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).

Effect of NFX-179 MEK inhibitor on cutaneous neurofibromas in persons with neurofibromatosis type 1.

This phase 2a trial investigated the efficacy of NFX-179 Topical Gel, a metabolically labile MEK inhibitor, in the treatment of cutaneous neurofibromas (cNFs) in neurofibromatosis type 1. Forty-eight participants were randomized to four treatment arms: NFX-179 Topical Gel 0.05%, 0.15%, and 0.5% or vehicle applied once daily to five target cNFs for 28 days. Treatment with NFX-179 Topical Gel resulted in a dose-dependent reduction in p-ERK levels in cNFs at day 28, with a 47% decrease in the 0.5% NFX-179 group compared to the vehicle (P = 0.0001). No local or systemic toxicities were observed during the treatment period, and systemic concentrations of NFX-179 remained below 1 ng/ml. In addition, 20% of cNFs treated with 0.5% NFX-179 Topical Gel showed a ≥50% reduction in volume compared to 6% in the vehicle group by ruler measurement with calculated volume (P = 0.021). Thus, NFX-179 Topical Gel demonstrated significant inhibition of MEK in cNF with excellent safety and potential therapeutic benefit.

Raman difference spectroscopy and U-Net convolutional neural network for molecular analysis of cutaneous neurofibroma.

In Neurofibromatosis type 1 (NF1), peripheral nerve sheaths tumors are common, with cutaneous neurofibromas resulting in significant aesthetic, painful and functional problems requiring surgical removal. To date, determination of adequate surgical resection margins-complete tumor removal while attempting to preserve viable tissue-remains largely subjective. Thus, residual tumor extension beyond surgical margins or recurrence of the disease may frequently be observed. Here, we introduce Shifted-Excitation Raman Spectroscopy in combination with deep neural networks for the future perspective of objective, real-time diagnosis, and guided surgical ablation. The obtained results are validated through established histological methods. In this study, we evaluated the discrimination between cutaneous neurofibroma (n = 9) and adjacent physiological tissues (n = 25) in 34 surgical pathological specimens ex vivo at a total of 82 distinct measurement loci. Based on a convolutional neural network (U-Net), the mean raw Raman spectra (n = 8,200) were processed and refined, and afterwards the spectral peaks were assigned to their respective molecular origin. Principal component and linear discriminant analysis was used to discriminate cutaneous neurofibromas from physiological tissues with a sensitivity of 100%, specificity of 97.3%, and overall classification accuracy of 97.6%. The results enable the presented optical, non-invasive technique in combination with artificial intelligence as a promising candidate to ameliorate both, diagnosis and treatment of patients affected by cutaneous neurofibroma and NF1.

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.

Surgical Management of Intraosseous Neurofibroma in Cervical Spine: A Case Report.

CASE: A 30-year-old man had cervical radiculomyelopathy and neck pain caused by a massive intraosseous neurofibroma (IONF) originating from the C6 vertebrae. We performed posterior tumor resection with spinal instrumentation and fusion from C3 to T2 and a follow-up resection procedure of the remaining C6 anterior tumor, sacrificing the affected vertebral artery (VA), which accordingly required bypass surgery at 2 months recovery. Reconstruction using a titanium mesh cage was successfully performed. There were no local recurrences at 2 years postoperatively. CONCLUSIONS: Total tumor resection split into 2 stages with sacrifice of the affected VA is a feasible option for treatment of IONF.

A Giant Scrotal Neurofibroma in a Child Masquerading as Filariasis: Uncommon Presentation of a Common Disease.

Neurofibroma of the scrotum is a very uncommon benign neoplasm, specifically when it affects teenagers and is not associated with neurofibromatosis type I. To the best of our knowledge, only a couple of cases of neurofibroma in children have been documented. Here, we report a case study of a 17-year-old boy who had a giant scrotal lump for ten years masquerading clinically as filariasis. A provisional diagnosis of benign nerve sheath neoplasm was made based on cytology findings. The lump was surgically removed from the patient, and a histopathological and immunohistochemistry examination established the diagnosis of neurofibroma. The combined clinical, preoperative cytological, histological, and immunohistochemistry findings were not presented in the literature in any of the formerly documented cases of scrotal neurofibroma. The current case expands the spectrum of differential diagnoses for scrotal tumours that clinicians have previously observed.

