Skip to main content
    • Aa
    • Aa

Malignant peripheral nerve sheath tumour (MPNST): the clinical implications of cellular signalling pathways

  • Daniela Katz (a1), Alexander Lazar (a2) and Dina Lev (a3)

Malignant peripheral nerve sheath tumour (MPNST) is a rare malignancy accounting for 3–10% of all soft tissue sarcomas. Most MPNSTs arise in association with peripheral nerves or deep neurofibromas and may originate from neural crest cells, although the specific cell of origin is uncertain. Approximately half of MPNSTs occur in the setting of neurofibromatosis type 1 (NF1), an autosomal dominant disorder with an incidence of approximately one in 3500 persons; the remainder of MPNSTs develop sporadically. In addition to a variety of clinical manifestations, approximately 8–13% of NF1 patients develop MPNSTs, which are the leading cause of NF1-related mortality. Surgical resection is the mainstay of MPNST clinical management. However, because of invasive growth, propensity to metastasise, and limited sensitivity to chemotherapy and radiation, MPNST has a guarded to poor prognosis. Five-year survival rates of only 20–50% indicate an urgent need for improved therapeutic approaches. Recent work in this field has identified several altered intracellular signal transduction cascades and deregulated tyrosine kinase receptors, posing the possibility of personalised, targeted therapeutics. However, expanded knowledge of MPNST molecular pathobiology will be needed to meaningfully apply such approaches for the benefit of afflicted patients.

Corresponding author
*Corresponding author: Dina Lev, Department of Cancer Biology and Sarcoma Research Center, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1104, Houston, TX 77030, USA. Tel: +1 713 792 1637; Fax: +1 713 563 1185; E-mail:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

2 D.V. Cashen (2004) Survival data for patients with malignant schwannoma. Clinical Orthopaedics and Related Research 426, 69-73

3 M. Anghileri (2006) Malignant peripheral nerve sheath tumors: prognostic factors and survival in a series of patients treated at a single institution. Cancer 107, 1065-1074

4 L. Angelov (1998) Neurogenic sarcomas: experience at the University of Toronto. Neurosurgery 43, 56-64; discussion 64-55

5 D.G. Evans (2002) Malignant peripheral nerve sheath tumours in neurofibromatosis 1. Journal of Medical Genetics 39, 311-314

6 B.S. Ducatman (1986) Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer 57, 2006-2021

8 T. Tucker (2005) Association between benign and malignant peripheral nerve sheath tumors in NF1. Neurology 65, 205-211

9 J.M. Friedman (1999) Epidemiology of neurofibromatosis type 1. American Journal of Medical Genetics 89, 1-6

10 D.H. Gutmann (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. Journal of the American Medical Association 278, 51-57

11 G. Zadeh (2007) Radiation induced peripheral nerve tumors: case series and review of the literature. Journal of Neuro-Oncology 83, 205-212

13 G. Gupta , A. Mammis and A. Maniker (2008) Malignant peripheral nerve sheath tumors. Neurosurgery Clinics of North America 19, 533-543

14 J.N. Vauthey , J.M. Woodruff and M.F. Brennan (1995) Extremity malignant peripheral nerve sheath tumors (neurogenic sarcomas): a 10-year experience. Annals of Surgical Oncology 2, 126-131

15 B.H. Van Herendael (2006) The value of magnetic resonance imaging in the differentiation between malignant peripheral nerve-sheath tumors and non-neurogenic malignant soft-tissue tumors. Skeletal Radiology 35, 745-753

16 S. Cardona (2003) Evaluation of F18-deoxyglucose positron emission tomography (FDG-PET) to assess the nature of neurogenic tumours. European Journal of Surgical Oncology 29, 536-541

18 B.T. Lin , L.M. Weiss and L.J. Medeiros (1997) Neurofibroma and cellular neurofibroma with atypia: a report of 14 tumors. American Journal of Surgical Pathology 21, 1443-1449

