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.

Association of plexiform and diffuse neurofibromas with malignant peripheral nerve sheath tumor in NF I patients: a whole-body MRI assessment.

OBJECTIVE: The aim of this study is to evaluate neurofibromatosis type 1 (NF1) patients with whole-body MRI (WBMRI) to investigate the frequency of plexiform neurofibromas (pNFs), diffuse neurofibromas (dNFs), and malignant peripheral nerve sheath tumors (MPNSTs). MATERIALS AND METHODS: In this retrospective cross-sectional study, between the years 2015 and 2023, 83 consecutive patients with known NF1 underwent a total of 110 WBMRI screenings for MPNST using a standardized institutional protocol. The lesions are categorized as discrete lesions, pNFs, dNFs, and MPNSTs. Histopathology served as the reference standard for all MPNSTs. RESULTS: Among the 83 patients analyzed, 53 (64%) were women and 30 were men (36%) of ages 36.94±14.43 years (range, 15-66 years). Of the 83 patients, 33 have a positive family history of NF1 and positive genetic studies. Seven of 83 (8%) have only dNF, 20/83 (24%) have pNF, 28/83 (34%) have both dNF and pNF, and 28/83 (34%) have neither. Of the 83 patients, eight (9.6%) were diagnosed with nine total MPNSTs. Age range for patients with MPNSTs at time of diagnosis was 22-51, with an average age of 33.4 years. Only one MPNST (11%) developed from underlying pNF 4 years after WBMRI along the right bronchial tree. Three of eight (37.5%) patients with MPNST died within 5 years of pathologic diagnosis. CONCLUSION: This study suggests the absence of a predisposition for development of MPNST from pNFs and dNFs in the setting of NF1. As such, these lesions may not need special surveillance compared to discrete peripheral nerve sheath tumors.

Plexiform neurofibroma (Hamartoma) of the median nerve: A two-case report.

Plexiform neurofibroma is a benign peripheral nerve-sheath tumor, rarely involving major nerves of the extremities. In the literature, there are no clear treatment strategies for plexiform neurofibroma of major peripheral nerves. Our experience encountered two patients with plexiform neurofibroma of the median nerve, presenting with a palmar mass and symptoms of carpal tunnel compression. Preoperatively, plexiform neurofibroma was diagnosed on MRI and clinical examination. Both patients also experienced significant neurological deterioration, with finger numbness and increased nerve/tumor size. Potential malignant transformation was also considered. For these reasons, resection of the involved area of the nerve and repair were indicated. In both patients, intraoperative pathological diagnosis was plexiform neurofibroma. The 45-year-old male patient refused further surgery after carpal tunnel release, which was performed under axillary block. One year postoperatively, nerve compression symptoms decreased moderately. In the other patient, a 7-year-old boy, a significantly enlarged area of the median nerve was resected, and neurorrhaphy was performed. One year postoperatively, median nerve motor-sensory functions recovered completely. Four years postoperatively, no enlargement of the residual tumor was observed.

Solitary plexiform neurofibroma of the tongue: report of a case with no evidence of neurofibromatosis type 1.

Neurofibromas are frequently present in the skin, but are uncommon in the oral and maxillofacial region. There are three histological variants of neurofibroma: localized, diffuse, and plexiform. The plexiform histological variant of neurofibroma is the least common and is a rare occurrence in the oral cavity. Furthermore, plexiform neurofibroma is usually pathognomonic of neurofibromatosis type 1. A case of solitary plexiform neurofibroma of the tongue with no evidence of neurofibromatosis in a 50-year-old female Chinese patient is reported here. The lesion presented as a single, large, well-circumscribed rounded mass in the left hemi-tongue. The tumour was completely excised. No recurrence was observed at the 6-month follow-up.

Neurofibromatosis Type 1 with a Giant Diffuse Plexiform Neurofibroma Invading the Liver.

Plexiform neurofibromas (PNs) occur in approximately 50% of patients with neurofibromatosis type 1 (NF1). PNs are rare in the abdominal cavity and especially rare in hepatobiliary lesions. A 31-year-old man with NF1 had a tumor extending along the celiac artery, superior mesenteric artery, and intrahepatic portal vein. We diagnosed him with diffuse PN based on liver tumor biopsy findings and the tumor form. Because the tumor had invaded along the intrahepatic portal vein, surgical resection was deemed difficult, and the patient was followed up with imaging studies. The patient remained asymptomatic without tumor growth.

Primary lacrimal gland plexiform neurofibroma: a case report and review of the literature.

