Changes

==Primary Author(s)*==

==Primary Author(s)*==

Madina Sukhanova, PhD, FACMG Northwestern University

Madina Sukhanova, PhD FACMG Northwestern University

__TOC__

__TOC__

==Cancer Category/Type==

==Cancer Category/Type==

==Cancer Sub-Classification / Subtype==

==Cancer Sub-Classification / Subtype==

==Epidemiology / Prevalence==

==Epidemiology / Prevalence==

The 2021 WHO classified this entity as pediatric-type based on well defined studies characterized by negative molecular features of H3 and IDH  <ref name=":1" /><ref>{{Cite journal|last=Mackay|first=Alan|last2=Burford|first2=Anna|last3=Molinari|first3=Valeria|last4=Jones|first4=David T. W.|last5=Izquierdo|first5=Elisa|last6=Brouwer-Visser|first6=Jurriaan|last7=Giangaspero|first7=Felice|last8=Haberler|first8=Christine|last9=Pietsch|first9=Torsten|date=2018-05-14|title=Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial|url=https://pubmed.ncbi.nlm.nih.gov/29763623|journal=Cancer Cell|volume=33|issue=5|pages=829–842.e5|doi=10.1016/j.ccell.2018.04.004|issn=1878-3686|pmc=5956280|pmid=29763623}}</ref><ref name=":2">{{Cite journal|last=Korshunov|first=Andrey|last2=Schrimpf|first2=Daniel|last3=Ryzhova|first3=Marina|last4=Sturm|first4=Dominik|last5=Chavez|first5=Lukas|last6=Hovestadt|first6=Volker|last7=Sharma|first7=Tanvi|last8=Habel|first8=Antje|last9=Burford|first9=Anna|date=2017-09|title=H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers|url=https://pubmed.ncbi.nlm.nih.gov/28401334|journal=Acta Neuropathologica|volume=134|issue=3|pages=507–516|doi=10.1007/s00401-017-1710-1|issn=1432-0533|pmid=28401334}}</ref> which have focused only on pediatric patients; thus, the frequency of this tumor type in adults in unknown. Median reported age of patients at the time of diagnosis was 9.8 years. One study reported male prevalence.<ref name=":2" />

The 2021 WHO classified this entity as pediatric-type, based on well defined studies focusing on a pediatric population with gliomas characterised by IDH-/H3-wildtype status<ref name=":1" /><ref>{{Cite journal|last=Mackay|first=Alan|last2=Burford|first2=Anna|last3=Molinari|first3=Valeria|last4=Jones|first4=David T. W.|last5=Izquierdo|first5=Elisa|last6=Brouwer-Visser|first6=Jurriaan|last7=Giangaspero|first7=Felice|last8=Haberler|first8=Christine|last9=Pietsch|first9=Torsten|date=2018-05-14|title=Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial|url=https://pubmed.ncbi.nlm.nih.gov/29763623|journal=Cancer Cell|volume=33|issue=5|pages=829–842.e5|doi=10.1016/j.ccell.2018.04.004|issn=1878-3686|pmc=5956280|pmid=29763623}}</ref><ref name=":2">{{Cite journal|last=Korshunov|first=Andrey|last2=Schrimpf|first2=Daniel|last3=Ryzhova|first3=Marina|last4=Sturm|first4=Dominik|last5=Chavez|first5=Lukas|last6=Hovestadt|first6=Volker|last7=Sharma|first7=Tanvi|last8=Habel|first8=Antje|last9=Burford|first9=Anna|date=2017-09|title=H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers|url=https://pubmed.ncbi.nlm.nih.gov/28401334|journal=Acta Neuropathologica|volume=134|issue=3|pages=507–516|doi=10.1007/s00401-017-1710-1|issn=1432-0533|pmid=28401334}}</ref>. Therefore, the frequency of this tumor type in adults in unknown. The median reported age of patients at the time of diagnosis was 9.8 years. One study reported male prevalence.<ref name=":2" />

