[A case of pleural metastasis of malignant peripheral nerve sheath tumor].

Malignant peripheral nerve sheath tumor (MPNST) frequently metastasizes to the lungs, although pleural metastasis is rare. This article reported a case of pleural metastasis of MPNST. The patient was a young man who presented with 1 week of shortness of breath with dry cough. He had a history of malignant peripheral nerve sheath tumor. The patient was diagnosed with MPNST pleural metastasis after a thoracoscopic pleural biopsy, which revealed short spindle cell hyperplasia, immunohistochemical staining for S-100(+), SOX-10(+), Ki-67(+) with a positive index of 20%, and H3K27Me3(-) in the pleural pathology.

Thiophenyl Derivatives of Nicotinamide Are Metabolized by the NAD Salvage Pathway into Unnatural NAD Derivatives That Inhibit IMPDH and Are Toxic to Peripheral Nerve Cancers.

N-Pyridinylthiophene carboxamide (compound 21) displays activity against peripheral nerve sheath cancer cells and mouse xenografts by an unknown mechanism. Through medicinal chemistry, we identified a more active derivative, compound 9, and found that only analogues with structures similar to nicotinamide retained activity. Genetic screens using compound 9 found that both NAMPT and NMNAT1, enzymes in the NAD salvage pathway, are necessary for activity. Compound 9 is metabolized by NAMPT and NMNAT1 into an adenine dinucleotide (AD) derivative in a cell-free system, cultured cells, and mice, and inhibition of this metabolism blocked compound activity. AD analogues derived from compound 9 inhibit IMPDH in vitro and cause cell death by inhibiting IMPDH in cells. These findings nominate these compounds as preclinical candidates for the development of tumor-activated IMPDH inhibitors to treat neuronal cancers.

Identifying, Diagnosing, and Grading Malignant Peripheral Nerve Sheath Tumors in Genetically Engineered Mouse Models.

Patients with the autosomal dominant tumor susceptibility syndrome neurofibromatosis type 1 (NF1) commonly develop plexiform neurofibromas (PNs) that subsequently transform into highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). Understanding the process by which a PN transforms into an MPNST would be facilitated by the availability of genetically engineered mouse (GEM) models that accurately replicate the PN-MPNST progression seen in humans with NF1. Unfortunately, GEM models with Nf1 ablation do not fully recapitulate this process. This led us to develop P0-GGFß3 mice, a GEM model in which overexpression of the Schwann cell mitogen neuregulin-1 (NRG1) in Schwann cells results in the development of PNs that progress to become MPNSTs with high frequency. However, to determine whether tumorigenesis and neoplastic progression in P0-GGFß3 mice accurately model the processes seen in NF1 patients, we had to first prove that the pathology of P0-GGFß3 peripheral nerve sheath tumors recapitulates the pathology of their human counterparts. Here, we describe the specialized methodologies used to accurately diagnose and grade peripheral nervous system neoplasms in GEM models, using P0-GGFß3 and P0-GGFß3;Trp53+/- mice as an example. We describe the histologic, immunohistochemical, and histochemical methods used to diagnose PNs and MPNSTs, how to distinguish these neoplasms from other tumor types that mimic their pathology, and how to grade these neoplasms. We discuss the establishment of early-passage cultures from GEM MPNSTs, how to characterize these cultures using immunocytochemistry, and how to verify their tumorigenicity by establishing allografts. Collectively, these techniques characterize the pathology of PNs and MPNSTs that arise in GEM models and critically compare the pathology of these murine tumors to their human counterparts.

[Successful surgical excision of a melanoma and a rare peripheral nerve sheath tumor in 2 cattle]. / Erfolgreiche chirurgische Exzision eines Melanoms und eines seltenen peripheren Nervenscheidentumors bei 2 Rindern.

A heifer and a dairy cow were presented to our practice with cutaneous masses on the left side of their necks. Each mass had a diameter of approximately 20 cm. Both tumors had increased in size in recent weeks and were now prone to injuries from the stable equipment. Both animal owners agreed to surgical removal, which was performed under sedation and local anesthesia on a bovine treatment crush. The subsequent histopathological examinations of the extirpates revealed a melanocytoma in the young heifer and a cutaneous peripheral nerve sheath tumor (PNST) in the dairy cow. Both cases were benign tumors. The postoperative course was without complications and no recurrences were observed even more than a year later. No comparable tumors were found in related animals or in the offspring.

