Difference between revisions of "Diffuse astrocytoma"

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* Usually shows progression to [[glioblastoma]] sooner or later.
* Usually shows progression to [[glioblastoma]] sooner or later.


Previously categorized as follows:{{Ref WHOCNS|25}}
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 ICD-O: 9400/3
*Diffuse astrocytoma, IDH-mutant  ICD-O: 9400/3 - most frequent.
**Fibrillary astrocytoma ICD-O: 9420/3 - most frequent
**Gemistocytic astrocytoma, IDH-mutant ICD-O:9411/3
**Gemistocytic astrocytoma ICD-O:9411/3
*Diffuse astrocytoma, IDH-wildtype ICD-O: 9400/3
**Protoplasmatic astrocytoma ICD-O:9410/3 - rare
*Diffuse astrocytoma,NOS ICD-O: 9400/3 - genetic data missing.
Note: This subtyping is no longer in use!
 
''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==
*Mass effect.
*Seizures.
*Neurologic decifit.
*Usually not contrast-enhanching, T2 bright.
 
==Macroscopy==
*No clear demarcation from white matter
*May contain larger cysts
*No  necrosis


==Histology==
==Histology==
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.
**Monotony of atypical nuclei hints at neoplasm.
**Monotony of atypical nuclei and irregular distribution indicates neoplasm.
**"naked nuclei" without recognizeable processes.
**No prominent nucleolus.
*Cytoplasm highly variable (even within the same tumour).  
*Cytoplasm highly variable (even within the same tumour).  
**In normal CNS the cytoplasm blends within the neuropil.
**In normal CNS the cytoplasm blends within the neuropil.
*Mitoses absent or very rare.
*Mitoses absent or very rare.
*Microcystic changes of the background (none to extensive).
*Microcystic spaces of the background (none to extensive).
*No necrosis, no vascular proliferations.
*No necrosis, no vascular proliferations.
**Except radiation necrosis.
*Lymphocytic cuffing (mostly in gemistocytic type)
*Abent to few rosenthal fibers.


===IHC===
<gallery>
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>
 
 
==IHC==
*[[GFAP]]+ve.
*[[GFAP]]+ve.
*[[MAP2]]+ve (especially in cell processes).
*[[MAP2]]+ve (especially in cell processes).
*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).
*MIB-1: 0-5% (mean: 2%).
*MIB-1: 0-5% (mean: 2%).
*[[IDH-1]] (R132H)+ve in 60-70%.
*[[IDH-1]] (R132H)+ve in 60-70%.
*[[ATRX]] loss in 70%.
**'Note:'' This antibody does not detect other rare IDH1/2 mutations.
*[[ATRX]] nuclear loss in 70%.


===Molecular===
<gallery>
*Absence of LOH 1p/19q.
File:GFAP astrocytoma.jpg| GFAP in astrocytoma (WC/jensflorian)
File:Neuropathology case II 04.jpg | ATRX loss in astrocytoma (WC/jensflorian)
</gallery>
 
==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>
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>
**Most adult cases show genetic alterations compatible with glioblastoma.<ref>{{Cite journal  | last1 = Hasselblatt | first1 = M. | last2 = Jaber | first2 = M. | last3 = Reuss | first3 = D. | last4 = Grauer | first4 = O. | last5 = Bibo | first5 = A. | last6 = Terwey | first6 = S. | last7 = Schick | first7 = U. | last8 = Ebel | first8 = H. | last9 = Niederstadt | first9 = T. | title = Diffuse Astrocytoma, IDH-Wildtype: A Dissolving Diagnosis. | journal = J Neuropathol Exp Neurol | volume =  | issue =  | pages =  | month = Feb | year = 2018 | doi = 10.1093/jnen/nly012 | PMID = 29444314 }}</ref>
**Molecular upgrade according to cIMPACT-NOW Update 3 consensus (one of these is sufficient):<ref>{{Cite journal  | last1 = Brat | first1 = DJ. | last2 = Aldape | first2 = K. | last3 = Colman | first3 = H. | last4 = Holland | first4 = EC. | last5 = Louis | first5 = DN. | last6 = Jenkins | first6 = RB. | last7 = Kleinschmidt-DeMasters | first7 = BK. | last8 = Perry | first8 = A. | last9 = Reifenberger | first9 = G. | title = cIMPACT-NOW update 3: recommended diagnostic criteria for "Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV". | journal = Acta Neuropathol | volume = 136 | issue = 5 | pages = 805-810 | month = Nov | year = 2018 | doi = 10.1007/s00401-018-1913-0 | PMID = 30259105 }}</ref>
***EGFR amplification
***Combined whole chromosome 7 gain and whole chromosome 10 loss (+ 7/− 10)
***TERT promoter mutation
**Suggested Sign-out: <pre> Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV</pre>
**WHO grade II diffuse gliomas IDH-wt/H3-wt in children and adolescents have an indolent clinical behavior and rare anaplastic progression.
***Most tumors show a BRAFV600E mutation, an FGFR alteration, or a MYB or MYBL1 rearrangement.<ref>{{Cite journal  | last1 = Ellison | first1 = DW. | last2 = Hawkins | first2 = C. | last3 = Jones | first3 = DTW. | last4 = Onar-Thomas | first4 = A. | last5 = Pfister | first5 = SM. | last6 = Reifenberger | first6 = G. | last7 = Louis | first7 = DN. | title = cIMPACT-NOW update 4: diffuse gliomas characterized by MYB, MYBL1, or FGFR1 alterations or BRAF | journal = Acta Neuropathol | volume = 137 | issue = 4 | pages = 683-687 | month = Apr | year = 2019 | doi = 10.1007/s00401-019-01987-0 | PMID = 30848347 }}</ref>
***Glial morphology can be astrocytic or oligodendrocytic.
**Suggested sign-out:
<pre>
    Diffuse glioma, MYB-altered.
    Diffuse glioma, MYBL1-altered.
    Diffuse glioma, FGFR1 TKD-duplicated.
    Diffuse glioma, FGFR1-mutant.
    Diffuse glioma, BRAF V600E-mutant.
    Diffuse glioma, other MAPK pathway alteration.
</pre>


