lunes, 8 de agosto de 2016

Ependimoma infantil (PDQ®)—Versión para profesionales de salud - National Cancer Institute

Ependimoma infantil (PDQ®)—Versión para profesionales de salud - National Cancer Institute

Instituto Nacional Del Cáncer

Ependimoma infantil: Tratamiento (PDQ®)–Versión para profesionales de salud



SECCIONES



Información general sobre el ependimoma infantil

Los sumarios de tratamiento del PDQ sobre los tumores encefálicos infantiles se organizan principalmente de acuerdo con la clasificación de tumores del sistema nervioso establecida por la Organización Mundial de la Salud (OMS).[1,2] Para una descripción completa de la clasificación de los tumores del sistema nervioso y un enlace al sumario de tratamiento correspondiente a cada tipo de tumor encefálicos, consultar el sumario del PDQ sobre Descripción del tratamiento de tumores de cerebro y de médula espinal infantiles.
Se han logrado mejoras notables en la supervivencia de niños y adolescentes con cáncer. Entre 1975 y 2010, la mortalidad por cáncer infantil disminuyó en más de 50%.[3] Los niños y adolescentes sobrevivientes de cáncer necesitan un seguimiento muy cuidadoso, ya que los efectos secundarios del tratamiento de cáncer pueden persistir o presentarse meses o años después de este. (Para obtener información específica sobre la incidencia, el tipo y la vigilancia de los efectos tardíos en los niños y adolescentes sobrevivientes de cáncer, consultar el sumario del PDQ sobre Efectos tardíos del tratamiento anticanceroso en la niñez).
Los tumores encefálicos primarios son un grupo diverso de enfermedades que, juntas, constituyen el tumor sólido más común de la niñez. Para el diagnóstico y la clasificación de los tumores, se usan cada vez más los análisis inmunohistoquímicos, los hallazgos citogenéticos y genético moleculares, y las mediciones de la actividad mitótica. Los tumores encefálicos se clasifican según su histología, pero la ubicación del tumor y su grado de diseminación son factores importantes que afectan el tratamiento y el pronóstico.
Los ependimomas surgen de las células ependimarias que revisten los ventrículos y los pasajes en el encéfalo y el centro de la médula espinal. Las células ependimarias producen líquido cefalorraquídeo (LCR). Estos tumores se clasifican como supratentoriales o infratentoriales. En los niños, la mayoría de los ependimomas son tumores infratentoriales que surgen en el cuarto ventrículo o alrededor de este. De acuerdo con la clasificación de tumores encefálicos de la OMS, los tumores ependimarios se clasifican en los subtipos principales siguientes:
  • Subependimoma (Grado I de la OMS).
  • Ependimoma mixopapilar (Grado I de la OMS).
  • Ependimoma (Grado II de la OMS).
  • Ependimoma anaplásico (Grado III de la OMS).
La ubicación del tumor determina la presentación clínica. El tratamiento comienza con cirugía. El tipo de terapia adyuvante que se administre, como una segunda cirugía, quimioterapia o radioterapia, depende de los siguientes aspectos:
  • Subtipo de ependimoma.
  • Si el tumor se extirpó completamente durante la cirugía inicial.
  • Si el tumor se diseminó por todo el sistema nervioso central.
  • La edad del niño.

Incidencia

El ependimoma infantil comprende aproximadamente 9% de todos los tumores encefálicos infantiles, lo que representa aproximadamente 200 casos por años en los Estados Unidos.[4,5]

Características anatómicas

AMPLIARDibujo del interior del encéfalo que muestra la región supratentorial (la porción superior del encéfalo) y la fosa posterior o región infratentorial (la porción inferior y posterior del encéfalo). La región supratentorial contiene el cerebro, un ventrículo lateral, el tercer ventrículo, el plexo coroideo, el hipotálamo, la glándula pineal, la hipófisis y un nervio óptico. La fosa posterior o región infratentorial contiene el cerebelo, la tienda del cerebelo, el cuarto ventrículo y el tronco encefálico (protuberancia y  bulbo raquídeo). También se muestra el techo del mesencéfalo  y la médula espinal.
Anatomía del interior del encéfalo: se muestran la glándula pineal y la hipófisis, el nervio óptico, los ventrículos (con el líquido cefalorraquídeo en azul), y otras partes del encéfalo. La tienda del cerebelo separa el cerebro del cerebelo. La región infratentorial (fosa posterior) está debajo de la tienda del cerebelo que contiene el tronco cerebral, el cerebelo y el cuarto ventrículo. La región supratentorial está por encima de la tienda del cerebelo y señala la región que contiene el cerebro.

