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Current status of sporadic and neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors

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Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas that rarely occur in the general population but have a lifetime incidence of 8% to 13% in those with neurofibromatosis type 1 (NF1). Complete surgical resection is the standard treatment for MPNSTs. Unresectable MPNSTs carry a poor prognosis, and survival appears to be worse in NF1-associated tumors than in sporadic tumors. The response rate of MPNSTs to standard chemotherapeutic agents used to treat pediatric and adult soft tissue sarcomas is unknown and is currently undergoing evaluation in a multi-institutional clinical trial. With an increasing understanding of the molecular pathogenesis of MPNSTs, clinical trials with targeted agents have become available and have established that histology-specific trials in this rare malignancy are feasible. This knowledge, coupled with the availability of preclinical MPNST models, likely will accelerate the development of effective treatments for this malignancy.

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References and Recommended Reading

  1. Ferner RE, Gutmann DH: International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis. Cancer Res 2002, 62:1573–1577.

    PubMed  CAS  Google Scholar 

  2. Carli M, Ferrari A, Mattke A, et al.: Pediatric malignant peripheral nerve sheath tumor: the Italian and German soft tissue sarcoma cooperative group. J Clin Oncol 2005, 23:8422–8430.

    Article  PubMed  Google Scholar 

  3. Evans DG, Baser ME, McGaughran J, et al.: Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 2002, 39:311–314.

    Article  PubMed  CAS  Google Scholar 

  4. Leppig KA, Kaplan P, Viskochil D, et al.: Familial neurofibromatosis 1 microdeletions: cosegregation with distinct facial phenotype and early onset of cutaneous neurofibromata. Am J Med Genet 1997, 73:197–204.

    Article  PubMed  CAS  Google Scholar 

  5. Ferner RE: Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet Neurol 2007, 6:340–351.

    Article  PubMed  Google Scholar 

  6. Friedman JM: Neurofibromatosis 1: clinical manifestations and diagnostic criteria. J Child Neurol 2002, 17:548–554; discussion 571–572, 646–651.

    Article  PubMed  CAS  Google Scholar 

  7. Korf BR: Clinical features and pathobiology of neurofibromatosis 1. J Child Neurol 2002, 17:573–577; discussion 602–604, 646–651.

    Article  PubMed  Google Scholar 

  8. Cichowski K, Jacks T: NF1 tumor suppressor gene function: narrowing the GAP. Cell 2001, 104:593–604.

    Article  PubMed  CAS  Google Scholar 

  9. Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 1988, 45:575–578.

  10. Messiaen LM, Callens T, Mortier G, et al.: Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat 2000, 15:541–555.

    Article  PubMed  CAS  Google Scholar 

  11. Korf BR: Plexiform neurofibromas. Am J Med Genet 1999, 89:31–37.

    Article  PubMed  CAS  Google Scholar 

  12. Korf BR: Malignancy in neurofibromatosis type 1. Oncologist 2000, 5:477–485.

    Article  PubMed  CAS  Google Scholar 

  13. Zhou H, Coffin CM, Perkins SL, et al.: Malignant peripheral nerve sheath tumor: a comparison of grade, immunophenotype, and cell cycle/growth activation marker expression in sporadic and neurofibromatosis 1-related lesions. Am J Surg Pathol 2003, 27:1337–1345.

    Article  PubMed  Google Scholar 

  14. Needle MN, Cnaan A, Dattilo J, et al.: Prognostic signs in the surgical management of plexiform neurofibroma: the Children’s Hospital of Philadelphia experience, 1974–1994. J Pediatr 1997, 131:678–682.

    Article  PubMed  CAS  Google Scholar 

  15. Packer R, Gutmann D, Rubenstein A, et al.: Plexiform neurofibromas in NF1: toward biologic-based therapy. Neurology 2002, 58:1461–1470.

    PubMed  CAS  Google Scholar 

  16. Mautner VF, Friedrich RE, von Deimling A, et al.: Malignant peripheral nerve sheath tumours in neurofibromatosis type 1: MRI supports the diagnosis of malignant plexiform neurofibroma. Neuroradiology 2003, 45:618–625.

    Article  PubMed  CAS  Google Scholar 

  17. Ferner RE, Golding JF, Smith M, et al.: [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) as a diagnostic tool for neurofibromatosis 1 (NF1) associated malignant peripheral nerve sheath tumours (MPNSTs): a long-term clinical study. Ann Oncol 2008, 19:390–394.

