Pediatric Ependymoma
Encyclopedia
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 ependymoma
s in which gene
s and chromosome
s 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. Symptom
s associated with the development of pediatric ependymomas are varied, much like symptom
s for a number of other pediatric brain tumor
s 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
.
s display a radial-glial like phenotype
, expressing neuron
al 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 ependymoma
s.
syndromes are associated with the development of ependymoma
, including neurofibromatosis type II
(NF2), Turcot syndrome
B, and MEN1
syndrome. However, gene
mutation
s linked to the familial syndromes are rarely found in sporadic cases of ependymoma
. For example, NF2 mutation
s have rarely been observed in ependymoma
s and MEN1
mutation
s have only been found in a small number of cases of ependymoma
recurrences.
, 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 metallothionein
s are associated with recurrence in ependymoma
s. 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.
(CGH) experiments have shown pediatric ependymomas possess a number of genomic anomalies not seen in adult ependymoma
s. 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.
s 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 gene
s, 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
.
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 factor
s 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.
While p53
(TP53) mutations are not often observed in pediatric ependymoma, the p53 pathway is suggested to play a role in radiation therapy resistance and tumor progression, possibly via over-expression of MDM2
. Further, up-regulation of p73
(TP73), a homolog of p53
, and deletion of the p53 pathway gene p14arf/p16/INK4A (CDKN2A
) have also been found in pediatric ependymomas.
Over-expression of components of SHH
pathway such as GLI1
, GLI2
, and STK36
implicates deregulation of the SHH
pathway in ependymomas. Moreover, over-expression of SHH
targets IGFBP2
, IGFBP3
, and IGFBP5
in ependymoma is also suggestive of a role for SHH
and insulin-like growth factor
(IGF
) signaling in the pathogenesis
of pediatric ependymomas.
expression was associated with a young age at diagnosis of pilocytic astrocytoma
or ependymoma. Telomerase
activity is found in childhood ependymoma. In addition, telomerase
reactivation and maintenance of telomere
s appears to be required for progression. Low expression nucleolin
, a interacting protein of telomerase
, was the single most important biological predictor of outcome, low expression correlates with better prognosis.
s present 1–36 months before diagnosis
, and can vary depending on age, tumor grade, and location. Increased intracranial pressure
can induce vomiting, headache, irritability, lethargy, changes in gait
, and in children less than 2, feeding problems, involuntary eye movements, and hydrocephalus
are often noticeable. Seizure
s occur in about 20% of pediatric patients. Loss of cognitive function and even sudden death could occur if the tumor is located at a crucial location for CSF flow. Pediatric ependymomas most often occur in the posterior cranial fossa
, in contrast with adult ependymoma
s which usually occur along the spine
. Ependymomas present as low-density masses on CT scans, and are hyperintense on T2-weighted MRI images.
2007 classification lists subependymoma
(grade I), myxopapillary ependymoma (grade I), ependymoma (grade II), and anaplastic ependymoma (grade IV) as the primary classifications. This classification scheme further designates four subtypes within the ependymoma group. However, there are several recognized subtypes of ependymoma with differing pathologies
. These include myxopapillary ependymoma (MEPN) which tend to grow slowly and are restricted to the conus medullaris
-cauda equina
-filum terminale
region of the spinal cord
, intracranial, infratentorial (posterior fossa
), intracranial supratentorial, and spinal
ependymoma, and subependymomas. Reports have shown that location-based classification is most relevant to the molecular characteristics, implicating underlying tissue-specificity effects.
Ependymomas arise from oncogenic events mutating normal ependymal cells into cancerous cells. Recent evidence suggests the primary cells are radial glia
. Genetic
alterations are fairly heterogeneous among histologically
similar ependymoma tumors.
(CGH
) experiments have shown pediatric tumors possess a number of genomic anomalies not seen in adult ependymoma
s, with a high prevalence of whole chromosome
imbalances. Epithelial membrane antigen has been shown to help distinguish ependymomas from other pediatric CNS
tumors. Neuraxis MR imaging and lumbar CSF cytology evaluation are widely accepted methods for determining tumor dissemination.
s, diffuse astrocytomas, pilocytic astrocytoma
s, and ependymomas remain in the differential diagnosis as posterior fossa
tumors. However, only pilocytic astrocytoma
s and ependymomas stain positively for Galectin-3
. The subtype of ependymoma can also be narrowed down by molecular means. For instance, the myxopapillary ependyomas have been found to have higher expression of HOXB5
, PLA2G5
, and ITIH2
. A gene expression profiling experiment has shown that three members of the SOX
family of transcription factor
s also possessed discriminatory power between medulloblastoma
s and ependymomas. Without histology
, it is difficult to differentiate grade II versus grade III anaplastic ependymomas because there are no anatomical differences on magnetic resonance imaging
.
