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{{Infobox medical condition (new)
{{Infobox medical condition (new)
| name = Medulloblastoma
| name = Medulloblastoma
| synonyms =
| synonyms =
| image = CT brain scan of child with medulloblastoma and resulting hydrocephalus.jpg
| image = CT brain scan of child with medulloblastoma and resulting hydrocephalus.jpg
| caption = CT scan, showing a tumorous mass in the [[Posterior cranial fossa|posterior fossa]], giving rise to obstructive [[hydrocephalus]], in a six-year-old girl
| caption = CT scan, showing a tumorous mass in the [[Posterior cranial fossa|posterior fossa]], giving rise to obstructive [[hydrocephalus]], in a six-year-old girl
| pronounce = {{IPAc-en|m|ə|ˌ|d|ʌ|l|oʊ-|b|l|æ|ˈ|s|t|oʊ|m|ə}}
| pronounce = {{IPAc-en|m|ə|ˌ|d|ʌ|l|oʊ-|b|l|æ|ˈ|s|t|oʊ|m|ə}}
| field = [[Oncology]], [[neurosurgery]]
| field = [[Neuro-oncology]], [[neurosurgery]]
| symptoms = Headaches<br>Nausea<br>Vomiting<br>Tiredness<br>Clumsiness<br>Dizziness<br>Change in vision<br>Handwriting problems<ref name="StJude">{{cite web |url=https://www.stjude.org/disease/medulloblastoma.html|title= Medulloblastoma|website=[[St. Jude Children's Research Hospital]]|access-date=March 8, 2023}}</ref>
| symptoms =
| complications =
| complications =
| onset =
| onset = Between 5 and 9 years old<ref name="StJude"/>
| duration =
| duration =
| types =
| types =
| causes =
| causes =
| risks =
| risks =
| diagnosis =
| diagnosis =
| differential =
| differential =
| prevention =
| prevention =
| treatment =
| treatment =
| medication =
| medication =
| prognosis = [[Five-year survival rate]]: 72.1%<ref name="NCI">{{cite web |url=https://www.cancer.gov/rare-brain-spine-tumor/tumors/medulloblastoma|title= Medulloblastoma Diagnosis and Treatment|website=[[National Cancer Institute]]|date= 17 September 2018|access-date=March 8, 2023}}</ref>
| prognosis =
| frequency =
| frequency = About 500 children diagnosed annually in the United States<ref name="StJude"/>
| deaths =
| deaths =
}}
}}
'''Medulloblastoma''' is the most common type of primary [[brain tumor|brain cancer]] in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the [[cerebellum]], or [[posterior cranial fossa|posterior fossa]].<ref name=":0">{{cite journal | vauthors = Roussel MF, Hatten ME | title = Cerebellum development and medulloblastoma | volume = 94 | pages = 235–82 | date = 2011 | pmid = 21295689 | pmc = 3213765 | doi = 10.1016/B978-0-12-380916-2.00008-5 | isbn = 9780123809162 | series = Current Topics in Developmental Biology }}</ref>
'''Medulloblastoma''' is a common type of primary [[brain tumor|brain cancer]] in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the [[cerebellum]], or [[posterior cranial fossa|posterior fossa]].<ref name=":0">{{cite book | vauthors = Roussel MF, Hatten ME | title = Cerebellum development and medulloblastoma | chapter = Cerebellum | volume = 94 | pages = 235–82 | date = 2011 | pmid = 21295689 | pmc = 3213765 | doi = 10.1016/B978-0-12-380916-2.00008-5 | isbn = 9780123809162 | series = Current Topics in Developmental Biology }}</ref>


The brain is divided into two main parts, the larger [[cerebrum]] on top and the smaller [[cerebellum]] below towards the back. They are separated by a membrane called the [[tentorium cerebelli|tentorium]]. Tumors that originate in the cerebellum or the surrounding region below the tentorium are, therefore, called [[infratentorial neoplasms|infratentorial]].
The brain is divided into two main parts, the larger [[cerebrum]] on top and the smaller [[cerebellum]] below towards the back. They are separated by a membrane called the [[tentorium cerebelli|tentorium]]. Tumors that originate in the cerebellum or the surrounding region below the tentorium are, therefore, called [[infratentorial neoplasms|infratentorial]].


Historically medulloblastomas have been classified as a [[primitive neuroectodermal tumor]] (PNET), but it is now known that medulloblastoma is distinct from supratentorial PNETs and they are no longer considered similar entities.<ref>{{cite book | last1 = Hinz | first1 = Chris | last2 = Hesser | first2 = Deneen | name-list-format = vanc | title = Focusing On Brain Tumors: Medulloblastoma | publisher = American Brain Tumor Association | isbn = 0-944093-67-1 | url = http://hope.abta.org/mdl | access-date = 2007-03-09 | archive-url = https://web.archive.org/web/20080908050856/http://hope.abta.org/mdl | archive-date = 2008-09-08 | url-status = dead }}{{page needed|date=February 2015}}</ref>
Historically, medulloblastomas have been classified as a [[primitive neuroectodermal tumor]] (PNET), but it is now known that medulloblastoma is distinct from supratentorial PNETs and they are no longer considered similar entities.<ref>{{cite book | last1 = Hinz | first1 = Chris | last2 = Hesser | first2 = Deneen | name-list-style = vanc | title = Focusing On Brain Tumors: Medulloblastoma | year = 2006 | publisher = American Brain Tumor Association | isbn = 0-944093-67-1 | url = http://hope.abta.org/mdl | access-date = 2007-03-09 | archive-url = https://web.archive.org/web/20080908050856/http://hope.abta.org/mdl | archive-date = 2008-09-08 | url-status = dead }}{{page needed|date=February 2015}}</ref>


Medulloblastomas are invasive, rapidly growing tumors that, unlike most brain tumors, spread through the [[cerebrospinal fluid]] and frequently [[Metastasis|metastasize]] to different locations along the surface of the brain and spinal cord. Metastasis all the way down to the [[cauda equina]] at the base of the spinal cord is termed "drop metastasis".
Medulloblastomas are invasive, rapidly growing tumors that, unlike most brain tumors, spread through the [[cerebrospinal fluid]] and frequently [[Metastasis|metastasize]] to different locations along the surface of the brain and spinal cord. Metastasis all the way down to the [[cauda equina]] at the base of the spinal cord is termed "drop metastasis".
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==Signs and symptoms==
==Signs and symptoms==
Signs and symptoms are mainly due to secondary increased [[intracranial pressure]] due to blockage of the [[fourth ventricle]] and tumors are usually present for 1 to 5 months before diagnosis is made. The child typically becomes listless, with repeated episodes of vomiting, and a morning headache, which may lead to a misdiagnosis of gastrointestinal disease or [[migraine]].<ref name=":1">{{cite journal | vauthors = Polkinghorn WR, Tarbell NJ | title = Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification | journal = Nature Clinical Practice. Oncology | volume = 4 | issue = 5 | pages = 295–304 | date = May 2007 | pmid = 17464337 | doi = 10.1038/ncponc0794 }}</ref> Soon after, the child will develop a stumbling gait, [[truncal ataxia]], frequent falls, [[diplopia]], [[papilledema]], and [[Sixth nerve palsy|sixth cranial nerve palsy]]. Positional dizziness and [[pathologic nystagmus|nystagmus]] are also frequent, and facial sensory loss or motor weakness may be present. [[Decerebrate]] attacks appear late in the disease.
Signs and symptoms are mainly due to secondary increased [[intracranial pressure]] due to blockage of the [[fourth ventricle]] and tumors are usually present for 1 to 5 months before diagnosis is made. The child typically becomes listless, with repeated episodes of vomiting, and a morning headache, which may lead to a misdiagnosis of gastrointestinal disease or [[migraine]].<ref name=":1">{{cite journal | vauthors = Polkinghorn WR, Tarbell NJ | title = Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification | journal = Nature Clinical Practice. Oncology | volume = 4 | issue = 5 | pages = 295–304 | date = May 2007 | pmid = 17464337 | doi = 10.1038/ncponc0794 | s2cid = 24461280 }}</ref> Soon after, the child will develop a stumbling gait, [[truncal ataxia]], frequent falls, [[diplopia]], [[papilledema]], and [[Sixth nerve palsy|sixth cranial nerve palsy]]. [[Positional vertigo]] and [[pathologic nystagmus|nystagmus]] are also frequent, and facial sensory loss or motor weakness may be present. [[Decerebrate]] attacks appear late in the disease.


Extraneural metastasis to the rest of the body is rare, and when it occurs, it is in the setting of relapse, more commonly in the era prior to routine chemotherapy.
Extraneural metastasis to the rest of the body is rare, and when it occurs, it is in the setting of relapse, more commonly in the era prior to routine chemotherapy.


==Pathogenesis==
==Pathogenesis==
Medulloblastomas usually found in the vicinity of the fourth ventricle, between the [[brainstem]] and the cerebellum. Tumors with similar appearance and characteristics originate in other parts of the brain, but they are not identical to medulloblastoma.<ref>{{cite web | first = Roger | last = Packer | name-list-format = vanc | url = http://virtualtrials.com/medullo.cfm | title = Medulloblastoma | work = Clinical Trials and Noteworthy Treatments for Brain Tumors | date = 2002 }}</ref>
Medulloblastomas are usually found in the vicinity of the fourth ventricle, between the [[brainstem]] and the cerebellum. Tumors with similar appearance and characteristics originate in other parts of the brain, but they are not identical to medulloblastoma.<ref>{{cite web | first = Roger | last = Packer | name-list-style = vanc | url = http://virtualtrials.com/medullo.cfm | title = Medulloblastoma | work = Clinical Trials and Noteworthy Treatments for Brain Tumors | date = 2002 }}</ref>


