Successful utilization of topical trametinib for neurofibromatosis type I-associated plexiform neurofibroma.

An 11-year-old female with neurofibromatosis type 1 (NF-1) and history of optic glioma presented with a progressive cutaneous plexiform neurofibroma of the breast. The lesion was treated with topical application of a mitogen-activated protein kinase inhibitor, trametinib, resulting in stable, non-progression cutaneous plexiform neurofibroma for greater than 2 years. This case demonstrates the potential application of topical trametinib for NF1-associated superficial cutaneous plexiform neurofibroma without the toxicities associated with systemic treatment.

Comparing 3D imaging devices for the measurement of cutaneous neurofibromas in patients with Neurofibromatosis Type 1.

BACKGROUND: Cutaneous neurofibromas (cNFs) are a major cause of disfigurement in patients with Neurofibromatosis Type 1 (NF1). However, clinical trials investigating cNF treatments lack standardised outcome measures to objectively evaluate changes in cNF size and appearance. 3D imaging has been proposed as an objective standardised outcome measure however various systems exist with different features that affect useability in clinical settings. The aim of this study was to compare the accuracy, precision, feasibility, reliability and accessibility of three imaging systems. MATERIALS AND METHODS: We compared the Vectra-H1, LifeViz-Micro and Cherry-Imaging systems. A total of 58 cNFs from 13 participants with NF1 were selected for imaging and analysis. The primary endpoint was accuracy as measured by comparison of measurements between imaging systems. Secondary endpoints included reliability between two operators, precision as measured with the average coefficient of variation, feasibility as determined by time to capture and analyse an image and accessibility as determined by cost. RESULTS: There was no significant difference in accuracy between the three devices for length or surface area measurements (p > 0.05), and reliability and precision were similar. Volume measurements demonstrated the most variability compared to other measurements; LifeViz-Micro demonstrated the least measurement variability for surface area and image capture and analysis were fastest with LifeViz-Micro. LifeViz-Micro was better for imaging smaller number of cNFs (1-3), Vectra-H1 better for larger areas and Cherry for uneven surfaces. CONCLUSIONS: All systems demonstrated excellent reliability but possess distinct advantages and limitations. Surface area is the most consistent and reliable parameter for measuring cNF size in clinical trials.

Minimally invasive tubular removal of spinal schwannoma and neurofibroma - a case series of 49 patients and review of the literature.

To evaluate the efficacy and safety of minimally invasive tubular removal of spinal schwannoma and neurofibroma. In this single-centre study, we retrospectively analysed 49 consecutive patients who underwent minimally invasive removal of a total of 51 benign spinal nerve sheath tumors using a non-expandable (n = 18) or expandable tubular retractor (n = 33) retractor system between June 2007 and December 2019. The extent of resection, surgical complications, neurological outcome, operative time, and estimated blood loss were recorded. Histopathology revealed 41 schwannomas and 10 neurofibromas. After a mean follow-up of 30.8 months, postoperative MRI showed gross total resection in 93.7%, and subtotal resection in 6.3% of the tumors. Three patients were lost to follow up. Of the subtotal resections, one was a schwannoma (2.4% subtotal resections in schwannomas) and two were neurofibromas (20.0% subtotal resections in neurofibromas). Intraspinal and paraspinal tumor localizations were equally accessible by minimally invasive tubular surgery. Conversion to open surgery was not required in any case. The mean operative time was 167 ± 68 min, and estimated blood loss was 138 ± 145 ml. We observed no major surgical complications. Spinal schwannoma and neurofibroma can be removed effectively and safely using a minimally invasive tubular approach, with satisfying extent of tumor resection comparable to the conventional open surgical technique and no increased risk for neurological deterioration.

Diffuse scalp neurofibromas: Case series and Clinicoradiological characteristics of a rare vascular lesion.

Diffuse neurofibroma of the head and neck are rare tumours which have unique clinical and radiological findings. Presurgical diagnosis is important as these lesions are usually highly vascular and pre-operative embolisation can reduce the risk of intra-operative haemorrhage. In this article we describe four cases; two which underwent pre-operative embolisation, which should aid the reader in successfully diagnosing this entity before biopsy/surgery.

Reduced PTPRS expression promotes epithelial-mesenchymal transition of Schwann cells in NF1-related plexiform neurofibromas.