s, and ependymomas of younger pediatric patients are less favorable than ependymomas of older pediatric patients (reviewed in ). Tumors that occur in the posterior fossa
have also been shown to have a less favorable prognosis. Expression of TERT in pediatric intracranial ependymomas is correlated with telomerase
activity and tumor progression and negatively correlated with survival. The protein nucleolin
and expression of MMP2
and MMP14
have been found to inversely correlate with progression free survival in cases of pediatric ependymoma, though RTK-1 family members were not correlated. Tumor microinvasion, even in tumors appearing well-demarcated using various imaging modalities, was also found to be inversely associated with|progression-free and overall survival. Some evidence suggests chromosome 6q25.3 deletion may provide additional survival benefit in pediatric ependymomas.
regimens for pediatric ependymomas have produced only modest benefit and degree of resection remains the most conspicuous factor in recurrence and survival.
The association of TERT expression with poor outcome in pediatric ependymomas has driven some researchers to suggest that telomerase
inhibition may be an effective adjuvant therapy for pediatric ependymomas. Further, data from in vitro experiments using primary tumor isolate cells suggest that inhibition of telomerase
activity may inhibit cell proliferation and increase sensitivity of cells to DNA
damaging agents, consistent with the observation of high telomerase
activity in primary tumors. Additionally, because apurinic/apyrimidinic endonuclease (APE1) has been found to confer radiation resistance in pediatric ependymomas, it has been suggested that inhibitors of Ap endo activity might also restore radiation sensitivity.
Within the infratentorial group of pediatric ependymomas, radiotherapy was found to significantly increase 5-year survival. However, a retrospective review of sterotactic radiosurgery showed it provided only a modest benefit to patients who had previously undergone resection and radiation. Though other supratentorial tumors tend to have a better prognosis, supratentorial anaplastic ependymomas are the most aggressive ependymoma and neither total excision nor postoperative irradiation was found to be effective in preventing early recurrence.
Following resection of infratentorial ependymomas, residual tumor is more likely in lateral versus medial tumors, classified radiologically pre-operatively. Specific techniques, such as cerebellomedullary fissure dissection have been proposed to aid in complete resection while avoiding iatrogenic effects in these cases. Surveillance neuroimaging for recurrence provides additional survival to patients over observation alone.
are crucial markers for prognosis and response to therapy. High hTERT and low yH2AX
expression is associated with poor response to therapy. Patients with both high or low expression of these markers make up the moderate response groups.
inhibitors such as Imetelstat seem to have very low toxicity compared to other chemotherapy
. The only known side effect of most telomerase
inhibitors is dose-induced neutropenia
. Neuropsychological deficits can result from resection, chemotherapy
, and radiation, as well as endocrinopathies. Additionally, an increase in gastrointestinal complications has been observed in survivors of pediatric cancers.
Ependymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...
in that they are thought to arise from radial glial cells lining the ventricular system
Ventricular system
The ventricular system is a set of structures containing cerebrospinal fluid in the brain. It is continuous with the central canal of the spinal cord.-Components:The system comprises four ventricles:* right and left lateral ventricles* third ventricle...
. However, they differ from adult ependymoma
Ependymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...
s in which gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s and chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
s are most often affected, the region of the brain they are most frequently found in, and the prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
of the patients. Children with certain hereditary diseases, such as neurofibromatosis type II (NF2)
Neurofibromatosis type II
Neurofibromatosis Type II is an inherited disease. The main manifestation of the disease is the development of symmetric, non-malignant brain tumours in the region of the cranial nerve VIII, which is the auditory-vestibular nerve that transmits sensory information from the inner ear to the...
, have been found to be more frequently afflicted with this class of tumors, but a firm genetic
Genetic
Genetic may refer to:*Genetics, in biology, the science of genes, heredity, and the variation of organisms**Genetic, used as an adjective, refers to heredity of traits**Gene, a unit of heredity in the genome of an organism...
link remains to be established. Symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s associated with the development of pediatric ependymomas are varied, much like symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s for a number of other pediatric brain tumor
Brain tumor
A brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...
s including vomiting, headache, irritability, lethargy, and changes in gait
Gait
Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency...
. 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
Relapse
Relapse, in relation to drug misuse, is resuming the use of a drug or a dependent substance after one or more periods of abstinence. The term is a landmark feature of both substance dependence and substance abuse, which are learned behaviors, and is maintained by neuronal adaptations that mediate...
.
