Schwannoma Research Articles

Abstract 2251: Gene expression analysis by RNA-sequencing highlights differential regulated pathways involved in cell cycle and inflammation in orbitofacial neurofibromas

Abstract Although most commonly benign, neurofibromas (NFs) can have devastating functional and cosmetic effects in addition to the possibility of malignant transformation. Orbitofacial NFs in particular may cause progressive, disfiguring tumors of the lid, brow, temple, face and orbit, and anecdotal evidence suggest that they may have increased local aggressiveness compared to NFs developing at other sites. The purpose of this study was to identify biological differences between orbitofacial NFs and those occurring at other anatomic sites. We performed global RNA-sequencing in orbitofacial (n=10) and non-orbitofacial (n=9) NFs. A total of 880 mRNA transcripts were differentially expressed between the two groups (adjusted p>0.05), The top 10 genes relatively overexpressed in orbitofacial NF included NEFL, TREM2, CST1, GAP43, ADORA3, MIA, SYT6, FCGR3A, SPP1, and FCGR1A. The top 10 genes relatively underexpressed in orbitofacial NF included XG, WISP2, MMP27, CXCL14, MFAP5, APLNR, MYOC, SLITRK6, STMN2, and TDRD1. Gene enrichment analyses demonstrated a variety of gene sets differentially affected including pathways involved in cell proliferation, interferon and immune related pathways. Comparisons with publicly available databases of various Schwann cell tumors and models using CAT plots demonstrated the highest overlap with differentially expressed genes in plexiform NF vs MPNST (>10%). In summary, we identified gene expression differences between orbitofacial NF and NFs occurring at other anatomic locations. Further investigation may be warranted, given that orbitofacial NF are notoriously difficult to treat and associated with disproportionate morbidity. Citation Format: Eddie L. Imada, Deepak P. Edward, Antje Arnold, Hailah Al-Hussain, Diego Strianese, Luigi Marchionni, Fausto J. Rodriguez. Gene expression analysis by RNA-sequencing highlights differential regulated pathways involved in cell cycle and inflammation in orbitofacial neurofibromas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2251.

Abstract 1164: Human endogenous retrovirus type K promotes proliferation of Merlin negative schwannoma and meningioma which can be inhibited by anti-retroviral and anti-TEAD drugs

Abstract Deficiency of the tumor suppressor Merlin causes the development of schwannoma, meningioma and ependymoma tumors. These can occur spontaneously or in the hereditary disease Neurofibromatosis type 2 (NF2). Merlin mutations are also relevant in a variety of other tumors. Currently available treatments are surgery or radiosurgery which are only partially effective, with tumors frequently reoccurring and in case of meningioma often as a higher grade. There is an urgent need for effective drug treatments.In this study, we investigated the role of Human Endogenous Retrovirus Type K (HERV-K) and its targetability in Merlin negative schwannoma and meningioma tumors by using tissues and primary cells isolated form patients employing immunohistochemistry, immunocytochemistry, western blotting and proliferation assays. We demonstrate that HERV-K proteins are overexpressed in Merlin negative schwannoma and all meningioma grades. Furthermore, we implicate CRL4DCAF1 and YAPT/EAD Hippo pathway in this overexpression and suggest that exosome transport of the HERV-K Envelope (Env) protein might contribute to schwannoma development. We also show that: (i) Ectopic overexpression of HERV-K Env in normal Schwann cells increased proliferation and upregulated the transcription factor c-Jun. Env overexpression also increased activity of the extracellular signal-regulated kinase 1/2 (pERK1/2), a known mitogenic pathway in schwannoma. (ii) An anti-Env monoclonal antibody decreased pERK1/2 and reduced proliferation of schwannoma cells. iii) FDA-approved retroviral protease inhibitors Ritonavir, Atazanavir and Lopinavir decreased pERK1/2 and cyclin D1 and reduced proliferation of schwannoma and grade I meningioma cells. We provide evidence for HERV-K Env contributing to the development of NF2-associated schwannomas and meningiomas. Considering the urgent need of drugs to treat NF2, we suggest the trialling of antiretroviral protease inhibitors, and consideration of anti-HERV-K Env immunotherapy, as well as TEAD-specific inhibitors in these patients. The above treatments would also be potentially beneficial for patients with other tumors caused by Merlin deficiency. Citation Format: Sylwia Ammoun, Emmanuel A. Maze, Bora Agit, Robert Belshaw, C Oliver Hanemann. Human endogenous retrovirus type K promotes proliferation of Merlin negative schwannoma and meningioma which can be inhibited by anti-retroviral and anti-TEAD drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1164.