Giant gluteal and vesical plexiform neurofibromas in a patient with neurofibromatosis type 1: a case report.

BACKGROUND: Neurofibromatosis type 1 is a neurocutaneous genetic disorder caused by mutations in the NF1 gene, resulting in the formation of benign tumors called neurofibromas. The most common type of tumor seen in patients with neurofibromatosis type 1 is the slow-growing and benign neurofibroma, with a subtype called plexiform neurofibroma being particularly common and causing pain, functional impairment, and cosmetic disfigurement. CASE PRESENTATION: We report the case of a 20-year-old North African female patient with a history of neurofibromatosis type 1 who presented with a growing mass in her right gluteal region, which was later diagnosed as a giant cutaneous neurofibroma. Imaging studies revealed infiltration in several regions, including the urinary bladder wall, resulting in significant bilateral hydronephrosis. The patient is currently being monitored, and no excisional procedures are planned. CONCLUSIONS: Neurofibromatosis type 1 can cause a variety of clinical symptoms, including the development of large plexiform neurofibromas. It is important to closely monitor patients with neurofibromatosis type 1 for the early detection of neurofibromas. Early detection and prompt surgical intervention are essential for preventing complications.

Characterization of Immune Cell Populations of Cutaneous Neurofibromas in Neurofibromatosis 1.

Cutaneous neurofibromas (cNFs) are characteristic of neurofibromatosis 1 (NF1), yet their immune microenvironment is incompletely known. A total of 61 cNFs from 10 patients with NF1 were immunolabeled for different types of T cells and macrophages, and the cell densities were correlated with clinical characteristics. Eight cNFs and their overlying skin were analyzed for T cell receptor CDR domain sequences, and mass spectrometry of 15 cNFs and the overlying skin was performed to study immune-related processes. Intratumoral T cells were detected in all cNFs. Tumors from individuals younger than the median age of the study participants (33 years), growing tumors, and tumors smaller than the data set median showed increased T cell density. Most samples displayed intratumoral or peritumoral aggregations of CD3-positive cells. T cell receptor sequencing demonstrated that the skin and cNFs host distinct T cell populations, whereas no dominant cNF-specific T cell clones were detected. Unique T cell clones were fewer in cNFs than in skin, and mass spectrometry suggested lower expression of proteins related to T cell-mediated immunity in cNFs than in skin. CD163-positive cells, suggestive of M2 macrophages, were abundant in cNFs. Human cNFs have substantial T cell and macrophage populations that may be tumor-specific.

Perspectives of adolescents with neurofibromatosis 1 and cutaneous neurofibromas: Implications for clinical trials.