Características clínicas

La presentación clínica del ependimoma depende de la ubicación del tumor.
  • Ependimoma infratentorial (fosa posterior): en los niños, aproximadamente 65 a 75% de los ependimomas surgen en la fosa posterior.[6] Los niños con ependimoma en la fosa posterior pueden presentar signos y síntomas de hidrocefalia obstructiva debidos a la obstrucción a la altura del cuarto ventrículo. También pueden presentar ataxia, dolor de cuello o parálisis de los nervios craneales.
  • Ependimoma supratentorial: el ependimoma supratentorial puede producir cefalea, convulsiones o déficits neurológicos focales que dependen de su ubicación.
  • Ependimoma de la médula espinal: los ependimomas de la médula espinal, que son a menudo la variante mixopapilar, tienden a producir dorsalgia, debilidad en las extremidades inferiores o disfunción del intestino y de la vejiga.

Evaluación diagnóstica

Todo paciente con presunción de ependimoma se debe evaluar con imágenes de diagnóstico de todo el encéfalo y la médula espinal. El método más sensible disponible para evaluar las metástasis subaracnoideas en la médula espinal es la imaginología por resonancia magnética (IRM) espinal con gadolinio. En condiciones ideales, se realiza antes de la cirugía para evitar la confusión con la sangre posoperatoria. Si se utiliza la IRM, generalmente se puede visualizar toda la columna al menos en dos planos con cortes contiguos en la IRM, después del realce con gadolinio. Si es viable, se debe realizar una evaluación citológica del LCR.[7]

Factores pronósticos

Los factores desfavorables que afectan el desenlace (excepto cuando se indique) son los siguientes:
  • Ganancia del cromosoma 1q25. La ganancia del cromosoma 1q25 está presente en aproximadamente 20% de los casos pediátricos de ependimoma intracraneal y varios grupos de investigación lo notificaron como factor pronóstico negativo.[8-11]
  • Perfil de expresión génica.
    El ependimoma de la fosa posterior se puede dividir en los siguientes dos grupos sobre la base de patrones distintivos de la expresión génica.[12,13]
    • Un grupo de expresión definida se presenta principalmente en los niños pequeños y se caracteriza por un perfil genómico equilibrado en gran parte, con un aumento de la aparición de ganancia del cromosoma 1q y la expresión de genes y proteínas que anteriormente se observó que se relacionaban con un pronóstico precario, tales como tenascina C y el receptor del factor de crecimiento epidérmico.[8,14]
    • El segundo grupo de expresión definida se presenta principalmente en niños mayores y adultos, y se caracteriza por un pronóstico más favorable y por numerosas anomalías citogenéticas que afectan cromosomas enteros o brazos cromosómicos.[12]
    Otros factores que se notificaron que se relacionan con un pronóstico precario del ependimoma infantil incluyen la expresión de la subunidad enzimática de la telomerasa (hTERT) [15-17] y la expresión del marcador de células madre neurales nestin.[18][Grado de comprobación: 3iiiA]
  • Localización del tumor. Las variantes craneales del ependimoma tienen un desenlace menos favorable que los ependimomas de la médula espinal primarios.[19,20] La localización dentro de la médula espinal también puede afectar el desenlace: los tumores en la parte inferior de la médula espinal tienen un pronóstico más precario.[21][Grado de comprobación: 3iiiA]
  • Edad menor en el momento del diagnóstico.[22][Grado de comprobación: 3iiiDii]
  • Características histológicas de anaplasia.[22-24]; [25][Grado de comprobación: 3iA]; [26][Grado de comprobación: 3iiiDi]
  • Resección subtotal.[22]
  • Dosis más bajas de radiación.[27]
  • En pruebas inmunohistoquímicas, se identificó un aumento de la expresión de marcadores de proliferación (por ejemplo, Ki-67 y MIB-1) [28,29] y un aumento de la expresión de EZH2, una proteína del complejo polycomb que participa en la regulación epigenética de la expresión génica como un factor pronóstico de mayor riesgo de fracaso terapéutico.[30]

