Central nervous system primitive neuroectodermal tumor: Difference between revisions

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{{Infobox medical condition

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, 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 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 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 and cerebrum and can have multiple sites of origins, with a high probability of metastasis through 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" />

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TheA Central'''central Nervousnervous Systemsystem Primitiveprimitive Neuroectodermalneuroectodermal Tumortumor''', often abbreviated as '''PNET''', '''supratentorial PNET''', or '''CNS-PNET''',<ref name=":0">{{Cite journalbook|date=2015|editor-last=Karajannis|editor-first=Matthias A.|editor2-last=Zagzag|editor2-first=David |titlevolume=Molecular Pathology of Nervous System Tumors8|urldoi=http://dx.doi.org/10.1007/978-1-4939-1830-0|journalissn=Molecular Pathology Library1935-987X|doiisbn=10.1007/978-1-4939-18301829-04 |issntitle=1935-987XMolecular Pathology of Nervous System Tumors |series=Molecular Pathology Library }}</ref> is one of the 3 types of embryonal central nervous system tumors defined by the World Health Organization ([[medulloblastoma]], [[atypical teratoid rhabdoid tumor]], and PNET).<ref name=":1">{{Cite journalbook|date=2014|editor-last=Hayat|editor-first=M.A. |titlevolume=Tumors of the Central Nervous System, Volume 13|urldoi=http://dx.doi.org/10.1007/978-94-007-7602-9|journalissn=2215-096X|isbn=978-94-007-7601-2 |title=Tumors of the Central Nervous System|doi=10.1007/978-94-007-7602-9|issn=2215-096X, Volume 13 }}</ref> It is considered an embryonal tumor because it arises from cells partially differentiated or still undifferentiated from birth or partially differentiated .<ref name=":0" /> Those cells are usually [[neuroepithelial cellscell]]s,<ref name=":0" /><ref name=":1" /><ref name=":2">{{Citation|last=Fuller|first=Christine E.|titlechapter=Oligodendroglial Tumors|date=2009-10-23|urlpages=http://dx.39–46|publisher=Springer New York|isbn=9781441910615|doi.org/=10.1007/978-1-4419-1062-2_4|worktitle=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 neurons[[neuron]]s.<ref name=":3">{{Cite journal|last=Nelesen|first=Richard A|date=March 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|s2cid=54349873|issn=0301-0511}}</ref> It can occur anywhere within the [[spinal cord]] and [[cerebrum]] and can have multiple sites of origins, with a high probability of [[metastasis]] through [[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" />

[Lead section will be expanded with summary of the sections below]

PNET has five subtypes of tumors: [[neuroblastoma]], [[ganglioneuroblastoma]], [[medulloepithelioma]], ependymoblastoma, and not otherwise specified PNET.<ref name=":0" /> It is similar to [[medulloblastoma]] regarding histology but different regarding genetic factors and tumor site. It is a rare disease occurring mostly among children,<ref name=":0" /><ref name=":1" /> accounting for 1.9 to 7% of childhood brain tumors.<ref name=":1" /> Symptoms involve emotional, visual, motor, and speech defects.<ref name=":1" /> [[Magnetic resonance imaging]] (MRI) and [[CT scan|computed tomography]] (CT) are used to diagnose PNETs.<ref name=":1" /> Even though a universal treatment plan hasn't been stablished yet, common strategies involve [[chemotherapy]] and [[Radiation therapy|radiotherapy]] for individuals older than 3 years of age.<ref name=":0" /><ref name=":1" /> Their efficacy, however, is still controversial.<ref name=":1" /> Surgery can be used to remove mass affected by tumorous cells.<ref name=":1" /> The prognosis of the disease is more positive for adults than for children, who have a higher probability of having sequelae from the tumor.<ref name=":0" /><ref name=":1" />

[Image of MRI or other scan will be added]

It is important to note that this classification term has been removed from the latest WHO classification of CNS tumors as of 2016. Instead PNETs are now included into the category of "Embryonal Tumors with Multilayered Rosettes" along with ependymoblastoma and embryonal tumor with abundant neuropil and true rosettes (ETANTR).<ref>Louis DN, Ohgaki H, Wiestler OD, Cavenee WK "WHO Classification of Tumours of the Central Nervous System. 4th Edition Revised"</ref>

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[Article and language, specially sentence structure, still need to be adjusted to be easier to read]

== 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, 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" /> Neuroblastomas are PNETS that involve the process of cell differentiation into neurons,<ref name=":0" /><ref name=":1" /> while 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. <ref name=":0" /><ref name=":1" /><ref name=":2" /> 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" /> 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" />