Integrated Epigenetic and Transcriptomic Analysis Identifies Interleukin 17 DNA Methylation Signature of Malignant Peripheral Nerve Sheath Tumor Progression and Metastasis.

PURPOSE: Sarcomas are a complex group of highly aggressive and metastatic tumors with over 100 distinct subtypes. Because of their diversity and rarity, it is challenging to generate multisarcoma signatures that are predictive of patient outcomes. MATERIALS AND METHODS: Here, we identify a DNA methylation signature for progression and metastasis of numerous sarcoma subtypes using multiple epigenetic and genomic patient data sets. Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly metastatic sarcomas with frequent loss of the histone methyltransferase, PRC2. Loss of PRC2 is associated with MPNST metastasis and plays a critical noncanonical role in DNA methylation. RESULTS: We found that over 900 5'-C-phosphate-G-3' (CpGs) were hypermethylated in MPNSTs with PRC2 loss. Furthermore, we identified eight differentially methylated CpGs in the IL17D/RD family that correlate with the progression and metastasis of MPNSTs in two independent patient data sets. Similar trends were identified in other sarcoma subtypes, including osteosarcoma, rhabdomyosarcoma, and synovial sarcoma. Analysis of scRNAseq data sets determined that IL17D/RD expression occurs in both the tumor cells and the surrounding stromal populations. CONCLUSION: These results might have broad implications for the clinical management and surveillance of sarcoma.

Peripheral nerve tumors.

The chapter is focused on the neoplastic peripheral nerve lesions, which primarily involve "cranial and paraspinal nerves," as outlined in the CNS volume (WHO_Classification_of_Tumours_Editorial_Board, 2021). These include classic peripheral nerve sheath tumors such as schwannoma, neurofibroma, intraneural perineurioma, and malignant peripheral nerve sheath tumors, with their variants as well as new and more precisely defined entities, including hybrid nerve sheath tumors and malignant melanotic nerve sheath tumor (previously melanotic schwannoma).

Incidental finding of Psuedomyxoma Peritonei in Malignant Peripheral Nerve Sheath Tumour.

Psuedomyxoma peritonei is an infrequent clinical entity characterised by intraperitoneal mucinous/gelatinous ascites produced by the cancerous cells. It has been associated with gastrointestinal, gynaecological, lung and breast tumours. It is commonly asymptomatic and is most often detected incidentally on abdominopelvic imaging or laparoscopy. Higher histological grade of the tumour shows increased metabolic activity on 18F-Fluorodeoxyglucose (FDG) positron-emission tomography (PET) computed tomography (CT). It has been rarely reported in patients with sarcoma. We hereby present an interesting case of incidentally diagnosed pseudomyxoma peritonei on 18FDG PET-CT scan of a patient with soft tissue sarcoma of peripheral nerve sheath.

Contemporary Approach to Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors.

Most malignant peripheral nerve sheath tumors (MPNSTs) are clinically aggressive high-grade sarcomas, arising in individuals with neurofibromatosis type 1 (NF1) at a significantly elevated estimated lifetime frequency of 8%-13%. In the setting of NF1, MPNSTs arise from malignant transformation of benign plexiform neurofibroma and borderline atypical neurofibromas. Composed of neoplastic cells from the Schwannian lineage, these cancers recur in approximately 50% of individuals, and most patients die within five years of diagnosis, despite surgical resection, radiation, and chemotherapy. Treatment for metastatic disease is limited to cytotoxic chemotherapy and investigational clinical trials. In this article, we review the pathophysiology of this aggressive cancer and current approaches to surveillance and treatment.

Low-grade malignant peripheral nerve sheath tumour presenting as retroperitoneal spindle cell neoplasm.

Retroperitoneal spindle cell neoplasms are diagnostically challenging. Malignant peripheral nerve sheath tumours (MPNSTs) can sometimes present as sporadic primary retroperitoneal tumours. MPNSTs are usually high-grade and highly aggressive tumours and are associated with a poor prognosis. Low-grade MPNSTs are very rarely described. This current case report describes a case of sporadic primary low-grade MPNST presenting as retroperitoneal spindle cell neoplasm. The diagnosis, imaging and immunohistopathological findings, as well as its successful surgical management, are presented.

[Malignant melanotic nerve sheath tumor of the posterior mediastinum]. / Tumor maligno melanocítico de la vaina neural en mediastino posterior.

