The rare primary bone sarcomas: imaging-pathological correlation.

Rare primary bone sarcomas are challenging entities both radiologically and pathologically. These include the diagnoses of spindle cell sarcoma (leiomyosarcoma, fibrosarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumor), pleomorphic liposarcoma, and undifferentiated pleomorphic sarcoma. The radiographic and cross-sectional imaging features of each of these tumors are presented, along with current key pathological concepts. Frequently non-specific, the radiological appearances must be correlated with all clinical and pathological information available to enable an accurate diagnosis.

Current status and recommendations for imaging in neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis.

Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN) are three clinically distinct tumor predisposition syndromes with a shared tendency to develop peripheral and central nervous system neoplasms. Disease expression and complications of NF1, NF2, and SWN are highly variable, necessitating a multidisciplinary approach to care in order to optimize outcomes. This review will discuss the imaging appearance of NF1, NF2, and SWN and highlight the important role that imaging plays in informing management decisions in people with tumors associated with these syndromes. Recent technological advances, including the role of both whole-body and localized imaging strategies, routine anatomic and advanced magnetic resonance (MR) imaging sequences such as diffusion-weighted imaging (DWI) with quantitative apparent diffusion coefficient (ADC) mapping, and metabolic imaging techniques (MR spectroscopy and positron emission testing) are discussed in the context of the diagnosis and management of people with NF1, NF2, and SWN based on the most up-to-date clinical imaging studies.

Malignant peripheral nerve sheath tumor in the paraspinal region mimicking a benign peripheral nerve sheath tumor: a case report.

PURPOSE: Malignant peripheral nerve sheath tumors are extremely rare in the general population and display a predilection for metastasis to the lungs. Here, we present a rare case of a malignant peripheral nerve sheath tumor located in the paraspinal region and highlight the importance of preoperative biopsy in diagnosis of spinal epidural peripheral nerve sheath tumors. METHODS: We describe the clinical course of the patient as well as the radiological and pathological findings of the tumor. RESULTS: A 14-year-old girl presented with a six-month history of sacral pain. Occasionally she experienced left leg pain and abnormal gait. General physical examination revealed sensorial loss in the L5-S1 regions. T1-weighted sagittal MRI showed a hypointense oval mass and the contrast-enhanced T1-weighted axial MRI image showed heterogeneous enhancement of the tumor. On CT imaging, this tumor characteristically appears as a dumbbell-like mass with punctate calcification and widening L5-S1 intervertebral foramen. Complete resection was performed using an anterior approach. Intraoperative pathological examination revealed evidence of malignancy and subsequent immunohistochemical analysis of the tumor confirmed the diagnosis of MPNST. The postoperative course was uneventful and the patient has had significant improvement in her symptoms 1 month postoperatively. CONCLUSIONS: Preoperative biopsy should be routinely performed for pathological differential diagnosis of spinal epidural PNSTs as well as surgical decision-making. Furthermore a combination of clinical manifestation, radiological findings and biopsy should also be pursued for diagnosing these tumors.

Cardiac tumor comprising a malignant peripheral nerve sheath tumor and spontaneous atrial osseous metaplasia in a sheep.

Primary cardiac tumors in animals are very rare. The purpose of this report was to describe the first case of a cardiac tumor comprising a malignant peripheral nerve sheath tumor and spontaneous atrial osseous metaplasia in a Corriedale sheep. Histologically, the tumor in the bilateral atrial pericardium consisted of dense cellular components comprising tumor cells and a sparse cellular area, and non-neoplastic mature bone tissue. The tumor cells were spindle-shaped, round, or polygonal, and proliferating, with fascicular, storiform, palisading, and sheet patterns. Immunohistochemically, the tumor cells were positive for vimentin, S-100, occasionally positive for myeline basic protein, glial fibrillary acidic protein, neurofilament, neuron specific enolase, and neuron growth factor receptor suggesting that they originated from the nervous system. On the basis of these findings, the final diagnosis was a malignant peripheral nerve sheath tumor and spontaneous atrial osseous metaplasia.

Radiation-Induced Intraosseous Malignant Peripheral Nerve Sheath Tumor: A Case Report.