Breast Shwannoma - Time to explore alternative management strategy?

Schwannoma (SCH) is a benign peripheral nerve sheath neoplasm of Schwann cell origin. It can be observed anywhere whilst the breast is uncommon site. Preliminary investigations are not entirely diagnostic and surgical excision is often required to reach a conclusion. We conducted a retrospective review in two European Breast units to know more about this rare condition. Herein, we provide a comprehensive review and we question whether the surgical approach to management can be changed.

Atypical Adrenaliemmas

Introduction: Adrenal Incidentalomas (AI) are increasingly found with recent proliferation in imaging techniques. The precise prevalence of AI is not well established but estimated to be about 5%. Such findings require thorough work and follow up plans to assess for hormonal functionality and differentiate between benign or a malignant entity. Adrenocortical carcinoma (AC), schwannoma (SCH), ganglioneuroma (GN), myelolipoma (ML), neuroblastoma (NB), and ganglioneuroblastoma (GNB) are a rare presentation of AIs. In this case series, we present 2 cases of uncommon AIs. Cases Series: Case 1: A 55-year-old man presented to the hospital with episodic dizziness, nausea, vomiting, and diaphoresis. His physical examination and blood workup were unremarkable. He takes multiple antihypertensive medications at home. CT abdomen revealed an incidental 5 cm mass adjacent to the left adrenal gland which was confirmed to be of adrenal origin on MRI. The hormonal workup was negative. and patient. Laparoscopic left adrenalectomy was performed. Histopathological diagnosis pointed to a benign nerve sheath tumor. Tumor cells stained positive for S-100 and negative for CD34 and epithelial membrane antigen. The morphologic features and immunohistochemical profile consistent with adrenal SCH diagnoses, confirmed by two histopathologists. Postoperatively, Blood pressure improved, and the patient has no evidence of recurrence on subsequent follow-ups. Case 2: A 38-year-old female presented to the hospital with severe right groin pain. During the workup, a CT abdomen revealed a homogeneous, lobulated, minimally enhanced, 5.8 cm right adrenal mass with no calcifications. The hormonal workup was negative. FDG-PET scan showed low uptake in the right adrenal mass. Adrenalectomy was performed and histological examination revealed Schwan cells and neurites with occasional ganglion cells compatible with benign GN. Discussion: SCHs originate from Schwann cells in peripheral nerve sheaths. Adrenal SCHs are rare, they represent about 0.5% of all SCHs. Surgical resection is the initial management as imagings are non-diagnostic and appearance does not distinguish benign from malignant lesions. Adrenal GNs originate from neural crest cells in the adrenal medulla and represents between 20–30% of all GNs. They may be primary or evolve from differentiating NB. The majority of them are sporadic. GNs are typically benign and asymptomatic. However, larger GNs are associated with an increased risk of malignancy, a 33% risk for 5 cm compared to 92% for 6 cm. Surgical resection is necessary, especially for larger masses. Conclusion: Besides the common adrenal incidentalomas and their proper work and follow up plans, a clinician should consider atypical adrenal tumors with unusual presentation. Surgical treatment and histological examination are essential for an accurate diagnosis.

Transposon Mutagenesis-Guided CRISPR/Cas9 Screening Strongly Implicates Dysregulation of Hippo/YAP Signaling in Malignant Peripheral Nerve Sheath Tumor Development.

