Pediatric ependoma has properties similar to that of ependymoma because it is thought to originate in radial glial cells lining the ventricular system. However, they differ from adult ependimomas in which genes and chromosomes are most commonly affected, most commonly found brain areas, and patient prognosis. Children with certain hereditary diseases, such as type II neurofibromatosis (NF2), have been found more commonly affected by this class tumor, but strong genetic relationships still have to be established. Symptoms associated with the development of pediatric ependimomas vary, such as symptoms for a number of other child's brain tumors including vomiting, headache, irritability, lethargy, and gait changes. Although younger children and children with invasive tumor type generally experience less favorable results, total tumor removal is the most prominent prognosis factor for survival and recurrence.
Video Pediatric ependymoma
Basic biology
Original cell
Ependymoma is believed to originate from radial glial cells. Tumorspheres derived from ependymomas display radial-glial-like phenotypes, express CD133 and nestin neuron cell stem markers, as well as RC2-specific glial radial markers and brain lipid-binding proteins (BLBP/FABP7). Bone tumors with radial glial characteristics form tumors in orthotopic rat xenografts, showing radial glials as origin cells for ependymomas.
Inheritance
A number of genetic syndromes are associated with the development of ependymoma, including type II neurofibromatosis (NF2), Turcot syndrome B, and MEN1 syndrome. However, gene mutations associated with familial syndrome are rare in sporadic ependymoma cases. For example, NF2 mutations are rarely observed in ependymoma and MEN1 mutations are found only in a small number of cases of relapse of ependymoma.
Oncogenic lesions
ERBB2 , ERBB4 , and the expression of the human telomerase reverse transcriptase ( TERT) genome promotes tumor cell proliferation, contributing to aggressive tumor behavior. High expression of epidermal growth factor receptors ( EGFR ) correlates with unfavorable outcomes. Over-expression of kinetochorous proteins and down-regulation metallothioneins is associated with recurrence in ependymomas. KIT receptor tyrosine kinase and phospho-KIT are present in pediatric ependymoma and may be involved in angiogenesis associated with the tumor. Chromosome changes
Comparative genomic hybridization experiments (CGH) have shown pediatric ependymoma to have a number of unseen genomic anomalies in adult ependimomas. In addition, the ependymoma of different sites in the central nervous system (spinal, supratentorial, and infratentorial) can be distinguished by their chromosomal, immunohistochemical, and gene expression differences.
Amplification of 1q chromosome and loss of 6q, 17p and 22q are the most common numerical chromosome changes in the child ependimoma. The chromosomal gain of 1q (1q21.1-32.1) is more common in pediatric populations and is associated with tumor recurrence in the intracranial ependymoma. Moreover, the acquisition of chromosome 1q25 has been found for independent prognostic value for recurrent and overall relapse survival. The loss of 22q has been found in both sporadic and family cases, supporting the presence of tumor suppressor genes in this location. However, the loss of 22q is more common in adult forms than in pediatric cases. As NF2 lies in 22q12.2, it is hypothesized to be involved in the development of ependymoma. Although mutations in NF2 are rarely found in sporadic ependymomas other than spinal forms, SCHIP1 , the interaction gene NF2 , significantly decreased in the child's ependimoma, supporting the role for the path NF2 in ependymoma initiation.
Oncogenes and tumor suppressor genes
Various oncogenes and tumor suppressor genes have been found to mutate or have an altered expression in the child's ependimoma. KIT receptor tyrosine kinase and phospho-KIT have been suggested to play a role in the development of pediatric ependimoma, the NOTCH1 mutations have been found in about 8% of pediatric ependimoma, and MEN1 mutations sometimes found in child ependimoma. 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 in the chromosomal region that usually changes in the child's ependimoma, the chromosome 1q25 and the 22q12-q13 chromosome. The expression of two additional candidate genes, S100A6 and S100A4 on the 1q chromosome has also been found to be associated with the development of supratentorial tumors and tumors that occur before 3 years of age, although it is unclear what role played this gene in etiology.
