, Volume 14, Issue 2, pp 298–306 | Cite as

Cancer of the Peripheral Nerve in Neurofibromatosis Type 1

  • Verena Staedtke
  • Ren-Yuan Bai
  • Jaishri O’Neill Blakeley


The RASopathy neurofibromatosis 1 is an autosomal dominant hereditary cancer syndrome that represents a major risk for the development of malignancies, particularly malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are unique sarcomas that originate from the peripheral nerve and represent the only primary cancer of the peripheral nervous system. To date, surgery is the only treatment modality proven to have survival benefit for MPNSTs and even when maximal surgery is feasible, these tumors are rarely curable, despite the use of chemotherapy and radiation. In this review, we discuss the current state-of-the-art treatments for MPNSTs, latest therapeutic developments, and critical aspects of the underlying molecular and pathophysiology that appear promising for therapeutic developments in the future. In particular, we discuss the specific elements of cancer in the peripheral nerve and how that may impel development of unique therapies for this form of sarcoma.


Malignant peripheral nerve sheath tumor Malignant transformation Sarcoma Neurofibromatosis Treatment Chemoprevention 

Supplementary material

13311_2017_518_MOESM1_ESM.pdf (1.2 mb)
ESM 1Required Author FormsDisclosure forms provided by the authors are available with the online version of this article. (PDF 1224 kb)


