Online first
Review paper
Published online: 2024-02-27

open access

Page views 337
Article views/downloads 107
Get Citation

Connect on Social Media

Connect on Social Media

Malignant peripheral nerve sheath tumor — from genetics to multidisciplinary treatment

Anna M. Czarnecka1, Paulina Chmiel1, Paweł Sobczuk1, Ewa Bartnik23, Mateusz Spałek14, Anna Szumera-Ciećkiewicz5, Marcin Zdzienicki1, Sławomir Falkowski1, Piotr Rutkowski1

Abstract

Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma (STS); it originates from nervous tissue and typically develops in proximity to nerve trunks in the limbs and trunk. These tumors, constituting approximately 5% of soft tissue sarcomas, can either form spontaneously or arise frompre-existing neurofibromas. The majority (90%) of cases occur in individuals between the 2nd and 5th decades of life. Themain risk factor for MPNST is von Recklinghausen disease (type 1 neurofibromatosis). The cornerstone of MPNST management involves radical surgicalmeasures, specifically tumor excision within healthy tissue boundaries (wide local excision), which is complemented by adjuvant radiotherapy. In case of metastatic disease, palliative chemotherapy employing doxorubicin or a combination of doxorubicin and ifosfamide is utilized. Approximately 25–30% of patients experience clinical improvement after chemotherapy. Looking ahead, advancements in research on molecular biology may lead to the development of inhibitors demonstrating greater efficacy than traditional chemotherapy for MPNST patients. At present, ongoing clinical trials of the therapeutic management of MPNST encompass pembrolizumab, the combination of nivolumab with ipilimumab, pexydartinib (an inhibitor targeting KIT, CSF1R, and FLT3) in conjunction with sirolimus, sapanisertib (a TORC1/2 inhibitor), or LOXO-195 (an inhibitor of neurotrophic tyrosine kinase receptors NTRK type 1, 2, and 3). 

Article available in PDF format

View PDF Download PDF file

References

  1. WHO Classification of Tumours Editorial Board. Soft Tissue and Bone Tumours. WHO Classification of Tumours, 5th Edition. World Health Organization 2013.
  2. Hirbe A, Gutmann D. The management of neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors: challenges, progress, and future prospects. Expert Opinion on Orphan Drugs. 2017; 5(8): 623–631.
  3. Pala-Sadza A, Zajączkiewicz H, Banaś-Samson R, et al. Rzadki przypadek złośliwego nerwiaka osłonkowego jamy nosa. Polski Przegląd Otorynolaryngologiczny. 2014; 3(4): 210–213.
  4. Boczej R, Walas R, Motyka M. Olbrzymi guz złośliwy nerwów obwodowych. Chirurgia Polska. 2013; 15(2): 141–145.
  5. De Raedt T, Brems H, Wolkenstein P, et al. Elevated risk for MPNST in NF1 microdeletion patients. Am J Hum Genet. 2003; 72(5): 1288–1292.
  6. Evans DGR, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002; 39(5): 311–314.
  7. Mackel CE, Medeiros I, Moore BE, et al. Intracranial Malignant Peripheral Nerve Sheath Tumors Not Associated with a Cranial Nerve: Systematic Review and Illustrative Case. World Neurosurg. 2021; 156: 76–91.
  8. Miao R, Wang H, Jacobson A, et al. Radiation-induced and neurofibromatosis-associated malignant peripheral nerve sheath tumors (MPNST) have worse outcomes than sporadic MPNST. Radiother Oncol. 2019; 137: 61–70.
  9. Farid M, Demicco EG, Garcia R, et al. Malignant peripheral nerve sheath tumors. Oncologist. 2014; 19(2): 193–201.
  10. Shurell E, Tran LM, Nakashima J, et al. Gender dimorphism and age of onset in malignant peripheral nerve sheath tumor preclinical models and human patients. BMC Cancer. 2014; 14: 827.
  11. Mowery A, Clayburgh D. Malignant peripheral nerve sheath tumors: Analysis of the national cancer database. Oral Oncol. 2019; 98: 13–19.
  12. Brohl AS, Kahen E, Yoder SJ, et al. The genomic landscape of malignant peripheral nerve sheath tumors: diverse drivers of Ras pathway activation. Sci Rep. 2017; 7(1): 14992.
  13. Brosseau JP, Le LuQ. Heterozygous Tumor Suppressor Microenvironment in Cancer Development. Trends Cancer. 2019; 5(9): 541–546.
  14. Pemov A, Li H, Patidar R, et al. NISC Comparative Sequencing Program, NCI DCEG Cancer Genomics Research Laboratory. The primacy of NF1 loss as the driver of tumorigenesis in neurofibromatosis type 1-associated plexiform neurofibromas. Oncogene. 2017; 36(22): 3168–3177.