INTRODUCTION: The significance of radiation therapy in cancer treatment comes with associated complications, including fibrosis, osteonecrosis, and the development of secondary malignancies, such as malignant peripheral nerve sheath tumors (MPNSTs). We emphasize the importance of understanding these complications for an effective patient management. METHODS: We report a 47-year-old man with a history of squamous cell carcinoma of the tongue, treated with surgery, chemotherapy, and radiation therapy. The patient later presented with symptoms that led to the discovery of an intraosseous MPNST. RESULTS: Histopathological examination revealed characteristic features of MPNST, including spindle cells arranged is sweeping fascicles with contrasting hypercellular and hypocellular areas, producing a marble-like pattern, with atypical wavy, buckled, hyperchromatic nuclei, and brisk mitotic activity. Immunohistochemical analysis showed patchy positive staining for S100 and SOX10, and a complete loss of H3K27me3 expression. This report underscores the challenge of diagnosing secondary malignancies post-radiation therapy and the importance of careful histological examination to differentiate them from other conditions. CONCLUSIONS: In conclusion, radiation-induced secondary malignancies are a significant late side effect of radiation therapy that can profoundly impact treatment decision-making and requires a high index of suspicion during post radiation surveillance. Malignant peripheral nerve sheath tumor serves as a pertinent example, highlighting the importance of considering long-term risks when developing optimal management plans for cancer patients.

Decorin suppresses stemness and migration potential of malignant peripheral nerve sheath tumor through inhibiting epidermal growth factor receptor signaling.

Cancer stem cells (CSCs) play pivotal roles in the growth, invasion, metastasis, chemo-resistance in malignant peripheral nerve sheath tumor (MPNST). The current characterization of CSCs in MPNST is not complete. Decorin is a critical regulator of microenvironment, but its expression and function in CSCs of MPNST has not been studied. In the current study, Decorin levels and its relationship with lung and liver metastasis were determined in clinical specimens. Decorin expression in CD133-positive or CD44-positive CSCs was analyzed by RT-qPCR on cytospun MPNST cells after flow cytometry-based cell sorting. Decorin-positive cells were separated from Decorin-negative cells in transfected MPNST cell lines using a designed plasmid expressing red fluorescent protein (RFP) under a Decorin promoter. Tumor sphere formation, tumor growth, cell invasion, cell migration, and the resistance to chemotherapy-induced apoptosis were determined on Decorin-positive versus Decorin-negative MPNST cells. In vivo tumor growth was analyzed in mice receiving subcutaneous transplantation of Decorin-positive versus Decorin-negative MPNSTs. We found that Decorin levels were significantly downregulated in MPNST specimens, compared to non-tumorous adjacent tissue. Significantly lower Decorin levels were detected in MPNSTs with lung or liver metastasis compared to those without. Poorer patient survival was detected in Decorin-low MPNST, compared to Decorin-high subjects. More Decorin-negative cells were detected in CD133-positive MPNST cells than CD133-negative MPNST cells, and in CD44-positive MPNST cells than in CD44-negative MPNST cells. Compared to Decorin-positive MPNST cells, Decorin-negative MPNST cells generated significantly more tumor spheres in culture, were more invasive and migratory, and were more resistant to chemotherapy-induced apoptosis, likely due to the inhibition of epidermal growth factor receptor signaling by Decorin. Decorin-negative MPNST cells grew significantly larger tumor in vivo. Thus, depletion of Decorin may occur in CSCs in MPNSTs, serving possibly as a new therapeutic target.

Conditionally replicative adenovirus as a therapy for malignant peripheral nerve sheath tumors.

Oncolytic adenoviruses (Ads) stand out as a promising strategy for the targeted infection and lysis of tumor cells, with well-established clinical utility across various malignancies. This study delves into the therapeutic potential of oncolytic Ads in the context of neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs). Specifically, we evaluate conditionally replicative adenoviruses (CRAds) driven by the cyclooxygenase 2 (COX2) promoter, as selective agents against MPNSTs, demonstrating their preferential targeting of MPNST cells compared with non-malignant Schwann cell control. COX2-driven CRAds, particularly those with modified fiber-knobs exhibit superior binding affinity toward MPNST cells and demonstrate efficient and preferential replication and lysis of MPNST cells, with minimal impact on non-malignant control cells. In vivo experiments involving intratumoral CRAd injections in immunocompromised mice with human MPNST xenografts significantly extend survival and reduce tumor growth rate compared with controls. Moreover, in immunocompetent mouse models with MPNST-like allografts, CRAd injections induce a robust infiltration of CD8+ T cells into the tumor microenvironment (TME), indicating the potential to promote a pro-inflammatory response. These findings underscore oncolytic Ads as promising, selective, and minimally toxic agents for MPNST therapy, warranting further exploration.

