Astrocytoma, IDH-mutant

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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 is mandatory for diagnosis and are frequently associated with ATRX and TP53 mutations.

General

The current WHO classification recognizes three tumour grades:

  • Astrocytoma, IDH mutant grade 2 (ICD-O: 9400/3)
  • Astrocytoma, IDH mutant grade 3 (ICD-O: 9401/3)
  • Astrocytoma, IDH mutant grade 4 (ICD-O: 9445/3)
  • Diffuse astrocytoma,NOS (ICD-O 9400/3) - genetic testing still missing.

Radiology/Clinic

  • Mass effect.
  • Seizures.
  • Neurologic decifit.
  • CNS grade 2: Usually not contrast-enhanching, T2 bright.
  • CNS grade 3 and 4: The majority are contrast-enhanching, T2 bright.

Macroscopy

  • No clear demarcation from white matter.
  • Softer consistency and opacity.
  • May contain larger cysts
  • Invaded structures may appear enlarged.
  • CNS grade 2 and 3: No necrosis.

Histology

CNS grade 2 features: [1]

  • 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).
  • Lymphocytic cuffing (mostly in gemistocytic type)
  • Abent to few rosenthal fibers.

CNS grade 3 features: [1]

  • Increased cellularity (compared to CNS grade 2).
  • Mitoses present (a single mitosis in a small specimen indicates a high-grade tumor).
    • Specimens with low cellularity but plenty of mitoses are also considered grade 3.
  • Distinct nuclear atypia and pleomorphism.
    • May include multinucleated cells.
  • 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

  • GFAP+ve.
  • MAP2+ve (especially in cell processes).
  • OLIG2 +ve.
  • Vimentin+ve (often perinuclear).
  • S-100+ve.
  • p53: Nuclear staining in 30% of the tumours (usually few cells).
  • MIB-1: CNS grade 2: 0-5% (mean: 2%); CNS grade 3 usu. 5-10%.
  • IDH-1 (R132H)+ve in 60-70%.
    • 'Note: The mutation-specific antibody does not detect other less common IDH1/2 hotspot mutations.
  • 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 astrocytomas.
  • Usually shows progression to glioblastoma sooner or later.

WHO 2016 categorization combines morphology and genetics into following groups:[2]

  • 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)[3] 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 gliomas.[4]
  • 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).
  • MGMT promotor methylated in approx. 50%.
  • CDKN2A/B homozygous deletion in IDH mutant diffuse astrocytoma has unfavourable prognosis.[5][6]

Note:

  • The existence of diffuse astrocytoma, IDH wildtype is challenged.[7]
    • Most adult cases show genetic alterations compatible with glioblastoma.[8]
    • Molecular upgrade according to cIMPACT-NOW Update 3 consensus (one of these is sufficient):[9]
      • 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.[10]
      • Glial morphology can be astrocytic or oligodendrocytic.


  • GFAP in astrocytoma (WC/jensflorian)

  • ATRX loss in astrocytoma (WC/jensflorian)

  • 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)

DDx

For CNS grade 2 tumours:

  • Reactive astrocytosis.
  • Demyelinisation.
  • Grade 3 astrocytoma, IDH mutant - increased mitotic activity.
  • Oligodendroglioma, IDH-mutant and 1p/19q codeleted - esp. protoplasmatic forms. LOH 1p/19q testing required.
  • SEGA - esp. gemistocytic forms.
  • Diffuse glioma, MYB- or MYBL1-altered.

For CNS grade 3 tumours:

For CNS grade 4 tumours:




WHO 2016 categorization combines morphology and genetics into following groups:[11]

  • 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.[12]
  • Anaplastic astrocytoma, IDH-wildtype perform worse than glioblastoma, IDH-mutant despite grading differences.[13]



  • Marked mitotic activity in anaplastic astrocytoma (WC/jensflorian).

  • Marked nuclear pleomorphism (AFIP).


Molecular

  • TERT promotor mutations in 20-25%[14][15]
  • Approximately 80 % of IDH wildtype astrocytomas in fact represent underdiagnosed GBM.[16]

Outdated terminologies

  • Diffuse astrocytoma
  • Gemistocytic astrocytoma
  • Diffuse astrocytoma, IDH-wildtype


Note: Older terminologies included Fibrillary astrocytoma (ICD-O: 9420/3) and Protoplasmatic astrocytoma (ICD-O:9410/3)[3] This subtyping is no longer in use. These tumors are now classified according their IDH mutation status.

See also

  1. ↑ 1.0 1.1 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.
  2. ↑ 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.
  3. ↑ 3.0 3.1 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.
  4. ↑ Ohgaki, H.; Kleihues, P. (Jun 2005). "Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas.". J Neuropathol Exp Neurol 64 (6): 479-89. PMID 15977639.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ Reuss, DE.; Mamatjan, Y.; Schrimpf, D.; Capper, D.; Hovestadt, V.; Kratz, A.; Sahm, F.; Koelsche, C. et al. (Jun 2015). "IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO.". Acta Neuropathol 129 (6): 867-73. doi:10.1007/s00401-015-1438-8. PMID 25962792.
  13. ↑ Hartmann, C.; Hentschel, B.; Wick, W.; Capper, D.; Felsberg, J.; Simon, M.; Westphal, M.; Schackert, G. et al. (Dec 2010). "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.". Acta Neuropathol 120 (6): 707-18. doi:10.1007/s00401-010-0781-z. PMID 21088844.
  14. ↑ Lee, Y.; Koh, J.; Kim, SI.; Won, JK.; Park, CK.; Choi, SH.; Park, SH. (Aug 2017). "The frequency and prognostic effect of TERT promoter mutation in diffuse gliomas.". Acta Neuropathol Commun 5 (1): 62. doi:10.1186/s40478-017-0465-1. PMID 28851427.
  15. ↑ Koelsche, C.; Sahm, F.; Capper, D.; Reuss, D.; Sturm, D.; Jones, DT.; Kool, M.; Northcott, PA. et al. (Dec 2013). "Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system.". Acta Neuropathol 126 (6): 907-15. doi:10.1007/s00401-013-1195-5. PMID 24154961.
  16. ↑ 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.
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