  15. 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(6): 541–555, doi: 10.1002/1098-1004(200006)15:6<541::AID-HUMU6>3.0.CO;2-N.
  16. Jadayel D, Fain P, Upadhyaya M, et al. Paternal origin of new mutations in Von Recklinghausen neurofibromatosis. Nature. 1990; 343(6258): 558–559.
  17. Kahen EJ, Brohl A, Yu D, et al. Neurofibromin level directs RAS pathway signaling and mediates sensitivity to targeted agents in malignant peripheral nerve sheath tumors. Oncotarget. 2018; 9(32): 22571–22585.
  18. Lee S, Rauch J, Kolch W. Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity. Int J Mol Sci. 2020; 21(3).
  19. Zou Z, Tao T, Li H, et al. mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges. Cell & Bioscience. 2020; 10(1).
  20. Watson AL, Keller BJ, Williams KA, et al. Correction: Co-targeting the MAPK and PI3K/AKT/mTOR pathways in two genetically engineered mouse models of schwann cell tumors reduces tumor grade and multiplicity. Oncotarget. 2020; 11(39): 3618–3620.
  21. Arshad T. A novel pan-RAS inhibitor for malignant peripheral nerve sheath tumors. J Clin Oncol. 2022; 40(16_suppl): e23531–e23531.
  22. Endo M, Yamamoto H, Setsu N, et al. Prognostic significance of AKT/mTOR and MAPK pathways and antitumor effect of mTOR inhibitor in NF1-related and sporadic malignant peripheral nerve sheath tumors. Clin Cancer Res. 2013; 19(2): 450–461.
  23. Varin J, Poulain L, Hivelin M, et al. Dual mTORC1/2 inhibition induces anti-proliferative effect in NF1-associated plexiform neurofibroma and malignant peripheral nerve sheath tumor cells. Oncotarget. 2016; 7(24): 35753–35767.
  24. Zou CY, Smith KD, Zhu QS, et al. Dual targeting of AKT and mammalian target of rapamycin: a potential therapeutic approach for malignant peripheral nerve sheath tumor. Mol Cancer Ther. 2009; 8(5): 1157–1168.
  25. Adnane L, Trail PA, Taylor I, et al. Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 2006; 407: 597–612.
  26. Gudena V, Verma N, Post G, et al. Metastatic chest wall malignant schwannoma responding to sorafenib: case report and literature review. Cancer Biol Ther. 2008; 7(6): 810–813.
  27. D'Adamo DR, Keohan ML, Carvajal RD, et al. A phase II trial of sorafenib (S) and dacarbazine (D) in leiomyosarcoma (LMS), synovial sarcoma (SS), and malignant peripheral nerve sheath tumor (MPNST). J Clin Oncol. 2011; 29(15_suppl): 10025–10025.
  28. 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(12): 3943–3955.
  29. Jessen WJ, Miller SJ, Jousma E, et al. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Invest. 2013; 123(1): 340–347.
  30. Fischer-Huchzermeyer S, Dombrowski A, Wilke G, et al. MEK inhibitors enhance therapeutic response towards ATRA in NF1 associated malignant peripheral nerve sheath tumors (MPNST) in-vitro. PLoS One. 2017; 12(11): e0187700.
  31. Hitchen N, Cross M, Laking G, et al. Sporadic Metastatic Malignant Peripheral Nerve Sheath Tumour with an NF1 Mutation Responding to Trametinib: A Case Report. Case Rep Oncol. 2023; 16(1): 1–6.
  32. Nagabushan S, Lau L, Barahona P, et al. Efficacy of MEK inhibition in a recurrent malignant peripheral nerve sheath tumor. npj Precision Oncology. 2021; 5(1).
  33. Widemann BC, Lu Y, Reinke D, et al. Targeting Sporadic and Neurofibromatosis Type 1 (NF1) Related Refractory Malignant Peripheral Nerve Sheath Tumors (MPNST) in a Phase II Study of Everolimus in Combination with Bevacizumab (SARC016). Sarcoma. 2019; 2019: 7656747.
  34. Kim A, Lu Y, Okuno SH, et al. Targeting Refractory Sarcomas and Malignant Peripheral Nerve Sheath Tumors in a Phase I/II Study of Sirolimus in Combination with Ganetespib (SARC023). Sarcoma. 2020; 2020: 5784876.
  35. Peacock JD, Cherba D, Kampfschulte K, et al. Molecular-guided therapy predictions reveal drug resistance phenotypes and treatment alternatives in malignant peripheral nerve sheath tumors. J Transl Med. 2013; 11: 213.
  36. Brosius S, Roth K, Carroll S. Combinatorial treatment of malignant peripheral nerve sheath tumors with tyrosine kinase inhibitors hinders proliferation and survival. The FASEB Journal. 2013; 27(S1).