19 C. Zou (2009) Clinical, pathological, and molecular variables predictive of malignant peripheral nerve sheath tumor outcome. Annals of Surgery 249, 1014-1022

20 T. De Raedt (2003) Elevated risk for MPNST in NF1 microdeletion patients. American Journal of Human Genetics 72, 1288-1292

21 V.S. Warbey (2009) [18F]FDG PET/CT in the diagnosis of malignant peripheral nerve sheath tumours in neurofibromatosis type-1. European Journal of Nuclear Medicine and Molecular Imaging 36, 751-757

22 D. Furniss (2008) A 10-year review of benign and malignant peripheral nerve sheath tumors in a single center: clinical and radiographic features can help to differentiate benign from malignant lesions. Plastic and Reconstructive Surgery 121, 529-533

24 H.P. Kourea (1998) Subdiaphragmatic and intrathoracic paraspinal malignant peripheral nerve sheath tumors: a clinicopathologic study of 25 patients and 26 tumors. Cancer 82, 2191-2203

25 W.W. Wong (1998) Malignant peripheral nerve sheath tumor: analysis of treatment outcome. International Journal of Radiation Oncology Biology Physics 42, 351-360

26 S. Sharif (2006) Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. Journal of Clinical Oncology 24, 2570-2575

27 P.P. Sordillo (1981) Malignant schwannoma–clinical characteristics, survival, and response to therapy. Cancer 47, 2503-2509

28 M. Carli (2005) Pediatric malignant peripheral nerve sheath tumor: the Italian and German soft tissue sarcoma cooperative group. Journal of Clinical Oncology 23, 8422-8430

29 A.N. D'Agostino , E.H. Soule and R.H. Miller (1963) Sarcomas of the Peripheral Nerves and Somatic Soft Tissues Associated with Multiple Neurofibromatosis (Von Recklinghausen's Disease). Cancer 16, 1015-1027

31 A. Perry (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. American Journal of Pathology 159, 57-61

32 I. Bottillo (2009) Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours. Journal of Pathology 217, 693-701

33 N. Holtkamp (2007) MMP-13 and p53 in the progression of malignant peripheral nerve sheath tumors. Neoplasia 9, 671-677

34 A.G. Menon (1990) Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. Proceedings of the National Academy of Sciences of the United States of America 87, 5435-5439

35 S. Birindelli (2001) Rb and TP53 pathway alterations in sporadic and NF1-related malignant peripheral nerve sheath tumors. Laboratory Investigation 81, 833-844

36 E. Legius (1994) TP53 mutations are frequent in malignant NF1 tumors. Genes Chromosomes and Cancer 10, 250-255

37 C.M. Johannessen (2005) The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proceedings of the National Academy of Sciences of the United States of America 102, 8573-8578

38 G. Ambrosini (2008) Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells. Molecular Cancer Therapeutics 7, 890-896

39 F. Perrone (2009) PDGFRA, PDGFRB, EGFR, and downstream signalling activation in malignant peripheral nerve sheath tumor. Neuro-Oncology Feb 26; [Epub ahead of print]

40 M.A. Watson (2004) Gene expression profiling reveals unique molecular subtypes of Neurofibromatosis Type I-associated and sporadic malignant peripheral nerve sheath tumors. Brain Pathology 14, 297-303

41 Y.Y. Mahller (2006) Malignant peripheral nerve sheath tumors with high and low Ras-GTP are permissive for oncolytic herpes simplex virus mutants. Pediatric Blood and Cancer 46, 745-754

42 R.R. Mattingly (2006) The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD184352 (CI-1040) selectively induces apoptosis in malignant schwannoma cell lines. Journal of Pharmacology and Experimental Therapeutics 316, 456-465

43 Y. Tang (1998) A role for Pak protein kinases in Schwann cell transformation. Proceedings of the National Academy of Sciences of the United States of America 95, 5139-5144

44 D.A. Ingram (2001) Hyperactivation of p21(ras) and the hematopoietic-specific Rho GTPase, Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro. Journal of Experimental Medicine 194, 57-69

