Skip to main content
SpringerLink
Log in

Diagnostic revision of 206 adult gliomas (including 40 oligoastrocytomas) based on ATRX, IDH1/2 and 1p/19q status

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

The diagnosis of 206 low and high grade adult gliomas, including 40 oligoastrocytomas, was revised based on the immunohistochemical reactivity for the ATRX protein, IDH1/2 mutation status and 1p/19q chromosomal status. All oligodendrogliomas kept the initial diagnosis. Astrocytomas did not change diagnosis in 30 of 36 cases (83.3 %); four of 36 (11.1 %) cases were reclassified as oligodendroglioma, one (2.8 %) as DNT and the other (2.8 %) as reactive gliosis. Oligoastrocytomas changed diagnosis in 35 of 40 (87.5 %) cases, being reclassified 22 of 40 (55 %) as astrocytoma, 11 of 40 (27.5 %) as oligodendroglioma and two of 40 (5 %) as reactive gliosis. Four (10 %) remained unclassifiable. In one case only (2.5 %), the diagnosis of oligoastrocytoma could not be excluded since tumor astrocytes and tumor oligodendrocytes coexisted in mixed tumor areas. In the GBM tumor subgroup, GBMO disappeared because they were not substantiated by molecular genetics. Pilocytic astrocytomas retained ATRX expression. Loss of nuclear ATRX protein expression was strongly associated to IDH1/2 mutations (p = 0.0001) and mutually exclusive with total 1p/19q co-deletion (p = 0.0001). In astrocytic tumors, loss of immunoreactivity for the ATRX protein was significantly associated to the ALT phenotype (p = 0.0003). The constitutive ATRX expression in microglia/macrophages may be misleading, especially in the identification of an oligodendroglial tumor infiltration. Of paramount importance in the recognition of oligodendroglial and astrocytic tumor cells were the double immunostainings for ATRX/GFAP, ATRX/IDH1R132H, ATRX/Iba-1 and ATRX/CD68.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2007) WHO classification of tumours of the central nervous system, 4th edn. IARC Press, Lyon, pp 1–309

  2. 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 79:1381–1393

    Article  CAS  PubMed  Google Scholar 

  3. Krouwer HG, van Duinen SG, Kamphorst W, van der Valk P, Algra A (1997) Oligoastrocytomas: a clinicopathological study of 52 cases. J Neurooncol 33:223–238

    Article  CAS  PubMed  Google Scholar 

  4. Cooper ERA (1935) The relation of oligocytes and astrocytes in cerebral tumours. J Pathol 41:259–266

    Article  Google Scholar 

  5. Hart MN, Petito CK, Earle KM (1974) Mixed gliomas. Cancer 33:134–140

    Article  CAS  PubMed  Google Scholar 

  6. Daumas-Duport C, Varlet P, Tucker ML, Beuvon F, Cervera P et al (1997) Oligodendrogliomas. Part I: patterns of growth, histological diagnosis, clinical and imaging correlations: a study of 153 cases. J Neurooncol 34:37–59

    Article  CAS  PubMed  Google Scholar 

  7. de Armond SJ, Eng LF, Rubinstein LJ (1980) The application of glial fibrillary acidic (GFA) protein immunohistochemistry in neurooncology. A progress report. Pathol Res Pract 168:374–394

    Article  PubMed  Google Scholar 

  8. van der Meulen JD, Houthoff HJ, Ebels EJ (1978) Glial fibrillary acidic protein in human gliomas. Neuropathol Appl Neurobiol 4:177–190

    Article  PubMed  Google Scholar 

  9. Herpers MJ, Budka H (1984) Glial fibrillary acidic protein (GFAP) in oligodendroglial tumors: gliofibrillary oligodendroglioma and transitional oligoastrocytoma as subtypes of oligodendroglioma. Acta Neuropathol 64:265–272

    Article  CAS  PubMed  Google Scholar 

  10. Choi BH, Kim RC (1984) Expression of glial fibrillary acidic protein in immature oligodendroglia. Science 223:407–409

    Article  CAS  PubMed  Google Scholar 

  11. Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH et al (2011) Altered telomeres in tumors with ATRX and DAXX mutations. Science 333:425. doi:10.1126/science.1207313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kannan K, Inagaki A, Silber J, Gorovets D, Zhang J et al (2012) Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma. Oncotarget 3:1194–1203

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jiao Y, Killela PJ, Reitman ZJ, Rasheed AB, Heaphy CM et al (2012) Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 3:709–722

    Article  PubMed  PubMed Central  Google Scholar 

  14. Liu XY, Gerges N, Korshunov A, Sabha N, Khuong-Quang DA et al (2012) Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations. Acta Neuropathol 124:615–625. doi:10.1007/s00401-012-1031-3

