Central nervous system primitive neuroectodermal tumor: Difference between revisions

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The Central Nervous System Primitive Neuroectodermal Tumor, often abbreviated as PNET, supratentorial PNET, or CNS-PNET,<ref name=":0">{{Cite journal|date=2015|editor-last=Karajannis|editor-first=Matthias A.|editor2-last=Zagzag|editor2-first=David|title=Molecular Pathology of Nervous System Tumors|url=http://dx.doi.org/10.1007/978-1-4939-1830-0|journal=Molecular Pathology Library|doi=10.1007/978-1-4939-1830-0|issn=1935-987X}}</ref> is one of the 3 types of embryonal central nervous system tumors defined by the [[World Health Organization]] ([[medulloblastoma]], [[Atypical teratoid rhabdoid tumor|atypical teratoid rhabdoid tumor]], and PNET).<ref name=":1">{{Cite journal|date=2014|editor-last=Hayat|editor-first=M.A.|title=Tumors of the Central Nervous System, Volume 13|url=http://dx.doi.org/10.1007/978-94-007-7602-9|journal=Tumors of the Central Nervous System|doi=10.1007/978-94-007-7602-9|issn=2215-096X}}</ref> It is considered an embryonal tumor because it arises from cells still undifferentiated from birth or partially differentiated .<ref name=":0" /> Those cells are usually [[Neuroepithelial cell|neuroepithelial cells]],<ref name=":0" /><ref name=":1" /><ref name=":2">{{Citation|last=Fuller|first=Christine E.|title=Oligodendroglial Tumors|date=2009-10-23|url=http://dx.doi.org/10.1007/978-1-4419-1062-2_4|work=Atlas of Pediatric Brain Tumors|pages=39–46|publisher=Springer New York|isbn=9781441910615|access-date=2019-02-24}}</ref> stem cells destined to turn into [[glia]] or [[Neuron|neurons]].<ref name=":3">{{Cite journal|last=Nelesen|first=Richard A|date=2000-03|title=Biological Psychology: An Introduction to Behavioral, Cognitive, and Clinical Neuroscience, 2nd edition. Mark R. Rosenweig, Arnold L. Leiman, and S. Marc Breedlove, Sinauer Associates, Inc., Sunderland MA, 1999. 561+92 pp. ISBN 0-87893-791-9|url=http://dx.doi.org/10.1016/s0301-0511(99)00025-3|journal=Biological Psychology|volume=52|issue=2|pages=185–186|doi=10.1016/s0301-0511(99)00025-3|issn=0301-0511}}</ref> It can occur anywhere within the [[Spinal cord|spinal cord]] and [[cerebrum]] and can have multiple sites of origins, with a high probability of [[metastasis]] through [[Cerebrospinal fluid|cerebrospinal fluid]] (CSF).<ref name=":0" /><ref name=":1" /> It is a rare tumor occurring mostly among children, <ref name=":0" /><ref name=":1" /> accounting for 1.9 to 7% of childhood brain tumors.<ref name=":1" />

PNETs have five subtypes of tumors: neuroblastoma, ganglioneuroblastoma, medulloepithelioma, ependymoblastoma, and not otherwise specified PNET.<ref name=":0" /> They are similar to medulloblastomas in regards to histology but different in regards to site of tumor and genetic factors. It is a rare tumor occurring mostly among children, <ref name=":0" /><ref name=":1" /> accounting for 1.9 to 7% of childhood brain tumors.<ref name=":1" /> Its diagnosis can be acquired through magnetic resonance imaging (MRI) or computed tomography (CT).<ref name=":1" /> There isn't a standardized procedure, but common strategies involve chemotherapy and radiotherapy for individuals older than 3 years of age.<ref name=":0" /><ref name=":1" /> Their effectiveness is still controversial.<ref name=":1" /> Surgery is used to remove mass affected by the tumorous cells.<ref name=":1" /> The prognosis of the disease is more positive for adults than for children, who have a higher probability of developing side effects.<ref name=":0" /><ref name=":1" />

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== Classification ==

[[File:Medulloepithelioma Histology.jpg|thumb|Histology of Medulloepithelioma]]

The [[World Health Organization]] has classified the Central Nervous System Primitive Neuroectodermal Tumor into 5 subtypes: [[neuroblastoma]], [[ganglioneuroblastoma]], [[medulloepithelioma]], [[Primitive neuroectodermal tumor|ependymoblastoma]], and not otherwise specified PNET.<ref name=":0" /> The last one encompasses the PNETs with varying characteristics that hasn't been well defined yet.<ref name=":0" /> [[Neuroblastoma|Neuroblastomas]] are PNETS that involve the process of cell differentiation into neurons,<ref name=":0" /><ref name=":1" /> while [[Ganglioneuroblastoma|ganglioneuroblastomas]] are PNETs that involve ganglion cells.<ref name=":0" /> [[Medulloepithelioma]], on the other hand, are tumors involving the constant cell division on the [[epithelium]] tissue where bundle of neuron endings are located.<ref name=":0" /> Such tissue will differentiate into a similar form as the embryonic neural tube, also known as the starting structure of the [[Central nervous system|central nervous system]]. <ref name=":0" /><ref name=":1" /><ref name=":2" /> [[Medulloepithelioma|Medulloepitheliomas]] also present a pattern known as rosettes, characterized by the arrangement of a bundle of cells into circular shapes and around a center or a neuropil.<ref name=":0" /> [[Primitive neuroectodermal tumor|Ependymoblastoma]] also present rosettes as well as a higher density of cells.<ref name=":0" /><ref name=":2" /> It involves the process of differentiation into ependymal cells.<ref name=":1" /><ref name=":2" />

