jueves, 26 de junio de 2014

Childhood Astrocytomas Treatment (PDQ®) - National Cancer Institute

Childhood Astrocytomas Treatment (PDQ®) - National Cancer Institute

06/24/2014 04:43 AM EDT

Source: National Cancer Institute
Related MedlinePlus Page: Childhood Brain Tumors

National Cancer Institute at the National Institutes of Health

Treatment Options for Childhood Astrocytomas

Newly Diagnosed Childhood Low-Grade Astrocytomas
Recurrent Childhood Low-Grade Astrocytomas
Newly Diagnosed Childhood High-Grade Astrocytomas
Recurrent Childhood High-Grade Astrocytomas

Newly Diagnosed Childhood Low-Grade Astrocytomas

When the tumor is first diagnosed, treatment for childhood low-grade astrocytoma depends where the tumor is, and is usually surgery. An MRI is done after surgery to see if there is tumor remaining.

If the tumor was completely removed by surgery, more treatment may not be needed and the child is closely watched to see if signs or symptoms appear or change. This is called observation.

If there is tumor remaining after surgery, treatment may include the following:

In some cases, observation is used for children who have a visual pathway glioma. In other cases, treatment may include surgery to remove the tumor, radiation therapy, or chemotherapy. A goal of treatment is to save as much vision as possible. The effect of tumor growth on the child's vision will be closely followed during treatment.

Children with neurofibromatosis type 1 (NF1) may not need treatment unless the tumor grows or signs or symptoms, such as vision problems, appear. When the tumor grows or signs or symptoms appear, treatment may include surgery to remove the tumor, radiation therapy, and/or chemotherapy.

Children with tuberous sclerosis may develop benign (not cancer) tumors in the brain calledsubependymal giant cell astrocytomas (SEGAs). Targeted therapy with everolimus or sirolimus may be used instead of surgery, to shrink the tumors.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients withchildhood low-grade untreated astrocytoma or other tumor of glial origin. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your child's doctor about clinical trials that may be right for your child. General information about clinical trials is available from the NCI Web site.
Recurrent Childhood Low-Grade Astrocytomas
Before more cancer treatment is given, imaging testsbiopsy, or surgery are done to find out if there is cancer and how much there is.

Treatment of recurrent childhood low-grade astrocytoma may include the following:

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients withrecurrent childhood astrocytoma or other tumor of glial origin. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your child's doctor about clinical trials that may be right for your child. General information about clinical trials is available from the NCI Web site.
Newly Diagnosed Childhood High-Grade Astrocytomas
Treatment of childhood high-grade astrocytoma may include the following:

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients withchildhood high-grade untreated astrocytoma or other tumor of glial origin. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your child's doctor about clinical trials that may be right for your child. General information about clinical trials is available from the NCI Web site.
Recurrent Childhood High-Grade Astrocytomas
Before more cancer treatment is given, imaging testsbiopsy, or surgery are done find out if there is cancer and how much there is.

Treatment of recurrent childhood high-grade astrocytoma may include the following:

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients withrecurrent childhood astrocytoma or other tumor of glial origin. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your child's doctor about clinical trials that may be right for your child. General information about clinical trials is available from the NCI Web site.
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General Information About Childhood Astrocytomas