Although medulloblastomas are thought to originate from immature or embryonal cells at their earliest stage of development, the cell of origin depends on the subgroup of medulloblastoma. WNT tumors originate from the lower rhombic lip of the brainstem, while SHH tumors originate from the external granular layer.{{Citation needed|date=March 2008}}
Although medulloblastomas are thought to originate from immature or embryonal cells at their earliest stage of development, the cell of origin depends on the subgroup of medulloblastoma. WNT tumors originate from the lower rhombic lip of the brainstem, while SHH tumors originate from the external granular layer.<ref>{{cite web |url= https://www.lecturio.com/concepts/medulloblastoma/| title= Medulloblastoma|website=The Lecturio Medical Concept Library |access-date= 10 August 2021}}</ref>
⚫
Currently, medulloblastomas are thought to arise from cerebellar stem cells that have been prevented from dividing and differentiating into their normal cell types. This accounts for the histologic variants seen on biopsy. Both [[Palisade_(pathology)#Perivascular pseudorosette|perivascular pseudorosette]] and [[Palisade_(pathology)#Homer_Wright_pseudorosette|Homer Wright pseudorosette]] formations are highly characteristic of medulloblastomas, and are seen in up to half of cases.<ref>{{cite book | last1 = White | first1 = Lucile E. | last2 = Levy | first2 = Ross M. | last3 = Alam | first3 = Murad | name-list-format = vanc |chapter=Ch. 127. Neoplasias and Hyperplasias of Muscular and Neural Origin |chapterurl=http://www.accessmedicine.com/content.aspx?aID=2983360 |veditors=Wolff K, Goldsmith LA, Katz SI, Gilchrest B, Paller AS, Leffell DJ |title=Fitzpatrick's Dermatology in General Medicine |publisher=McGraw-Hill Medical |year=2008 |edition=7e }}</ref> The classic rosette with tumor cells around a central lumen can be seen.<ref>{{cite book |vauthors=Ropper AH, Samuels MA |chapter=Ch. 31. Intracranial Neoplasms and Paraneoplastic Disorders |chapterurl=http://www.accessmedicine.com/content.aspx?aID=3637579 |veditors=Ropper AH, Samuels MA |title=Adams and Victor's Principles of Neurology |edition=9e}}</ref>


⚫
Currently, medulloblastomas are thought to arise from cerebellar stem cells that have been prevented from dividing and differentiating into their normal cell types. This accounts for the histologic variants seen on biopsy. Both [[Palisade (pathology)#Perivascular pseudorosette|perivascular pseudorosette]] and [[Palisade (pathology)#Homer Wright pseudorosette|Homer Wright pseudorosette]] formations are highly characteristic of medulloblastomas and are seen in up to half of cases.<ref>{{cite book | last1 = White | first1 = Lucile E. | last2 = Levy | first2 = Ross M. | last3 = Alam | first3 = Murad |chapter=Ch. 127. Neoplasias and Hyperplasias of Muscular and Neural Origin |chapter-url=http://www.accessmedicine.com/content.aspx?aID=2983360 |veditors=Wolff K, Goldsmith LA, Katz SI, Gilchrest B, Paller AS, Leffell DJ |title=Fitzpatrick's Dermatology in General Medicine |publisher=McGraw-Hill Medical |year=2008 |edition=7e }}</ref> The classic rosette with tumor cells around a central lumen can be seen.<ref>{{cite book |vauthors=Ropper AH, Samuels MA |chapter=Ch. 31. Intracranial Neoplasms and Paraneoplastic Disorders |chapter-url=http://www.accessmedicine.com/content.aspx?aID=3637579 |veditors=Ropper AH, Samuels MA |title=Adams and Victor's Principles of Neurology |edition=9e}}</ref>
⚫
In the past, medulloblastoma was classified using histology, but recent integrated genomic studies have revealed that medulloblastoma is composed of four distinct molecular and clinical variants termed WNT/β-catenin, [[Sonic hedgehog (protein)|Sonic Hedgehog]], Group 3, and Group 4.<ref>{{cite journal | vauthors = Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool M, Pfister SM | display-authors = 6 | title = Molecular subgroups of medulloblastoma: the current consensus | journal = Acta Neuropathologica | volume = 123 | issue = 4 | pages = 465–72 | date = April 2012 | pmid = 22134537 | pmc = 3306779 | doi = 10.1007/s00401-011-0922-z }}</ref> Of these subgroups, WNT patients have an excellent prognosis and group 3 patients have a dismal prognosis. Also, a subgroup-specific alternative splicing further confirms the existence of distinct subgroups and highlights the transcriptional heterogeneity between subgroups.<ref>{{cite journal | vauthors = Dubuc AM, Morrissy AS, Kloosterhof NK, Northcott PA, Yu EP, Shih D, Peacock J, Grajkowska W, van Meter T, Eberhart CG, Pfister S, Marra MA, Weiss WA, Scherer SW, Rutka JT, French PJ, Taylor MD | display-authors = 6 | title = Subgroup-specific alternative splicing in medulloblastoma | journal = Acta Neuropathologica | volume = 123 | issue = 4 | pages = 485–499 | date = April 2012 | pmid = 22358458 | pmc = 3984840 | doi = 10.1007/s00401-012-0959-7 }}</ref> Amplification of the [[Sonic hedgehog (protein)|Sonic Hedgehog]] pathway is the best characterized subgroup, with 25% of human tumors having mutations in Patched, Sufu (Suppressor of Fused Homolog), Smoothened, or other genes in this pathway.<ref name=":2">{{cite journal | vauthors = Marino S | title = Medulloblastoma: developmental mechanisms out of control | journal = Trends in Molecular Medicine | volume = 11 | issue = 1 | pages = 17–22 | date = January 2005 | pmid = 15649818 | doi = 10.1016/j.molmed.2004.11.008 }}</ref><ref name=":3">{{cite journal | vauthors = Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, Kranenburg TA, Hogg T, Poppleton H, Martin J, Finkelstein D, Pounds S, Weiss A, Patay Z, Scoggins M, Ogg R, Pei Y, Yang ZJ, Brun S, Lee Y, Zindy F, Lindsey JC, Taketo MM, Boop FA, Sanford RA, Gajjar A, Clifford SC, Roussel MF, McKinnon PJ, Gutmann DH, Ellison DW, Wechsler-Reya R, Gilbertson RJ | display-authors = 6 | title = Subtypes of medulloblastoma have distinct developmental origins | journal = Nature | volume = 468 | issue = 7327 | pages = 1095–9 | date = December 2010 | pmid = 21150899 | pmc = 3059767 | doi = 10.1038/nature09587 | bibcode = 2010Natur.468.1095G }}</ref> Medulloblastomas are also seen in [[Gorlin syndrome]] as well as [[Turcot syndrome]]. Recurrent mutations in the genes ''[[CTNNB1]], [[PTCH1]], [[MLL2]], [[SMARCA4]], [[DDX3X]], [[CTDNEP1]], [[KDM6A]]'', and ''[[TBR1]]'' were identified in individuals with medulloblastoma.<ref>{{cite journal | vauthors = Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, Cho YJ, Pugh TJ, Hovestadt V, Stütz AM, Rausch T, Warnatz HJ, Ryzhova M, Bender S, Sturm D, Pleier S, Cin H, Pfaff E, Sieber L, Wittmann A, Remke M, Witt H, Hutter S, Tzaridis T, Weischenfeldt J, Raeder B, Avci M, Amstislavskiy V, Zapatka M, Weber UD, Wang Q, Lasitschka B, Bartholomae CC, Schmidt M, von Kalle C, Ast V, Lawerenz C, Eils J, Kabbe R, Benes V, van Sluis P, Koster J, Volckmann R, Shih D, Betts MJ, Russell RB, Coco S, Tonini GP, Schüller U, Hans V, Graf N, Kim YJ, Monoranu C, Roggendorf W, Unterberg A, Herold-Mende C, Milde T, Kulozik AE, von Deimling A, Witt O, Maass E, Rössler J, Ebinger M, Schuhmann MU, Frühwald MC, Hasselblatt M, Jabado N, Rutkowski S, von Bueren AO, Williamson D, Clifford SC, McCabe MG, Collins VP, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott PA, Taylor MD, Meyerson M, Pomeroy SL, Yaspo ML, Korbel JO, Korshunov A, Eils R, Pfister SM, Lichter P | display-authors = 6 | title = Dissecting the genomic complexity underlying medulloblastoma | journal = Nature | volume = 488 | issue = 7409 | pages = 100–5 | date = August 2012 | pmid = 22832583 | pmc = 3662966 | doi = 10.1038/nature11284 | bibcode = 2012Natur.488..100J }}</ref> Additional pathways disrupted in some medulloblastomas include [[Myc|MYC]], [[Notch signaling pathway|Notch]], [[Bone morphogenetic protein|BMP]], and [[Transforming growth factor beta|TGF-β]] signaling pathways.<ref name=":2" /><ref name=":3" /><ref name=":1"/><ref name="Ellison 2010">{{cite journal | vauthors = Ellison DW | title = Childhood medulloblastoma: novel approaches to the classification of a heterogeneous disease | journal = Acta Neuropathologica | volume = 120 | issue = 3 | pages = 305–16 | date = September 2010 | pmid = 20652577 | doi = 10.1007/s00401-010-0726-6 }}</ref><ref>{{cite journal | vauthors = Cho YJ, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H, Berhoukim R, Amani V, Goumnerova L, Eberhart CG, Lau CC, Olson JM, Gilbertson RJ, Gajjar A, Delattre O, Kool M, Ligon K, Meyerson M, Mesirov JP, Pomeroy SL | display-authors = 6 | title = Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome | journal = Journal of Clinical Oncology | volume = 29 | issue = 11 | pages = 1424–30 | date = April 2011 | pmid = 21098324 | pmc = 3082983 | doi = 10.1200/JCO.2010.28.5148 }}</ref><ref>{{cite journal | vauthors = Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Stütz AM, Korshunov A, Reimand J, Schumacher SE, Beroukhim R, Ellison DW, Marshall CR, Lionel AC, Mack S, Dubuc A, Yao Y, Ramaswamy V, Luu B, Rolider A, Cavalli FM, Wang X, Remke M, Wu X, Chiu RY, Chu A, Chuah E, Corbett RD, Hoad GR, Jackman SD, Li Y, Lo A, Mungall KL, Nip KM, Qian JQ, Raymond AG, Thiessen NT, Varhol RJ, Birol I, Moore RA, Mungall AJ, Holt R, Kawauchi D, Roussel MF, Kool M, Jones DT, Witt H, Fernandez-L A, Kenney AM, Wechsler-Reya RJ, Dirks P, Aviv T, Grajkowska WA, Perek-Polnik M, Haberler CC, Delattre O, Reynaud SS, Doz FF, Pernet-Fattet SS, Cho BK, Kim SK, Wang KC, Scheurlen W, Eberhart CG, Fèvre-Montange M, Jouvet A, Pollack IF, Fan X, Muraszko KM, Gillespie GY, Di Rocco C, Massimi L, Michiels EM, Kloosterhof NK, French PJ, Kros JM, Olson JM, Ellenbogen RG, Zitterbart K, Kren L, Thompson RC, Cooper MK, Lach B, McLendon RE, Bigner DD, Fontebasso A, Albrecht S, Jabado N, Lindsey JC, Bailey S, Gupta N, Weiss WA, Bognár L, Klekner A, Van Meter TE, Kumabe T, Tominaga T, Elbabaa SK, Leonard JR, Rubin JB, Liau LM, Van Meir EG, Fouladi M, Nakamura H, Cinalli G, Garami M, Hauser P, Saad AG, Iolascon A, Jung S, Carlotti CG, Vibhakar R, Ra YS, Robinson S, Zollo M, Faria CC, Chan JA, Levy ML, Sorensen PH, Meyerson M, Pomeroy SL, Cho YJ, Bader GD, Tabori U, Hawkins CE, Bouffet E, Scherer SW, Rutka JT, Malkin D, Clifford SC, Jones SJ, Korbel JO, Pfister SM, Marra MA, Taylor MD | display-authors = 6 | title = Subgroup-specific structural variation across 1,000 medulloblastoma genomes | journal = Nature | volume = 488 | issue = 7409 | pages = 49–56 | date = August 2012 | pmid = 22832581 | pmc = 3683624 | doi = 10.1038/nature11327 | bibcode = 2012Natur.488...49N }}</ref><ref>{{cite journal | vauthors = Hatten ME, Roussel MF | title = Development and cancer of the cerebellum | journal = Trends in Neurosciences | volume = 34 | issue = 3 | pages = 134–42 | date = March 2011 | pmid = 21315459 | pmc = 3051031 | doi = 10.1016/j.tins.2011.01.002 }}</ref><ref>{{cite journal | vauthors = Roussel MF, Hatten ME | title = Cerebellum development and medulloblastoma | volume = 94 | pages = 235–82 | date = 2011 | pmid = 21295689 | pmc = 3213765 | doi = 10.1016/B978-0-12-380916-2.00008-5 | isbn = 9780123809162 | series = Current Topics in Developmental Biology }}</ref>{{citation overkill|date=June 2020}}