  1. 1.
    Carey JC, Baty BJ, Johnson JP, Morrison T, Skolnick M, Kivlin J. The genetic aspects of neurofibromatosis. Ann N Y Acad Sci 1986; 486: 45-56.CrossRefPubMedGoogle Scholar
  2. 2.
    NIH. National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, Md., USA, July 13–15, 1987. Neurofibromatosis 1988; 1: 172-178.Google Scholar
  3. 3.
    Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997; 278: 51-57.CrossRefPubMedGoogle Scholar
  4. 4.
    Abramowicz A, Gos M. Neurofibromin in neurofibromatosis type 1—mutations in NF1gene as a cause of disease. Dev Period Med 2014; 18: 297-306.PubMedGoogle Scholar
  5. 5.
    Ratner N, Miller SJ. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer 2015; 15: 290-301.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Sabbagh A, Pasmant E, Laurendeau I, et al. Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Hum Mol Genet 2009; 18: 2768-2778.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Pasmant E, Sabbagh A, Spurlock G, et al. NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat 2010; 31: E1506-E1518.CrossRefPubMedGoogle Scholar
  8. 8.
    De Raedt T, Brems H, Wolkenstein P, et al. Elevated risk for MPNST in NF1 microdeletion patients. Am J Hum Genet 2003; 72: 1288-1292.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Huson SHR. The neurofibromatoses: a pathogenic and clinical overview. London: Chapman and Hall; 1994.Google Scholar
  10. 10.
    Mautner VF, Asuagbor FA, Dombi E, et al. Assessment of benign tumor burden by whole-body MRI in patients with neurofibromatosis 1. Neuro Oncol 2008; 10: 593-598.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Nguyen R, Jett K, Harris GJ, Cai W, Friedman JM, Mautner VF. Benign whole body tumor volume is a risk factor for malignant peripheral nerve sheath tumors in neurofibromatosis type 1. J Neurooncol 2014; 116: 307-313.CrossRefPubMedGoogle Scholar
  12. 12.
    Porter DE, Prasad V, Foster L, Dall GF, Birch R, Grimer RJ. Survival in malignant peripheral nerve sheath tumours: a comparison between sporadic and neurofibromatosis type 1-associated tumours. Sarcoma 2009; 2009: 756395.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wasa J, Nishida Y, Tsukushi S, et al. MRI features in the differentiation of malignant peripheral nerve sheath tumors and neurofibromas. AJR Am J Roentgenol 2010; 194: 1568-1574.CrossRefPubMedGoogle Scholar
  14. 14.
    Ahlawat S, Blakeley J, Montgomery E, Subramaniam RM, Belzberg A, Fayad LM. Schwannoma in neurofibromatosis type 1: a pitfall for detecting malignancy by metabolic imaging. Skeletal Radiol 2013; 42: 1317-1322.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Meany H, Dombi E, Reynolds J, et al. 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) evaluation of nodular lesions in patients with neurofibromatosis type 1 and plexiform neurofibromas (PN) or malignant peripheral nerve sheath tumors (MPNST). Pediatr Blood Cancer 2013; 60: 59-64.CrossRefPubMedGoogle Scholar
  16. 16.
    Beert E, Brems H, Daniels B, et al. Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. Genes Chromosomes Cancer 2011; 50: 1021-1032.CrossRefPubMedGoogle Scholar
  17. 17.
    Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 2002; 39: 311-314.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Rubin JB, Gutmann DH. Neurofibromatosis type 1—a model for nervous system tumour formation? Nat Rev Cancer 2005; 5: 557-564.CrossRefPubMedGoogle Scholar
  19. 19.
    Lee W, Teckie S, Wiesner T, et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat Genet 2014; 46: 1227-1232.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    De Raedt T, Beert E, Pasmant E, et al. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 2014; 514: 247-251.PubMedGoogle Scholar
  21. 21.
    Carroll SL. The challenge of cancer genomics in rare nervous system neoplasms: malignant peripheral nerve sheath tumors as a paradigm for cross-species comparative oncogenomics. Am J Pathol 2016; 186: 464-477.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Zou C, Smith KD, Liu J, et al. Clinical, pathological, and molecular variables predictive of malignant peripheral nerve sheath tumor outcome. Ann Surg 2009; 249: 1014-1022.CrossRefPubMedGoogle Scholar
  23. 23.
    Rodriguez FJ, Folpe AL, Giannini C, Perry A. Pathology of peripheral nerve sheath tumors: diagnostic overview and update on selected diagnostic problems. Acta Neuropathol 2012; 123: 295-319.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Stucky CC, Johnson KN, Gray RJ, et al. Malignant peripheral nerve sheath tumors (MPNST): the Mayo Clinic experience. Ann Surg Oncol 2012; 19: 878-885.CrossRefPubMedGoogle Scholar
  25. 25.
    Kaushal A, Citrin D. The role of radiation therapy in the management of sarcomas. Surg Clin North Am 2008; 88: 629-646.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kahn J, Gillespie A, Tsokos M, et al. Radiation therapy in management of sporadic and neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. Front Oncol 2014; 4: 324.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Watson KL, Al Sannaa GA, Kivlin CM, et al. Patterns of recurrence and survival in sporadic, neurofibromatosis Type 1-associated, and radiation-associated malignant peripheral nerve sheath tumors. J Neurosurg 2017;126:319-329.CrossRefPubMedGoogle Scholar
