lunes, 15 de agosto de 2016

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

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

National Cancer Institute

Childhood Ependymoma Treatment (PDQ®)–Health Professional Version


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.


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


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.2011.07.007Copyright © 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.
  1. Louis DN, Ohgaki H, Wiestler OD: WHO Classification of Tumours of the Central Nervous System. 4th rev.ed. Lyon, France: IARC Press, 2016.
  2. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
  3. 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.
  4. 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.
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  6. 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]
  7. Mack SC, Witt H, Piro RM, et al.: Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506 (7489): 445-50, 2014. [PUBMED Abstract]
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  10. Pietsch T, Wohlers I, Goschzik T, et al.: Supratentorial ependymomas of childhood carry C11orf95-RELA fusions leading to pathological activation of the NF-κB signaling pathway. Acta Neuropathol 127 (4): 609-11, 2014. [PUBMED Abstract]
  11. Figarella-Branger D, Lechapt-Zalcman E, Tabouret E, et al.: Supratentorial clear cell ependymomas with branching capillaries demonstrate characteristic clinicopathological features and pathological activation of nuclear factor-kappaB signaling. Neuro Oncol 18 (7): 919-27, 2016. [PUBMED Abstract]
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  33. 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]
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  • Updated: August 12, 2016

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