BACKGROUND/AIMS: More than 99% of individuals with neurofibromatosis 1 develop cutaneous neurofibromas, benign nerve sheath tumors that manifest as nodules on the skin. These cutaneous neurofibromas emerge with age, appearing most commonly in adolescence. Nevertheless, few data have been published on how adolescents with neurofibromatosis 1 feel about cutaneous neurofibromas. The purpose of this study was to assess the perspectives of adolescents with neurofibromatosis 1 and their caregivers regarding cutaneous neurofibroma morbidity, treatment options, and acceptable risks-benefits of treatment. METHODS: An online survey was distributed through the world's largest NF registry. Eligibility criteria included self-reported neurofibromatosis 1 diagnosis, adolescent child ages 12-17 years, ≥1 cutaneous neurofibroma, and ability to read English. The survey was designed to collect details about the adolescent's cutaneous neurofibromas, views on morbidity related to cutaneous neurofibromas, social and emotional impact of cutaneous neurofibromas, communication regarding cutaneous neurofibromas, and views regarding current and potential future cutaneous neurofibroma treatment. RESULTS: Survey respondents included 28 adolescents and 32 caregivers. Adolescents reported having several negative feelings about cutaneous neurofibromas, particularly feeling worried about the potential progression of their cutaneous neurofibromas (50%). Pruritus (34%), location (34%), appearance (31%), and number (31%) were the most bothersome cutaneous neurofibroma features. Topical medication (77%-96%), followed by oral medication (54%-93%), was the most preferred treatment modality. Adolescents and caregivers most often replied that cutaneous neurofibroma treatment should be initiated when cutaneous neurofibromas become bothersome. The majority of respondents were willing to treat cutaneous neurofibromas for at least 1 year (64%-75%). Adolescent and caregivers were least willing to risk pain (72%-78%) and nausea/vomiting (59%-81%) as a cutaneous neurofibroma treatment side effect. CONCLUSIONS: These data indicate that adolescents with neurofibromatosis 1 are negatively impacted by their cutaneous neurofibromas, and that both adolescents and their caregivers would be willing to try longer-term experimental treatments.

Neurofibroma: Case Series with Clinical Features and Recommendations.

Neurofibroma is an autosomal benign disorder. It can be localized, diffuse or invasive like plexiform neurofibroma that involves the nerves, muscle, tissues, skeleton. It represents itself as a destructive variant of neurofibroma, mostly present as orbital or periorbital neurofibroma or may be associated with autosomal dominant disease. Clinical diagnosis of neurofibromatosis (NF) according to National Institutes of Health (NIH) criteria should have more than two of the seven features including lisch nodules, cafe'- au-lait spots, plexiform neurofibroma, optic glioma, freckling, first degree relative with NF or dysplasia of cortical bones. However, proper early diagnosis is still crucial due to its various presentation such as cheek mass, painless swelling on skin, chalazion, intratracheal tumor, genital swelling or ptosis. It is reported that neurofibroma often represents as ocular or facial swelling. Here we are presenting features of neurofibroma of eight cases of patients from Civil Hospital, Karachi. These cases had main complain of overhanging skin mass mainly on orbital or periorbital region that damage the area and with poor daily activities. Multiple nodules on face and body along with them Cafe'-au-lait spots and lisch nodules were main signs. While, other signs i.e. ptosis, pterygium, telecanthus and muddy discoloration of conjunctiva need further evaluation for correlation with neurofibromatosis. Debulking surgery was planned for most of the cases but the huge disfigurement caused by overhanging skin mass and nodules made it a challenge for plastic surgeons to provide good outcomes with minimum damage. Keywords: neurofibroma; lisch nodules; ptosis; Cafe'-au-lait spot; periorbital; overhanging skin.

A Case of Superficial Papular Neuroma: A Rare Neural Neoplasm.

ABSTRACT: A case of 67-year-old male patient with superficial papular neuroma (SPN) on the occiput is reported. This is the second report of SPN and the first with clinical images. Histologically, in the superficial dermis and periadnexa, the specimen exhibits a nodule of bland spindle cells with an S-shaped and spindle nucleus, surrounded by eosinophilic collagen fibers and scattered mast cells, which forms focally peripheral nerve-like structures. Lichen simplex chronicus-like changes are observed. Immunostaining result revealed that the tumor cells are positive for S-100, neurofilament, collagen IV, and CD34 but negative for Melan A, epithelial membrane antigen, and glial fibrillary acidic protein. Histological differential diagnosis includes prurigo nodularis, neurotized nevus, benign peripheral nerve sheath tumor, such as neurofibroma or schwannoma, a type of neuroma, such as traumatic neuroma, mucosal neuroma, and palisaded encapsulated neuroma, or a type of neural hamartoma. A careful histological investigation will enable dermatopathologists to make a diagnosis of SPN.

Econazole selectively induces cell death in NF1-homozygous mutant tumor cells.