  37. Cichowski K, Shih TS, Schmitt E, et al. Mouse models of tumor development in neurofibromatosis type 1. Science. 1999; 286(5447): 2172–2176.
  38. 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(3): 437–448.
  39. 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(7521): 247–251.
  40. Legius E, Dierick H, Wu R, et al. TP53 mutations are frequent in malignant NF1 tumors. Genes Chromosomes Cancer. 1994; 10(4): 250–255.
  41. 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(8): 702–709.
  42. Zhang M, Wang Y, Jones S, et al. Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nat Genet. 2014; 46(11): 1170–1172.
  43. Beert E, Brems H, Daniëls B, et al. Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. Genes Chromosomes Cancer. 2011; 50(12): 1021–1032.
  44. Thomas LE, Winston J, Rad E, et al. Evaluation of copy number variation and gene expression in neurofibromatosis type-1-associated malignant peripheral nerve sheath tumours. Hum Genomics. 2015; 9(1): 3.
  45. Brekke HR, Ribeiro FR, Kolberg M, et al. Genomic changes in chromosomes 10, 16, and X in malignant peripheral nerve sheath tumors identify a high-risk patient group. J Clin Oncol. 2010; 28(9): 1573–1582.
  46. Yang J, Du X. Genomic and molecular aberrations in malignant peripheral nerve sheath tumor and their roles in personalized target therapy. Surg Oncol. 2013; 22(3): e53–e57.
  47. 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(24): 4586–4591.
  48. Amirnasr A, Verdijk RM, van Kuijk PF, et al. Expression and inhibition of BRD4, EZH2 and TOP2A in neurofibromas and malignant peripheral nerve sheath tumors. PLoS One. 2017; 12(8): e0183155.
  49. 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(15): 4507–4513.
  50. Wu J, Patmore DM, Jousma E, et al. EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors. Oncogene. 2014; 33(2): 173–180.
  51. Albritton KH, Rankin C, Coffin CM, et al. Phase II study of erlotinib in metastatic or unresectable malignant peripheral nerve sheath tumors (MPNST). J Clin Oncol. 2006; 24(18_suppl): 9518–9518.
  52. Suppiah S, Mansouri S, Mamatjan Y, et al. Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities. Nat Commun. 2023; 14(1): 2696.
  53. Amirnasr A, Verdijk RM, van Kuijk PF, et al. Deregulated microRNAs in neurofibromatosis type 1 derived malignant peripheral nerve sheath tumors. Sci Rep. 2020; 10(1): 2927.
  54. Subramanian S, Thayanithy V, West RB, et al. Genome-wide transcriptome analyses reveal p53 inactivation mediated loss of miR-34a expression in malignant peripheral nerve sheath tumours. J Pathol. 2010; 220(1): 58–70.
  55. Feber A, Wilson GA, Zhang Lu, et al. Comparative methylome analysis of benign and malignant peripheral nerve sheath tumors. Genome Res. 2011; 21(4): 515–524.
  56. Presneau N, Eskandarpour M, Shemais T, et al. MicroRNA profiling of peripheral nerve sheath tumours identifies miR-29c as a tumour suppressor gene involved in tumour progression. Br J Cancer. 2013; 108(4): 964–972.
  57. Röhrich M, Koelsche C, Schrimpf D, et al. Methylation-based classification of benign and malignant peripheral nerve sheath tumors. Acta Neuropathol. 2016; 131(6): 877–887.
  58. Cassier PA, Lefranc A, Amela EY, et al. A phase II trial of panobinostat in patients with advanced pretreated soft tissue sarcoma. A study from the French Sarcoma Group. Br J Cancer. 2013; 109(4): 909–914.
  59. Seno N, Fukushima T, Gomi D, et al. Successful treatment with doxorubicin and ifosfamide for mediastinal malignant peripheral nerve sheath tumor with loss of H3K27me3 expression. Thorac Cancer. 2017; 8(6): 720–723.
  60. Wassef M, Luscan A, Aflaki S, et al. EZH1/2 function mostly within canonical PRC2 and exhibit proliferation-dependent redundancy that shapes mutational signatures in cancer. Proc Natl Acad Sci U S A. 2019; 116(13): 6075–6080.
  61. Katz D, Lazar A, Lev D. Malignant peripheral nerve sheath tumour (MPNST): the clinical implications of cellular signalling pathways. Expert Rev Mol Med. 2009; 11: e30.
  62. Fukushima S, Endo M, Matsumoto Y, et al. Hypoxia-inducible factor 1 alpha is a poor prognostic factor and potential therapeutic target in malignant peripheral nerve sheath tumor. PLoS One. 2017; 12(5): e0178064.
