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.

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).

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.

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.

[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.

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.

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.

[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.

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.

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.

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.

[Interdisciplinary Treatment Of Tumorous And Tumour-Like Lesions Of Peripheral Nerves]. / Interdisziplinäre Behandlung von Raumforderungen in Assoziation zu peripheren Nerven: Tumore und tumorähnliche Läsionen.

Tumorous or tumour-like lesions of peripheral nerves are generally rare, heterogeneous and challenging to diagnose and treat. They may become apparent by a palpable swelling (lump) near nerves, sensory and/or motor deficits, pain to touch or neuropathic pain. In 91% of cases, tumours are benign. The differentiation of entities and their characteristics as well as a function-preserving resection strategy are highly relevant. Misdiagnosis and inadequate treatment can lead to severe deficits and pain syndromes. Benign tumours include schwannomas and neurofibromas, which can occur sporadically but can also be associated with neurogenetic tumour disposition syndromes if they occur more frequently. Rarer benign nerve tumours include perineuriomas, lipomas, aggressive fibrosis (desmoid tumours), paragangliomas and haemangiomas. Ganglion cysts are described as tumour-like lesions. The association of nerve tumours with neurogenetic syndromes and the correct classification of potentially malignant lesions such as MPNST (malignant peripheral nerve sheath tumour) or intermediate stages such as ANNUBPs (atypical neurofibromatous neoplasms with unknown biological potential) pose particular challenges. Interdisciplinarity is highly relevant for clinical treatment and a correct diagnosis. The aim of our work is to provide an overview of the relevant entities, diagnostic evaluation and contemporary treatment strategies based on the current data situation and taking into account the recently published interdisciplinary AWMF S2k guideline "Diagnosis and Treatment of Peripheral Nerve Tumours".

Malignant peripheral nerve sheath tumour with divergent epithelioid differentiation in a cat.

Divergent differentiation, mainly towards various subsets of mesenchymal cells, is encountered sporadically in human malignant peripheral nerve sheath tumours (MPNSTs) but this is the first report of epithelioid components within this neoplasm in a cat. An 8-year-old, spayed female Domestic Shorthaired cat was presented for surgical removal of a subcutaneous mass on the right flank. Morphological and immunohistochemical analysis revealed a malignant neoplasm with spindloid cells intermixed with an epithelioid component that had squamous differentiation. There was intense immunolabelling of vimentin, S100 protein, neuron-specific enolase, laminin and glial fibrillary acidic protein in the spindloid cell component and for cytokeratin (CK) AE1/AE3 and CK5/6 in the epithelial elements. Melanoma-associated antigen, desmin, α-smooth muscle actin, CD18, CD31, ionized calcium binding adapter molecule-1 and CK8/18 were not expressed, which helped differentiate the tumour from other feline spindloid cell neoplasms. These features are characteristic of divergent epithelioid differentiation of MPNST.

Intramuscular Hybrid Nerve Sheath Tumor of the Thigh: Case Report and Literature Review.

BACKGROUND/AIM: Hybrid nerve sheath tumor (HNST) is a benign peripheral nerve sheath tumor with combined features of more than one histological type, such as schwannoma, neurofibroma, and perineurioma. It remains under-recognized in routine clinical practice. Herein, we describe an unusual case of intramuscular HNST of the thigh. CASE REPORT: The patient was a 41-year-old man with no history of trauma who presented with a 3-month history of a palpable mass in the right thigh. Physical examination revealed a 4-cm, elastic hard, mobile, nontender mass. Magnetic resonance imaging exhibited a well-circumscribed intramuscular mass with low-to-intermediate signal intensity on T1-weighted sequences and higher signal intensity peripherally and lower signal intensity centrally, representing a target sign, on T2-weighted sequences. Complete surgical excision of the tumor was carried out. Microscopically, the tumor showed dual histological components of both schwannoma and neurofibroma. Immunohistochemically, the schwannomatous component was strongly and diffusely positive for S-100 protein and negative for CD34, while the neurofibromatous component contained CD34-positive fibroblasts and S-100 protein-positive Schwann cells. Epithelial membrane antigen was negative for both components. These findings were consistent with a diagnosis of HNST (hybrid schwannoma/neurofibroma). The patient had no evidence of local recurrence and no neurological deficit at the final follow-up. CONCLUSION: Although extremely rare, HNST should be included in the extended differential diagnosis of a well-circumscribed, intramuscular soft-tissue mass in the extremities, particularly in young and early middle-aged adults.

