martes, 28 de febrero de 2017

Cancer Information Highlights ► Childhood Astrocytomas Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Childhood Astrocytomas Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Childhood Astrocytomas Treatment (PDQ®)–Health Professional Version


General Information About Childhood 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 2010, 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 are thought to arise from glial precursor 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 classified further as low-grade (grades I and II) or 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 less favorable prognosis, but this is somewhat dependent on subtype.


Childhood astrocytomas can occur anywhere in the central nervous system (CNS). Refer to Table 3 for the most common CNS location for each tumor type.
ENLARGEDrawing of the inside of the brain showing  the supratentorial area (the upper part of the brain) and the posterior fossa/infratentorial area (the lower back part of the brain). The supratentorial area contains the cerebrum, lateral ventricle, third ventricle, choroid plexus, hypothalamus, pineal gland, pituitary gland, and optic nerve. The posterior fossa/infratentorial area contains the cerebellum, tectum, fourth ventricle, and   brain stem (pons and medulla). The tentorium and spinal cord are also shown.
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. Spinal MRI is sometimes performed in conjunction with the initial brain MRI to exclude neuraxis metastases. Computed tomography (CT) scans and positron emission tomography (PET) scans are not typically used for characterization of suspected gliomas. Similarly, lumbar punctures examining the cerebrospinal fluid for circulating tumor cells are not commonly performed in this disease.

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 putative 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 for astrocytic tumors

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).
The 2016 WHO criteria began to utilize molecular data in the diagnosis of some tumors because of the accumulation of published evidence supporting that tumor behavior is typically driven by common biological alterations. Within glial CNS tumors, this was most evident in changes in the classification of the diffuse gliomas, which were grouped together based on genetic driver mutations rather than histopathological similarities.[2] Two diffuse gliomas are no longer considered distinct entities: fibrillary astrocytoma and protoplasmic astrocytoma. Epithelioid glioblastoma is a new, provisionally included variant that is categorized as one subtype of IDH-wildtype glioblastoma.
Table 1. World Health Organization (WHO) Histologic Grade and Corresponding Classification for Tumors of the Central Nervous System
WHO Histologic GradeGrade Classification
ILow grade
IILow grade
IIIHigh grade
IVHigh grade
Table 2. 2016 World Health Organization (WHO) Classification and Histologic Grade of Astrocytic Tumorsa
TypeWHO Histologic Grade
aAdapted from Louis et al.[2]
bIn 2007, the WHO 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] In 2016, the WHO suggested not grading the pilomyxoid variant until further studies clarify their behavior.[2]
Diffuse Astrocytic Tumors:
—Diffuse astrocytoma, IDH-mutantII
—Anaplastic astrocytoma, IDH-mutantIII
—Glioblastoma, IDH-wildtypeIV
—Glioblastoma, IDH-mutantIV
—Diffuse midline glioma, H3K27M-mutantIV
Other Astrocytic Tumors:
—Pilocytic astrocytomaI
—Pilomyxoid astrocytomaGrade uncertainb
—Pleomorphic xanthoastrocytomaII
—Anaplastic pleomorphic xanthoastrocytomaIII
—Subependymal giant cell astrocytomaI
Other Gliomas:
—Angiocentric gliomaI
—Choroid glioma of the third ventricleII
—AstroblastomaGrade uncertainb

CNS location

Childhood astrocytomas and other tumors of glial origin can occur anywhere in the CNS, although each tumor type tends to have common CNS locations (refer to Table 3).
Table 3. Common Central Nervous System (CNS) Locations for Childhood Astrocytomas and Other Tumors of Glial Origin
Tumor TypeCommon 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 astrocytomaCerebrum (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
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 with the H3K27M-mutant genotype).[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 no longer considered a distinct entity, but rather to be a growth pattern found in some diffuse gliomas. However, this description encompasses widespread involvement of the cerebral hemispheres, often extending 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 diffuse higher-grade astrocytomas.[2,5,15-17]
In general, treatment is not required for incidental tumors found with surveillance neuroimaging. Symptomatic lesions or those that have radiographically progressed may require treatment.[18]

Tuberous sclerosis

Patients with tuberous sclerosis have a predilection for low-grade glioma development, especially subependymal giant cell astrocytomas.[19] Mutations in either TSC1 or TSC2 cause pathway alterations that impact the mammalian target of rapamycin (mTOR) pathway, leading to increases in proliferation. Subependymal giant cell astrocytomas have been sensitive to targeted approaches via inhibition of the mTOR pathway.[20]