==Clinical Features==

==Clinical Features==

Other sites: brainstem, and cerebellum.<ref name=":2" />

Other sites: brainstem, and cerebellum.<ref name=":2" />

Although most of molecular subtypes of dpHGG involve supratentorial brain (96% of dpHGG RTK2, 86% of dpHGG MYCN, and 82% of dpHGG RTK1 tumors), 4% of dpHGG RTK2, 14% of dpHGG MYCN, and 18% of dpHGG RTK1 cases can involve infratentorial/brainstem sites.<ref name=":2" />

Although most of molecular subtypes of dpHGG involve the supratentorial compartment (96% of dpHGG RTK2; 86% of dpHGG MYCN; 82% of dpHGG RTK1 tumors), a lesser proporton can involve infratentorial/brainstem sites (4% of dpHGG RTK2;14% of dpHGG MYCN; 18% of dpHGG RTK1 cases).<ref name=":2" />

==Morphologic Features==

==Morphologic Features==

Morphology of dHGGs, H3-/IDH-wildtype, is consistent with glioblastoma-like features with high cellularity, mitotic activity, microvascular proliferation, and necrosis; however, undifferentiated morphology and areas of glial differentiation can also be noted. pHGG MYCN molecular subtype often consists of large cells with distinct nucleoli, spindle-shaped and epithelioid cells and also reveals areas of diffuse infiltration and circumscribed nodules.<ref name=":3" />  

The morphology of dHGGs, H3-/IDH-wildtype, shows glioblastoma-like features with high cellularity, mitotic activity, microvascular proliferation, and necrosis; however, undifferentiated, primitive morphology and areas of glial differentiation can also be noted within the same case. The pHGG MYCN molecular subtype often consists of large cells with distinct nucleoli admixed with spindle-shaped and epithelioid cells; the architecture of these tumours can show areas of diffuse infiltration, in combinaiton with circumscribed nodules.<ref name=":3" />  

==Immunophenotype==

==Immunophenotype==

!Finding!!Marker

!Finding!!Marker

|-

|-

|Positive (universal)||Neoplastic glial component – GFAP, and/or OLIG2.<ref name=":0" /><ref name=":1" />

|Positive (universal)||Neoplastic glial component – GFAP, and/or OLIG2<ref name=":0" /><ref name=":1" />

|-

|-

|Positive (subset)||dpHGG MYCN molecular subtype can be positive for neuronal markers.

|Positive (subset)||dpHGG MYCN molecular subtype can be positive for neuronal markers

|-

|-

|Negative (universal)|| IDH1 R132H (normal retained pattern of staining).

|Negative (universal)|| IDH1 R132H

H3 p.K28me3 (K27me4) (preserved expression).<ref name=":3" />

H3 p.K28me3 (K27me3) (preserved expression)<ref name=":3" />

|-

|-

|Negative (subset)||dpHGG MYCN molecular subtype can be negative for glial marker GFAP, and/or OLIG2.

|Negative (subset)||dpHGG MYCN molecular subtype can be negative for glial marker GFAP, and/or OLIG2

|}

|}

|2

|2

|Amplification

|Amplification

|chr2:15,940,550-15,947,004 [hg38]

|chr2:15,940,550-15,947,004 [GRCh38]

|2p24.3

|2p24.3

|Yes [50% dpHGG MYCN subtype]

|Yes [50% dpHGG MYCN subtype]

