Difference between revisions of "Astrocytoma, IDH-mutant"

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Astrocytoma, IDH-mutant (view source)

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* Diffuse astrocytoma,NOS (ICD-O 9400/3) - genetic testing still missing.
* Diffuse astrocytoma,NOS (ICD-O 9400/3) - genetic testing still missing.


==Radiology/Clinic==
==Astrocytoma, IDH mutant grade 2==
* Most common CNS grade 2 WHO glioma in adults (peaks between 30-40 years).
* 10-15% of all [[astrocytoma]]s.
* Usually shows progression to WHO CNS grade 3 sooner or later. <ref>{{Cite journal  | last1 = Louis | first1 = DN. | last2 = Perry | first2 = A. | last3 = Reifenberger | first3 = G. | last4 = von Deimling | first4 = A. | last5 = Figarella-Branger | first5 = D. | last6 = Cavenee | first6 = WK. | last7 = Ohgaki | first7 = H. | last8 = Wiestler | first8 = OD. | last9 = Kleihues | first9 = P. | title = The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. | journal = Acta Neuropathol | volume = 131 | issue = 6 | pages = 803-20 | month = Jun | year = 2016 | doi = 10.1007/s00401-016-1545-1 | PMID = 27157931 }}</ref>
 
==Astrocytoma, IDH mutant grade 3==
* Most common CNS grade 3 WHO glioma in adults (peaks between 40-50 years).
* Approx 5% of all [[glioma]]s.<ref>{{Cite journal  | last1 = Ohgaki | first1 = H. | last2 = Kleihues | first2 = P. | title = Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. | journal = J Neuropathol Exp Neurol | volume = 64 | issue = 6 | pages = 479-89 | month = Jun | year = 2005 | doi =  | PMID = 15977639 }}</ref>
* Usually shows progression to WHO CNS grade 4 sooner or later.
*Overall prognosis is rather poor (average survival 2-3 years).
*Grade 3 tumors share a similiar prognosis to grade 2 IDH-mutant tumors.<ref>{{Cite journal  | last1 = Reuss | first1 = DE. | last2 = Mamatjan | first2 = Y. | last3 = Schrimpf | first3 = D. | last4 = Capper | first4 = D. | last5 = Hovestadt | first5 = V. | last6 = Kratz | first6 = A. | last7 = Sahm | first7 = F. | last8 = Koelsche | first8 = C. | last9 = Korshunov | first9 = A. | title = IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO. | journal = Acta Neuropathol | volume = 129 | issue = 6 | pages = 867-73 | month = Jun | year = 2015 | doi = 10.1007/s00401-015-1438-8 | PMID = 25962792 }}</ref>
==Astrocytoma, IDH mutant grade 4==
* Formely called glioblastoma, IDH-mutant or "secondary glioblastoma".
* CDKN2A deletion in grade 2 or grade 3 tumors results in upgrading to CNS WHO grade 4.
 
=Radiology/Clinic=
*Mass effect.
*Mass effect.
*Seizures.
*Seizures.
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*CNS grade 3 and 4: The majority are contrast-enhanching, T2 bright.
*CNS grade 3 and 4: The majority are contrast-enhanching, T2 bright.


==Macroscopy==
=Macroscopy=
*No clear demarcation from white matter.
*No clear demarcation from white matter.
*Softer consistency and opacity.  
*Softer consistency and opacity.  
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*CNS grade 2 and 3: No necrosis.
*CNS grade 2 and 3: No necrosis.


==Histology==
=Histology=
CNS grade 2 features: <ref name=AFIP2007>{{Ref AFIP2007|34}}</ref>
CNS grade 2 features: <ref name=AFIP2007>{{Ref AFIP2007|34}}</ref>
*Cell density higher than normal brain.
*Cell density higher than normal brain.
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*Necrosis (less common than in [[glioblastoma]]).
*Necrosis (less common than in [[glioblastoma]]).


==IHC==
=IHC=
*[[GFAP]]+ve.
*[[GFAP]]+ve.
*[[MAP2]]+ve (especially in cell processes).
*[[MAP2]]+ve (especially in cell processes).
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*[[ATRX]] nuclear loss.
*[[ATRX]] nuclear loss.


