Nerve Sheath Tumors Research Articles

EXTH-62. FOCAL ADHESION KINASE (FAK) IN CHROMOSOME 8 GAIN-ASSOCIATED MALIGNANT PERIPHERAL NERVE SHEATH TUMORS (MPNST)

Abstract OBJECTIVES Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas often associated with Neurofibromatosis type 1 (NF1), a genetic syndrome driven by overactivation of the RAS pathway. MEK inhibitors (MEKi) target downstream components of the RAS pathway and have been approved for NF1 patients with plexiform neurofibromas (PN). However, MPNST often develop resistance to MEKi. Our lab recently discovered the critical role of chromosome 8 (Chr8) genes in MPNST. The Chr8 gene, protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK) is overexpressed in multiple cancers, suggesting its importance in tumor progression. In this study, we aim to evaluate FAK as a therapeutic target for MPNST and investigate the FAKi and RAF/MEKi combination. METHODS A CRISPR gRNA screen was used to identify Chr8 genes involved in MPNST survival. The effect of FAK shRNA knockdown and a FAK inhibitor (FAKi), alone or combined with a MEKi, in MPNST cells was assessed using IncuCyte proliferation assays and multiple murine models. RESULTS The CRISPR gRNA screen identified 57 genes on Chr8 important for MPNST cell survival, including PTK2/FAK. Knockdown of FAK by shRNA in MPNST inhibited cell proliferation in vitro and reduced tumorigenesis in vivo. Consistently, the FAKi defactinib significantly inhibited the proliferation of MPNST (IC50-values: 1.72-4.65μM). Moreover, the defactinib/avutometinib combination was synergistic in vitro and the combination of FAKi with RAF/MEKi reduced tumor growth more that either drug alone in Chr8-gain MPNST PDX models. Avutometinib induced compensatory activation of FAK, while defactinib/avutometinib combination decreased phosphorylation of FAK, ERK1/2 and STAT3, and augmented cleavage of Caspase-3 and PARP-1, shown using the WES protein simple system. CONCLUSION These results demonstrate the potential therapeutic efficacy of FAK inhibitors, both alone and in combination with RAF/MEKi, for the treatment of MPNST.

RBIO-07. IMMUNOMODULATORY PATHWAYS MEDIATE RADIOTHERAPY RESPONSE IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS

Abstract PURPOSE Malignant peripheral nerve sheath tumors (MPNSTs) are the most common cause of death in neurofibromatosis type 1 (NF-1) and are resistant to radiation therapy (RT), yet the mechanisms underlying RT response are poorly understood. Here, we elucidate mechanisms of RT response in NF-1 associated peripheral nerve sheath tumors through genome-wide CRISPRi screens, genomic analysis of mouse models, and molecular analysis of patient-derived tumor specimens. METHODS Patient derived NF1 mutant plexiform neurofibroma (pNF) cells (NF9511b, NF95.6), and MPNST cells (ST88-14; JH2-002) were used to measure RT responses by cell counts and flow cytometry. Genome-wide CRISPRi screens were used to identify functional modifiers of RT response in ST88-14 and JH2-002 MPNST cells. Nf1-/-; Tp53-/- mouse MPNSTs were subcutaneously implanted in immunocompetent C57/B6 mice, irradiated (2Gyx5), and dissociated for single-cell RNA sequencing (scRNA-seq) using 10x Genomics. Human MPNST tumor specimens (n=45) were analyzed with targeted DNA mutation sequencing and methylation arrays for cell type deconvolution. RESULTS Radiation single-dose response curves revealed MPNST cells (IC50 6.85Gy) were radioresistant compared to pNF cells (IC50 3.13Gy). Genome wide CRISPRi screens in ST88-14 and JH2-002 MPNST cells converged on cell cycle, DNA repair, and immunomodulatory gene sets mediating RT sensitivity. Irradiation of subcutaneous mouse Nf1-/-; Tp53-/- MPNSTs significantly decreased tumor growth (p=0.01, t-test). scRNA-seq of 32,763 cells from 4 irradiated and 3 unirradiated mouse Nf1-/-; Tp53-/- MPNSTs identified 8 tumor clusters and 7 non-tumor clusters. Irradiation demonstrated a pro-inflammatory effect with increased T-cell presence (5.8% versus 3.3%, p=0.04, t-test) and greater activation of immunostimulatory genes (Cxcl10, Stat1, Irf7) in T cells. In human MPNSTs, CDKN2A/B deletion (p=0.04, log-rank test) and decreased immune cell composition (p=0.03, log-rank test) were associated with significantly worse overall survival in response to RT. CONCLUSION MPNST RT responses may depend on immunomodulatory mechanisms that could be leveraged to improve clinical RT response.

