Skip to main content

Advertisement

SpringerLink
Log in

Neurofibromin specific antibody differentiates malignant peripheral nerve sheath tumors (MPNST) from other spindle cell neoplasms

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Malignant peripheral nerve sheath tumors (MPNST) derive from the Schwann cell or perineurial cell lineage and occur either sporadically or in association with the tumor syndrome neurofibromatosis type 1 (NF1). MPNST often pose a diagnostic challenge due to their frequent lack of pathognomonic morphological or immunohistochemical features. Mutations in the NF1 tumor suppressor gene are found in all NF1-associated and many sporadic MPNST. The presence of NF1 mutation may have the potential to differentiate MPNST from several morphologically similar neoplasms; however, mutation detection is hampered by the size of the gene and the lack of mutational hot spots. Here we describe a newly developed monoclonal antibody binding to the C-terminus of neurofibromin (clone NFC) which was selected for optimal performance in routinely processed formalin-fixed and paraffin-embedded tissue. NFC immunohistochemistry revealed loss of neurofibromin in 22/25 (88 %) of NF1-associated and 26/61 (43 %) of sporadic MPNST. There was a strong association of neurofibromin loss with deletions affecting the NF1 gene (P < 0.01). In a series of 256 soft tissue tumors of different histotypes NFC staining showed loss of neurofibromin in 2/8 myxofibrosarcomas, 2/12 (16 %) pleomorphic liposarcomas, 1/16 (6 %) leiomyosarcomas, and 4/28 (14 %) unclassified undifferentiated pleomorphic sarcomas. However, loss of neurofibromin was not observed in 22 synovial sarcomas, 27 schwannomas, 23 solitary fibrous tumors, 14 low-grade fibromyxoid sarcomas, 50 dedifferentiated liposarcomas, 27 myxoid liposarcomas, 13 angiosarcomas, 9 extraskeletal myxoid chondrosarcomas, and 7 epitheloid sarcomas. Immunohistochemistry using antibody NFC may substantially facilitate sarcoma research and diagnostics.

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

Similar content being viewed by others

References

  1. Afsar CU, Kara IO, Kozat BK, Demiryurek H, Duman BB, Doran F (2013) Neurofibromatosis type 1, gastrointestinal stromal tumor, leiomyosarcoma and osteosarcoma: four cases of rare tumors and a review of the literature. Crit Rev Oncol Hematol 86:191–199. doi:10.1016/j.critrevonc.2012.11.001

    Article  PubMed  Google Scholar 

  2. Barretina J, Taylor BS, Banerji S et al (2010) Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat Genet 42:715–721. doi:10.1038/ng.619

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Bottillo I, Ahlquist T, Brekke H et al (2009) Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours. J Pathol 217:693–701. doi:10.1002/path.2494

    Article  CAS  PubMed  Google Scholar 

  4. Chang T, Krisman K, Theobald EH et al (2013) Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Investig 123:335–339. doi:10.1172/JCI63193

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Dodd RD, Mito JK, Eward WC et al (2013) NF1 deletion generates multiple subtypes of soft-tissue sarcoma that respond to MEK inhibition. Mol Cancer Ther 12(9):1906–1917. doi:10.1158/1535-7163.MCT-13-0189

    Article  CAS  PubMed  Google Scholar 

  6. Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F (eds) (2013) WHO classification of tumours of soft tissue and bone. IARC, Lyon

  7. Harlow E, Lane D (1988) Antibodies: a laboratory manual. Cold Spring Harbor Laboratory, New York

    Google Scholar 

  8. Jett K, Friedman JM (2010) Clinical and genetic aspects of neurofibromatosis 1. Genet Med 12:1–11. doi:10.1097/GIM.0b013e3181bf15e3

    Article  PubMed  Google Scholar 

  9. Jhanwar SC, Chen Q, Li FP, Brennan MF, Woodruff JM (1994) Cytogenetic analysis of soft tissue sarcomas. Recurrent chromosome abnormalities in malignant peripheral nerve sheath tumors (MPNST). Cancer Genet Cytogenet 78:138–144

    Article  CAS  PubMed  Google Scholar 

  10. Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497

    Article  CAS  PubMed  Google Scholar 

  11. Laycock-van Spyk S, Thomas N, Cooper DN, Upadhyaya M (2011) Neurofibromatosis type 1-associated tumours: their somatic mutational spectrum and pathogenesis. Hum Genomics 5:623–690

    Article  PubMed  Google Scholar 

  12. Legius E, Marchuk DA, Collins FS, Glover TW (1993) Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nat Genet 3:122–126. doi:10.1038/ng0293-122

    Article  CAS  PubMed  Google Scholar 

  13. Lothe RA, Slettan A, Saeter G, Brogger A, Borresen AL, Nesland JM (1995) Alterations at chromosome 17 loci in peripheral nerve sheath tumors. J Neuropathol Exp Neurol 54:65–73

    Article  CAS  PubMed  Google Scholar 

  14. McGillicuddy LT, Fromm JA, Hollstein PE et al (2009) Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis. Cancer Cell 16:44–54. doi:10.1016/j.ccr.2009.05.009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Messiaen LM, Callens T, Mortier G et al (2000) Exhaustive mutation analysis of the NF1 gene allows identification of 95 % of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat 15:541–555. doi:10.1002/1098-1004(200006)15:6<541:AID-HUMU6>3.0.CO;2-N