Cell of origin
Ependymomas are believed to arise from radial glial cells. Tumorspheres derived from ependymomaEpendymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...
s display a radial-glial like phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
, expressing neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
al stem cell markers CD133
CD133
CD133, originally known as AC133. CD133 is a glycoprotein also known in humans and rodents as Prominin 1 . Currently the function of CD133 is unknown...
and nestin
Nestin
Nestin may refer to:* Neštin, a village in Srem, Vojvodina, Serbia.* Nestin , a type VI intermediate filament protein....
, as well as radial glial specific markers RC2 and brain lipid binding protein (BLBP/FABP7
FABP7
Fatty acid binding protein 7, brain , is a human gene.FABP7 is expressed, during development, in radial glia by the activation of Notch receptors...
). Tumorspheres with radial glial characteristics form tumors in orthotopic mouse xenografts, suggesting radial glial as cell of origin for ependymoma
Ependymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...
s.
Inheritance
A number of geneticGenetic
Genetic may refer to:*Genetics, in biology, the science of genes, heredity, and the variation of organisms**Genetic, used as an adjective, refers to heredity of traits**Gene, a unit of heredity in the genome of an organism...
syndromes are associated with the development of ependymoma
Ependymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...
, including neurofibromatosis type II
Neurofibromatosis type II
Neurofibromatosis Type II is an inherited disease. The main manifestation of the disease is the development of symmetric, non-malignant brain tumours in the region of the cranial nerve VIII, which is the auditory-vestibular nerve that transmits sensory information from the inner ear to the...
(NF2), Turcot syndrome
Turcot syndrome
Mismatch repair cancer syndrome is a condition associated with biallelic DNA mismatch repair mutations. It is also known as Turcot syndrome after Jacques Turcot who described the condition in 1959.-Genetics:...
B, and MEN1
MEN1
Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1....
syndrome. However, gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s linked to the familial syndromes are rarely found in sporadic cases of ependymoma
Ependymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...
. For example, NF2 mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s have rarely been observed in ependymoma
Ependymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...
s and MEN1
MEN1
Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1....
mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s have only been found in a small number of cases of ependymoma
Ependymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...
recurrences.
Oncogenic lesions
ERBB2, ERBB4ERBB4
Receptor tyrosine-protein kinase erbB-4 is an enzyme that in humans is encoded by the ERBB4 gene. Alternatively spliced variants that encode different protein isoforms have been described; however, not all variants have been fully characterized....
, and human telomerase reverse transcriptase (TERT) gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
promote tumor cell proliferation, contributing to aggressive tumor behavior. High expression of epidermal growth factor receptor
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(EGFR) correlates with unfavorable outcome. Over-expression of kinetochore
Kinetochore
The kinetochore is the protein structure on chromatids where the spindle fibers attach during cell division to pull sister chromatids apart....
proteins and down-regulation of metallothionein
Metallothionein
Metallothionein is a family of cysteine-rich, low molecular weight proteins. They are localized to the membrane of the Golgi apparatus...
s are associated with recurrence in ependymoma
Ependymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...
s. KIT
CD117
Mast/stem cell growth factor receptor also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117 is a protein that in humans is encoded by the KIT gene...
receptor tyrosine kinase and phospho
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
-KIT
CD117
Mast/stem cell growth factor receptor also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117 is a protein that in humans is encoded by the KIT gene...
were found to be present in pediatric ependymomas and may be involved in angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
associated with those tumors.
Chromosomal changes
Comparative genomic hybridizationComparative genomic hybridization
Comparative genomic hybridization or Chromosomal Microarray Analysis is a molecular-cytogenetic method for the analysis of copy number changes in the DNA content of a given subject's DNA and often in tumor cells....
(CGH) experiments have shown pediatric ependymomas possess a number of genomic anomalies not seen in adult ependymoma
Ependymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...
s. In addition, ependymomas from different locations within the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(spinal, supratentorial
Supratentorial
In anatomy, the supratentorial region of the brain is the area located above the tentorium cerebelli. The area of the brain below the tentorium cerebelli is the infratentorial region. The supratentorial region contains the cerebrum, while the infratentorial region contains the cerebellum....
, and infratentorial) can be distinguished by their chromosomal, immunohistochemical
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
, and gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
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
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
at this location. However, loss of 22q is more common in the adult form
Ependymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...
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.