BIOM-37. EXPLORING L-TYPE AMINO ACID TRANSPORTER 1 (LAT1) AS A DIAGNOSTIC MARKER AND THERAPEUTIC TARGET IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS (MPNST)

Abstract OBJECTIVES Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that frequently arise from benign plexiform neurofibromas (PN). Approximately half of MPNST are associated with Neurofibromatosis type 1 (NF1). Despite partial elucidation of the molecular mechanisms underlying MPNST, diagnosis remains challenging, and prognosis is poor. Previously, we found that MPNST cells have elevated βIII-spectrin, a cytoskeletal protein involved in cell morphology and regulation of transporters, including L-type Amino Acid Transporter 1 (LAT1). LAT1 facilitates transport of large neutral amino acids and is upregulated in other cancer types. Our objective is to investigate LAT1 as a diagnostic marker and therapeutic target for MPNST. METHODS Gene and protein expression were determined by qPCR and WES protein analysis, respectively. The effect of shRNA knockdown of LAT1 in MPNST cells was assessed using IncuCyte proliferation assays as well as multiple mouse models. Tumor uptake of [18F] FDOPA, primarily transported by LAT1, in MPNST PDX tumors was assessed using PET/CT imaging. RESULTS LAT1 was expressed in MPNST (n=14) vs. benign PN tissues (n=6). Additionally, in human and murine MPNST cells, shRNA-mediated knockdown of LAT1 suppressed proliferation of MPNST cells in vitro and tumor growth in vivo. In a subcutaneous tumor growth model, intratumor injection of shLAT1 lentivirus reduced tumor volume to approximately 50% of control. Furthermore, uptake of [18F] FDOPA by LAT1 in MPNST PDX tumors was detected by PET/CT imaging. WU-356 PDX tissues exhibited higher LAT1 expression as well as increased uptake of [18F] FDOPA in tumors. Conversely, PET imaging showed significantly lower uptake of [18F] FDOPA in LAT1 knockdown tumors (p<0.05). CONCLUSIONS These results suggest that LAT1 promotes the growth and survival of MPNST cells. In addition, these findings demonstrate the potential use of LAT1 and the radiotracer [18F] FDOPA as a diagnostic biomarker in the management of MPNST.

CNSC-13. CROSSTALK BETWEEN SENSORY NEURONAL ACTIVITY AND TUMOR CELLS PROMOTES MALIGNANCY AND CANCER PAIN

Abstract BACKGROUND Nerve infiltration of solid tumors is associated with poor prognosis in multiple cancer types. Understanding the role of neuronal activity in cancer progression offers innovative approaches for treating malignancies and cancer-associated neurological issues such as pain. Pain perception is mediated by the activity of peripheral sensory neurons. Many cancer types induce pain, and sensory innervation could support tumor growth, raising the interesting hypothesis that cancer pain-associated neuronal activity promotes malignancies. Our study aims to test the hypothesis using malignant peripheral nerve sheath tumor (MPNST) as the experimental platform. METHODS in vivo allograft models were established by implanting mouse MPNST cells into the sciatic nerves of male and female mice, followed by performing pain behavior assays (von Frey, Hargreaves, and conditioned place preference tests) and tumor growth measurements. Primary mouse dorsal root ganglion (DRG) sensory neuron cultures were prepared for calcium imaging and neuron-tumor co-culture experiments. RESULTS MPNST tumor-bearing mice exhibited hypersensitivity to noxious and non-noxious stimuli (evoked pain) and ongoing pain, compared to the sham controls. MPNST-conditioned media increased intracellular calcium concentration and ATF3 (indicator for nerve injury/stress) expression in primary sensory neuron culture, suggesting that MPNST tumor cell secretory factors may induce pain by triggering sensory neuron injury/stress responses that increase sensory neuron activity/sensitivity. Reciprocally, we found that stimulation of sensory neuron activity accelerates MPNST tumor growth. The conditioned media from stimulated sensory neurons increased tumor proliferation (EdU assay) in vitro, suggesting that sensory neuron activity-induced paracrine factors increase MPNST cell growth. CONCLUSIONS MPNST is a devastating cancer that grows within peripheral nerves which induce intractable pain. Our findings demonstrate a feedforward cycle where the cancer cells induce sensory neuron hypersensitivity/hyperactivity (pain) which in turn further accelerates tumor growth. Future studies will identify the molecular mechanisms underlying this crosstalk between MPNST and sensory neuron activity.

