Advertisement

Acta Neuropathologica

, Volume 121, Issue 2, pp 241–252 | Cite as

Mutation-specific IDH1 antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology

  • David Capper
  • David Reuss
  • Jens Schittenhelm
  • Christian Hartmann
  • Juliane Bremer
  • Felix Sahm
  • Patrick N. Harter
  • Astrid Jeibmann
  • Andreas von Deimling
Original Paper

Abstract

Isocitrate dehydrogenase 1 (IDH1) mutations are frequent in astrocytomas, oligoastrocytomas and oligodendrogliomas. We previously reported the generation of a mutation-specific antibody that specifically detects R132H mutated IDH1 protein (clone H09). Here, we investigate the feasibility of H09 immunohistochemistry to differentiate between oligodendrogliomas/oligoastrocytomas and other tumors with similar morphology. A total of 274 brain tumors presenting with focal or extensive clear cell morphology were investigated. High numbers of H09-positive cases were observed in adult grade II oligodendrogliomas (67 of 74, 91%), grade III oligodendrogliomas (65 of 69, 94%), grade II oligoastrocytomas (11 of 14, 79%) and grade III oligoastrocytomas (10 of 11, 91%). All cases of pediatric oligodendrogliomas (n = 7), neurocytomas (n = 41, 35 central, 4 extraventricular, 2 cerebellar liponeurocytomas), dysembryoplastic neuroepithelial tumors (n = 21), clear cell ependymomas (n = 8), clear cell meningiomas (n = 9) as well as 12 primary glioblastomas with oligodendroglial differentiation and 5 pilocytic astrocytomas with oligodendroglial-like differentiation were negative for H09 immunohistochemistry. Three oligodendrogliomas with neurocytic differentiation had evidence of IDH1/IDH2 mutations either by H09 immunohistochemistry or direct sequencing. We conclude that in tumors with an oligodendroglioma-like morphology, binding of H09 is highly specific for oligodendrogliomas or oligoastrocytomas and substantially helps in the discrimination from other clear cell tumors. Negative H09 immunohistochemistry of an adult oligodendroglioma or oligoastrocytoma should prompt the consideration of other clear cell neoplasms. Further, our observations firmly assign oligodendrogliomas with neurocytic differentiation to the group of oligodendrogliomas and demonstrate that H09 is especially helpful for the difficult discrimination of such lesions from extraventricular neurocytomas.

Keywords

Isocitrate dehydrogenase IDH1 R132H Antibody Oligodendroglioma Clear cell 

Notes

Acknowledgments

We would like to thank Jochen Meyer and Franziska Moessler for excellent technical assistance. This work was supported by the Bundesministerium für Bildung und Forschung (BMBF–01ES0730 and 01GS0883).

Conflict of interest

Under a licensing agreement between DIANOVA GmbH, Hamburg, Germany, and the German Cancer Research Center, Dr. Capper, Dr. Hartmann and Dr. von Deimling are entitled to a share of royalties received by the German Cancer Research Center on the sales of H09 antibody. The terms of this arrangement are being managed by the German Cancer Research Center in accordance with its conflict of interest policies.