Enhanced IL-12 transgene expression improves oncolytic viroimmunotherapy.

Introduction: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with unacceptably low cure rates occurring often in patients with neurofibromatosis 1 defects. To investigate oncolytic Herpes Simplex Virus (oHSV) as an immunotherapeutic approach, we compared viral replication, functional activity, and immune response between unarmed and interleukin 12 (IL-12)-armed oncolytic viruses in virus-permissive (B109) and -resistant (67C-4) murine MPNSTs. Methods: This study compared two attenuated IL-12-oHSVs with γ134.5 gene deletions (Δγ134.5) and the same transgene expression cassette. The primary difference in the IL-12-oHSVs was in their ability to counter the translational arrest response in infected cells. Unlike M002 (Δγ134.5, mIL-12), C002 (Δγ134.5, mIL-12, IRS1) expresses an HCMV IRS1 gene and evades dsRNA activated translational arrest in infected cells. Results and discussion: Our results show that oHSV replication and gene expression results in vitro were not predictive of oHSV direct oncolytic activity in vivo. Tumors that supported viral replication in cell culture studies resisted viral replication by both oHSVs and restricted M002 transgene expression in vivo. Furthermore, two IL-12-oHSVs with equivalent transcriptional activity differed in IL-12 protein production in vivo, and the differences in IL-12 protein levels were reflected in immune infiltrate activity changes as well as tumor growth suppression differences between the IL-12-oHSVs. C002-treated tumors exhibited sustained IL-12 production with improved dendritic cells, monocyte-macrophage activity (MHCII, CD80/CD86 upregulation) and a polyfunctional Th1-cell response in the tumor infiltrates. Conclusion: These results suggest that transgene protein production differences between oHSVs in vivo, in addition to replication differences, can impact OV-therapeutic activity.

Malignant Peripheral Nerve Sheath Tumor Arising from Small Bowel Mesentery: an Extremely Rare Case with Review of Literature.

PURPOSE: Malignant peripheral nerve sheath tumor (MPNST) of small bowel mesentery is a rare tumor. We report a rare case of MPNST of small bowel mesentery in a patient without neurofibromatosis (NF). METHODS: A 50-year-old male, with no features suggestive of NF1, presented to us with complaints of pain abdomen. Contrast-enhanced computed tomography (CECT) of the abdomen revealed a mass in the infrarenal region. On laparotomy, mass was seen to be arising from the mesentery of the jejunum. En-bloc resection of the tumor was done, and histopathological examination was suggestive of malignant peripheral nerve sheath tumor of the small bowel mesentery. RESULT: Patient received adjuvant external beam radiotherapy to a dose of 50.4 Gy to the tumor bed. The patient was planned for chemotherapy but absconded and later came with recurrence. The patient finally succumbed to disease. CONCLUSION: Surgery is the mainstay of treatment. Adjuvant treatment should be based on histopathological report.

Case Report of a Patient With Malignant Peripheral Nerve Sheath Tumor Treated With Wide Resection.

Malignant peripheral nerve sheath tumors are soft tissue sarcomas originating from peripheral nerves. They are more frequently diagnosed in individuals with neurofibromatosis and tend to affect young men more often than women. The most common sites for these tumors within the peripheral nerve sheath are in the pelvis and the distal femur. Although chemotherapy and radiotherapy are not frequently used, it should be noted that in some cases, postoperative radiotherapy and chemotherapy may be beneficial. The primary treatment approach typically involves the complete surgical removal of the tumor. Here, we discuss the case of our patient whom we successfully treated with extensive resection and followed up with postoperative radiotherapy at our clinic.

A 20.5 cm Malignant Peripheral Nerve Sheath Tumor of the Anterior Mediastinum Showing Response to Neoadjuvant Therapy.

