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Acta Neuropathologica

, Volume 128, Issue 4, pp 551–559 | Cite as

Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma

  • Felix Sahm
  • David Reuss
  • Christian Koelsche
  • David Capper
  • Jens Schittenhelm
  • Stephanie Heim
  • David T. W. Jones
  • Stefan M. Pfister
  • Christel Herold-Mende
  • Wolfgang Wick
  • Wolf Mueller
  • Christian Hartmann
  • Werner Paulus
  • Andreas von Deimling
Original Paper

Abstract

Astrocytoma and oligodendroglioma are histologically and genetically well-defined entities. The majority of astrocytomas harbor concurrent TP53 and ATRX mutations, while most oligodendrogliomas carry the 1p/19q co-deletion. Both entities share high frequencies of IDH mutations. In contrast, oligoastrocytomas (OA) appear less clearly defined and, therefore, there is an ongoing debate whether these tumors indeed constitute an entity or whether they represent a mixed bag containing both astrocytomas and oligodendrogliomas. We investigated 43 OA diagnosed in different institutions employing histology, immunohistochemistry and in situ hybridization addressing surrogates for the molecular genetic markers IDH1R132H, TP53, ATRX and 1p/19q loss. In all but one OA the combination of nuclear p53 accumulation and ATRX loss was mutually exclusive with 1p/19q co-deletion. In 31/43 OA, only alterations typical for oligodendroglioma were observed, while in 11/43 OA, only indicators for mutations typical for astrocytomas were detected. A single case exhibited a distinct pattern, nuclear expression of p53, ATRX loss, IDH1 mutation and partial 1p/19q loss. However, this was the only patient undergoing radiotherapy prior to surgery, possibly contributing to the acquisition of this uncommon combination. In OA with oligodendroglioma typical alterations, the portions corresponding to astrocytic part were determined as reactive, while in OA with astrocytoma typical alterations the portions corresponding to oligodendroglial differentiation were neoplastic. These data provide strong evidence against the existence of an independent OA entity.

Keywords

Mixed glioma Oligoastrocytoma 1p/19q ATRX TP53 IDH1 

Notes

Acknowledgments

The study was supported by the Medical Faculty Heidelberg PostDoc Fellowship and the DKFZ Intramural Funding Program, Priority Topic Intratumoral Heterogeneity, to FS. We wish to thank Tanja Goeck and Katrin Kalis for skillful technical assistance.

Supplementary material

401_2014_1326_MOESM1_ESM.pdf (4.7 mb)
Supplementary material 1 (PDF 4820 kb)
401_2014_1326_MOESM2_ESM.docx (37 kb)
Supplementary material 2 (DOCX 37 kb)

