lunes, 15 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 August 12, 2016.
  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 August 12, 2016.
  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]
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Clasificación histopatológica de los tumores ependimarios infantiles
  • Actualización: 24 de junio de 2016












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





National Cancer Institute

Childhood Ependymoma Treatment (PDQ®)–Health Professional Version



SECTIONS







General Information About Childhood Ependymoma

The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization (WHO) classification of nervous system tumors.[1] 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%.[2] 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 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. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis.
Ependymomas arise from ependymal cells that line the ventricles and passageways in the brain and the center of the spinal cord. Ependymal cells produce cerebrospinal fluid (CSF). These tumors are classified as supratentorial or infratentorial. In children, most ependymomas are infratentorial tumors that arise in or around the fourth ventricle. According to the 2016 revision to the WHO classification of tumors of the central nervous system, ependymal tumors are classified into the following five main subtypes:[1]
  • Subependymoma (WHO Grade I).
  • Myxopapillary ependymoma (WHO Grade I).
  • Ependymoma (WHO Grade II).
  • Ependymoma, RELA fusion–positive (WHO Grade II or Grade III).
  • Anaplastic ependymoma (WHO Grade III).
The location of the tumor determines the clinical presentation. Treatment begins with surgery. The type of adjuvant therapy given, such as a second surgery, chemotherapy, or radiation therapy, depends on the following:
  • Subtype of ependymoma.
  • Whether the tumor was completely removed during the initial surgery.
  • Whether the tumor has disseminated throughout the central nervous system.
  • Child's age.

Incidence

Childhood ependymoma comprises approximately 9% of all childhood brain tumors, representing about 200 cases per year in the United States.[3,4]

Anatomy

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.
Figure 1. Anatomy of the inside of the brain, showing the pineal and pituitary glands, optic nerve, ventricles (with cerebrospinal fluid shown in blue), and other parts of the brain. The tentorium separates the cerebrum from the cerebellum. The infratentorium (posterior fossa) is the region below the tentorium that contains the brain stem, cerebellum, and fourth ventricle. The supratentorium is the region above the tentorium and denotes the region that contains the cerebrum.