  63. 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(39): 64300–64308.
  64. Lehnhardt M, Daigeler A, Homann HH, et al. [Importance of specialized centers in diagnosis and treatment of extremity-soft tissue sarcomas. Review of 603 cases]. Chirurg. 2009; 80(4): 341–347.
  65. Sandrucci S, Trama A, Quagliuolo V, et al. Accreditation for centers of sarcoma surgery. Updates Surg. 2017; 69(1): 1–7.
  66. Le Guellec S, Decouvelaere AV, Filleron T, et al. Malignant Peripheral Nerve Sheath Tumor Is a Challenging Diagnosis: A Systematic Pathology Review, Immunohistochemistry, and Molecular Analysis in 160 Patients From the French Sarcoma Group Database. Am J Surg Pathol. 2016; 40(7): 896–908.
  67. Rodriguez FJ, Folpe AL, Giannini C, et al. Pathology of peripheral nerve sheath tumors: diagnostic overview and update on selected diagnostic problems. Acta Neuropathol. 2012; 123(3): 295–319.
  68. Kim A, Stewart DR, Reilly KM, et al. Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies. Sarcoma. 2017; 2017: 7429697.
  69. Krawczyk MA, Karpinsky G, Izycka-Swieszewska E, et al. Immunohistochemical assessment of cyclin D1 and p53 is associated with survival in childhood malignant peripheral nerve sheath tumor. Cancer Biomark. 2019; 24(3): 351–361.
  70. 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(10): 1337–1345.
  71. Kamran SC, Howard SA, Shinagare AB, et al. Malignant peripheral nerve sheath tumors: prognostic impact of rhabdomyoblastic differentiation (malignant triton tumors), neurofibromatosis 1 status and location. Eur J Surg Oncol. 2013; 39(1): 46–52.
  72. Mito JK, Qian X, Doyle LA, et al. Role of Histone H3K27 Trimethylation Loss as a Marker for Malignant Peripheral Nerve Sheath Tumor in Fine-Needle Aspiration and Small Biopsy Specimens. Am J Clin Pathol. 2017; 148(2): 179–189.
  73. Ito Y, Kohashi K, Endo M, et al. Clinicopathological and prognostic significance of H3K27 methylation status in malignant peripheral nerve sheath tumor: correlation with skeletal muscle differentiation. Virchows Arch. 2021; 479(6): 1233–1244.
  74. Wilson MP, Katlariwala P, Low G, et al. Diagnostic Accuracy of MRI for the Detection of Malignant Peripheral Nerve Sheath Tumors: A Systematic Review and Meta-Analysis. AJR Am J Roentgenol. 2021; 217(1): 31–39.
  75. Yun JS, Lee MH, Lee SM, et al. Peripheral nerve sheath tumor: differentiation of malignant from benign tumors with conventional and diffusion-weighted MRI. Eur Radiol. 2021; 31(3): 1548–1557.
  76. Benz MR, Czernin J, Dry SM, et al. Quantitative F18-fluorodeoxyglucose positron emission tomography accurately characterizes peripheral nerve sheath tumors as malignant or benign. Cancer. 2010; 116(2): 451–458.
  77. Nishida Y, Ikuta K, Ito S, et al. Limitations and benefits of FDG-PET/CT in NF1 patients with nerve sheath tumors: A cross-sectional/longitudinal study. Cancer Sci. 2021; 112(3): 1114–1122.
  78. Assadi M, Velez E, Najafi MH, et al. PET Imaging of Peripheral Nerve Tumors. PET Clin. 2019; 14(1): 81–89.
  79. Pendleton C, Howe BM, Spinner RJ. Percutaneous image-guided biopsy in malignant peripheral nerve sheath tumors. Acta Neurochir (Wien). 2021; 163(2): 515–519.
  80. Pianta M, Chock E, Schlicht S, et al. Accuracy and complications of CT-guided core needle biopsy of peripheral nerve sheath tumours. Skeletal Radiol. 2015; 44(9): 1341–1349.
  81. Graham DS, Russell TA, Eckardt MA, et al. Oncologic Accuracy of Image-guided Percutaneous Core-Needle Biopsy of Peripheral Nerve Sheath Tumors at a High-volume Sarcoma Center. Am J Clin Oncol. 2019; 42(10): 739–743.
  82. Wakely PE, Ali SZ, Bishop JA. The cytopathology of malignant peripheral nerve sheath tumor: a report of 55 fine-needle aspiration cases. Cancer Cytopathol. 2012; 120(5): 334–341.
  83. Tonsgard JH. Clinical manifestations and management of neurofibromatosis type 1. Semin Pediatr Neurol. 2006; 13(1): 2–7.
  84. Evans DGR, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002; 39(5): 311–314.
  85. 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(4): 593–598.