⚫
In the past, medulloblastoma was classified using histology, but integrated genomic studies have revealed that medulloblastoma is composed of four distinct molecular and clinical variants termed WNT/β-catenin, [[Sonic hedgehog (protein)|Sonic Hedgehog]], Group 3, and Group 4.<ref name="Molecular subgroups of medulloblast">{{cite journal | vauthors = Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool M, Pfister SM | display-authors = 6 | title = Molecular subgroups of medulloblastoma: the current consensus | journal = Acta Neuropathologica | volume = 123 | issue = 4 | pages = 465–72 | date = April 2012 | pmid = 22134537 | pmc = 3306779 | doi = 10.1007/s00401-011-0922-z }}</ref> Of these subgroups, WNT patients have an excellent prognosis and group 3 patients have a poor prognosis. Also, a subgroup-specific alternative splicing further confirms the existence of distinct subgroups and highlights the transcriptional heterogeneity between subgroups.<ref>{{cite journal | vauthors = Dubuc AM, Morrissy AS, Kloosterhof NK, Northcott PA, Yu EP, Shih D, Peacock J, Grajkowska W, van Meter T, Eberhart CG, Pfister S, Marra MA, Weiss WA, Scherer SW, Rutka JT, French PJ, Taylor MD | display-authors = 6 | title = Subgroup-specific alternative splicing in medulloblastoma | journal = Acta Neuropathologica | volume = 123 | issue = 4 | pages = 485–499 | date = April 2012 | pmid = 22358458 | pmc = 3984840 | doi = 10.1007/s00401-012-0959-7 }}</ref> Amplification of the [[Sonic hedgehog (protein)|Sonic Hedgehog]] pathway is the best characterized subgroup, with 25% of human tumors having mutations in Patched, Sufu (Suppressor of Fused Homolog), Smoothened, or other genes in this pathway.<ref name=":2">{{cite journal | vauthors = Marino S | title = Medulloblastoma: developmental mechanisms out of control | journal = Trends in Molecular Medicine | volume = 11 | issue = 1 | pages = 17–22 | date = January 2005 | pmid = 15649818 | doi = 10.1016/j.molmed.2004.11.008 }}</ref><ref name=":3">{{cite journal | vauthors = Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, Kranenburg TA, Hogg T, Poppleton H, Martin J, Finkelstein D, Pounds S, Weiss A, Patay Z, Scoggins M, Ogg R, Pei Y, Yang ZJ, Brun S, Lee Y, Zindy F, Lindsey JC, Taketo MM, Boop FA, Sanford RA, Gajjar A, Clifford SC, Roussel MF, McKinnon PJ, Gutmann DH, Ellison DW, Wechsler-Reya R, Gilbertson RJ | display-authors = 6 | title = Subtypes of medulloblastoma have distinct developmental origins | journal = Nature | volume = 468 | issue = 7327 | pages = 1095–9 | date = December 2010 | pmid = 21150899 | pmc = 3059767 | doi = 10.1038/nature09587 | bibcode = 2010Natur.468.1095G }}</ref> Medulloblastomas are also seen in [[Gorlin syndrome]] as well as [[Turcot syndrome]]. Recurrent mutations in the genes ''[[CTNNB1]], [[PTCH1]], [[MLL2]], [[SMARCA4]], [[DDX3X]], [[CTDNEP1]], [[KDM6A]]'', and ''[[TBR1]]'' were identified in individuals with medulloblastoma.<ref>{{cite journal | vauthors = Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, Cho YJ, Pugh TJ, Hovestadt V, Stütz AM, Rausch T, Warnatz HJ, Ryzhova M, Bender S, Sturm D, Pleier S, Cin H, Pfaff E, Sieber L, Wittmann A, Remke M, Witt H, Hutter S, Tzaridis T, Weischenfeldt J, Raeder B, Avci M, Amstislavskiy V, Zapatka M, Weber UD, Wang Q, Lasitschka B, Bartholomae CC, Schmidt M, von Kalle C, Ast V, Lawerenz C, Eils J, Kabbe R, Benes V, van Sluis P, Koster J, Volckmann R, Shih D, Betts MJ, Russell RB, Coco S, Tonini GP, Schüller U, Hans V, Graf N, Kim YJ, Monoranu C, Roggendorf W, Unterberg A, Herold-Mende C, Milde T, Kulozik AE, von Deimling A, Witt O, Maass E, Rössler J, Ebinger M, Schuhmann MU, Frühwald MC, Hasselblatt M, Jabado N, Rutkowski S, von Bueren AO, Williamson D, Clifford SC, McCabe MG, Collins VP, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott PA, Taylor MD, Meyerson M, Pomeroy SL, Yaspo ML, Korbel JO, Korshunov A, Eils R, Pfister SM, Lichter P | display-authors = 6 | title = Dissecting the genomic complexity underlying medulloblastoma | journal = Nature | volume = 488 | issue = 7409 | pages = 100–5 | date = August 2012 | pmid = 22832583 | pmc = 3662966 | doi = 10.1038/nature11284 | bibcode = 2012Natur.488..100J }}</ref> Additional pathways disrupted in some medulloblastomas include [[Myc|MYC]], [[Notch signaling pathway|Notch]], [[Bone morphogenetic protein|BMP]], and [[Transforming growth factor beta|TGF-β]] signaling pathways.<ref name=":2" /><ref name=":3" /><ref name=":1"/><ref name="Ellison 2010">{{cite journal | vauthors = Ellison DW | title = Childhood medulloblastoma: novel approaches to the classification of a heterogeneous disease | journal = Acta Neuropathologica | volume = 120 | issue = 3 | pages = 305–16 | date = September 2010 | pmid = 20652577 | doi = 10.1007/s00401-010-0726-6 | s2cid = 29093769 }}</ref><ref>{{cite journal | vauthors = Cho YJ, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H, Berhoukim R, Amani V, Goumnerova L, Eberhart CG, Lau CC, Olson JM, Gilbertson RJ, Gajjar A, Delattre O, Kool M, Ligon K, Meyerson M, Mesirov JP, Pomeroy SL | display-authors = 6 | title = Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome | journal = Journal of Clinical Oncology | volume = 29 | issue = 11 | pages = 1424–30 | date = April 2011 | pmid = 21098324 | pmc = 3082983 | doi = 10.1200/JCO.2010.28.5148 }}</ref><ref>{{cite journal | vauthors = Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Stütz AM, Korshunov A, Reimand J, Schumacher SE, Beroukhim R, Ellison DW, Marshall CR, Lionel AC, Mack S, Dubuc A, Yao Y, Ramaswamy V, Luu B, Rolider A, Cavalli FM, Wang X, Remke M, Wu X, Chiu RY, Chu A, Chuah E, Corbett RD, Hoad GR, Jackman SD, Li Y, Lo A, Mungall KL, Nip KM, Qian JQ, Raymond AG, Thiessen NT, Varhol RJ, Birol I, Moore RA, Mungall AJ, Holt R, Kawauchi D, Roussel MF, Kool M, Jones DT, Witt H, Fernandez-L A, Kenney AM, Wechsler-Reya RJ, Dirks P, Aviv T, Grajkowska WA, Perek-Polnik M, Haberler CC, Delattre O, Reynaud SS, Doz FF, Pernet-Fattet SS, Cho BK, Kim SK, Wang KC, Scheurlen W, Eberhart CG, Fèvre-Montange M, Jouvet A, Pollack IF, Fan X, Muraszko KM, Gillespie GY, Di Rocco C, Massimi L, Michiels EM, Kloosterhof NK, French PJ, Kros JM, Olson JM, Ellenbogen RG, Zitterbart K, Kren L, Thompson RC, Cooper MK, Lach B, McLendon RE, Bigner DD, Fontebasso A, Albrecht S, Jabado N, Lindsey JC, Bailey S, Gupta N, Weiss WA, Bognár L, Klekner A, Van Meter TE, Kumabe T, Tominaga T, Elbabaa SK, Leonard JR, Rubin JB, Liau LM, Van Meir EG, Fouladi M, Nakamura H, Cinalli G, Garami M, Hauser P, Saad AG, Iolascon A, Jung S, Carlotti CG, Vibhakar R, Ra YS, Robinson S, Zollo M, Faria CC, Chan JA, Levy ML, Sorensen PH, Meyerson M, Pomeroy SL, Cho YJ, Bader GD, Tabori U, Hawkins CE, Bouffet E, Scherer SW, Rutka JT, Malkin D, Clifford SC, Jones SJ, Korbel JO, Pfister SM, Marra MA, Taylor MD | display-authors = 6 | title = Subgroup-specific structural variation across 1,000 medulloblastoma genomes | journal = Nature | volume = 488 | issue = 7409 | pages = 49–56 | date = August 2012 | pmid = 22832581 | pmc = 3683624 | doi = 10.1038/nature11327 | bibcode = 2012Natur.488...49N }}</ref><ref>{{cite journal | vauthors = Hatten ME, Roussel MF | title = Development and cancer of the cerebellum | journal = Trends in Neurosciences | volume = 34 | issue = 3 | pages = 134–42 | date = March 2011 | pmid = 21315459 | pmc = 3051031 | doi = 10.1016/j.tins.2011.01.002 }}</ref><ref name=":0"/>{{citation overkill|date=June 2020}}