Simple SummaryMalignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive tumors with a complex genetic landscape. Patients with neurofibromatosis type 1 syndrome (NF1) are at a high risk of MPNSTs, which usually develop from pre-existing benign Schwann cell tumors called plexiform neurofibromas. In this study, we aimed to find genes that, when altered, resulted in MPNST development. Our results suggest that the functional genetic landscape of human MPNST is complex and implicates the hippo/Yes Activated Protein (YAP) pathway in the transformation of neurofibromas. Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive, genomically complex, have soft tissue sarcomas, and are derived from the Schwann cell lineage. Patients with neurofibromatosis type 1 syndrome (NF1), an autosomal dominant tumor predisposition syndrome, are at a high risk for MPNSTs, which usually develop from pre-existing benign Schwann cell tumors called plexiform neurofibromas. NF1 is characterized by loss-of-function mutations in the NF1 gene, which encode neurofibromin, a Ras GTPase activating protein (GAP) and negative regulator of RasGTP-dependent signaling. In addition to bi-allelic loss of NF1, other known tumor suppressor genes include TP53, CDKN2A, SUZ12, and EED, all of which are often inactivated in the process of MPNST growth. A sleeping beauty (SB) transposon-based genetic screen for high-grade Schwann cell tumors in mice, and comparative genomics, implicated Wnt/β-catenin, PI3K-AKT-mTOR, and other pathways in MPNST development and progression. We endeavored to more systematically test genes and pathways implicated by our SB screen in mice, i.e., in a human immortalized Schwann cell-based model and a human MPNST cell line, using CRISPR/Cas9 technology. We individually induced loss-of-function mutations in 103 tumor suppressor genes (TSG) and oncogene candidates. We assessed anchorage-independent growth, transwell migration, and for a subset of genes, tumor formation in vivo. When tested in a loss-of-function fashion, about 60% of all TSG candidates resulted in the transformation of immortalized human Schwann cells, whereas 30% of oncogene candidates resulted in growth arrest in a MPNST cell line. Individual loss-of-function mutations in the TAOK1, GDI2, NF1, and APC genes resulted in transformation of immortalized human Schwann cells and tumor formation in a xenograft model. Moreover, the loss of all four of these genes resulted in activation of Hippo/Yes Activated Protein (YAP) signaling. By combining SB transposon mutagenesis and CRISPR/Cas9 screening, we established a useful pipeline for the validation of MPNST pathways and genes. Our results suggest that the functional genetic landscape of human MPNST is complex and implicate the Hippo/YAP pathway in the transformation of neurofibromas. It is thus imperative to functionally validate individual cancer genes and pathways using human cell-based models, to determinate their role in different stages of MPNST development, growth, and/or metastasis.

Solitary intrascrotal neurofibroma in a child: A case report

Background: Neurofibroma (NF) remains a rare entity among various scrotal masses in the pediatric age group. We report a case of solitary intrascrotal extra testicular plexiform neurofibroma in a 6-year-old child with the clinical management of this rare entity and review of the literature. Case Summary: A 6-year-old male presented with incidentally noticed intrascrotal swelling. Clinical examination confirmed the presence of solitary intrascrotal swelling with normal testis. Radiological imaging showed the presence of a hypoechoic mass in the left hemiscrotum with normal both testes. Surgical exploration showed the presence of unencapsulated soft tissue mass and histopathological examination (HPE) confirmed the diagnosis of plexiform neurofibroma. Thorough evaluation ruled out features of neurofibromatosis 1 thus confirming the diagnosis of solitary intrascrotal extratesticular plexiform neurofibroma. Complete surgical excision resulted in satisfactory recovery with no recurrence on follow-up Conclusion: Neurofibroma although rare should be considered as a differential in the diagnosis of an intrascrotal mass in the pediatric age group. The benign nature of the lesion and extratesticular origin usually makes testis sparing surgical excision feasible which remains the treatment of choice with excellent prognosis and minimal chances of recurrence. A thorough histopathological examination is mandatory to rule out neurofibromatosis.

Neurofibroma in the Breast: Diagnosis and Management Considerations.

Neurofibroma (NF) of the breast is an uncommon benign entity that occurs sporadically or in association with neurofibromatosis type 1 (NF1). Sporadic NF of the breast is very rare and can present at any age. Neurofibroma of the breast associated with NF1 is more common. Neurofibroma commonly presents as oval, circumscribed masses that overlap with many benign entities. The histopathologic diagnosis of NF of the breast can present a management dilemma for the breast radiologist. An NF that is not associated with NF1 has good post-resection prognosis if superficial, sporadic, and solitary. However, NF of the breast diagnosed in an otherwise healthy patient should prompt evaluation for NF1 and formal genetic risk assessment. Patients diagnosed with NF1 have a higher lifetime risk for developing breast cancer and therefore may benefit from both initiating screening mammography at a younger age and supplemental screening MRI.

