Brain Tumor Pathology

, Volume 31, Issue 1, pp 40–46 | Cite as

Genetic and pathologic evolution of early secondary gliosarcoma

  • Kari-Elise T. Codispoti
  • Stacy Mosier
  • Robert Ramsey
  • Ming-Tseh Lin
  • Fausto J. Rodriguez
Case Report


Gliosarcoma is a subset of glioblastoma with glial and mesenchymal components. True secondary gliosarcomas (i.e. progressing from lower-grade precursors) in the absence of radiation therapy are very rare. We report the unique case of a 61-year-old male who developed a fibrillary astrocytoma (WHO grade II). In the absence of adjuvant therapy the tumor recurred 3 years later as a gliosarcoma comprising an infiltrating glial component and a curious, early high-grade sarcomatous component surrounding intratumoral vessels. DNA was extracted from formalin fixed paraffin-embedded tissues from the precursor low-grade glioma and from the glioma and sarcomatous components at progression. Samples were hybridized separately to a 300 k Illumina SNP array. IDH1(R132H) mutant protein immunohistochemistry was positive in all tissue components. Alterations identified in all samples included dup(1)(q21q41), del(1)(q41qter), del(2)(q31.1), del(2)(q36.3qter), del(4)(q35.1qter), dup(7)(q22.2q36.3), del(7)(q36.3qter), del(9)(p21.3pter), dup(10)(p13pter), del(10)(q26.13q26.3), dup(17) (q12qter), and copy neutral LOH(20)(p11.23p11.21). The recurrent tumor had additional alterations, including del(3)(p21.31q13.31), del(18)(q21.2qter), and a homozygous del(9)(p21.3)(CDKN2A locus) and the sarcoma component had, in addition, del(4)(p14pter), del(6)(q12qter), del(11)(q24.3qter), and del(16)(p11.2pter). In conclusion, unique copy number alterations were identified during tumor progression from a low-grade glioma to gliosarcoma. A subset of alterations developed specifically in the sarcomatous component.


