An algorithmic approach to the management of peripheral nerve tumours.

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

Evaluation and management of benign tumors of the eye and eyelid.

Benign tumors of the eye and eyelid are common in children and adults, and they rarely undergo malignant transformation. Their workup and management have evolved over the years with increasing advancements in surgical and laser therapies. This contribution focuses on describing the following benign eye and eyelid tumors and their diagnostic and treatment approaches: congenital and acquired melanocytic nevi; nevus of Ota (Hori nevus); conjunctival papilloma; seborrheic keratosis; epidermoid cyst; dermoid cyst; milium; xanthelasma; hemangioma (cherry angioma and pyogenic granuloma); neurofibroma; neurilemmoma (schwannoma); and fibroepithelial polyp. Surgical removal is the primary treatment approach for many of these benign tumors. With advancements in laser technologies, there are now several laser types that can be used in the treatment of these benign eye and eyelid tumors. Other treatment modalities include cryosurgery, electrosurgery, and topical or intralesional medications. We hope this review will provide a reference to dermatologists and ophthalmologists in their approach to evaluation and management of benign eye and eyelid tumors.

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.

[Treatment and progress of cutaneous neurofibroma].

Objective: To summarize current widely-used therapies for cutaneous neurofibroma (cNF) and related research progress. Methods: Based on extensive investigation of domestic and foreign research, the existing treatment of cNF, including the indications, effectiveness and trials of targeted drugs were reviewed. Results: cNF is a hallmark feature of neurofibromatosis type 1 and has a dramatic negative impact on patient appearance and quality of life. At present, there is no standard management of cNF. Invasive treatment is a commonly-used treatment. Surgical removal gives excellent cosmetic results, but it is difficult for multiple tumors; CO2 laser ablation, laser photocoagulation, electro-drying, and radiofrequency ablation are effective in treating lots of cNF at one time. Although fast and effective, these therapies can lead to depigmentation, hyperpigmentation, or extensive scarring. There is no targeted drug approval for cNF, and a series of studies have been carried out on the Ras-MEK pathway, Ras-mTOR pathway, receptor tyrosine kinase, et al. Conclusion: The treatment of cNF has developed rapidly in recent years and has broad prospects, but the individualization and precision of the treatment still needs further clinical research.

Perspective of Adults With Neurofibromatosis 1 and Cutaneous Neurofibromas: Implications for Clinical Trials.

OBJECTIVE: To assess the perspectives of adults with neurofibromatosis 1 (NF1) regarding cutaneous neurofibroma (cNF) morbidity, treatment options, and acceptable risk-benefit ratio to facilitate the design of patient-centered clinical trials. METHODS: An online survey developed by multidisciplinary experts and patient representatives of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) cNF Working Group was distributed to adults with NF1 (n = 3,734) in the largest international database of individuals with any form of NF. Eligibility criteria included self-reported NF1 diagnosis, age ≥18 years, ≥1 cNF, and ability to read English. RESULTS: A total of 548 adults with NF1 responded to the survey. Respondents ranked appearance, number, and then location as the most bothersome features of raised cNF. Seventy-five percent of respondents considered a partial decrease of 33%-66% in the number or size of cNF as a meaningful response to experimental treatments. Most respondents (48%-58%) were willing to try available cNF treatments but were not aware of options outside of surgical removal. Regarding experimental agents, respondents favored topical, then oral medications. Most individuals (>65%) reported being "very much" or "extremely willing" to try experimental treatments, especially those with the highest cNF burden. Many respondents were not willing to tolerate side effects like nausea/vomiting (51%) and rash (46%). The greatest barriers to participation in cNF clinical trials were cost of participation and need to take time off work. CONCLUSIONS: Most adults with NF1 are willing to consider experimental therapies for treatment of cNF. These data will guide the design of patient-centered clinical trials for adults with cNF.

Neurofibromatose tipo 1 com acometimento do nervo infraorbital: relato de caso / Neurofibromatosis type 1 with infraorbital nerve involvement: a case report

A neurofibromatose tipo 1 é uma doença autossômica dominante rara, com manifestações clínicas diversas. Sua apresentação mais marcante é a presença de neurofibromas (tumores da bainha neural) cutâneos ou internos, que também podem ocorrer de forma esporádica, associados a outras manifestações sistêmicas, como manchas café com leite e lesões oculares. Por serem tumores da bainha de mielina, os neurofibromas podem acometer diversos nervos periféricos, incluindo nervos da face. Apresentamos o caso de um paciente de 1 ano, portador de neurofibromatose tipo 1, com neurofibroma em nervo infraorbital direito, com o acesso proposto para tratamento cirúrgico que fornecesse ampla visualização e acesso a lesão, sem comprometimento estético importante, permitindo preservação de partes moles e adequado crescimento facial.