    Article  CAS  PubMed  Google Scholar 

  16. Network CGAR (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

    Article  Google Scholar 

  17. Network CGAR (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474:609–615. doi:10.1038/nature10166

    Article  Google Scholar 

  18. Patil S, Chamberlain RS (2012) Neoplasms associated with germline and somatic NF1 gene mutations. Oncologist 17:101–116. doi:10.1634/theoncologist.2010-0181

    Article  PubMed Central  PubMed  Google Scholar 

  19. Perry A, Roth KA, Banerjee R, Fuller CE, Gutmann DH (2001) NF1 deletions in S-100 protein-positive and negative cells of sporadic and neurofibromatosis 1 (NF1)-associated plexiform neurofibromas and malignant peripheral nerve sheath tumors. Am J Pathol 159:57–61. doi:10.1016/S0002-9440(10)61673-2

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Ratner N, Williams JP, Kordich JJ, Kim HA (2006) Schwann cell preparation from single mouse embryos: analyses of neurofibromin function in Schwann cells. Methods Enzymol 407:22–33. doi:10.1016/S0076-6879(05)07003-5

    Article  CAS  PubMed  Google Scholar 

  21. Reuss DE, Deimling A (2008) Biomarkers for malignant peripheral nerve sheath tumours. Expert Opin Med Diagn 2:801–811. doi:10.1517/17530059.2.7.801

    Article  CAS  PubMed  Google Scholar 

  22. Reuss DE, Mucha J, Hagenlocher C et al (2013) Sensitivity of malignant peripheral nerve sheath tumor cells to TRAIL is augmented by loss of NF1 through modulation of MYC/MAD and is potentiated by curcumin through induction of ROS. PLoS ONE 8:e57152. doi:10.1371/journal.pone.0057152

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Rodriguez FJ, Folpe AL, Giannini C, Perry A (2012) Pathology of peripheral nerve sheath tumors: diagnostic overview and update on selected diagnostic problems. Acta Neuropathol 123:295–319. doi:10.1007/s00401-012-0954-z

    Article  PubMed Central  PubMed  Google Scholar 

  24. See WL, Tan IL, Mukherjee J, Nicolaides T, Pieper RO (2012) Sensitivity of glioblastomas to clinically available MEK inhibitors is defined by neurofibromin 1 deficiency. Cancer Res 72:3350–3359

    Article  CAS  PubMed  Google Scholar 

  25. Serrano C, Simonetti S, Hernandez-Losa J et al (2013) BRAF V600E and KRAS G12S mutations in peripheral nerve sheath tumours. Histopathology 62:499–504. doi:10.1111/his.12021

    Article  PubMed  Google Scholar 

  26. Upadhyaya M, Kluwe L, Spurlock G et al (2008) Germline and somatic NF1 gene mutation spectrum in NF1-associated malignant peripheral nerve sheath tumors (MPNSTs). Hum Mutat 29:74–82. doi:10.1002/humu.20601

    Article  CAS  PubMed  Google Scholar 

  27. Zhu Y, Parada LF (2001) Neurofibromin, a tumor suppressor in the nervous system. Exp Cell Res 264:19–28

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Tanja Göck and Viktoria Zeller for excellent technical assistance.

Author information

Authors and Affiliations

  1. German Cancer Consortium (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center, DKFZ, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany

    David E. Reuss, Christian Hagenlocher, Jana Mucha, Jochen Meyer, David Capper, Pierre-Olivier Frappart & Andreas von Deimling

  2. Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany

    David E. Reuss, Antje Habel, David Capper & Andreas von Deimling

  3. Monoclonal Antibody Facility, German Cancer Research Center, Heidelberg, Germany

    Ulrike Ackermann & Claudia Tessmer

  4. Department of Translational Immunology, German Cancer Research Center, Heidelberg, Germany

    Gerhard Moldenhauer

  5. Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Victor Mautner

  6. Department of Neuropathology, Institute of Pathology and Neuropathology, University Tübingen, Tübingen, Germany

    Jens Schittenhelm

  7. Department of Neuropathology, Institute of Pathology, Medizinische Hochschule Hannover, Hannover, Germany

    Christian Hartmann

  8. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Christian Hagel

  9. Institute of Pathology, University Hospital of Jena, Jena, Germany

    Kathrin Katenkamp & Iver Petersen

  10. Institute of Pathology, University of Heidelberg, Heidelberg, Germany

    Gunhild Mechtersheimer

Authors
  1. David E. Reuss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antje Habel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christian Hagenlocher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jana Mucha
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ulrike Ackermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Claudia Tessmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jochen Meyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David Capper
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gerhard Moldenhauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Victor Mautner
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Pierre-Olivier Frappart
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jens Schittenhelm
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Christian Hartmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Christian Hagel
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kathrin Katenkamp
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Iver Petersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Gunhild Mechtersheimer
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Andreas von Deimling
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas von Deimling.

Additional information

G. Mechtersheimer and A. von Deimling contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reuss, D.E., Habel, A., Hagenlocher, C. et al. Neurofibromin specific antibody differentiates malignant peripheral nerve sheath tumors (MPNST) from other spindle cell neoplasms. Acta Neuropathol 127, 565–572 (2014). https://doi.org/10.1007/s00401-014-1246-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-014-1246-6

Keywords

Search

Navigation