Diagnostic potential of NRG1 in benign nerve sheath tumors and its influence on the PI3K-Akt signaling and tumor immunity.

OBJECTIVE: Benign nerve sheath tumors (BNSTs) present diagnostic challenges due to their heterogeneous nature. This study aimed to determine the significance of NRG1 as a novel diagnostic biomarker in BNST, emphasizing its involvement in the PI3K-Akt pathway and tumor immune regulation. METHODS: Differential genes related to BNST were identified from the GEO database. Gene co-expression networks, protein-protein interaction networks, and LASSO regression were utilized to pinpoint key genes. The CIBERSORT algorithm assessed immune cell infiltration differences, and functional enrichment analyses explored BNST signaling pathways. Clinical samples helped establish PDX models, and in vitro cell lines to validate NRG1's role via the PI3K-Akt pathway. RESULTS: Nine hundred eighty-two genes were upregulated, and 375 downregulated in BNST samples. WGCNA revealed the brown module with the most significant difference. Top hub genes included NRG1, which was also determined as a pivotal gene in disease characterization. Immune infiltration showed significant variances in neutrophils and M2 macrophages, with NRG1 playing a central role. Functional analyses confirmed NRG1's involvement in key pathways. Validation experiments using PDX models and cell lines further solidified NRG1's role in BNST. CONCLUSION: NRG1 emerges as a potential diagnostic biomarker for BNST, influencing the PI3K-Akt pathway, and shaping the tumor immune microenvironment.

Impact of CT and MRI in the diagnostic workup of malignant triton tumour-a monocentric analysis and review of the literature.

OBJECTIVES: Malignant triton tumours (MTTs) are rare but aggressive subtypes of malignant peripheral nerve sheath tumours (MPNSTs) with a high recurrence rate and 5-year survival of 14%. Systematic imaging data on MTTs are scarce and mainly based on single case reports. Therefore, we aimed to identify typical CT and MRI features to improve early diagnosis rates of this uncommon entity. METHODS: A systematic review on literature published until December 2022 on imaging characteristics of MTTs was performed. Based on that, we conducted a retrospective, monocentric analysis of patients with histopathologically proven MTTs from our department. Explorative data analysis was performed. RESULTS: Initially, 29 studies on 34 patients (31.42 ± 22.6 years, 12 female) were evaluated: Literature described primary MTTs as huge, lobulated tumours (108 ± 99.3 mm) with central necrosis (56% [19/34]), low T1w (81% [17/21]), high T2w signal (90% [19/21]) and inhomogeneous enhancement on MRI (54% [7/13]). Analysis of 16 patients (48.9 ± 13.8 years; 9 female) from our institution revealed comparable results: primary MTTs showed large, lobulated masses (118 mm ± 64.9) with necrotic areas (92% [11/12]). MRI revealed low T1w (100% [7/7]), high T2w signal (100% [7/7]) and inhomogeneous enhancement (86% [6/7]). Local recurrences and soft-tissue metastases mimicked these features, while nonsoft-tissue metastases appeared unspecific. CONCLUSIONS: MTTs show characteristic features on CT and MRI. However, these do not allow a reliable differentiation between MTTs and other MPNSTs based on imaging alone. Therefore, additional histopathological analysis is required. ADVANCES IN KNOWLEDGE: This largest published systematic analysis on MTT imaging revealed typical but unspecific imaging features that do not allow a reliable, imaging-based differentiation between MTTs and other MPNSTs. Hence, additional histopathological analysis remains essential.

Malignant peripheral nerve sheath tumor in the kidney of a dog.

A 12-year-old castrated male poodle presented with vomiting and diarrhea. Ultrasonography and computed tomography revealed a protruding mass at the caudal pole of the left kidney. Grossly, the poorly circumscribed abnormal mass was 1.6 × 1.8 × 1.9 cm in size and had multifocal dark-red foci. Microscopically, it was composed of densely or loosely packed variable-sized short spindle or ovoid cells. These neoplastic cells showed high pleomorphism, mitotic figures, and invasive tendency to the adjacent tissue. Immunohistochemically, the neoplastic spindle cells expressed vimentin, S100, neuron-specific enolase, nerve growth factor receptor, and laminin. Therefore, the mass was diagnosed as a malignant peripheral nerve sheath tumor (MPNST). To our knowledge, this is the first report of primary renal MPNST in a dog.