46 S. Donovan (2002) Hyperactivation of protein kinase B and ERK have discrete effects on survival, proliferation, and cytokine expression in Nf1-deficient myeloid cells. Cancer Cell 2, 507-514

47 N. Lau (2000) Loss of neurofibromin is associated with activation of RAS/MAPK and PI3-K/AKT signaling in a neurofibromatosis 1 astrocytoma. Journal of Neuropathology and Experimental Neurology 59, 759-767

48 Y.Y. Zhang (1998) Nf1 regulates hematopoietic progenitor cell growth and ras signaling in response to multiple cytokines. Journal of Experimental Medicine 187, 1893-1902

49 N. Holtkamp (2008) EGFR and erbB2 in malignant peripheral nerve sheath tumors and implications for targeted therapy. Neuro-Oncology 10, 946-957

50 C. Mawrin (2002) Immunohistochemical and molecular analysis of p53, RB, and PTEN in malignant peripheral nerve sheath tumors. Virchows Archiv 440, 610-615

51 R. Schneider-Stock (1997) p53 gene mutations in soft-tissue sarcomas–correlations with p53 immunohistochemistry and DNA ploidy. Journal of Cancer Research and Clinical Oncology 123, 211-218

52 L.G. Kindblom (1995) Immunohistochemical and molecular analysis of p53, MDM2, proliferating cell nuclear antigen and Ki67 in benign and malignant peripheral nerve sheath tumours. Virchows Archiv 427, 19-26

53 H.P. Kourea (1999) Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but not in neurofibromas. American Journal of Pathology 155, 1855-1860

54 G.P. Nielsen (1999) Malignant transformation of neurofibromas in neurofibromatosis 1 is associated with CDKN2A/p16 inactivation. American Journal of Pathology 155, 1879-1884

55 H.P. Kourea (1999) 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. American Journal of Pathology 155, 1885-1891

56 A. Perry (2002) Differential NF1, p16, and EGFR patterns by interphase cytogenetics (FISH) in malignant peripheral nerve sheath tumor (MPNST) and morphologically similar spindle cell neoplasms. Journal of Neuropathology and Experimental Neurology 61, 702-709

57 K.K. Mantripragada (2008) High-resolution DNA copy number profiling of malignant peripheral nerve sheath tumors using targeted microarray-based comparative genomic hybridization. Clinical Cancer Research 14, 1015-1024

58 A. Theos and B.R. Korf (2006) Pathophysiology of neurofibromatosis type 1. Annals of Internal Medicine 144, 842-849

59 R. Ballester (1990) The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63, 851-859

60 G.F. Xu (1990) The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 63, 835-841

61 G. Daum (1994) The ins and outs of Raf kinases. Trends in Biochemical Sciences 19, 474-480

63 I. Rubio (1999) Farnesylation of Ras is important for the interaction with phosphoinositide 3-kinase gamma. European Journal of Biochemistry 266, 70-82

64 A.D. Basso , P. Kirschmeier and W.R. Bishop (2006) Lipid posttranslational modifications. Farnesyl transferase inhibitors. Journal of Lipid Research 47, 15-31

65 S. Roy (2005) Individual palmitoyl residues serve distinct roles in H-ras trafficking, microlocalization, and signaling. Molecular and Cellular Biology 25, 6722-6733

66 W.W. Wong (2002) HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia 16, 508-519

67 M.A. Morgan , A. Ganser and C.W. Reuter (2003) Therapeutic efficacy of prenylation inhibitors in the treatment of myeloid leukemia. Leukemia 17, 1482-1498

70 J.W. Wojtkowiak (2008) Induction of apoptosis in neurofibromatosis type 1 malignant peripheral nerve sheath tumor cell lines by a combination of novel farnesyl transferase inhibitors and lovastatin. Journal of Pharmacology and Experimental Therapeutics 326, 1-11

71 L.C. Krab (2008) Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. Journal of the American Medical Association 300, 287-294