References

  1. 1.
    Balss J, Meyer J, Mueller W et al (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116:597–602CrossRefPubMedGoogle Scholar
  2. 2.
    Bleeker FE, Lamba S, Leenstra S et al (2009) IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat 30:7–11CrossRefPubMedGoogle Scholar
  3. 3.
    Blumcke I, Muller S, Buslei R et al (2004) Microtubule-associated protein-2 immunoreactivity: a useful tool in the differential diagnosis of low-grade neuroepithelial tumors. Acta Neuropathol 108:89–96CrossRefPubMedGoogle Scholar
  4. 4.
    Capper D, Weissert S, Balss J et al (2010) Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors. Brain Pathol 20:245–254CrossRefPubMedGoogle Scholar
  5. 5.
    Capper D, Zentgraf H, Balss J et al (2009) Monoclonal antibody specific for IDH1 R132H mutation. Acta Neuropathol 118:599–601CrossRefPubMedGoogle Scholar
  6. 6.
    Chou S, Varikatt W, Dexter M et al (2010) Extraventricular neurocytoma with atypical features and ganglionic differentiation. J Clin Neurosci 17:920–922CrossRefPubMedGoogle Scholar
  7. 7.
    Dang L, White DW, Gross S et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744CrossRefPubMedGoogle Scholar
  8. 8.
    Fujisawa H, Marukawa K, Hasegawa M et al (2002) Genetic differences between neurocytoma and dysembryoplastic neuroepithelial tumor and oligodendroglial tumors. J Neurosurg 97:1350–1355CrossRefPubMedGoogle Scholar
  9. 9.
    Hartmann C, Meyer J, Balss J et al (2009) Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 118:469–474CrossRefPubMedGoogle Scholar
  10. 10.
    Ichimura K, Pearson DM, Kocialkowski S et al (2009) IDH1 mutations are present in the majority of common adult gliomas but are rare in primary glioblastomas. Neuro Oncol 11:341–347CrossRefPubMedGoogle Scholar
  11. 11.
    Idbaih A, Marie Y, Pierron G et al (2005) Two types of chromosome 1p losses with opposite significance in gliomas. Ann Neurol 58:483–487CrossRefPubMedGoogle Scholar
  12. 12.
    Koperek O, Gelpi E, Birner P et al (2004) Value and limits of immunohistochemistry in differential diagnosis of clear cell primary brain tumors. Acta Neuropathol 108:24–30CrossRefPubMedGoogle Scholar
  13. 13.
    Korshunov A, Meyer J, Capper D et al (2009) Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol 118:401–405CrossRefPubMedGoogle Scholar
  14. 14.
    Kreiger PA, Okada Y, Simon S et al (2005) Losses of chromosomes 1p and 19q are rare in pediatric oligodendrogliomas. Acta Neuropathol 109:387–392CrossRefPubMedGoogle Scholar
  15. 15.
    Kuhlmann T, Gutenberg A, Schulten HJ et al (2008) Nogo-a expression in glial CNS tumors: a tool to differentiate between oligodendrogliomas and other gliomas? Am J Surg Pathol 32:1444–1453CrossRefPubMedGoogle Scholar
  16. 16.
    Labussiere M, Idbaih A, Wang XW et al (2010) All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2. Neurology 74:1886–1890CrossRefPubMedGoogle Scholar
  17. 17.
    Louis DN, Ohgaki H, Wiestler OD et al (2007) WHO classification of tumors of the central nervous system. IARC, LyonGoogle Scholar
  18. 18.
    Mardis ER, Ding L, Dooling DJ et al (2009) Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361:1058–1066CrossRefPubMedGoogle Scholar
  19. 19.
    Mrak RE, Yasargil MG, Mohapatra G et al (2004) Atypical extraventricular neurocytoma with oligodendroglioma-like spread and an unusual pattern of chromosome 1p and 19q loss. Hum Pathol 35:1156–1159CrossRefPubMedGoogle Scholar
  20. 20.
    Mueller W, Lass U, Veelken J et al (2006) 45-year-old male with symptomatic mass in the frontal lobe. Brain Pathol 16:89–90, 93Google Scholar
  21. 21.
    Mut M, Guler-Tezel G, Lopes MB et al (2005) Challenging diagnosis: oligodendroglioma versus extraventricular neurocytoma. Clin Neuropathol 24:225–229PubMedGoogle Scholar
  22. 22.
    Ng H, Ko H, Tse C (1994) Immunohistochemical and ultrastructural studies of oligodendrogliomas revealed features of neuronal differentiation. Int J Surg Pathol 2:47–56CrossRefGoogle Scholar
  23. 23.
    Nobusawa S, Watanabe T, Kleihues P et al (2009) IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas. Clin Cancer Res 15:6002–6007CrossRefPubMedGoogle Scholar
  24. 24.
    Ohgaki H, Kleihues P (2005) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64:479–489PubMedGoogle Scholar
  25. 25.
    Perry A, Burton SS, Fuller GN et al (2010) Oligodendroglial neoplasms with ganglioglioma-like maturation: a diagnostic pitfall. Acta Neuropathol 120:237–252CrossRefPubMedGoogle Scholar
  26. 26.
    Perry A, Fuller CE, Banerjee R et al (2003) Ancillary FISH analysis for 1p and 19q status: preliminary observations in 287 gliomas and oligodendroglioma mimics. Front Biosci 8:a1–a9CrossRefPubMedGoogle Scholar