Malignant Peripheral Nerve Sheath Tumour in the Setting of a Rare Germline BAP1 Disease Causing Variant presenting as a Metastatic Melanoma Mimic.

A 47-year-old male presented with a 9-year history of a subcutaneous swelling on his right, his initial diagnosis was a stage IV metastatic melanoma deposit on the right wrist originating from a pT4a BAP1 inactivated primary melanoma on the back. Due to the unusual nature of the presentation further input from a specialist skin cancer multidisciplinary team with an interest in BAP1 tumour predisposition syndrome (BAP1-TPDS) led to a revised diagnosis of a Malignant Peripheral Nerve Sheath Tumour (MPNST) on the wrist.

QLTI-20. BRIDGING THE GAP: UNDERSTANDING THE CURRENT TREATMENT RESPONSES TO ENHANCE THE STANDARD OF CARE AND OUTCOMES FOR MALIGNANT PERIPHERAL NERVE SHEATH TUMORS

Abstract Malignant peripheral nerve sheath tumor (MPNST) are a rare and aggressive cancer that make up 5-10% of all sarcomas. There is currently no effective targeted therapy to treat MPNST and surgical resection remains the mainstay of treatment, though often not feasible due to location, size of the tumor, or presence of metastases. Evaluation of MPNST treatment response to palliative chemotherapy regimens could serve as a reference point for target response rates in clinical trials going forward. We performed a retrospective electronic health record analysis of patients with biopsy-proven diagnoses of MPNST at Washington University and Johns Hopkins University. We evaluated tumor characteristics along with treatment response, overall survival (OS), and progression free survival (PFS) rates for different chemotherapeutic regimens. The cohort comprises 140 patients, with ages at diagnosis ranging from 21 to 40 years. Most patients had tumors located in the extremities, with sizes ranging from 5-10 cm at the time of diagnosis. We identified 66 patients who received adjuvant chemotherapy, 44 received neoadjuvant chemotherapy and 28 did not receive any chemotherapy. We will present objective response rate (ORR) and clinical benefit rate (CBR) for neoadjuvant chemotherapy. Among patients with metastatic disease (n=53), 12 chemotherapy regimens were assessed. All regimens other than gemcitabine-docetaxel chemotherapy regimen performed better than the median PFS of 1.77 months which has been observed in clinical trials of targeted agents to date with the most compelling response to vincristine-irinotecan-temozolomide regimen. Despite advancements in our understanding of MPNST pathogenesis, these tumors carry a poor prognosis. Our study has identified several systemic therapies which should be further evaluated prospectively to improve treatment options and outcomes for patients with this aggressive sarcoma. These results can serve as a benchmark for future clinical trials.