72 J. Sun (1998) Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts. Oncogene 16, 1467-1473

73 C.A. Rowell (1997) Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. Journal of Biological Chemistry 272, 14093-14097

75 B.C. Widemann (2006) Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and plexiform neurofibromas. Journal of Clinical Oncology 24, 507-516

76 F. Chang (2003) Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 17, 1263-1293

77 J.N. Lavoie (1996) Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. Journal of Biological Chemistry 271, 20608-20616

78 M.E. Katz and F. McCormick (1997) Signal transduction from multiple Ras effectors. Current Opinion in Genetics and Development 7, 75-79

79 B.I. Rini (2007) Sunitinib. Expert Opinion on Pharmacotherapy 8, 2359-2369

81 G. Diwakar (2008) Neurofibromin as a regulator of melanocyte development and differentiation. Journal of Cell Science 121, 167-177

82 J.T. Dilworth (2006) Molecular targets for emerging anti-tumor therapies for neurofibromatosis type 1. Biochemical Pharmacology 72, 1485-1492

83 G. Johansson (2008) Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors. Molecular Cancer Therapeutics 7, 1237-1245

84 D.A. Guertin and D.M. Sabatini (2005) An expanding role for mTOR in cancer. Trends in Molecular Medicine 11, 353-361

85 J. LoPiccolo (2008) Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resistance Updates 11, 32-50

86 C.Y. Zou (2009) Dual targeting of AKT and mammalian target of rapamycin: A potential therapeutic approach for malignant peripheral nerve sheath tumor. Molecular Cancer Therapeutics May 5; [Epub ahead of print]

87 C. Vezina , A. Kudelski and S.N. Sehgal (1975) Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. Journal of Antibiotics 28, 721-726

89 X. Wan and L.J. Helman (2007) The biology behind mTOR inhibition in sarcoma. Oncologist 12, 1007-1018

90 M. Guba (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nature Medicine 8, 128-135

91 S.Y. Sun (2005) Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Research 65, 7052-7058

92 X. Wang (2007) Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and Mnk-mediated eukaryotic translation initiation factor 4E phosphorylation. Molecular and Cellular Biology 27, 7405-7413

93 M.M. Mita (2008) Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. Journal of Clinical Oncology 26, 361-367

97 F.I. Raynaud (2007) Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Research 67, 5840-5850

99 Y. Yarden (2001) The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. European Journal of Cancer 37 (Suppl 4), S3-8

100 J.E. DeClue (2000) Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models. Journal of Clinical Investigation 105, 1233-1241

101 H. Tawbi (2008) Epidermal growth factor receptor expression and mutational analysis in synovial sarcomas and malignant peripheral nerve sheath tumors. Oncologist 13, 459-466

104 B.C. Ling (2005) Role for the epidermal growth factor receptor in neurofibromatosis-related peripheral nerve tumorigenesis. Cancer Cell 7, 65-75

105 N. Holtkamp (2004) Subclassification of nerve sheath tumors by gene expression profiling. Brain Pathology 14, 258-264

106 D. Keizman (2009) Expression and significance of EGFR in malignant peripheral nerve sheath tumor. Journal of Neuro-Oncology 94, 383-388

107 E. Raymond , S. Faivre and J.P. Armand (2000) Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs 60 (Suppl 1), 15-23; discussion 41-12

108 W. Su (2003) Malignant peripheral nerve sheath tumor cell invasion is facilitated by Src and aberrant CD44 expression. Glia 42, 350-358

109 Y.Y. Mahller (2007) Oncolytic HSV and erlotinib inhibit tumor growth and angiogenesis in a novel malignant peripheral nerve sheath tumor xenograft model. Molecular Therapy 15, 279-286