Neurofibromatosis type 1 (NF1) affects cell growth in neural tissues, resulting in neurofibromas of the internal organs, peripheral nerves and/or autonomic nerves. We describe a highly unusual case of plexiform neurofibroma presenting with lacrimal gland enlargement in an 18 year old male, which led to a diagnosis of NF1.

Clinical and Sonographic Classification of Neurofibromas in Children with Neurofibromatosis Type 1 - A Cluster Analysis.

PURPOSE: High-frequency ultrasound allows the accurate identification of neurofibromas in neurofibromatosis type 1 (NF1). This study aimed to analyze the ultrasound features of neurofibromas in children with NF1, to establish a classification based on the clinical and sonographic patterns of the different types of neurofibromas, and to evaluate the interobserver correlation coefficient (κ) of this classification. MATERIALS AND METHODS: In this prospective, single referral center observational study, clinical and ultrasound findings of neurofibromas in children diagnosed with NF 1 were analyzed. To identify the ultrasound patterns, a cluster analysis allowing the inclusion of both clinical and ultrasound data was designed. The κ coefficient was calculated using 9 external evaluators. RESULTS: 265 ultrasound scans were performed on a total of 242 neurofibromas from 108 children diagnosed with NF1. Cluster analysis allowed the identification of 9 patterns (Snedecor's F, P < 0.001) classified as "classic" cutaneous neurofibroma, blue-red neurofibroma, pseudoatrophic neurofibroma, nodular subcutaneous neurofibroma, diffuse subcutaneous neurofibroma, congenital cutaneous neurofibroma, congenital plexiform neurofibroma, congenital diffuse and plexiform neurofibroma, and subfascial neurofibroma. The κ coefficient of the interobserver ratings was 0.82. CONCLUSION: Patterns identified in the cluster analysis allow neurofibromas to be classified with a very high interobserver correlation.

Ten-Year Follow-up of Internal Neurofibroma Growth Behavior in Adult Patients With Neurofibromatosis Type 1 Using Whole-Body MRI.

BACKGROUND AND OBJECTIVES: Internal neurofibromas, including plexiform neurofibromas (PNF), can cause significant morbidity in patients with neurofibromatosis type 1 (NF1). PNF growth is most pronounced in children and young adults, with more rapid growth thought to occur in a subset of PNF termed distinct nodular lesions (DNL). Growth behavior of internal neurofibromas and DNL in older adults is not well documented; yet knowledge thereof is important for patient risk stratification and clinical trial design. The primary objective of this study was to evaluate the long-term growth behavior of internal neurofibromas in adults with NF1. Secondary objectives were to correlate tumor growth behavior with patient-specific, tumor-specific, and patient-reported variables. METHODS: In this prospective cohort study, internal neurofibromas were identified on coronal short TI inversion recovery sequences on baseline and follow-up whole-body MRIs (WBMRIs). Tumor growth and shrinkage were defined as a volume change ≥20%. The association between tumor growth and patient-specific (baseline age, sex, and genotype), tumor-specific (morphology, location, DNL presence on baseline WBMRI, and maximum standardized uptake value on baseline PET imaging), and patient-reported variables (endogenous and exogenous hormone exposure, pain intensity, and quality of life) was assessed using the Spearman correlation coefficient and Kruskal-Wallis test. RESULTS: Of 106 patients with a baseline WBMRI obtained as part of a previous research study, 44 had a follow-up WBMRI. Three additional patients with WBMRIs acquired for clinical care were included, generating 47 adults for this study. The median age during baseline WBMRI was 42 years (range 18-70). The median time between WBMRIs was 10.4 years. Among 324 internal neurofibromas, 62.8% (56% of PNF and 62.1% of DNL) shrank spontaneously without treatment and 17.1% (17.9% of PNF and 13.8% of DNL) grew. Growth patterns were heterogeneous within participants. Patient-specific, tumor-specific, and patient-reported variables (including endogenous and exogenous hormone exposure) were not strong predictors of tumor growth. DISCUSSION: Internal neurofibroma growth behavior in older adults differs fundamentally from that in children and young adults, with most tumors, including DNL, demonstrating spontaneous shrinkage. Better growth models are needed to understand factors that influence tumor growth. These results will inform clinical trial design for internal neurofibromas.

Endovascular embolization of spontaneous massive hemorrhage of a facial plexiform neurofibroma: case report and literature review.

BACKGROUND: As a subtype of neurofibromatosis, the plexiform neurofibroma is a benign, autosomally inherited disorder and predisposed to tumour formation. However, life-threatening haemorrhage into facial plexiform neurofibroma is extremely rare. CASE INFORMATION: In the current study, we showed a facial plexiform neurofibroma case with massive haemorrhage in the cranio-maxillofacial region. An emergent selective angiography of the external carotid artery was performed to identify the offending artery, which was then selectively occluded by the combination of detachable coils and Onyx-34. Thus, the minimally invasive drainage surgery was successfully performed to evacuate the haematoma. CONCLUSION: We believe the endovascular embolization achieved its purpose by providing an initial salvage strategy for stopping active haemorrhage in plexiform neurofibroma, allowing surgeons to perform open surgery with lower complications rate.