==Diagnosis==
==Diagnosis==
The tumor is distinctive on T1- and T2-weighted [[MRI]] with heterogeneous enhancement and a typical location adjacent to and extension into the fourth ventricle. Histologically, the tumor is solid, pink-gray in color, and is well circumscribed. The tumor is very cellular, with high [[Mitosis|mitotic activity]], little [[cytoplasm]], and a tendency to form clusters and rosettes.
The tumor is distinctive on T1- and T2-weighted [[MRI]] with heterogeneous enhancement and a typical location adjacent to and extension into the fourth ventricle. Histologically, the tumor is solid, pink-gray in color, and is well circumscribed. The tumor is very cellular, with high [[Mitosis|mitotic activity]], little [[cytoplasm]], and a tendency to form clusters and rosettes.


The Chang staging system can be used in making the diagnosis [https://www.wikidoc.org/index.php/Medulloblastoma_staging].
The Chang staging system can be used in making the diagnosis.<ref>{{cite web | vauthors = Allaham H | title = Medulloblastoma staging | url = https://www.wikidoc.org/index.php/Medulloblastoma_staging | work = wikidoc }}</ref>

DNA methylation profiling of medulloblastoma allows robust sub-classification and improved outcome prediction using formalin-fixed biopsies. <ref name="pmid23291781">{{cite journal | vauthors = Schwalbe EC, Williamson D, Lindsey JC, Hamilton D, Ryan SL, Megahed H, Garami M, Hauser P, Dembowska-Baginska B, Perek D, Northcott PA, Taylor MD, Taylor RE, Ellison DW, Bailey S, Clifford SC | title = DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies | journal = Acta Neuropathol | volume = 125 | issue = 3 | pages = 359–71 | date = March 2013 | pmid = 23291781 | pmc = 4313078 | doi = 10.1007/s00401-012-1077-2 }}</ref>


Correct diagnosis of medulloblastoma may require ruling out [[ATRT|atypical teratoid rhabdoid tumor]].<ref>{{cite journal | vauthors = Burger PC, Yu IT, Tihan T, Friedman HS, Strother DR, Kepner JL, Duffner PK, Kun LE, Perlman EJ | display-authors = 6 | title = Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group study | journal = The American Journal of Surgical Pathology | volume = 22 | issue = 9 | pages = 1083–92 | date = September 1998 | pmid = 9737241 | doi = 10.1097/00000478-199809000-00007 }}</ref>
Correct diagnosis of medulloblastoma may require ruling out [[ATRT|atypical teratoid rhabdoid tumor]].<ref>{{cite journal | vauthors = Burger PC, Yu IT, Tihan T, Friedman HS, Strother DR, Kepner JL, Duffner PK, Kun LE, Perlman EJ | display-authors = 6 | title = Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group study | journal = The American Journal of Surgical Pathology | volume = 22 | issue = 9 | pages = 1083–92 | date = September 1998 | pmid = 9737241 | doi = 10.1097/00000478-199809000-00007 }}</ref>
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== Treatment==
==Treatment==
Treatment begins with maximal [[Segmental resection|surgical removal]] of the tumor. The addition of radiation to the entire neuraxis and [[chemotherapy]] may increase the disease-free survival. Some evidence indicates that [[Proton therapy|proton beam irradiation]] reduces the impact of radiation on the cochlear and cardiovascular areas and reduces the cognitive late effects of cranial irradiation.<ref>{{cite journal | vauthors = Merchant TE, Hua CH, Shukla H, Ying X, Nill S, Oelfke U | title = Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function | journal = Pediatric Blood & Cancer | volume = 51 | issue = 1 | pages = 110–7 | date = July 2008 | pmid = 18306274 | doi = 10.1002/pbc.21530 }}</ref><ref>{{cite journal | vauthors = Blomstrand M, Brodin NP, Munck Af Rosenschöld P, Vogelius IR, Sánchez Merino G, Kiil-Berthlesen A, Blomgren K, Lannering B, Bentzen SM, Björk-Eriksson T | display-authors = 6 | title = Estimated clinical benefit of protecting neurogenesis in the developing brain during radiation therapy for pediatric medulloblastoma | journal = Neuro-Oncology | volume = 14 | issue = 7 | pages = 882–9 | date = July 2012 | pmid = 22611031 | pmc = 3379806 | doi = 10.1093/neuonc/nos120 }}</ref>
Treatment begins with maximal [[Segmental resection|surgical removal]] of the tumor. The addition of radiation to the entire neuraxis and [[chemotherapy]] may increase the disease-free survival. This combination may permit a 5-year survival in more than 80% of cases. Some evidence indicates that [[Proton therapy|proton beam irradiation]] reduces the impact of radiation on the cochlear and cardiovascular areas and reduces the cognitive late effects of cranial irradiation.<ref>{{cite journal | vauthors = Merchant TE, Hua CH, Shukla H, Ying X, Nill S, Oelfke U | title = Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function | journal = Pediatric Blood & Cancer | volume = 51 | issue = 1 | pages = 110–7 | date = July 2008 | pmid = 18306274 | doi = 10.1002/pbc.21530 | s2cid = 36735536 }}</ref><ref>{{cite journal | vauthors = Blomstrand M, Brodin NP, Munck Af Rosenschöld P, Vogelius IR, Sánchez Merino G, Kiil-Berthlesen A, Blomgren K, Lannering B, Bentzen SM, Björk-Eriksson T | display-authors = 6 | title = Estimated clinical benefit of protecting neurogenesis in the developing brain during radiation therapy for pediatric medulloblastoma | journal = Neuro-Oncology | volume = 14 | issue = 7 | pages = 882–9 | date = July 2012 | pmid = 22611031 | pmc = 3379806 | doi = 10.1093/neuonc/nos120 }}</ref>

This combination may permit a 5-year survival in more than 80% of cases. The presence of desmoplastic features such as connective tissue formation offers a better prognosis. Prognosis is worse if the child is less than 3 years old, degree of resection is inadequate, or if any CSF, spinal, supratentorial, or systemic spread occurs. Dementia after radiotherapy and chemotherapy is a common outcome appearing two to four years following treatment. Side effects from radiation treatment can include cognitive impairment, psychiatric illness, bone growth retardation, hearing loss, and endocrine disruption.<ref name=":0" /><ref name=":1" /><ref name="Ellison 2010"/> Increased [[intracranial pressure]] may be controlled with [[corticosteroids]] or a ventriculoperitoneal [[shunt (medical)|shunt]].
The presence of desmoplastic features such as connective tissue formation offers a better prognosis. Prognosis is worse if the child is less than 3 years old, degree of resection is inadequate, or if any CSF, spinal, supratentorial, or systemic spread occurs. Dementia after radiotherapy and chemotherapy is a common outcome appearing two to four years following treatment. Side effects from radiation treatment can include cognitive impairment, psychiatric illness, bone growth retardation, hearing loss, and endocrine disruption.<ref name=":0" /><ref name=":1" /><ref name="Ellison 2010"/> Increased [[intracranial pressure]] may be controlled with [[corticosteroids]] or a ventriculoperitoneal [[shunt (medical)|shunt]]. An approach to monitor tumor development and treatment response by [[liquid biopsy]] is promising, but remains challenging.<ref>{{cite journal | vauthors = Eibl RH, Schneemann, M | title = Liquid biopsy for monitoring medulloblastoma. | journal = Extracell Vesicles Circ Nucleic Acids | volume = 3 | pages = 263–74 | date = Sep 2022 | issue = 3 | doi = 10.20517/evcna.2022.36 | s2cid = 252638651 | doi-access = free }}</ref>


===Chemotherapy===
===Chemotherapy===
Chemotherapy is often used as part of treatment. Evidence of benefit, however, is not clear as of 2013.<ref>{{cite journal | vauthors = Michiels EM, Schouten-Van Meeteren AY, Doz F, Janssens GO, van Dalen EC | title = Chemotherapy for children with medulloblastoma | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD006678 | date = January 2015 | pmid = 25879092 | doi = 10.1002/14651858.CD006678.pub2 }}</ref> A few different chemotherapeutic regimens for medulloblastoma are used; most involve a combination of [[lomustine]], [[cisplatin]], [[carboplatin]], [[vincristine]], or [[cyclophosphamide]]. In younger patients (less than 3–4 years of age), chemotherapy can delay, or in some cases possibly even eliminate, the need for radiotherapy. However, both chemotherapy and radiotherapy often have long-term toxicity effects, including delays in physical and cognitive development, higher risk of second cancers, and increased cardiac disease risks.<ref>{{cite journal | vauthors = Fossati P, Ricardi U, Orecchia R | title = Pediatric medulloblastoma: toxicity of current treatment and potential role of protontherapy | journal = Cancer Treatment Reviews | volume = 35 | issue = 1 | pages = 79–96 | date = February 2009 | pmid = 18976866 | doi = 10.1016/j.ctrv.2008.09.002 }}</ref><ref>{{cite journal | vauthors = Crawford JR, MacDonald TJ, Packer RJ | title = Medulloblastoma in childhood: new biological advances | journal = The Lancet. Neurology | volume = 6 | issue = 12 | pages = 1073–85 | date = December 2007 | pmid = 18031705 | doi = 10.1016/S1474-4422(07)70289-2 }}</ref>
Chemotherapy is often used as part of treatment. Evidence of benefit, however, is not clear as of 2013.<ref>{{cite journal | vauthors = Michiels EM, Schouten-Van Meeteren AY, Doz F, Janssens GO, van Dalen EC | title = Chemotherapy for children with medulloblastoma | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD006678 | date = January 2015 | issue = 1 | pmid = 25879092 | doi = 10.1002/14651858.CD006678.pub2 | pmc = 10651941 }}</ref> A few different chemotherapeutic regimens for medulloblastoma are used; most involve a combination of [[lomustine]], [[cisplatin]], [[carboplatin]], [[vincristine]], or [[cyclophosphamide]]. In younger patients (less than 3–4 years of age), chemotherapy can delay, or in some cases possibly even eliminate, the need for radiotherapy. However, both chemotherapy and radiotherapy often have long-term toxicity effects, including delays in physical and cognitive development, higher risk of second cancers, and increased cardiac disease risks.<ref>{{cite journal | vauthors = Fossati P, Ricardi U, Orecchia R | title = Pediatric medulloblastoma: toxicity of current treatment and potential role of protontherapy | journal = Cancer Treatment Reviews | volume = 35 | issue = 1 | pages = 79–96 | date = February 2009 | pmid = 18976866 | doi = 10.1016/j.ctrv.2008.09.002 }}</ref><ref>{{cite journal | vauthors = Crawford JR, MacDonald TJ, Packer RJ | title = Medulloblastoma in childhood: new biological advances | journal = The Lancet. Neurology | volume = 6 | issue = 12 | pages = 1073–85 | date = December 2007 | pmid = 18031705 | doi = 10.1016/S1474-4422(07)70289-2 | s2cid = 13013757 }}</ref>


