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CNS5:Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (view source)
Revision as of 11:58, 4 November 2022
, 11:58, 4 November 2022no edit summary
==Primary Author(s)*==
==Primary Author(s)*==
Madina Sukhanova, PhD, Northwestern University
Madina Sukhanova, PhD, FACMG Northwestern University
__TOC__
__TOC__
==Cancer Category/Type==
==Cancer Category/Type==
Glioneuronal tumour
==Cancer Sub-Classification / Subtype==
==Cancer Sub-Classification / Subtype==
Paediatric-type diffuse high-grade gliomas with three molecular subtypes: RTK2, RTK1, and MYCN
==Definition / Description of Disease==
==Definition / Description of Disease==
This is a distinct entity in the World Health Organization (WHO) classification system within the section of paediatric-type diffuse high-grade gliomas. Distinct methylation profiles and molecular alterations define three subtypes: dpHGG RTK1, dpHGG RTK2, and dpHGG MYCN. Gliomas arising after therapeutic radiation are predominantly of the pHGG RTK1 subtype. Known tumorigenic drivers include TP53, MYCN, ID2, and genes from RAS/MAPK and PI3K pathways.<ref>{{Cite journal|last=Buczkowicz|first=Pawel|last2=Hoeman|first2=Christine|last3=Rakopoulos|first3=Patricia|last4=Pajovic|first4=Sanja|last5=Letourneau|first5=Louis|last6=Dzamba|first6=Misko|last7=Morrison|first7=Andrew|last8=Lewis|first8=Peter|last9=Bouffet|first9=Eric|date=2014-05|title=Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations|url=https://pubmed.ncbi.nlm.nih.gov/24705254|journal=Nature Genetics|volume=46|issue=5|pages=451–456|doi=10.1038/ng.2936|issn=1546-1718|pmc=3997489|pmid=24705254}}</ref> <ref>{{Cite journal|last=Sturm|first=Dominik|last2=Orr|first2=Brent A.|last3=Toprak|first3=Umut H.|last4=Hovestadt|first4=Volker|last5=Jones|first5=David T. W.|last6=Capper|first6=David|last7=Sill|first7=Martin|last8=Buchhalter|first8=Ivo|last9=Northcott|first9=Paul A.|date=2016-02-25|title=New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs|url=https://pubmed.ncbi.nlm.nih.gov/26919435|journal=Cell|volume=164|issue=5|pages=1060–1072|doi=10.1016/j.cell.2016.01.015|issn=1097-4172|pmc=5139621|pmid=26919435}}</ref> <ref name=":0">{{Cite journal|last=Korshunov|first=Andrey|last2=Ryzhova|first2=Marina|last3=Hovestadt|first3=Volker|last4=Bender|first4=Sebastian|last5=Sturm|first5=Dominik|last6=Capper|first6=David|last7=Meyer|first7=Jochen|last8=Schrimpf|first8=Daniel|last9=Kool|first9=Marcel|date=2015-05|title=Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers|url=https://pubmed.ncbi.nlm.nih.gov/25752754|journal=Acta Neuropathologica|volume=129|issue=5|pages=669–678|doi=10.1007/s00401-015-1405-4|issn=1432-0533|pmid=25752754}}</ref> <ref name=":1">{{Cite journal|last=Mackay|first=Alan|last2=Burford|first2=Anna|last3=Carvalho|first3=Diana|last4=Izquierdo|first4=Elisa|last5=Fazal-Salom|first5=Janat|last6=Taylor|first6=Kathryn R.|last7=Bjerke|first7=Lynn|last8=Clarke|first8=Matthew|last9=Vinci|first9=Mara|date=2017-10-09|title=Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma|url=https://pubmed.ncbi.nlm.nih.gov/28966033|journal=Cancer Cell|volume=32|issue=4|pages=520–537.e5|doi=10.1016/j.ccell.2017.08.017|issn=1878-3686|pmc=5637314|pmid=28966033}}</ref>
==Synonyms / Terminology==
==Synonyms / Terminology==
None
==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" />
==Clinical Features==
==Clinical Features==
The clinical features are dependent on the tumour location. Symptoms can include seizures and motor or sensory deficits.
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|'''Signs and Symptoms'''
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
|Seizures and motor or sensory deficits.
|-
|-
|'''Laboratory Findings'''
|'''Imaging Findings'''
|EXAMPLE Cytopenias
|MRI characteristics are comparable to other high-grade glioma tumour types. MRI typically reveals well-defined margins and homogeneous contrast-enhancement and mild perilesional edema.<ref name=":3">{{Cite journal|last=Tauziède-Espariat|first=A.|last2=Debily|first2=M.-A.|last3=Castel|first3=D.|last4=Grill|first4=J.|last5=Puget|first5=S.|last6=Roux|first6=A.|last7=Saffroy|first7=R.|last8=Pagès|first8=M.|last9=Gareton|first9=A.|date=2020-07-09|title=The pediatric supratentorial MYCN-amplified high-grade gliomas methylation class presents the same radiological, histopathological and molecular features as their pontine counterparts|url=https://pubmed.ncbi.nlm.nih.gov/32646492|journal=Acta Neuropathologica Communications|volume=8|issue=1|pages=104|doi=10.1186/s40478-020-00974-x|issn=2051-5960|pmc=7346460|pmid=32646492}}</ref><ref>{{Cite journal|last=Tauziède-Espariat|first=A.|last2=Debily|first2=M.-A.|last3=Castel|first3=D.|last4=Grill|first4=J.|last5=Puget|first5=S.|last6=Sabel|first6=M.|last7=Blomgren|first7=K.|last8=Gareton|first8=A.|last9=Dangouloff-Ros|first9=V.|date=2019-06-10|title=An integrative radiological, histopathological and molecular analysis of pediatric pontine histone-wildtype glioma with MYCN amplification (HGG-MYCN)|url=https://pubmed.ncbi.nlm.nih.gov/31177990|journal=Acta Neuropathologica Communications|volume=7|issue=1|pages=87|doi=10.1186/s40478-019-0738-y|issn=2051-5960|pmc=6556947|pmid=31177990}}</ref>
|}
|}
==Sites of Involvement==
==Sites of Involvement==
Main site: supratentorial brain.
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" />
==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" />
==Immunophenotype==
==Immunophenotype==
{| class="wikitable sortable"
{| class="wikitable sortable"
!Finding!!Marker
!Finding!!Marker
|-
|-
|Positive (universal)||EXAMPLE CD1
|Positive (universal)||Neoplastic glial component – GFAP, and/or OLIG2.<ref name=":0" /><ref name=":1" />
|-
|-
|Positive (subset)||EXAMPLE CD2
|Positive (subset)||dpHGG MYCN molecular subtype can be positive for neuronal markers.
|-
|-
|Negative (universal)||EXAMPLE CD3
|Negative (universal)|| IDH1 R132H (normal retained pattern of staining).
H3 p.K28me3 (K27me4) (preserved expression).<ref name=":3" />
|-
|-
|Negative (subset)||EXAMPLE CD4
|Negative (subset)||dpHGG MYCN molecular subtype can be negative for glial marker GFAP, and/or OLIG2.
|}
|}
==Chromosomal Rearrangements (Gene Fusions)==
==Chromosomal Rearrangements (Gene Fusions)==
{| class="wikitable sortable"
{| class="wikitable sortable"