[[File:Ependymoblastomatous Rosette.jpg|thumb|Rosettes in Ependymoblastoma histology]]

Further classification types have come up but not yet approved by the [[World Health Organization]].<ref name=":0" /> The term "embryonal tumor with abundant neuropil and true rosettes", or ETANTR, has been proposed as a sixth subtype of PNET.<ref name=":0" /> However, the still unofficial term "embryonal tumor with multilayered rosettes" (ETMR) has been more frequently used and encompasses ETANTRs, [[Medulloepithelioma|medulloepitheliomas]], [[Primitive neuroectodermal tumor|ependymoblastomas]], and variants of PNETs with presence of rosettes and with no well defined classification.<ref name=":2" />

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=== PNET vs. Medulloblastoma ===

The differentiation between primitive neuroectodermal tumor in the central nervous system and [[medulloblastoma]] is recent.<ref name=":0" /><ref name=":1" /> According to the [[World Health Organization|World Health Organization,]] both tumors have the same histology but primitive neuroectodermal tumors occur outside the [[cerebellum]].<ref name=":1" /> Moreover, it has been documented that both have different genetic expression and mutations.<ref name=":0" /><ref name=":1" /> Another essential difference between them is the ___location of their respective blood vessels within the brain. <ref name=":1" /> It has also been theorized that PNETs influence mainly [[glia]] cells while [[Medulloblastoma|medulloblastomas]] influence mainly [[Neuron|neural]] behavior, however such theory hasn't been confirmed yet.<ref name=":0" /> [[Medulloblastoma|Medulloblastomas]] are more frequent than PNETs, representing 10% of all child deaths caused by cancer.<ref name=":1" /> They also present better prognosis: children affected by [[medulloblastoma]] reach the 5 year survival mark in 70-80% of cases, while children affected by PNET reach the 5 year survival mark in less than 50% of cases.<ref name=":0" />

== Risk Factors ==

The rate of PNETs in not correlated with sex, but it is correlated with age.<ref name=":0" /> Most cases occur on children around 5 years of age while the frequency of PNETs in adults is very low. <ref name=":0" /> Regarding genetic mutations, a specific type of gene alteration that directly leads to this tumor hasn't been defined. <ref name=":0" /> However, a positive correlation between individuals with [[Li–Fraumeni syndrome|Li-Fraumeni syndrome]] with a mutation in the [[P53|gene ''p53'']] and PNET has been reported.<ref name=":1" /> A significant number of individuals with mutations on the [[Retinoblastoma protein|''rb'' tumor supressor gene]], encoding for the protein Rb responsible for stopping the cell cycle at the [[G1 phase]]<ref name=":4">{{Cite journal|last=Baker|first=Henry V|date=2003-06|title=Essential Genetics: A Genomics Perspective. Third Edition. By Daniel L Hartl and , Elizabeth W Jones. Sudbury (Massachusetts): Jones and Bartlett Publishers. $78.95 (paper). xxvi + 613 p; ill.; index. ISBN: 0–7637–1852–1. 2002.|url=http://dx.doi.org/10.1086/377959|journal=The Quarterly Review of Biology|volume=78|issue=2|pages=225–226|doi=10.1086/377959|issn=0033-5770}}</ref>, have also developed the tumor.<ref name=":1" /> Another possible contributing factor are mutations in the [[CREB-binding protein]] CBP, whose function includes activating transcription,<ref name=":4" /> but this interaction still need to be studied further.<ref name=":1" /> It has also been presumed that the tumor can arise from cranial irradiation.<ref name=":1" />

== Diagnosis ==

[[File:MRI of PNET.jpg|thumb|Magnetic resonance image of PNET]]

Most children that develop primitive neuroectodermal tumors are diagnosed early in life, usually at around 3-6.8 years of age.<ref name=":1" /> Symptoms patients present at time of diagnosis include irritable mood, visual difficulties, [[lethargy]], and [[ataxia]].<ref name=":1" /> The circumference of the patient's head might also suffer an enlargement and they might be subject to seizures, especially if they have less than one year of life.<ref name=":1" />