Cutaneous neurofibromas (cNFs) are tumors that develop in more than 99% of individuals with neurofibromatosis type 1 (NF1). They develop in the dermis and can number in the thousands. cNFs can be itchy and painful and negatively impact self-esteem. There is no US Food and Drug Administration (FDA)-approved drug for their treatment. Here, we screen a library of FDA-approved drugs using a cNF cell model derived from human induced pluripotent stem cells (hiPSCs) generated from an NF1 patient. We engineer an NF1 mutation in the second allele to mimic loss of heterozygosity, differentiate the NF1+/- and NF1-/- hiPSCs into Schwann cell precursors (SCPs), and use them to screen a drug library to assess for inhibition of NF1-/- but not NF1+/- cell proliferation. We identify econazole nitrate as being effective against NF1-/- hiPSC-SCPs. Econazole cream selectively induces apoptosis in Nf1-/- murine nerve root neurosphere cells and human cNF xenografts. This study supports further testing of econazole for cNF treatment.

Perinatal folate levels do not influence tumor latency or multiplicity in a model of NF1 associated plexiform-like neurofibromas.

OBJECTIVE: In epidemiological and experimental research, high folic acid intake has been demonstrated to accelerate tumor development among populations with genetic and/or molecular susceptibility to cancer. Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder predisposing affected individuals to tumorigenesis, including benign plexiform neurofibromas; however, understanding of factors associated with tumor risk in NF1 patients is limited. Therefore, we investigated whether pregestational folic acid intake modified plexiform-like peripheral nerve sheath tumor risk in a transgenic NF1 murine model. RESULTS: We observed no significant differences in overall survival according to folate group. Relative to controls (180 days), median survival did not statistically differ in deficient (174 days, P = 0.56) or supplemented (177 days, P = 0.13) folate groups. Dietary folate intake was positively associated with RBC folate levels at weaning, (P = 0.023, 0.0096, and 0.0006 for deficient vs. control, control vs. supplemented, and deficient vs. supplemented groups, respectively). Dorsal root ganglia (DRG), brachial plexi, and sciatic nerves were assessed according to folate group. Mice in the folate deficient group had significantly more enlarged DRG relative to controls (P = 0.044), but no other groups statistically differed. No significant differences for brachial plexi or sciatic nerve enlargement were observed according to folate status.

Transcriptomic subtyping of malignant peripheral nerve sheath tumours highlights immune signatures, genomic profiles, patient survival and therapeutic targets.

BACKGROUND: Malignant peripheral nerve sheath tumour (MPNST) is an aggressive orphan disease commonly affecting adolescents or young adults. Current knowledge of molecular tumour biology has been insufficient for development of rational treatment strategies. We aimed to discover molecular subtypes of potential clinical relevance. METHODS: Fresh frozen samples of MPNSTs (n = 94) and benign neurofibromas (n = 28) from 115 patients in a European multicentre study were analysed by DNA copy number and/or transcriptomic profiling. Unsupervised transcriptomic subtyping was performed and the subtypes characterized for genomic aberrations, clinicopathological associations and patient survival. FINDINGS: MPNSTs were classified into two transcriptomic subtypes defined primarily by immune signatures and proliferative processes. "Immune active" MPNSTs (44%) had sustained immune signals relative to neurofibromas, were more frequently low-grade (P = 0.01) and had favourable prognostic associations in a multivariable model of disease-specific survival with clinicopathological factors (hazard ratio 0.25, P = 0.003). "Immune deficient" MPNSTs were more aggressive and characterized by proliferative signatures, high genomic complexity, aberrant TP53 and PRC2 loss, as well as high relative expression of several potential actionable targets (EGFR, ERBB2, EZH2, KIF11, PLK1, RRM2). Integrated gene-wise analyses suggested a DNA copy number-basis for proliferative transcriptomic signatures in particular, and the tumour copy number burden further stratified the transcriptomic subtypes according to patient prognosis (P < 0.01). INTERPRETATION: Approximately half of MPNSTs belong to an "immune deficient" transcriptomic subtype associated with an aggressive disease course, PRC2 loss and expression of several potential therapeutic targets, providing a rationale for molecularly-guided intervention trials. FUNDING: Research grants from non-profit organizations, as stated in the Acknowledgements.

