CNS5:Medulloblastoma, WNT-activated: Difference between revisions

·      Monosomy 6 is the most frequently reported genomic alteration, occurring within 80-85% of cases and commonly co-occurring with ''CTNNB1'' somatic mutations<ref name=":6">{{Cite journal|last=Thompson|first=Margaret C.|last2=Fuller|first2=Christine|last3=Hogg|first3=Twala L.|last4=Dalton|first4=James|last5=Finkelstein|first5=David|last6=Lau|first6=Ching C.|last7=Chintagumpala|first7=Murali|last8=Adesina|first8=Adekunle|last9=Ashley|first9=David M.|date=2006-04-20|title=Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations|url=https://pubmed.ncbi.nlm.nih.gov/16567768|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=24|issue=12|pages=1924–1931|doi=10.1200/JCO.2005.04.4974|issn=1527-7755|pmid=16567768}}</ref><ref name=":1">{{Cite journal|last=Northcott|first=Paul A.|last2=Buchhalter|first2=Ivo|last3=Morrissy|first3=A. Sorana|last4=Hovestadt|first4=Volker|last5=Weischenfeldt|first5=Joachim|last6=Ehrenberger|first6=Tobias|last7=Gröbner|first7=Susanne|last8=Segura-Wang|first8=Maia|last9=Zichner|first9=Thomas|date=2017-07-19|title=The whole-genome landscape of medulloblastoma subtypes|url=https://pubmed.ncbi.nlm.nih.gov/28726821|journal=Nature|volume=547|issue=7663|pages=311–317|doi=10.1038/nature22973|issn=1476-4687|pmc=5905700|pmid=28726821}}</ref><ref name=":7">{{Cite journal|last=Clifford|first=Steven C.|last2=Lusher|first2=Meryl E.|last3=Lindsey|first3=Janet C.|last4=Langdon|first4=Jacqueline A.|last5=Gilbertson|first5=Richard J.|last6=Straughton|first6=Debbie|last7=Ellison|first7=David W.|date=2006-11|title=Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis|url=https://pubmed.ncbi.nlm.nih.gov/17172831|journal=Cell Cycle (Georgetown, Tex.)|volume=5|issue=22|pages=2666–2670|doi=10.4161/cc.5.22.3446|issn=1551-4005|pmid=17172831}}</ref><ref name=":2">{{Cite journal|last=Northcott|first=Paul A.|last2=Robinson|first2=Giles W.|last3=Kratz|first3=Christian P.|last4=Mabbott|first4=Donald J.|last5=Pomeroy|first5=Scott L.|last6=Clifford|first6=Steven C.|last7=Rutkowski|first7=Stefan|last8=Ellison|first8=David W.|last9=Malkin|first9=David|date=2019-02-14|title=Medulloblastoma|url=https://pubmed.ncbi.nlm.nih.gov/30765705|journal=Nature Reviews. Disease Primers|volume=5|issue=1|pages=11|doi=10.1038/s41572-019-0063-6|issn=2056-676X|pmid=30765705}}</ref>.

·      With the exception of monosomy 6, this medulloblastoma subtype usually has a balanced genome<ref name=":8">{{Cite journal|last=Northcott|first=Paul A.|last2=Shih|first2=David J. H.|last3=Peacock|first3=John|last4=Garzia|first4=Livia|last5=Morrissy|first5=A. Sorana|last6=Zichner|first6=Thomas|last7=Stütz|first7=Adrian M.|last8=Korshunov|first8=Andrey|last9=Reimand|first9=Jüri|date=2012-08-02|title=Subgroup-specific structural variation across 1,000 medulloblastoma genomes|url=https://pubmed.ncbi.nlm.nih.gov/22832581|journal=Nature|volume=488|issue=7409|pages=49–56|doi=10.1038/nature11327|issn=1476-4687|pmc=3683624|pmid=22832581}}</ref>