    Article  PubMed  CAS  Google Scholar 

  18. Gupta G, Mammis A, Maniker A: Malignant peripheral nerve sheath tumors. Neurosurg Clin N Am 2008, 19:533–543, v.

    Article  PubMed  Google Scholar 

  19. Cai W, Kassarjian A, Bredella MA, et al.: Tumor burden in patients with neurofibromatosis types 1 and 2 and schwannomatosis: determination on whole-body MR images. Radiology 2009, 250:665–673.

    Article  PubMed  Google Scholar 

  20. 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.

    Article  PubMed  Google Scholar 

  21. Tucker T, Wolkenstein P, Revuz J, et al.: Association between benign and malignant peripheral nerve sheath tumors in NF1. Neurology 2005, 65:205–211.

    Article  PubMed  CAS  Google Scholar 

  22. Khosrotehrani K, Bastuji-Garin S, Riccardi VM, et al.: Subcutaneous neurofibromas are associated with mortality in neurofibromatosis 1: a cohort study of 703 patients. Am J Med Genet A 2005, 132A:49–53.

    Article  PubMed  Google Scholar 

  23. Ducatman BS, Scheithauer BW, Piepgras DG, et al.: Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer 1986, 57:2006–2021.

    Article  PubMed  CAS  Google Scholar 

  24. Sordillo PP, Helson L, Hajdu SI, et al.: Malignant schwannoma—clinical characteristics, survival, and response to therapy. Cancer 1981, 47:2503–2509.

    Article  PubMed  CAS  Google Scholar 

  25. Cashen DV, Parisien RC, Raskin K, et al.: Survival data for patients with malignant schwannoma. Clin Orthop Relat Res 2004, 69–73.

  26. Watson MA, Perry A, Tihan T, et al.: Gene expression profiling reveals unique molecular subtypes of Neurofibromatosis Type I-associated and sporadic malignant peripheral nerve sheath tumors. Brain Pathol 2004, 14:297–303.

    PubMed  CAS  Google Scholar 

  27. Ducatman BS, Scheithauer BW: Postirradiation neurofibrosarcoma. Cancer 1983, 51:1028–1033.

    Article  PubMed  CAS  Google Scholar 

  28. Costa J, Wesley RA, Glatstein E, et al.: The grading of soft tissue sarcomas. Results of a clinicohistopathologic correlation in a series of 163 cases. Cancer 1984, 53:530–541.

    Article  PubMed  CAS  Google Scholar 

  29. Trojani M, Contesso G, Coindre JM, et al.: Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system. Int J Cancer 1984, 33:37–42.

    Article  PubMed  CAS  Google Scholar 

  30. Kourea HP, Cordon-Cardo C, Dudas M, et al.: Expression of p27(kip) and other cell cycle regulators in malignant peripheral nerve sheath tumors and neurofibromas: the emerging role of p27(kip) in malignant transformation of neurofibromas. Am J Pathol 1999, 155:1885–1891.

    PubMed  CAS  Google Scholar 

  31. Woodruff JM, Chernik NL, Smith MC, et al.: Peripheral nerve tumors with rhabdomyosarcomatous differentiation (malignant “Triton” tumors). Cancer 1973, 32:426–439.

    Article  PubMed  CAS  Google Scholar 

  32. Brooks JS, Freeman M, Enterline HT: Malignant “Triton” tumors. Natural history and immunohistochemistry of nine new cases with literature review. Cancer 1985, 55:2543–2549.

    Article  PubMed  CAS  Google Scholar 

  33. Watanabe T, Oda Y, Tamiya S, et al.: Malignant peripheral nerve sheath tumours: high Ki67 labelling index is the significant prognostic indicator. Histopathology 2001, 39:187–197.

    Article  PubMed  CAS  Google Scholar 

  34. Scaife CL, Pisters PW: Combined-modality treatment of localized soft tissue sarcomas of the extremities. Surg Oncol Clin N Am 2003, 12:355–368.

    Article  PubMed  Google Scholar 

  35. Kattan MW, Leung DH, Brennan MF: Postoperative nomogram for 12-year sarcoma-specific death. J Clin Oncol 2002, 20:791–796.

    Article  PubMed  Google Scholar 

  36. Abbas JS, Holyoke ED, Moore R, et al.: The surgical treatment and outcome of soft-tissue sarcoma. Arch Surg 1981, 116:765–769.

    PubMed  CAS  Google Scholar 

  37. Yang JC, Chang AE, Baker AR, et al.: Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998, 16:197–203.

    PubMed  CAS  Google Scholar 

  38. Pisters PW, Leung DH, Woodruff J, et al.: Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 1996, 14:1679–1689.

    PubMed  CAS  Google Scholar 

  39. Wong WW, Hirose T, Scheithauer BW, et al.: Malignant peripheral nerve sheath tumor: analysis of treatment outcome. Int J Radiat Oncol Biol Phys 1998, 42:351–360.

