scholarly journals From Genes to -Omics: The Evolving Molecular Landscape of Malignant Peripheral Nerve Sheath Tumor

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 691
Author(s):  
Kathryn M. Lemberg ◽  
Jiawan Wang ◽  
Christine A. Pratilas
Keyword(s):  
Peripheral Nerve ◽  
Soft Tissue Sarcomas ◽  
Type I ◽  
Nerve Sheath Tumor ◽  
Genetic Changes ◽  
Genetic Syndrome ◽  
Genetic Sequencing ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath ◽  
Molecular Landscape

Malignant peripheral nerve sheath tumors (MPNST) are rare, aggressive soft tissue sarcomas that occur with significantly increased incidence in people with the neuro-genetic syndrome neurofibromatosis type I (NF1). These complex karyotype sarcomas are often difficult to resect completely due to the involvement of neurovascular bundles, and are relatively chemotherapy- and radiation-insensitive. The lifetime risk of developing MPNST in the NF1 population has led to great efforts to characterize the genetic changes that drive the development of these tumors and identify mutations that may be used for diagnostic or therapeutic purposes. Advancements in genetic sequencing and genomic technologies have greatly enhanced researchers’ abilities to broadly and deeply investigate aberrations in human MPNST genomes. Here, we review genetic sequencing efforts in human MPNST samples over the past three decades. Particularly for NF1-associated MPNST, these overall sequencing efforts have converged on a set of four common genetic changes that occur in most MPNST, including mutations in neurofibromin 1 (NF1), CDKN2A, TP53, and members of the polycomb repressor complex 2 (PRC2). However, broader genomic studies have also identified recurrent but less prevalent genetic variants in human MPNST that also contribute to the molecular landscape of MPNST and may inform further research. Future studies to further define the molecular landscape of human MPNST should focus on collaborative efforts across multiple institutions in order to maximize information gathered from large numbers of well-annotated MPNST patient samples, both in the NF1 and the sporadic MPNST populations.

scholarly journals The Role of Polycomb Repressive Complex in Malignant Peripheral Nerve Sheath Tumor

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 287 ◽  
Author(s):  
Xiyuan Zhang ◽  
Béga Murray ◽  
George Mo ◽  
Jack F. Shern
Keyword(s):  
Peripheral Nerve ◽  
Transcriptional Repression ◽  
Molecular Mechanisms ◽  
Significant Proportion ◽  
Soft Tissue Sarcomas ◽  
Nerve Sheath Tumor ◽  
Polycomb Repressive Complex ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath ◽  
Recurrent Mutations

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that can arise most frequently in patients with neurofibromatosis type 1 (NF1). Despite an increasing understanding of the molecular mechanisms that underlie these tumors, there remains limited therapeutic options for this aggressive disease. One potentially critical finding is that a significant proportion of MPNSTs exhibit recurrent mutations in the genes EED or SUZ12, which are key components of the polycomb repressive complex 2 (PRC2). Tumors harboring these genetic lesions lose the marker of transcriptional repression, trimethylation of lysine residue 27 on histone H3 (H3K27me3) and have dysregulated oncogenic signaling. Given the recurrence of PRC2 alterations, intensive research efforts are now underway with a focus on detailing the epigenetic and transcriptomic consequences of PRC2 loss as well as development of novel therapeutic strategies for targeting these lesions. In this review article, we will summarize the recent findings of PRC2 in MPNST tumorigenesis, including highlighting the functions of PRC2 in normal Schwann cell development and nerve injury repair, as well as provide commentary on the potential therapeutic vulnerabilities of a PRC2 deficient tumor cell.

scholarly journals Systemic Treatment for Advanced and Metastatic Malignant Peripheral Nerve Sheath Tumors—A Sarcoma Reference Center Experience

2020 ◽  
Vol 9 (10) ◽  
pp. 3157
Author(s):  
Paweł Sobczuk ◽  
Paweł Teterycz ◽  
Anna M. Czarnecka ◽  
Tomasz Świtaj ◽  
Hanna Koseła-Paterczyk ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Systemic Treatment ◽  
Treatment Options ◽  
Soft Tissue Sarcomas ◽  
Nerve Sheath Tumor ◽  
First Line ◽  
Rare Type ◽  
Reference Center ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath

Malignant peripheral nerve sheath tumor (MPNST) is a rare type of soft tissue sarcomas. The localized disease is usually treated with surgery along with perioperative chemo- or radiotherapy. However, up to 70% of patients can develop distant metastases. The study aimed to evaluate the modes and outcomes of systemic treatment of patients with diagnosed MPNST treated in a reference center. In total, 115 patients (56 female and 59 male) diagnosed with MPNST and treated due to unresectable or metastatic disease during 2000–2019 were included in the retrospective analysis. Schemes of systemic therapy and the outcomes—progression-free survival (PFS) and overall survival (OS)—were evaluated. The median PFS in the first line was 3.9 months (95% CI 2.5–5.4). Doxorubicin-based regimens were the most commonly used in the first line (50.4% of patients). There were no significant differences in PFS between chemotherapy regimens most commonly used in the first line (p = 0.111). The median OS was 15.0 months (95% CI 11.0–19.0) and the one-year OS rate was 63%. MPNST are resistant to the majority of systemic therapies, resulting in poor survival in advanced settings. Chemotherapy with doxorubicin and ifosfamide is associated with the best response and longest PFS. Future studies and the development of novel treatment options are necessary for the improvement of treatment outcomes.

scholarly journals A Rare Malignant Peripheral Nerve Sheath Tumor of the Maxilla Mimicking a Periapical Lesion

2016 ◽  
Vol 2016 ◽  
pp. 1-5
Author(s):  
José Alcides Arruda ◽  
Pamella Álvares ◽  
Luciano Silva ◽  
Alexandrino Pereira dos Santos Neto ◽  
Cleomar Donizeth Rodrigues ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Peripheral Nerve ◽  
Soft Tissue Sarcomas ◽  
Malignant Neoplasm ◽  
Surgical Approaches ◽  
Type I ◽  
Nerve Sheath Tumor ◽  
Peripheral Nerve Sheath Tumor ◽  
Nerve Sheath ◽  
Malignant Soft Tissue Tumor

Malignant peripheral nerve sheath tumor is a malignant neoplasm that is rarely found in the oral cavity. About 50% of this tumor occurs in patients with neurofibromatosis type I and comprises approximately 10% of all soft tissue sarcomas of head and neck region. Intraosseous malignant peripheral nerve sheath tumor of the maxilla is rare. This article is the first to address malignant peripheral nerve sheath tumor of the maxilla presenting as a periapical radiolucency on nonvital endodontically treated teeth in the English medical literature. Surgical approaches to malignant soft tissue tumor vary based on the extent of the disease, age of the patient, and pathological findings. A rare case of intraosseous malignant peripheral nerve sheath tumor is reported in a 16-year-old woman. The patient presented clinically with a pain involving the upper left incisors region and with defined unilocular periapical radiolucency lesion involved between the upper left incisors. An incisional biopsy was made. Histological and immunohistochemical examination were positive for S-100 protein and glial fibrillary acidic protein showed that the lesion was an intraosseous malignant peripheral nerve sheath tumor of the maxilla. Nine years after the surgery, no regional recurrence was observed.

scholarly journals Extradural malignant peripheral nerve sheath tumor of the thoracic spine: A rare case report

2021 ◽  
Vol 12 ◽  
pp. 560
Author(s):  
Ayu Yoniko Christi ◽  
Wisnu Baskoro ◽  
Bidari Kameswari ◽  
Irfaanstio Akbar Hakim ◽  
Vega Sola Gracia Pangaribuan ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Thoracic Spine ◽  
Soft Tissue Sarcomas ◽  
Cord Compression ◽  
Nerve Sheath Tumor ◽  
Total Excision ◽  
Peripheral Nerve Sheath Tumors ◽  
Immunohistochemistry Staining ◽  
Nerve Sheath ◽  
Progressive Paraparesis

Background: Malignant peripheral nerve sheath tumors (MPNSTs) typically found in the trunk, limbs, head, and neck represent 3–10% of all soft-tissue sarcomas. Although they typically originating from peripheral nerve Schwann cells, 2–3% arise from the spinal nerves and may be found within the spinal canal. Here, we present a 43-year-old male with an extradural thoracic MPNST contributing to marked cord compression and a progressive paraparesis. Case Description: A 43-year-old male presented with a progressive paraparesis of 16 months’ duration. The MRI showed a posterior T2-T4 extradural tumor in the thoracic spine resulting in significant cord compression. Following a T2-T4 laminectomy and gross total excision of the epidural mass, the patient regained modest neurological function. Immunohistochemistry staining supported the diagnosis of thoracic spinal MPNST. Conclusion: Rarely, spinal MPNST can be considered amongst the differential diagnoses of an extradural spinal tumor. In this case, gross total excision of a posterior T2-T4 epidural MPNST resulted in improvement in the patient’s original paraparesis. Notably, immunohistochemistry staining helped confirm the diagnosis of a MPNST.