|Yes – Monosomy 6 is associated with very good outcome in pediatric patients (PDQ)<ref>{{Cite journal|last=Pietsch|first=Torsten|last2=Schmidt|first2=Rene|last3=Remke|first3=Marc|last4=Korshunov|first4=Andrey|last5=Hovestadt|first5=Volker|last6=Jones|first6=David T. W.|last7=Felsberg|first7=Jörg|last8=Kaulich|first8=Kerstin|last9=Goschzik|first9=Tobias|date=2014-07|title=Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort|url=https://pubmed.ncbi.nlm.nih.gov/24791927|journal=Acta Neuropathologica|volume=128|issue=1|pages=137–149|doi=10.1007/s00401-014-1276-0|issn=1432-0533|pmc=4059991|pmid=24791927}}</ref><ref name=":9">{{Cite journal|last=Ellison|first=David W.|last2=Dalton|first2=James|last3=Kocak|first3=Mehmet|last4=Nicholson|first4=Sarah Leigh|last5=Fraga|first5=Charles|last6=Neale|first6=Geoff|last7=Kenney|first7=Anna M.|last8=Brat|first8=Dan J.|last9=Perry|first9=Arie|date=2011-03|title=Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups|url=https://pubmed.ncbi.nlm.nih.gov/21267586|journal=Acta Neuropathologica|volume=121|issue=3|pages=381–396|doi=10.1007/s00401-011-0800-8|issn=1432-0533|pmc=3519926|pmid=21267586}}</ref><ref>{{Cite journal|last=Gajjar|first=Amar|last2=Chintagumpala|first2=Murali|last3=Ashley|first3=David|last4=Kellie|first4=Stewart|last5=Kun|first5=Larry E.|last6=Merchant|first6=Thomas E.|last7=Woo|first7=Shaio|last8=Wheeler|first8=Greg|last9=Ahern|first9=Valerie|date=2006-10|title=Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial|url=https://pubmed.ncbi.nlm.nih.gov/17012043|journal=The Lancet. Oncology|volume=7|issue=10|pages=813–820|doi=10.1016/S1470-2045(06)70867-1|issn=1470-2045|pmid=17012043}}</ref>.

However, absence of monosomy 6 does not rule out the possibility of WNT-activated medulloblastoma<ref name=":1" />.  Furthermore, adult patients will be misdiagnosed if monosomy 6 is used alone as a diagnostic factor, as they cluster within WNT subtype β, which characteristically lacks this finding<ref name=":10">{{Cite journal|last=Cavalli|first=Florence M. G.|last2=Remke|first2=Marc|last3=Rampasek|first3=Ladislav|last4=Peacock|first4=John|last5=Shih|first5=David J. H.|last6=Luu|first6=Betty|last7=Garzia|first7=Livia|last8=Torchia|first8=Jonathon|last9=Nor|first9=Carolina|date=2017-06-12|title=Intertumoral Heterogeneity within Medulloblastoma Subgroups|url=https://pubmed.ncbi.nlm.nih.gov/28609654|journal=Cancer Cell|volume=31|issue=6|pages=737–754.e6|doi=10.1016/j.ccell.2017.05.005|issn=1878-3686|pmc=6163053|pmid=28609654}}</ref>.  

Outside of monosomy 6, other cytogenetic findings are rarely observed in this subtype<ref name=":11">{{Cite journal|last=Northcott|first=Paul A.|last2=Jones|first2=David T. W.|last3=Kool|first3=Marcel|last4=Robinson|first4=Giles W.|last5=Gilbertson|first5=Richard J.|last6=Cho|first6=Yoon-Jae|last7=Pomeroy|first7=Scott L.|last8=Korshunov|first8=Andrey|last9=Lichter|first9=Peter|date=2012-12|title=Medulloblastomics: the end of the beginning|url=https://pubmed.ncbi.nlm.nih.gov/23175120|journal=Nature Reviews. Cancer|volume=12|issue=12|pages=818–834|doi=10.1038/nrc3410|issn=1474-1768|pmc=3889646|pmid=23175120}}</ref>.

|Yes – Favorable prognosis<ref name=":3" />

*Medulloblastoma is the most common malignant pediatric brain tumor, though it can also occur in adults<ref name=":11" /><ref name=":5" /><ref>{{Cite journal|last=Ostrom|first=Quinn T.|last2=Gittleman|first2=Haley|last3=Truitt|first3=Gabrielle|last4=Boscia|first4=Alexander|last5=Kruchko|first5=Carol|last6=Barnholtz-Sloan|first6=Jill S.|date=2018-10-01|title=CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011-2015|url=https://pubmed.ncbi.nlm.nih.gov/30445539|journal=Neuro-Oncology|volume=20|issue=suppl_4|pages=iv1–iv86|doi=10.1093/neuonc/noy131|issn=1523-5866|pmc=6129949|pmid=30445539}}</ref>. Recurrent histopathologic, radiologic, and genomic findings have resulted in the establishment of four primary molecularly-defined subgroups: WNT-activated; SHH-activated and ''TP53''-wildtype; SHH-activated and ''TP53''-mutant; and non-WNT/non-SHH<ref name=":12">{{Cite journal|last=Kool|first=Marcel|last2=Korshunov|first2=Andrey|last3=Remke|first3=Marc|last4=Jones|first4=David T. W.|last5=Schlanstein|first5=Maria|last6=Northcott|first6=Paul A.|last7=Cho|first7=Yoon-Jae|last8=Koster|first8=Jan|last9=Schouten-van Meeteren|first9=Antoinette|date=2012-04|title=Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas|url=https://pubmed.ncbi.nlm.nih.gov/22358457|journal=Acta Neuropathologica|volume=123|issue=4|pages=473–484|doi=10.1007/s00401-012-0958-8|issn=1432-0533|pmc=3306778|pmid=22358457}}</ref>. Somatic variants that cause activation of these pathways (e.g., gain-of-function variants in ''CTNNB1'' for the WNT pathway) are considered diagnostic. Of note, a subset of cases can be due to germline loss-of-function variants in the ''APC'' gene (which also result in activation of WNT signaling), which are representative of the spectrum of disorders known as Familial Adenomatous Polyposis (historically referred to as Gardner syndrome; MIM: 175100). In summary, medulloblastoma, WNT-activated, is an embryonal tumor originating in the dorsal brainstem characterized by activation of the WNT signaling pathway.