Melanotic schwannoma (MS) is a rare and infrequent subtype of schwannoma characterized by cytoplasmic deposits of melanosomes (melanin). Unlike the other schwannomas, it could have malignant transformation. Due to distinctive characteristics and atypical behavior from classic schwannomas subtypes, MS were renamed and reclassified as "melanocytic malignant neural sheath tumor" in the 5th ed. of the World Health Organization's classification of central nervous system tumors in 2021. We present two cases of MS that underwent complete surgical resection.

El schwannoma melanótico (SM) es una variante rara e infrecuente caracterizada por el depósito citoplasmático de melanosomas (melanina). A diferencia de las otras variantes de schwannomas, tienen capacidad de malignización. Por poseer características y comportamiento distintos al resto de los schwannomas, fue reclasificado como "tumor maligno melanocítico de la vaina neural" en la 5ta edición de la clasificación de los tumores del sistema nervioso central de la Organización Mundial de la Salud en 2021. Presentamos dos casos de SM de ubicación mediastinal en los que se realizó una resección quirúrgica completa.

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.

A light in the darkness: sodium fluorescein-assisted peripheral nerve sheath tumors resection - a comprehensive systematic review and single-arm meta-analysis.

The treatment for peripheral nerve sheath tumors (PNSTs) is based on surgical excision and the primary goal is to improve symptoms whilst preserving neurological function. In order to improve this technique, surgeons may use sodium fluorescein (SF) to help visualize the neoplasm and, consequently, facilitate its removal. Aiming to assess the efficacy of this emerging surgical strategy, we conducted a systematic review and single-arm meta-analysis. We conducted a systematic search on the PubMed, Embase, and Web of Science databases, following the PRISMA guidelines. Studies without outcomes of interest, case series with less than four patients, letters, comments, technical notes, editorials, reviews, and basic research papers were excluded. The outcomes considered for this study were: the number of tumors that achieved total resection, subtotal resection, or near total resection, the approach/technique utilized by the surgeon, SF-related complications, and total complications. Five studies, with a total of 175 individuals, were included in our survey. Notably, 70% of the neoplasms presented by the patients were schwannomas. Considering extracranial lesions, we found a proportion of 96% (95% CI: 88 - 100%) in total resection, 0% (95% CI: 0-1%) in near total resection, and 4% (95% CI: 0-12%) in subtotal resection, all linked to an amount of 185 analyzed PNSTs. Furthermore, a proportion of 1% (95% CI: 0 - 2%) in SF-related complications was spotted among 183 patients. Finally, total complications analysis accounted for 11% (95% CI: 0 - 25%) among 183 individuals. We concluded that SF-assisted resection of PNSTs is a suitable and relatively safe technique, linked to minimum complications, of which the majority was not associated with the chemical compound itself. Future research is necessary to increase the number of patients available in the current literature and, therefore, enhance future analyses.

Bulky malignant peripheral nerve sheath tumour of the left thigh in a pregnant woman presenting with a pathological fracture of the proximal femur.

Malignant peripheral nerve sheath tumour (MPNST) is an aggressive soft tissue sarcoma with a poor prognosis, affecting most commonly the extremities. The lungs constitute the most frequent location for distant metastases. Half of all MPNSTs arise in patients with neurofibromatosis type 1, while approximately 10% are radiation induced and the rest are sporadic.The authors present a pregnant woman in her 40s with a sporadic MPNST of the lower limb and with lung metastases at diagnosis. Treatment consisted of interilioabdominal amputation, followed by adjuvant chemotherapy. Partial response and disease stabilisation were achieved with chemotherapy.Surgical resection with negative margins is the only potentially curative therapy, while radiation therapy and chemotherapy might be useful in the neoadjuvant or adjuvant setting, but their advantage in survival is not demonstrated. In the reported case, chemotherapy permitted the achievement of partial response and stabilisation of the disease.

STING activation reprograms the microenvironment to sensitize NF1-related malignant peripheral nerve sheath tumors for immunotherapy.

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene that encodes neurofibromin, a RAS GTPase-activating protein. Inactivating NF1 mutations cause hyperactivation of RAS-mediated signaling, resulting in the development of multiple neoplasms, including malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are an aggressive tumor and the main cause of mortality in patients with NF1. MPNSTs are difficult to resect and refractory to chemo- and radiotherapy, and no molecular therapies currently exist. Immune checkpoint blockade (ICB) is an approach to treat inoperable, undruggable cancers like MPNST, but successful outcomes require an immune cell-rich tumor microenvironment. While MPNSTs are noninflamed "cold" tumors, here, we converted MPNSTs into T cell-inflamed "hot" tumors by activating stimulator of IFN genes (STING) signaling. Mouse genetic and human xenograft MPNST models treated with a STING agonist plus ICB exhibited growth delay via increased apoptotic cell death. This strategy offers a potential treatment regimen for MPNSTs.