CNSC-53. SHH ACTIVATION IN DEDIFFERENTIATION DURING TUMOR PROGRESSION IN MPNST

Abstract BACKGROUND Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with little progress on outcomes and treatment strategies. Previously, unsupervised analyses of methylome and transcriptome profiles of 108 peripheral nerve sheath tumors uncovered two subgroups of MPNSTs that predict progression-free survival, MPNST-G1 (characterized by SHH-pathway activation) and MPNST-G2 (characterized by WNT/ß-catenin/CCND1-pathway activation). Further, single nuclear RNA sequencing revealed that MPNST-G1 and MPNST-G2 cells resemble neural crest-like and Schwann cell precursor-like cells, respectively. PURPOSE & HYPOTHESIS To examine whether the activation of the SHH pathway in MPNST-G1 cell lines induces overexpression of factors known to play canonical roles in early neural crest cell specification (TWIST1, SNAI2, PAX3, PAX6, SOX9, OTX2) and to investigate the role of Src activation on SHH pathway-induced dedifferentiation. We hypothesize that MPNST-G1 cells will exhibit SHH pathway activation, synergizing with Src to induce the overexpression of early neural crest cell (ENCC) transcription factors. METHODS SHH pathway activation, expression of ENCC transcription factors, and effects of inhibitors were analyzed in MPNST-G1 cells using RT-PCR, western blotting, Alamar Blue assay, Trypan Blue assay, and Soft Agar Transformation assay. RESULTS Compared to MPNST-G2 cells, MPNST-G1 cells displayed SHH-pathway activation, SMO-dependent activation of Src, and elevated expression of the ENCC transcription factors. Sonidegib (SMO inhibitor) and Dasatinib (Src inhibitor) were able to revert dedifferentiation. CONCLUSIONS The SHH-pathway cooperates with Src to promote expression of important transcription factors in dedifferentiation. This finding provides insights into the transformation process of MPNST and novel therapeutic options.

Two-year Local and Distant Control of Malignant Peripheral Nerve Sheath Tumor (MPNST) in NF1 Patients After Multiple Recurrences: A Case Report

Malignant peripheral nerve sheath tumors (MPNSTs) are rare, biologically high-grade sarcomas that tend to recur and metastasize. The known risk factors for MPNSTs include neurofibromatosis type 1, highly aggressive MPNSTs, and dismal survival outcomes. Multimodality therapies, including surgical resection, radiotherapy, chemotherapy, targeted therapy, and combination therapy, are available. This case report describes a young woman with NF1 who was referred to us with a history of three local recurrences of MPNSTs in the proximal part of her left thigh after several surgical attempts. Successful local and distant control was achieved via preoperative radiotherapy and chemotherapy prior to the latest surgery. With preoperative RT and chemotherapy, more long-term and successful local and distant control was achieved, particularly in high-risk NF1- associated MPNST patients with a history of recurrence. Trials with larger sample sizes may show improvements in local control (LC), disease-free survival (DFS), and overall survival (OS) with neoadjuvant interventions in such patients.

Multiomic Analyses Reveal New Targets of Polycomb Repressor Complex 2 in Schwann Lineage Cells and Malignant Peripheral Nerve Sheath Tumors

Abstract Background Malignant peripheral nerve sheath tumors (MPNST) can arise from atypical neurofibromas (ANF). Loss of the polycomb repressor complex 2 (PRC2) is a common event. Previous studies on PRC2-regulated genes in MPNST used genetic addback experiments in highly aneuploid MPNST cell lines which may miss PRC2-regulated genes in NF1-mutant ANF-like precursor cells. A set of PRC2-regulated genes in human Schwann cells has not been defined. We hypothesized PRC2 loss has direct and indirect effects on gene expression resulting in MPNST, so we sought to identify PRC2-regulated genes in immortalized human Schwann cells (iHSCs). Methods We engineered NF1-deficient iHSCs with loss of function SUZ12 or EED mutations. RNA sequencing revealed 1,327 differentially expressed genes to define PRC2-regulated genes. To investigate MPNST pathogenesis we compared genes in iHSCs to consistent gene expression differences between ANF and MPNSTs. Chromatin immunoprecipitation sequencing was used to further define targets. Methylome and proteomic analyses were performed to further identify enriched pathways. Results We identified potential PRC2-regulated drivers of MPNST progression. Pathway analysis indicates many upregulated cancer-related pathways. We found transcriptional evidence for activated Notch and Sonic Hedgehog signaling in PRC2-deficient iHSCs. Functional studies confirm Notch signaling is active in MPNST cell lines, patient-derived xenografts, and transient cell models of PRC2 deficiency. A combination of MEK and γ-secretase inhibition shows synergy in MPNST cell lines. Conclusions We identified PRC2-regulated genes and potential drivers of MPNSTs. Our findings support the Notch pathway as a druggable target in MPNSTs. Our identification of PRC2-regulated genes and pathways could result in more novel therapeutic approaches.