 
=Molecular=
==Astrocytoma, IDH mutant grade 2==
*IDH1 R132- or IDH2 R172-hotspot mutations are mandatory.
 
*Absence of LOH 1p/19q (otherwise classify tumor as [[oligodendroglioma]], IDH-mutant and 1p/19q codeleted).
* Most common CNS grade 2 WHO glioma in adults (peaks between 30-40 years).
* 10-15% of all [[astrocytoma]]s.
* Usually shows progression to [[glioblastoma]] sooner or later.
 
WHO 2016 categorization combines morphology and genetics into following groups:<ref>{{Cite journal  | last1 = Louis | first1 = DN. | last2 = Perry | first2 = A. | last3 = Reifenberger | first3 = G. | last4 = von Deimling | first4 = A. | last5 = Figarella-Branger | first5 = D. | last6 = Cavenee | first6 = WK. | last7 = Ohgaki | first7 = H. | last8 = Wiestler | first8 = OD. | last9 = Kleihues | first9 = P. | title = The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. | journal = Acta Neuropathol | volume = 131 | issue = 6 | pages = 803-20 | month = Jun | year = 2016 | doi = 10.1007/s00401-016-1545-1 | PMID = 27157931 }}</ref>
*Diffuse astrocytoma, IDH-mutant  ICD-O: 9400/3 - most frequent.
**Gemistocytic astrocytoma, IDH-mutant ICD-O:9411/3
*Diffuse astrocytoma, IDH-wildtype ICD-O: 9400/3
*Diffuse astrocytoma,NOS ICD-O: 9400/3 - genetic data missing.
 
''Note:'' Older terminologies included Fibrillary astrocytoma (ICD-O: 9420/3) and Protoplasmatic astrocytoma (ICD-O:9410/3)<ref name=WHOCNS>{{Ref WHOCNS|25}}</ref> This subtyping is no longer in use. These tumors are now classified according their IDH mutation status.
 
==Astrocytoma, IDH mutant grade 3==
 
* Most common CNS grade 3 WHO glioma in adults (peaks between 40-50 years).
* Approx 5% of all [[glioma]]s.<ref>{{Cite journal  | last1 = Ohgaki | first1 = H. | last2 = Kleihues | first2 = P. | title = Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. | journal = J Neuropathol Exp Neurol | volume = 64 | issue = 6 | pages = 479-89 | month = Jun | year = 2005 | doi =  | PMID = 15977639 }}</ref>
* Usually shows progression to [[glioblastoma]] sooner or later.
 
 
 
 
 
