Difference between revisions of "Astrocytoma, IDH-mutant"

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Astrocytoma, IDH-mutant (view source)

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'''Astrocytoma, IDH-mutant''' is a diffusely-growing, infiltrating astrocytoma of the adult occurring in the CNS white matter. IDH1 codon 132 or IDH2 codon 172 mutations are frequently associated with ATRX and TP53 mutations.
'''Astrocytoma, IDH-mutant''' is a diffusely-growing, infiltrating astrocytoma of the adult occurring in the CNS white matter. IDH1 codon 132 or IDH2 codon 172 mutations is mandatory for diagnosis and are frequently associated with ATRX and TP53 mutations.


=General=
=General=
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* Astrocytoma, IDH mutant grade 4 (ICD-O: 9445/3)
* Astrocytoma, IDH mutant grade 4 (ICD-O: 9445/3)
* Diffuse astrocytoma,NOS (ICD-O 9400/3) - genetic testing still missing.
* Diffuse astrocytoma,NOS (ICD-O 9400/3) - genetic testing still missing.
==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 [[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.


==Radiology/Clinic==
==Radiology/Clinic==
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*Seizures.
*Seizures.
*Neurologic decifit.
*Neurologic decifit.
*Usually not contrast-enhanching, T2 bright.
*CNS grade 2: Usually not 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.
*May contain larger cysts
*May contain larger cysts
*No necrosis
*Invaded structures may appear enlarged.
*CNS grade 2 and 3: No necrosis.


==Histology==
==Histology==
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.
*Mild to moderate nuclear pleomorphism.
*Mild to moderate nuclear pleomorphism.
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*Mitoses absent or very rare.
*Mitoses absent or very rare.
*Microcystic spaces of the background (none to extensive).
*Microcystic spaces of the background (none to extensive).
*No necrosis, no vascular proliferations.
**Except radiation necrosis.
*Lymphocytic cuffing (mostly in gemistocytic type)
*Lymphocytic cuffing (mostly in gemistocytic type)
*Abent to few rosenthal fibers.
*Abent to few rosenthal fibers.


<gallery>
CNS grade 3 features: <ref name=AFIP2007>{{Ref AFIP2007|34}}</ref>
File:Diffuse_astrocytoma_HE_stain.jpg | Diffuse astrocytoma, [[H&E]] (WC/jensflorian)
*Increased cellularity (compared to CNS grade 2).
File:Image NP T2a 0002.JPG | Diffuse astrocytoma, [[H&E]] (WC/jensflorian)
*Mitoses present (a single mitosis in a small specimen indicates a high-grade tumor).
File:Astrocytoma whoII HE.jpg | Astrocytoma, fibrillary type (WC/jensflorian)
**Specimens with low cellularity but plenty of mitoses are also considered grade 3.
File:Neuropathology case II 02.jpg | Astrocytoma, protoplasmatic type (WC/jensflorian)
*Distinct nuclear atypia and  pleomorphism.
File:Gemistocytic astrocytoma.jpg | Gemistocytic astrocytoma (WC/jensflorian)
**May include multinucleated cells.
</gallery>
*Cytoplasm highly variable (even within the same tumour).
*Microcystic spaces of the background (none to extensive).
*No necrosis, no vascular proliferations.
**Except radiation necrosis after pretreatment.


CNS grade 4 features:
*Increased cellularity (compared to CNS grade 2).
*Mitoses frequently present.
*Distinct nuclear atypia and  pleomorphism.
*Multinucleated cells.
*Microvascular proliferation.
*Necrosis (less common than in [[glioblastoma]]).


==IHC==
==IHC==
*[[GFAP]]+ve.
*[[GFAP]]+ve.
*[[MAP2]]+ve (especially in cell processes).
*[[MAP2]]+ve (especially in cell processes).
*OLIG2 +ve.
*Vimentin+ve (often perinuclear).
*Vimentin+ve (often perinuclear).
*S-100+ve.
*S-100+ve.
*p53: Nuclear staining in 30% of the tumours (usually few cells).
*p53: Nuclear staining in 30% of the tumours (usually few cells).
*MIB-1: 0-5% (mean: 2%).
*MIB-1: CNS grade 2: 0-5% (mean: 2%); CNS grade 3 usu. 5-10%.
*[[IDH-1]] (R132H)+ve in 60-70%.
*[[IDH-1]] (R132H)+ve in 60-70%.
**'Note:'' This antibody does not detect other rare IDH1/2 mutations.
**'Note:'' The mutation-specific antibody does not detect other less common IDH1/2 hotspot mutations.
*[[ATRX]] nuclear loss in 70%.
*[[ATRX]] nuclear loss.
 