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease with multiple clinical manifestations. Its most significant presentation is cutaneous or subcutaneous neurofibromas (myelin sheath tumors), which may be associated with other systemic manifestations such as caféau- lait spots and eye involvement. Neurofibromas can affect several peripheral nerves, including the facial nerves. This report presents a case of a 1-year-old patient with NF1 with right infraorbital nerve neurofibroma in which the proposed access for surgical treatment allowed adequate visualization of the tumor with good aesthetic results, preservation of the soft tissues, and normal facial growth.

Peripheral nerve injuries in the pediatric population: a review of the literature. Part III: peripheral nerve tumors in children.

INTRODUCTION: Peripheral nerve tumors type, inciedence and treatment in the pediatric population should be analyzed. METHODS: We have performed an extense literature review of this subject. RESULTS: incidence and distribution are similar to those observed in adults. The most common peripheral nerve tumors in children are neurofibromas and schwannomas. Malignant peripheral nerve sheath tumors are also observed, specially associated with genetic syndromes, like neurofibromatosis and Carney complex. CONCLUSION: In this review, peripheral nerve tumors have been divided into three categories to aid with understanding: reactive and hyperplastic lesions, benign tumors, and malignant tumors. The most frequent lesions have been described.

Creating a comprehensive research strategy for cutaneous neurofibromas.

OBJECTIVE: Outside of procedural-based methods, there are currently no established medical treatments for cutaneous neurofibroma (cNF), which afflict up to 99% of patients with NF1. Further, adult patients often report cNF are the greatest burden of living with NF1. The Neurofibromatosis Therapeutic Acceleration Program (NTAP) launched a think tank to address core questions to facilitate development of effective therapeutics for cNF in people with NF1. METHODS: Experts (with and without explicit experience with NF1 or cNF) from multiple scientific and medical disciplines, representing the ranks of academia, industry, and government agencies, were invited to become a member of a team addressing a specific subset of questions pertinent to cNF. Teams met monthly to review published and unpublished materials, and created summaries about the material known and unknown that may influence therapeutic development for cNF. Teams prioritized questions and organized supporting data, which was presented to the entire body of experts by each team at a research summit. RESULTS: Four themes were identified as being relevant to creating a comprehensive research strategy for cNF: (1) establishing definitions of cNF, (2) determining the biology of cNF with respect to tumor initiation, progression, and maintenance, (3) outlining the factors that guide therapies development, and (4) defining core considerations for clinical trials design and optimization for cNF. CONCLUSION: Considerations and key questions for each of the thematic areas were identified and provided basis for a request for applications launched by NTAP focused on cNF and are described in the accompanying articles of this supplement.

Clinical trial design for cutaneous neurofibromas.

OBJECTIVE: Several clinical trials targeting cutaneous neurofibromas (cNF) have been conducted; however, none has resulted in meaningful changes to care. The Clinical Trial Design and Development subgroup's goals were to (1) define key considerations in the design of clinical trials for cNF, (2) summarize existing data in relation to these considerations, and (3) provide consensus recommendations about key elements of trial design to accelerate the clinical development of therapies for cNF. METHODS: The subgroup, with experts from genetics, dermatology, neurology, oncology, and basic science, spanning academia, government research, and regulatory programs, and industry, reviewed published and unpublished data on clinical trials for cNF and other diseases in the skin. Discussions of these data resulted in formulation of a list of priority issues to address in order to develop efficient and effective clinical trials for cNF. RESULTS: The subgroup identified 2 natural history studies of cNF, 4 priority outcome measures, and 6 patient-reported outcome tools for potential use in efficacy trials of cNF. Time to initiate intervention, patient eligibility, mechanism of action, route of administration, safety monitoring, and regulatory agency interactions were identified as key factors to consider when designing clinical trials for cNF. CONCLUSIONS: Alignment on endpoints and methods for the measurement and quantification of cNF represent a priority for therapeutic development for cNF. Advances in technological methods and outcome tools utilized in other skin diseases may be applicable to cNF studies. Patient age is an important factor guiding trial design and clinical development path.

Not so mass effect? Finding of a remarkable 'incidentaloma' in a teenager with neurofibromatosis.

A 13-year-old boy with neurofibromatosis type 1 presented to the emergency department twice in a fortnight with moderate intermittent abdominal pain, radiating to the back and associated with nausea and vomiting. He examined as a well child with a soft abdomen and minimal tenderness. A history of constipation was identified but he failed to respond to a trial of laxatives. Subsequent ultrasound abdomen demonstrated a large mass surrounding the porta hepatis. MRI further characterised a focal, non-aggressive lesion extending from his liver, encapsulating his pancreas, portal vessels and laterally displacing his spleen and left kidney. Biopsy performed at a specialist cancer treatment hospital of our reference later confirmed this to be a benign neurofibroma of a size not previously reported in the literature. He will be managed conservatively with surveillance imaging and the potential for chemotherapy should the lesion continue to grow.