==DDx==
==DDx==
*Reactive astrocytosis.
*Reactive astrocytosis.
*Demyelinisation.
*Demyelinisation.
*[[Anaplastic astrocytoma]] - increased mitotic activity.
*[[Oligoastrocytoma]], NOS - esp. when genetic data on IDH and LOH 1p/19q are lacking.
*[[Oligodendroglioma]] - esp. protoplasmatic forms. LOH 1p/19q testing required.
*[[SEGA]] - esp. gemistocytic forms.


<gallery>
File:Astrocytoma whoII HE.jpg | Astrocytoma, fibrillary type (WC/jensflorian)
File:Neuropathology case II 02.jpg | Astrocytoma, protoplasmatic type (WC/jensflorian)
</gallery>


=See also=
=See also=

Latest revision as of 08:12, 27 May 2019

Diffuse astrocytoma (AKA: diffuse, low-grade astrocytoma) is a infiltrating astrocytoma occurring in the CNS white matter.

  • Most common grade II WHO glioma in adults (peaks between 30-40 years).
  • 10-15% of all astrocytomas.
  • Usually shows progression to glioblastoma sooner or later.

WHO 2016 categorization combines morphology and genetics into following groups:[1]

  • 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)[2] This subtyping is no longer in use. These tumors are now classified according their IDH mutation status.

Radiology/Clinic

  • Mass effect.
  • Seizures.
  • Neurologic decifit.
  • Usually not contrast-enhanching, T2 bright.

Macroscopy

  • No clear demarcation from white matter
  • May contain larger cysts
  • No necrosis

Histology

Features: [3]

  • Cell density higher than normal brain.
  • Mild to moderate nuclear pleomorphism.
    • Monotony of atypical nuclei and irregular distribution indicates neoplasm.
    • "naked nuclei" without recognizeable processes.
    • No prominent nucleolus.
  • Cytoplasm highly variable (even within the same tumour).
    • In normal CNS the cytoplasm blends within the neuropil.
  • Mitoses absent or very rare.
  • Microcystic spaces of the background (none to extensive).
  • No necrosis, no vascular proliferations.
    • Except radiation necrosis.
  • Lymphocytic cuffing (mostly in gemistocytic type)
  • Abent to few rosenthal fibers.

  • Diffuse astrocytoma, H&E (WC/jensflorian)

  • Diffuse astrocytoma, H&E (WC/jensflorian)

  • Astrocytoma, fibrillary type (WC/jensflorian)

  • Astrocytoma, protoplasmatic type (WC/jensflorian)

  • Gemistocytic astrocytoma (WC/jensflorian)


IHC

  • GFAP+ve.
  • MAP2+ve (especially in cell processes).
  • Vimentin+ve (often perinuclear).
  • S-100+ve.
  • p53: Nuclear staining in 30% of the tumours (usually few cells).
  • MIB-1: 0-5% (mean: 2%).
  • IDH-1 (R132H)+ve in 60-70%.
    • 'Note: This antibody does not detect other rare IDH1/2 mutations.
  • ATRX nuclear loss in 70%.