Molecular Features

Molecular characterization studies have identified several biological subtypes of ependymoma based on their distinctive DNA methylation and gene expression profiles and on their distinctive spectrum of genomic alterations.[5-7]
  • Infratentorial tumors.
    • Posterior fossa A, CpG island methylator phenotype (CIMP)-positive ependymoma, termed EPN-PFA.
    • Posterior fossa B, CIMP-negative ependymoma, termed EPN-PFB.
  • Supratentorial tumors.
    • C11orf95-RELA–positive ependymoma.
    • C11orf95-RELA–negative and YAP1 fusion–positive ependymoma.
  • Spinal tumors.
ENLARGEGraph showing key molecular and clinical characteristics of ependymal tumor subgroups.
Figure 2. Graphical summary of key molecular and clinical characteristics of ependymal tumor subgroups.Schematic representation of key genetic and epigenetic findings in the nine molecular subgroups of ependymal tumors as identified by methylation profiling. CIN, Chromosomal instability. Reprinted from Cancer Cell, Volume 27, Kristian W. Pajtler, Hendrik Witt, Martin Sill, David T.W. Jones, Volker Hovestadt, Fabian Kratochwil, Khalida Wani, Ruth Tatevossian, Chandanamali Punchihewa, Pascal Johann, Juri Reimand, Hans-Jorg Warnatz, Marina Ryzhova, Steve Mack, Vijay Ramaswamy, David Capper, Leonille Schweizer, Laura Sieber, Andrea Wittmann, Zhiqin Huang, Peter van Sluis, Richard Volckmann, Jan Koster, Rogier Versteeg, Daniel Fults, Helen Toledano, Smadar Avigad, Lindsey M. Hoffman, Andrew M. Donson, Nicholas Foreman, Ekkehard Hewer, Karel Zitterbart, Mark Gilbert, Terri S. Armstrong, Nalin Gupta, Jeffrey C. Allen, Matthias A. Karajannis, David Zagzag, Martin Hasselblatt, Andreas E. Kulozik, Olaf Witt, V. Peter Collins, Katja von Hoff, Stefan Rutkowski, Torsten Pietsch, Gary Bader, Marie-Laure Yaspo, Andreas von Deimling, Peter Lichter, Michael D. Taylor, Richard Gilbertson, David W. Ellison, Kenneth Aldape, Andrey Korshunov, Marcel Kool, and Stefan M. Pfister, Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups, Pages 728–743, Copyright (2015), with permission from Elsevier.
Approximately two-thirds of childhood ependymomas arise in the posterior fossa, and two major genomically defined subtypes of posterior fossa tumors are recognized. Similarly, most pediatric supratentorial tumors can be categorized into one of two genomic subtypes. These subtypes and their associated clinical characteristics are described below.[5]
The most common posterior fossa ependymoma subtype is EPN-PFA and is characterized by the following:
  • Presentation in young children (median age, 3 years).[5]
  • Low rates of mutations that affect protein structure (approximately five per genome), with no recurring mutations.[6]
  • A balanced chromosomal profile (refer to Figure 3) with few chromosomal gains or losses.[5,6]
    ENLARGEChart showing the identification of subgroup-specific copy number alterations in the posterior fossa ependymoma genome.
    Figure 3. Identification of Subgroup-Specific Copy Number Alterations in the Posterior Fossa Ependymoma Genome. (A) Copy number profiling of 75 PF ependymomas using 10K array-CGH identifies disparate genetic landscapes between Group A and Group B tumors. Toronto and Heidelberg copy number datasets have been combined and summarized in a heatmap. The heatmap also displays the association of tumors to cytogenetic risk groups 1, 2, and 3 (Korshunov et al., 2010). Statistically significant chromosomal aberrations (black boxes) are also displayed between both subgroups, calculated by Fisher's exact test. 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,doi:10.1016/j.ccr.2011.07.007. Copyright © 2011 Elsevier Inc. All rights reserved.
  • Gain of chromosome 1q, a known poor prognostic factor for ependymomas,[8] in approximately 25% of cases.[5,7]
  • Presence of the CIMP (i.e., CIMP positive).[7]
  • High rates of disease recurrence (33% progression-free survival [PFS] at 5 years) and low survival rates compared with other subtypes (68% at 5 years).[5]
The EPN-PFB subtype is less common than the EPN-PFA subtype in children and is characterized by the following:
  • Presentation primarily in adolescents and young adults (median age, 30 years).[5]
  • Low rates of mutations that affect protein structure (approximately five per genome), with no recurring mutations.[7]
  • Numerous cytogenetic abnormalities (refer to Figure 3), primarily involving the gain/loss of whole chromosomes.[5,7]
  • Absence of the CIMP (i.e., CIMP negative).[7]
  • Favorable outcome in comparison to EPN-PFA, with 5-year PFS of 73% and overall survival (OS) of 100%.[5]
The largest subset of pediatric supratentorial (ST) ependymomas are characterized by gene fusions involving RELA,[9,10] a transcriptional factor important in NF-κB pathway activity. This subtype is termed ST-EPN-RELA and is characterized by the following:
  • Represents approximately 70% of supratentorial ependymomas in children,[9,10] and presents at a median age of 8 years.[5]
  • Presence of C11orf95-RELA fusions resulting from chromothripsis involving chromosome 11q13.1.[9]
  • Evidence of NF-κB pathway activation at the protein and RNA level.[9]
  • Low rates of mutations that affect protein structure and absence of recurring mutations outside of C11orf95-RELA fusions.[9]
  • Presence of homozygous deletions of CDKN2A, a known poor prognostic factor for ependymomas,[8] in approximately 15% of cases.[5]
  • Gain of chromosome 1q, a known poor prognostic factor for ependymomas, in approximately one-quarter of cases.[5]
  • Unfavorable outcome in comparison to other ependymoma subtypes, with 5-year PFS of 29% and OS of 75%.[5]
  • Supratentorial clear cell ependymomas with branching capillaries commonly show theC11orf95-RELA fusion,[11] and one series of 20 patients with a median age of 10.4 years showed a relatively favorable prognosis (5-year PFS of 68% and OS of 72%).[11]
A second, less common subset of supratentorial ependymomas, termed ST-EPN-YAP1, has fusions involving YAP1 and are characterized by the following:
  • Median age at diagnosis of 1.4 years.[5]
  • Presence of a gene fusion involving YAP1, with MAMLD1 being the most common fusion partner.[5,9]
  • A relatively stable genome with few chromosomal changes other than the YAP1 fusion.[5]
  • Relatively favorable prognosis (although based on small numbers), with a 5-year PFS of 66% and OS of 100%.[5]
Clinical implications of genomic alterations
The absence of recurring mutations in the EPN-PFA and EPN-PFB subtypes at diagnosis precludes using their genomic profiles to guide therapy. The RELA and YAP1 fusion genes present in supratentorial ependymomas are not directly targetable with agents in the clinic, but can provide leads for future research.