Gliosarcoma IDH1 SNP array Secondary glioblastoma Brain 


  1. 1.
    Han SJ, Yang I, Tihan T, Prados MD, Parsa AT (2010) Primary gliosarcoma: key clinical and pathologic distinctions from glioblastoma with implications as a unique oncologic entity. J Neurooncol 96:313–320PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Boerman RH, Anderl K, Herath J, Borell T, Johnson N, Schaeffer-Klein J, Kirchhof A, Raap AK, Scheithauer BW, Jenkins RB (1996) The glial and mesenchymal elements of gliosarcomas share similar genetic alterations. J Neuropathol Exp Neurol 55:973–981PubMedCrossRefGoogle Scholar
  3. 3.
    Actor B, Cobbers JM, Buschges R, Wolter M, Knobbe CB, Lichter P, Reifenberger G, Weber RG (2002) Comprehensive analysis of genomic alterations in gliosarcoma and its two tissue components. Genes Chromosomes Cancer 34:416–427PubMedCrossRefGoogle Scholar
  4. 4.
    Han SJ, Yang I, Otero JJ, Ahn BJ, Tihan T, McDermott MW, Berger MS, Chang SM, Parsa AT (2010) Secondary gliosarcoma after diagnosis of glioblastoma: clinical experience with 30 consecutive patients. J Neurosurg 112:990–996PubMedCrossRefGoogle Scholar
  5. 5.
    Reis RM, Konu-Lebleblicioglu D, Lopes JM, Kleihues P, Ohgaki H (2000) Genetic profile of gliosarcomas. Am J Pathol 156:425–432PubMedCrossRefGoogle Scholar
  6. 6.
    Harada S, Henderson LB, Eshleman JR, Gocke CD, Burger P, Griffin CA, Batista DA (2011) Genomic changes in gliomas detected using single nucleotide polymorphism array in formalin-fixed, paraffin-embedded tissue: superior results compared with microsatellite analysis. J Mol Diagn 13:541–548PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Kent WJSC, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D (2002) The human genome browser at UCSC. Genome Res 12:10Google Scholar
  8. 8.
    Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. NEJM 360:765–773PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Kok K, Naylor SL, Buys CH (1997) Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes. Adv Cancer Res 71:27–92PubMedGoogle Scholar
  10. 10.
    Dammann R, Schagdarsurengin U, Seidel C, Strunnikova M, Rastetter M, Baier K, Pfeifer GP (2005) The tumor suppressor RASSF1A in human carcinogenesis: an update. Histol Histopathol 20:645–663PubMedGoogle Scholar
  11. 11.
    Agathanggelou A, Cooper WN, Latif F (2005) Role of the Ras-association domain family 1 tumor suppressor gene in human cancers. Cancer Res 65:3497–3508PubMedCrossRefGoogle Scholar
  12. 12.
    Lorente A, Mueller W, Urdangarin E, Lazcoz P, Lass U, von Deimling A, Castresana JS (2009) RASSF1A, BLU, NORE1A, PTEN and MGMT expression and promoter methylation in gliomas and glioma cell lines and evidence of deregulated expression of de novo DNMTs. Brain Pathol 19:279–292PubMedCrossRefGoogle Scholar
  13. 13.
    Gao Y, Guan M, Su B, Liu W, Xu M, Lu Y (2004) Hypermethylation of the RASSF1A gene in gliomas. Clin Chim Acta 349:173–179PubMedCrossRefGoogle Scholar
  14. 14.
    Hesson L, Bieche I, Krex D, Criniere E, Hoang-Xuan K, Maher ER, Latif F (2004) Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas. Oncogene 23:2408–2419PubMedCrossRefGoogle Scholar
  15. 15.
    Inda MM, Castresana JS (2007) RASSF1A promoter is highly methylated in primitive neuroectodermal tumors of the central nervous system. Neuropathology 27:341–346PubMedCrossRefGoogle Scholar
  16. 16.
    Banham AH, Beasley N, Campo E, Fernandez PL, Fidler C, Gatter K, Jones M, Mason DY, Prime JE, Trougouboff P, Wood K, Cordell JL (2001) The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p. Cancer Res 61:8820–8829PubMedGoogle Scholar
  17. 17.
    Molina JR, Agarwal NK, Morales FC, Hayashi Y, Aldape KD, Cote G, Georgescu MM (2012) PTEN, NHERF1 and PHLPP form a tumor suppressor network that is disabled in glioblastoma. Oncogene 31:1264–1274PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Crespo I, Vital AL, Nieto AB, Rebelo O, Tao H, Lopes MC, Oliveira CR, French PJ, Orfao A, Tabernero MD (2011) Detailed characterization of alterations of chromosomes 7, 9, and 10 in glioblastomas as assessed by single-nucleotide polymorphism arrays. J Mol Diagn 13:634–647PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Ohgaki H, Kleihues P (2007) Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170:1445–1453PubMedCrossRefGoogle Scholar
