Adult brain tumors classification

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Classification Based on Type of Tumor

Neuroepithelial tumors

Glial 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.

• Pilocytic astrocytoma: 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.
• Diffuse astrocytoma (including fibrillary, protoplasmic, and gemistocytic): 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.
• Anaplastic astrocytoma: 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.
• Glioblastoma (including giant cell glioblastoma, and gliosarcoma): 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.
• Pleomorphic xanthoastrocytoma: 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: 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]

• 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: 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]
• Anaplastic oligodendroglioma: 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]

• Mixed gliomas.

• Oligoastrocytoma: 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
• Anaplastic oligoastrocytoma: 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.

• Ependymal tumors.

• Myxopapillary ependymoma: 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: 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 (including cellular, papillary, clear cell, and tanycytic): 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: 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.

• Neuroepithelial tumors of uncertain origin.

• Astroblastoma: 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: 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: 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 (some glial component may be present)

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

• Gangliocytoma: Gangliocytoma (WHO grade I) and ganglioglioma (WHO grade I or II) are well-differentiated, slow-growing neuroepithelial tumors comprised of neoplastic, mature ganglion cells, either alone (gangliocytoma) or in combination with neoplastic glial cells (ganglioglioma).[28]
• Ganglioglioma: 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 / ganglioglioma: 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: 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: 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: 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: 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.

Nonglial Tumors

• Embryonal tumors.

• Ependymoblastoma: 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: 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): 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%.

• Choroid plexus tumors.

• Choroid plexus papilloma: 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 carcinoma: 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.

• Pineoblastoma: 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.
• Pineocytoma: 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%.
• Pineal parenchymal tumor of intermediate differentiation: 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.

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.

• Meningioma: Meningiomas (WHO grades I–III) 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:

• 1. WHO grade I: meningothelial, fibrous (fibroblastic), transitional (mixed), psammomatous, angiomatous, microcystic, secretory, lymphoplasmacyte-rich, and metaplastic.
• 2. WHO grade II: atypical, chordoid, and clear cell.
• 3. 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: 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 lesion: 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.

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 × YY) and a variety of anomalies that include testicular atrophy, gynecomastia, eunuchoid habitus, and elevated serum gonadotrophins.[46-48] Cytogenetically, chromosome 12 abnormalities and aneuploidy appear to delineate a group of germ cell tumors harboring primordial germ cell–like 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.

• Germinoma.
• Embryonal carcinoma.
• Yolk-sac tumor (endodermal-sinus tumor).
• Choriocarcinoma.
• Teratoma.
• Mixed germ cell tumor.

Tumors of the Sellar Region

Pituitary tumors occur most frequently in the sellar region, but they are traditionally grouped separately.

• Pituitary adenoma.
• Pituitary carcinoma.
• Craniopharyngioma: Craniopharyngioma (WHO grade I) is a benign, partly cystic epithelial tumor of the sellar region presumably derived from Rathke pouch epithelium.[49] Two clinicopathological forms are distinguished: adamantinomatous and papillary. This type of tumor accounts for 1.2% to 4.6% of all brain tumors. The age incidence is bimodal; peaks are observed in children aged 5 to 14 years and in adults older than 50 years. The most common localization is suprasellar with an intrasellar component. Among these, 30% extend anteriorly, 23% extend into the middle fossa, and 20% extend into the retroclival area. In a large series, 60% to 93% of patients had a 10-year recurrence-free survival. The most significant prognostic factor associated with tumor recurrence is the extent of surgical resection; lesions larger than 5 cm carry a worse prognosis. The recurrence rate is significantly higher after incomplete resection.

Tumors of Uncertain Histogenesis

• Capillary hemangioblastoma: Capillary hemangioblastoma (WHO grade I) occurs sporadically and is associated with the familial tumor syndrome von Hippel-Lindau (VHL) disease.[50] VHL disease is inherited through an autosomal dominant trait and is characterized by the following: capillary hemangioblastomas of the CNS and retina, clear cell renal carcinoma, pheochromocytoma, pancreatic tumors, and inner ear tumors. The syndrome is related to germline mutations of the VHL tumor suppressor gene, which is located on chromosome 3p25-26. VHL disease is estimated to occur at rates of 1:36,000 to 1:45,500 of the world population. Capillary hemangioblastomas typically occur in adults; the mean age of patients with VHL-associated tumors is 29 years. Capillary hemangioblastomas may occur in any part of the CNS; sporadic tumors occur primarily in the cerebellum. VHL patients often have multiple capillary hemangioblastomas at various sites, including the cerebellum, brain stem, and spinal cord. Because of advances in microsurgical techniques, mortality and morbidity are low for sporadic capillary hemangioblastomas. In VHL disease, hemangioblastoma is the most common cause of death, followed by renal cell carcinoma. The median life expectancy of VHL patients has been reported to be 49 years. Periodic screening of VHL patients with magnetic resonance imaging should start in those older than 10 years.

Tumors of peripheral nerves that affect the CNS

• Schwannoma: Schwannoma (WHO grade I), also known as neurilemoma and neurinoma, is usually an encapsulated benign tumor composed of differentiated neoplastic Schwann cells.[51] This is a common tumor of the peripheral nerves that accounts for an estimated 8% of brain tumors and 29% of primary spinal tumors. Schwannomas occur frequently in patients with NF2. The peak incidence is in the fourth to sixth decades of life. Three histologic variants include cellular schwannoma, melanotic schwannoma, and plexiform schwannoma. Inactivating mutations of the NF2 gene on chromosome 22q12 have been detected in approximately 60% of schwannomas. Schwannomas are slow-growing benign tumors that only rarely undergo malignant change.

Metastatic Tumors

Metastatic tumors involve the CNS and originate from, but are discontinuous with, primary systemic neoplasms. The most common primary cancers metastasizing to the brain are lung cancer (50%), breast cancer (15%–20%), cancer of unknown primary site (10%–15%), melanoma (10%), and colon cancer (5%).[52,53] Multiple metastases to the brain occur in more than 70% of cases, but solitary metastases also occur.[53] Eighty percent of brain metastases are located in the arterial border zones of the cerebral hemispheres,15% are found in the cerebellum, and 3% are found in the basal ganglia.

As many as 40% to 50% of intramedullary spinal cord metastases originate from primary lung neoplasms. The most common primary cancers causing epidural spinal cord compression include breast cancer (22%), lung cancer (15%), prostate cancer (10%), and lymphoma (10%).[54] Leukemias, lymphomas, breast cancer, and gastrointestinal carcinomas are associated with diffuse infiltration of the leptomeninges.

Prognostic factors include younger age (<60 years), high Karnofsky performance status (>70), number (<3 lesions) and location of CNS metastases, sensitivity of the tumor to therapy, and progression of the primary neoplasm.[52,54] The median survival for patients with multiple brain metastases treated with radiation is 3 to 6 months.[54] Patients with single brain metastases and limited extracranial disease who are treated with surgery and whole brain radiation therapy have a median survival time of approximately 10 to 16 months.[52] Breast cancer patients with brain metastases typically have more favorable prognoses than patients with brain metastases from other types of primary tumor; however, patients with brain metastases from colorectal carcinoma tend to have poorer prognoses.

Classification Based on Tumor Grade

The WHO grading of CNS tumors establishes a malignancy scale based on histologic features of the tumor. 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.

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