Plexiform neurofibromas (PNFs) are a prevalent and severe phenotype associated with NF1, characterized by a high teratogenic rate and potential for malignant transformation. The growth and recurrence of PNFs are attributed to aberrant proliferation and migration of Nf1-deficient Schwann cells. Protein tyrosine phosphatase receptor S (PTPRS) is believed to modulate cell migration and invasion by inhibiting the EMT process in NF1-derived malignant peripheral nerve sheath tumors. Nevertheless, the specific role of PTPRS in NF1-derived PNFs remains to be elucidated. The study utilized the GEO database and tissue microarray to illustrate a decrease in PTPRS expression in PNF tissues, linked to tumor recurrence. Furthermore, the down- and over-expression of PTPRS in Nf1-deficient Schwann cell lines resulted in the changes of cell migration and EMT processes. Additionally, RTK assay and WB showed that PTPRS knockdown can promote EGFR expression and phosphorylation. The restoration of EMT processes disrupted by alterations in PTPRS levels in Schwann cells can be achieved through EGFR knockdown and EGFR inhibitor. Moreover, high EGFR expression has been significantly correlated with poor prognosis. These findings underscore the potential role of PTPRS as a tumor suppressor in the recurrence of PNF via the regulation of EGFR-mediated EMT processes, suggesting potential targets for future clinical interventions.

Plexiform's perplexities: a tale of two plexiform neurofibromas.

Plexiform neurofibroma (PF) is a rare benign variant belonging to a subtype of neurofibromatosis type 1 that forms bulging or deforming masses arising from the peripheral nerve sheath. These masses involve surrounding connective tissue or dermal layers, leading to multiple cutaneous changes and certain characteristic appearances. It is these appearances that aid in the diagnosis of PF. We have encountered two distinct patients diagnosed with this disorder. While one patient was clinically and pathologically confirmed for PF, the other had no characteristic cutaneous changes. The diagnosis was made with postoperative histopathology and confirmed with an immunohistochemical examination. There are various modalities in the management of PFs, with surgery being a mainstay in the treatment of disfiguring large PFs, especially in resource-restrained settings. In view of high recurrence rates, postoperative clinical follow-up is a must. This paper describes these patients' typical and atypical clinical presentation and subsequent management.

Pathological findings in enucleated eyes of patients with neurofibromatosis type 1: report of a case with 15-year follow-up and review of 14 patients in the literature.

BACKGROUNDS: Iris nodules are frequently noted as clinical manifestations of neurofibromatosis type 1 but the other intraocular manifestations are rare. The purpose of this study is to present a patient with a phthisic eye who underwent enucleation for a cosmetic reason after 15-year follow-up and also to review 14 patients with enucleation described in the literature. CASE PRESENTATION: A 17-year-old man with neurofibromatosis type 1 from infancy underwent the enucleation of phthisic left eye and also had the resection of eyelid subcutaneous mass lesions on the left side for a cosmetic reason. He had undergone four-time preceding surgeries for eyelid and orbital mass reduction on the left side in childhood and had developed total retinal detachment 10 years previously. Pathologically, the enucleated eye showed massive retinal gliosis positive for both S-100 and glial fibrillary acidic protein (GFAP) in the area with involvement of the detached retinal neuronal layer, together with a more fibrotic lesion along the choroid which were, in contrast, negative for both S-100 and GFAP. The choroid, ciliary body, and iris did not show apparent neurofibroma while episcleral neurofibroma was present. LITERATURE REVIEW: In review of enucleated eyes of 14 patients in the literature, buphthalmic eyes with early-onset glaucoma on the unilateral side was clinically diagnosed in 9 patients who frequently showed varying extent of hemifacial neurofibromatosis which involved the eyelid and orbit on the same side. Pathologically, neurofibromas in varying extent were found in the choroid of 12 patients. One patient showed choroidal malignant melanoma on the left side and fusiform enlargement of the optic nerve on the right side suspected of optic nerve glioma. The phthisic eye in another patient showed massive retinal gliosis similar to the present patient. CONCLUSIONS: In summary of the 15 patients with neurofibromatosis type 1, including the present patient, buphthalmic or phthisic eyes with no vision were enucleated for cosmetic reasons and showed choroidal neurofibroma in most patients and massive retinal gliosis in two patients including the present patient.

Left distal sciatic giant solitary myxoid neurofibroma: a case report & literature review.