Tumor Progression
Ependymoma has been suggested to emerge from radial glial cells, suggesting neurological stem cell maintenance pathways such as Notch, sonic hedgehog (SHH), and p53 are important for the pathogenesis of ependymoma.
The notch signal pathway and the HOX family of transcription factors are set respectively in the supratentorial and spinal ependymomas. Over-expression of Notch lithers, receptors, and target genes ( HES1 , HEY2 , and MYC ), as well as setting Down on Notch Replorer (Fbxw7) found in child ependymoma. Notch road inhibition damages in vitro tumor growth . ErbB2 target stocks are regulated in most ependymomas, associated with poor results.
While p53 ( TP53 ) mutations are not often observed in pediatric ependimomas, p53 pathways are suggested to play a role in radiation therapy resistance and tumor progression, possibly through overdose MDM2 TP73 ), a p53 homologue, and deletion of p53 pathway p143/p16/INK4A ( CDKN2A ) have also been found in the child's ependimoma.
Over-expression of SHH path components such as GLI1 , GLI2 , and STK36 imply deregulation of SHH paths in ependymomas. Additionally, over-expression of the target SHH IGFBP2 , IGFBP3 , and IGFBP5 in ependymoma also suggests a role for SHH and growth like insulin. factor (IGF) signaling in the pathogenesis of pediatric ependymoma.
Level of development
The expression of endothelial cell KIT is associated with young age at the diagnosis of pilocytic astrocytoma or ependymoma. Telomerase activity is found in childhood ependymoma. In addition, telomere telomerase reactivation and maintenance seem to be necessary for development. Lower nukleolin expression, interacting telomerase protein, is found to be the single most important biological predictor of outcome, where low expression correlates with a more favorable prognosis.
Maps Pediatric ependymoma
Clinical biology
Presentations
Symptoms show 1-36 months before diagnosis, and may vary depending on age, tumor level, and location. Increased intracranial pressure can cause vomiting, headaches, irritability, lethargy, changes in gait, and in children less than 2, eating problems, unconscious eye movements, and hydrocephalus are often seen. Seizures occur in about 20% of pediatric patients. Loss of cognitive function and even sudden death may occur if the tumor is located in an important location for CSF flow. Childhood ependymomas occur most commonly in the posterior cranial fossa, in contrast to the adult ependimomas that usually occur along the spine. Ependymoma is present as a low-density mass on CT scan, and hyperintense in T2-weighted MRI images.
Pathology
Significant debates remain above the ependymoma assessment, although the WHO 2007 classification contains subependymoma (level I), myxopapillary ependymoma (level I), ependymoma (class II), and anaplastic ependymoma (class III) as the main classification. This classification scheme further establishes four subtypes in the ependymoma group. However, there are several subtypes of ependymoma that are recognized with different pathologies. These include myxopapillary ependymoma (MEPN) which tend to grow slowly and confined to the conull medullaris-cauda equina-phylum terminale region of the spinal, intracranial, infratentorial (posterior fossa), intracranial supratentorial, and spinal ependymoma and subependymomas cones. Reports have shown that location-based classification is most relevant to molecular characteristics, involving specific network effects.
Ependymoma arises from oncogenic events that convert normal ependymal cells into cancer cells. Recent evidence suggests the primary cells are radial glia. Genetic changes are quite heterogeneous among similar histologic ependymoma tumors.
Diagnostic features
Comparative genomic hybridization experiments (CGH) have shown pediatric tumors to have a number of unseen genomic anomalies in adult ependimomas, with a high prevalence of all chromosomal imbalances. Epithelial membrane antigens have been shown to help differentiate ependymoma from other pediatric CNS tumors. Neuraxis MR imaging and CSF lumbar cytology evaluation is a widely accepted method for determining tumor spread.