110 R.S. Herbst (2002) Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. Journal of Clinical Oncology 20, 3815-3825

111 S. Benvenuti (2007) Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Research 67, 2643-2648

112 N. van Zandwijk (2007) EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer. Annals of Oncology 18, 99-103

113 F. Perrone (2009) PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Annals of Oncology 20, 84-90

114 M. Frattini (2007) PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. British Journal of Cancer 97, 1139-1145

115 C.E. Geyer (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. New England Journal of Medicine 355, 2733-2743

116 C.H. Heldin and B. Westermark (1984) Growth factors: mechanism of action and relation to oncogenes. Cell 37, 9-20

117 C. Betsholtz , L. Karlsson and P. Lindahl (2001) Developmental roles of platelet-derived growth factors. Bioessays 23, 494-507

118 A. Badache and G.H. De Vries (1998) Neurofibrosarcoma-derived Schwann cells overexpress platelet-derived growth factor (PDGF) receptors and are induced to proliferate by PDGF BB. Journal of Cellular Physiology 177, 334-342

119 N. Holtkamp (2004) Differentially expressed genes in neurofibromatosis 1-associated neurofibromas and malignant peripheral nerve sheath tumors. Acta Neuropathologica 107, 159-168

120 N. Holtkamp (2006) Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors, and its implications for imatinib sensitivity. Carcinogenesis 27, 664-671

121 I. Dang and G.H. DeVries (2005) Schwann cell lines derived from malignant peripheral nerve sheath tumors respond abnormally to platelet-derived growth factor-BB. Journal of Neuroscience Research 79, 318-328

122 S.M. Jones and A. Kazlauskas (2000) Connecting signaling and cell cycle progression in growth factor-stimulated cells. Oncogene 19, 5558-5567

123 M. Aoki (2007) Imatinib mesylate inhibits cell invasion of malignant peripheral nerve sheath tumor induced by platelet-derived growth factor-BB. Laboratory Investigation 87, 767-779

125 A. Badache , N. Muja and G.H. De Vries (1998) Expression of Kit in neurofibromin-deficient human Schwann cells: role in Schwann cell hyperplasia associated with type 1 neurofibromatosis. Oncogene 17, 795-800

126 K.M. Reilly and T. Van Dyke (2008) It takes a (dysfunctional) village to raise a tumor. Cell 135, 408-410

127 Y. Zhu (2002) Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296, 920-922

128 S. DuBois and G. Demetri (2007) Markers of angiogenesis and clinical features in patients with sarcoma. Cancer 109, 813-819

129 D.J. Hicklin and L.M. Ellis (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. Journal of Clinical Oncology 23, 1011-1027

130 S.J. Harper and D.O. Bates (2008) VEGF-A splicing: the key to anti-angiogenic therapeutics? Nature Reviews Cancer 8, 880-887

131 J. Wasa (2008) Differential expression of angiogenic factors in peripheral nerve sheath tumors. Clinical and Experimental Metastasis 25, 819-825

133 D.R. D'Adamo (2005) Phase II study of doxorubicin and bevacizumab for patients with metastatic soft-tissue sarcomas. Journal of Clinical Oncology 23, 7135-7142

135 M.L. Hensley (2002) Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. Journal of Clinical Oncology 20, 2824-2831

S.R. Grobmyer (2008) Malignant peripheral nerve sheath tumor: molecular pathogenesis and current management considerations. Journal of Surgical Oncology 97, 340-349

J.B. Rubin and D.H. Gutmann (2005) Neurofibromatosis type 1 – a model for nervous system tumour formation? Nature Reviews Cancer 5, 557-564

A. Gschwind , O.M. Fischer and A. Ullrich (2004) The discovery of receptor tyrosine kinases: targets for cancer therapy. Nature Reviews Cancer 4, 361-370

J.S. Sebolt-Leopold and R. Herrera (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nature Reviews Cancer 4, 937-947

D.M. Sabatini (2006) mTOR and cancer: insights into a complex relationship. Nature Reviews Cancer 6, 729-734

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Expert Reviews in Molecular Medicine
  • ISSN: -
  • EISSN: 1462-3994
  • URL: /core/journals/expert-reviews-in-molecular-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Full text views

Total number of HTML views: 4
Total number of PDF views: 26 *
Loading metrics...

Abstract views

Total abstract views: 208 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 23rd March 2017. This data will be updated every 24 hours.