  27. 27.
    Perry A, Scheithauer BW, Macaulay RJ et al (2002) Oligodendrogliomas with neurocytic differentiation. A report of 4 cases with diagnostic and histogenetic implications. J Neuropathol Exp Neurol 61:947–955PubMedGoogle Scholar
  28. 28.
    Preusser M, Budka H, Rossler K et al (2007) OLIG2 is a useful immunohistochemical marker in differential diagnosis of clear cell primary CNS neoplasms. Histopathology 50:365–370CrossRefPubMedGoogle Scholar
  29. 29.
    Preusser M, Laggner U, Haberler C et al (2006) Comparative analysis of NeuN immunoreactivity in primary brain tumours: conclusions for rational use in diagnostic histopathology. Histopathology 48:438–444CrossRefPubMedGoogle Scholar
  30. 30.
    Pusch S, Sahm F, Meyer J et al (2010) Glioma IDH1 mutation patterns off the beaten track. Neuropathol Appl NeurobiolGoogle Scholar
  31. 31.
    Raghavan R, Balani J, Perry A et al (2003) Pediatric oligodendrogliomas: a study of molecular alterations on 1p and 19q using fluorescence in situ hybridization. J Neuropathol Exp Neurol 62:530–537PubMedGoogle Scholar
  32. 32.
    Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8:138–140PubMedGoogle Scholar
  33. 33.
    Rodriguez FJ, Mota RA, Scheithauer BW et al (2009) Interphase cytogenetics for 1p19q and t(1;19)(q10;p10) may distinguish prognostically relevant subgroups in extraventricular neurocytoma. Brain Pathol 19:623–629CrossRefPubMedGoogle Scholar
  34. 34.
    Rodriguez FJ, Scheithauer BW, Robbins PD et al (2007) Ependymomas with neuronal differentiation: a morphologic and immunohistochemical spectrum. Acta Neuropathol 113:313–324CrossRefPubMedGoogle Scholar
  35. 35.
    Sahm F, Capper D, Meyer J et al (2010) Immunohistochemical analysis of 1844 human epithelial and hematopoietic tumors and sarcomas for IDH1R132H mutation. HistopathologyGoogle Scholar
  36. 36.
    Sanson M, Marie Y, Paris S et al (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27:4150–4154CrossRefPubMedGoogle Scholar
  37. 37.
    Soylemezoglu F, Onder S, Tezel GG et al (2003) Neuronal nuclear antigen (NeuN): a new tool in the diagnosis of central neurocytoma. Pathol Res Pract 199:463–468CrossRefPubMedGoogle Scholar
  38. 38.
    Takeuchi H, Kubota T, Kitai R et al (2009) Chromosome 1p and 19q deletions in malignant glioneuronal tumors with oligodendroglioma-like component. J Neurooncol 91:33–38CrossRefPubMedGoogle Scholar
  39. 39.
    Vajtai I, Arnold M, Vassella E (2005) Oligodendroglioma with neurocytic differentiation and characteristic loss of heterozygosity on chromosomes 1p and 19q. Acta Neuropathol 110:520–522CrossRefPubMedGoogle Scholar
  40. 40.
    Vallat-Decouvelaere AV, Gauchez P, Varlet P et al (2000) So-called malignant and extra-ventricular neurocytomas: reality or wrong diagnosis? A critical review about two overdiagnosed cases. J Neurooncol 48:161–172CrossRefPubMedGoogle Scholar
  41. 41.
    Ward PS, Patel J, Wise DR et al (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17:225–234CrossRefPubMedGoogle Scholar
  42. 42.
    Watanabe T, Nobusawa S, Kleihues P et al (2009) IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 174:1149–1153CrossRefPubMedGoogle Scholar
  43. 43.
    Wharton SB, Chan KK, Hamilton FA et al (1998) Expression of neuronal markers in oligodendrogliomas: an immunohistochemical study. Neuropathol Appl Neurobiol 24:302–308CrossRefPubMedGoogle Scholar
  44. 44.
    Wolf HK, Buslei R, Blumcke I et al (1997) Neural antigens in oligodendrogliomas and dysembryoplastic neuroepithelial tumors. Acta Neuropathol 94:436–443CrossRefPubMedGoogle Scholar
  45. 45.
    Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • David Capper
    • 1
    • 2
  • David Reuss
    • 1
    • 2
  • Jens Schittenhelm
    • 3
  • Christian Hartmann
    • 1
    • 2
  • Juliane Bremer
    • 4
  • Felix Sahm
    • 1
  • Patrick N. Harter
    • 5
  • Astrid Jeibmann
    • 6
  • Andreas von Deimling
    • 1
    • 2
  1. 1.Department of Neuropathology, Institute of PathologyRuprecht-Karls-Universität HeidelbergHeidelbergGermany
  2. 2.Clinical Cooperation Unit NeuropathologyGerman Cancer Research CenterHeidelbergGermany
  3. 3.Institute of Brain ResearchUniversity Hospital TuebingenTübingenGermany
  4. 4.Institute of NeuropathologyUniversity Hospital of ZürichZürichSwitzerland
  5. 5.Institute of Neurology (Edinger Institute)Goethe University School of MedicineFrankfurt am MainGermany
  6. 6.Institute of NeuropathologyUniversity Hospital MünsterMünsterGermany

Personalised recommendations