Surgical Outcome of Trigeminal Schwannomas.

Simple SummaryTrigeminal schwannomas are the most common among non-vestibular schwannomas. Treatment of trigeminal schwannomas may be challenging due to critical anatomical relations and involvement of different aspects of the skull base. Advances in microsurgery have led to improved outcomes over the last decades, whereas in contrast, some advocate stereotactic radiotherapy as an effective therapy, controlling the tumor volume with few complications. In this manuscript, we present outcome and adverse events in a contemporary cohort of trigeminal schwannomas and discuss surgical advantages and disadvantages of different performed classic skull-base approaches. (1) Background: As resection of trigeminal schwannomas is challenging, due to anatomical involvement of the anterior, middle and posterior fossa, the appropriate approach is important. We report our experience with surgical resection of trigeminal schwannomas by simple and classic skull-base approaches. (2) Methods: We performed a retrospective single-center study including patients who underwent surgery for trigeminal schwannoma tumors between June 2007 and May 2020, concentrating on surgical technique, extent of resection, postoperative outcome and complications. (3) Results: We included 13 patients (median age 57.5 with range of 36-83 years, 53.8% (7/13) female. The most common preoperative clinical presentations were facial pain in six (46.2%), hypoacusis in four (30.8%), trigeminal nerve hypesthesia in 11 (V1 46.2% (6/13), V2 (61.5% (8/13), V3 46.2% (6/13)) and headache in three (23.1%) patients. In three cases, the tumor was resected in a two-stage technique. The intradural subtemporal approach was performed in six cases, the extradural technique in two cases, the retrosigmoid approach in five cases, a Kawase approach in two cases and the transnasal endoscopic approach in one case. The gross total resection rate was 76.9% (10/13) and the median follow-up time 24.0 (0–136) months. Three (23.1%) patients developed postoperative anesthesia in at least one branch of the trigeminal nerve. Trigeminal motor function was preserved in 11 (84.6%) patients. Ten of the 11 patients (76.9%) who reported decreased gustation, cerebellar ataxia, visual impairment, or headache improved postoperatively. Two (15.4%) patients exhibited minimal facial palsy (House and Brackmann II–III), which resolved during the follow-up. The total adverse event rate requiring surgical intervention during follow-up was 7.7%. Surgery-related mortality was 0%. (4) Conclusions: Trigeminal schwannomas are rare benign lesions with intra- and extracranial extension. Considering the low operative morbidity and satisfying functional outcome, gross total resection of trigeminal schwannomas is achievable by classic, but also individually tailored approaches. More invasive or combined techniques were not needed with meticulous surgical planning.

Melanocytic Tumors

Primary melanocytic neoplasms of the central nervous system(CNS)presumably arise from leptomeningeal melanocytes that are derived from the neural crest. Melanocytic neoplasms associated with neurocutaneous melanosis likely derive from melanocyte precursor cells that reach the CNS after somatic mutations, mostly, of the NRAS. They should be distinguished from other melanotic tumors involving the CNS, including metastatic melanoma and other primary tumors that undergo melanization, such as melanocytic schwannomas, medulloblastomas, paragangliomas, and various gliomas, because these lesions require different patient workups and therapy. Primary melanocytic neoplasms of the CNS that are diffuse and do not form macroscopic masses are called melanocytoses, whereas malignant diffuse or multifocal lesions are collectively called melanomatoses. Benign and intermediate-grade tumoral lesions are called melanocytomas. Discrete malignant tumors are called melanomas. CT and MRI of melanocytosis and melanomatosis show diffuse thickening and enhancement of the leptomeninges, often with focal or multifocal nodularity. Depending on the melanin content, diffuse and circumscribed melanocytic tumors of the CNS may show some characteristics on CT and MRI: iso- to hyperattenuation on CT and paramagnetic properties of melanin on MRI resulting in an isointense signal on T1WIs and iso- to hypointensity on T2WIs.

The Patients' Experiences of Burden of Neurofibromatosis: A Qualitative Study.