Genomic Alterations

Low-grade gliomas

Genomic alterations involving activation of BRAF and the ERK/MAPK pathway are very common in sporadic cases of pilocytic astrocytoma, a type of low-grade glioma.
BRAF activation in pilocytic astrocytoma occurs most commonly through a BRAF-KIAA1549 gene fusion, producing a fusion protein that lacks the BRAF regulatory domain.[21-25] This fusion is seen in most infratentorial and midline pilocytic astrocytomas, but is present at lower frequency in supratentorial (hemispheric) tumors.[21,22,26-31]
Presence of the BRAF-KIAA1549 fusion predicted a better clinical outcome (progression-free survival [PFS] and overall survival [OS]) in one report that described children with incompletely resected low-grade gliomas.[30] However, other factors such as CDKN2A deletion, whole chromosome 7 gain, and tumor location may modify the impact of the BRAF mutation on outcome.[32]; [33][Level of evidence: 3iiiDiii] Progression to high-grade glioma is rare for pediatric low-grade glioma with the BRAF-KIAA1549 fusion.[34]
BRAF activation through the BRAF-KIAA1549 fusion has also been described in other pediatric low-grade gliomas (e.g., pilomyxoid astrocytoma).[29,30]
Other genomic alterations in pilocytic astrocytomas that can activate the ERK/MAPK pathway (e.g., alternative BRAF gene fusions, RAF1 rearrangements, RAS mutations, and BRAF V600E point mutations) are less commonly observed.[22,24,25,35BRAF V600E point mutations are also observed in nonpilocytic pediatric low-grade gliomas, including ganglioglioma, desmoplastic infantile ganglioglioma, and approximately two-thirds of pleomorphic xanthoastrocytomas.[36-38] 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 tumors that did not stain for V600E (about 80%).[39] Similarly, children with diencephalic low-grade astrocytomas with a BRAF V600E mutation had a 5-year PFS of 22%, compared with a 52% PFS in children who were BRAF wildtype.[40][Level of evidence: 3iiiDiii] The frequency of the BRAF V600E mutation was significantly higher in pediatric low-grade glioma that transformed to high-grade glioma (8 of 18 cases) than was the frequency of mutation in cases that did not transform (10 of 167 cases).[34]
Angiocentric gliomas have been noted to largely harbor MYB-QKI fusions, a putative driver mutation for this relatively rare class of gliomas.[41]
As with neurofibromatosis type 1 (NF1) deficiency in activating the ERK/MAPK pathway, activating BRAF genomic alterations are uncommon in pilocytic astrocytoma associated with NF1.[28]
Activating mutations in FGFR1PTPN11, and in NTRK2 fusion genes have also been identified in noncerebellar pilocytic astrocytomas.[42] In pediatric grade II diffuse astrocytomas, the most common alterations reported (up to 53% of tumors) are rearrangements in the MYB family of transcription factors.[43,44]
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 activation of the mammalian target of rapamycin (mTOR) complex 1. These children are at risk of developing subependymal giant cell astrocytomas, cortical tubers, and subependymal nodules. Because subependymal giant cell astrocytomas are driven by mTOR activation, mTOR inhibitors are active agents that can induce tumor regression in children with these tumors.[45]