Clinical Features
Diagnostic Evaluation
Clinicopathologic Classification of Childhood Astrocytomas and Other Tumors of Glial Origin
        WHO histologic grade
        CNS location
        Neurofibromatosis type 1 (NF1)
Genomic Alterations
        Low-grade gliomas
        High-grade astrocytomas
        Low-grade astrocytomas
        High-grade astrocytomas
The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization (WHO) classification of nervous system tumors.[1,2] For a full description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality decreased by more than 50%.[3] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.
Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification.
Gliomas arise from glial cells that are present in the brain and spinal cord. Gliomas are named according to their clinicopathologic and histologic subtype. For example, astrocytomas originate from astrocytes, oligodendroglial tumors from oligodendrocytes, and mixed gliomas from a mix of oligodendrocytes, astrocytes, and ependymal cells. Astrocytoma is the most commonly diagnosed type of glioma in children. According to the WHO classification of brain tumors, gliomas are further classified as low-grade (grades I and II) and high-grade (grades III and IV) tumors. Children with low-grade tumors have a relatively favorable prognosis, especially when the tumors can be completely resected. Children with high-grade tumors generally have a poor prognosis, unless the tumor is an anaplastic astrocytoma that can be completely resected.
Childhood astrocytomas can occur anywhere in the central nervous system (CNS). Refer to Table 3 for the preferential CNS location for each tumor type.
Drawing of the inside of the brain showing  the lateral ventricle, third ventricle, and fourth ventricle, cerebrum, choroid plexus, hypothalamus, pineal gland, pituitary gland, optic nerve, tentorium, cerebellum,  brain stem, pons, medulla, and spinal cord.
Anatomy of the inside of the brain, showing the cerebrum, cerebellum, brain stem, spinal cord, optic nerve, hypothalamus, and other parts of the brain.
Clinical Features
Presenting symptoms for childhood astrocytomas depend on the following:
  • CNS location.
  • Size of the tumor.
  • Rate of tumor growth.
  • Chronologic and developmental age of the child.
In infants and young children, low-grade astrocytomas presenting in the hypothalamus may result in diencephalic syndrome, which is manifested by failure to thrive in an emaciated, seemingly euphoric child. Such children may have little in the way of other neurologic findings, but can have macrocephaly, intermittent lethargy, and visual impairment.[4]
Diagnostic Evaluation
The diagnostic evaluation for astrocytoma is often limited to a magnetic resonance imaging (MRI) of the brain or spine. Additional imaging, when clinically indicated, would consist of an MRI of the remainder of the neuraxis.
Clinicopathologic Classification of Childhood Astrocytomas and Other Tumors of Glial Origin
The pathologic classification of pediatric brain tumors is a specialized area that is evolving. Examination of the diagnostic tissue by a neuropathologist who has particular expertise in this area is strongly recommended.
Tumor types are based on the glial cell type of origin:
  • Astrocytomas (astrocytes).
  • Oligodendroglial tumors (oligodendrocytes).
  • Mixed gliomas (cell types of origin include oligodendrocytes, astrocytes, and ependymal cells).
  • Mixed neuronal-glial tumors.
WHO histologic grade
According to the WHO histologic typing of CNS tumors, childhood astrocytomas and other tumors of glial origin are classified according to clinicopathologic and histologic subtype and are graded (grade I to IV).[1]
WHO histologic grades are commonly referred to as low-grade gliomas or high-grade gliomas (refer to Table 1).
Table 1. World Health Organization (WHO) Histologic Grade and Corresponding Classification for Tumors of the Central Nervous System
WHO Histologic Grade Grade Classification 
ILow grade
IILow grade
IIIHigh grade
IVHigh grade

Table 2. Histologic Grade of Childhood Astrocytomas and Other Tumors of Glial Origin
Type WHO Histologic Grade 
aIn 2007, the WHO further categorized astrocytomas, oligodendroglial tumors, and mixed gliomas according to histopathologic features and biologic behavior. It was determined that the pilomyxoid variant of pilocytic astrocytoma may be an aggressive variant that is more likely to disseminate, and it was reclassified as a grade II tumor.[1,2,5]
Astrocytic Tumors:
Pilocytic astrocytomaI
Pilomyxoid astrocytomaaII
Pleomorphic xanthoastrocytomaII
Subependymal giant cell astrocytomaI
Diffuse astrocytoma:
Gemistocytic astrocytomaII
Protoplasmic astrocytomaII
Fibrillary astrocytomaII
Anaplastic astrocytomaIII
Oligodendroglial Tumors:
Anaplastic oligodendrogliomaIII
Mixed Gliomas:
Anaplastic oligoastrocytomaIII

CNS location
Childhood astrocytomas and other tumors of glial origin can occur anywhere in the CNS, although each tumor type tends to have preferential CNS locations (refer to Table 3).
Table 3. Childhood Astrocytomas and Other Tumors of Glial Origin and Preferential Central Nervous System (CNS) Location
Tumor Type Preferential CNS Location 
Pilocytic astrocytomaOptic nerve, optic chiasm/hypothalamus, thalamus and basal ganglia, cerebral hemispheres, cerebellum, and brain stem; and spinal cord (rare)
Pleomorphic xanthoastrocytomaSuperficial location in cerebrum (temporal lobe preferentially)
Diffuse astrocytoma (including fibrillary)Cerebrum (frontal and temporal lobes), brain stem, spinal cord, optic nerve, optic chiasm, optic pathway, hypothalamus, and thalamus
Anaplastic astrocytoma, glioblastomaCerebrum; occasionally cerebellum, brain stem, and spinal cord
OligodendrogliomasCerebrum (frontal lobe preferentially followed by temporal, parietal, and occipital lobes), cerebellum, brain stem, and spinal cord
OligoastrocytomaCerebral hemispheres (frontal lobe preferentially followed by the temporal lobe)
Gliomatosis cerebriCerebrum with or without brain stem involvement, cerebellum, and spinal cord