  86. Derlin T, Tornquist K, Münster S, et al. Comparative effectiveness of 18F-FDG PET/CT versus whole-body MRI for detection of malignant peripheral nerve sheath tumors in neurofibromatosis type 1. Clin Nucl Med. 2013; 38(1): e19–e25.
  87. Well L, Salamon J, Kaul MG, et al. Differentiation of peripheral nerve sheath tumors in patients with neurofibromatosis type 1 using diffusion-weighted magnetic resonance imaging. Neuro Oncol. 2019; 21(4): 508–516.
  88. Baca N, Majlessipour F, Xie Y, et al. Characterization of pre-malignant lesions in patients with pediatric neurofibromatosis type 1 using a novel whole-body magnetic resonance imaging technique. J Clin Oncol. 2023; 41(16_suppl): TPS10637–TPS10637.
  89. 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(2): 390–394.
  90. Salamon J, Veldhoen S, Apostolova I, et al. 18F-FDG PET/CT for detection of malignant peripheral nerve sheath tumours in neurofibromatosis type 1: tumour-to-liver ratio is superior to an SUVmax cut-off. Eur Radiol. 2014; 24(2): 405–412.
  91. Chirindel A, Chaudhry M, Blakeley JO, et al. 18F-FDG PET/CT qualitative and quantitative evaluation in neurofibromatosis type 1 patients for detection of malignant transformation: comparison of early to delayed imaging with and without liver activity normalization. J Nucl Med. 2015; 56(3): 379–385.
  92. Azizi AA, Slavc I, Theisen BE, et al. Monitoring of plexiform neurofibroma in children and adolescents with neurofibromatosis type 1 by [ F]FDG-PET imaging. Is it of value in asymptomatic patients? Pediatr Blood Cancer. 2018; 65(1).
  93. Krzakowski M, Rutkowski P, Jassem J, et al. Zalecenia w zakresie zastosowania badań pozytonowej emisyjnej tomografii w onkologii. NOWOTWORY Journal of Oncology. 2011; 61(1): 57–69.
  94. Ahlawat S, Blakeley JO, Rodriguez FJ, et al. Imaging biomarkers for malignant peripheral nerve sheath tumors in neurofibromatosis type 1. Neurology. 2019; 93(11): e1076–e1084.
  95. Tovmassian D, Razak MA, London K. The Role of [18F]FDG-PET/CT in Predicting Malignant Transformation of Plexiform Neurofibromas in Neurofibromatosis-1. Int J Surg Oncol. 2016; 2016: 1–7.
  96. Szymanski JJ, Sundby RT, Jones PA, et al. Cell-free DNA ultra-low-pass whole genome sequencing to distinguish malignant peripheral nerve sheath tumor (MPNST) from its benign precursor lesion: A cross-sectional study. PLoS Med. 2021; 18(8): e1003734.
  97. Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007; 44(2): 81–88.
  98. Casali PG, Abecassis N, Bauer S, et al. Soft tissue and visceral sarcomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018; 29(Suppl 4): iv51–iv67.
  99. 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(33): 8422–8430.
  100. Higham CS, Steinberg SM, Dombi E, et al. SARC006: Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated Chemotherapy-Naive Malignant Peripheral Nerve Sheath Tumors. Sarcoma. 2017; 2017: 8685638.
  101. Gronchi A, Stacchiotti S, Verderio P, et al. Short, full-dose adjuvant chemotherapy (CT) in high-risk adult soft tissue sarcomas (STS): long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. Ann Oncol. 2016; 27(12): 2283–2288.
  102. Hirbe AC, Cosper PF, Dahiya S, et al. Neoadjuvant Ifosfamide and Epirubicin in the Treatment of Malignant Peripheral Nerve Sheath Tumors. Sarcoma. 2017; 2017: 3761292.
  103. Gronchi A, Ferrari S, Quagliuolo V, et al. Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol. 2017; 18(6): 812–822.
  104. Gronchi A, Palmerini E, Quagliuolo V, et al. Neoadjuvant Chemotherapy in High-Risk Soft Tissue Sarcomas: Final Results of a Randomized Trial From Italian (ISG), Spanish (GEIS), French (FSG), and Polish (PSG) Sarcoma Groups. J Clin Oncol. 2020; 38(19): 2178–2186.
  105. Karpinsky G, Krawczyk MA, Izycka-Swieszewska E, et al. Tumor expression of survivin, p53, cyclin D1, osteopontin and fibronectin in predicting the response to neo-adjuvant chemotherapy in children with advanced malignant peripheral nerve sheath tumor. J Cancer Res Clin Oncol. 2018; 144(3): 519–529.
  106. Weiss A, Chen YL, Scharschmidt T, et al. Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. 2020; 21(8): 1110–1122.