==Outcomes==
==Outcomes==
[[Virtual Karyotype|Array-based karyotyping]] of 260 medulloblastomas resulted in the following clinical subgroups based on cytogenetic profiles:<ref>{{cite journal | vauthors = Pfister S, Remke M, Benner A, Mendrzyk F, Toedt G, Felsberg J, Wittmann A, Devens F, Gerber NU, Joos S, Kulozik A, Reifenberger G, Rutkowski S, Wiestler OD, Radlwimmer B, Scheurlen W, Lichter P, Korshunov A | display-authors = 6 | title = Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci | journal = Journal of Clinical Oncology | volume = 27 | issue = 10 | pages = 1627–36 | date = April 2009 | pmid = 19255330 | doi = 10.1200/JCO.2008.17.9432 | url = https://semanticscholar.org/paper/569ed4bc0ff262d677aad84c5f79f97249a72aa9 }}</ref>
[[Virtual Karyotype|Array-based karyotyping]] of 260 medulloblastomas resulted in the following clinical subgroups based on cytogenetic profiles:<ref>{{cite journal | vauthors = Pfister S, Remke M, Benner A, Mendrzyk F, Toedt G, Felsberg J, Wittmann A, Devens F, Gerber NU, Joos S, Kulozik A, Reifenberger G, Rutkowski S, Wiestler OD, Radlwimmer B, Scheurlen W, Lichter P, Korshunov A | display-authors = 6 | title = Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci | journal = Journal of Clinical Oncology | volume = 27 | issue = 10 | pages = 1627–36 | date = April 2009 | pmid = 19255330 | doi = 10.1200/JCO.2008.17.9432 | s2cid = 21794571 | doi-access = free }}</ref>
*Poor prognosis: gain of [[Chromosome 6 (human)|6q]] or amplification of MYC or [[MYCN]]
* Poor prognosis: gain of [[Chromosome 6 (human)|6q]] or amplification of MYC or [[MYCN]]
*Intermediate: gain of 17q or an i(17q) without gain of 6q or amplification of MYC or MYCN
* Intermediate: gain of 17q or an i(17q) without gain of 6q or amplification of MYC or MYCN
*Excellent prognosis: 6q and 17q balanced or 6q deletion
* Excellent prognosis: 6q and 17q balanced or 6q deletion


Transcriptional profiling shows the existence of four main subgroups (Wnt, Shh, Group 3, and Group 4).<ref>{{cite journal | vauthors = Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool M, Pfister SM | display-authors = 6 | title = Molecular subgroups of medulloblastoma: the current consensus | journal = Acta Neuropathologica | volume = 123 | issue = 4 | pages = 465–72 | date = April 2012 | pmid = 22134537 | pmc = 3306779 | doi = 10.1007/s00401-011-0922-z }}</ref>
Transcriptional profiling shows the existence of four main subgroups (Wnt, Shh, Group 3, and Group 4).<ref name="Molecular subgroups of medulloblast"/>
*Very good prognosis: WNT group,'' CTNNB''1 mutation
* Very good prognosis: WNT group,'' CTNNB''1 mutation
*Infants good prognosis, others intermediate: SHH group, ''PTCH1/SMO/SUFU'' mutation, ''GLI2'' amplification, or ''MYCN'' amplification
* Infants good prognosis, others intermediate: SHH group, ''PTCH1/SMO/SUFU'' mutation, ''GLI2'' amplification, or ''MYCN'' amplification
*Poor prognosis: Group 3, ''MYC'' amplification, photoreceptor/GABAergic gene expression
* Poor prognosis: Group 3, ''MYC'' amplification, photoreceptor/GABAergic gene expression
*Intermediate prognosis: Group 4, gene expression of neuronal/glutamatergic, ''CDK6'' amplification, ''MYCN'' amplification
* Intermediate prognosis: Group 4, gene expression of neuronal/glutamatergic, ''CDK6'' amplification, ''MYCN'' amplification


===Survival===
===Survival===
The historical cumulative relative survival rate for all age groups and histology follow-up was 60%, 52%, and 47% at 5 years, 10 years, and 20 years, respectively. Patients diagnosed with a medulloblastoma or PNET are 50 times more likely to die than a matched member of the general population.
The historical cumulative relative survival rate for all age groups and histology follow-up was 60%, 52%, and 47% at 5 years, 10 years, and 20 years, respectively. Patients diagnosed with a medulloblastoma or PNET are 50 times more likely to die than a matched member of the general population.
The most recent population-based (SEER) [[Five-year survival rate|5-year relative survival rates]] are 69% overall: 72% in children (1–9 years) and 67% in adults (20+ years). The 20-year survival rate is 51% in children. Children and adults have different survival profiles, with adults faring worse than children only after the fourth year after diagnosis (after controlling for increased background mortality). Before the fourth year, survival probabilities are nearly identical.<ref name="Small">{{cite journal | vauthors = Smoll NR | title = Relative survival of childhood and adult medulloblastomas and primitive neuroectodermal tumors (PNETs) | journal = Cancer | volume = 118 | issue = 5 | pages = 1313–22 | date = March 2012 | pmid = 21837678 | doi = 10.1002/cncr.26387 }}</ref> Long-term sequelae of standard treatment include hypothalamic-pituitary and thyroid dysfunction and intellectual impairment. The hormonal and intellectual deficits created by these therapies causes significant impairment of the survivors.<ref>{{cite web |title=Medulloblastoma |first=Roger J. |last=Packer |year=2010 |url=http://www.childhoodbraintumor.org/medical-information/brain-tumor-types-and-imaging/item/88-updated-2010}}{{self-published inline|date=February 2015}}</ref>
A population-based (SEER) [[Five-year survival rate|5-year relative survival rates]] indicated 69% overall: 72% in children (1–9 years) and 67% in adults (20+ years). The 20-year survival rate is 51% in children. Children and adults have different survival profiles, with adults faring worse than children only after the fourth year after diagnosis (after controlling for increased background mortality). Before the fourth year, survival probabilities are nearly identical.<ref name="Small">{{cite journal | vauthors = Smoll NR | title = Relative survival of childhood and adult medulloblastomas and primitive neuroectodermal tumors (PNETs) | journal = Cancer | volume = 118 | issue = 5 | pages = 1313–22 | date = March 2012 | pmid = 21837678 | doi = 10.1002/cncr.26387 | s2cid = 8490276 | doi-access = free }}</ref> Long-term sequelae of standard treatment include hypothalamic-pituitary and thyroid dysfunction and intellectual impairment. The hormonal and intellectual deficits created by these therapies causes significant impairment of the survivors.<ref>{{cite web |title=Medulloblastoma |first=Roger J. |last=Packer |year=2010 |url=http://www.childhoodbraintumor.org/medical-information/brain-tumor-types-and-imaging/item/88-updated-2010 |access-date=2015-02-22 |archive-date=2017-11-07 |archive-url=https://web.archive.org/web/20171107011636/http://www.childhoodbraintumor.org/medical-information/brain-tumor-types-and-imaging/item/88-updated-2010 |url-status=dead }}</ref>{{self-published inline|date=February 2015}}


In current clinical studies, the patients are divided into low-, standard- and high-risk groups:
In current clinical studies, the patients are divided into low-, standard- and high-risk groups:

* Depending on the study, healing rates of up to 100% are achieved in the '''low-risk group''' (usually WNT-activated).<ref>{{Cite web|url=http://www.medscape.com/viewarticle/904596|title=Identifying Low-Risk Medulloblastoma to De-escalate Therapy|website=Medscape|access-date=2020-01-03}}</ref> The current efforts are therefore moving in the direction of reducing the intensity of the therapy and thus the negative long-term consequences while confirming the high healing rates.<ref name = NCT02066220 />
* Depending on the study, healing rates of up to 100% are achieved in the '''low-risk group''' (usually WNT-activated).<ref>{{Cite web|url=http://www.medscape.com/viewarticle/904596|title=Identifying Low-Risk Medulloblastoma to De-escalate Therapy|website=Medscape|access-date=2020-01-03}}</ref> The current efforts are therefore moving in the direction of reducing the intensity of the therapy and thus the negative long-term consequences while confirming the high healing rates.<ref name = NCT02066220 />
* In the HIT-SIOP PNET 4 study, in which 340 children and adolescents of the '''standard-risk group''' between the ages of four and 21 from several European countries participated, the 5-year survival rate was between 85% and 87% depending on the randomization. Around 78% of the patients remained without relapse for 5 years and are therefore considered to be cured.<ref>{{cite journal | vauthors = Lannering B, Rutkowski S, Doz F, Pizer B, Gustafsson G, Navajas A, Massimino M, Reddingius R, Benesch M, Carrie C, Taylor R, Gandola L, Björk-Eriksson T, Giralt J, Oldenburger F, Pietsch T, Figarella-Branger D, Robson K, Forni M, Clifford SC, Warmuth-Metz M, von Hoff K, Faldum A, Mosseri V, Kortmann R | display-authors = 6 | title = Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: results from the randomized multicenter HIT-SIOP PNET 4 trial | journal = Journal of Clinical Oncology | volume = 30 | issue = 26 | pages = 3187–93 | date = September 2012 | pmid = 22851561 | doi = 10.1200/JCO.2011.39.8719 }}</ref> After a relapse, the prognosis was very poor. Despite intensive treatment, only four of 66 patients were still alive 5 years after a relapse.<ref>{{cite journal | vauthors = Sabel M, Fleischhack G, Tippelt S, Gustafsson G, Doz F, Kortmann R, Massimino M, Navajas A, von Hoff K, Rutkowski S, Warmuth-Metz M, Clifford SC, Pietsch T, Pizer B, Lannering B | display-authors = 6 | title = Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study | journal = Journal of Neuro-Oncology | volume = 129 | issue = 3 | pages = 515–524 | date = September 2016 | pmid = 27423645 | pmc = 5020107 | doi = 10.1007/s11060-016-2202-1 }}</ref>
* In the HIT-SIOP PNET 4 study, in which 340 children and adolescents of the '''standard-risk group''' between the ages of four and 21 from several European countries participated, the 5-year survival rate was between 85% and 87% depending on the randomization. Around 78% of the patients remained without relapse for 5 years and are therefore considered to be cured.<ref>{{cite journal | vauthors = Lannering B, Rutkowski S, Doz F, Pizer B, Gustafsson G, Navajas A, Massimino M, Reddingius R, Benesch M, Carrie C, Taylor R, Gandola L, Björk-Eriksson T, Giralt J, Oldenburger F, Pietsch T, Figarella-Branger D, Robson K, Forni M, Clifford SC, Warmuth-Metz M, von Hoff K, Faldum A, Mosseri V, Kortmann R | display-authors = 6 | title = Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: results from the randomized multicenter HIT-SIOP PNET 4 trial | journal = Journal of Clinical Oncology | volume = 30 | issue = 26 | pages = 3187–93 | date = September 2012 | pmid = 22851561 | doi = 10.1200/JCO.2011.39.8719 | doi-access = free }}</ref> After a relapse, the prognosis was very poor. Despite intensive treatment, only four of 66 patients were still alive 5 years after a relapse.<ref>{{cite journal | vauthors = Sabel M, Fleischhack G, Tippelt S, Gustafsson G, Doz F, Kortmann R, Massimino M, Navajas A, von Hoff K, Rutkowski S, Warmuth-Metz M, Clifford SC, Pietsch T, Pizer B, Lannering B | display-authors = 6 | title = Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study | journal = Journal of Neuro-Oncology | volume = 129 | issue = 3 | pages = 515–524 | date = September 2016 | pmid = 27423645 | pmc = 5020107 | doi = 10.1007/s11060-016-2202-1 }}</ref>
* A US study involved 161 patients between the ages of three and 21 with a '''high-risk profile'''. Depending on the randomization, half of the patients additionally received [[carboplatin]] daily during the radiation. The 5-year survival rate of patients with carboplatin was 82%, those without 68%.<ref>{{cite journal | vauthors = Jakacki RI, Burger PC, Zhou T, Holmes EJ, Kocak M, Onar A, Goldwein J, Mehta M, Packer RJ, Tarbell N, Fitz C, Vezina G, Hilden J, Pollack IF | display-authors = 6 | title = Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children's Oncology Group Phase I/II study | journal = Journal of Clinical Oncology | volume = 30 | issue = 21 | pages = 2648–53 | date = July 2012 | pmid = 22665539 | pmc = 4559602 | doi = 10.1200/JCO.2011.40.2792 }}</ref> The European SIOP PNET 5 study is currently taking place and will run until April 2024, in which an attempt is made to confirm the promising results with carboplatin during [[Radiation therapy|irradiation]] in the standard risk group.<ref name = NCT02066220 >{{ClinicalTrialsGov|NCT02066220|International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma}}</ref>
* A US study involved 161 patients between the ages of three and 21 with a '''high-risk profile'''. Depending on the randomization, half of the patients additionally received [[carboplatin]] daily during the radiation. The 5-year survival rate of patients with carboplatin was 82%, those without 68%.<ref>{{cite journal | vauthors = Jakacki RI, Burger PC, Zhou T, Holmes EJ, Kocak M, Onar A, Goldwein J, Mehta M, Packer RJ, Tarbell N, Fitz C, Vezina G, Hilden J, Pollack IF | display-authors = 6 | title = Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children's Oncology Group Phase I/II study | journal = Journal of Clinical Oncology | volume = 30 | issue = 21 | pages = 2648–53 | date = July 2012 | pmid = 22665539 | pmc = 4559602 | doi = 10.1200/JCO.2011.40.2792 }}</ref> The European SIOP PNET 5 study is currently taking place and will run until April 2024, in which an attempt is made to confirm the promising results with carboplatin during [[Radiation therapy|irradiation]] in the standard risk group.<ref name = NCT02066220 >{{ClinicalTrialsGov|NCT02066220|International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma}}</ref>


==Epidemiology==
==Epidemiology==
Medulloblastomas affect just under two people per million per year, and affect children 10 times more than adults.<ref name="Smoll 2012">{{cite journal | vauthors = Smoll NR, Drummond KJ | title = The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children | journal = Journal of Clinical Neuroscience | volume = 19 | issue = 11 | pages = 1541–4 | date = November 2012 | pmid = 22981874 | doi = 10.1016/j.jocn.2012.04.009 }}</ref> Medulloblastoma is the second-most frequent brain tumor in children after [[pilocytic astrocytoma]]<ref>{{cite web | title = Chapter 7: Tumors of the Central Nervous System | url = http://neuropathology-web.org/chapter7/chapter7cMedulloblastoma.html | archive-url = https://web.archive.org/web/20120312041034/http://neuropathology-web.org/chapter7/chapter7cMedulloblastoma.html | archive-date = 12 March 2012 | work = Neuropathology | publisher = NEOMED }}</ref> and the most common malignant brain tumor in children, comprising 14.5% of newly diagnosed brain tumors.<ref name="seer">{{cite book | last1 = Gurney | first1 = James G. | last2 = Smith | first2 = Malcolm A. | last3 = Bunin | first3 = Greta R. | name-list-format = vanc |chapter=CNS and Miscellaneous Intracranial and Intraspinal Neoplasms |chapter-url= http://seer.cancer.gov/publications/childhood/cns.pdf |format=PDF |veditors=Ries LA, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR |title=Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975–1995 |publisher=National Cancer Institute |location=Bethesda MD |year=1999 |id=NIH Pub. No. 99-4649 |url=http://seer.cancer.gov/publications/childhood/}}</ref> In adults, medulloblastoma is rare, comprising fewer than 2% of CNS malignancies.<ref>{{cite web | url = http://cbtrus.org/2005-2006/tables/2006.table12.pdf | title = Selected Primary Brain and Central Nervous System Tumor Age-Specific Incidence Rates | work = Central Brain Tumor Registry of the United States, 1998–2002 }}</ref>
Medulloblastomas affect just under two people per million per year, and affect children 10 times more than adults.<ref name="Smoll 2012">{{cite journal | vauthors = Smoll NR, Drummond KJ | title = The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children | journal = Journal of Clinical Neuroscience | volume = 19 | issue = 11 | pages = 1541–4 | date = November 2012 | pmid = 22981874 | doi = 10.1016/j.jocn.2012.04.009 | s2cid = 7922631 }}</ref> Medulloblastoma is the second-most frequent brain tumor in children after [[pilocytic astrocytoma]]<ref>{{cite web | title = Chapter 7: Tumors of the Central Nervous System | url = http://neuropathology-web.org/chapter7/chapter7cMedulloblastoma.html | archive-url = https://web.archive.org/web/20120312041034/http://neuropathology-web.org/chapter7/chapter7cMedulloblastoma.html | archive-date = 12 March 2012 | work = Neuropathology | publisher = NEOMED }}</ref> and the most common malignant brain tumor in children, comprising 14.5% of newly diagnosed brain tumors.<ref name="seer">{{cite book | last1 = Gurney | first1 = James G. | last2 = Smith | first2 = Malcolm A. | last3 = Bunin | first3 = Greta R. |chapter=CNS and Miscellaneous Intracranial and Intraspinal Neoplasms |chapter-url= http://seer.cancer.gov/publications/childhood/cns.pdf |format=PDF |veditors=Ries LA, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR |title=Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975–1995 |publisher=National Cancer Institute |location=Bethesda MD |year=1999 |id=NIH Pub. No. 99-4649 |url=http://seer.cancer.gov/publications/childhood/}}</ref> In adults, medulloblastoma is rare, comprising fewer than 2% of CNS malignancies.<ref>{{cite web | url = http://cbtrus.org/2005-2006/tables/2006.table12.pdf | title = Selected Primary Brain and Central Nervous System Tumor Age-Specific Incidence Rates | work = Central Brain Tumor Registry of the United States, 1998–2002 | access-date = 2007-03-09 | archive-date = 2007-09-27 | archive-url = https://web.archive.org/web/20070927210152/http://cbtrus.org/2005-2006/tables/2006.table12.pdf | url-status = dead }}</ref>