Seguimiento posterior al tratamiento

Después del tratamiento del ependimoma, por lo general, se recomienda la vigilancia con neuroimaginología, junto con evaluaciones clínicas. La frecuencia y duración se han determinado de modo arbitrario y la utilidad es incierta.[31] La mayoría de los médicos obtienen imágenes por resonancia magnética del encéfalo o la médula espinal cada 3 meses durante los primeros 1 a 2 años posteriores al tratamiento. Después de 2 años, a menudo se obtienen imágenes cada 6 meses durante los 3 años siguientes.
Bibliografía
  1. Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007.
  2. Louis DN, Ohgaki H, Wiestler OD, et al.: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114 (2): 97-109, 2007. [PUBMED Abstract]
  3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
  4. Gurney JG, Smith MA, Bunin GR: CNS and miscellaneous intracranial and intraspinal neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, Chapter 3, pp 51-63. Also available online. Last accessed September 25, 2015.
  5. Central Brain Tumor Registry of the United States: Statistical Report: Primary Brain Tumors in the United States, 1997-2001. Hinsdale, Ill: Central Brain Tumor Registry of the United States, 2004. Also available online. Last accessed September 25, 2015.
  6. Andreiuolo F, Puget S, Peyre M, et al.: Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. Neuro Oncol 12 (11): 1126-34, 2010. [PUBMED Abstract]
  7. Moreno L, Pollack IF, Duffner PK, et al.: Utility of cerebrospinal fluid cytology in newly diagnosed childhood ependymoma. J Pediatr Hematol Oncol 32 (6): 515-8, 2010. [PUBMED Abstract]
  8. Mendrzyk F, Korshunov A, Benner A, et al.: Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma. Clin Cancer Res 12 (7 Pt 1): 2070-9, 2006. [PUBMED Abstract]
  9. Korshunov A, Witt H, Hielscher T, et al.: Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 28 (19): 3182-90, 2010. [PUBMED Abstract]
  10. Kilday JP, Mitra B, Domerg C, et al.: Copy number gain of 1q25 predicts poor progression-free survival for pediatric intracranial ependymomas and enables patient risk stratification: a prospective European clinical trial cohort analysis on behalf of the Children's Cancer Leukaemia Group (CCLG), Societe Francaise d'Oncologie Pediatrique (SFOP), and International Society for Pediatric Oncology (SIOP). Clin Cancer Res 18 (7): 2001-11, 2012. [PUBMED Abstract]
  11. Godfraind C, Kaczmarska JM, Kocak M, et al.: Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas. Acta Neuropathol 124 (2): 247-57, 2012. [PUBMED Abstract]
  12. Wani K, Armstrong TS, Vera-Bolanos E, et al.: A prognostic gene expression signature in infratentorial ependymoma. Acta Neuropathol 123 (5): 727-38, 2012. [PUBMED Abstract]
  13. Witt H, Mack SC, Ryzhova M, et al.: Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20 (2): 143-57, 2011. [PUBMED Abstract]
  14. Korshunov A, Golanov A, Timirgaz V: Immunohistochemical markers for intracranial ependymoma recurrence. An analysis of 88 cases. J Neurol Sci 177 (1): 72-82, 2000. [PUBMED Abstract]
  15. Tabori U, Ma J, Carter M, et al.: Human telomere reverse transcriptase expression predicts progression and survival in pediatric intracranial ependymoma. J Clin Oncol 24 (10): 1522-8, 2006. [PUBMED Abstract]