Background:Neurofibromatosis Type 1 (NF1) is a common autosomal disorder; the criteria for the diagnosis of NF1 includes café au lait spots, freckling, and Neurofibromas (NF). Skin symptoms have a major impact on patients' Quality of Life (QOL) but little is known about the burden of the disease on patients. The aim of this study was to explore the experiences of patients with NF.Materials and Methods:Using purposive sampling, 20 participants were enrolled in this qualitative content analysis study. The study was carried out between 2019 and 2020. Unstructured interviews and field notes were used to gather data. Data collection was stopped when data saturation was achieved.Results:Data analysis revealed 14 subcategories and 4 categories including “failing and falling behind in life”, “deprivation and restriction”, “social isolation”, and “ineffective adaptation to the disease”, which indicate the perception of patients with NF.Conclusions:In addition to the physical burden due to physical complications and problems, NF imposes a high degree of psychological and social burden on patients causing mental conflicts, which in turn results in them failing and falling behind in life. These findings illustrate the need to develop strategies and use multidisciplinary approaches to support patients, and thus to reduce the burden of NF.

Çocukta Dilde Yerleşen Schwannoma

Çocukta Dilde Yerleşen Schwannoma

Ankle Malignant Peripheral Nerve Sheath Tumor in A Neurofibromatosis I Patient: A Case Report and Review the Literature

1.1. Introduction: Malignant Peripheral Nerve Sheath Tumors (MPNST) are rare and aggressive sarcomata’s tumors with an overall incidence of 0.001% [1] derived from Schwann cells or pluripotent cells of the neural crest [2-8]. MPNSTs are typically seen in patients aged 20-50 years, and usually in the setting of Neuro Fibromatosis Type 1(NF1) and following radiation therapy [8]. The most common sites are the trunk and extremities followed by the head and neck area [7, 8]. 1.2. Presentation of The Case: This case reports a 50-year-old man with a previous diagnosis five years ago of a Plexiform Neuro Fibroma (NF) in the posterior distal third of the right leg and ankle. In this case, we review the most important pathological findings and review the literature by reason of the rarity of this lesion. Actually, the patient is currently on regular follow-up and ongoing disease extension study in another hospital for surgical or oncologic treatment decision. 1.3. Discussion: The majority of MPNSTs are derived from neuro fibroma or they arise de novo in normal peripheral nerves [9, 2]. It is important to focus on the correct diagnosis and especially in the differential diagnosis with other tumors that can mimic MPNST, which include desmoplastic and metastatic melanomas, as well as synovial sarcoma and fibrosarcomatous dermatofibrosarcoma protuberans [10, 11]. In this article, we discuss a case of a patient with a previous diagnosis of plexiform neuro fibroma that some years later presents as an enlarging painful mass that extends to the ankle, a rare location for these tumors as described on the pathological findings and review in the literature. 1.4. Conclusion: MPNSTs are very rare sheath tumors that must be suspected in patients with NF1, especially with a previous diagnosis or another benign lesion, because this is very aggressive and rapidly growing disease.

Immunoexpression of BDNF, TrkB, and p75NTR receptors in peripheral neural lesions of the head and neck.

Brain-derived neurotrophic factor (BDNF) and neurotrophin receptors have been recognized as fundamental regulators of normal brain development, homeostasis, and plasticity. They have also been studied in the behavior of central nervous system tumors. Here, we studied the pattern of BDNF, TrkB and p75NTR immunoexpression in peripheral benign and malignant neural lesions in head and neck. This cross-sectional analytical study included 79 cases of head and neck neural lesions. Nineteen cases of traumatic neuromas (TN), 20 cases of granular cell tumors (GCT), 16 cases of neurofibromas (NF), 20 cases of schwannomas (SC), and 4 malignant peripheral nerve sheath tumor (MPNST) were submitted to immunohistochemistry with BDNF, TrkB, and p75NTR antibodies. A semi-quantitative analysis was performed. The analysis of BDNF demonstrated a high percentage of positive cells in TN, GCT and SC with a decrease in cases of NF and MPNST. TrkB presented a lower significant immunoexpression in GCT in relation to the TN, NF, SC, and MPNST (P<.0001); and TN showed less percentage of positive cell compared to SC (P=.0017). Regarding p75NTR, the percentage of positive cell was significantly reduced in MPNST compared GCT (P=.009), NF (P=.0138) and SC (P=.0069). Also, a decrease in TN compared to GCT (P=.007) was observed. Our results showed the immunoreactivity of BDNF, TrkB, and p75NTR in head and neck peripheral neural lesions. Reduction of BDNF and p75NTR in MPNST might suggest down-regulation during the acquisition of malignant phenotype.