Differential diagnosis
After suspected tumors, medulloblastomas, diffuse astrocytomas, pilocytic astrocytomas, and ependymoma remain in the differential diagnosis as posterior fossa tumors. However, only pilocytic astrocytomas and ependymomas are stained positively for Galectin-3. The ependymoma subtype may also be narrowed by molecular means. For example, the ependyoma myxopapillary has been found to have a higher expression of HOXB5 , PLA2G5 , and ITIH2 . Experimental gene expression profiles show that three members of the transcriptional factor family also have discriminatory forces between medulloblastomas and ependymoma. Without histology, it is difficult to distinguish grade anaplastic epitheloma II versus class III because there is no anatomical difference in magnetic resonance imaging.
Prognosis feature
In general, pediatric ependymoma is associated with a less favorable prognosis than adult ependimoma, and the ependimoma of younger pediatric patients is less favorable than that of older pediatric patients (reviewed in). Tumors that occur in the posterior fossa have also been shown to have a less favorable prognosis. Expression TERT in pediatric intracranial ependymoma correlates with telomerase activity and tumor progression and is negatively correlated with survival. Nucleoline proteins and expression MMP2 and MMP14 have been found to correlate inversely with progression-free survival in cases of child ependymoma, although family members of RTK-1 are not correlated. Tumors of microinvasion, even in tumors that appear to be borderline using various imaging modalities, are also found to be inversely proportional to progressive and overall free survival. Some evidence suggests the removal of chromosome 6q25.3 may provide additional survival benefits in the child's ependimoma.
Treatment
Chemotherapy regimens for childhood ependimoma have resulted in only a small amount of benefit and the rate of resection remains the most prominent factor in recurrence and survival.
The expression of TERT relationships with poor outcomes in childhood ependimoma has prompted some researchers to demonstrate that telomerase inhibition may be an effective adjuvant therapy for childhood ependymoma. Furthermore, data from in vitro experiments using primary tumor cell isolates showed that inhibition of telomerase activity could inhibit cell proliferation and increase cell sensitivity against DNA-damaging agents, consistent with observations of high telomerase activity in primary tumors.. Additionally, since apurinic/apyrimidinic (APE1 ) endonucleases have been found to provide radiation resistance in pediatric ependymoma, it has been suggested that Ap endo-inhibitory activity may also restore radiation sensitivity.
In the infratentorial ependimoma group of children, radiotherapy was found to significantly improve 5-year survival. However, a retrospective review of sterotactic radiosurgery suggests it provides only modest benefits to patients who have previously undergone resection and radiation. Although other supratentorial tumors tend to have a better prognosis, supracentorial anaplastic ependymomas are the most aggressive ependymoma and no total excision or postoperative irradiation is found to be effective in preventing early recurrence.
After resection of infratentorial ependymomas, residual tumors are more likely to be medial lateral than medial tumors, classified radiologically preoperatively. Specific techniques, such as cerebellomedullary fiss dissection have been proposed to assist in complete resection while avoiding iatrogenic effects in this case. Surveillance of neuroimaging for relapse provides additional survival for patients more than observation alone.
Biochemical marker
HTERT and yH2AX are important markers for prognosis and response to therapy. The high expression of hTERT and low yH2AX is associated with poor response to therapy. Patients with high or low expression of these markers form a moderate response group.
Relapse
5-year disease-free survival for age & gt; 5 years is 50-60%. Other reports found the same 5-year survival in about 65% with 51% free survival progression. 10 years disease-free survival is 40-50%. The younger age indicates a lower 5 and 10 year survival rate. A 2006 study looking at 133 patients found 31 (23.3%) had a recurrence of the disease within a five year period.
Long-term consequences of treatment
The use of telomerase inhibitors such as Imetelstat appears to have very low toxicity compared with other chemotherapy. The only known side-effect of most telomerase inhibitors is dose-induced neutropenia. Neuropsychological deficits can occur due to resection, chemotherapy, and radiation, and endocrineopathy. In addition, an increase in gastrointestinal complications has been observed in pediatric cancer survivors.
References
External links
- National Cancer Institute website
- wiki.medpedia.com
- Pediatric Ependymoma in eMedicine
- cern-foundation.org
- childrenshospital.org
- atlasgeneticsoncology.org
- cancer.net
- umgcc.org
- MedPix Imaging and Diagnosis
Source of the article : Wikipedia
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