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Acta Neuropathologica

, Volume 127, Issue 4, pp 565–572 | Cite as

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

  • David E. Reuss
  • Antje Habel
  • Christian Hagenlocher
  • Jana Mucha
  • Ulrike Ackermann
  • Claudia Tessmer
  • Jochen Meyer
  • David Capper
  • Gerhard Moldenhauer
  • Victor Mautner
  • Pierre-Olivier Frappart
  • Jens Schittenhelm
  • Christian Hartmann
  • Christian Hagel
  • Kathrin Katenkamp
  • Iver Petersen
  • Gunhild Mechtersheimer
  • Andreas von DeimlingEmail author
Original Paper

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.

Keywords

Malignant Peripheral Nerve Sheath Tumor Solitary Fibrous Tumor Myxoid Liposarcomas Undifferentiated Pleomorphic Sarcoma Extraskeletal Myxoid Chondrosarcomas 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

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

References

  1. 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 PubMedCrossRefGoogle Scholar
  2. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  3. 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 PubMedCrossRefGoogle Scholar
  4. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  5. 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 PubMedCrossRefGoogle Scholar
  6. 6.
    Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F (eds) (2013) WHO classification of tumours of soft tissue and bone. IARC, LyonGoogle Scholar
  7. 7.
    Harlow E, Lane D (1988) Antibodies: a laboratory manual. Cold Spring Harbor Laboratory, New YorkGoogle Scholar
  8. 8.
    Jett K, Friedman JM (2010) Clinical and genetic aspects of neurofibromatosis 1. Genet Med 12:1–11. doi: 10.1097/GIM.0b013e3181bf15e3 PubMedCrossRefGoogle Scholar
  9. 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 78:138–144PubMedCrossRefGoogle Scholar
  10. 10.
    Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497PubMedCrossRefGoogle Scholar
  11. 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 5:623–690PubMedCrossRefGoogle Scholar
  12. 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 PubMedCrossRefGoogle Scholar
  13. 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 54:65–73PubMedCrossRefGoogle Scholar
  14. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  15. 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 PubMedCrossRefGoogle Scholar
  16. 16.
    Network CGAR (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068CrossRefGoogle Scholar
  17. 17.
    Network CGAR (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474:609–615. doi: 10.1038/nature10166 CrossRefGoogle Scholar
  18. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  19. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  20. 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 PubMedCrossRefGoogle Scholar
  21. 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 PubMedCrossRefGoogle Scholar
  22. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  23. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  24. 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 72:3350–3359PubMedCrossRefGoogle Scholar
  25. 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 PubMedCrossRefGoogle Scholar
  26. 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 PubMedCrossRefGoogle Scholar
  27. 27.
    Zhu Y, Parada LF (2001) Neurofibromin, a tumor suppressor in the nervous system. Exp Cell Res 264:19–28PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • David E. Reuss
    • 1
    • 2
  • Antje Habel
    • 2
  • Christian Hagenlocher
    • 1
  • Jana Mucha
    • 1
  • Ulrike Ackermann
    • 3
  • Claudia Tessmer
    • 3
  • Jochen Meyer
    • 1
  • David Capper
    • 1
    • 2
  • Gerhard Moldenhauer
    • 4
  • Victor Mautner
    • 5
  • Pierre-Olivier Frappart
    • 1
  • Jens Schittenhelm
    • 6
  • Christian Hartmann
    • 7
  • Christian Hagel
    • 8
  • Kathrin Katenkamp
    • 9
  • Iver Petersen
    • 9
  • Gunhild Mechtersheimer
    • 10
  • Andreas von Deimling
    • 1
    • 2
    Email author
  1. 1.German Cancer Consortium (DKTK), Clinical Cooperation Unit NeuropathologyGerman Cancer Research Center, DKFZHeidelbergGermany
  2. 2.Department of Neuropathology, Institute of PathologyRuprecht-Karls-University HeidelbergHeidelbergGermany
  3. 3.Monoclonal Antibody FacilityGerman Cancer Research CenterHeidelbergGermany
  4. 4.Department of Translational ImmunologyGerman Cancer Research CenterHeidelbergGermany
  5. 5.Department of NeurologyUniversity Hospital Hamburg-EppendorfHamburgGermany
  6. 6.Department of Neuropathology, Institute of Pathology and NeuropathologyUniversity TübingenTübingenGermany
  7. 7.Department of Neuropathology, Institute of PathologyMedizinische Hochschule HannoverHannoverGermany
  8. 8.Institute of NeuropathologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  9. 9.Institute of PathologyUniversity Hospital of JenaJenaGermany
  10. 10.Institute of PathologyUniversity of HeidelbergHeidelbergGermany

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