Rare primary intrapulmonary malignant peripheral nerve sheath tumor showing significant response to sintilimab: A case report and literature review.

Primary pulmonary malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with a low incidence, poor prognosis and limited treatment options. The present study reported a case of lung MPNST in a 63-year-old male patient without any pulmonary symptoms. Immunohistochemical analysis of the tumor indicated a programmed death-ligand 1 (PD-L1) expression tumor proportion score of 60%. A total of six courses of sintilimab were used in this patient and a remarkable response was achieved. In summary, sintilimab single-agent immunotherapy may be a novel treatment for pulmonary MPNST. When encountering analogous cases in the future, oncologists can test for the expression of PD-L1 in patients to guide the therapy's design.

TRPS1 expression in MPNST is correlated with PRC2 inactivation and loss of H2K27me3.

Initially described as a highly specific immunohistochemical marker for carcinomas of mammary origin, trichorhinophalangeal syndrome type 1 (TRPS1) has subsequently been detected in a variety of other non-mammary tumors. In this study, we examined the immunohistochemical expression of TRPS1 in 116 peripheral nerve sheath tumors, including 43 malignant peripheral nerve sheath tumors (MPNSTs), 58 schwannomas, including 9 cellular neurofibromas, and 13 neurofibromas, including 1 atypical neurofibroma. Notably, TRPS1 was expressed in 49% of MPNSTs and was absent in all schwannomas and neurofibromas. All MPNSTs showed TRPS1 labeling in >50% of nuclei, with 95% of cases demonstrating diffuse labeling. Most cases (67%) showed weak TRPS1 immunoreactivity, while a smaller subset showed moderate (24%) or strong (9%) intensity staining. Analysis of publicly available gene expression datasets revealed higher levels of TRPS1 mRNA in MPNSTs with PRC2 inactivation. In keeping with this finding, TRPS1 expression was more commonly observed in MPNSTs with loss of H3K27me3, suggesting a potential relationship between TRPS1 and the PRC2 complex. This study further broadens the spectrum of TRPS1-expressing tumors to include MPNST.

High-Grade Malignant Peripheral Nerve Sheath Tumor Arising From Common Peroneal Nerve Neurofibroma.

This article presents a case report of a 45-year-old male with neurofibromatosis type I (NF1) who developed a high-grade malignant peripheral nerve sheath tumor (MPNST) originating from a neurofibroma within the common peroneal nerve over popliteal fossa. MPNSTs are aggressive tumors associated with NF1, causing significant mortality. The patient underwent tumor resection surgery and received postoperative radiation therapy. Follow-up examinations showed no impairment of motor function and no tumor recurrence after regular MRI evaluation for four years. This article explores the challenges of distinguishing benign neurofibromas from malignant MPNST via MRI image and biopsy, and achieving a balance between tumor excision and preserving nerve functionality during surgical treatment. However, caution is warranted due to the risk of recurrence.

Enhanced IL-12 transgene expression improves oncolytic viroimmunotherapy.

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

Outcomes of Head and Neck Neurogenic Tumors.

BACKGROUND: Lateral neck mass management frequently challenges surgeons. Nerve tissue neoplasms are an uncommon cause of such nodules. Neurogenic tumors form a tiny percentage of the head and neck neoplastic lesions. Considering the number of nerves in this area, it is surprising that such neoplasms are not more frequently seen. METHODS: A retrospective study was conducted on all patients who presented to the National Cancer Institute of Cairo, Egypt, with head and neck neurogenic neoplasms. RESULTS: During the last 10 years at the National Cancer Institute of Egypt (2006-2015), 40 cases of neurogenic tumors of the head and neck were treated at the head and neck unit. Patients' ages ranged from two to 78 years with a mean age of 34.7 years. Childhood neurogenic tumors accounted for nine cases (22.5%) only in this study. Male patients diagnosed with these tumors comprised 16 cases, while female patients comprised 24 cases, with a female-to-male ratio of 1.5:1. Patient presentation depends on the biological behavior of the tumor; for instance, some of them present by slowly growing painless well-circumscribed mobile swelling, and others present by rapidly growing swelling with neurological deficit. Clinical picture and imaging studies such as CT and MRI raise suspicion and may help delineate such tumors, but a definitive diagnosis is obtained by tissue biopsy. Surgery is the mainstay of treatment in most head and neck neurogenic tumors, whereas adjuvant therapy is of limited benefit in some types of neurogenic tumors. The five-year survival rate was 60% for the malignant group, while death was reported in six out of 15 cases (40%).  Conclusion: Most neurogenic head and neck tumors are benign. Accurate preoperative assessment and a high degree of suspicion are the initial steps in the management. Proper treatment involves complete surgical excision; however, debulking procedures have an important role. Malignant neurogenic tumors are aggressive and are treated with combined radical surgical resection and radiation. Chemotherapy is tried for locally advanced unresectable or metastatic disease.