Malignant peripheral nerve sheath tumors (MPNST) are a rare form of sarcoma derived from Schwann cells. Major risk factors for development are neurofibromatosis 1 (NF1) and prior radiation exposure. Tumor location is highly variable. We present a case of an extremely large MPNST tumor in the anterior mediastinum in a 66-year-old male. To the best of our knowledge, the 20.5 cm tumor is the first of its kind in a patient without clinical signs of NF1 or prior radiation exposure. The localization of this tumor to the anterior mediastinum is rarer, as the most common tumors presenting in this area are thyroid neoplasms, thymomas, teratomas, and lymphomas. The patient's tumor responded to doxorubicin-ifosfamide-mesna-based therapy. The tumor decreased from 20.5 cm to 9.0 cm on subsequent imaging. Thus, this is an interesting and valuable case to learn about the presentation and potential treatments of such a rare pathology.

'Triton' Tumor of the Lower Alveolus: An Aggressive Variant of Malignant Peripheral Nerve Sheath Tumour.

Malignant Triton tumor (MTT) is a rare variant of malignant peripheral nerve sheath tumor which harbingers a poor prognosis owing to its aggressive behavior. We report a case of a gentleman, who presented with MTT of the lower alveolus, and management with extensive extirpative surgery and adjuvant radiotherapy.

Primary Urethral Malignant Peripheral Neural Sheath Tumor in a 58-Year-Old Female in the Absence of Neurofibromatosis Type 1.

A malignant peripheral neural sheath tumor (MPNST) is a malignant soft tissue neoplasm with cellular origin arising from the outer lining of peripheral nerves. Approximately 10 cases have been identified to date where the lower urinary tract was affected. We discuss the case of a female patient that presented with primary MPNST that arose in the urethral tract in the absence of neurofibromatosis type 1 (NF1) or prior malignancies. This patient presented with pain and acute urinary tract symptoms secondary to urethral obstruction by a protruding vaginal mass. The patient underwent an incomplete initial resection to alleviate symptoms and to obtain a tissue diagnosis. Three months after the first hospitalization, the patient was re-hospitalized due to the recurrence of symptoms and subsequently underwent a complete tumor excision. The initial resection showed a 7.0 x 4.5 x 4.5 cm aggregate of tan-red to gray tumor masses. Microscopic examination showed a spindle cell neoplasm with malignant cytological features (hypercellularity, atypical mitoses, nuclear pleomorphism, and indistinct borders). Tumor cells stained positive for SOX10, S-100 (10% of tumor), with a "mosaic pattern" of H3K27ME3 (50% of tumor nuclei positive). Other lineage-specific and keratin markers stained negative. In the absence of other patient known primaries, the findings were consistent with a primary MPNST of the urinary tract. Residual tumor was identified on MRI scans one month after the follow-up. The completely excised tumor specimen on the second admission showed identical morphology when compared to the first specimen. While MPNSTs typically carry a poor prognosis, knowledge of behavior and prognosis of primary MPNSTs in the bladder is limited, due to the few relative numbers of available case reports. Further research is needed to study the clinical behavior, morphology, immunophenotypes, and genetics of primary MPNSTs arising from the lower urinary tract.

Scalp Plexiform Neurofibrosarcoma With Intrathoracic Fibrosarcoma: A Case Report.

Neurofibromatosis type 1 (NF1) is the most common form of neurofibromatosis. It is associated with neurofibromas, gliomas, neurofibrosarcomas, and neuroendocrine and hematopoietic tumors. We present a case of scalp plexiform neurofibromatosis associated with intrathoracic fibrosarcoma. An 18-year-old female presented with a 15-year history of plexiform scalp mass. She had multiple café-au-lait patches on her trunk and extremities and a first-degree relative with a plexiform right shoulder mass. She was managed by a multidisciplinary team of plastic and reconstructive surgeons, neurosurgeons, cardiothoracic surgeons, otorhinolaryngologists, ophthalmologists, pulmonologists, and pathologists. The histology of the excised scalp mass was that of a malignant peripheral nerve sheath tumor (neurofibrosarcoma). She subsequently developed upper chest and back pain with associated breathlessness and was found to have an intra-thoracic tumor. She had two sessions of exploratory right thoracotomy with subtotal excision of an aggressive, highly hemorrhagic, infiltrative mucinous tumor. The histology was a fibrosarcoma. The patient died a few hours following the second thoracotomy. NF1 is associated with several tumors, among which are neurofibrosarcomas. Intra-thoracic fibrosarcoma requires aggressive surgical resection; recurrence may be delayed with radiotherapy and chemotherapy. The prognosis is however poor, and survival beyond one year is unusual. Once one tumor is found, other body systems should be evaluated for the possibility of other tumors.