An algorithmic approach to the management of peripheral nerve tumours.

This article reviews the pathology and management of peripheral nerve tumours, including a framework for investigation and decision-making. Most tumours are benign, including schwannomas and neurofibromas, but malignant peripheral nerve sheath tumours can occur. The risk of malignant change is remote for schwannomas but higher for neurofibromas, particularly in neurofibromatosis type 1. Magnetic resonance imaging is useful for defining the relationship of a swelling with adjacent nerves but is not definitive for tissue diagnosis. Increasing size, pain and neurological deficit suggest malignant change and TruCut needle biopsy is indicated, although there is a risk of sampling error. Excision biopsy preserving nerve function may be carried out for benign tumours to relieve symptoms. Malignant tumours require a multidisciplinary approach. Complete surgical excision with clear margins is the only curative treatment and may be supplemented with radiotherapy and chemotherapy. However, prognosis remains poor, particularly for patients with neurofibromatosis.

PRRX1-TOP2A interaction is a malignancy-promoting factor in human malignant peripheral nerve sheath tumours.

BACKGROUND: Paired related-homeobox 1 (PRRX1) is a transcription factor in the regulation of developmental morphogenetic processes. There is growing evidence that PRRX1 is highly expressed in certain cancers and is critically involved in human survival prognosis. However, the molecular mechanism of PRRX1 in cancer malignancy remains to be elucidated. METHODS: PRRX1 expression in human Malignant peripheral nerve sheath tumours (MPNSTs) samples was detected immunohistochemically to evaluate survival prognosis. MPNST models with PRRX1 gene knockdown or overexpression were constructed in vitro and the phenotype of MPNST cells was evaluated. Bioinformatics analysis combined with co-immunoprecipitation, mass spectrometry, RNA-seq and structural prediction were used to identify proteins interacting with PRRX1. RESULTS: High expression of PRRX1 was associated with a poor prognosis for MPNST. PRRX1 knockdown suppressed the tumorigenic potential. PRRX1 overexpressed in MPNSTs directly interacts with topoisomerase 2 A (TOP2A) to cooperatively promote epithelial-mesenchymal transition and increase expression of tumour malignancy-related gene sets including mTORC1, KRAS and SRC signalling pathways. Etoposide, a TOP2A inhibitor used in the treatment of MPNST, may exhibit one of its anticancer effects by inhibiting the PRRX1-TOP2A interaction. CONCLUSION: Targeting the PRRX1-TOP2A interaction in malignant tumours with high PRRX1 expression might provide a novel tumour-selective therapeutic strategy.

p53 modulates kinase inhibitor resistance and lineage plasticity in NF1-related MPNSTs.

Malignant peripheral nerve sheath tumors (MPNSTs) are chemotherapy resistant sarcomas that are a leading cause of death in neurofibromatosis type 1 (NF1). Although NF1-related MPNSTs derive from neural crest cell origin, they also exhibit intratumoral heterogeneity. TP53 mutations are associated with significantly decreased survival in MPNSTs, however the mechanisms underlying TP53-mediated therapy responses are unclear in the context of NF1-deficiency. We evaluated the role of two commonly altered genes, MET and TP53, in kinome reprograming and cellular differentiation in preclinical MPNST mouse models. We previously showed that MET amplification occurs early in human MPNST progression and that Trp53 loss abrogated MET-addiction resulting in MET inhibitor resistance. Here we demonstrate a novel mechanism of therapy resistance whereby p53 alters MET stability, localization, and downstream signaling leading to kinome reprogramming and lineage plasticity. Trp53 loss also resulted in a shift from RAS/ERK to AKT signaling and enhanced sensitivity to MEK and mTOR inhibition. In response to MET, MEK and mTOR inhibition, we observed broad and heterogeneous activation of key differentiation genes in Trp53-deficient lines suggesting Trp53 loss also impacts lineage plasticity in MPNSTs. These results demonstrate the mechanisms by which p53 loss alters MET dependency and therapy resistance in MPNSTS through kinome reprogramming and phenotypic flexibility.