  16. Tabori U, Wong V, Ma J, et al.: Telomere maintenance and dysfunction predict recurrence in paediatric ependymoma. Br J Cancer 99 (7): 1129-35, 2008. [PUBMED Abstract]
  17. Modena P, Buttarelli FR, Miceli R, et al.: Predictors of outcome in an AIEOP series of childhood ependymomas: a multifactorial analysis. Neuro Oncol 14 (11): 1346-56, 2012. [PUBMED Abstract]
  18. Milde T, Hielscher T, Witt H, et al.: Nestin expression identifies ependymoma patients with poor outcome. Brain Pathol 22 (6): 848-60, 2012. [PUBMED Abstract]
  19. McGuire CS, Sainani KL, Fisher PG: Both location and age predict survival in ependymoma: a SEER study. Pediatr Blood Cancer 52 (1): 65-9, 2009. [PUBMED Abstract]
  20. Benesch M, Frappaz D, Massimino M: Spinal cord ependymomas in children and adolescents. Childs Nerv Syst 28 (12): 2017-28, 2012. [PUBMED Abstract]
  21. Oh MC, Sayegh ET, Safaee M, et al.: Prognosis by tumor location for pediatric spinal cord ependymomas. J Neurosurg Pediatr 11 (3): 282-8, 2013. [PUBMED Abstract]
  22. Tamburrini G, D'Ercole M, Pettorini BL, et al.: Survival following treatment for intracranial ependymoma: a review. Childs Nerv Syst 25 (10): 1303-12, 2009. [PUBMED Abstract]
  23. Merchant TE, Jenkins JJ, Burger PC, et al.: Influence of tumor grade on time to progression after irradiation for localized ependymoma in children. Int J Radiat Oncol Biol Phys 53 (1): 52-7, 2002. [PUBMED Abstract]
  24. Korshunov A, Golanov A, Sycheva R, et al.: The histologic grade is a main prognostic factor for patients with intracranial ependymomas treated in the microneurosurgical era: an analysis of 258 patients. Cancer 100 (6): 1230-7, 2004. [PUBMED Abstract]
  25. Amirian ES, Armstrong TS, Aldape KD, et al.: Predictors of survival among pediatric and adult ependymoma cases: a study using Surveillance, Epidemiology, and End Results data from 1973 to 2007. Neuroepidemiology 39 (2): 116-24, 2012. [PUBMED Abstract]
  26. Tihan T, Zhou T, Holmes E, et al.: The prognostic value of histological grading of posterior fossa ependymomas in children: a Children's Oncology Group study and a review of prognostic factors. Mod Pathol 21 (2): 165-77, 2008. [PUBMED Abstract]
  27. Vaidya K, Smee R, Williams JR: Prognostic factors and treatment options for paediatric ependymomas. J Clin Neurosci 19 (9): 1228-35, 2012. [PUBMED Abstract]
  28. Wolfsberger S, Fischer I, Höftberger R, et al.: Ki-67 immunolabeling index is an accurate predictor of outcome in patients with intracranial ependymoma. Am J Surg Pathol 28 (7): 914-20, 2004. [PUBMED Abstract]
  29. Kurt E, Zheng PP, Hop WC, et al.: Identification of relevant prognostic histopathologic features in 69 intracranial ependymomas, excluding myxopapillary ependymomas and subependymomas. Cancer 106 (2): 388-95, 2006. [PUBMED Abstract]
  30. Li AM, Dunham C, Tabori U, et al.: EZH2 expression is a prognostic factor in childhood intracranial ependymoma: a Canadian Pediatric Brain Tumor Consortium study. Cancer 121 (9): 1499-507, 2015. [PUBMED Abstract]
  31. Good CD, Wade AM, Hayward RD, et al.: Surveillance neuroimaging in childhood intracranial ependymoma: how effective, how often, and for how long? J Neurosurg 94 (1): 27-32, 2001. [PUBMED Abstract]
  • Actualización: 24 de junio de 2016