Sporadic Malignant Perineurioma: A Rare Diagnosis Among Malignant Peripheral Nerve Sheath Tumors.

BACKGROUND: Malignant perineurioma is a rare subset of malignant peripheral nerve sheath tumors (MPNSTs) with ultrastructural and immunohistochemical features of perineurial differentiation, distinguishing it from other MPNSTs, which typically demonstrate Schwannian features. The clinical course and prognosis of this rare tumor is not well defined. METHODS: The electronic medical records were searched for patients with a diagnosis of MPNST. Patients with a pathologic diagnosis of malignant perineurioma or MPNST with perineurial features were identified and further evaluated. RESULTS: Five patients with malignant perineurioma, or MPNST with perineurial features, were identified. Four patients (2 male and 2 female) were included with tumors associated with a common digital nerve, small muscular branch to the deltoid, sciatic nerve, and accessory nerve. One patient with the pathology diagnosis meeting inclusion criteria was excluded, as no clinical information was available for this patient. CONCLUSIONS: Patients in our series presented at varied stages of disease. Clinical courses after diagnosis of malignant perineurioma, where follow-up was available, were largely uncomplicated with regard to recurrence and metastatic disease. Careful follow-up is indicated, and further work is needed to characterize the clinical course of these rare tumors.

Primary pulmonary epithelioid malignant peripheral nerve sheath tumor in a child: a case report.

Primary pulmonary malignant peripheral nerve sheath tumors (MPNSTs) are uncommon sarcomas originating from intrapulmonary nerve sheath and have been rarely observed in children. Here, we report a case of a 16-year-old child who presented with a mass located in the upper lobe of right lung. The patient underwent a sleeve lobectomy and the pathological diagnosis of the tumor was primary pulmonary epithelioid MPNST. Despite the radical resection, multiple suspected metastasis occurred in heart, lung and muscles less than 2 years after the operation and the patient died 6 months after the metastasis.

KIF11 and KIF15 mitotic kinesins are potential therapeutic vulnerabilities for malignant peripheral nerve sheath tumors.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) constitutes the leading cause of neurofibromatosis type 1-related mortality. MPNSTs contain highly rearranged hyperploid genomes and exhibit a high division rate and aggressiveness. We have studied in vitro whether the mitotic kinesins KIF11, KIF15, and KIF23 have a functional role in maintaining MPNST cell survival and can represent potential therapeutic vulnerabilities. METHODS: We studied the expression of kinesin mRNAs and proteins in tumors and cell lines and used several in vitro functional assays to analyze the impact of kinesin genetic suppression (KIF15, KIF23) and drug inhibition (KIF11) in MPNST cells. We also performed in vitro combined treatments targeting KIF11 together with other described MPNST targets. RESULTS: The studied kinesins were overexpressed in MPNST samples. KIF15 and KIF23 were required for the survival of MPNST cell lines, which were also more sensitive than benign control fibroblasts to the KIF11 inhibitors ispinesib and ARRY-520. Co-targeting KIF11 and BRD4 with ARRY-520 and JQ1 reduced MPNST cell viability, synergistically killing a much higher proportion of MPNST cells than control fibroblasts. In addition, genetic suppression of KIF15 conferred an increased sensitivity to KIF11 inhibitors alone or in combination with JQ1. CONCLUSIONS: The mitotic spindle kinesins KIF11 and KIF15 and the cytokinetic kinesin KIF23 play a clear role in maintaining MPNST cell survival and may represent potential therapeutic vulnerabilities. Although further in vivo evidences are still mandatory, we propose a simultaneous suppression of KIF11, KIF15, and BRD4 as a potential therapy for MPNSTs.

Loss of Expression of a Novel Chromatin Remodeler SMARCA1 in Soft Tissue Sarcoma.