  107. Shurell-Linehan E, DiPardo BJ, Elliott IA, et al. Pathologic Response to Neoadjuvant Therapy is Associated With Improved Long-term Survival in High-risk Primary Localized Malignant Peripheral Nerve Sheath Tumors. Am J Clin Oncol. 2019; 42(5): 426–431.
  108. Valentin T, Le Cesne A, Ray-Coquard I, et al. Management and prognosis of malignant peripheral nerve sheath tumors: The experience of the French Sarcoma Group (GSF-GETO). Eur J Cancer. 2016; 56: 77–84.
  109. Hwang InK, Hahn SM, Kim HS, et al. Outcomes of Treatment for Malignant Peripheral Nerve Sheath Tumors: Different Clinical Features Associated with Neurofibromatosis Type 1. Cancer Res Treat. 2017; 49(3): 717–726.
  110. Longhi A, Errani C, Magagnoli G, et al. High grade malignant peripheral nerve sheath tumors: outcome of 62 patients with localized disease and review of the literature. J Chemother. 2010; 22(6): 413–418.
  111. Bishop AJ, Zagars GK, Torres KE, et al. Malignant Peripheral Nerve Sheath Tumors: A Single Institution's Experience Using Combined Surgery and Radiation Therapy. Am J Clin Oncol. 2018; 41(5): 465–470.
  112. Stucky CC, Johnson K, Gray R, et al. Malignant Peripheral Nerve Sheath Tumors (MPNST): The Mayo Clinic Experience. Ann Surg Oncol. 2011; 19(3): 878–885.
  113. Pervaiz N, Colterjohn N, Farrokhyar F, et al. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008; 113(3): 573–581.
  114. Anghileri M, Miceli R, Fiore M, et al. Malignant peripheral nerve sheath tumors. Cancer. 2006; 107(5): 1065–1074.
  115. 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(2): 351–360.
  116. DeLaney TF, Liebsch NJ, Pedlow FX, et al. Long-term results of Phase II study of high dose photon/proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas. J Surg Oncol. 2014; 110(2): 115–122.
  117. Jensen AD, Uhl M, Chaudhri N, et al. Carbon Ion irradiation in the treatment of grossly incomplete or unresectable malignant peripheral nerve sheaths tumors: acute toxicity and preliminary outcome. Radiat Oncol. 2015; 10: 109.
  118. Voth C, Wu X, Keirns D, et al. Analysis of demographic characteristics of malignant peripheral nerve sheath tumor in adults: A National Cancer Database study. J Clin Oncol. 2023; 41(16_suppl): e23555–e23555.
  119. 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(6): 1014–1022.
  120. Kolberg M, Høland M, Agesen TH, et al. Survival meta-analyses for >1800 malignant peripheral nerve sheath tumor patients with and without neurofibromatosis type 1. Neuro Oncol. 2013; 15(2): 135–147.
  121. Hirozane T, Nakayama R, Yamaguchi S, et al. Recurrent malignant peripheral nerve sheath tumor presenting as an asymptomatic intravenous thrombus extending to the heart: a case report. World J Surg Oncol. 2022; 20(1): 8.
  122. Lee CS, Huh JiS, Chang JW, et al. The early detection of recurrence of malignant peripheral nerve sheath tumor by frequent magnetic resonance imaging. J Korean Neurosurg Soc. 2010; 47(1): 51–54.
  123. Marickar YM, Abraham B. Malignant peripheral nerve sheath tumour - A long story: Case report. Int J Surg Case Rep. 2020; 77: 618–623.
  124. Gronchi A, Miah AB, Tos APD, et al. Soft tissue and visceral sarcomas: ESMO–EURACAN–GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up☆. Ann Oncol. 2021; 32(11): 1348–1365.
  125. Kahn J, Gillespie A, Ondos J, et al. Radiation Therapy in Management of Sporadic and Neurofibromatosis Type 1 (NF1) Associated Malignant Peripheral Nerve Sheath Tumors (MPNST). International Journal of Radiation Oncology*Biology*Physics. 2012; 84(3): S638.
  126. Boyce-Fappiano D, Damron EP, Farooqi A, et al. Hypofractionated Radiation Therapy for Unresectable or Metastatic Sarcoma Lesions. Adv Radiat Oncol. 2022; 7(3): 100913.
  127. Kroep JR, Ouali M, Gelderblom H, et al. First-line chemotherapy for malignant peripheral nerve sheath tumor (MPNST) versus other histological soft tissue sarcoma subtypes and as a prognostic factor for MPNST: an EORTC Soft Tissue and Bone Sarcoma Group study. Ann Oncol. 2011; 22(1): 207–214.
  128. 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(7): 1537–1545.
  129. Judson I, Verweij J, Gelderblom H, et al. European Organisation and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014; 15(4): 415–423.