|Yes, worst OS<ref name=":1" /><ref name=":2" />

|Worse OS<ref name=":1" /><ref name=":2" />

|No

|Unknown

|MYCN amplification<ref name=":2" /><ref name=":5">{{Cite journal|last=Capper|first=David|last2=Jones|first2=David T. W.|last3=Sill|first3=Martin|last4=Hovestadt|first4=Volker|last5=Schrimpf|first5=Daniel|last6=Sturm|first6=Dominik|last7=Koelsche|first7=Christian|last8=Sahm|first8=Felix|last9=Chavez|first9=Lukas|date=2018-03-22|title=DNA methylation-based classification of central nervous system tumours|url=https://pubmed.ncbi.nlm.nih.gov/29539639|journal=Nature|volume=555|issue=7697|pages=469–474|doi=10.1038/nature26000|issn=1476-4687|pmc=6093218|pmid=29539639}}</ref>

|MYCN amplification<ref name=":2" /><ref name=":5">{{Cite journal|last=Capper|first=David|last2=Jones|first2=David T. W.|last3=Sill|first3=Martin|last4=Hovestadt|first4=Volker|last5=Schrimpf|first5=Daniel|last6=Sturm|first6=Dominik|last7=Koelsche|first7=Christian|last8=Sahm|first8=Felix|last9=Chavez|first9=Lukas|date=2018-03-22|title=DNA methylation-based classification of central nervous system tumours|url=https://pubmed.ncbi.nlm.nih.gov/29539639|journal=Nature|volume=555|issue=7697|pages=469–474|doi=10.1038/nature26000|issn=1476-4687|pmc=6093218|pmid=29539639}}</ref>

|-

|-

|2

|2

|Amplification

|Amplification

|Unknown

|chr2:8,682,056-8,684,461 [GRCh38]

|2p25.1

|2p25.1

|No, but recurrent secondary finding [66% of dpHGG MYCN subtype]

|No, but recurrent secondary finding [66% of dpHGG MYCN subtype]

|Unknown

|Unknown

|No

|Unknown

|ID2 amplification is often (66%) co-amplified with MYCN<ref name=":2" /><ref name=":5" />

|ID2 amplification is often (66%) co-amplified with MYCN<ref name=":2" /><ref name=":5" />

|-

|-

|4

|4

|Amplification/Mutation

|Amplification/Mutation

|4:51819533-54425718 [GRCh38]

|chr4:51819533-54425718 [GRCh38]

|4q12

|4q12

|Yes [33% of dpHGG RTK1 subtype]

|Yes [33% of dpHGG RTK1 subtype]

|No<ref name=":2" />

|No<ref name=":2" />

|No

|Unknown

|PDGFRA alterations<ref name=":2" />

|PDGFRA alterations<ref name=":2" /><ref name=":6">WHO Classification of Tumours Editorial Board. Central nervous system tumours. Lyon (France): International Agency for Research on Cancer; 2021. (WHO classification of tumours series, 5th ed.; vol. 6). <nowiki>https://publications.iarc.fr/601</nowiki>.</ref>

|-

|-

|7

|7

|Yes [50% of dpHGG RTK2 subtype]

|Yes [50% of dpHGG RTK2 subtype]

|No<ref name=":2" />

|No<ref name=":2" />

|No

|Unknown

|EGFR amplification<ref name=":2" />

|EGFR amplification<ref name=":2" />

|-

|-

|No, but recurrent in dpHGG MYCN subtype [8%]

|No, but recurrent in dpHGG MYCN subtype [8%]

|Unknown

|Unknown

|No

|Unknown

|MYC amplification

|MYC amplification<ref name=":2" />

|-

|-

|9

|9

|Homozygous loss

|Homozygous loss

|Variable

|CDKN2A - chr9:21,967,752-21,995,324 [GRCh38]

|9p21.3

|9p21.3

|No

|No

|Yes

|Worse outcome<ref name=":2" />

|No

|No

|Deletions result in bi-allelic loss of CDKN2A/B: seen in 6% MYCN subtype, 27% RTK1 subtype; 72% RTK2 subtype.<ref name=":2" /><ref name=":4" />

|Unknown

|Ampifications of CDK4/6 seen in 22% MYCN subtype, 9% RTK1 subtype; 17% RTK2 subtype.<ref name=":2" />