INTRODUCTION: Vital cellular processes such as proliferation and differentiation are regulated by chromatin remodeling complexes. A variety of neoplasms have been discovered to have genomic alterations (GAs) and loss of immunohistochemical (IHC) expression of chromatin remodelers ARID1A (BAF250A), SMARCA2 (BRM), SMARCA4 (BRG1), and SMARCB1 (INI1). SMARCA1 (SNF2L) is another member of the chromatin remodelers, and has not yet been studied in neoplasia. As SMARCA1 is located on chromosome X, could be potentially inactivated by a single hit. We aimed to evaluate GAs and protein expression of SMARCA1 in soft tissue tumors. METHOD: The publically available cBioPortal.32e34 platform was queried to analyze data on soft tissue tumors from The Cancer Genome Atlas project (TCGA) related to SMARCA1 GAs. Our institutional archives were queried to collect 26 cases of soft tissue tumors including 10 undifferentiated sarcomas, 5 leiomyosarcomas, 6 liposarcomas, and 5 malignant peripheral sheath tumors (MPNST). IHC for SMARCA1 with an SNF 2C4 monoclonal antibody was performed on whole tissue sections. RESULTS: SMARCA1 GAs were present in 8/261 soft tissue sarcomas (3%) in the TCGA dataset. Leiomyosarcomas had most common SMARCA1 GAs in 6/99 cases. SMARCA1 deletions existed in 1/56 dedifferentiated liposarcomas and 1/48 undifferentiated sarcomas. No SMARCA1 GAs occurred in other sarcoma subtypes. SMARCA1 IHC was studied in the sarcoma subtypes with potential SMARCA1 alterations in our institutional cases. SMARCA1 nuclear expression was lost in 3/10 cases (30%) of undifferentiated sarcoma, and 2/5 cases of MPNST (40%). SMARCA1 expression was intact in all cases of leiomyosarcoma and liposarcoma. CONCLUSION: This is the first study to demonstrate loss of expression of SMARCA1 in soft tissue sarcomas subtypes, including undifferentiated sarcoma. Our study highlights merit for further investigation on the role of SMARCA1 in the differentiation process and molecular mechanisms of SMARCA1 inactivation.

The promise of signal transduction in genetically driven sarcomas of the nerve.

Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome. Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas arising from peripheral nerve sheaths, and the most commonly lethal feature associated with NF1. The hallmark of NF1 and NF1-related MPNST is the loss of neurofibromin expression. Loss of neurofibromin is considered a tumor-promoting event, and leads to constitutive activation of RAS and its downstream effectors. However, RAS activation alone is not sufficient for MPNST formation, and additional tumor suppressors and signaling pathways have been implicated in tumorigenesis of MPNST. Taking advantage of the rapid development of novel therapeutics targeting key molecular pathways across all cancer types, the best-in-class modulators of these pathways can be assessed in pre-clinical models and translated into clinical trials for patients with MPNST. Here, we describe the genetic changes and molecular pathways that drive MPNST formation and highlight the promise of signal transduction to identify therapies that may treat these tumors more effectively.

Components of the eIF4F complex are potential therapeutic targets for malignant peripheral nerve sheath tumors and vestibular schwannomas.

BACKGROUND: The eukaryotic initiation factor 4F (eIF4F) complex plays a pivotal role in protein translation initiation; however, its importance in malignant and benign Schwann cell tumors has not been explored, and whether blocking eIF4F function is effective for treating these tumors is not known. METHODS: Immunostaining was performed on human malignant peripheral nerve sheath tumors (MPNSTs) and vestibular schwannomas (VSs) for eIF4F components. The role of eIF4A and eIF4E in cell growth was assessed by RNA interference. Various natural compounds were screened for their growth-inhibitory activity. Flow cytometry and Western blotting were performed to characterize the action of silvestrol, and its antitumor activity was verified in orthotopic mouse models. RESULTS: MPNSTs and VSs frequently overexpressed eIF4A, eIF4E, and/or eIF4G. Depletion of eIF4A1, eIF4A2, and eIF4E substantially reduced MPNST cell growth. From screening a panel of plant-derived compounds, the eIF4A inhibitor silvestrol was identified as a leading agent with nanomolar IC50 values in MPNST and VS cells. Silvestrol induced G2/M arrest in both NF1-deficient and NF1-expressing MPNST cells and primary VS cells. Silvestrol consistently decreased the levels of multiple cyclins, Aurora A, and mitogenic kinases AKT and ERKs. Silvestrol treatment dramatically suppressed tumor growth in mouse models for NF1(-/-) MPNST and Nf2(-/-) schwannoma. This decreased tumor growth was accompanied by elevated phospho-histone H3 and TUNEL labeling, consistent with G2/M arrest and apoptosis in silvestrol-treated tumor cells. CONCLUSIONS: The eIF4F complex is a potential therapeutic target in MPNSTs and VS, and silvestrol may be a promising agent for treating these tumors.