The rate of new cases of childhood medulloblastoma is higher in males (62%) than females (38%), a feature which is not seen in adults.<ref name="Smoll 2012"/><ref>{{cite web | url = http://cbtrus.org/2005-2006/tables/2006.table13.pdf | title = Selected Childhood Primary Brain and Central Nervous System Tumor Incidence Rates by Major Histology Groupings, Histology and Gender | work = Central Brain Tumor Registry of the United States, 1998–2002}}</ref> Medulloblastoma and other PNET`s are more prevalent in younger children than older children. About 40% of medulloblastoma patients are diagnosed before the age of five, 31% are between the ages of 5 and 9, 18.3% are between the ages of 10 and 14, and 12.7% are between the ages of 15 and 19.<ref>{{cite web | url = http://cbtrus.org/2005-2006/tables/2006.table15.pdf | title = Selected Childhood Primary Brain and Central Nervous System Tumor Age-Specific Incidence Rates | work = Central Brain Tumor Registry of the United States, 1998–2002 }}</ref>
The rate of new cases of childhood medulloblastoma is higher in males (62%) than females (38%), a feature that is not seen in adults.<ref name="Smoll 2012"/><ref>{{cite web | url = http://cbtrus.org/2005-2006/tables/2006.table13.pdf | title = Selected Childhood Primary Brain and Central Nervous System Tumor Incidence Rates by Major Histology Groupings, Histology and Gender | work = Central Brain Tumor Registry of the United States, 1998–2002 | access-date = 2007-03-14 | archive-date = 2007-09-27 | archive-url = https://web.archive.org/web/20070927210105/http://cbtrus.org/2005-2006/tables/2006.table13.pdf | url-status = dead }}</ref> Medulloblastoma and other PNET`s are more prevalent in younger children than older children. About 40% of medulloblastoma patients are diagnosed before the age of five, 31% are between the ages of 5 and 9, 18.3% are between the ages of 10 and 14, and 12.7% are between the ages of 15 and 19.<ref>{{cite web | url = http://cbtrus.org/2005-2006/tables/2006.table15.pdf | title = Selected Childhood Primary Brain and Central Nervous System Tumor Age-Specific Incidence Rates | work = Central Brain Tumor Registry of the United States, 1998–2002 | access-date = 2007-03-14 | archive-date = 2007-09-27 | archive-url = https://web.archive.org/web/20070927210146/http://cbtrus.org/2005-2006/tables/2006.table15.pdf | url-status = dead }}</ref>


==Research models==
==Research models==
Using gene transfer of SV40 large T-antigen in neuronal precursor cells of rats, a brain tumor model was established. The PNETs were histologically indistinguishable from the human counterparts and have been used to identify new genes involved in human brain tumor carcinogenesis.<ref>{{cite journal | vauthors = Eibl RH, Kleihues P, Jat PS, Wiestler OD | title = A model for primitive neuroectodermal tumors in transgenic neural transplants harboring the SV40 large T antigen | journal = The American Journal of Pathology | volume = 144 | issue = 3 | pages = 556–64 | date = March 1994 | pmid = 8129041 | pmc = 1887088 }}</ref> The model was used to confirm'' p53'' as one of the genes involved in human medulloblastomas, but since only about 10% of the human tumors showed mutations in that gene, the model can be used to identify the other binding partners of SV40 Large T- antigen, other than ''p53''.<ref>{{cite journal | vauthors = Ohgaki H, Eibl RH, Wiestler OD, Yasargil MG, Newcomb EW, Kleihues P | title = p53 mutations in nonastrocytic human brain tumors | journal = Cancer Research | volume = 51 | issue = 22 | pages = 6202–5 | date = November 1991 | pmid = 1933879 | url = http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=1933879 }}</ref>
Using gene transfer of SV40 large T-antigen in neuronal precursor cells of rats, a brain tumor model was established. The PNETs were histologically indistinguishable from the human counterparts and have been used to identify new genes involved in human brain tumor carcinogenesis.<ref>{{cite journal | vauthors = Eibl RH, Kleihues P, Jat PS, Wiestler OD | title = A model for primitive neuroectodermal tumors in transgenic neural transplants harboring the SV40 large T antigen | journal = The American Journal of Pathology | volume = 144 | issue = 3 | pages = 556–64 | date = March 1994 | pmid = 8129041 | pmc = 1887088 }}</ref> The model was used to confirm'' p53'' as one of the genes involved in human medulloblastomas, but since only about 10% of the human tumors showed mutations in that gene, the model can be used to identify the other binding partners of SV40 Large T- antigen, other than ''p53''.<ref>{{cite journal | vauthors = Ohgaki H, Eibl RH, Wiestler OD, Yasargil MG, Newcomb EW, Kleihues P | title = p53 mutations in nonastrocytic human brain tumors | journal = Cancer Research | volume = 51 | issue = 22 | pages = 6202–5 | date = November 1991 | pmid = 1933879 | url = http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=1933879 }}</ref><ref>{{cite journal | vauthors = Eibl RH, Schneemann M | title = From TP53 Mutations to Molecular Classification and Liquid Biopsy | journal = Biology | volume = 12 | issue = 2 | pages = 267 | date = February 2023 | doi = 10.3390/biology12020267 | pmid = 36829544 | pmc = 9952923 | doi-access = free }}</ref>
Recently, it has been generated a SHH-type mouse model with high-frequency of medulloblastoma, a Patched 1 heterozygous mice knockout for the medulloblastoma suppressor Tis21 (Patched1+-/Tis21 KO).<ref name="pmid23115191">{{cite journal | vauthors = Farioli-Vecchioli S, Cinà I, Ceccarelli M, Micheli L, Leonardi L, Ciotti MT, De Bardi M, Di Rocco C, Pallini R, Cavallaro S, Tirone F | display-authors = 6 | title = Tis21 knock-out enhances the frequency of medulloblastoma in Patched1 heterozygous mice by inhibiting the Cxcl3-dependent migration of cerebellar neurons | journal = The Journal of Neuroscience | volume = 32 | issue = 44 | pages = 15547–64 | date = October 2012 | pmid = 23115191 | pmc = 6621585 | doi = 10.1523/JNEUROSCI.0412-12.2012 }}</ref> The high medulloblastoma frequency appears to be caused by the down regulation of Cxcl3, being Cxcl3 induced by Tis21.<ref name="pmid23115191"/> Consistently, the treatment with Cxcl3 completely prevents the growth of medulloblastoma lesions in a Shh-type mouse model of medulloblastoma.<ref>{{cite journal | vauthors = Ceccarelli M, Micheli L, Tirone F | title = Suppression of Medulloblastoma Lesions by Forced Migration of Preneoplastic Precursor Cells with Intracerebellar Administration of the Chemokine Cxcl3 | journal = Frontiers in Pharmacology | volume = 7 | pages = 484 | year = 2016 | pmid = 28018222 | pmc = 5159413 | doi = 10.3389/fphar.2016.00484 }}</ref> Thus, CXCL3 is a target for medulloblastoma therapy.
In a mouse model, high medulloblastoma frequency appears to be caused by the down regulation of Cxcl3, with Cxcl3 being induced by [[Protein BTG2#Medulloblastoma suppressor|Tis21]].<ref name="pmid23115191">{{cite journal | vauthors = Farioli-Vecchioli S, Cinà I, Ceccarelli M, Micheli L, Leonardi L, Ciotti MT, De Bardi M, Di Rocco C, Pallini R, Cavallaro S, Tirone F | display-authors = 6 | title = Tis21 knock-out enhances the frequency of medulloblastoma in Patched1 heterozygous mice by inhibiting the Cxcl3-dependent migration of cerebellar neurons | journal = The Journal of Neuroscience | volume = 32 | issue = 44 | pages = 15547–64 | date = October 2012 | pmid = 23115191 | pmc = 6621585 | doi = 10.1523/JNEUROSCI.0412-12.2012 }}</ref> Consistently, the treatment with Cxcl3 completely prevents the growth of medulloblastoma lesions in a Shh-type mouse model of medulloblastoma.<ref>{{cite journal | vauthors = Ceccarelli M, Micheli L, Tirone F | title = Suppression of Medulloblastoma Lesions by Forced Migration of Preneoplastic Precursor Cells with Intracerebellar Administration of the Chemokine Cxcl3 | journal = Frontiers in Pharmacology | volume = 7 | pages = 484 | year = 2016 | pmid = 28018222 | pmc = 5159413 | doi = 10.3389/fphar.2016.00484 | doi-access = free }}</ref> Thus, CXCL3 is a target for medulloblastoma therapy.


== References ==
== References ==
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== External links ==
== External links ==
* [https://web.archive.org/web/20080513082649/http://www.ninds.nih.gov/disorders/brainandspinaltumors/detail_brainandspinaltumors.htm Brain and Spinal Tumors: Hope Through Research (National Institute of Neurological Disorders and Stroke)]
* [https://web.archive.org/web/20080513082649/http://www.ninds.nih.gov/disorders/brainandspinaltumors/detail_brainandspinaltumors.htm Brain and Spinal Tumors: Hope Through Research (National Institute of Neurological Disorders and Stroke)]
* [http://rad.usuhs.edu/medpix/medpix.html?mode=image_finder&action=search&srchstr=medulloblastoma&srch_type=all#top Medulloblastoma Images] MedPix Medical Image Database
* [http://rad.usuhs.edu/medpix/medpix.html?mode=image_finder&action=search&srchstr=medulloblastoma&srch_type=all#top Medulloblastoma Images] {{Webarchive|url=https://web.archive.org/web/20090130091014/http://rad.usuhs.edu/medpix/medpix.html?mode=image_finder&action=search&srchstr=medulloblastoma&srch_type=all#top |date=2009-01-30 }} MedPix Medical Image Database


{{Medical resources
{{Medical resources
| DiseasesDB = 31105
| DiseasesDB = 31105
| ICD10 =
| ICD10 =
| ICD9 =
| ICD9 =
| ICDO = {{ICDO|9470|3}}
| ICDO = {{ICDO|9470|3}}
| OMIM = 155255
| OMIM = 155255
| MedlinePlus =
| MedlinePlus =
| eMedicineSubj = neuro
| eMedicineSubj = neuro
| eMedicineTopic = 624
| eMedicineTopic = 624
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}}
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{{Nervous tissue tumors}}
{{Nervous tissue tumors}}
{{Small blue round cell tumors}}


[[Category:Small blue round cell tumor]]
[[Category:Small-blue-round-cell tumors]]
[[Category:Brain tumor]]
[[Category:Brain tumor]]
[[Category:Pediatric cancers]]

Latest revision as of 22:51, 26 April 2024

Medulloblastoma
CT scan, showing a tumorous mass in the posterior fossa, giving rise to obstructive hydrocephalus, in a six-year-old girl
Pronunciation
SpecialtyNeuro-oncology, neurosurgery
SymptomsHeadaches
Nausea
Vomiting
Tiredness
Clumsiness
Dizziness
Change in vision
Handwriting problems[1]
Usual onsetBetween 5 and 9 years old[1]
PrognosisFive-year survival rate: 72.1%[2]
FrequencyAbout 500 children diagnosed annually in the United States[1]

Medulloblastoma is a common type of primary brain cancer in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the cerebellum, or posterior fossa.[3]

The brain is divided into two main parts, the larger cerebrum on top and the smaller cerebellum below towards the back. They are separated by a membrane called the tentorium. Tumors that originate in the cerebellum or the surrounding region below the tentorium are, therefore, called infratentorial.