|}

|}

==Characteristic Chromosomal Patterns==

==Characteristic Chromosomal Patterns==

!Notes

!Notes

|-

|-

|Gain of chromosome 7 and loss of chromosome 10

|Chromosome 7 gain

|No

|No

|Yes

|Yes

|No

|No

|Recurrent finding in 42~47% MYCN subtype; 12% RTK1 subtype; 28~50% RTK2 subtype.<ref name=":2" />

|Recurrent finding in 47% MYCN subtype; 12% RTK1 subtype; 28% RTK2 subtype.<ref name=":2" />

|Recurrent finding in 42% MYCN subtype; 12% RTK1 subtype; 50% RTK2 subtype.<ref name=":2" />

|}

|}

==Gene Mutations (SNV/INDEL)==

==Gene Mutations (SNV/INDEL)==

!Therapeutic Significance (Yes, No or Unknown)

!Therapeutic Significance (Yes, No or Unknown)

!Notes

!Notes

|-

|-

|PDGFRA

|PDGFRA

|Receptor

|Receptor

|

|Not stated in literature; referred to in the WHO Classification<ref name=":6" />

|unclear

|unclear

|IDH1/2, H3<br />

|IDH1/2, H3<br />

|Unknown

|Unknown

|Unknown

|Unknown

|No

|Unknown

|

|

|-

|-

|Unknown

|Unknown

|Unknown

|Unknown

|No

|Unknown

|

|

|-

|-

|Unknown

|Unknown

|Unknown

|Unknown

|No

|Unknown

|

|

|}

|}

==Epigenomic Alterations==

==Epigenomic Alterations==

Methylation profiling can be used in the diagnosis of this tumor entity and can help to differentiate between three molecular profiles, pHGG RTK1, pHGG RTK2, and pHGG MYCN. Methylation of MGMT has been noted in 11% of pHGG MYCN cases and 18% of RTK1 cases.<ref name=":2" />

Methylation profiling can be used in the diagnosis of this tumor entity and can help to differentiate between three molecular profiles, pHGG RTK1, pHGG RTK2, and pHGG MYCN. Methylation of MGMT has been noted in 11% of pHGG MYCN cases and 18% of RTK1 cases.<ref name=":2" /> ''MGMT'' promoter methylation can be seen in 18% of the RTK1 subtype, 11% in the MYCN subtype and is rare in the RTK2 subtype.

==Genes and Main Pathways Involved==

==Genes and Main Pathways Involved==

The pHGG, H3/IDH-wildtype frequently reveals variants in genes encoding members of the TAS/MAPK and PI3K pathways.  

The pHGG, H3/IDH-wildtype frequently reveals variants in genes encoding members of the TAS/MAPK and PI3K pathways.<ref name=":4" />

{| class="wikitable sortable"

{| class="wikitable sortable"