More than 80% of astrocytomas located in the cerebellum are low grade (pilocytic grade I) and often cystic; most of the remainder are diffuse grade II astrocytomas. Malignant astrocytomas in the cerebellum are rare.[1,2] The presence of certain histologic features (e.g., MIB-1 rate, anaplasia) has been used retrospectively to predict event-free survival for pilocytic astrocytomas arising in the cerebellum or other location.[6-8]
Astrocytomas arising in the brain stem may be either high grade or low grade, with the frequency of either type being highly dependent on the location of the tumor within the brain stem.[9,10] Tumors not involving the pons are overwhelmingly low-grade gliomas (e.g., tectal gliomas of the midbrain), whereas tumors located exclusively in the pons without exophytic components are largely high-grade gliomas (e.g., diffuse intrinsic pontine gliomas).[9,10] (Refer to the PDQ summary on Childhood Brain Stem Glioma Treatment for more information.)
High-grade astrocytomas are often locally invasive and extensive and tend to occur above the tentorium in the cerebrum.[11,12] Spread via the subarachnoid space may occur. Metastasis outside of the CNS has been reported but is extremely infrequent until multiple local relapses have occurred.
Gliomatosis cerebri is a diffuse glioma that involves widespread involvement of the cerebral hemispheres in which it may be confined, but it often extends caudally to affect the brain stem, cerebellum, and/or spinal cord.[1] It rarely arises in the cerebellum and spreads rostrally.[13] The neoplastic cells are most commonly astrocytes, but in some cases, they are oligodendroglia. They may respond to treatment initially, but overall have a poor prognosis.[14]
Neurofibromatosis type 1 (NF1)
Children with NF1 have an increased propensity to develop WHO grade I and grade II astrocytomas in the visual (optic) pathway; approximately 20% of all patients with NF1 will develop an optic pathway glioma. In these patients, the tumor may be found on screening evaluations when the child is asymptomatic or has apparent static neurologic and/or visual deficits.
Pathologic confirmation is frequently not obtained in asymptomatic patients; when biopsies have been performed, these tumors have been found to be predominantly pilocytic (grade I) rather than fibrillary (grade II) astrocytomas.[2,5,15-17]
In general, treatment is not required for incidental tumors found with surveillance scans. Symptomatic lesions or those that have radiographically progressed may require treatment.[18]
Genomic Alterations