*This subtype accounts for approximately 10% of all medulloblastomas<ref name=":8" /><ref name=":11" /><ref name=":12" /><ref name=":13">{{Cite journal|last=Taylor|first=Michael D.|last2=Northcott|first2=Paul A.|last3=Korshunov|first3=Andrey|last4=Remke|first4=Marc|last5=Cho|first5=Yoon-Jae|last6=Clifford|first6=Steven C.|last7=Eberhart|first7=Charles G.|last8=Parsons|first8=D. Williams|last9=Rutkowski|first9=Stefan|date=2012-04|title=Molecular subgroups of medulloblastoma: the current consensus|url=https://pubmed.ncbi.nlm.nih.gov/22134537|journal=Acta Neuropathologica|volume=123|issue=4|pages=465–472|doi=10.1007/s00401-011-0922-z|issn=1432-0533|pmc=3306779|pmid=22134537}}</ref>.

*Most frequently observed in older children (median age 10 years<ref name=":8" /><ref name=":11" />; with a balanced male:female ratio<ref name=":13" />; Of note, this medulloblastoma subtype rarely occurs in infants and rarely metastasizes<ref>{{Cite journal|last=Kumar|first=Rahul|last2=Liu|first2=Anthony P. Y.|last3=Northcott|first3=Paul A.|date=2020-05|title=Medulloblastoma genomics in the modern molecular era|url=https://pubmed.ncbi.nlm.nih.gov/31799776|journal=Brain Pathology (Zurich, Switzerland)|volume=30|issue=3|pages=679–690|doi=10.1111/bpa.12804|issn=1750-3639|pmc=8018047|pmid=31799776}}</ref>

*Excellent prognosis for patients <16 years of age at diagnosis: >95% have a five-year overall survival<ref name=":6" /><ref name=":7" /><ref>{{Cite journal|last=Ellison|first=David W.|last2=Onilude|first2=Olabisi E.|last3=Lindsey|first3=Janet C.|last4=Lusher|first4=Meryl E.|last5=Weston|first5=Claire L.|last6=Taylor|first6=Roger E.|last7=Pearson|first7=Andrew D.|last8=Clifford|first8=Steven C.|last9=United Kingdom Children's Cancer Study Group Brain Tumour Committee|date=2005-11-01|title=beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee|url=https://pubmed.ncbi.nlm.nih.gov/16258095|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=23|issue=31|pages=7951–7957|doi=10.1200/JCO.2005.01.5479|issn=0732-183X|pmid=16258095}}</ref><ref>{{Cite journal|last=Fattet|first=Sarah|last2=Haberler|first2=Christine|last3=Legoix|first3=Patricia|last4=Varlet|first4=Pascale|last5=Lellouch-Tubiana|first5=Arielle|last6=Lair|first6=Severine|last7=Manie|first7=Elodie|last8=Raquin|first8=Marie-Anne|last9=Bours|first9=Danielle|date=2009-05|title=Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics|url=https://pubmed.ncbi.nlm.nih.gov/19197950|journal=The Journal of Pathology|volume=218|issue=1|pages=86–94|doi=10.1002/path.2514|issn=1096-9896|pmid=19197950}}</ref>