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

National Cancer Institute



Childhood Ependymoma Treatment (PDQ®)–Health Professional Version

SECTIONS





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 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.

Anatomy

Childhood astrocytomas can occur anywhere in the central nervous system (CNS). Refer toTable 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. 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 GradeGrade Classification
ILow grade
IILow grade
IIIHigh grade
IVHigh grade
Table 2. Histologic Grade of Childhood Astrocytomas and Other Tumors of Glial Origin
TypeWHO 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
GlioblastomaIV
Oligodendroglial Tumors: 
OligodendrogliomaII
Anaplastic oligodendrogliomaIII
Mixed Gliomas: 
OligoastrocytomaII
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 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 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 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-KIAA1549gene 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 a better clinical outcome (progression-free survival [PFS] and overall survival [OS]) 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 of the BRAF mutation on outcome.[29] Progression to high-grade glioma is rare for pediatric low-grade glioma with the BRAF-KIAA1549 fusion.[30]
BRAF activation through the BRAF-KIAA1549 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 activate the ERK/MAPK pathway (e.g., alternative BRAF gene fusions, RAF1 rearrangements, RAS mutations, andBRAF V600E point mutations) are less commonly observed.[20,22,23,31BRAF V600E point mutations are also observed in nonpilocytic pediatric low-grade gliomas, including ganglioglioma, desmoplastic infantile ganglioglioma, and approximately two-thirds of pleomorphic xanthoastrocytoma cases.[32-34] 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%).[35] 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).[30]
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.[26]
Activating mutations in FGFR1PTPN11, and in NTRK2 fusion genes have also been identified in noncerebellar pilocytic astrocytomas.[36] 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.[37,38]
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 mammalian target of rapamycin (mTOR) complex 1. These children are at risk of developing subependymal giant cell astrocytomas, cortical tubers, and subependymal nodules.

High-grade gliomas

Pediatric high-grade gliomas, especially glioblastoma multiforme, are biologically distinct from those arising in adults.[39-42] Pediatric high-grade gliomas have PTEN and EGFRgenomic alterations less frequently and PDGF/PDGFR genomic alterations and mutations inhistone H3.3 genes more frequently than do adult tumors. Although it was believed that pediatric glioblastoma multiforme tumors were more closely related to adult secondaryglioblastoma 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 childhood glioblastoma multiforme tumors.[43-45]
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.[45]
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 TP53mutations. Thalamic high-grade gliomas in older adolescents and young adults also show a high rate of H3F3A K27 mutations.[46]
  • 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 TP53 mutations 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.[47] Both mutations induce distinctive DNA methylation patterns compared with the patterns observed in IDH-mutated tumors, which occur in young adults.[43-45,47,48]
Other pediatric glioblastoma multiforme subgroups include the RTK PDGFRA andmesenchymal clusters, both of which occur over a wide age range, affecting both children and adults. The RTK PDGFRA and mesenchymal subtypes are predominantly composed of cortical tumors, with cerebellar glioblastoma multiforme tumors rarely observed; both subtypes have a poor prognosis.[45]
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 (approximately 40%) of 18 patients with secondary high-grade glioma had BRAF V600E mutations, with CDKN2A alterations present in 8 (57%) of 14 cases.[30]

Oligodendroglioma

The molecular profile of pediatric patients with oligodendrogliomas rarely demonstrates deletions of 1p and 19q, as found in 40% to 80% of adult cases. Similarly, IDH1 mutations are also uncommon. When 1p19q codeletion or IDH1 mutations are present in pediatric oligodendroglioma, they are observed primarily in patients older than 15 years.[37,49,50] Like other diffuse pediatric low-grade gliomas, pediatric oligodendrogliomas were noted to have FGFR1 tyrosine kinase domain duplications (3 of 5 cases studied), with an MYB fusion gene observed in one of the two remaining cases.[37]

Prognosis

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.[11,12,51-55] Tumor spread, when it occurs, is usually by contiguous extension; dissemination to other CNS sites is uncommon, but does occur.[56,57] 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:[58-60]
  • Young age.
  • Fibrillary histology.
  • Inability to obtain a complete resection.
  • Diencephalic syndrome.
  • Intracranial hypertension at initial presentation.
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.[61-64]; [65][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.[61,66]

High-grade astrocytomas

Biologic markers, such as p53 overexpression and mutation status, may be useful predictors of outcome in patients with high-grade gliomas.[5,67,68] 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.[69]
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.[53,70,71]

Oligodendrogliomas

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.[72]
This summary does not address the treatment of children with oligodendrogliomas.
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  • Updated: August 5, 2016

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