|-

|-

==Genetic Diagnostic Testing Methods==

==Genetic Diagnostic Testing Methods==

* ·Chromosome microarray  

*Chromosome microarray  

* ·Next generation sequencing  

*Next generation sequencing  

* ·DNA methylation profiling

*DNA methylation profiling

==Familial Forms==

==Familial Forms==

Germline mutations of genes involved in the mismatch repair (MMR) system can be associated with a proportion of pHGG cases,<ref>{{Cite journal|last=Dodgshun|first=Andrew J.|last2=Fukuoka|first2=Kohei|last3=Edwards|first3=Melissa|last4=Bianchi|first4=Vanessa J.|last5=Das|first5=Anirban|last6=Sexton-Oates|first6=Alexandra|last7=Larouche|first7=Valérie|last8=Vanan|first8=Magimairajan I.|last9=Lindhorst|first9=Scott|date=2020-11|title=Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns|url=https://pubmed.ncbi.nlm.nih.gov/32895736|journal=Acta Neuropathologica|volume=140|issue=5|pages=765–776|doi=10.1007/s00401-020-02209-8|issn=1432-0533|pmid=32895736}}</ref><ref>{{Cite journal|last=Alphones|first=Sheena|last2=Chatterjee|first2=Uttara|last3=Singh|first3=Angad|last4=Das|first4=Anirban|last5=Zameer|first5=Lateef|last6=Achari|first6=Rimpa|last7=Bhattacharya|first7=Arpita|last8=Roy|first8=Paromita|date=2021-08|title=Immunohistochemical screening for mismatch repair protein deficiency in paediatric high-grade gliomas - institutional experience and review of literature|url=https://pubmed.ncbi.nlm.nih.gov/34097097|journal=Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery|volume=37|issue=8|pages=2521–2530|doi=10.1007/s00381-021-05229-1|issn=1433-0350|pmid=34097097}}</ref><ref>{{Cite journal|last=Amayiri|first=Nisreen|last2=Tabori|first2=Uri|last3=Campbell|first3=Brittany|last4=Bakry|first4=Doua|last5=Aronson|first5=Melyssa|last6=Durno|first6=Carol|last7=Rakopoulos|first7=Patricia|last8=Malkin|first8=David|last9=Qaddoumi|first9=Ibrahim|date=2016-01-15|title=High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan|url=https://pubmed.ncbi.nlm.nih.gov/26293621|journal=International Journal of Cancer|volume=138|issue=2|pages=380–385|doi=10.1002/ijc.29724|issn=1097-0215|pmid=26293621}}</ref> typically of the pHGG RTK1 subtype.

Germline mutations of genes involved in the mismatch repair (MMR) system can be associated with a proportion of pHGG cases,<ref>{{Cite journal|last=Dodgshun|first=Andrew J.|last2=Fukuoka|first2=Kohei|last3=Edwards|first3=Melissa|last4=Bianchi|first4=Vanessa J.|last5=Das|first5=Anirban|last6=Sexton-Oates|first6=Alexandra|last7=Larouche|first7=Valérie|last8=Vanan|first8=Magimairajan I.|last9=Lindhorst|first9=Scott|date=2020-11|title=Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns|url=https://pubmed.ncbi.nlm.nih.gov/32895736|journal=Acta Neuropathologica|volume=140|issue=5|pages=765–776|doi=10.1007/s00401-020-02209-8|issn=1432-0533|pmid=32895736}}</ref><ref>{{Cite journal|last=Alphones|first=Sheena|last2=Chatterjee|first2=Uttara|last3=Singh|first3=Angad|last4=Das|first4=Anirban|last5=Zameer|first5=Lateef|last6=Achari|first6=Rimpa|last7=Bhattacharya|first7=Arpita|last8=Roy|first8=Paromita|date=2021-08|title=Immunohistochemical screening for mismatch repair protein deficiency in paediatric high-grade gliomas - institutional experience and review of literature|url=https://pubmed.ncbi.nlm.nih.gov/34097097|journal=Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery|volume=37|issue=8|pages=2521–2530|doi=10.1007/s00381-021-05229-1|issn=1433-0350|pmid=34097097}}</ref><ref>{{Cite journal|last=Amayiri|first=Nisreen|last2=Tabori|first2=Uri|last3=Campbell|first3=Brittany|last4=Bakry|first4=Doua|last5=Aronson|first5=Melyssa|last6=Durno|first6=Carol|last7=Rakopoulos|first7=Patricia|last8=Malkin|first8=David|last9=Qaddoumi|first9=Ibrahim|date=2016-01-15|title=High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan|url=https://pubmed.ncbi.nlm.nih.gov/26293621|journal=International Journal of Cancer|volume=138|issue=2|pages=380–385|doi=10.1002/ijc.29724|issn=1097-0215|pmid=26293621}}</ref> typically of the pHGG RTK1 subtype.

==References==

==References==

<references />

<references />

 

 

==Notes==

==Notes==

<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.

<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.