Introduction: Neurofibroma, a rare benign tumor of the peripheral nervous system, can manifest anywhere along a nerve from the dorsal ganglion to its terminal branches. Myxoid neurofibroma can present as a solitary non-tender nodule and is often confirmed by positive immunohistochemical staining for S-100 protein. However, in 50% of cases, neurofibromas are associated with neurofibromatosis. Case presentation: We present a case of a 34-year-old male with mild pain in the posterior part of his left thigh, accompanied by a slowly-growing swelling particularly noticeable when flexing his knee. It had gradually increased in size over several months, which the patient observed as a decrease in the degree of knee extension. Initial biopsy indicated schwannoma with no evidence of malignancy. Four years later, the swelling increased in size and necessitated resection surgery, revealing an irregular giant tumor measuring 8 *6 *4.5 cm, adherent to adjacent structures, including the femur, muscles, popliteal artery and vein, and a branch of the sciatic nerve. Pathological analysis reclassified the diagnosis to low-grade myxoid neurofibroma. Follow-up MRI three months later showed gross total resection without residual or recurrence of the tumor. Discussion: Solitary neurofibromas are often small in size, ranging from 1 to 2 cm in the greatest dimension. Alternatively, tumors that occur as a part of genetic neurofibromatosis tend to be multiple and often grow to large sizes. In our case, the patient didn't have neurofibromatosis as he didn't meet its diagnostic criteria despite having a giant tumor measuring approximately 8*6*4.5 cm. To our knowledge, this is the first report of giant myxoid solitary neurofibroma of the thigh apart from neurofibromatosis. Thus, this type of tumor should be considered in the differential diagnosis of tumors at this location.

Ossification of neurofibroma in neurofibromatosis type 1, a case report of a rare presentation.

INTRODUCTION: Although musculoskeletal involvement of Neurofibromatosis type 1 (NF1) has been well documented, bone formation, or ossification, within neurofibroma, has been scarcely documented in literature. Here, we report a rare case of ossified neurofibroma in a patient with long history of NF1. PRESENTATION OF CASE: 73-Year-old female with childhood-onset NF1 and surgical history of resection for multiple neurofibromas, presented with right ptosis and eyebrow ptosis. A growing tumor on the right eyebrow was surgically resected. Microscopically, the dermal tumor consists of bland spindle cells with thin, wavy nuclei, without atypia, showing S100 immunoreactivity, consistent with neurofibroma. Multiple metaplastic bone formation composed of mature bone trabeculae surrounding adipose tissue were apparent. DISCUSSION: Up to date, ossification of neurofibroma has been scarcely reported in literature. The etiology is unclear but might involve the response to chronic stress and tissue damage over the years, and/or might indicate the potential differentiation plasticity of mesenchymal stem cell-like population. CONCLUSION: The unusual presentation of ossification provides insights on the pathogenesis and differentiation plasticity of neurofibroma.

Plexiform Neurofibroma: A Case Report.

Neurofibromatosis is a group of genetic disorders that primarily impact the growth of neural tissues, leading to multiple tumors on nerve tissues in the brain, spinal cord, and peripheral nerves. As an autosomal dominant condition, it involves mutations in the neurofibromatosis type 1 (NF1) tumor-suppressor gene, inherited in a recessive manner. Plexiform neurofibroma is a rare manifestation. It is a benign peripheral nerve sheath tumor that grows beneath the skin or deeper within tissues without clear boundaries. The diverse presentations of NF1 necessitate careful, personalized medical management to address the disorder's effects on various organs. Due to its progressive nature, early diagnosis is crucial to prevent complications. Comprehensive care, including psychological support and long-term monitoring, is essential for enhancing the quality of life of NF1 patients. By adopting a proactive and holistic approach, healthcare providers can better assist patients in managing this complex condition.

A Case Report of Neurofibroma of the Tongue Presented as a Solitary Lesion.

Neurofibroma are rare occurrences in the oral cavity with the tongue as the most common location in the oral cavity being affected by neurofibroma. Neurofibroma are usually asymptomatic, irregular tissue masses of benign nature with a small rate of malignant conversion. Recurrence rates are also low in the neurofibromas of the oral cavity. It is rare in India with only a few cases reported to date. Hence, we report this case of a 63-year-old female with a tissue mass present on the right side of her tongue for the last five years, with a progressive nature. The mass was associated with pain during chewing food for the last three months. She was managed by a wide local incision and was reported well recovering at a three-month follow-up.

A Rare Case of Solitary Neurofibroma Misdiagnosed as Diabetic Foot Ulcer in the Toe Tip Region.