Introduction to the Special Issue, “Proceedings of the 8th Quadrennial International Conference on Vestibular Schwannoma and Other Cerebellopontine Angle Tumors”

Introduction to the Special Issue, “Proceedings of the 8th Quadrennial International Conference on Vestibular Schwannoma and Other Cerebellopontine Angle Tumors”

EPCO-04. GENOMIC AND EPIGENOMIC HALLMARKS OF SCHWANNOMATOSIS SCHWANNOMAS

Abstract Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often, painful neuronal tumors called schwannomas (SWNs). Very little is known about the epigenomic and genomic alterations in SWNTS related SWNs (SWNTS-SWNs) other than germline mutations in SMARCB1 and LZTR1 plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q. Herein, we have comprehensively established the specific molecular signatures of SWNTS-SWNs. We found that tumor anatomic location was associated with pain and distinct DNA methylation and transcriptional signatures. DNA sequencing revealed several novel non-22q deletions, specifically in LZTR1-mutant cases. Whole-genome sequencing identified novel recurrent structural rearrangements. Further, chromosomal aberrations in SWNTS-SWNs were accompanied by increased transcription of mismatch repair genes. Our transcriptome analysis detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, more commonly in LZTR1-mutant tumors. In addition, we identified the specific genetic, epigenetic, and transcriptional hallmarks of painful SWNs that may be harnessed to develop new treatments for this debilitating syndrome.

Cdkn2a Loss in a Model of Neurofibroma Demonstrates Stepwise Tumor Progression to Atypical Neurofibroma and MPNST.

Plexiform neurofibromas are benign nerve sheath Schwann cell tumors characterized by biallelic mutations in the neurofibromatosis type 1 (NF1) tumor suppressor gene. Atypical neurofibromas show additional frequent loss of CDKN2A/Ink4a/Arf and may be precursor lesions of aggressive malignant peripheral nerve sheath tumors (MPNST). Here we combined loss of Nf1 in developing Schwann cells with global Ink4a/Arf loss and identified paraspinal plexiform neurofibromas and atypical neurofibromas. Upon transplantation, atypical neurofibromas generated genetically engineered mice (GEM)-PNST similar to human MPNST, and tumors showed reduced p16INK4a protein and reduced senescence markers, confirming susceptibility to transformation. Superficial GEM-PNST contained regions of nerve-associated plexiform neurofibromas or atypical neurofibromas and grew rapidly on transplantation. Transcriptome analyses showed similarities to corresponding human tumors. Thus, we recapitulated nerve tumor progression in NF1 and provided preclinical platforms for testing therapies at each tumor grade. These results support a tumor progression model in which loss of NF1 in Schwann cells drives plexiform neurofibromas formation, additional loss of Ink4a/Arf contributes to atypical neurofibromas formation, and further changes underlie transformation to MPNST. SIGNIFICANCE: New mouse models recapitulate the stepwise progression of NF1 tumors and will be useful to define effective treatments that halt tumor growth and tumor progression in NF1.

Abstract PO-043: Plexiform neurofibroma microenvironment at single-cell resolution