References

  1. 1.
    Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116:597–602PubMedCrossRefGoogle Scholar
  2. 2.
    Bo H, Ghazizadeh M, Shimizu H et al (2004) Effect of ionizing irradiation on human esophageal cancer cell lines by cDNA microarray gene expression analysis. J Nippon Med Sch Nippon Ika Daigaku zasshi 71:172–180CrossRefGoogle Scholar
  3. 3.
    Boiardi A, Silvani A, Pozzi A et al (1997) Advantage of treating anaplastic gliomas with aggressive protocol combining chemotherapy and radiotherapy. J Neurooncol 34:179–185PubMedCrossRefGoogle Scholar
  4. 4.
    Burger PC, Minn AY, Smith JS et al (2001) Losses of chromosomal arms 1p and 19q in the diagnosis of oligodendroglioma. A study of paraffin-embedded sections. Mod Pathol Off J US Can Acad Pathol Inc 14:842–853Google Scholar
  5. 5.
    Cairncross G, Wang M, Shaw E et al (2013) Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol Off J Am Soc Clin Oncol 31:337–343CrossRefGoogle Scholar
  6. 6.
    Camelo-Piragua S, Jansen M, Ganguly A, Kim JC, Louis DN, Nutt CL (2010) Mutant IDH1-specific immunohistochemistry distinguishes diffuse astrocytoma from astrocytosis. Acta Neuropathol 119:509–511PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Capper D, Sahm F, Hartmann C (2010) Application of mutant IDH1 antibody to differentiate diffuse glioma from non-neoplastic central nervous system lesions and therapy induced changes. Am J Surg Pathol 34:1199–1204PubMedCrossRefGoogle Scholar
  8. 8.
    Capper D, Weissert S, Balss J et al (2010) Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors. Brain Pathol 20:245–254PubMedCrossRefGoogle Scholar
  9. 9.
    Capper D, Zentgraf H, Balss J, Hartmann C, von Deimling A (2009) Monoclonal antibody specific for IDH1 R132H mutation. Acta Neuropathol 118:599–601PubMedCrossRefGoogle Scholar
  10. 10.
    Coons SW, Johnson PC, Scheithauer BW, Yates AJ, Pearl DK (1997) Improving diagnostic accuracy and interobserver concordance in the classification and grading of primary gliomas. Cancer 79:1381–1393PubMedCrossRefGoogle Scholar
  11. 11.
    Cooper ERA (1935) The relation of oligocytes and astrocytes in cerebral tumours. J Pathol Bacteriol 41:259–266CrossRefGoogle Scholar
  12. 12.
    Daumas-Duport C, Varlet P, Tucker ML, Beuvon F, Cervera P, Chodkiewicz JP (1997) Oligodendrogliomas. Part I: patterns of growth, histological diagnosis, clinical and imaging correlations: a study of 153 cases. J Neurooncol 34:37–59PubMedCrossRefGoogle Scholar
  13. 13.
    Devaux BC, O’Fallon JR, Kelly PJ (1993) Resection, biopsy, and survival in malignant glial neoplasms. A retrospective study of clinical parameters, therapy, and outcome. J Neurosurg 78:767–775PubMedCrossRefGoogle Scholar
  14. 14.
    Fuller CE, Schmidt RE, Roth KA et al (2003) Clinical utility of fluorescence in situ hybridization (FISH) in morphologically ambiguous gliomas with hybrid oligodendroglial/astrocytic features. J Neuropathol Exp Neurol 62:1118–1128PubMedGoogle Scholar
  15. 15.
    Hart MN, Petito CK, Earle KM (1974) Mixed gliomas. Cancer 33:134–140PubMedCrossRefGoogle Scholar
  16. 16.
    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 118:469–474PubMedCrossRefGoogle Scholar
  17. 17.
    Henson JW, Hobbs W, Chakravarti A, Louis DN (2005) Alterations in p53, p21, and MIB-1 labeling index in primary human astrocytomas following radiation therapy. J Neurooncol 74:151–154PubMedCrossRefGoogle Scholar
  18. 18.
    Jiao Y, Killela PJ, Reitman ZJ et al (2012) Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 3:709–722PubMedPubMedCentralGoogle Scholar
  19. 19.
    Kannan K, Inagaki A, Silber J et al (2012) Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma. Oncotarget 3:1194–1203PubMedPubMedCentralGoogle Scholar
  20. 20.
    Lammie GA, Beckett A, Courtney R, Scaravilli F (1994) An immunohistochemical study of p53 and proliferating cell nuclear antigen expression in progressive multifocal leukoencephalopathy. Acta Neuropathol 88:465–471PubMedCrossRefGoogle Scholar
  21. 21.
    Lass U, Hartmann C, Capper D et al (2013) Chromogenic in situ hybridization is a reliable alternative to fluorescence in situ hybridization for diagnostic testing of 1p and 19q loss in paraffin-embedded gliomas. Brain Pathol 23:311–318PubMedCrossRefGoogle Scholar
  22. 22.
    Lass U, Numann A, von Eckardstein K et al (2012) Clonal analysis in recurrent astrocytic, oligoastrocytic and oligodendroglial tumors implicates IDH1-mutation as common tumor initiating event. PLoS One 7:e41298PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Liu XY, Gerges N, Korshunov A et al (2012) Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations. Acta Neuropathol 124:615–625PubMedCrossRefGoogle Scholar
  24. 24.
    Louis DN (1994) The p53 gene and protein in human brain tumors. J Neuropathol Exp Neurol 53:11–21PubMedCrossRefGoogle Scholar
  25. 25.
    Louis DN, Cavenee WK, Ohgaki H, Wiestler OD (2007) WHO classification of tumours of the central nervous system. World Health Organization, LyonGoogle Scholar
  26. 26.
    Louis DN, von Deimling A, Chung RY et al (1993) Comparative study of p53 gene and protein alterations in human astrocytic tumors. J Neuropathol Exp Neurol 52:31–38PubMedCrossRefGoogle Scholar
  27. 27.
    Maintz D, Fiedler K, Koopmann J et al (1997) Molecular genetic evidence for subtypes of oligoastrocytomas. J Neuropathol Exp Neurol 56:1098–1104PubMedCrossRefGoogle Scholar