Neurofibromas, rare benign tumors of the peripheral nerve sheath, present diagnostic challenges, particularly in diabetic patients with toe ulcers. This case involves a 55-year-old female with type 2 diabetes mellitus who developed an enlarging ulcer on her right second toe. The initial evaluation suggested a diabetic ulcer; however, advanced imaging revealed a mass-like lesion. Partial excision and biopsy confirmed a neurofibroma with spindle cells within the myxoid stroma and S100 protein expression. One month later, total excision and Z-plasty reconstruction were performed under general anesthesia. The patient's postoperative recovery was uneventful, and the patient was discharged without complications. Follow-up revealed successful healing with no recurrence or functional issues. This case highlights the importance of considering neurofibromas in the differential diagnosis of diabetic toe ulcers to avoid misdiagnosis and ensure appropriate management.

Total Knee Arthroplasty in a Patient With Neurofibromatosis 1.

Neurofibromatosis 1 (NF1) is a rare genetic syndrome that leads to the development of neurofibromas and increases the risk of malignancy, including malignant peripheral nerve sheath tumors. Patients with NF1 often have other orthopaedic manifestations, including short stature, osteopenia, and dysplasia. A 47-year-old patient with a history of NF1 and multiple neurofibromas of the right lower extremity presented with a severe valgus deformity, instability, and osteoarthritis of the right knee that was debilitating to daily life. Over time, the patient lost proprioception and potentially some sensation to the right knee with neurofibroma formation, leading to the development of Charcot arthropathy of the right knee with secondary osteoarthritis. The preoperative workup consisted of a magnetic resonance imaging of the knee to confirm no malignancy was present and templating to ensure the standard implant size was amenable for the patient. A primary total knee arthroplasty was performed with a cemented-stemmed hinged knee implant. At 6 months post-surgery, the patient had a dramatic improvement in her pain and quality of life.

NSD3::NUTM1 Fusion Sarcoma Mimicking Malignant Peripheral Nerve Sheath Tumor with Prolonged Survival.

Nuclear Protein in Testis (NUT)-rearranged tumors comprise predominantly NUT carcinoma but also include certain lymphomas, leukemias, skin appendage tumors, and sarcomas. Although histologically diverse, all are genetically identified by oncogenic rearrangement in the NUTM1 gene. Many fusion partners occur, and NSD3 is NUT carcinoma's third most common partner. Herein, we present a case of a 26-year-old man with an NSD3::NUTM1 fusion sarcoma. The patient presented at the age of 13 months with a scalp nodule. Over the next 24 years, he experienced five local recurrences and ultimately expired of a rapidly progressive recurrence. His treatment included surgical resections, radiation, and various chemotherapies. Deceptively, the clinical presentation and histopathology aligned with a malignant peripheral nerve sheath tumor, a diagnosis rendered at initial resection with concurrence by a national soft tissue tumor expert. The patient's exceptionally long survival could be due to NSD3 as the fusion partner, aided by the initial small tumor size and young patient age. Thus, this case expands NUT fusion sarcomas' histologic and immunohistochemical profile to include mimicking a malignant peripheral nerve sheath tumor (MPNST). Additionally, it indicates that the NSD3::NUTM1 fusion can drive sarcoma genesis.

Solitary neurofibroma confined to inferior rectus muscle tendon: a case report.

The present study reports a case of solitary neurofibroma attached to the Inferior Rectus (IR) muscle tendon in a 24-year-old healthy woman and reviews the relevant literature regarding the clinical presentation, diagnosis, and management of this uncommon tumor. The patient underwent successful surgical resection of the tumor, leading to the resolution of associated symptoms (left lower eyelid protrusion and redness). Pathological examination confirmed the diagnosis of neurofibroma based on characteristic histopathological and immunohistochemical markers. This case report underscores the rarity of solitary neurofibromas and primary neoplasms of orbit and ocular adnexa. We also discuss the background of solitary neurofibromas originating from orbit and ocular adnexa. The successful management of this case through surgical resection highlights the importance of accurate diagnosis and tailored treatment strategies. To the best of our knowledge, this is the first reported solitary neurofibroma confined solely to the IR tendon.

Orbital and Lumbosacral Plexiform Neurofibroma with PTPN11 Mutation: A Form of the RASopathy.