Forelimb lameness caused by Malignant peripheral nerve sheath tumors of the median nerve in a dog: a case report.

An 8-year-old Portuguese Water Dog presented with a 5-month history of left forelimb lameness. There was palmar pain. Ultrasonography revealed enlargement of the left median nerve. Subsequent MRI also showed enlargement of the median nerve in the distal palmar to the mid-forearm region. Rapid intraoperative diagnosis suggested Malignant peripheral nerve sheath tumors (MPNST) and a neurotomy was performed. The lameness had almost disappeared in 1 month after surgery. Recurrence occurred 26 months postoperatively and the forelimb was amputated. At 950 days after the neurotomy, radiography revealed lung metastasis, and the dog died 988 days after the neurotomy. Neurotomy for MPNST should be performed with caution until more information is available regarding methods for early detection, margin determination, and indication determination for neurotomy.

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).

Images in Immunotherapy and Precision Oncology: A Case Report of Neurofibromatosis-1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that primarily causes the growth of tumors along nerves. Additionally, the germline mutations involved in NF1 predispose patients to develop further malignancies. The mainstay initial treatment for these malignancies is surgical removal at diagnosis, although targeted therapies are under evaluation in the relapsed setting. We report a case of malignant peripheral nerve sheath tumor (MPNST), gastrointestinal stromal tumor (GIST), and pheochromocytoma in a patient with NF1 who presented with an infected right shoulder lesion that was confirmed to be spindle cell sarcoma via biopsy. She was treated with antibiotics; however, she rapidly deteriorated and opted for hospice care. NF1 germline mutations increase the risk of patients developing various types of cancer. Recent studies have shown that there is a role for using MEK inhibitors such as selumetinib for treating patients with NF1.

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

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

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

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

A Cerebral Embolism Caused by a Malignant Peripheral Nerve Sheath Tumor in a Patient with Neurofibromatosis Type 1.

A 31-year-old man with neurofibromatosis type 1 (NF-1) had undergone resection of a malignant peripheral nerve sheath tumor (MPNST) on the buttock 3 months previously. He subsequently underwent mechanical thrombectomy for a hyperacute left middle cerebral artery embolism. Histopathologically, the emboli comprised neurofilament-positive pleomorphic tumor cells with geographic necrosis and conspicuous mitosis and were identified as MPNST. The patient died of respiratory failure due to lung MPNST metastasis on day 15 of hospitalization. To our knowledge, this is the first report of a spontaneous cerebral embolism due to MPNST in a NF-1 patient.

Malignant peripheral nerve sheath tumor of the femoral nerve: imaging findings and correlation with histopathology.

Malignant peripheral nerve sheath tumors (MPNST) are rare and aggressive soft tissue sarcomas. MPNST diagnosis is made based on biopsy, but distinct features are present on ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI). We present a case of a 24-year-old man presenting with abdominal pain and lower-extremity weakness found to have a large MPNST originating from the left femoral nerve and describe findings on imaging and their histopathologic correlation.

Intracranial malignant peripheral nerve sheath tumor: A case report and comprehensive literature review.

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are rare malignant soft-tissue sarcomas arising from peripheral nerves. Little data exist regarding MPNST originating intracranially. Here, we present a 7th/8th nerve complex MPNST, discuss the treatment strategy and patient outcome, and provide a comprehensive review of existing literature. Methods: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, PubMed and crossed references were queried, yielding 37 publications from 1952 to the present. Fifty-three cases of primary intracranial and extra-axial MPNST were identified. Results: We additionally report a 40-year-old female presented with acute onset dizziness and subsequent hearing loss with associated right-sided facial numbness. Magnetic resonance imaging revealed a 0.5 cm × 1.7 cm enhancing lesion within the right internal auditory canal extending into the cerebellopontine angle. The patient was initially treated with retro sigmoid craniotomy for tumor resection followed by a trans labyrinth approach for residual tumor resection. She completed adjuvant fractionated radiation therapy and underwent facial nerve transfer to restore complete hemifacial paralysis. The most common cranial nerves involved were V and VIII (43.4% each), with 66% of patients male and 34% female. The average age was 43.4 ± 17.4 years. The mean survival time for reported non-survivors after tissue diagnosis was 15 ± 4 months. Two-year survival for patients receiving gross total resection was 33.3% versus 22.8% with subtotal resection. Conclusion: MPNSTs comprise a group of highly aggressive neoplasms that rarely arise intracranially. Gross total surgical resection should be pursued when feasible.