Dysregulation of miRNAs in Soft Tissue Sarcomas

MicroRNAs (miRNAs) are pivotal regulators of gene expression, influencing key cellular processes such as proliferation, differentiation, apoptosis, and metastasis. In the realm of sarcomas—a diverse group of malignant tumors affecting soft tissues and bone sarcomas—miRNAs have emerged as crucial players in tumorigenesis and tumor progression. This review delves into the intricate roles of miRNAs across various soft tissue sarcoma subtypes, including rhabdomyosarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, fibrosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma (UPS), and malignant peripheral nerve sheath tumor (MPNST). We explore how dysregulated miRNAs function as oncogenes or tumor suppressors, modulating critical pathways that define the aggressive nature of these cancers. Furthermore, we discuss the diagnostic and prognostic potential of specific miRNAs and highlight their promise as therapeutic targets. By understanding the miRNA-mediated regulatory networks, this review aims to provide a comprehensive overview of current research while pointing towards future directions for miRNA-based therapies. Our findings underscore the potential of miRNAs to transform the landscape of sarcoma treatment, offering hope for more precise, personalized, and effective therapeutic strategies.

Profiling the cancer-prone microenvironment in a zebrafish model for MPNST.

Microenvironmental contributions to soft tissue sarcoma progression are relatively undefined, particularly during sarcoma onset. Use of animal models to reveal these contributions is impeded by difficulties in discriminating between microenvironmental, precancerous, and cancer cells, and challenges in defining a precancerous microenvironment. We developed a zebrafish model that allows segregation of microenvironmental, precancerous, and cancerous cell populations by fluorescence-activated cell sorting. This model has high predilection for malignant peripheral nerve sheath tumor (MPNST), a type of soft tissue sarcoma that exhibits rapid, aggressive growth. Using RNA-seq, we profiled the transcriptomes of microenvironmental, precancerous, and cancer cells from our zebrafish MPNST model. We show broad activation of inflammation/immune-associated signaling networks, describe gene expression patterns that uniquely characterize the transition from precancerous to cancer ME, and identify macrophages as potential contributors to microenvironmental phenotypes. We identify conserved gene expression changes and candidate genes of interest by comparative genomics analysis of MPNST versus benign lesions in both humans and zebrafish. Finally, we functionally validate a candidate extracellular matrix protein, periostin (POSTN), in human MPNST. This work provides insight into how the microenvironment may regulate MPNST initiation and progression.

Perioperative Observations and Outcome in Surgical Treatment of Malignant Peripheral Nerve Sheath Tumors

Perioperative Observations and Outcome in Surgical Treatment of Malignant Peripheral Nerve Sheath Tumors

Consensus recommendations for an integrated diagnostic approach to peripheral nerve sheath tumors arising in the setting of Neurofibromatosis type 1 (NF1).

Consensus recommendation published in 2017 histologically defining atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP) and malignant peripheral nerve sheath tumor (MPNST) were codified in the 2021 WHO Classification of Tumors of the Central Nervous System and the 2022 WHO Classification of Tumors of Soft Tissue and Bone. However, given the shift in diagnostic pathology toward the use of integrated histopathologic and genomic approaches, the incorporation of additional molecular strata in the classification of Neurofibromatosis Type 1 (NF1)-associated peripheral nerve sheath tumors should be formalized to aid in accurate diagnosis and early identification of malignant transformation to enable appropriate intervention for affected patients. To this end, we assembled a multi-institutional expert pathology working group as part of a "Symposium on Atypical Neurofibroma: State of the Science". Herein, we provide a suggested framework for adequate interventional radiology and surgical sampling, and recommend molecular profiling for clinically or radiologically worrisome non-cutaneous lesions in patients with NF1 to identify diagnostically-relevant molecular features, including CDKN2A/B inactivation for ANNUBP, as well as SUZ12, EED, or TP53 inactivating mutations, or significant aneuploidy for MPNST. We also propose renaming "low-grade MPNST" to "ANNUBP with increased proliferation" to avoid the use of the "malignant" term in this group of tumors with persistent unknown biologic potential. This refined integrated diagnostic approach for NF1-associated peripheral nerve sheath tumors should continue to evolve in concert with our understanding of these neoplasms.