Human stem cell modeling in neurofibromatosis type 1 (NF1).

The future of precision medicine is heavily reliant on the use of human tissues to identify the key determinants that account for differences between individuals with the same disorder. This need is exemplified by the neurofibromatosis type 1 (NF1) neurogenetic condition. As such, individuals with NF1 are born with a germline mutation in the NF1 gene, but may develop numerous distinct neurological problems, ranging from autism and attention deficit to brain and peripheral nerve sheath tumors. Coupled with accurate preclinical mouse models, the availability of NF1 patient-derived induced pluripotent stem cells (iPSCs) provides new opportunities to define the critical factors that underlie NF1-associated nervous system disease pathogenesis and progression. In this review, we discuss the generation and potential applications of iPSC technology to the study of NF1.

Rectal carcinoma and multiple gastrointestinal stromal tumors (GIST) of the small intestine in a patient with neurofibromatosis type 1: a case report.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomally dominant inherited disorder characterized by multiple pigmented skin spots (café-au-lait spots) and neurofibroma. NF1 is associated with a wide variety of benign or malignant tumors. We report a NF1 patient who received surgical treatment for rectal carcinoma and multifocal small intestinal gastrointestinal stromal tumors (GISTs). CASE PRESENTATION: A 70-year-old female patient with NF1 was referred to our hospital after a positive fecal occult blood test. Locally advanced rectal carcinoma was detected in the upper rectum using colonoscopy. A submucosal tumor 20 mm in diameter was detected in the duodenal bulb during the upper gastrointestinal endoscopy. The biopsy specimen from the duodenum was GIST with positive immunostaining of KIT and CD34 microscopically. Laparoscopic low anterior resection for rectal carcinoma and local excision of the duodenal GIST were performed successfully. During the operation, five white small nodules were found on the serosa of the jejunum. One nodule was excised for histological examination. The resected rectal tumor was a well-differentiated adenocarcinoma with multiple lymph nodes metastases according to the histology. The duodenal tumor was found to be low-risk GIST. Moreover, the nodule from the jejunum was very low risk GIST. An excised skin wart was neurofibroma according to the histology. CONCLUSIONS: GIST or carcinomas have been reported to occasionally occur in the digestive tract of the patients with NF1. We present a rare case of a NF1 patient with GISTs and colorectal carcinoma.

Management of Giant Facial Neurofibroma With Intratumoral Hematoma in Neurofibromatosis Type 1 Patient.

Type-1 neurofibromatosis, a common autosomal dominant disease, is also known as von Recklinghausen disease. Surgical procedures to treat this condition are challenging because of the brittleness of the surrounding blood vessels and soft tissues that bring the risk of causing fatal bleeding. With improvements in neurovascular embolization procedures, some literatures have been published about the application of preoperative embolization for neurofibromatosis. This case report describes a 60-year-old female with Type-1 neurofibromatosis, who presented giant facial neurofibromas with intratumoral hemorrhage on both cheeks. This patient demonstrates that these huge and challenging lesions can be successfully treated with preoperative embolization and surgical treatment. We also discuss the timing of surgical treatment with such lesions.

Bronchoscopic Multimodal Management of Tracheal Neurofibroma.

Neurofibromas involving airways are rare and their management is usually surgical. Herein, we report the case of an endotracheal polypoid neurofibroma successfully treated by multimodal interventional bronchoscopy and cryotherapy.

A neurogenic tumor containing a low-grade malignant peripheral nerve sheath tumor (MPNST) component with loss of p16 expression and homozygous deletion of CDKN2A/p16: a case report showing progression from a neurofibroma to a high-grade MPNST.

Development of malignant peripheral nerve sheath tumors (MPNSTs) is a stepwise process that involves the alteration of many cell cycle regulators and the double inactivation of the NF1 gene. Inactivation of the TP53 gene and deletion of the CDKN2A/p16 gene are known to play an important role in the process. Herein, we present a 19-year-old man with a familial history of neurofibromatosis type 1, in whom the tumor arose from the intercostal nerve and showed 3 components: a neurofibroma, a low-grade MPNST, and a high-grade MPNST. Loss of p16 expression and homozygous deletion of the CDKN2A/p16 gene were observed in both the low-grade and the high-grade MPNST. In contrast to low-grade MPNSTs, high-grade MPNSTs generally tend to lose expression of p16 and harbor homozygous deletion of the CDKN2A/p16 gene. Loss of p16 expression and homozygous deletion of the CDKN2A/p16 gene in low-grade MPNST in our case might be related to its progression to high-grade MPNST. To the best of our knowledge, this is the first study correlating the p16 expression status and CDKN2A/p16 gene alteration in low-grade MPNSTs.