Historically, medulloblastomas have been classified as a primitive neuroectodermal tumor (PNET), but it is now known that medulloblastoma is distinct from supratentorial PNETs and they are no longer considered similar entities.[4]

Medulloblastomas are invasive, rapidly growing tumors that, unlike most brain tumors, spread through the cerebrospinal fluid and frequently metastasize to different locations along the surface of the brain and spinal cord. Metastasis all the way down to the cauda equina at the base of the spinal cord is termed "drop metastasis".

The cumulative relative survival rate for all age groups and histology follow-up was 60%, 52%, and 47% at 5 years, 10 years, and 20 years, respectively, with children doing better than adults.[5]

Signs and symptoms

[edit]

Signs and symptoms are mainly due to secondary increased intracranial pressure due to blockage of the fourth ventricle and tumors are usually present for 1 to 5 months before diagnosis is made. The child typically becomes listless, with repeated episodes of vomiting, and a morning headache, which may lead to a misdiagnosis of gastrointestinal disease or migraine.[6] Soon after, the child will develop a stumbling gait, truncal ataxia, frequent falls, diplopia, papilledema, and sixth cranial nerve palsy. Positional vertigo and nystagmus are also frequent, and facial sensory loss or motor weakness may be present. Decerebrate attacks appear late in the disease.

Extraneural metastasis to the rest of the body is rare, and when it occurs, it is in the setting of relapse, more commonly in the era prior to routine chemotherapy.

Pathogenesis

[edit]

Medulloblastomas are usually found in the vicinity of the fourth ventricle, between the brainstem and the cerebellum. Tumors with similar appearance and characteristics originate in other parts of the brain, but they are not identical to medulloblastoma.[7]

Although medulloblastomas are thought to originate from immature or embryonal cells at their earliest stage of development, the cell of origin depends on the subgroup of medulloblastoma. WNT tumors originate from the lower rhombic lip of the brainstem, while SHH tumors originate from the external granular layer.[8]

Currently, medulloblastomas are thought to arise from cerebellar stem cells that have been prevented from dividing and differentiating into their normal cell types. This accounts for the histologic variants seen on biopsy. Both perivascular pseudorosette and Homer Wright pseudorosette formations are highly characteristic of medulloblastomas and are seen in up to half of cases.[9] The classic rosette with tumor cells around a central lumen can be seen.[10]

In the past, medulloblastoma was classified using histology, but integrated genomic studies have revealed that medulloblastoma is composed of four distinct molecular and clinical variants termed WNT/β-catenin, Sonic Hedgehog, Group 3, and Group 4.[11] Of these subgroups, WNT patients have an excellent prognosis and group 3 patients have a poor prognosis. Also, a subgroup-specific alternative splicing further confirms the existence of distinct subgroups and highlights the transcriptional heterogeneity between subgroups.[12] Amplification of the Sonic Hedgehog pathway is the best characterized subgroup, with 25% of human tumors having mutations in Patched, Sufu (Suppressor of Fused Homolog), Smoothened, or other genes in this pathway.[13][14] Medulloblastomas are also seen in Gorlin syndrome as well as Turcot syndrome. Recurrent mutations in the genes CTNNB1, PTCH1, MLL2, SMARCA4, DDX3X, CTDNEP1, KDM6A, and TBR1 were identified in individuals with medulloblastoma.[15] Additional pathways disrupted in some medulloblastomas include MYC, Notch, BMP, and TGF-β signaling pathways.[13][14][6][16][17][18][19][3][excessive citations]

Diagnosis

[edit]

The tumor is distinctive on T1- and T2-weighted MRI with heterogeneous enhancement and a typical location adjacent to and extension into the fourth ventricle. Histologically, the tumor is solid, pink-gray in color, and is well circumscribed. The tumor is very cellular, with high mitotic activity, little cytoplasm, and a tendency to form clusters and rosettes.

The Chang staging system can be used in making the diagnosis.[20]

DNA methylation profiling of medulloblastoma allows robust sub-classification and improved outcome prediction using formalin-fixed biopsies. [21]

Correct diagnosis of medulloblastoma may require ruling out atypical teratoid rhabdoid tumor.[22]

  • Cerebellar medulloblastoma in an adult
    Cerebellar medulloblastoma in an adult
  • Cerebellar medulloblastoma in an adult
    Cerebellar medulloblastoma in an adult

Treatment

[edit]

Treatment begins with maximal surgical removal of the tumor. The addition of radiation to the entire neuraxis and chemotherapy may increase the disease-free survival. This combination may permit a 5-year survival in more than 80% of cases. Some evidence indicates that proton beam irradiation reduces the impact of radiation on the cochlear and cardiovascular areas and reduces the cognitive late effects of cranial irradiation.[23][24]

The presence of desmoplastic features such as connective tissue formation offers a better prognosis. Prognosis is worse if the child is less than 3 years old, degree of resection is inadequate, or if any CSF, spinal, supratentorial, or systemic spread occurs. Dementia after radiotherapy and chemotherapy is a common outcome appearing two to four years following treatment. Side effects from radiation treatment can include cognitive impairment, psychiatric illness, bone growth retardation, hearing loss, and endocrine disruption.[3][6][16] Increased intracranial pressure may be controlled with corticosteroids or a ventriculoperitoneal shunt. An approach to monitor tumor development and treatment response by liquid biopsy is promising, but remains challenging.[25]

Chemotherapy

[edit]

Chemotherapy is often used as part of treatment. Evidence of benefit, however, is not clear as of 2013.[26] A few different chemotherapeutic regimens for medulloblastoma are used; most involve a combination of lomustine, cisplatin, carboplatin, vincristine, or cyclophosphamide. In younger patients (less than 3–4 years of age), chemotherapy can delay, or in some cases possibly even eliminate, the need for radiotherapy. However, both chemotherapy and radiotherapy often have long-term toxicity effects, including delays in physical and cognitive development, higher risk of second cancers, and increased cardiac disease risks.[27][28]

Outcomes

[edit]

Array-based karyotyping of 260 medulloblastomas resulted in the following clinical subgroups based on cytogenetic profiles:[29]

  • Poor prognosis: gain of 6q or amplification of MYC or MYCN
  • Intermediate: gain of 17q or an i(17q) without gain of 6q or amplification of MYC or MYCN
  • Excellent prognosis: 6q and 17q balanced or 6q deletion

Transcriptional profiling shows the existence of four main subgroups (Wnt, Shh, Group 3, and Group 4).[11]

  • Very good prognosis: WNT group, CTNNB1 mutation
  • Infants good prognosis, others intermediate: SHH group, PTCH1/SMO/SUFU mutation, GLI2 amplification, or MYCN amplification
  • Poor prognosis: Group 3, MYC amplification, photoreceptor/GABAergic gene expression
  • Intermediate prognosis: Group 4, gene expression of neuronal/glutamatergic, CDK6 amplification, MYCN amplification

Survival

[edit]

The historical cumulative relative survival rate for all age groups and histology follow-up was 60%, 52%, and 47% at 5 years, 10 years, and 20 years, respectively. Patients diagnosed with a medulloblastoma or PNET are 50 times more likely to die than a matched member of the general population. A population-based (SEER) 5-year relative survival rates indicated 69% overall: 72% in children (1–9 years) and 67% in adults (20+ years). The 20-year survival rate is 51% in children. Children and adults have different survival profiles, with adults faring worse than children only after the fourth year after diagnosis (after controlling for increased background mortality). Before the fourth year, survival probabilities are nearly identical.[5] Long-term sequelae of standard treatment include hypothalamic-pituitary and thyroid dysfunction and intellectual impairment. The hormonal and intellectual deficits created by these therapies causes significant impairment of the survivors.[30][self-published source?]

In current clinical studies, the patients are divided into low-, standard- and high-risk groups:

  • Depending on the study, healing rates of up to 100% are achieved in the low-risk group (usually WNT-activated).[31] The current efforts are therefore moving in the direction of reducing the intensity of the therapy and thus the negative long-term consequences while confirming the high healing rates.[32]
  • In the HIT-SIOP PNET 4 study, in which 340 children and adolescents of the standard-risk group between the ages of four and 21 from several European countries participated, the 5-year survival rate was between 85% and 87% depending on the randomization. Around 78% of the patients remained without relapse for 5 years and are therefore considered to be cured.[33] After a relapse, the prognosis was very poor. Despite intensive treatment, only four of 66 patients were still alive 5 years after a relapse.[34]
  • A US study involved 161 patients between the ages of three and 21 with a high-risk profile. Depending on the randomization, half of the patients additionally received carboplatin daily during the radiation. The 5-year survival rate of patients with carboplatin was 82%, those without 68%.[35] The European SIOP PNET 5 study is currently taking place and will run until April 2024, in which an attempt is made to confirm the promising results with carboplatin during irradiation in the standard risk group.[32]

Epidemiology

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Medulloblastomas affect just under two people per million per year, and affect children 10 times more than adults.[36] Medulloblastoma is the second-most frequent brain tumor in children after pilocytic astrocytoma[37] and the most common malignant brain tumor in children, comprising 14.5% of newly diagnosed brain tumors.[38] In adults, medulloblastoma is rare, comprising fewer than 2% of CNS malignancies.[39]

The rate of new cases of childhood medulloblastoma is higher in males (62%) than females (38%), a feature that is not seen in adults.[36][40] Medulloblastoma and other PNET`s are more prevalent in younger children than older children. About 40% of medulloblastoma patients are diagnosed before the age of five, 31% are between the ages of 5 and 9, 18.3% are between the ages of 10 and 14, and 12.7% are between the ages of 15 and 19.[41]

Research models

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Using gene transfer of SV40 large T-antigen in neuronal precursor cells of rats, a brain tumor model was established. The PNETs were histologically indistinguishable from the human counterparts and have been used to identify new genes involved in human brain tumor carcinogenesis.[42] The model was used to confirm p53 as one of the genes involved in human medulloblastomas, but since only about 10% of the human tumors showed mutations in that gene, the model can be used to identify the other binding partners of SV40 Large T- antigen, other than p53.[43][44] In a mouse model, high medulloblastoma frequency appears to be caused by the down regulation of Cxcl3, with Cxcl3 being induced by Tis21.[45] Consistently, the treatment with Cxcl3 completely prevents the growth of medulloblastoma lesions in a Shh-type mouse model of medulloblastoma.[46] Thus, CXCL3 is a target for medulloblastoma therapy.

References

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