Low-grade gliomas
Genomic alterations involving BRAF activation are very common in sporadic cases of pilocytic astrocytoma, resulting in activation of the ERK/MAPK pathway.
BRAF activation in pilocytic astrocytoma occurs most commonly through a KIAA1549-BRAF gene fusion, producing a fusion protein that lacks the BRAF regulatory domain.[19-23] This fusion is seen in most infratentorial and midline pilocytic astrocytomas, but is present at lower frequency in supratentorial (hemispheric) tumors.[19,20,24-28]
Presence of the BRAF-KIAA1549 fusion predicted for better clinical outcome (progression-free survival [PFS] and overall survival) in one report that described children with incompletely resected low-grade gliomas.[28] However, other factors such as p16 deletion and tumor location may modify the impact ofBRAF mutation on outcome.[29]
BRAF activation through the KIAA1549-BRAF fusion has also been described in other pediatric low-grade gliomas (e.g., pilomyxoid astrocytoma).[27,28]
Other genomic alterations in pilocytic astrocytomas that can also activate the ERK/MAPK pathway (e.g., alternative BRAF gene fusions, RAF1 rearrangements, RAS mutations, and BRAF V600E point mutations) are less commonly observed.[20,22,23,30BRAF (V600E) point mutations are observed in nonpilocytic pediatric low-grade gliomas as well, including approximately two-thirds of pleomorphic xanthoastrocytoma cases and in ganglioglioma and desmoplastic infantile ganglioglioma.[31-33] One retrospective study of 53 children with gangliogliomas demonstrated BRAF V600E staining in approximately 40% of tumors. Five-year recurrence-free survival was worse in the V600E-mutated tumors (about 60%) than in the tumors that did not stain for V600E (about 80%).[34]
As expected, given the role of NF1 deficiency in activating the ERK/MAPK pathway, activating BRAFgenomic alterations are uncommon in pilocytic astrocytoma associated with NF1.[26]
Activating mutations in FGFR1 and PTPN11, as well as NTRK2 fusion genes, have also been identified in noncerebellar pilocytic astrocytomas.[35] In pediatric grade II diffuse astrocytomas, the most common alterations reported are rearrangements in the MYB family of transcription factors in up to 53% of tumors.[36,37]
Most children with tuberous sclerosis have a mutation in one of two tuberous sclerosis genes (TSC1/hamartin or TSC2/tuberin). Either of these mutations results in an overexpression of the mTOR complex 1. These children are at risk of developing subependymal giant cell astrocytomas, in addition to cortical tubers and subependymal nodules.
High-grade astrocytomas
Pediatric high-grade gliomas, especially glioblastoma multiforme, are biologically distinct from those arising in adults.[38-41] Pediatric high-grade gliomas, compared with adult tumors, less frequently havePTEN and EGFR genomic alterations, and more frequently have PDGF/PDGFR genomic alterations and mutations in histone H3.3 genes. Although it was believed that pediatric glioblastoma multiforme tumors were more closely related to adult secondary glioblastoma multiforme tumors in which there is stepwise transformation from lower-grade into higher-grade gliomas and in which most tumors haveIDH1 and IDH2 mutations, the latter mutations are rarely observed in childhood glioblastoma multiforme tumors.[42-44]
Based on epigenetic patterns (DNA methylation), pediatric glioblastoma multiforme tumors are separated into relatively distinct subgroups with distinctive chromosome copy number gains/losses and gene mutations.[44]
Two subgroups have identifiable recurrent H3F3A mutations, suggesting disrupted epigenetic regulatory mechanisms, with one subgroup having mutations at K27 (lysine 27) and the other group having mutations at G34 (glycine 34). The subgroups are the following:
  • H3F3A mutation at K27: The K27 cluster occurs predominately in mid-childhood (median age, approximately 10 years), is mainly midline (thalamus, brainstem, and spinal cord), and carries a very poor prognosis. These tumors also frequently have TP53 mutations.
  • H3F3A mutation at G34: The second H3F3A mutation tumor cluster, the G34 grouping, is found in somewhat older children and young adults (median age, 18 years), arises exclusively in the cerebral cortex, and carries a somewhat better prognosis. The G34 clusters also have TP53mutations and widespread hypomethylation across the whole genome.
The H3F3A K27 and G34 mutations appear to be unique to high-grade gliomas and have not been observed in other pediatric brain tumors.[45] Both mutations induce distinctive DNA methylation patterns compared with the patterns observed in IDH-mutated tumors, which occur in young adults.[42-46]
Other pediatric glioblastoma multiforme subgroups include the RTK PDGFRA and mesenchymalclusters, both of which occur over a wide age range, affecting both children and adults. The RTK PDGFRA and mesenchymal subtypes are comprised predominantly of cortical tumors, with cerebellar glioblastoma multiforme tumors being rarely observed; they both carry a poor prognosis.[44]
The molecular profile of pediatric patients with oligodendroglioma does not demonstrate deletions of 1p or 19q, as found in 40% to 80% of adult cases. Pediatric oligodendrogliomas harbor MGMT gene promoter methylation in the majority of tumors.[47]

Low-grade astrocytomas
Low-grade astrocytomas (grade I [pilocytic] and grade II) have a relatively favorable prognosis, particularly for circumscribed, grade I lesions where complete excision may be possible.[11,12,48-51] Tumor spread, when it occurs, is usually by contiguous extension; dissemination to other CNS sites is uncommon, but does occur.[52,53] Although metastasis is uncommon, tumors may be of multifocal origin, especially when associated with NF1.
Unfavorable prognostic features for childhood low-grade astrocytomas include the following:[54]
  • Young age.
  • Fibrillary histology.
  • Inability to obtain a complete resection.
In patients with pilocytic astrocytoma, elevated MIB-1 labeling index, a marker of cellular proliferative activity, is associated with shortened PFS.[8] A BRAF-KIAA fusion, found in pilocytic tumors, confers a better clinical outcome.[28]
Children with isolated optic nerve tumors have a better prognosis than those with lesions that involve the chiasm or that extend along the optic pathway.[55-58]; [59][Level of evidence: 3iiC] Children with NF1 also have a better prognosis, especially when the tumor is found in asymptomatic patients at the time of screening.[55,60]
High-grade astrocytomas
Biologic markers, such as p53 overexpression and mutation status, may be useful predictors of outcome in patients with high-grade gliomas.[5,61,62] MIB-1 labeling index is predictive of outcome in childhood malignant brain tumors. Both histologic classification and proliferative activity evaluation have been shown to be independently associated with survival.[63]
Although high-grade astrocytomas generally carry a poor prognosis in younger patients, those with anaplastic astrocytomas in whom a gross-total resection is possible may fare better.[50,64,65]
Oligodendrogliomas are rare in children and have a relatively favorable prognosis; however, children younger than 3 years who have less than a gross-total resection have a less favorable prognosis.[66]
This summary does not address the treatment of children with oligodendrogliomas.
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