Oncogenes and tumor suppressor genes
A variety of oncogenes and tumor suppressor geneTumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
s have been found to be mutated or possess altered expression in pediatric ependymomas. KIT receptor tyrosine kinase
CD117
Mast/stem cell growth factor receptor also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117 is a protein that in humans is encoded by the KIT gene...
and phospho
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
-KIT
CD117
Mast/stem cell growth factor receptor also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117 is a protein that in humans is encoded by the KIT gene...
have been suggested to play a role in the development of pediatric ependymomas, NOTCH1
NOTCH1
Notch homolog 1, translocation-associated , also known as NOTCH1, is a human gene encoding a single-pass transmembrane receptor.A deficiency can be associated with bicuspid aortic valve....
mutations have been found in approximately 8% of pediatric ependymomas, and MEN1
MEN1
Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1....
mutations are occasionally found in pediatric ependymomas. MMP2
MMP2
72 kDa type IV collagenase also known as matrix metalloproteinase-2 and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene....
and MMP14
MMP14
Matrix metalloproteinase-14 is an enzyme that in humans is encoded by the MMP14 gene.Proteins of the matrix metalloproteinase family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well...
appear to also play a role in tumor growth and progression in intracranial cases. Two candidate genes, TPR
TPR
TPR may refer to:*True Positive Rate, a statistical measure*Tarbes Pyrénées Rugby, a french rugby club*The Paris Review, an American literary magazine*The Planetary Report, the Planetary Society's magazine about space exploration...
and CHIBBY, have been identified on commonly altered chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
regions in pediatric ependymomas, chromosomes 1q25 and chromosome 22q12-q13. Expression of two additional candidate gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s, S100A6
S100A6
Protein S100-A6 is a protein that in humans is encoded by the S100A6 gene.-Interactions:S100A6 has been shown to interact with S100B and SUGT1.-Further reading:...
and S100A4
S100A4
Protein S100-A4 is a protein that in humans is encoded by the S100A4 gene.-Interactions:S100A4 has been shown to interact with S100 calcium binding protein A1.-Further reading:...
on chromosome 1q have also been found to correspond to supratentorial
Supratentorial
In anatomy, the supratentorial region of the brain is the area located above the tentorium cerebelli. The area of the brain below the tentorium cerebelli is the infratentorial region. The supratentorial region contains the cerebrum, while the infratentorial region contains the cerebellum....
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
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
.
Tumor progression
Ependymomas have been suggested to arise from radial glial cells, suggesting neural stem cellStem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
maintenance pathways such as Notch
Notch
Notch may refer to:* The nock of an arrow* Notch , a Hip hop, R&B, reggae, dancehall and reggaeton artist* Notch signaling pathway, a cell signaling system present in most multicellular organisms...
, Sonic Hedgehog
Sonic hedgehog
Sonic hedgehog homolog is one of three proteins in the mammalian signaling pathway family called hedgehog, the others being desert hedgehog and Indian hedgehog . SHH is the best studied ligand of the hedgehog signaling pathway. It plays a key role in regulating vertebrate organogenesis, such as...
(SHH
SHH
SHH can refer to:* Summer Heights High, an Australian TV series* Sonic hedgehog, an important protein during vertebrate organogenesis* Students Helping Honduras, an international non-governmental organization operating in the U.S. and Honduras...
), and p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
are important for the pathogenesis
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of ependymomas.
Notch
Notch
Notch may refer to:* The nock of an arrow* Notch , a Hip hop, R&B, reggae, dancehall and reggaeton artist* Notch signaling pathway, a cell signaling system present in most multicellular organisms...
signaling pathway and HOX family of transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s are up regulated in supratentorial
Supratentorial
In anatomy, the supratentorial region of the brain is the area located above the tentorium cerebelli. The area of the brain below the tentorium cerebelli is the infratentorial region. The supratentorial region contains the cerebrum, while the infratentorial region contains the cerebellum....
and spinal
Vertebral column
In human anatomy, the vertebral column is a column usually consisting of 24 articulating vertebrae, and 9 fused vertebrae in the sacrum and the coccyx. It is situated in the dorsal aspect of the torso, separated by intervertebral discs...
ependymomas respectively. Over-expression of Notch
Notch
Notch may refer to:* The nock of an arrow* Notch , a Hip hop, R&B, reggae, dancehall and reggaeton artist* Notch signaling pathway, a cell signaling system present in most multicellular organisms...
ligands, receptors, and target genes (HES1
HES1
Transcription factor HES-1 is a protein that in humans is encoded by the HES1 gene.-Interactions:HES1 has been shown to interact with TLE2 and Sirtuin 1.- External links :...
, HEY2
HEY2
Hairy/enhancer-of-split related with YRPW motif protein 2 also known as cardiovascular helix-loop-helix factor 1 is a protein that in humans is encoded by the HEY2 gene.- Function :...
, and MYC
Myc
Myc is a regulator gene that codes for a transcription factor. In the human genome, Myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes through binding on Enhancer Box sequences and recruiting histone acetyltransferases...