    Article  CAS  PubMed  Google Scholar 

  15. Wiestler B, Capper D, Holland-Letz T, Korshunov A, von Deimling A 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 126:443–451. doi:10.1007/s00401-013-1156-z

    Article  CAS  PubMed  Google Scholar 

  16. Cryan JB, Haidar S, Ramkissoon LA, Bi WL, Knoff DS et al (2014) Clinical multiplexed exome sequencing distinguishes adult oligodendroglial neoplasms from astrocytic and mixed lineage gliomas. Oncotarget 5:8083–8092

    Article  PubMed  PubMed Central  Google Scholar 

  17. Leeper HE, Caron AA, Decker PA, Jenkins RB, Lachance DH et al (2015) IDH mutation, 1p19q codeletion and ATRX loss in WHO grade II gliomas. Oncotarget 6:30295–30305. doi:10.18632/oncotarget.4497

    PubMed  PubMed Central  Google Scholar 

  18. Clynes D, Higgs DR, Gibbons RJ (2013) The chromatin remodeller ATRX: a repeat offender in human disease. Trends Biochem Sci 38:461–466. doi:10.1016/j.tibs.2013.06.011

    Article  CAS  PubMed  Google Scholar 

  19. Goldberg AD, Banaszynski LA, Noh KM, Lewis PW, Elsaesser SJ et al (2010) Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140:678–691. doi:10.1016/j.cell.2010.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lewis PW, Elsaesser SJ, Noh KM, Stadler SC, Allis CD (2010) Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc Natl Acad Sci USA 107:14075–14080. doi:10.1073/pnas.1008850107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nguyen DN, Heaphy CM, de Wilde RF, Orr BA, Odia Y et al (2013) Molecular and morphologic correlates of the alternative lengthening of telomeres phenotype in high-grade astrocytomas. Brain Pathol 23:237–243. doi:10.1111/j.1750-3639.2012.00630

    Article  PubMed  Google Scholar 

  22. Sahm F, Reuss D, Koelsche C, Capper D, Schittenhelm J et al (2014) Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma. Acta Neuropathol 128:551–559. doi:10.1007/s00401-014-1326-7

    Article  CAS  PubMed  Google Scholar 

  23. Reuss DE, Sahm F, Schrimpf D, Wiestler B, Capper D et al (2015) ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an “integrated” diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma. Acta Neuropathol 129:133–146. doi:10.1007/s00401-014-1370-3

    Article  CAS  PubMed  Google Scholar 

  24. Louis DN, Perry A, Burger P, Ellison DW, Reifenberger G et al (2014) International Society Of Neuropathology-Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol 24:429–435. doi:10.1111/bpa.12171

    Article  PubMed  Google Scholar 

  25. Weller M, Berger H, Hartmann C, Schramm J, Westphal M et al (2007) Combined 1p/19q loss in oligodendroglial tumors: predictive or prognostic biomarker? Clin Cancer Res 13:6933–6937

    Article  CAS  PubMed  Google Scholar 

  26. Mellai M, Piazzi A, Caldera V, Monzeglio O, Cassoni P et al (2011) IDH1 and IDH2 mutations, immunohistochemistry and associations in a series of brain tumors. J Neurooncol 105:345–357. doi:10.1007/s11060-011-0596-3

    Article  CAS  PubMed  Google Scholar 

  27. Mellai M, Caldera V, Annovazzi L, Schiffer D (2013) The distribution and significance of IDH mutation in gliomas. In: Lichtor T (ed) Evolution of the molecular biology of brain tumors and therapeutic implications. Rjieka, Croatia, pp. 299–342

  28. Bosone I, Cavalla P, Chiadò-Piat L, Vito ND, Schiffer D (2001) Cyclin D1 expression in normal oligodendroglia and microglia cells: its use in the differential diagnosis of oligodendrogliomas. Neuropathology 21:155–161

    Article  CAS  PubMed  Google Scholar 

  29. Wilcox P, Li CC, Lee M, Shivalingam B, Brennan J et al (2015) Oligoastrocytomas: throwing the baby out with the bathwater? Acta Neuropathol 129:147–149. doi:10.1007/s00401-014-1353-4

    Article  PubMed  Google Scholar 

  30. Huse JT, Diamond EL, Wang L, Rosenblum MK (2015) Mixed glioma with molecular features of composite oligodendroglioma and astrocytoma: a true “oligoastrocytoma”? Acta Neuropathol 129:151–153. doi:10.1007/s00401-014-1359-y

    Article  PubMed  Google Scholar 

  31. Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J et al (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27:4150–4154. doi:10.1200/JCO.2009.21.9832