The [[World Health Organization]] has classified the central nervous system primitive neuroectodermal tumors into five subtypes: [[neuroblastoma]], [[ganglioneuroblastoma]], [[medulloepithelioma]], 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]]s are PNETS that involve the process of cell differentiation into neurons,<ref name=":0" /><ref name=":1" /> while [[ganglioneuroblastoma]]s are PNETs that involve [[ganglion cell]]s.<ref name=":0" />

The World Health Organization has classified the Central Nervous System Primitive Neuroectodermal Tumor into 5 subtypes: neuroblastoma, ganglioneuroblastoma, medulloepithelioma, 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" /> Neuroblastomas are PNETS that involve the process of cell differentiation into neurons,<ref name=":0" /><ref name=":1" /> while 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]]. <ref name=":0" /><ref name=":1" /><ref name=":2" /> 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" /> 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" />

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, medulloepitheliomas, ependymoblastomas, and variants of PNETs with presence of rosettes and with no well defined classification.<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, medulloepitheliomas[[medulloepithelioma]]s, ependymoblastomas, and variants of PNETs with presence of rosettes and with no well defined classification.<ref name=":2" />

== Risk Factorsfactors ==

[Image of rosettes or pathology will be added]

The rate of PNETs in not correlated with sex, but it isshows correlateda correlation with age.<ref name=":0" /> Most cases occur onin children around 5 years of age, whilehaving thea frequencyvery oflow PNETsfrequency 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. yet.<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 supressorsuppressor gene]] have also developed the tumor.<ref name=":1" /> Such gene, encodingencodes 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=June 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 (paperPaper). xxviXxvi + 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=[https://archive.org/details/essentialgenetic0000hart/page/225 225–226]|doi=10.1086/377959|issn=0033-5770|url-access=registration|url=https://archive.org/details/essentialgenetic0000hart/page/225}}</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" />

=== 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, 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 medulloblastomas influence mainly neural behavior, however such theory hasn't been confirmed yet.<ref name=":0" /> 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. 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 with a mutation in the gene ''p53'' and PNET has been reported.<ref name=":1" /> A significant number of individuals with mutations on the ''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 imaging|Magnetic resonance]] image of PNET]]

Most children that develop primitive neuroectodermal tumors are diagnosed early in life, usually at around 3-63–6.8 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 sufferbecome an enlargementenlarged and they might be subject to seizures, especially if they have less than one year of life.<ref name=":1" />

Several analysis can takebe placeused to determine the presence of the tumordisease. 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]] (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 scansscan]]s, 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]] (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]].<ref name=":1" />

== Treatment ==

There is not a standardized procedure to treat primitive neuroectodermal tumors.<ref name=":1" /> BetterCommon outcomes,strategies however, have been seen when patients are treated withinvolve risk-adapted [[Radiation therapy|radiotherapy]] combined with [[chemotherapy]] and stem cell rescue.<ref name=":0" /> For patients younger than 2-32–3 years of age, treatment with radiation areis 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" /> [The term "total resection' will be defined] 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]] is relatively high.<ref name=":2" /> The prognosisoutcome of PNET is 5more yearspositive ofwhen survivalthe forindividual lessis thanan 50%adult, independent of childrenage subgroups, or an older child.<ref name=":01" /> while theLess mostthan common50% prognosisof forchildren adultssurvive ismore 7than 5 years.,<ref name=":10" /> Moreover, children havewhile the probabilitymajority of developingadults deficiencieslive into cognitive7 processes, problems in the endocrine system, and psychological obstacles after the diseaseyears.<ref name=":1" /> Adults,The onreason the otherprognosis hand,for don'tsuch showtumor suchis results.<refworst name=":1"in />children Theis outcomedue forto PNETthe ishigher moreprobability positive whenof the individualtumor isspreading anto adult,the independentrest of agethe subgroups,[[nervous orsystem]] anthrough olderthe child[[cerebrospinal fluid]] and growing again.<ref name=":1" /> TheMoreover, reasonchildren have the prognosisprobability forof suchdeveloping tumor is worstdeficiencies in childrencognitive isprocesses, dueproblems toin the high[[endocrine probabilitysystem]], ofand thepsychological tumorobstacles spreading toafter the restdisease.<ref ofname=":1" the/> nervousAdults, system throughon the cerebrospinalother fluidhand, anddon't growingshow againsuch propensity.<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 3three suffering fromdevelop tumors originating in places other than the [[pineal gland]] are treated with [[chemotherapy]], they present better outcomes than those sufferingwith from[[Pineal gland|pineal]] tumors and treated with [[chemotherapy]].<ref name=":1" />

== References ==

{{Reflist}}

[[Category:Nervous system neoplasia]]

[MAYBE - Section about current research on the topic]

[More references will be added]

== References ==