  20. 20.
    Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512PubMedCrossRefGoogle Scholar
  21. 21.
    Luo W, Lin SC (2004) Axin: a master scaffold for multiple signaling pathways. Neurosignals 13:99–113PubMedCrossRefGoogle Scholar
  22. 22.
    Kishida S, Yamamoto H, Ikeda S, Kishida M, Sakamoto I, Koyama S, Kikuchi A (1998) Axin, a negative regulator of the wnt signaling pathway, directly interacts with adenomatous polyposis coli and regulates the stabilization of beta-catenin. J Biol Chem 273:10823–10826PubMedCrossRefGoogle Scholar
  23. 23.
    Nager M, Bhardwaj D, Canti C, Medina L, Nogues P and Herreros J (2012) Beta-catenin signalling in glioblastoma multiforme and glioma-initiating cells. Chemother Res Pract (Epub ahead of print)Google Scholar
  24. 24.
    Nikuseva Martic T, Pecina-Slaus N, Kusec V, Kokotovic T, Musinovic H, Tomas D, Zeljko M (2010) Changes of AXIN-1 and beta-catenin in neuroepithelial brain tumors. Pathol Oncol Res 16:75–79PubMedCrossRefGoogle Scholar
  25. 25.
    Wienecke R, Guha A, Maize JC Jr, Heideman RL, DeClue JE, Gutmann DH (1997) Reduced TSC2 RNA and protein in sporadic astrocytomas and ependymomas. Ann Neurol 42:230–235PubMedCrossRefGoogle Scholar
  26. 26.
    Parry L, Maynard JH, Patel A, Hodges AK, von Deimling A, Sampson JR, Cheadle JP (2000) Molecular analysis of the TSC1 and TSC2 tumour suppressor genes in sporadic glial and glioneuronal tumours. Hum Gen 107:350–356CrossRefGoogle Scholar
  27. 27.
    Nagaishi M, Kim YH, Mittelbronn M, Giangaspero F, Paulus W, Brokinkel B, Vital A, Tanaka Y, Nakazato Y, Legras-Lachuer C, Lachuer J, Ohgaki H (2012) Amplification of the STOML3, FREM2, and LHFP genes is associated with mesenchymal differentiation in gliosarcoma. Am J Pathol 180:1816–1823PubMedCrossRefGoogle Scholar
  28. 28.
    Nagaishi M, Paulus W, Brokinkel B, Vital A, Tanaka Y, Nakazato Y, Giangaspero F, Ohgaki H (2012) Transcriptional factors for epithelial-mesenchymal transition are associated with mesenchymal differentiation in gliosarcoma. Brain Pathol 22:670–676PubMedCrossRefGoogle Scholar
  29. 29.
    Huang W, Zhang Y, Varambally S, Chinnaiyan AM, Banerjee M, Merajver SD, Kleer CG (2008) Inhibition of CCN6 (Wnt-1-induced signaling protein 3) down-regulates E-cadherin in the breast epithelium through induction of snail and ZEB1. Am J Pathol 172:893–904PubMedCrossRefGoogle Scholar
  30. 30.
    Yang L, Lin C, Liu ZR (2006) P68 RNA helicase mediates PDGF-induced epithelial mesenchymal transition by displacing Axin from beta-catenin. Cell 127:139–155PubMedCrossRefGoogle Scholar
  31. 31.
    Joseph NM, Phillips J, Dahiya S, M Felicella M, Tihan T, Brat DJ, Perry A (2012) Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants. Mod Pathol (Epub ahead of print)Google Scholar
  32. 32.
    Motomura K, Mittelbronn M, Paulus W, Brokinkel B, Keyvani K, Sure U, Wrede K, Nakazato Y, Tanaka Y, Pierscianek D, Kim YH, Mariani L, Vital A, Ohgaki H (2012) DMBT1 homozygous deletion in diffuse astrocytomas is associated with unfavorable clinical outcome. J Neuropathol Exp Neurol 71:702–707Google Scholar

Copyright information

© The Japan Society of Brain Tumor Pathology 2013

Authors and Affiliations

  • Kari-Elise T. Codispoti
    • 1
    • 3
  • Stacy Mosier
    • 1
  • Robert Ramsey
    • 2
  • Ming-Tseh Lin
    • 1
  • Fausto J. Rodriguez
    • 1
    • 4
  1. 1.Department of PathologyJohns Hopkins UniversityBaltimoreUSA
  2. 2.Department of PathologyBanner Good Samaritan Medical CenterPhoenixUSA
  3. 3.Children’s National Medical CenterWashington, DCUSA
  4. 4.Division of NeuropathologyJohns Hopkins HospitalBaltimoreUSA

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