  28. 28.
    Widemann B, et al. SARC006: Phase II trial of chemotherapy in sporadic and neurofibromatosis type 1 (NF1)-associated high-grade malignant peripheral nerve sheath tumors (MPNSTs). J Clin Oncol 2013; 31.Google Scholar
  29. 29.
    Perrone F, Da Riva L, Orsenigo M, et al. PDGFRA, PDGFRB, EGFR, and downstream signaling activation in malignant peripheral nerve sheath tumor. Neuro Oncol 2009; 11: 725-736.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000; 103: 211-225.CrossRefPubMedGoogle Scholar
  31. 31.
    Torres KE, Zhu QS, Bill K, et al. Activated MET is a molecular prognosticator and potential therapeutic target for malignant peripheral nerve sheath tumors. Clin Cancer Res 2011; 17: 3943-3955.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Holtkamp N, Okuducu AF, Mucha J, et al. Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors, and its implications for imatinib sensitivity. Carcinogenesis 2006; 27: 664-671.CrossRefPubMedGoogle Scholar
  33. 33.
    Rahrmann EP, Watson AL, Keng VW, et al. Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis. Nat Genet 2013; 45: 756-766.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wu J, Patmore DM, Jousma E, et al. EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors. Oncogene 2014; 33: 173-180.CrossRefPubMedGoogle Scholar
  35. 35.
    Holtkamp N, Malzer E, Zietsch J, et al. EGFR and erbB2 in malignant peripheral nerve sheath tumors and implications for targeted therapy. Neuro Oncol 2008; 10: 946-957.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ling BC, Wu J, Miller SJ, et al. Role for the epidermal growth factor receptor in neurofibromatosis-related peripheral nerve tumorigenesis. Cancer Cell 2005; 7: 65-75.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    DeClue JE, Heffelfinger S, Benvenuto G, et al. Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models. J Clin Invest 2000; 105: 1233-1241.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Tabone-Eglinger S, Bahleda R, Cote JF, et al. Frequent EGFR positivity and overexpression in high-grade areas of human MPNSTs. Sarcoma 2008; 2008: 849156.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Albritton K, et al. Phase II trial of erlotinib in metastatic or unresectable malignant peripheral nerve sheath tumor (MPNST). J Clin Oncol 2006; 24.Google Scholar
  40. 40.
    Holtkamp N, Mautner VF, Friedrich RE, et al. Differentially expressed genes in neurofibromatosis 1-associated neurofibromas and malignant peripheral nerve sheath tumors. Acta Neuropathol 2004; 107: 159-168.CrossRefPubMedGoogle Scholar
  41. 41.
    Kilvaer TK, Smeland E, Valkov A, et al. The VEGF- and PDGF-family of angiogenic markers have prognostic impact in soft tissue sarcomas arising in the extremities and trunk. BMC Clin Pathol 2014; 14: 5.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Cao R, Brakenhielm E, Li X, et al. Angiogenesis stimulated by PDGF-CC, a novel member in the PDGF family, involves activation of PDGFR-alphaalpha and -alphabeta receptors. FASEB J 2002; 16: 1575-1583.CrossRefPubMedGoogle Scholar
  43. 43.
    Ki DH, He S, Rodig S, Look AT. Overexpression of PDGFRA cooperates with loss of NF1 and p53 to accelerate the molecular pathogenesis of malignant peripheral nerve sheath tumors. Oncogene 2016 Aug 1 [Epub ahead of print].Google Scholar
  44. 44.
    Aoki M, Nabeshima K, Koga K, et al. Imatinib mesylate inhibits cell invasion of malignant peripheral nerve sheath tumor induced by platelet-derived growth factor-BB. Lab Invest 2007; 87: 767-779.CrossRefPubMedGoogle Scholar
  45. 45.
    Chugh R, Wathen JK, Maki RG, et al. Phase II multicenter trial of imatinib in 10 histologic subtypes of sarcoma using a bayesian hierarchical statistical model. J Clin Oncol 2009; 27: 3148-3153.CrossRefPubMedGoogle Scholar
  46. 46.
    Maki RG, D'Adamo DR, Keohan ML, et al. Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol 2009; 27: 3133-3140.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Schuetze S, et al. Results of a Sarcoma Alliance for Research through Collaboration (SARC) phase II trial of Dasatinib in previously treated, highgrade, advanced sarcoma. J Clin Oncol 2010; 28.Google Scholar
  48. 48.
    Abe N, Cavalli V. Nerve injury signaling. Curr Opin Neurobiol 2008; 18: 276-283.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    De Raedt T, Walton Z, Yecies JL, et al. Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. Cancer Cell 2011; 20: 400-413.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Jessen WJ, Miller SJ, Jousma E, et al. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Invest 2013; 123: 340-347.CrossRefPubMedGoogle Scholar
  51. 51.
    Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016 Dec 29;375(26):2550-2560.​ Google Scholar