==Molecular==
*IDH1 R132- or IDH2 R172-hotsopt mutations classify the tumors as Diffuse astrocytoma, IDH-mutant.
*Absence of LOH 1p/19q (otherwise classify tumor as oligodendroglioma).
*Tp53 mutations in approx. 60% (80-90% in gemistocytic, 50% in fibrillary types).
*Tp53 mutations in approx. 60% (80-90% in gemistocytic, 50% in fibrillary types).
*MGMT promotor methylated in approx. 50%.
*MGMT promotor methylated in approx. 50%.
*CDKN2A/B homozygous deletion in IDH mutant diffuse astrocytoma has unfavourable prognosis.<ref>{{Cite journal  | last1 = Shirahata | first1 = M. | last2 = Ono | first2 = T. | last3 = Stichel | first3 = D. | last4 = Schrimpf | first4 = D. | last5 = Reuss | first5 = DE. | last6 = Sahm | first6 = F. | last7 = Koelsche | first7 = C. | last8 = Wefers | first8 = A. | last9 = Reinhardt | first9 = A. | title = Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. | journal = Acta Neuropathol | volume = 136 | issue = 1 | pages = 153-166 | month = Jul | year = 2018 | doi = 10.1007/s00401-018-1849-4 | PMID = 29687258 }}</ref><ref>{{Cite journal  | last1 = Aoki | first1 = K. | last2 = Nakamura | first2 = H. | last3 = Suzuki | first3 = H. | last4 = Matsuo | first4 = K. | last5 = Kataoka | first5 = K. | last6 = Shimamura | first6 = T. | last7 = Motomura | first7 = K. | last8 = Ohka | first8 = F. | last9 = Shiina | first9 = S. | title = Prognostic relevance of genetic alterations in diffuse lower-grade gliomas. | journal = Neuro Oncol | volume = 20 | issue = 1 | pages = 66-77 | month = 01 | year = 2018 | doi = 10.1093/neuonc/nox132 | PMID = 29016839 }}</ref>
*CDKN2A/B homozygous deletion results in CNS grade 4<ref>{{Cite journal  | last1 = Shirahata | first1 = M. | last2 = Ono | first2 = T. | last3 = Stichel | first3 = D. | last4 = Schrimpf | first4 = D. | last5 = Reuss | first5 = DE. | last6 = Sahm | first6 = F. | last7 = Koelsche | first7 = C. | last8 = Wefers | first8 = A. | last9 = Reinhardt | first9 = A. | title = Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. | journal = Acta Neuropathol | volume = 136 | issue = 1 | pages = 153-166 | month = Jul | year = 2018 | doi = 10.1007/s00401-018-1849-4 | PMID = 29687258 }}</ref><ref>{{Cite journal  | last1 = Aoki | first1 = K. | last2 = Nakamura | first2 = H. | last3 = Suzuki | first3 = H. | last4 = Matsuo | first4 = K. | last5 = Kataoka | first5 = K. | last6 = Shimamura | first6 = T. | last7 = Motomura | first7 = K. | last8 = Ohka | first8 = F. | last9 = Shiina | first9 = S. | title = Prognostic relevance of genetic alterations in diffuse lower-grade gliomas. | journal = Neuro Oncol | volume = 20 | issue = 1 | pages = 66-77 | month = 01 | year = 2018 | doi = 10.1093/neuonc/nox132 | PMID = 29016839 }}</ref>
Note:
Note:
*The existence of diffuse astrocytoma, IDH wildtype is challenged.<ref>{{Cite journal  | last1 = Reuss | first1 = DE. | last2 = Kratz | first2 = A. | last3 = Sahm | first3 = F. | last4 = Capper | first4 = D. | last5 = Schrimpf | first5 = D. | last6 = Koelsche | first6 = C. | last7 = Hovestadt | first7 = V. | last8 = Bewerunge-Hudler | first8 = M. | last9 = Jones | first9 = DT. | title = Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities. | journal = Acta Neuropathol | volume = 130 | issue = 3 | pages = 407-17 | month = Sep | year = 2015 | doi = 10.1007/s00401-015-1454-8 | PMID = 26087904 }}</ref>
*The existence of diffuse astrocytoma, IDH wildtype is challenged.<ref>{{Cite journal  | last1 = Reuss | first1 = DE. | last2 = Kratz | first2 = A. | last3 = Sahm | first3 = F. | last4 = Capper | first4 = D. | last5 = Schrimpf | first5 = D. | last6 = Koelsche | first6 = C. | last7 = Hovestadt | first7 = V. | last8 = Bewerunge-Hudler | first8 = M. | last9 = Jones | first9 = DT. | title = Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities. | journal = Acta Neuropathol | volume = 130 | issue = 3 | pages = 407-17 | month = Sep | year = 2015 | doi = 10.1007/s00401-015-1454-8 | PMID = 26087904 }}</ref>
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***Glial morphology can be astrocytic or oligodendrocytic.
***Glial morphology can be astrocytic or oligodendrocytic.