Extraneural Soft Tissue Perineurioma: A Report of a Rare Case of Peripheral Nerve Sheath Tumor

Extraneural Soft Tissue Perineurioma: A Report of a Rare Case of Peripheral Nerve Sheath Tumor

089. TACE for Residive Malignant Peripheral Nerve Sheath Tumor and Leiomyosarcoma: Case Series

Background: Malignant peripheral nerve sheath tumors (MPNST) are malignant, locally aggressive soft tissue sarcomas (STS) of the peripheral nerve or nerve sheath cells. Leiomyosarcomas are malignant tumors originating from the smooth muscle. Transarterial chemoembolization (TACE) is an interventional treatment to deliver chemoembolic materials. Case: First case is a 50-year-old male visited Oncology Surgery Polyclinic due to the presence of a tumor on his left forearm that was progressively increasing in size during the past two months. The MRI was done, the diagnosis of a residive malignant peripheral nerve sheath tumor was made. Second case is a 40-year-old female visited the Oncology Surgery Polyclinic due to the presence of a tumor on her right breast that was progressively increasing in size and the diagnosis of a Leiomyosarcoma at the right breast was made. Transarterial chemoembolization (TACE) was performed to both of the cases. Conclusion: MPNST and Leiomyosarcoma are malignant tumor that can be treated with doxorubicin chemotherapy through the TACE procedure.

Whole-body MRI-based long-term evaluation of pediatric NF1 patients without initial tumor burden with evidence of newly developed peripheral nerve sheath tumors

BackgroundPatients with neurofibromatosis type 1 (NF1) can develop plexiform neurofibromas (PN). Large tumor burden is a predictor for the development of malignant peripheral nerve sheath tumors. Whole-body magnetic resonance imaging (WB-MRI) is the recommended imaging method for the evaluation of PN. WB-MRI is recommended for NF1 patients at transition from adolescence to adulthood. In the absence of internal PN further follow-up WB-MRI is not considered necessary. PN are often detected in early childhood, leading to the assumption that they may be congenital lesions. It remains unclear whether this invariably applies to all patients or whether patients who initially displayed no tumors can still develop PN over time. Therefore, we retrospectively reviewed WB-MRI scans of pediatric patients with NF1 without initial tumor burden and compared these with long-term follow-up scans for presence of newly developed PN.MethodsWe retrospectively reviewed WB-MRI scans of 17 NF1-children (twelve male; median age at initial scan: 9 [IQR 6.1–11.9] years) who initially displayed no PN. MRI scans with a follow-up interval of at least 6 years (median follow-up interval: 9 [IQR 5.6–12.4] years) were reviewed in consensus by two radiologists regarding the development of new PN over time.ResultsNew PN were identified in two out of 17 children without initial tumor burden in follow-up examinations. One of these two patients developed two larger distinct PN of 4.5 cm on the right upper arm and of 2.5 cm on the left thoracic wall between the age of ten and twelve. The second child developed multiple smaller PN along the major peripheral nerves between the age of eleven and 16. In addition, 15 of the children without initial tumor burden did not develop any distinct tumors for a period of at least 6 years.ConclusionOur results indicate that PN can be newly detected in pediatric patients over time, even if no PN were detected on initial MRI scans. Therefore, it seems reasonable to perform at least a second MRI in pediatric NF1 patients at transition to adulthood, even if they did not display any tumor burden on initial MRI, and when the MRI was performed significantly under the age of 18. With this approach, tumors that may have developed between scans can be detected and patients at risk for complications can be identified.

Excision of a supergiant spinal schwannoma: illustrative case.

The authors report on a patient who presented with an extremely large presacral schwannoma and subsequent mass effect-induced hydronephrosis and kidney failure. To the authors' knowledge, this case represents the largest radiographically verified spinal schwannoma in the medical literature. The tumor presented here was more than three times as large as a typical giant schwannoma. While smaller presacral schwannomas are usually uncomplicated surgical cases, the supergiant schwannomas described here create significant surgical challenges. The extremely large size of this nerve sheath tumor introduced a level of surgical complexity not seen in most spinal schwannoma cases. The authors hope that this case informs surgeons regarding the approach to excision of giant spinal schwannomas. The resection of giant spinal schwannomas is likely to involve one or more lengthy surgeries, and the resection volume can be limited by excessive bleeding. Physicians approaching these large, benign spinal tumors should be aware of the challenges of surgery duration and hemostasis before approaching a tumor of this kind. https://thejns.org/doi/10.3171/CASE24224.

