabdoid, and papillary.

Malignant behavior, including brain invasion, may occur with any grade of meningioma.

These types of tumors are known to be induced by ionizing radiation, with an average time interval to tumor appearance of 19 to 35 years, depending on the dose of radiation. Most patients with radiation-induced meningiomas have a history of low-dose radiation to the scalp for tinea capitis; the second largest number of radiation-induced meningiomas occurs in patients who have received high-dose radiation for primary brain tumors. Multiple meningiomas often occur in patients with neurofibromatosis 2 (NF2) and in other, non-NF2 families with a hereditary predisposition to meningioma.

The most common cytogenetic alteration in meningiomas involves a deletion of chromosome 22. Molecular genetics findings indicate that approximately 50% of meningiomas have allelic losses that involve band q12 on chromosome 22. Allelic losses of chromosomal arms 6q, 9p, 10q, and 14q are seen in both atypical and anaplastic meningiomas. Genetic and cytogenetic alterations accumulate with progression from WHO grade I to WHO grade III lesions. Mutations in the NF2 gene have been detected in as much as 60% of sporadic meningiomas. After surgical resection, benign meningiomas (WHO grade I) recur in about 7% to 20% of cases, atypical meningiomas (WHO grade II) recur in 29% to 40% of cases, and anaplastic meningiomas recur in about 50% to 78% of cases. Malignant histologic features correlate with shorter survival times; one series has reported a median survival of less than 2 years for patients with anaplastic meningiomas. Brain invasion indicates a greater likelihood of recurrence, regardless of histology.

Hemangiopericytoma of the CNS was long considered a meningioma, but it is now recognized as a mesenchymal, nonmeningothelial tumor histologically indistinguishable from hemangiopericytomas occurring in soft tissue and with a tendency to recur and to metastasize outside the CNS. It is a highly cellular and richly vascularized tumor that is almost always attached to the dura. 43 Histologic criteria for grading are not firmly established; however, these types of tumors appear to correspond histologically to WHO grade II or III. Meningeal hemangiopericytomas comprise approximately 0.4% of all primary CNS tumors. These types of tumors tend to appear at a younger age than meningiomas, and they occur more often in men than in women. No specific chromosomal abnormalities or molecular genetics exist with this tumor. After surgical resection, most hemangiopericytomas recur; in two series, they recurred in 91% and 85% of cases after 15 years. Postoperative radiation therapy delays recurrence. Most meningeal hemangiopericytomas eventually metastasize. In a series of 28 patients who survived primary resection, the probability of tumor-related death was 61% at 15 years.

Melanocytic lesions are diffuse or circumscribed, benign, or malignant tumors arising from melanocytes of the leptomeninges. 44 They include diffuse melanocytosis (diffuse melanosis) and neurocutaneous melanosis, melanocytoma, and malignant melanoma. Intermediate or mixed cases may occur. Melanocytoma accounts for 0.06% to 0.1% of brain tumors; the other melanocytic lesions are rarer. These lesions typically occur in the fifth decade of life with a female to male ratio of 2:1. Diffuse melanocytosis involves the supratentorial and infratentorial leptomeninges; melanocytomas occur as solid masses in the cranial and spinal compartments. Diffuse melanocytosis and malignant melanoma both carry a poor prognosis.

(Refer to the Meningeal Tumors section of this summary for treatment information.)

Germ cell tumors

As a group, CNS germ cell tumors vary widely in their incidence. 45 In Europe and North America, they comprise 0.3% to 0.5% of all primary brain tumors; in Asia, these types of tumors account for at least 2.0% of all primary brain tumors. Germ cell tumors are primarily neoplasms of the young; incidence peaks at ages 10 to 12 years. Like other extragonadal germ cell tumors, CNS variants hug the midline; 80% or more arise in structures around the third ventricle, with the area of the pineal gland their most common site of origin followed by the suprasellar compartment.

The histologic types of germ cell tumors include germinoma, teratoma (mature, immature, and with malignant transformation), yolk sac tumor, embryonal carcinoma, and choriocarcinoma. No WHO histologic grades are available for these types of tumors. An increased risk of intracranial germ cell tumor is associated with Klinefelter syndrome (47 í YY) and a variety of anomalies that include testicular atrophy, gynecomastia, eunuchoid habitus, and elevated serum gonadotrophins. 46 47 48 Cytogenetically, chromosome 12 abnormalities and aneuploidy appear to delineate a group of germ cell tumors harboring primordial germ celllike elements (e.g., germinoma or seminoma) from pure teratomas and yolk sac tumors of congenital or infantile onset. No specific molecular genetics exist with these types of tumors.

Most localized germinomas can be cured with radiation therapy alone, and they have 5-year survival rates ranging from 65% to 95%. Patients with germ cell tumors of other histologic types do not fare as well, except for those who can tolerate gross total resection of mature teratomas, which tend to be noninvasive and amenable to complete excision.

(Refer to the Germ Cell Tumors section of this summary for treatment information. Refer to the PDQ® summary on Childhood Brain and Spinal Cord Tumors Treatment Overview for more information.)

Tumors of the sellar region

Pituitary tumors occur most frequently in the sellar region, but they are traditionally grouped separately. (Refer to the PDQ® summary on Pi

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TABLE OF CONTENTS

General Information

References:

Classification