==Molecular==
*TERT promotor mutations in 20-25%<ref>{{Cite journal  | last1 = Lee | first1 = Y. | last2 = Koh | first2 = J. | last3 = Kim | first3 = SI. | last4 = Won | first4 = JK. | last5 = Park | first5 = CK. | last6 = Choi | first6 = SH. | last7 = Park | first7 = SH. | title = The frequency and prognostic effect of TERT promoter mutation in diffuse gliomas. | journal = Acta Neuropathol Commun | volume = 5 | issue = 1 | pages = 62 | month = Aug | year = 2017 | doi = 10.1186/s40478-017-0465-1 | PMID = 28851427 }}</ref><ref>{{Cite journal  | last1 = Koelsche | first1 = C. | last2 = Sahm | first2 = F. | last3 = Capper | first3 = D. | last4 = Reuss | first4 = D. | last5 = Sturm | first5 = D. | last6 = Jones | first6 = DT. | last7 = Kool | first7 = M. | last8 = Northcott | first8 = PA. | last9 = Wiestler | first9 = B. | title = Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system. | journal = Acta Neuropathol | volume = 126 | issue = 6 | pages = 907-15 | month = Dec | year = 2013 | doi = 10.1007/s00401-013-1195-5 | PMID = 24154961 }}</ref>
*Approximately 80 % of IDH wildtype astrocytomas in fact represent underdiagnosed GBM.<ref>{{Cite journal  | last1 = Reuss | first1 = DE. | last2 = Kratz | first2 = A. | last3 = Sahm | first3 = F. | last4 = Capper | first4 = D. | last5 = Schrimpf | first5 = D. | last6 = Koelsche | first6 = C. | last7 = Hovestadt | first7 = V. | last8 = Bewerunge-Hudler | first8 = M. | last9 = Jones | first9 = DT. | title = Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities. | journal = Acta Neuropathol | volume = 130 | issue = 3 | pages = 407-17 | month = Sep | year = 2015 | doi = 10.1007/s00401-015-1454-8 | PMID = 26087904 }}</ref>


<gallery>
<gallery>
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File:Neuropathology case II 02.jpg | Astrocytoma, protoplasmatic type (WC/jensflorian)
File:Neuropathology case II 02.jpg | Astrocytoma, protoplasmatic type (WC/jensflorian)
File:Gemistocytic astrocytoma.jpg | Gemistocytic astrocytoma (WC/jensflorian)
File:Gemistocytic astrocytoma.jpg | Gemistocytic astrocytoma (WC/jensflorian)
File:Mitoses_astro_III.jpg | Marked mitotic activity in anaplastic astrocytoma (WC/jensflorian).
File:405551M-ANAPLASTIC_ASTROCYTOMA.jpg | Marked nuclear pleomorphism (AFIP).
</gallery>
</gallery>