  130. Zehou O, Fabre E, Zelek L, et al. Chemotherapy for the treatment of malignant peripheral nerve sheath tumors in neurofibromatosis 1: a 10-year institutional review. Orphanet J Rare Dis. 2013; 8: 127.
  131. Torres KE, Liu J, Young E, et al. Expression of 'drugable' tyrosine kinase receptors in malignant peripheral nerve sheath tumour: potential molecular therapeutic targets for a chemoresistant cancer. Histopathology. 2011; 59(1): 156–159.
  132. Tawbi H, Thomas D, Lucas DR, et al. Epidermal growth factor receptor expression and mutational analysis in synovial sarcomas and malignant peripheral nerve sheath tumors. Oncologist. 2008; 13(4): 459–466.
  133. Albritton KH, Rankin C, Coffin CM, et al. Phase II study of erlotinib in metastatic or unresectable malignant peripheral nerve sheath tumors (MPNST). J Clin Oncol. 2006; 24(18_suppl): 9518–9518.
  134. Widemann B, Meyer C, Cote G, et al. SARC016: Phase II study of everolimus in combination with bevacizumab in sporadic and neurofibromatosis type 1 (NF1) related refractory malignant peripheral nerve sheath tumors (MPNST). J Clin Oncol. 2016; 34(15_suppl): 11053–11053.
  135. Kim A, Reinke D, Cichowski K, et al. SARC023: Phase I/II trial of ganetespib in combination with sirolimus for refractory sarcomas and malignant peripheral nerve sheath tumors (MPNST). J Clin Oncol. 2014; 32(15_suppl): TPS10603–TPS10603.
  136. 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(19): 3148–3153.
  137. 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(19): 3133–3140.
  138. Akshintala S, Mallory N, Lu Y, et al. Outcome of patients with refractory malignant peripheral nerve sheath tumors (MPNST) enrolled on phase 2 trials. J Clin Oncol. 2019; 37(15_suppl): e22534–e22534.
  139. Manji G, Patwardhan P, Lee S, et al. Phase 1/2 study of combination therapy with pexidartinib and sirolimus to target tumor-associated macrophages in malignant peripheral nerve sheath tumors. J Clin Oncol. 2016; 34(15_suppl): TPS11070–TPS11070.
  140. Manji GA, Van Tine BA, Lee SM, et al. A Phase I Study of the Combination of Pexidartinib and Sirolimus to Target Tumor-Associated Macrophages in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumors. Clin Cancer Res. 2021; 27(20): 5519–5527.
  141. Davis L, Latour E, Burch R, et al. A phase Ib study of ribociclib in combination with doxorubicin in advanced soft tissue sarcomas (aSTS). J Clin Oncol. 2020; 38(15_suppl): 11548–11548.
  142. Striefler JK, Brandes F, Baur A, et al. Combination therapy with Olaratumab/doxorubicin in advanced or metastatic soft tissue sarcoma -a single-Centre experience. BMC Cancer. 2020; 20(1): 68.
  143. Tap WD, Wagner AJ, Schöffski P, et al. ANNOUNCE Investigators. Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial. JAMA. 2020; 323(13): 1266–1276.
  144. Hyman D, Kummar S, Farago A, et al. Abstract CT127: Phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi). Cancer Res. 2019; 79(13_Supplement): CT127–CT127.
  145. Yoo KH, Kim HS, Lee SuJ, et al. Efficacy of pazopanib monotherapy in patients who had been heavily pretreated for metastatic soft tissue sarcoma: a retrospective case series. BMC Cancer. 2015; 15: 154.
  146. Nakamura T, Matsumine A, Kawai A, et al. The clinical outcome of pazopanib treatment in Japanese patients with relapsed soft tissue sarcoma: A Japanese Musculoskeletal Oncology Group (JMOG) study. Cancer. 2016; 122(9): 1408–1416.
  147. Nishida Y, Urakawa H, Nakayama R, et al. Phase II clinical trial of pazopanib for patients with unresectable or metastatic malignant peripheral nerve sheath tumors. Int J Cancer. 2020; 148(1): 140–149.
  148. Ryan C, Degnin C, Cranmer L, et al. A randomized phase II study of gemcitabine (G) alone or with pazopanib (P) in refractory soft tissue sarcoma (STS). J Clin Oncol. 2020; 38(15_suppl): 11515–11515.
  149. Ingham M, Mahoney M, Remotti F, et al. A randomized phase II study of MLN0128 (M) versus pazopanib (P) in patients (pt) with advanced sarcoma (Alliance A091304). J Clin Oncol. 2020; 38(15_suppl): 11562–11562.