  28. 28.
    Mueller W, Hartmann C, Hoffmann A et al (2002) Genetic signature of oligoastrocytomas correlates with tumor location and denotes distinct molecular subsets. Am J Pathol 161:313–319PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Nguyen DN, Heaphy CM, de Wilde RF et al (2013) Molecular and morphologic correlates of the alternative lengthening of telomeres phenotype in high-grade astrocytomas. Brain Pathol 23:237–243PubMedCrossRefGoogle Scholar
  30. 30.
    Perry A (2001) Oligodendroglial neoplasms: current concepts, misconceptions, and folklore. Adv Anat Pathol 8:183–199PubMedCrossRefGoogle Scholar
  31. 31.
    Pusch S, Sahm F, Meyer J, Mittelbronn M, Hartmann C, von Deimling A (2010) Glioma IDH1 mutation patterns off the beaten track. Neuropathol Appl Neurobiol 37:428–430CrossRefGoogle Scholar
  32. 32.
    Qu M, Olofsson T, Sigurdardottir S et al (2007) Genetically distinct astrocytic and oligodendroglial components in oligoastrocytomas. Acta Neuropathol 113:129–136PubMedCrossRefGoogle Scholar
  33. 33.
    Rubio MP, von Deimling A, Yandell DW, Wiestler OD, Gusella JF, Louis DN (1993) Accumulation of wild type p53 protein in human astrocytomas. Cancer Res 53:3465–3467PubMedGoogle Scholar
  34. 34.
    Sahm F, Koelsche C, Meyer J et al (2012) CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas. Acta Neuropathol 123:853–860PubMedCrossRefGoogle Scholar
  35. 35.
    Schwartzentruber J, Korshunov A, Liu XY et al (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231PubMedCrossRefGoogle Scholar
  36. 36.
    Shaw EG, Scheithauer BW, O’Fallon JR, Davis DH (1994) Mixed oligoastrocytomas: a survival and prognostic factor analysis. Neurosurgery 34:577–582 (discussion 582)PubMedCrossRefGoogle Scholar
  37. 37.
    Sturm D, Witt H, Hovestadt V et al (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437PubMedCrossRefGoogle Scholar
  38. 38.
    Ueki K, Nishikawa R, Nakazato Y et al (2002) Correlation of histology and molecular genetic analysis of 1p, 19q, 10q, TP53, EGFR, CDK4, and CDKN2A in 91 astrocytic and oligodendroglial tumors. Clin Cancer Res Off J Am Assoc Cancer Res 8:196–201Google Scholar
  39. 39.
    van den Bent MJ, Brandes AA, Taphoorn MJ et al (2013) Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol Off J Am Soc Clin Oncol 31:344–350CrossRefGoogle Scholar
  40. 40.
    Watanabe T, Nakamura M, Kros JM et al (2002) Phenotype versus genotype correlation in oligodendrogliomas and low-grade diffuse astrocytomas. Acta Neuropathol 103:267–275PubMedCrossRefGoogle Scholar
  41. 41.
    Wick W, Hartmann C, Engel C et al (2009) NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol Off J Am Soc Clin Oncol 27:5874–5880CrossRefGoogle Scholar
  42. 42.
    Wiestler B, Capper D, Holland-Letz T et al (2013) ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis. Acta Neuropathol 126:443–451PubMedCrossRefGoogle Scholar
  43. 43.
    Wiestler B, Capper D, Sill M et al (2014) Integrated DNA methylation and copy-number profiling identifies three clinically and biologically relevant groups of anaplastic glioma. Acta Neuropathologica (in press)Google Scholar
  44. 44.
    Wiestler B, Capper D, Volker Hovestadt V et al (2014) Assessing CpG island methylator phenotype, 1p/19q codeletion and MGMT promoter methylation from epigenome-wide data in the biomarker cohort of the NOA-04 trial. Neuro Oncol (in press)Google Scholar
  45. 45.
    Wolter M, Reifenberger J, Blaschke B et al (2001) Oligodendroglial tumors frequently demonstrate hypermethylation of the CDKN2A (MTS1, p16INK4a), p14ARF, and CDKN2B (MTS2, p15INK4b) tumor suppressor genes. J Neuropathol Exp Neurol 60:1170–1180PubMedGoogle Scholar
  46. 46.
    Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Felix Sahm
    • 1
    • 2
  • David Reuss
    • 1
    • 2
  • Christian Koelsche
    • 1
    • 2
  • David Capper
    • 1
    • 2
  • Jens Schittenhelm
    • 3
  • Stephanie Heim
    • 4
  • David T. W. Jones
    • 5
  • Stefan M. Pfister
    • 5
    • 6
  • Christel Herold-Mende
    • 7
  • Wolfgang Wick
    • 8
    • 9
  • Wolf Mueller
    • 10
  • Christian Hartmann
    • 11
  • Werner Paulus
    • 4
  • Andreas von Deimling
    • 1
    • 2
  1. 1.Department of Neuropathology, Institute of PathologyRuprecht-Karls-University HeidelbergHeidelbergGermany
  2. 2.Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK)German Cancer Research Center (DKFZ)HeidelbergGermany
  3. 3.Department of Neuropathology, Institute of Pathology and NeuropathologyUniversity TübingenTübingenGermany
  4. 4.Institute of NeuropathologyUniversity Hospital MünsterMünsterGermany
  5. 5.Division of Pediatric NeurooncologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  6. 6.Department of Pediatric Oncology, Haematology and ImmunologyHeidelberg University HospitalHeidelbergGermany
  7. 7.Department of NeurosurgeryUniversity Hospital HeidelbergHeidelbergGermany
  8. 8.Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK)German Cancer Research Center (DKFZ)HeidelbergGermany
  9. 9.Department of Neurooncology at the National Center for Tumor DiseasesHeidelberg University HospitalHeidelbergGermany
  10. 10.Department of NeuropathologyUniversity Hospital LeipzigLeipzigGermany
  11. 11.Department for NeuropathologyInstitute of Pathology, Medizinische Hochschule HannoverHannoverGermany

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