High-grade gliomas

Pediatric high-grade gliomas, especially glioblastoma multiforme, are biologically distinct from those arising in adults.[46-49] Pediatric high-grade gliomas have PTEN and EGFR genomic alterations less frequently and PDGF/PDGFR genomic alterations and mutations in histone genes (primarily histone 3.3 [H3F3A], but also histone 3.1 [HIST1H3B]) more frequently than do adult tumors. 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 have IDH1 and IDH2 mutations, the latter mutations are rarely observed in children younger than 15 years with high-grade gliomas.[50-52IDH1 mutations are observed in older adolescents with high-grade gliomas.[49,52,53]
Pediatric glioblastoma multiforme tumors are separated into relatively distinct subgroups on the basis of epigenetic patterns (DNA methylation), with distinctive chromosome copy number gains/losses and gene mutations.[52,53]
Two subgroups have identifiable recurrent mutations in H3F3A (the gene encoding histone 3.3), suggesting disrupted epigenetic regulatory mechanisms, with the most recognized 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, brain stem, and spinal cord), and carries a very poor prognosis. These tumors also frequently have TP53 mutations. Thalamic high-grade gliomas in older adolescents and young adults also show a high rate of H3F3A K27 mutations.[54] The 2016 WHO classification groups these cancers into a single entity, diffuse midline glioma, H3 K27M-mutant.[2]
  • H3F3A mutation at G34: The second H3F3A mutation tumor cluster, the G34 grouping, is found in somewhat older children and young adults (median age, 14–18 years), arises exclusively in the cerebral cortex, and carries a somewhat better prognosis.[52,53] The G34 clusters also have TP53 mutations and widespread hypomethylation across the whole genome. Patients with H3F3A mutations are at high risk of treatment failure, but the prognosis is not as poor as it is for patients with K27M mutations.[53]
The H3F3A K27 and G34 mutations appear to be unique to high-grade gliomas and have not been observed in other pediatric brain tumors.[55] Both mutations induce distinctive DNA methylation patterns compared with the patterns observed in IDH-mutated tumors, which occur in young adults.[50-52,55,56]
Pediatric glioblastoma multiforme patients whose tumors have IDH1 mutations are almost exclusively older adolescents (median age in a pediatric population, 16 years) with hemispheric tumors. IDH1-mutated cases often show TP53 mutations, MGMT promoter methylation, and a glioma-CpG island methylator phenotype (G-CIMP).[52,53] Pediatric patients with IDH1 mutations show a more favorable prognosis than do other pediatric glioblastoma multiforme patients.
A fourth group of pediatric glioblastoma multiforme patients identified by DNA methylation analysis are those lacking both histone mutations and IDH1 mutations. This is a heterogeneous group with higher rates of gene amplifications than other pediatric glioblastoma multiforme subtypes. The most commonly amplified genes are PDGFRAEGFRCCND/CDK, and MYC/MYCN.[52,53]
DNA methylation analysis of tumor tissue may identify pediatric tumors with a histologic diagnosis of glioblastoma multiforme, but with the molecular characteristics of other pediatric gliomas. For example, one study found that approximately 14% of patients with a diagnosis of glioblastoma multiforme had molecular characteristics that are associated with pleomorphic xanthoastrocytomas (e.g., high rates of BRAF V600E mutations).[53]
Infants and young children with a glioblastoma multiforme diagnosis appear to have tumors with distinctive molecular characteristics when compared with tumors of older children. One report that applied DNA methylation analysis to glioblastoma multiforme tumors observed a group of patients (representing approximately 7% of pediatric patients with a histologic diagnosis of glioblastoma multiforme) whose tumors had molecular characteristics consistent with low-grade gliomas. The median age for this group of patients was 1 year, and they showed a favorable prognosis (3-year overall survival, approximately 90%).[53] A second report investigated gene copy number gains and losses and mutation status of selected genes for glioblastoma multiforme tumors from children younger than 36 months.[57] Molecular alterations observed at appreciable rates in older children (e.g., K27M, CDKN2A loss, PDGFRA amplification, and TERT promoter mutations) were rare in the tumors of these young children, and novel abnormalities (e.g., loss of SNORD on chromosome 14q32) were observed in some cases.
Childhood secondary high-grade glioma (high-grade glioma that is preceded by a low-grade glioma) is uncommon (2.9% in a study of 886 patients). No pediatric low-grade gliomas with the BRAF-KIAA1549 fusion transformed to a high-grade glioma, whereas low-grade gliomas with the BRAF V600E mutations were associated with increased risk of transformation. Seven of 18 patients (approximately 40%) with secondary high-grade glioma had BRAF V600E mutations, with CDKN2A alterations present in 8 of 14 cases (57%).[34]


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.[11,12,58-62] Tumor spread, when it occurs, is usually by contiguous extension; dissemination to other CNS sites is uncommon, but does occur.[63,64] 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:[65-67]
  • Young age.
  • Diffuse histology, especially IDH-mutant.
  • Inability to obtain a complete resection.
  • Diencephalic syndrome.
  • Intracranial hypertension at initial presentation.
  • Metastases. When metastasis does occur, it is associated with a poorer long-term outcome.[68] However, it is increasingly evident that prognosis is largely dependent on specific molecular features integrated with standard pathological grouping.
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.[30]
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.[69-72]; [73][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.[69,74]

High-grade astrocytomas

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,[60,75,76] as well as those with non-H3K27M–mutant tumors.
Molecular subtypes of pediatric glioblastoma multiforme show prognostic significance.[53] Patients whose tumors have histone K27M mutations have the poorest prognosis, with 3-year survival rates below 5%. Patients whose tumors have IDH1 mutations appear to have the most favorable prognosis among pediatric glioblastoma multiforme cases, while those with histone G34 mutations and those lacking both histone and IDH1 mutations have an intermediate prognosis (3-year OS, approximately 30%). In a multivariate analysis that included both molecular and clinical factors, the presence of gene amplifications and K27M mutations were associated with a poorer prognosis, while the presence of IDH1 mutations was associated with a more favorable prognosis.[53]

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    • Updated: January 27, 2017

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