), as well as down-regulation of Notch
Notch
Notch may refer to:* The nock of an arrow* Notch , a Hip hop, R&B, reggae, dancehall and reggaeton artist* Notch signaling pathway, a cell signaling system present in most multicellular organisms...
repressor (Fbxw7) are found in pediatric ependymoma. Inhibition of Notch
Notch
Notch may refer to:* The nock of an arrow* Notch , a Hip hop, R&B, reggae, dancehall and reggaeton artist* Notch signaling pathway, a cell signaling system present in most multicellular organisms...
pathway impairs tumor growth in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
. Notch
Notch
Notch may refer to:* The nock of an arrow* Notch , a Hip hop, R&B, reggae, dancehall and reggaeton artist* Notch signaling pathway, a cell signaling system present in most multicellular organisms...
target ErbB2 is up-regulated in most ependymomas, correlating with poor outcome.
While p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
(TP53) mutations are not often observed in pediatric ependymoma, the p53 pathway is suggested to play a role in radiation therapy resistance and tumor progression, possibly via over-expression of MDM2
Mdm2
Mdm2 is an important negative regulator of the p53 tumor suppressor. It is the name of a gene as well as the protein encoded by that gene. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain of the p53 tumor suppressor and an inhibitor of...
. Further, up-regulation of p73
P73
p73 is a protein related to the p53 tumor protein. Because of its structural resemblance to p53, it has also been considered a tumor suppressor. It is involved in cell cycle regulation, and induction of apoptosis. Like p53, p73 is characterized by the presence of different isoforms of the protein...
(TP73), a homolog of p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, and deletion of the p53 pathway gene p14arf/p16/INK4A (CDKN2A
CDKN2A
CDKN2A can refer to:* P16 * p14arf...
) have also been found in pediatric ependymomas.
Over-expression of components of SHH
SHH
SHH can refer to:* Summer Heights High, an Australian TV series* Sonic hedgehog, an important protein during vertebrate organogenesis* Students Helping Honduras, an international non-governmental organization operating in the U.S. and Honduras...
pathway such as GLI1
Gli1
Gli1 is a protein originally isolated in human glioblastoma.-Overview:The Gli proteins are the effectors of Hedgehog signaling and have been shown to be involved in cell fate determination, proliferation and patterning in many cell types and most organs during embryo development.The Gli...
, GLI2
Gli2
Zinc finger protein GLI2 also known as GLI family zinc finger 2 is a protein that in humans is encoded by the GLI2 gene. The protein encoded by this gene is a transcription factor....
, and STK36
STK36
Serine/threonine-protein kinase 36 is an enzyme that in humans is encoded by the STK36 gene.-Further reading:...
implicates deregulation of the SHH
SHH
SHH can refer to:* Summer Heights High, an Australian TV series* Sonic hedgehog, an important protein during vertebrate organogenesis* Students Helping Honduras, an international non-governmental organization operating in the U.S. and Honduras...
pathway in ependymomas. Moreover, over-expression of SHH
SHH
SHH can refer to:* Summer Heights High, an Australian TV series* Sonic hedgehog, an important protein during vertebrate organogenesis* Students Helping Honduras, an international non-governmental organization operating in the U.S. and Honduras...
targets IGFBP2
IGFBP2
Insulin-like growth factor-binding protein 2 is a protein that in humans is encoded by the IGFBP2 gene.-Further reading:...
, IGFBP3
IGFBP3
Insulin-like growth factor-binding protein 3, also known as IGFBP3, is a protein that, in humans, is encoded by the IGFBP3 gene.- Function :...
, and IGFBP5
IGFBP5
Insulin-like growth factor-binding protein 5 is a protein that in humans is encoded by the IGFBP5 gene.-Further reading:...
in ependymoma is also suggestive of a role for SHH
SHH
SHH can refer to:* Summer Heights High, an Australian TV series* Sonic hedgehog, an important protein during vertebrate organogenesis* Students Helping Honduras, an international non-governmental organization operating in the U.S. and Honduras...
and insulin-like growth factor
Insulin-like growth factor
The insulin-like growth factors are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment...
(IGF
IGF
IGF may stand for:* Insulin-like growth factor* Independent Games Festival* Internet Governance Forum* Identity Governance Framework* Inoki Genome Federation* International Golf Federation* International Gymnastics Federation* International Go Federation...
) signaling in the pathogenesis
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of pediatric ependymomas.