Several analysis can take place to determine the presence of the tumor. Physical examinations showing [[papilledema]], visual field defects, cranial nerves [[Cerebral palsy|palsy]], dysphasia, and focal neurological deficits are evidences for possible tumor.<ref name=":1" /> PNETs can also be spotted through [[CT scan|computed tomography]] (CT) and [[Magnetic resonance imaging|magnetic resonance imaging]] (MRI).<ref name=":1" /> In images produced by [[Magnetic resonance imaging|MRIs]], an irregular augmentation among a solid mass will indicated the presence of tumor.<ref name=":2" /> However, the results of MRIs are usually ambiguous in defining the presence for this specific tumor.<ref name=":1" /> In [[CT scan|CT scans]], the presence of PNETs will be indicated by an elevated density and an increase in volume of the brain.<ref name=":1" /> The [[CT scan]] can also show [[calcification]]<ref name=":2" />, which is present in 41-44% of PNET cases.<ref name=":1" /> Since the tumor can be replicated in other parts of the nervous system through the [[Cerebrospinal fluid|cerebrospinal fluid]] (CSF), a CSF analysis can also be conducted.<ref name=":1" /> A spinal MRI is a fourth type of analysis that is useful in investigating the level of tumor propagation to the [[Spinal cord|spinal cord]].<ref name=":1" />

== Treatment ==

There is not a standardized procedure to treat primitive neuroectodermal tumors.<ref name=":1" /> Better outcomes, however, have been seen when patients are treated with risk-adapted [[Radiation therapy|radiotherapy]] combined with [[chemotherapy]] and stem cell rescue.<ref name=":0" /> For patients younger than 2-3 years of age, treatment with radiation are not used, once they are in a more vulnerable phase and, thus, more prone to risks in development. <ref name=":0" /> Examinations such as CSF analysis and spinal MRIs are used to investigate the effectiveness of treatment in preventing [[metastasis]].<ref name=":1" />

A method for eliminating tumorous mass is surgery, where the best outcome would be total resection, meaning the complete removal of the tumor.<ref name=":1" /> Along with the surgery, several measures that contribute to a safe procedure can be taken: urine exams, transfusion, and the constant supervision of arterial pressure.<ref name=":1" /> Possible problems that arise from the surgery include [[Bleeding|hemorrhage]], [[Cerebral edema|brain edema]], and [[hemiparesis]].<ref name=":1" /> [[Magnetic resonance imaging|MRIs]] are typically done after 1 or 2 days of postoperative in order to inspect the amount of tumor remaining.<ref name=":1" />

== Prognosis ==

The probability of primitive neuroectodermal tumors to have recurrence and [[Metastasis|metastasize]] through [[Cerebrospinal fluid|cerebrospinal fluid]] is relatively high.<ref name=":2" /> The prognosis of PNET is 5 years of survival for less than 50% of children, <ref name=":0" /> while the most common prognosis for adults is 7 years.<ref name=":1" /> Moreover, children have the probability of developing deficiencies in cognitive processes, problems in the [[Endocrine system|endocrine system]], and psychological obstacles after the disease.<ref name=":1" /> Adults, on the other hand, don't show such results.<ref name=":1" /> The outcome for PNET is more positive when the individual is an adult, independent of age subgroups, or an older child.<ref name=":1" /> The reason the prognosis for such tumor is worst in children is due to the high probability of the tumor spreading to the rest of the [[Nervous system|nervous system]] through the [[Cerebrospinal fluid|cerebrospinal fluid]] and growing again.<ref name=":1" /> As a consequence, 37.7% of children affected by the tumor live to 4 years.<ref name=":1" />

The effect of treatment strategies such as chemotherapy and radiation therapy on the prognosis of the disease is still controversial, with studies claiming either their benefits or their ineffectiveness.<ref name=":1" /> The same holds true for the relationship between volume of tumor removed by surgery and survival.<ref name=":1" /> Furthermore, factors such as tumor size, ___location of origin, race, and sex of individual don't show any influence on the outcome of the disease.<ref name=":1" /> However, interactions of some factors such as tumor site, age, and treatment strategy can affect one's prognosis.<ref name=":1" /> For instance, when younger children below the age of 3 suffering from tumors originating in places other than the pineal gland are treated with chemotherapy, they present better outcomes than those suffering from pineal tumors.<ref name=":1" />

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The effect of treatment strategies such as [[chemotherapy]] and [[Radiation therapy|radiation therapy]] on the prognosis of the disease is still controversial, with studies claiming either their benefits or their ineffectiveness.<ref name=":1" /> The same holds true for the relationship between volume of tumor removed by surgery and survival.<ref name=":1" /> Furthermore, factors such as tumor size, ___location of origin, race, and sex of individual don't show any influence on the outcome of the disease.<ref name=":1" /> However, interactions of some factors such as tumor site, age, and treatment strategy can affect one's prognosis.<ref name=":1" /> For instance, when younger children below the age of 3 suffering from tumors originating in places other than the [[Pineal gland|pineal gland]] are treated with [[chemotherapy]], they present better outcomes than those suffering from [[Pineal gland|pineal]] tumors.<ref name=":1" />

== References ==