Clinical Features

The clinical presentation of ependymoma is dependent on tumor location.
  • Infratentorial (posterior fossa) ependymoma: In children, approximately 65% to 75% of ependymomas arise in the posterior fossa.[12] Children with posterior fossa ependymoma may present with signs and symptoms of obstructive hydrocephalus due to obstruction at the level of the fourth ventricle. They may also present with ataxia, neck pain, or cranial nerve palsies.
  • Supratentorial ependymoma: Supratentorial ependymoma may result in headache, seizures, or location-dependent focal neurologic deficits.
  • Spinal cord ependymoma: Spinal cord ependymomas, which are often the myxopapillary variant, tend to cause back pain, lower extremity weakness, and/or bowel and bladder dysfunction.

Diagnostic Evaluation

Every patient suspected of having ependymoma is evaluated with diagnostic imaging of the whole brain and spinal cord. The most sensitive method available for evaluating spinal cord subarachnoid metastasis is spinal magnetic resonance imaging (MRI) performed with gadolinium. This is ideally done before surgery to avoid confusion with postoperative blood. If MRI is used, the entire spine is generally imaged in at least two planes with contiguous MRI slices performed after gadolinium enhancement. If feasible, CSF cytological evaluation is conducted.[13]

Prognostic Factors

Unfavorable factors affecting outcome (except as noted) include the following:
  • Gene expression profile.
    Posterior fossa ependymoma can be divided into the following two groups based on distinctive patterns of gene expression.[5,6,14,15]
    • EPN-PFA occurs primarily in young children and is characterized by a largely balanced genomic profile with an increased occurrence of chromosome 1q gain [8,16-18] and expression of genes and proteins previously shown to be associated with poor prognosis, such as tenascin C and epidermal growth factor receptor.[16,19]
    • In contrast, EPN-PFB occurs primarily in older children and adults and is characterized by a more favorable prognosis and by numerous cytogenetic abnormalities involving whole chromosomes or chromosomal arms.[14]
    Other factors that have been reported to be associated with poor prognosis for pediatric ependymoma include expression of the enzymatic subunit of telomerase (hTERT) [20-22] and expression of the neural stem cell marker Nestin.[23][Level of evidence: 3iiiA]
  • Tumor location. Cranial variants of ependymoma have a less favorable outcome than primary spinal cord ependymomas.[24,25] Location within the spinal cord may also affect outcome, with tumors in the lower portion of the spinal cord having a worse prognosis.[26][Level of evidence: 3iiiA]
  • Younger age at diagnosis.[27][Level of evidence: 3iiiDii]
  • Anaplastic histology.[27-29]; [30][Level of evidence: 3iA]; [31][Level of evidence: 3iiiDi]
  • Subtotal resection.[27]
  • Lower doses of radiation.[32]
  • Immunohistochemical testing has identified increased expression of markers of proliferation (e.g., Ki-67 and MIB-1) [33,34] and increased expression of EZH2, a polycomb complex protein involved in epigenetic regulation of gene expression, as prognostic factors for greater risk of treatment failure.[35]

Follow-up After Treatment

Surveillance neuroimaging, coupled with clinical assessments, are generally recommended after treatment for ependymoma. The frequency and duration have been arbitrarily determined and the utility is uncertain.[36] Most practitioners obtain MRI imaging of the brain and/or spinal cord every 3 months for the first 1 to 2 years after treatment. After 2 years, imaging every 6 months for the next 3 years is often undertaken.
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Histopathologic Classification of Childhood Ependymal Tumors
  • Updated: August 12, 2016
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