Rate of progression
Endothelial cell KITCD117
Mast/stem cell growth factor receptor also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117 is a protein that in humans is encoded by the KIT gene...
expression was associated with a young age at diagnosis of pilocytic astrocytoma
Pilocytic astrocytoma
Pilocytic astrocytoma or juvenile pilocytic astrocytoma or cystic cerebellar astrocytoma is a neoplasm of the brain that occurs more often in children and young adults...
or ependymoma. Telomerase
Telomerase
Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...
activity is found in childhood ependymoma. In addition, telomerase
Telomerase
Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...
reactivation and maintenance of telomere
Telomere
A telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos "end" and merοs "part"...
s appears to be required for progression. Low expression nucleolin
Nucleolin
Nucleolin is a protein that in humans is encoded by the NCL gene.- Gene :The human NCL gene is located on chromosome 2 and consists of 14 exons with 13 introns and spans approximately 11kb...
, a interacting protein of telomerase
Telomerase
Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...
, was the single most important biological predictor of outcome, low expression correlates with better prognosis.
Presentation
SymptomSymptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s present 1–36 months before diagnosis
Diagnosis
Diagnosis is the identification of the nature and cause of anything. Diagnosis is used in many different disciplines with variations in the use of logics, analytics, and experience to determine the cause and effect relationships...
, and can vary depending on age, tumor grade, and location. Increased intracranial pressure
Intracranial pressure
Intracranial pressure is the pressure inside the skull and thus in the brain tissue and cerebrospinal fluid . The body has various mechanisms by which it keeps the ICP stable, with CSF pressures varying by about 1 mmHg in normal adults through shifts in production and absorption of CSF...
can induce vomiting, headache, irritability, lethargy, changes in gait
Gait
Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency...
, and in children less than 2, feeding problems, involuntary eye movements, and hydrocephalus
Hydrocephalus
Hydrocephalus , also known as "water in the brain," is a medical condition in which there is an abnormal accumulation of cerebrospinal fluid in the ventricles, or cavities, of the brain. This may cause increased intracranial pressure inside the skull and progressive enlargement of the head,...
are often noticeable. Seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s occur in about 20% of pediatric patients. Loss of cognitive function and even sudden death could occur if the tumor is located at a crucial location for CSF flow. Pediatric ependymomas most often occur in the posterior cranial fossa
Posterior cranial fossa
The posterior cranial fossa is part of the intracranial cavity, located between the foramen magnum and tentorium cerebelli. It contains the brainstem and cerebellum.This is the most inferior of the fossae. It houses the cerebellum, medulla and pons....
, in contrast with adult ependymoma
Ependymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...
s which usually occur along the spine
Vertebral column
In human anatomy, the vertebral column is a column usually consisting of 24 articulating vertebrae, and 9 fused vertebrae in the sacrum and the coccyx. It is situated in the dorsal aspect of the torso, separated by intervertebral discs...
. Ependymomas present as low-density masses on CT scans, and are hyperintense on T2-weighted MRI images.
Pathology
Significant debate remains over grading of ependymomas, though the WHOWho
Who may refer to:* Who , an English-language pronoun* who , a Unix command* Who?, one of the Five Ws in journalism- Art and entertainment :* Who? , a 1958 novel by Algis Budrys...
2007 classification lists subependymoma
Subependymoma
A subependymoma is a type of brain tumor; specifically, it is a rare form of ependymal tumor.The prognosis for a subependymoma is better than for most ependymal tumors, and is considered a grade I/IV tumor in the World Health Organization classification.They are classically found within the fourth...
(grade I), myxopapillary ependymoma (grade I), ependymoma (grade II), and anaplastic ependymoma (grade IV) as the primary classifications. This classification scheme further designates four subtypes within the ependymoma group. However, there are several recognized subtypes of ependymoma with differing pathologies
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
. These include myxopapillary ependymoma (MEPN) which tend to grow slowly and are restricted to the conus medullaris
Conus medullaris
The conus medullaris is the terminal end of the spinal cord. It occurs near lumbar vertebral levels 1 and 2 . After the spinal cord tapers out, the spinal nerves continue as dangling nerve roots called cauda equina. This terminal nerve root tail is referred to as the filum terminale...
-cauda equina
Cauda equina
The cauda equina is a structure within the lower end of the spinal column of most vertebrates, that consists of nerve roots and rootlets from above...
-filum terminale
Filum terminale
The filum terminale , is a delicate strand of fibrous tissue, about 20 cm. in length, proceeding downward from the apex of the conus medullaris. It gives longitudinal support to the spinal cord and consists of two parts:...
region of the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
, intracranial, infratentorial (posterior fossa
Posterior fossa
Posterior fossa may refer to:* Posterior cranial fossa* Posterior intercondyloid fossa...