Surgical Management of Giant Scalp Neurofibroma After Ultra-Selective Embolization of Nutrient Artery.

OBJECTIVES: Neurofibroma, a common benign tumor in soft tissue, continues to grow, so it often appears to be giant. Surgical management of giant neurofibroma is a challenge due to the risk of excessive bleeding. Embolization of tumor's nutrient artery may reduce the blood loss in operation. This study introduces the surgical management of giant scalp neurofibroma with preoperative ultra-selective embolization of nutrient artery. METHODS: From January 2006 to December 2013, 9 patients with giant scalp neurofibroma were enrolled into the study. Digital subtraction angiography (DSA) showed tumor's nutrient artery. Ultra-catheter was inserted into the nutrient artery and its branches as close as possible to the tumor. Then ultra-selective embolization was performed with gelatin sponge particles. Surgical removal of tumor was performed in 3 days after embolization. The wound was repaired by skin graft. RESULTS: All of the 9 patients underwent successful DSA and ultra-selective embolization. Among them, occipital artery was embolized in 3 patients (left side in 1 patient and right side in 2 patients). Both occipital artery and superficial temporal artery were embolized in 6 patients (left side in 2 patients, right side in 3 patients, and both side in 1 patient). No complications, such as ectopic embolism, occurred in the patients. All of the tumors were resected completely without blood transfusion. The skin graft survived very well on the wounds. CONCLUSIONS: Preoperative ultra-selective embolization of nutrient artery is a feasible, safe, and effective method to reduce the blood loss in operation and facilitate the surgical management of giant scalp neurofibroma.

Massive Soft Tissue Neurofibroma (Elephantiasis Neuromatosa): Case Report and Review of Literature.

The authors review the literature on massive soft tissue neurofibroma. The methods included a review of 71 reports (PubMed search 1929-2012) with a total of 91 massive soft tissue neurofibroma patients and illustration of clinical and radiological progression of massive soft tissue neurofibroma on a patient with neurofibromatosis type 1. The mean age at initial examination was 21 years. Tumor onset was mostly in childhood years. The commonest affected body segment was the lower extremity (46%), followed by head/neck (30%). Surgical management was pursued in the majority of cases (79%). Bleeding was a common complication (25%). Recurrence was described in 12%; multiple resections cases were described. Malignant transformation occurred in 5%. Although massive soft tissue neurofibroma may be present early in life, massive tumor overgrowth may take years. Predicting disease progression and/or benefit of surgical intervention early in the disease course is challenging. Recurrence and malignant transformation are possible. Massive soft tissue neurofibroma does not respond to chemotherapy or radiotherapy and is associated with life-threatening surgical complications.

Neurofibroma Cantal Solitario: Reporte de Caso / Canthal Solitary Neurofibroma

Objetivos: presentar el caso de una paciente que desarrolló un neurofibroma solitario de localización cantal interna. Diseño de estudio: reporte de caso. Métodos: se reporta el caso de una paciente con un neurofibroma solitario localizado en el canto interno, a la vez que se presenta una breve revisión bibliográfica sobre esta patología infrecuente. Conclusiones: el neurofibroma solitario es una patología infrecuente de naturaleza benigna que puede comprometer el globo ocular, el párpado y la órbita, por lo que debe ser considerado dentro de los diagnósticos diferenciales de la patología tumoral de estas áreas anatómicas.

Objectives: to report the case of a patient with a solitary neurofibroma in the medial canthal area. Study design: case report. Methods: report the case of a patient with a solitary neurofibroma in the medial canthal area and review the pertinent literature. Conclusions: the solitary neurofibroma is a rare benign condition with the potential to compromise the eye, the eyelid and the orbit, so that should be considered in the differential diagnosis of tumoral pathology in these anatomic areas. Keywords: nerve sheath neoplasms, peripheral nervous system neoplasms, neurofibroma.

Benign tumors of the spine.

Benign tumors in the spine include osteoid osteoma, osteoblastoma, aneurysmal bone cyst, osteochondroma, neurofibroma, giant cell tumor of bone, eosinophilic granuloma, and hemangioma. Although some are incidental findings, some cause local pain, radicular symptoms, neurologic compromise, spinal instability, and deformity. The evaluation of spinal tumors includes a thorough history and physical examination, imaging, sometimes laboratory evaluation, and biopsy when indicated. Appropriate treatment may be observational (eg, eosinophilic granuloma) or ablative (eg, osteoid osteoma, neurofibroma, hemangioma), but generally is surgical, depending on the level of pain, instability, neurologic compromise, and natural history of the lesion. Knowledge of the epidemiology, common presentation, imaging, and treatment of benign bone tumors is essential for successful management of these lesions.