Subcutaneous Nasal Schwannoma in a Pediatric Patient: A Rare Case Report with Emphasis on Histopathology's Role in Differential Diagnosis.

BACKGROUND Schwannomas are rare and benign tumors of the nerve sheath, composed of Schwann cells, and they are extremely rare in the nasal area. Here, we report a case that presented to our clinic as a growing nasal mass and was found to be a unilateral subcutaneous schwannoma. There have been a few previous cases reported of such patients having nasal obstruction, epistaxis, or other symptoms, but our patient did not. We stress the importance of considering schwannoma in the differential diagnosis of nasal masses, even in pediatric patients, and the role of histopathology differentiating it from other diagnoses such as neurofibroma. CASE REPORT Our patient was a 9-year-old girl with a painless nasal swelling on the nasal bridge that she first noticed 2 years ago, which started growing gradually and began to become firm. She was otherwise asymptomatic and had no relevant family history. Histopathology revealed an encapsulated spindle cell tumor with both hypo- and hyper-cellular areas, and immunohistochemistry showed that the tumor was strongly positive for S-100 and negative for both desmin and CD34, with blood vessels marking. A final diagnosis of schwannoma was made. CONCLUSIONS We presented a case of nasal septal schwannoma, emphasizing the importance of considering schwannoma in the differential diagnosis of nasal masses, and the role of histopathology to rule out other possible diagnoses.

Target Product Profile for Cutaneous Neurofibromas: Clinical Trials to Prevent, Arrest, or Regress Cutaneous Neurofibromas.

Cutaneous neurofibromas (cNFs) are benign tumors of the skin that affect >95% of adults with neurofibromatosis type 1. Despite their benign histology, cNFs can significantly impact QOL due to disfigurement, pain, and pruritus. There are no approved therapies for cNFs. Existing treatments are limited to surgery or laser-based treatments that have had mixed success and cannot be readily applied to a large number of tumors. We review cNF treatment options that are currently available and under investigation, discuss the regulatory considerations specific to cNFs, and propose strategies to improve cNF clinical trial design and standardize clinical trial endpoints.

Current and Emerging Imaging Techniques for Neurofibromatosis Type 1-Associated Cutaneous Neurofibromas.

A consistent set of measurement techniques must be applied to reliably and reproducibly evaluate the efficacy of treatments for cutaneous neurofibromas (cNFs) in people with neurofibromatosis type 1 (NF1). cNFs are neurocutaneous tumors that are the most common tumor in people with NF1 and represent an area of unmet clinical need. This review presents the available data regarding approaches in use or development to identify, measure, and track cNFs, including calipers, digital imaging, and high-frequency ultrasound sonography. We also describe emerging technologies such as spatial frequency domain imaging and the application of imaging modalities such as optical coherence tomography that may enable the detection of early cNFs and prevention of tumor-associated morbidity.

Miniature Palpebral Plexiform Neurofibroma in Neurofibromatosis Type 2.

A 27-year-old woman with well-documented neurofibromatosis 2 developed a soft, painless, nodular lesion on the skin surface of the left upper eyelid over 2 years. Following excision, histopathology revealed a plexiform neurofibroma with intradermal nodules comprised of benign round and spindle cells that reacted diffusely with immunohistochemical stains SOX-10 and S100. A subset showed focal reactivity for neurofilament and CD34. A perineurium surrounded each nodule with cells staining positively for markers EMA (epithelial membrane antigen) and GLUT1 (glucose transporter 1). Plexiform neurofibromas are rare tumors that occur in 5%-15% of patients with neurofibromatosis 1. Cutaneous abnormalities in neurofibromatosis 2 have not been widely studied although reports have described schwannomas, plexiform schwannomas, and occasional neurofibromas. Plexiform neurofibromas in neurofibromatosis 2 have rarely been illustrated and the current case represents a unique bona fide eyelid example to date.