  52. 52.
    Patel AJ, Liao CP, Chen Z, Liu C, Wang Y, Le LQ. BET bromodomain inhibition triggers apoptosis of NF1-associated malignant peripheral nerve sheath tumors through Bim induction. Cell Rep 2014; 6: 81-92.CrossRefPubMedGoogle Scholar
  53. 53.
    Patel AV, Eaves D, Jessen WJ, et al. Ras-driven transcriptome analysis identifies aurora kinase A as a potential malignant peripheral nerve sheath tumor therapeutic target. Clin Cancer Res 2012; 18: 5020-5030.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Straussman R, Morikawa T, Shee K, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 2012; 487: 500-504.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Yang FC, Ingram DA, Chen S, et al. Nf1-dependent tumors require a microenvironment containing Nf1+/– and c-kit-dependent bone marrow. Cell 2008; 135: 437-448.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Yang FC, Ingram DA, Chen S, et al. Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/– mast cells. J Clin Invest 2003; 112: 1851-1861.CrossRefPubMedGoogle Scholar
  57. 57.
    Prada CE, Jousma E, Rizvi TA, et al. Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol 2013; 125: 159-168.CrossRefPubMedGoogle Scholar
  58. 58.
    Mo W, Chen J, Patel A, et al. CXCR4/CXCL12 mediate autocrine cell- cycle progression in NF1-associated malignant peripheral nerve sheath tumors. Cell 2013; 152: 1077-1090.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Patwardhan PP, Surriga O, Beckman MJ, et al. Sustained inhibition of receptor tyrosine kinases and macrophage depletion by PLX3397 and rapamycin as a potential new approach for the treatment of MPNSTs. Clin Cancer Res 2014; 20: 3146-3158.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015; 372: 2509-2520.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Shurell E, Singh AS, Crompton JG, et al. Characterizing the immune microenvironment of malignant peripheral nerve sheath tumor by PD-L1 expression and presence of CD8+ tumor infiltrating lymphocytes. Oncotarget 2016;7:64300-64308.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Russell SJ, Federspiel MJ, Peng KW, et al. Remission of disseminated cancer after systemic oncolytic virotherapy. Mayo Clin Proc 2014; 89: 926-933.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Grunwald GK, Vetter A, Klutz K, et al. Systemic image-guided liver cancer radiovirotherapy using dendrimer-coated adenovirus encoding the sodium iodide symporter as theranostic gene. J Nucl Med 2013; 54: 1450-1457.CrossRefPubMedGoogle Scholar
  64. 64.
    Dang LH, Bettegowda C, Huso DL, Kinzler KW, Vogelstein B. Combination bacteriolytic therapy for the treatment of experimental tumors. Proc Natl Acad Sci U S A 2001; 98: 15155-15160.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Diaz LA, Jr., Cheong I, Foss CA, et al. Pharmacologic and toxicologic evaluation of C. novyi-NT spores. Toxicol Sci 2005; 88: 562-575.CrossRefPubMedGoogle Scholar
  66. 66.
    Roberts NJ, Zhang L, Janku F, et al. Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. Sci Transl Med 2014; 6: 249ra111.Google Scholar
  67. 67.
    Staedtke V, Bai RY, Sun W, et al. Clostridium novyi-NT can cause regression of orthotopically implanted glioblastomas in rats. Oncotarget 2015; 6: 5536-5546.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Agrawal N, Bettegowda C, Cheong I, et al. Bacteriolytic therapy can generate a potent immune response against experimental tumors.Proc Natl Acad Sci U S A 2004; 101: 15172-15177.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    William WN, Jr., Heymach JV, Kim ES, Lippman SM. Molecular targets for cancer chemoprevention. Nat Rev Drug Discov 2009; 8: 213-225.CrossRefPubMedGoogle Scholar
  70. 70.
    Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420: 860-867.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Gately S, Li WW. Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. Semin Oncol 2004; 31: 2-11.CrossRefPubMedGoogle Scholar
  72. 72.
    Hakozaki M, Tajino T, Konno S, et al. Overexpression of cyclooxygenase-2 in malignant peripheral nerve sheath tumor and selective cyclooxygenase-2 inhibitor-induced apoptosis by activating caspases in human malignant peripheral nerve sheath tumor cells. PLOS ONE 2014; 9: e88035.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Frahm S, Kurtz A, Kluwe L, Farassati F, Friedrich RE, Mautner VF. Sulindac derivatives inhibit cell growth and induce apoptosis in primary cells from malignant peripheral nerve sheath tumors of NF1-patients. Cancer Cell Int 2004; 4: 4.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2017

Authors and Affiliations

  • Verena Staedtke
    • 1
    • 2
  • Ren-Yuan Bai
    • 3
  • Jaishri O’Neill Blakeley
    • 1
    • 2
    • 3
  1. 1.Department of NeurologyJohns Hopkins Medical InstitutionsBaltimoreUSA
  2. 2.Department of OncologyJohns Hopkins Medical InstitutionsBaltimoreUSA
  3. 3.Department of NeurosurgeryJohns Hopkins Medical InstitutionsBaltimoreUSA

Personalised recommendations