Malignant transformation of vestibular schwannoma after radiation therapy.

Stereotactic radiosurgery (SRS) is an effective treatment for vestibular schwannomas, offering high rates of tumor control and low neurological risks. Long-term complications of SRS are not fully understood, with several cases of malignant transformation reported in the literature. We report the case of a 50-year-old female with no prior history of neurofibromatosis who presented in 2013 with MRI evidence of a benign vestibular schwannoma. Despite treatment with CyberKnife SRS, she presented 6 years later with new onset neurologic symptoms. Further investigation showed stable lesion size with increasing vasogenic edema and a new area of enhancement in the brainstem, suspicious for malignant transformation. Subsequent treatment with partial craniectomy and histopathologic analysis was consistent with a malignant peripheral nerve sheath tumor diagnosis. Our case adds to a series of 24 similar cases in the literature, details of which have been summarized in our study. Overall, findings support the need for lifelong surveillance following SRS treatment of benign vestibular schwannomas. Patients should be educated on the potential risk of this complication, and clinicians must maintain a high level of suspicion for potential radiation-induced malignancy during the patient's clinical course.

Laser Interstitial Thermal Therapy as a Treatment Option for Malignant Peripheral Nerve Sheath Tumor Metastases to the Brain: A Case Report.

We present the unique case of a 60-year-old female with neurofibromatosis type 1 (NF1) who underwent laser interstitial thermal therapy (LITT) for metastatic malignant peripheral nerve sheath tumor (MPNST) of the brain. She presented to the emergency room complaining of one week of dysarthria and facial droop. An MRI of the brain demonstrated a homogeneously enhancing left frontal mass; although rare, given her history of pulmonary MPNST, brain invasion was considered likely. No generally accepted guidelines for the treatment of MPNST with cerebral metastases exist; however, LITT was chosen due to tumor morphology and proximity to eloquent brain structures. She did not experience any new or worsening neurological deficits post-operatively. Post-ablation MRI showed white matter edema surrounding the lesion, which is consistent with previously reported cases. This case illustrates the use of LITT for cytoreduction for rare brain metastases located near eloquent brain structures.

Discrimination of benign, atypical, and malignant peripheral nerve sheath tumors in neurofibromatosis type 1 using diffusion-weighted MRI.

Background: Neurofibromatosis type 1 (NF1) is associated with the development of benign (BPNST) and malignant (MPNST) peripheral nerve sheath tumors. Recently described atypical neurofibromas (ANF) are considered pre-malignant precursor lesions to MPNSTs. Previous studies indicate that diffusion-weighted magnetic resonance imaging (DW-MRI) can reliably discriminate MPNSTs from BPNSTs. We therefore investigated the diagnostic accuracy of DW-MRI for the discrimination of benign, atypical, and malignant peripheral nerve sheath tumors. Methods: In this prospective explorative single-center phase II diagnostic study, 44 NF1 patients (23 male; 30.1 ±â€…11.8 years) underwent DW-MRI (b-values 0-800 s/mm²) at 3T. Two radiologists independently assessed mean and minimum apparent diffusion coefficients (ADCmean/min) in areas of largest tumor diameters and ADCdark in areas of lowest signal intensity by manual contouring of the tumor margins of 60 BPNSTs, 13 ANFs, and 21 MPNSTs. Follow-up of ≥ 24 months (BPNSTs) or histopathological evaluation (ANFs + MPNSTs) served as diagnostic reference standard. Diagnostic ADC-based cut-off values for discrimination of the three tumor groups were chosen to yield the highest possible specificity while maintaining a clinically acceptable sensitivity. Results: ADC values of pre-malignant ANFs clustered between BPNSTs and MPNSTs. Best BPNST vs. ANF + MPNST discrimination was obtained using ADCdark at a cut-off value of 1.6 × 10-3 mm2/s (85.3% sensitivity, 93.3% specificity), corresponding to an AUC of 94.3% (95% confidence interval: 85.2-98.0). Regarding BPNST + ANF vs. MPNST, best discrimination was obtained using an ADCdark cut-off value of 1.4 × 10-3 mm2/s (83.3% sensitivity, 94.5% specificity). Conclusions: DW-MRI using ADCdark allows specific and noninvasive discrimination of benign, atypical, and malignant nerve sheath tumors in NF1.