Malignant Peripheral Nerve Sheath Tumors

2018 ◽  
Author(s):  
Marie-Noëlle Hébert-Blouin
Keyword(s):  
Decision Making ◽  
Soft Tissue ◽  
Peripheral Nerve ◽  
Soft Tissue Sarcomas ◽  
Nerve Sheath Tumor ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Adjuvant Therapies ◽  
Nerve Sheath ◽  
Schwann Cell Differentiation

Malignant peripheral nerve sheath tumors (PNSTs) are soft tissue sarcomas arising from a peripheral nerve or a pre-existing benign nerve sheath tumor or are sarcomas with features of Schwann-cell differentiation. Differentiating between benign and malignant PNSTs can be challenging. The chapter begins with a case example and then discusses assessment, investigations (including imaging), and diagnosis of malignant PNSTs, as well as the steps involved in decision-making about management of a malignant PNST. The surgical principles and goals for resection of a malignant PNST, the adjuvant therapies used in treatment, and the complications and outcomes of treatment are presented.

scholarly journals Metastatic Malignant Peripheral Nerve Sheath Tumor to the Brain Demonstrating Clonal Evolution by Cytogenetic Analysis

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S71-S72
Author(s):  
J T Suddock ◽  
C J Broehm ◽  
K S SantaCruz
Keyword(s):  
Peripheral Nerve ◽  
Cytogenetic Analysis ◽  
Clonal Evolution ◽  
Soft Tissue Sarcomas ◽  
Adjuvant Radiation ◽  
Nerve Sheath Tumor ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath ◽  
The Brain

Abstract Casestudy: Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive, uncommon soft tissue sarcomas that arise from peripheral nerves or pre-existing benign nerve sheath tumors. Local recurrence and metastases are known to occur, though metastasis to the brain is very rare. Limited treatment options impart the need to better characterize these tumors. We present a case of a 26-year-old female with a history of a 5.5 cm MPNST of the left chest, who presented with brain metastasis two years later. The tumors were found to have similar histologic and cytogenetic findings with clonal evolution evident in the metastasis. The original tumor exhibited a proliferation of spindled cells arranged in sweeping fascicles accompanied by numerous mitotic figures and areas of geographic necrosis. The malignant cells were patchy positive for S100 and CD34 and negative for SOX10 and GFAP. Cytogenetic analysis revealed three related abnormal clones, all of which demonstrated add(2)(p25) and add(22)(q12). Monosomy 6 was identified in one clone, and near triploidy and triploidy was identified in the other two clones. Additionally, numerous whole chromosome gains and losses were present. The patient underwent surgical resection and was treated with adjuvant radiation. Two years later, a PET scan revealed a hypermetabolic left temporal lobe mass. MRI revealed a 4.9 x 4.5 cm destructive lesion invading through the temporal bone and involving brain parenchyma. The mass was resected and submitted for pathologic evaluation revealing similar histologic findings to the original, though S100 and SOX-10 were negative. Cytogenetic analysis revealed two related abnormal clones which shared add(2)(p25) and add(22)(q12) as well as an additional copy of add(22)(q12). One clone showed near triploidy with loss of several whole chromosomes. These findings are remarkable for recurrent metastatic disease to the brain and uniquely show clonal evolution of the metastatic tumor.

scholarly journals Toward Understanding the Mechanisms of Malignant Peripheral Nerve Sheath Tumor Development

2021 ◽  
Vol 22 (16) ◽  
pp. 8620
Author(s):  
Teddy Mohamad ◽  
Camille Plante ◽  
Jean-Philippe Brosseau
Keyword(s):  
Peripheral Nerve ◽  
Tumor Development ◽  
Neurofibromatosis Type ◽  
Type I ◽  
Nerve Sheath Tumor ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Research Perspectives ◽  
Nerve Sheath ◽  
History Of

Malignant peripheral nerve sheath tumors (MPNSTs) originate from the neural crest lineage and are associated with the neurofibromatosis type I syndrome. MPNST is an unmet clinical need. In this review article, we summarize the knowledge and discuss research perspectives related to (1) the natural history of MPNST development; (2) the mouse models recapitulating the progression from precursor lesions to MPNST; (3) the role of the tumor microenvironment in MPNST development, and (4) the signaling pathways linked to MPNST development.

scholarly journals Neurofibromin Deficiency and Extracellular Matrix Cooperate to Increase Transforming Potential through FAK-Dependent Signaling

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2329
Author(s):  
Andrea Errico ◽  
Anna Stocco ◽  
Vincent M. Riccardi ◽  
Alberto Gambalunga ◽  
Franco Bassetto ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Peripheral Nerve ◽  
Neurofibromatosis Type ◽  
Mek Inhibitor ◽  
Colony Growth ◽  
Nerve Sheath Tumor ◽  
Genetic Syndrome ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath

Plexiform neurofibromas (Pnfs) are benign peripheral nerve sheath tumors that are major features of the human genetic syndrome, neurofibromatosis type 1 (NF1). Pnfs are derived from Schwann cells (SCs) undergoing loss of heterozygosity (LOH) at the NF1 locus in an NF1+/− milieu and thus are variably lacking in the key Ras-controlling protein, neurofibromin (Nfn). As these SCs are embedded in a dense desmoplastic milieu of stromal cells and abnormal extracellular matrix (ECM), cell–cell cooperativity (CCC) and the molecular microenvironment play essential roles in Pnf progression towards a malignant peripheral nerve sheath tumor (MPNST). The complexity of Pnf biology makes treatment challenging. The only approved drug, the MEK inhibitor Selumetinib, displays a variable and partial therapeutic response. Here, we explored ECM contributions to the growth of cells lacking Nfn. In a 3D in vitro culture, NF1 loss sensitizes cells to signals from a Pnf-mimicking ECM through focal adhesion kinase (FAK) hyperactivation. This hyperactivation correlated with phosphorylation of the downstream effectors, Src, ERK, and AKT, and with colony formation. Expression of the GAP-related domain of Nfn only partially decreased activation of this signaling pathway and only slowed down 3D colony growth of cells lacking Nfn. However, combinatorial treatment with both the FAK inhibitor Defactinib (VS-6063) and Selumetinib (AZD6244) fully suppressed colony growth. These observations pave the way for a new combined therapeutic strategy simultaneously interfering with both intracellular signals and the interplay between the various tumor cells and the ECM.

scholarly journals Retroperitoneal Malignant Peripheral Nerve Sheath Tumor Replacing an Absent Kidney in a Child

2013 ◽  
Vol 2013 ◽  
pp. 1-4 ◽  
Author(s):  
Samin Alavi ◽  
M. T. Arzanian ◽  
Yalda Nilipour
Keyword(s):  
Peripheral Nerve ◽  
Wilms Tumor ◽  
Abdominal Mass ◽  
Soft Tissue Sarcomas ◽  
Nerve Sheath Tumor ◽  
Peripheral Nerve Sheath Tumor ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath ◽  
First Case ◽  
Genitourinary Tract Anomalies

Malignant peripheral nerve sheath tumors (MPNSTs) are nonrhabdomyosarcoma soft tissue sarcomas with rare occurrence in children specially in the retroperitoneum. We describe a young child who presented with an abdominal mass. Both ultrasound and computed tomography revealed a large right-sided abdominal mass in the anatomic place of right kidney, while no kidney or ureter was observed at that side. He underwent surgical resection of the tumor with a primary impression of Wilms tumor. To the authors’ knowledge, this is the first case of retroperitoneal malignant peripheral nerve sheath tumor and absent kidney. This case suggests the very rare probability of association of MPNSTs in children with genitourinary tract anomalies such as renal agenesis.

scholarly journals Cranial nerve and intramedullary spinal malignant peripheral nerve sheath tumor associated with neurofibromatosis-1

2021 ◽  
Vol 12 ◽  
pp. 630
Author(s):  
Christopher Newell ◽  
Alan Chalil ◽  
Kristopher D. Langdon ◽  
Vahagn Karapetyan ◽  
Matthew O. Hebb ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Cranial Nerve ◽  
Case Reports ◽  
Neurofibromatosis Type ◽  
Optic Glioma ◽  
Type I ◽  
Nerve Sheath Tumor ◽  
Intramedullary Spinal Cord ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are uncommon but aggressive neoplasms associated with radiation exposure and neurofibromatosis Type I (NF1). Their incidence is low compared to other nervous system cancers, and intramedullary spinal lesions are exceedingly rare. Only a few case reports have described intramedullary spinal cord MPNST. Case Description: We describe the clinical findings, management, and outcome of a young patient with NF1 who developed aggressive cranial nerve and spinal MPNST tumors. This 35-year-old patient had familial NF1 and a history of optic glioma treated with radiation therapy (RT). She developed a trigeminal MPNST that was resected and treated with RT. Four years later, she developed bilateral lower extremity deficits related to an intramedullary cervical spine tumor, treated surgically, and found to be a second MPNST. Conclusion: To the best of our knowledge, this is the first report of cranial nerve and intramedullary spinal MPNSTs manifesting in a single patient, and only the third report of a confined intramedullary spinal MPNST. This unusual case is discussed in the context of a contemporary literature review.

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