    PubMed  CAS  Google Scholar 

  40. Verma S, Bramwell V: Dose-intensive chemotherapy in advanced adult soft tissue sarcoma. Expert Rev Anticancer Ther 2002, 2:201–215.

    Article  PubMed  CAS  Google Scholar 

  41. Antman KH, Montella D, Rosenbaum C, et al.: Phase II trial of ifosfamide with mesna in previously treated metastatic sarcoma. Cancer Treat Rep 1985, 69:499–504.

    PubMed  CAS  Google Scholar 

  42. Edmonson JH, Buckner JC, Long HJ, et al.: Phase II study of ifosfamide-etoposide-mesna in adults with advanced nonosseous sarcomas. J Natl Cancer Inst 1989, 81:863–866.

    Article  PubMed  CAS  Google Scholar 

  43. Raney B, Schnaufer L, Ziegler M, et al.: Treatment of children with neurogenic sarcoma. Experience at the Children’s Hospital of Philadelphia, 1958–1984. Cancer 1987, 59:1–5.

    Article  PubMed  CAS  Google Scholar 

  44. Valdes OS, Maurer HM: Combination therapy with vincristine sulfate (NSC-67574) and cyclophosphamide (NSC-26271) for generalized malignant schwannoma—a case report. Cancer Chemother Rep 1970, 54:65–68.

    PubMed  CAS  Google Scholar 

  45. Santoro A, Tursz T, Mouridsen H, et al.: Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1995, 13:1537–1545.

    PubMed  CAS  Google Scholar 

  46. Basu TN, Gutmann DH, Fletcher JA, et al.: Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 1992, 356:713–715.

    Article  PubMed  CAS  Google Scholar 

  47. DeClue JE, Papageorge AG, Fletcher JA, et al.: Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell 1992, 69:265–273.

    Article  PubMed  CAS  Google Scholar 

  48. Guha A, Lau N, Huvar I, et al.: Ras-GTP levels are elevated in human NF1 peripheral nerve tumors. Oncogene 1996, 12:507–513.

    PubMed  CAS  Google Scholar 

  49. Kluwe L, Friedrich RE, Mautner VF: Allelic loss of the NF1 gene in NF1-associated plexiform neurofibromas. Cancer Genet Cytogenet 1999, 113:65–69.

    Article  PubMed  CAS  Google Scholar 

  50. Perry A, Roth KA, Banerjee R, et al.: 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 2001, 159:57–61.

    PubMed  CAS  Google Scholar 

  51. Perry A, Kunz SN, Fuller CE, et al.: Differential NF1, p16, and EGFR patterns by interphase cytogenetics (FISH) in malignant peripheral nerve sheath tumor (MPNST) and morphologically similar spindle cell neoplasms. J Neuropathol Exp Neurol 2002, 61:702–709.

    PubMed  CAS  Google Scholar 

  52. 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.

    Article  PubMed  CAS  Google Scholar 

  53. Li H, Velasco-Miguel S, Vass WC, et al.: Epidermal growth factor receptor signaling pathways are associated with tumorigenesis in the Nf1:p53 mouse tumor model. Cancer Res 2002, 62:4507–4513.

    PubMed  CAS  Google Scholar 

  54. 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.

    Article  PubMed  CAS  Google Scholar 

  55. Keizman D, Issakov J, Meller I, et al.: Expression and significance of EGFR in malignant peripheral nerve sheath tumor. J Neurooncol 2009 Mar 28 (Epub ahead of print).

  56. Kranenburg O, Gebbink MF, Voest EE: Stimulation of angiogenesis by Ras proteins. Biochim Biophys Acta 2004, 1654:23–37.

    PubMed  CAS  Google Scholar 

  57. Rak J, Mitsuhashi Y, Bayko L, et al.: Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 1995, 55:4575–4580.

    PubMed  CAS  Google Scholar 

  58. Kawachi Y, Xu X, Ichikawa E, et al.: Expression of angiogenic factors in neurofibromas. Exp Dermatol 2003, 12:412–417.

    Article  PubMed  CAS  Google Scholar 

  59. Angelov L, Salhia B, Roncari L, et al.: Inhibition of angiogenesis by blocking activation of the vascular endothelial growth factor receptor 2 leads to decreased growth of neurogenic sarcomas. Cancer Res 1999, 59:5536–5541.

    PubMed  CAS  Google Scholar 

  60. Dasgupta B, Yi Y, Chen DY, et al.: Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res 2005, 65:2755–2760.

    Article  PubMed  CAS  Google Scholar 

  61. Johannessen CM, Reczek EE, James MF, et al.: The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci U S A 2005, 102:8573–8578.