  150. CT02601209. Sapanisertib or Pazopanib Hydrochloride in Treating Patients With Locally Advanced or Metastatic Sarcoma. December 2023. https://clinicaltrials.gov/study/NCT02601209.
  151. Patel SP, Othus M, Chae YK, et al. A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors. Clin Cancer Res. 2020; 26(10): 2290–2296.
  152. Movva S, Avutu V, Chi P, et al. A pilot study of lenvatinib plus pembrolizumab in patients with advanced sarcoma. J Clin Oncol. 2023; 41(16_suppl): 11517–11517.
  153. Somaiah N, Tine BV, Chmielowski B, et al. A phase 2 study of alrizomadlin, a novel MDM2/p53 inhibitor, in combination with pembrolizumab for treatment of patients with malignant peripheral nerve sheath tumor (MPNST). J Clin Oncol. 2023; 41(16_suppl): e14627–e14627.
  154. Yan P, Huang R, Hu P, et al. Nomograms for predicting the overall and cause-specific survival in patients with malignant peripheral nerve sheath tumor: a population-based study. J Neurooncol. 2019; 143(3): 495–503.
  155. 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(6): 1014–1022.
  156. LaFemina J, Qin LX, Moraco NH, et al. Oncologic outcomes of sporadic, neurofibromatosis-associated, and radiation-induced malignant peripheral nerve sheath tumors. Ann Surg Oncol. 2013; 20(1): 66–72.
  157. Wakeman KM, Zhang QS, Bandhlish A, et al. Fédération Nationale Des Centres de Lutte Contre Le Cancer (FNCLCC) Grading, Margin Status and Tumor Location Associate With Survival Outcomes in Malignant Peripheral Nerve Sheath Tumors. Am J Clin Oncol. 2022; 45(1): 28–35.
  158. Martin E, Muskens IS, Coert JH, et al. Treatment and survival differences across tumor sites in malignant peripheral nerve sheath tumors: a SEER database analysis and review of the literature. Neurooncol Pract. 2019; 6(2): 134–143.
  159. Kromer CM, Yacoub N, Xiong D, et al. Analysis of Survival Differences Between Cutaneous and Subcutaneous Malignant Peripheral Nerve Sheath Tumors. Dermatol Surg. 2023; 49(4): 322–329.
  160. Xu Y, Xu G, Liu Z, et al. Incidence and prognosis of distant metastasis in malignant peripheral nerve sheath tumors. Acta Neurochir (Wien). 2021; 163(2): 521–529.
  161. Sobczuk P, Teterycz P, Zdzienicki M, et al. Clinicopathological prognostic and predictive factors of malignant peripheral nerve sheath tumors (MPNST) survival and treatment efficacy. J Clin Oncol. 2019; 37(15_suppl): e22537–e22537.
  162. Porter DE, Prasad V, Foster L, et al. Survival in Malignant Peripheral Nerve Sheath Tumours: A Comparison between Sporadic and Neurofibromatosis Type 1-Associated Tumours. Sarcoma. 2009; 2009: 756395.
  163. Malbari F, Spira M, B Knight P, et al. Malignant Peripheral Nerve Sheath Tumors in Neurofibromatosis: Impact of Family History. J Pediatr Hematol Oncol. 2018; 40(6): e359–e363.
  164. Cai Z, Tang X, Liang H, et al. Prognosis and risk factors for malignant peripheral nerve sheath tumor: a systematic review and meta-analysis. World J Surg Oncol. 2020; 18(1): 257.
  165. Martin E, Coert JH, Flucke UE, et al. Neurofibromatosis-associated malignant peripheral nerve sheath tumors in children have a worse prognosis: A nationwide cohort study. Pediatr Blood Cancer. 2020; 67(4): e28138.
  166. van Noesel MM, Orbach D, Brennan B, et al. Outcome and prognostic factors in pediatric malignant peripheral nerve sheath tumors: An analysis of the European Pediatric Soft Tissue Sarcoma Group (EpSSG) NRSTS-2005 prospective study. Pediatr Blood Cancer. 2019; 66(10): e27833.
  167. Bartlett EK, Sharma A, Seier K, et al. Histology-Specific Prognostication for Radiation-Associated Soft Tissue Sarcoma. JCO Precis Oncol. 2022; 6: e2200087.
  168. Widemann BC, Italiano A. Biology and Management of Undifferentiated Pleomorphic Sarcoma, Myxofibrosarcoma, and Malignant Peripheral Nerve Sheath Tumors: State of the Art and Perspectives. J Clin Oncol. 2018; 36(2): 160–167.
  169. Widemann BC, Italiano A. Biology and Management of Undifferentiated Pleomorphic Sarcoma, Myxofibrosarcoma, and Malignant Peripheral Nerve Sheath Tumors: State of the Art and Perspectives. J Clin Oncol. 2018; 36(2): 160–167.