078. Malignant Peripheral Nerve Sheath Tumor Masquerading as Neurofibromatosis Type 1 in A 47-Year-Old Female: A Rare Case of Diagnostic Dilemma and Management Challenge

Background: Malignant Peripheral Nerve Sheath Tumor (MPNST) is a rare soft tissue sarcoma, often associated with Neurofibromatosis Type 1 (NF1), and can arise from benign neurofibromas. MPNST typically presents with rapidly enlarging masses, pain, or neurological deficits, but can sometimes be mistaken for benign lesions, delaying diagnosis. This case report discusses a 47-year-old female with NF1 whose benign lesion progressed into MPNST. Case: A 47-year-old female presented with a complaint of pus discharge from a lump in her buttock over the past four days. The lump had progressively enlarged for two years before discharging pus. The patient also described multiple lumps on her body since childhood, characteristic of NF1, but noted that only the lump on her buttock had grown significantly and hardened over time. Patient is unable to walk due to her condition since two years ago. Initial histopathological examination indicated benign neurofibroma, but two months later, the patient underwent surgical excision of the tumor as the primary treatment, and the specimen was examined for pathology and showed MPNST. Conclusion: MPNST should always be considered in NF1 patients with rapidly enlarging, firm masses, even when initial pathology indicates a benign process. Timely diagnosis and surgical intervention are critical for optimal outcomes.

TGF-β superfamily-induced transcriptional activation pathways establish the RAD52-dependent ALT machinery during malignant transformation of MPNSTs

To study telomere maintenance mechanism (TMM) activation during malignant transformation, we compared neurofibroma (NF) and malignant peripheral nerve sheath tumor (MPNST) in the same patient with type-1 neurofibromatosis (NF1), a total of 20 NF-MPNST pairs in 20 NF1 patients. These comparisons minimized genetic bias and contrasted only changes associated with malignant transformation, while subtracting changes that developed upon the transformation of normal cells to the benign tumor. TGF-β superfamily genes were found to activate the PAX and SOX transcription factors, leading to TMM activation. BMPER activates PAX6 through BMP2 and PAX7 through BMP4; BMP15 activates SOX14; and INHBC activates PAX9 and SOX14. The activated PAX and SOX genes sequentially establish the core architecture of the RAD52-dependent alternative lengthening of telomeres (ALT). Specifically, PAX7 activates the recombinase (RAD52) and a negative regulator (SLX4IP). PAX6 and SOX14 activate positive regulators (BLM and BRCA2, respectively). PAX9 and SOX14 activate RAD9B and FEN1, which are responsible for the stability of homologous recombination intermediates and increase, together with RAD52, the telomere length. Telomere elongation achieved by the activation of PAX7 and PAX9 is associated with a poor prognosis. We demonstrated that TGF-β superfamily-induced transcriptional activation pathways activated the RAD52-dependent ALT during malignant transformation of MPNSTs.

Spatial lipidomics reveals myelin defects and pro-tumor macrophage infiltration in MPNST adjacent nerves

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas arising from peripheral nerves, accounting for 3-5% of soft tissue sarcomas. MPNSTs often recur locally, leading to poor survival. Achieving tumor-free surgical margins is essential to prevent recurrence, but current methods for determining tumor margins are limited, highlighting the need for improved biomarkers. In this study we investigated the degree to which MPNST extends into nerves adjacent to tumors. Alterations to the lipidome of MPNST and adjacent peripheral nerves were assessed using spatial lipidomics. Tissue samples from 5 MPNST patients were analyzed, revealing alterations of the lipid profile extending into the peripheral nerves beyond what was expected based on macroscopic and histological observations. Integration of spatial lipidomics and high-resolution accurate mass profiling identified distinct lipid profiles associated with healthy nerves, connective tissue, and tumors. Notably, histologically normal nerves exhibited myelin degradation and infiltration of pro-tumoral M2 macrophages, particularly near the tumor. Furthermore, aberrant osmium staining patterns and loss of H3K27me3 staining in absence of atypia were observed in a case with tumor recurrence. This exploratory study thereby highlights the changes occurring in the nerves affected by MPNST beyond what is visible on H&E, and provides leads for further biomarker studies, including aberrant osmium staining, to assess resection margins in MPNST