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For CNS grade 4 tumours:
For CNS grade 4 tumours:
*[[Glioblastoma]] - vascular proliferations and / or necrosis.
*[[Glioblastoma]] - vascular proliferations and / or necrosis.
WHO 2016 categorization combines morphology and genetics into following groups:<ref>{{Cite journal  | last1 = Louis | first1 = DN. | last2 = Perry | first2 = A. | last3 = Reifenberger | first3 = G. | last4 = von Deimling | first4 = A. | last5 = Figarella-Branger | first5 = D. | last6 = Cavenee | first6 = WK. | last7 = Ohgaki | first7 = H. | last8 = Wiestler | first8 = OD. | last9 = Kleihues | first9 = P. | title = The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. | journal = Acta Neuropathol | volume = 131 | issue = 6 | pages = 803-20 | month = Jun | year = 2016 | doi = 10.1007/s00401-016-1545-1 | PMID = 27157931 }}</ref>
*Anaplastic astrocytoma, IDH-mutant  (ICD-O: 9401/3).
*Anaplastic astrocytoma, IDH-wildtype (ICD-O: 9401/3).
*Anaplastic astrocytoma,NOS (ICD-O: 9401/3) - genetic data missing.
==Prognosis==
*Overall prognosis is rather poor (average survival 2-3 years).
*IDH-mutant tumors share a similiar prognosis to grade II IDH-mutant tumors.<ref>{{Cite journal  | last1 = Reuss | first1 = DE. | last2 = Mamatjan | first2 = Y. | last3 = Schrimpf | first3 = D. | last4 = Capper | first4 = D. | last5 = Hovestadt | first5 = V. | last6 = Kratz | first6 = A. | last7 = Sahm | first7 = F. | last8 = Koelsche | first8 = C. | last9 = Korshunov | first9 = A. | title = IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO. | journal = Acta Neuropathol | volume = 129 | issue = 6 | pages = 867-73 | month = Jun | year = 2015 | doi = 10.1007/s00401-015-1438-8 | PMID = 25962792 }}</ref>
*Anaplastic astrocytoma, IDH-wildtype perform worse than glioblastoma, IDH-mutant despite grading differences.<ref>{{Cite journal  | last1 = Hartmann | first1 = C. | last2 = Hentschel | first2 = B. | last3 = Wick | first3 = W. | last4 = Capper | first4 = D. | last5 = Felsberg | first5 = J. | last6 = Simon | first6 = M. | last7 = Westphal | first7 = M. | last8 = Schackert | first8 = G. | last9 = Meyermann | first9 = R. | title = Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. | journal = Acta Neuropathol | volume = 120 | issue = 6 | pages = 707-18 | month = Dec | year = 2010 | doi = 10.1007/s00401-010-0781-z | PMID = 21088844 }}</ref>
<gallery>
File:Mitoses_astro_III.jpg | Marked mitotic activity in anaplastic astrocytoma (WC/jensflorian).
File:405551M-ANAPLASTIC_ASTROCYTOMA.jpg | Marked nuclear pleomorphism (AFIP).
</gallery>
==Molecular==
*TERT promotor mutations in 20-25%<ref>{{Cite journal  | last1 = Lee | first1 = Y. | last2 = Koh | first2 = J. | last3 = Kim | first3 = SI. | last4 = Won | first4 = JK. | last5 = Park | first5 = CK. | last6 = Choi | first6 = SH. | last7 = Park | first7 = SH. | title = The frequency and prognostic effect of TERT promoter mutation in diffuse gliomas. | journal = Acta Neuropathol Commun | volume = 5 | issue = 1 | pages = 62 | month = Aug | year = 2017 | doi = 10.1186/s40478-017-0465-1 | PMID = 28851427 }}</ref><ref>{{Cite journal  | last1 = Koelsche | first1 = C. | last2 = Sahm | first2 = F. | last3 = Capper | first3 = D. | last4 = Reuss | first4 = D. | last5 = Sturm | first5 = D. | last6 = Jones | first6 = DT. | last7 = Kool | first7 = M. | last8 = Northcott | first8 = PA. | last9 = Wiestler | first9 = B. | title = Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system. | journal = Acta Neuropathol | volume = 126 | issue = 6 | pages = 907-15 | month = Dec | year = 2013 | doi = 10.1007/s00401-013-1195-5 | PMID = 24154961 }}</ref>
*Approximately 80 % of IDH wildtype astrocytomas in fact represent underdiagnosed GBM.<ref>{{Cite journal  | last1 = Reuss | first1 = DE. | last2 = Kratz | first2 = A. | last3 = Sahm | first3 = F. | last4 = Capper | first4 = D. | last5 = Schrimpf | first5 = D. | last6 = Koelsche | first6 = C. | last7 = Hovestadt | first7 = V. | last8 = Bewerunge-Hudler | first8 = M. | last9 = Jones | first9 = DT. | title = Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities. | journal = Acta Neuropathol | volume = 130 | issue = 3 | pages = 407-17 | month = Sep | year = 2015 | doi = 10.1007/s00401-015-1454-8 | PMID = 26087904 }}</ref>


==Outdated terminologies==
==Outdated terminologies==
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*Gemistocytic astrocytoma
*Gemistocytic astrocytoma
*Diffuse astrocytoma, IDH-wildtype
*Diffuse astrocytoma, IDH-wildtype
 
*Glioblastoma; IDH-mutant
 
*Fibrillary astrocytoma (ICD-O: 9420/3)  
''Note:'' Older terminologies included Fibrillary astrocytoma (ICD-O: 9420/3) and Protoplasmatic astrocytoma (ICD-O:9410/3)<ref name=WHOCNS>{{Ref WHOCNS|25}}</ref> This subtyping is no longer in use. These tumors are now classified according their IDH mutation status.
*Protoplasmatic astrocytoma (ICD-O:9410/3)


=See also=
=See also=
Jensflorian
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