), intracranial supratentorial, and spinal
Vertebral column
In human anatomy, the vertebral column is a column usually consisting of 24 articulating vertebrae, and 9 fused vertebrae in the sacrum and the coccyx. It is situated in the dorsal aspect of the torso, separated by intervertebral discs...
ependymoma, and subependymomas. Reports have shown that location-based classification is most relevant to the molecular characteristics, implicating underlying tissue-specificity effects.
Ependymomas arise from oncogenic events mutating normal ependymal cells into cancerous cells. Recent evidence suggests the primary cells are radial glia
Radial glia
Radial glial cells are a pivotal cell type in the developing central nervous system involved in key developmental processes, from patterning and neuronal migration to their recently discovered role as precursors during neurogenesis. They arise early in development from neuroepithelial cells...
. Genetic
Genetic
Genetic may refer to:*Genetics, in biology, the science of genes, heredity, and the variation of organisms**Genetic, used as an adjective, refers to heredity of traits**Gene, a unit of heredity in the genome of an organism...
alterations are fairly heterogeneous among histologically
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
similar ependymoma tumors.
Diagnostic features
Comparative genomic hybridizationComparative genomic hybridization
Comparative genomic hybridization or Chromosomal Microarray Analysis is a molecular-cytogenetic method for the analysis of copy number changes in the DNA content of a given subject's DNA and often in tumor cells....
(CGH
CGH
CGH may stand for:* Comparative genomic hybridization* Computer generated holography* the IATA airport code of Congonhas-São Paulo International Airport* Changi General Hospital* cGh physics...
) experiments have shown pediatric tumors possess a number of genomic anomalies not seen in adult ependymoma
Ependymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...
s, with a high prevalence of whole chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
imbalances. Epithelial membrane antigen has been shown to help distinguish ependymomas from other pediatric CNS
CNS
-Science and medicine:* Cell, Nature, and Science, the three most prestigious scientific journals involved in biomedical research* Central nervous system, brain and spinal cord* Chronic nonbacterial prostatitis, a pelvic pain condition affecting men...
tumors. Neuraxis MR imaging and lumbar CSF cytology evaluation are widely accepted methods for determining tumor dissemination.
Differential diagnoses
Once a tumor is suspected, medulloblastomaMedulloblastoma
Medulloblastoma is a highly malignant primary brain tumor that originates in the cerebellum or posterior fossa.Previously, medulloblastomas were thought to represent a subset of primitive neuroectodermal tumor of the posterior fossa...
s, diffuse astrocytomas, pilocytic astrocytoma
Pilocytic astrocytoma
Pilocytic astrocytoma or juvenile pilocytic astrocytoma or cystic cerebellar astrocytoma is a neoplasm of the brain that occurs more often in children and young adults...
s, and ependymomas remain in the differential diagnosis as posterior fossa
Posterior fossa
Posterior fossa may refer to:* Posterior cranial fossa* Posterior intercondyloid fossa...
tumors. However, only pilocytic astrocytoma
Pilocytic astrocytoma
Pilocytic astrocytoma or juvenile pilocytic astrocytoma or cystic cerebellar astrocytoma is a neoplasm of the brain that occurs more often in children and young adults...
s and ependymomas stain positively for Galectin-3
Galectin-3
Galectin-3 is a member of the lectin family, of which 14 mammalian galectins have been identified. Galectin-3 is approximately 30 kDa and, like all galectins, contains a carbohydrate-recognition-binding domain of about 130 amino acids that enable the specific binding of β-galactosides. ...
. The subtype of ependymoma can also be narrowed down by molecular means. For instance, the myxopapillary ependyomas have been found to have higher expression of HOXB5
HOXB5
Homeobox protein Hox-B5 is a protein that in humans is encoded by the HOXB5 gene.-Further reading:...
, PLA2G5
PLA2G5
Calcium-dependent phospholipase A2 is an enzyme that in humans is encoded by the PLA2G5 gene.-Further reading:...
, and ITIH2
ITIH2
Inter-alpha-trypsin inhibitor heavy chain H2 is a protein that in humans is encoded by the ITIH2 gene....
. A gene expression profiling experiment has shown that three members of the SOX
SoX
Sound eXchange, abbreviated SoX, is a free cross-platform digital audio editor, licensed under the GNU General Public License, and distributed by Chris Bagwell through SourceForge.net...
family of transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s also possessed discriminatory power between medulloblastoma
Medulloblastoma
Medulloblastoma is a highly malignant primary brain tumor that originates in the cerebellum or posterior fossa.Previously, medulloblastomas were thought to represent a subset of primitive neuroectodermal tumor of the posterior fossa...
s and ependymomas. Without histology
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
, it is difficult to differentiate grade II versus grade III anaplastic ependymomas because there are no anatomical differences on magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
.