*Accounts for ~15% of all adult medulloblastomas, which may have a worse prognosis than pediatric WNT-activated medulloblastoma<ref name=":10" /><ref>{{Cite journal|last=Remke|first=Marc|last2=Hielscher|first2=Thomas|last3=Northcott|first3=Paul A.|last4=Witt|first4=Hendrik|last5=Ryzhova|first5=Marina|last6=Wittmann|first6=Andrea|last7=Benner|first7=Axel|last8=von Deimling|first8=Andreas|last9=Scheurlen|first9=Wolfram|date=2011-07-01|title=Adult medulloblastoma comprises three major molecular variants|url=https://pubmed.ncbi.nlm.nih.gov/21632505|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=29|issue=19|pages=2717–2723|doi=10.1200/JCO.2011.34.9373|issn=1527-7755|pmid=21632505}}</ref><ref>{{Cite journal|last=Clifford|first=Steven C.|last2=Lannering|first2=Birgitta|last3=Schwalbe|first3=Ed C.|last4=Hicks|first4=Debbie|last5=O'Toole|first5=Kieran|last6=Nicholson|first6=Sarah Leigh|last7=Goschzik|first7=Tobias|last8=Zur Mühlen|first8=Anja|last9=Figarella-Branger|first9=Dominique|date=2015-11-17|title=Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial|url=https://pubmed.ncbi.nlm.nih.gov/26420814|journal=Oncotarget|volume=6|issue=36|pages=38827–38839|doi=10.18632/oncotarget.5149|issn=1949-2553|pmc=4770740|pmid=26420814}}</ref><ref>{{Cite journal|last=Zhao|first=Fu|last2=Ohgaki|first2=Hiroko|last3=Xu|first3=Lei|last4=Giangaspero|first4=Felice|last5=Li|first5=Chunde|last6=Li|first6=Peng|last7=Yang|first7=Zhijun|last8=Wang|first8=Bo|last9=Wang|first9=Xingchao|date=2016-07|title=Molecular subgroups of adult medulloblastoma: a long-term single-institution study|url=https://pubmed.ncbi.nlm.nih.gov/27106407|journal=Neuro-Oncology|volume=18|issue=7|pages=982–990|doi=10.1093/neuonc/now050|issn=1523-5866|pmc=4896550|pmid=27106407}}</ref>

*Cranial and spinal MRI are used for diagnosis<ref name=":2" />

*Cerebellum, cerebellar peduncle or fourth ventricle<ref name=":4" /><ref>{{Cite journal|last=Patay|first=Z.|last2=DeSain|first2=L. A.|last3=Hwang|first3=S. N.|last4=Coan|first4=A.|last5=Li|first5=Y.|last6=Ellison|first6=D. W.|date=2015-12|title=MR Imaging Characteristics of Wingless-Type-Subgroup Pediatric Medulloblastoma|url=https://pubmed.ncbi.nlm.nih.gov/26338912|journal=AJNR. American journal of neuroradiology|volume=36|issue=12|pages=2386–2393|doi=10.3174/ajnr.A4495|issn=1936-959X|pmc=4827780|pmid=26338912}}</ref>

*Origin: cells in the extracerebellar lower rhombic lip<ref>{{Cite journal|last=Gibson|first=Paul|last2=Tong|first2=Yiai|last3=Robinson|first3=Giles|last4=Thompson|first4=Margaret C.|last5=Currle|first5=D. Spencer|last6=Eden|first6=Christopher|last7=Kranenburg|first7=Tanya A.|last8=Hogg|first8=Twala|last9=Poppleton|first9=Helen|date=2010-12-23|title=Subtypes of medulloblastoma have distinct developmental origins|url=https://pubmed.ncbi.nlm.nih.gov/21150899|journal=Nature|volume=468|issue=7327|pages=1095–1099|doi=10.1038/nature09587|issn=1476-4687|pmc=3059767|pmid=21150899}}</ref>

*Metastases are much less likely to occur in this subtype relative to other MB subtypes; staging is performed using the Chang classification<ref>{{Cite journal|last=Chang|first=C. H.|last2=Housepian|first2=E. M.|last3=Herbert|first3=C.|date=1969-12|title=An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas|url=https://pubmed.ncbi.nlm.nih.gov/4983156|journal=Radiology|volume=93|issue=6|pages=1351–1359|doi=10.1148/93.6.1351|issn=0033-8419|pmid=4983156}}</ref>

*The WNT-activated subgroup is most commonly observed as an embryonal tumor with classic histology located in the cerebellum and/or fourth ventricle<ref name=":4" />

*Rare examples with anaplastic histology have been described<ref name=":9" /><ref>{{Cite journal|last=Kaur|first=Kavneet|last2=Jha|first2=Prerana|last3=Pathak|first3=Pankaj|last4=Suri|first4=Vaishali|last5=Sharma|first5=Mehar Chand|last6=Garg|first6=Ajay|last7=Suri|first7=Ashish|last8=Sarkar|first8=Chitra|date=2019-07|title=Approach to molecular subgrouping of medulloblastomas: Comparison of NanoString nCounter assay versus combination of immunohistochemistry and fluorescence in-situ hybridization in resource constrained centres|url=https://pubmed.ncbi.nlm.nih.gov/31104222|journal=Journal of Neuro-Oncology|volume=143|issue=3|pages=393–403|doi=10.1007/s11060-019-03187-y|issn=1573-7373|pmid=31104222}}</ref>

*Molecular subtyping may be performed immunohistochemically using Filamin A, YAP1, GAB1 and beta-catenin<ref name=":9" /><ref name=":4" />