    Article  PubMed  CAS  Google Scholar 

  62. Johannessen CM, Johnson BW, Williams SM, et al.: TORC1 is essential for NF1-associated malignancies. Curr Biol 2008, 18:56–62.

    Article  PubMed  CAS  Google Scholar 

  63. Johansson G, Mahller YY, Collins MH, et al.: Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors. Mol Cancer Ther 2008, 7:1237–1245.

    Article  PubMed  CAS  Google Scholar 

  64. Hegedus B, Banerjee D, Yeh TH, et al.: Preclinical cancer therapy in a mouse model of neurofibromatosis-1 optic glioma. Cancer Res 2008, 68:1520–1528.

    Article  PubMed  CAS  Google Scholar 

  65. Skotheim RI, Kallioniemi A, Bjerkhagen B, et al.: Topoisomerase-II alpha is upregulated in malignant peripheral nerve sheath tumors and associated with clinical outcome. J Clin Oncol 2003, 21:4586–4591.

    Article  PubMed  CAS  Google Scholar 

  66. Badache A, De Vries GH: Neurofibrosarcoma-derived Schwann cells overexpress platelet-derived growth factor (PDGF) receptors and are induced to proliferate by PDGF BB. J Cell Physiol 1998, 177:334–342.

    Article  PubMed  CAS  Google Scholar 

  67. 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.

    Article  PubMed  CAS  Google Scholar 

  68. Dang I, Nelson J, DeVries G: C-kit receptor expression in normal human Schwann cells and Schwann cell lines derived from neurofibromatosis type 1 tumors. J Neurosci Res 2005, 82:465–471.

    Article  PubMed  CAS  Google Scholar 

  69. Holtkamp N, Atallah I, Okuducu AF, et al.: MMP-13 and p53 in the progression of malignant peripheral nerve sheath tumors. Neoplasia 2007, 9:671–677.

    Article  PubMed  CAS  Google Scholar 

  70. Miller SJ, Rangwala F, Williams J, et al.: Large-scale molecular comparison of human schwann cells to malignant peripheral nerve sheath tumor cell lines and tissues. Cancer Res 2006, 66:2584–2591.

    Article  PubMed  CAS  Google Scholar 

  71. 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.

    Article  PubMed  Google Scholar 

  72. Levy P, Vidaud D, Leroy K, et al.: Molecular profiling of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1, based on large-scale real-time RT-PCR. Mol Cancer 2004, 3:20.

    Article  PubMed  Google Scholar 

  73. Mantripragada KK, Spurlock G, Kluwe L, et al.: High-resolution DNA copy number profiling of malignant peripheral nerve sheath tumors using targeted microarray-based comparative genomic hybridization. Clin Cancer Res 2008, 14:1015–1024.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  75. Albritton KH, Rankin C, Coffin CM: Phase II study of erlotinib in metastatic or unresectable malignant peripheral nerve sheath tumors (MPNST) [abstract]. J Clin Oncol 2006, 24(June 20 Suppl):9518.

    Google Scholar 

  76. Maki RG, Keohan ML, Undevia SD: Updated results of a phase II study of oral multi-kinase inhibitor sorafenib in sarcomas, CTEP study #7060 [abstract]. J Clin Oncol 2008, 24(May 20 Suppl):10531.

    Google Scholar 

  77. Cichowski K, Shih TS, Schmitt E, et al.: Mouse models of tumor development in neurofibromatosis type 1. Science 1999, 286:2172–2176.

    Article  PubMed  CAS  Google Scholar 

  78. Gutmann DH, Hunter-Schaedle K, Shannon KM: Harnessing preclinical mouse models to inform human clinical cancer trials. J Clin Invest 2006, 116:847–852.

    Article  PubMed  CAS  Google Scholar 

  79. Hruban RH, Shiu MH, Senie RT, et al.: Malignant peripheral nerve sheath tumors of the buttock and lower extremity. A study of 43 cases. Cancer 1990, 66:1253–1265.

    Article  PubMed  CAS  Google Scholar 

  80. deCou JM, Rao BN, Parham DM, et al.: Malignant peripheral nerve sheath tumors: the St. Jude Children’s Research Hospital experience. Ann Surg Oncol 1995, 2:524–529.

    Article  PubMed  CAS  Google Scholar 

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  1. Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, Building 10 CRC, Room 1-5750, Bethesda, MD, 20892, USA

    Brigitte C. Widemann

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Widemann, B.C. Current status of sporadic and neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. Curr Oncol Rep 11, 322–328 (2009). https://doi.org/10.1007/s11912-009-0045-z

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