Abstract Plexiform neurofibromas (PN) are benign nerve sheath Schwann cell tumors, which occur in at least 50% of individuals with loss of function mutations in the NF1 tumor suppressor gene, an off signal for RAS-GTPases. Tumors form, at least in part, through activation of the RAS-MAPK pathway in Schwann cells. Though benign, PN can cause significant morbidity and are often inoperable due to integration with vital peripheral nerves. Recent clinical trials have shown that MEK inhibition can shrink most PN, but continued MEK inhibition is required for sustained response. It is recognized that PN contain many cell types in addition to Schwann cells, and that Schwann cells are present in varying proportions. However, biomarkers for many cell types have not yet been identified, and it is not known whether subpopulations of certain cell types exist within neurofibromas. To address these issues, we performed single cell RNA sequencing on PN using a genetically engineered mouse model which closely recapitulates human PN. We have characterized tumor composition, and identified PN Schwann cells, satellite glial cells, endothelial cells, fibroblasts, macrophages, T cells, dendritic cells, and other previously unreported cell types. We identified multiple subpopulations of Schwann cells, macrophages and fibroblasts within benign PN. Cluster by cluster comparison of PN to age-matched healthy nerve and to pretumor nerve tissue from the same mouse model revealed gene regulatory networks that are significantly altered in PN, after loss of NF1 function. Further, inference of cell-cell communication networks shows robust changes in PN that are absent before tumors form, and that are potentially targetable. Comparison to MEK inhibitor treated PN and to human PN sc-RNASeq is ongoing. Taken together, these approaches characterize PN, provide potential biomarkers for cell populations and identify targets for drug treatment. Supported by NIH (NINDS-28840) and the DOD Program on Neurofibromatosis. LK is supported by NIH Ruth L. Kirschstein T32. Citation Format: Leah J. Kershner, Jianqiang Wu, Nathan Salomonis, Nancy Ratner. Plexiform neurofibroma microenvironment at single-cell resolution [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-043.

Plexiform Schwannoma Masquerading as Giant Cell Tumor of Tendon Sheath- A Case Report

Plexiform schwannoma is a rare benign variant of Schwann cell tumor characterised by multinodular plexiform growth pattern. Usual location of this tumor includes trunk, head, neck and upper extremities but it may rarely be found in lower extremities. It generally affects young adults with no sex predilection. We report a case of 37 years old male who presented with gradually progressive swelling of right little finger of 28years duration that was diagnosed as giant cell tumor of tendon sheath clinically, radiologically and intraoperatively. Authors wish to discuss the case due to its clinical rarity and diagnostic difficulties due to many common histological mimickers at that site.

Frequent MN1 Gene Mutations in Malignant Peripheral Nerve Sheath Tumor.

Malignant peripheral nerve sheath tumor (MPNST) is a rare soft-tissue tumor, and its diagnosis is usually made histopathologically. The effectiveness of chemotherapy and radiotherapy has not been established. We elucidated prognostic factors, diagnostic markers, and therapeutic targets. Cases of MPNST were studied using next-generation sequencing. A total of 24 tumor samples, 11 from von Recklinghausen's disease-associated MPNST (vRH-MPNST), 11 from sporadic non-vRH MPNST, and two neurofibroma (NF) cases were retrieved, on which next-generation sequencing and survival analysis were performed. We identified NF1 gene mutations, including three mutations in two NFs, and 10 mutations in eight MPNSTs (five vRH-MPNSTs and three sporadic MPNSTs). Meningioma 1 (MN1) gene alteration was detected in six cases of vRH-MPNST. It is considered that MN1 gene alteration is related to the tumorigenesis of vRH-MPNST. MN1 gene mutation was detected in more than half of our cases, it may have potential for use as a therapeutic target in vRH-MPNST.

Epigenomic, genomic, and transcriptomic landscape of schwannomatosis

Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often painful neuronal tumors called schwannomas (SWNs). While germline mutations in SMARCB1 or LZTR1, plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q have been identified in a subset of patients, little is known about the epigenomic and genomic alterations that drive SWNTS-related SWNs (SWNTS-SWNs) in a majority of the cases. We performed multiplatform genomic analysis and established the molecular signature of SWNTS-SWNs. We show that SWNTS-SWNs harbor distinct genomic features relative to the histologically identical non-syndromic sporadic SWNs (NS-SWNS). We demonstrate the existence of four distinct DNA methylation subgroups of SWNTS-SWNs that are associated with specific transcriptional programs and tumor location. We show several novel recurrent non-22q deletions and structural rearrangements. We detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, with predominance in LZTR1-mutant tumors. In addition, we identified specific genetic, epigenetic, and actionable transcriptional programs associated with painful SWNTS-SWNs including PIGF, VEGF, MEK, and MTOR pathways, which may be harnessed for management of this syndrome.