The NF1+/- Immune Microenvironment: Dueling Roles in Neurofibroma Development and Malignant Transformation.

Neurofibromatosis type 1 (NF1) is a common genetic disorder resulting in the development of both benign and malignant tumors of the peripheral nervous system. NF1 is caused by germline pathogenic variants or deletions of the NF1 tumor suppressor gene, which encodes the protein neurofibromin that functions as negative regulator of p21 RAS. Loss of NF1 heterozygosity in Schwann cells (SCs), the cells of origin for these nerve sheath-derived tumors, leads to the formation of plexiform neurofibromas (PNF)-benign yet complex neoplasms involving multiple nerve fascicles and comprised of a myriad of infiltrating stromal and immune cells. PNF development and progression are shaped by dynamic interactions between SCs and immune cells, including mast cells, macrophages, and T cells. In this review, we explore the current state of the field and critical knowledge gaps regarding the role of NF1(Nf1) haploinsufficiency on immune cell function, as well as the putative impact of Schwann cell lineage states on immune cell recruitment and function within the tumor field. Furthermore, we review emerging evidence suggesting a dueling role of Nf1+/- immune cells along the neurofibroma to MPNST continuum, on one hand propitiating PNF initiation, while on the other, potentially impeding the malignant transformation of plexiform and atypical neurofibroma precursor lesions. Finally, we underscore the potential implications of these discoveries and advocate for further research directed at illuminating the contributions of various immune cells subsets in discrete stages of tumor initiation, progression, and malignant transformation to facilitate the discovery and translation of innovative diagnostic and therapeutic approaches to transform risk-adapted care.

Multiple Gastrointestinal Stromal Tumors, Malignant Peripheral Nerve Sheath Tumor and Atypical Neurofibromatous Neoplasm With Uncertain Biologic Potential Developing in A Single Patient With Neurofibromatosis Type 1 Syndrome.

Neurofibromatosis type 1 (NF1) is the most common human genetic disease. In these patients, the incidence of malignant peripheral nerve sheath tumors (MPNST) and gastrointestinal stromal tumors (GIST) is increased. A male patient in his forties with neurofibromatosis 1, presented with the coexistence of multiple GISTs located at intestinal and colonic mesentery, MPNST located at his leg and atypical neurofibromatous neoplasm with uncertain biologic potential located at colonic mesentery. By FISH, the MPNST harbored CDKN2A loss and recurred 1 year later. After reresection and radiotherapy, the patient is now disease-free without evidence of disease. Atypical neurofibromatous neoplasm with uncertain biologic potential is a newly defined entity, and it is important to discriminate it from low-grade MPNST, which requires more aggressive treatment methods. To the best of our knowledge, this is the first report describing synchronous GISTs, MPNST, and atypical neurofibromatous neoplasm with uncertain biologic potential developing in a single NF1 patient.

Shaping Our Understanding of Malignant Peripheral Nerve Sheath Tumor: A Bibliometric Analysis of the 100 Most-Cited Articles.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are rare yet highly aggressive soft tissue sarcomas of mesenchymal origin, characterized by a heterogeneous pathological spectrum, limited therapeutic options, and high metastatic potential. METHODS: Here, the authors conducted a comprehensive bibliometric analysis of the 100 most-cited MPNST articles by utilizing Elsevier's Scopus to identify all relevant published and indexed articles referring to MPNST, thereby aiming to elucidate the pertinent research findings regarding the disease's pathophysiology and therapeutic advancements. Articles were classified as basic science or clinical and analyzed for various bibliometric parameters. RESULTS: The majority of articles (75%) focused on clinical aspects, reflecting the extensive clinicopathological characterization of MPNSTs. Notable studies investigated prognostic factors, histological and immunohistochemical features, and diagnostic modalities. The identification of loss of function mutations in the polycomb repressive complex 2 emerged as a pivotal role, as it opened avenues for potential targets for novel therapeutic interventions. Newer articles (published in or after 2006) demonstrated higher citation rates, suggesting evolving impact and collaboration. CONCLUSIONS: This bibliometric analysis showed how developments in the understanding of MPNST pathophysiology and the creation of novel therapeutic strategies occurred throughout time. Changes that have been noticed recently could portend future innovative therapeutic approaches.