  • GFAP in astrocytoma (WC/jensflorian)

  • ATRX loss in astrocytoma (WC/jensflorian)

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).
  • MGMT promotor methylated in approx. 50%.
  • CDKN2A/B homozygous deletion in IDH mutant diffuse astrocytoma has unfavourable prognosis.[4][5]

Note:

  • The existence of diffuse astrocytoma, IDH wildtype is challenged.[6]
    • Most adult cases show genetic alterations compatible with glioblastoma.[7]
    • Molecular upgrade according to cIMPACT-NOW Update 3 consensus (one of these is sufficient):[8]
      • EGFR amplification
      • Combined whole chromosome 7 gain and whole chromosome 10 loss (+ 7/− 10)
      • TERT promoter mutation
    • Suggested Sign-out: 
       Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV
    • WHO grade II diffuse gliomas IDH-wt/H3-wt in children and adolescents have an indolent clinical behavior and rare anaplastic progression.
      • Most tumors show a BRAFV600E mutation, an FGFR alteration, or a MYB or MYBL1 rearrangement.[9]
      • Glial morphology can be astrocytic or oligodendrocytic.
    • Suggested sign-out:
    Diffuse glioma, MYB-altered.
    Diffuse glioma, MYBL1-altered.
    Diffuse glioma, FGFR1 TKD-duplicated.
    Diffuse glioma, FGFR1-mutant.
    Diffuse glioma, BRAF V600E-mutant.
    Diffuse glioma, other MAPK pathway alteration.

DDx


See also

  1. ↑ Louis, DN.; Perry, A.; Reifenberger, G.; von Deimling, A.; Figarella-Branger, D.; Cavenee, WK.; Ohgaki, H.; Wiestler, OD. et al. (Jun 2016). "The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.". Acta Neuropathol 131 (6): 803-20. doi:10.1007/s00401-016-1545-1. PMID 27157931.
  2. ↑ The International Agency for Research on Cancer (Editors: Louis, D.N.; Ohgaki, H.; Wiestler, O.D.; Cavenee, W.K.) (2007). Pathology and Genetics of Tumours of Tumors of the Central Nervous System (IARC WHO Classification of Tumours) (4th ed.). Lyon: World Health Organization. pp. 25. doi:10.1007/s00401-007-0243-4. ISBN 978-9283224303.
  3. ↑ Burger, P.C.; Scheithauer, B.W. (2007). Tumors of the Central Nervous System (Afip Atlas of Tumor Pathology) (4th ed.). Washington: American Registry of Pathology. pp. 34. ISBN 1933477016.
  4. ↑ Shirahata, M.; Ono, T.; Stichel, D.; Schrimpf, D.; Reuss, DE.; Sahm, F.; Koelsche, C.; Wefers, A. et al. (Jul 2018). "Novel, improved grading system(s) for IDH-mutant astrocytic gliomas.". Acta Neuropathol 136 (1): 153-166. doi:10.1007/s00401-018-1849-4. PMID 29687258.
  5. ↑ Aoki, K.; Nakamura, H.; Suzuki, H.; Matsuo, K.; Kataoka, K.; Shimamura, T.; Motomura, K.; Ohka, F. et al. (01 2018). "Prognostic relevance of genetic alterations in diffuse lower-grade gliomas.". Neuro Oncol 20 (1): 66-77. doi:10.1093/neuonc/nox132. PMID 29016839.
  6. ↑ Reuss, DE.; Kratz, A.; Sahm, F.; Capper, D.; Schrimpf, D.; Koelsche, C.; Hovestadt, V.; Bewerunge-Hudler, M. et al. (Sep 2015). "Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities.". Acta Neuropathol 130 (3): 407-17. doi:10.1007/s00401-015-1454-8. PMID 26087904.
  7. ↑ Hasselblatt, M.; Jaber, M.; Reuss, D.; Grauer, O.; Bibo, A.; Terwey, S.; Schick, U.; Ebel, H. et al. (Feb 2018). "Diffuse Astrocytoma, IDH-Wildtype: A Dissolving Diagnosis.". J Neuropathol Exp Neurol. doi:10.1093/jnen/nly012. PMID 29444314.
  8. ↑ Brat, DJ.; Aldape, K.; Colman, H.; Holland, EC.; Louis, DN.; Jenkins, RB.; Kleinschmidt-DeMasters, BK.; Perry, A. et al. (Nov 2018). "cIMPACT-NOW update 3: recommended diagnostic criteria for "Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV".". Acta Neuropathol 136 (5): 805-810. doi:10.1007/s00401-018-1913-0. PMID 30259105.
  9. ↑ Ellison, DW.; Hawkins, C.; Jones, DTW.; Onar-Thomas, A.; Pfister, SM.; Reifenberger, G.; Louis, DN. (Apr 2019). "cIMPACT-NOW update 4: diffuse gliomas characterized by MYB, MYBL1, or FGFR1 alterations or BRAF". Acta Neuropathol 137 (4): 683-687. doi:10.1007/s00401-019-01987-0. PMID 30848347.
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