    Article  CAS  PubMed  Google Scholar 

  32. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773. doi:10.1056/NEJMoa0808710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hartmann C, Meyer J, Balss J, Capper D, Mueller W 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 118:469–474. doi:10.1007/s00401-009-0561-9

    Article  PubMed  Google Scholar 

  34. Reifenberger J, Reifenberger G, Liu L, James CD, Wechsler W et al (1994) Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol 145:1175–1190

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM et al (1998) Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:1473–1479

    Article  CAS  PubMed  Google Scholar 

  36. Thon N, Eigenbrod S, Kreth S, Lutz J, Tonn JC et al (2012) IDH1 mutations in grade II astrocytomas are associated with unfavorable progression-free survival and prolonged postrecurrence survival. Cancer 118:452–460. doi:10.1002/cncr.26298

    Article  CAS  PubMed  Google Scholar 

  37. von Deimling A, Bender B, Jahnke R, Waha A, Kraus J et al (1994) Loci associated with malignant progression in astrocytomas: a candidate on chromosome 19q. Cancer Res 54:1397–1401

    Google Scholar 

  38. Hartmann C, Johnk L, Kitange G, Wu Y, Ashworth LK et al (2002) Transcript map of the 3.7-Mb D19S112-D19S246 candidate tumor suppressor region on the long arm of chromosome 19. Cancer Res 62:4100–4108

    CAS  PubMed  Google Scholar 

  39. Barbashina V, Salazar P, Holland EC, Rosenblum MK, Ladanyi M (2005) Allelic losses at 1p36 and 19q13 in gliomas: correlation with histologic classification, definition of a 150-kb minimal deleted region on 1p36, and evaluation of CAMTA1 as a candidate tumor suppressor gene. Clin Cancer Res 11:1119–1128

    CAS  PubMed  Google Scholar 

  40. Raghavan R, Balani J, Perry A, Margraf L, Vono MB et al (2003) Pediatric oligodendrogliomas: a study of molecular alterations on 1p and 19q using fluorescence in situ hybridization. J Neuropathol Exp Neurol 62:530–537

    Article  PubMed  Google Scholar 

  41. Kreiger PA, Okada Y, Simon S, Rorke LB, Louis DN et al (2005) Losses of chromosomes 1p and 19q are rare in pediatric oligodendrogliomas. Acta Neuropathol 109:387–392

    Article  PubMed  Google Scholar 

  42. Rodriguez FJ, Tihan T, Lin D, McDonald W, Nigro J et al (2014) Clinicopathologic features of pediatric oligodendrogliomas: a series of 50 patients. Am J Surg Pathol 38:1058–1070. doi:10.1097/PAS.0000000000000221

    PubMed  PubMed Central  Google Scholar 

  43. Prayson RA (2016) Oligodendroglioma look-alikes: the histopathologic differential diagnosis. In: Reeves C (ed) Oligodendrogliomas. Nova Science Publishers, Hauppauge, pp 83–118

  44. Sturm D, Bender S, Jones DT, Lichter P, Grill J et al (2014) Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer 14:92–107. doi:10.1038/nrc3655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Foote MB, Papadopoulos N, Diaz LA Jr (2015) Genetic classification of gliomas: refining histopathology. Cancer Cell 28:9–11. doi:10.1016/j.ccell.2015.06.014

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Marta Mazzucco was supported by a fellowship from Fondazione Cassa di Risparmio di Vercelli (Vercelli, Italy).

Author information

Authors and Affiliations

  1. Research Center, Policlinico di Monza Foundation, Via Pietro Micca, 29, 13100, Vercelli, Italy

    Marta Mellai, Laura Annovazzi, Marta Mazzucco & Davide Schiffer

  2. Unit of Pathology, Candiolo Cancer Institute, FPO, IRCCS Candiolo, Turin, Italy

    Rebecca Senetta & Carmine Dell’Aglio

  3. Department of Medical Sciences, University of Turin, Turin, Italy

    Paola Cassoni

Authors
  1. Marta Mellai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura Annovazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rebecca Senetta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carmine Dell’Aglio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marta Mazzucco
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paola Cassoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Davide Schiffer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Davide Schiffer.

Ethics declarations

Conflict of interest

Authors declare no potential conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mellai, M., Annovazzi, L., Senetta, R. et al. Diagnostic revision of 206 adult gliomas (including 40 oligoastrocytomas) based on ATRX, IDH1/2 and 1p/19q status. J Neurooncol 131, 213–222 (2017). https://doi.org/10.1007/s11060-016-2296-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-016-2296-5

Keywords

Search

Navigation