RASopathies are a group that encompasses a spectrum of related disorders caused by mutations linked to the RAS/mitogen-activated protein kinase (RAS/MAPK) pathway, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), neurofibromatosis-Noonan syndrome (NFNS), Noonan syndrome with multiple lentigines (NSML). Neurofibromas, as a hallmark of NF1, are extremely rare in patients with other RASopathies. Here we present a case of a 39-year-old Chinese male displaying orbital neurofibromas and lumbosacral plexiform neurofibromas. Histopathology of a CT-guided biopsy of the mass revealed it to be a neurofibroma. The targeted sequencing analysis did not find any pathogenic sequence alteration in the NF1 or NF2 causative genes in blood lymphocytes and hypertrophic nerve tissue, and no additional signs of NF1 were detected, thereby not meeting the diagnostic criteria for NF1. However, we identified a heterozygous mutation (c.836A>G, p.Y279C) in the PTPN11 gene, which is one of the key components of the RAS-MAPK signaling pathway and is associated with NS, NFNS, and NSML. Nonetheless, a thorough examination did not reveal any signs of these syndromes in the patient. Consequently, it was inferred that this patient likely falls within the spectrum of the RASopathies. This represents a unique case manifesting as orbital and lumbosacral plexiform neurofibromas carrying a PTPN11 gene mutation, thereby broadening the phenotype spectrum of PTPN11 mutations. Our results also highlight the overlap between RASopathies. Neurofibromas should be considered indicative of a broader spectrum of disorders resulting from mutations in RASopathies other than NF1.

Isolated Rectal Neurofibroma: A Case Report and Literature Review.

Neurofibromas are considered benign peripheral nerve sheath tumors containing Schwann cells, fibroblasts, and perineurial cells. They are commonly associated with familial disorders. Isolated colonic neurofibromas are very rare. In this report, we discuss a case of a patient who presented to the gastroenterology clinic with a week-long occurrence of abdominal pain and bleeding. She underwent a colonoscopy in which three sentinel polyps of benign appearance, ranging in size from 4 mm to 10 mm, were removed during the procedure. The pathology report indicated that the distal rectal polyp contained a submucosal neurofibroma with SOX10+, desmin-, CD117-, DOG1-, CD34+. While NF1-associated neurofibromas harbor the risk of malignant transformation into malignant peripheral nerve sheath tumors (MPNSTs), the malignancy potential for isolated colonic neurofibromas remains uncertain due to their rarity. The clinical significance of isolated colonic neurofibromas is yet to be defined; therefore, the optimal management strategy remains uncertain. Close monitoring is advocated to both exclude the possibility of neurofibromatosis and be vigilant about the risk of malignant transformation.

Laparoscopic-assisted Resection of a Retroperitoneal Lumbar Nerve Root Neurofibroma: A Case Report.

We present a case of a 59-year-old patient with chronic low back pain, caused by a retroperitoneal intraneural tumour. Laparoscopic excision was performed and histology revealed a spinal nerve root neurofibroma. Post-operatively, the patient developed partial motor and sensitive deficits due to tumoral nerve entrapment, with progressive recovery with rehabilitation. This report reviews the literature on this sparsely reported condition, highlighting the utility of laparoscopy in its management.

Safety and efficacy of selumetinib in pediatric and adult patients with neurofibromatosis type 1 and plexiform neurofibroma.

BACKGROUND: The MEK inhibitor, selumetinib, reduces plexiform neurofibroma (PN) in pediatric patients with neurofibromatosis type 1 (NF1). Its safety and efficacy in adults with PN and effectiveness in other NF1manifestations (e.g., neurocognitive function, growth reduction, and café-au-lait spots) are unknown. METHODS: This open-label, phase 2 trial enrolled 90 pediatric or adult NF1 patients with inoperable, symptomatic, or potentially morbid, measurable PN (≥ 3 cm). Selumetinib was administered at doses of 20 or 25 mg/m2 or 50 mg q 12 hrs for 2 years. Pharmacokinetics, PN volume, growth parameters, neurocognitive function, café-au-lait spots, and quality of life (QoL) were evaluated. RESULTS: Fifty-nine children and 30 adults (median age, 16 years; range, 3-47) received an average of 22±5 (4-26) cycles of selumetinib. Eighty-eight (98.9%) out of 89 per-protocol patients showed volume reduction in the target PN (median, 40.8%; 4.2%-92.2%), and 81 (91%) patients showed partial response (≥ 20% volume reduction). The response lasted until cycle 26. Scores of neurocognitive functions (verbal comprehension, perceptual reasoning, processing speed, and full-scale IQ) significantly improved in both pediatric and adult patients (P <0.05). Prepubertal patients showed increases in height score and growth velocity (P <0.05). Café-au-lait spot intensity decreased significantly (P <0.05). Improvements in QoL and pain scores were observed in both children and adults. All adverse events were CTCAE grade 1 or 2 and were successfully managed without drug discontinuation. CONCLUSION: Selumetinib decrease PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in non-malignant diverse NF1 manifestations.

TRPS1 expression in MPNST is correlated with PRC2 inactivation and loss of H3K27me3.

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 114 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.