Pediatric ependymoma

Pediatric ependymomas are similar in nature to the adult form of ependymoma in that they are thought to arise from radial glial cells lining the ventricular system. However, they differ from adult ependymomas in which genes and chromosomes are most often affected, the region of the brain they are most frequently found in, and the prognosis of the patients. Children with certain hereditary diseases, such as neurofibromatosis type II (NF2), have been found to be more frequently afflicted with this class of tumors, but a firm genetic link remains to be established. Symptoms associated with the development of pediatric ependymomas are varied, much like symptoms for a number of other pediatric brain tumors including vomiting, headache, irritability, lethargy, and changes in gait. Although younger children and children with invasive tumor types generally experience less favorable outcomes, total removal of the tumors is the most conspicuous prognostic factor for both survival and relapse. Pediatric ependymomas are similar in nature to the adult form of ependymoma in that they are thought to arise from radial glial cells lining the ventricular system. However, they differ from adult ependymomas in which genes and chromosomes are most often affected, the region of the brain they are most frequently found in, and the prognosis of the patients. Children with certain hereditary diseases, such as neurofibromatosis type II (NF2), have been found to be more frequently afflicted with this class of tumors, but a firm genetic link remains to be established. Symptoms associated with the development of pediatric ependymomas are varied, much like symptoms for a number of other pediatric brain tumors including vomiting, headache, irritability, lethargy, and changes in gait. Although younger children and children with invasive tumor types generally experience less favorable outcomes, total removal of the tumors is the most conspicuous prognostic factor for both survival and relapse. Ependymomas are believed to arise from radial glial cells. Tumorspheres derived from ependymomas display a radial-glial like phenotype, expressing neuronal stem cell markers CD133 and nestin, as well as radial glial specific markers RC2 and brain lipid binding protein (BLBP/FABP7). Tumorspheres with radial glial characteristics form tumors in orthotopic mouse xenografts, suggesting radial glial as cell of origin for ependymomas. A number of genetic syndromes are associated with the development of ependymoma, including neurofibromatosis type II (NF2), Turcot syndrome B, and MEN1 syndrome. However, gene mutations linked to the familial syndromes are rarely found in sporadic cases of ependymoma. For example, NF2 mutations have rarely been observed in ependymomas and MEN1 mutations have only been found in a small number of cases of ependymoma recurrences. ERBB2, ERBB4, and human telomerase reverse transcriptase (TERT) gene expression promote tumor cell proliferation, contributing to aggressive tumor behavior. High expression of epidermal growth factor receptor (EGFR) correlates with unfavorable outcome. Over-expression of kinetochore proteins and down-regulation of metallothioneins are associated with recurrence in ependymomas. KIT receptor tyrosine kinase and phospho-KIT were found to be present in pediatric ependymomas and may be involved in angiogenesis associated with those tumors. Comparative genomic hybridization (CGH) experiments have shown pediatric ependymomas possess a number of genomic anomalies not seen in adult ependymomas. In addition, ependymomas from different locations within the central nervous system (spinal, supratentorial, and infratentorial) can be distinguished by their chromosomal, immunohistochemical, and gene expression differences. Amplification of chromosome 1q and loss of 6q, 17p and 22q are the most common numerical chromosomal changes in pediatric ependymomas. Gain of chromosome 1q (1q21.1-32.1) is more common in the pediatric population and is associated with tumor recurrence in intracranial ependymomas. Moreover, gain of chromosome 1q25 has been found to independent prognostic value for recurrence-free and overall survival. Loss of 22q has been found in both sporadic and familial cases, supporting the presence of a tumor suppressor gene at this location. However, loss of 22q is more common in the adult form than pediatric cases. As NF2 is located on 22q12.2, it was hypothesized to be involved in the development of ependymoma. Though mutations in NF2 are rarely found in sporadic ependymomas other than the spinal form, SCHIP1, a NF2 interacting gene, is significantly down-regulated in pediatric ependymomas, supporting a role for the NF2 pathway in the initiation of ependymomas. A variety of oncogenes and tumor suppressor genes have been found to be mutated or possess altered expression in pediatric ependymomas. KIT receptor tyrosine kinase and phospho-KIT have been suggested to play a role in the development of pediatric ependymomas, NOTCH1 mutations have been found in approximately 8% of pediatric ependymomas, and MEN1 mutations are occasionally found in pediatric ependymomas. MMP2 and MMP14 appear to also play a role in tumor growth and progression in intracranial cases. Two candidate genes, TPR and CHIBBY, have been identified on commonly altered chromosome regions in pediatric ependymomas, chromosomes 1q25 and chromosome 22q12-q13. Expression of two additional candidate genes, S100A6 and S100A4 on chromosome 1q have also been found to correspond to supratentorial tumor development and tumors occurring before the age of 3 years old, though it is unclear exactly what role these genes play in the etiology. Ependymomas have been suggested to arise from radial glial cells, suggesting neural stem cell maintenance pathways such as Notch, sonic hedgehog (SHH), and p53 are important for the pathogenesis of ependymomas. Notch signaling pathway and HOX family of transcription factors are up regulated in supratentorial and spinal ependymomas respectively. Over-expression of Notch ligands, receptors, and target genes (HES1, HEY2, and MYC), as well as down-regulation of Notch repressor (Fbxw7) are found in pediatric ependymoma. Inhibition of Notch pathway impairs tumor growth in vitro. Notch target ErbB2 is up-regulated in most ependymomas, correlating with poor outcome.