 
==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 [[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.
 
 
 


<gallery>
File:GFAP astrocytoma.jpg| GFAP in astrocytoma (WC/jensflorian)
File:Neuropathology case II 04.jpg | ATRX loss in astrocytoma (WC/jensflorian)
</gallery>


==Molecular==
==Molecular==
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***Glial morphology can be astrocytic or oligodendrocytic.
***Glial morphology can be astrocytic or oligodendrocytic.


<gallery>
File:GFAP astrocytoma.jpg| GFAP in astrocytoma (WC/jensflorian)
File:Neuropathology case II 04.jpg | ATRX loss in astrocytoma (WC/jensflorian)
File:Diffuse_astrocytoma_HE_stain.jpg | Diffuse astrocytoma, [[H&E]] (WC/jensflorian)
File:Image NP T2a 0002.JPG | Diffuse astrocytoma, [[H&E]] (WC/jensflorian)
File:Astrocytoma whoII HE.jpg | Astrocytoma, fibrillary type (WC/jensflorian)
File:Neuropathology case II 02.jpg | Astrocytoma, protoplasmatic type (WC/jensflorian)
File:Gemistocytic astrocytoma.jpg | Gemistocytic astrocytoma (WC/jensflorian)
</gallery>


==DDx==
==DDx==
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For CNS grade 3 tumours:
For CNS grade 3 tumours:
*Anaplastic [[Oligodendroglioma]], when LOH 1p/19q is present.
*Anaplastic [[Oligodendroglioma]], when LOH 1p/19q is present.
For CNS grade 4 tumours:
*[[Glioblastoma]] - vascular proliferations and / or necrosis.
*[[Glioblastoma]] - vascular proliferations and / or necrosis.


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'''Anaplastic astrocytoma''' (AKA: ''high-grade astrocytoma'') is a infiltrating neoplasm of the diffuse astrocytic and oligodendroglial tumor group occurring in the CNS white matter.


* Most common grade III 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.


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>
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>
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*Anaplastic astrocytoma,NOS (ICD-O: 9401/3) - genetic data missing.
*Anaplastic astrocytoma,NOS (ICD-O: 9401/3) - genetic data missing.


==Radiology/Clinic==
 
*Mass effect.
*Seizures.
*Neurologic decifit.
*The majority are contrast-enhanching, T2 bright.


==Prognosis==
==Prognosis==
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*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>
*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>
   
   
==Macroscopy==
*No clear demarcation from white matter.
*Invaded structures may appear enlarged.
*Softer consistency and opacity.
*No  necrosis.


==Histology==
 
Features: <ref name=AFIP2007>{{Ref AFIP2007|34}}</ref>
 
*Increased cellularity (compared to [[Diffuse Astrocytoma]]).
**Specimens with low cellularity but plenty mitoses are also considered anaplastic.
*Distinct nuclear atypia and  pleomorphism.
**May include multinucleated cells.
*Cytoplasm highly variable (even within the same tumour).
*Mitoses present (a single mitosis in a small specimen indicates a high-grade tumor).
*Microcystic spaces of the background (none to extensive).
*No necrosis, no vascular proliferations.
**Except radiation necrosis after pretreatment.
*Lymphocytic cuffing (mostly in gemistocytic type).
*Rosenthal fibers usu. absent.


<gallery>
<gallery>
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</gallery>
</gallery>


==IHC==
*[[GFAP]]+ve.
*[[MAP2]]+ve (especially in cell processes).
*Vimentin+ve (often perinuclear).
*S-100+ve.
*MIB-1: usu. 5-10& (overlaps with grade II tumors).
*[[IDH-1]] (R132H)+ve in 60-70%.
**'Note:'' This antibody does not detect other rare IDH1/2 mutations.
*[[ATRX]] nuclear loss in 70%.




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