Prognostic features
In general, pediatric ependymomas are associated with less favorable prognoses than adult ependymomaEpendymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...
s, and ependymomas of younger pediatric patients are less favorable than ependymomas of older pediatric patients (reviewed in ). Tumors that occur in the posterior fossa
Posterior fossa
Posterior fossa may refer to:* Posterior cranial fossa* Posterior intercondyloid fossa...
have also been shown to have a less favorable prognosis. Expression of TERT in pediatric intracranial ependymomas is correlated with telomerase
Telomerase
Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...
activity and tumor progression and negatively correlated with survival. The protein nucleolin
Nucleolin
Nucleolin is a protein that in humans is encoded by the NCL gene.- Gene :The human NCL gene is located on chromosome 2 and consists of 14 exons with 13 introns and spans approximately 11kb...
and expression of MMP2
MMP2
72 kDa type IV collagenase also known as matrix metalloproteinase-2 and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene....
and MMP14
MMP14
Matrix metalloproteinase-14 is an enzyme that in humans is encoded by the MMP14 gene.Proteins of the matrix metalloproteinase family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well...
have been found to inversely correlate with progression free survival in cases of pediatric ependymoma, though RTK-1 family members were not correlated. Tumor microinvasion, even in tumors appearing well-demarcated using various imaging modalities, was also found to be inversely associated with|progression-free and overall survival. Some evidence suggests chromosome 6q25.3 deletion may provide additional survival benefit in pediatric ependymomas.
Treatment
ChemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
regimens for pediatric ependymomas have produced only modest benefit and degree of resection remains the most conspicuous factor in recurrence and survival.
The association of TERT expression with poor outcome in pediatric ependymomas has driven some researchers to suggest that telomerase
Telomerase
Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...
inhibition may be an effective adjuvant therapy for pediatric ependymomas. Further, data from in vitro experiments using primary tumor isolate cells suggest that inhibition of telomerase
Telomerase
Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...
activity may inhibit cell proliferation and increase sensitivity of cells to DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
damaging agents, consistent with the observation of high telomerase
Telomerase
Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...
activity in primary tumors. Additionally, because apurinic/apyrimidinic endonuclease (APE1) has been found to confer radiation resistance in pediatric ependymomas, it has been suggested that inhibitors of Ap endo activity might also restore radiation sensitivity.
Within the infratentorial group of pediatric ependymomas, radiotherapy was found to significantly increase 5-year survival. However, a retrospective review of sterotactic radiosurgery showed it provided only a modest benefit to patients who had previously undergone resection and radiation. Though other supratentorial tumors tend to have a better prognosis, supratentorial anaplastic ependymomas are the most aggressive ependymoma and neither total excision nor postoperative irradiation was found to be effective in preventing early recurrence.
Following resection of infratentorial ependymomas, residual tumor is more likely in lateral versus medial tumors, classified radiologically pre-operatively. Specific techniques, such as cerebellomedullary fissure dissection have been proposed to aid in complete resection while avoiding iatrogenic effects in these cases. Surveillance neuroimaging for recurrence provides additional survival to patients over observation alone.
Biochemical markers
hTERT and yH2AXH2AFX
H2AX is one of several genes coding for histone H2A. In humans and other eukaryotes, the DNA is wrapped around histone-groups, consisting of core histones H2A, H2B, H3 and H4. Thus, the H2AX contributes to the histone-formation and therefore the structure of DNA.H2AX becomes phosphorylated on...
are crucial markers for prognosis and response to therapy. High hTERT and low yH2AX
H2AFX
H2AX is one of several genes coding for histone H2A. In humans and other eukaryotes, the DNA is wrapped around histone-groups, consisting of core histones H2A, H2B, H3 and H4. Thus, the H2AX contributes to the histone-formation and therefore the structure of DNA.H2AX becomes phosphorylated on...
expression is associated with poor response to therapy. Patients with both high or low expression of these markers make up the moderate response groups.
Relapse
The 5-year disease-free survival for age >5 years is 50-60%. Another report found a similar 5-year survival at about 65% with 51% progression-free survival. The 10-year disease-free survival is 40-50%. Younger ages showed lower 5 and 10-year survival rates. A 2006 study that observed 133 patients found 31 (23.3%) had a recurrence of the disease within a five year period.Long-term consequences of treatment
Use of telomeraseTelomerase
Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...
inhibitors such as Imetelstat seem to have very low toxicity compared to other chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
. The only known side effect of most telomerase
Telomerase
Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...
inhibitors is dose-induced neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
. Neuropsychological deficits can result from resection, chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, and radiation, as well as endocrinopathies. Additionally, an increase in gastrointestinal complications has been observed in survivors of pediatric cancers.