Posterior-Anterior Cephalometric Study of Neurofibromatosis Type 1 Patients With Facial Plexiform Neurofibroma: Analysis of Skeletal Symmetry Concerning Midfacial and Skull Base Reference Points (Zygomatic Arch, Mastoid, and Juga).

BACKGROUND/AIM: Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that is also characterized by skeletal abnormalities. In the cranial region, skeletal dysplasia is observed that is associated with a characteristic peripheral nerve sheath tumor, the plexiform neurofibroma (PNF). The aim of the study was to determine PNF-associated skeletal asymmetries of the mid-skull and skull base as an indicator of local tumor development. PATIENTS AND METHODS: The distances of the zygomatic arch, mastoid, and juga measurement points from the interorbital horizontal plane and median sagittal plane were examined on anterior-posterior cephalograms of 168 NF1 patients (females: 82, males: 86) and compared with the findings of a control group. A distinction was made as to whether the patients had developed a facial PNF. RESULTS: The distances of the measurement points from the reference planes differed between the patient and control group (p<0.05). Within the NF1 patients, differences between certain distances were noted when comparing patients with PNF and without PNF (p<0.05). In PNF patients, discrete changes in the skull contour were also detectable on the non-affected side (p<0.05). The caudal measurement point of the skull base showed no changes in the group comparison. CONCLUSION: The individually very variable facial PNF in NF1 is associated with deformations and misalignments of midfacial bones that follow a pattern quantifiable with cephalometric analysis.

Double Head: Giant Solitary Occipital Scalp Plexiform Neurofibroma Without Neurofibromatosis.

A 16-year-old male presented with solitary occipital plexiform neurofibroma, which had grown slowly over several years to reach giant size, thereby mimicking a "double head." There were no features of neurofibromatosis type 1. Total excision of the neurofibroma was done by infiltrating adrenaline circumferentially around the tumor before scalp incision. The feeding arteries were identified in the dense connective tissue above the aponeurosis and ligated or cauterized. Dissection was then carried out in the loose areolar tissue preserving the periosteal layer. There was no evidence of malignant transformation on histopathology, and 5-year follow-up showed no tumor recurrence.

Treatment of Plexiform Neurofibromas with MEK Inhibitors: First Results with a New Therapeutic Option.

Neurofibromatosis type-1 (NF1)-associated plexiform neurofibromas (PN) are peripheral nerve sheath tumors that can significantly affect the quality of life. Until recently, surgery was the only treatment for these tumors. However, in most cases, surgery cannot achieve complete tumor removal and carries a high risk of postoperative deficits. Therefore, the recent approval of the MEK inhibitor selumetinib for the treatment of NF1-associated PN provides a long-awaited novel therapeutic option. Here, we report our experience with MEK inhibitor treatment in 12 pediatric NF1 patients with inoperable symptomatic PN. Eight patients received trametinib (median therapy duration 12.13 months and range 4-29 months), and four patients received selumetinib (median therapy duration 6.25 months and range 4-11 months). Volumetric magnetic resonance imaging (MRI) after 6 months of treatment was available for seven trametinib patients (median tumor volume reduction of 26.5% and range 11.3-55.7%) and two selumetinib patients (21.3% tumor volume reduction in one patient and +3% tumor volume change in the other one). All patients reported clinical benefits such as improved range of motion or reduced disfigurement. Therapy-related adverse events occurred in 58.3% of patients and mainly consisted of skin toxicity, paronychia, and gastrointestinal symptoms. Two patients discontinued trametinib treatment after 14 and 29 months when severe skin toxicity occurred and no further reduction of tumor size was observed. In one patient, discontinuation of therapy resulted in a 27.2% tumor volume increase as demonstrated on volumetric MRI 6 months later. Our data show that MEK inhibition is a novel therapeutic approach for inoperable PN with promising results and a manageable safety profile.

[Musculoskeletal manifestations of neurofibromatosis type 1 (von Recklinghausen's disease) and tuberous sclerosis (Bourneville's disease)]. / Muskuloskeletale Manifestationen der Neurofibromatose Typ 1 (M. von Recklinghausen) und der tuberösen Sklerose (M. Bourneville).

CLINICAL PROBLEM: Neurofibromatosis type 1 (NF1) and tuberous sclerosis (TS) are among the most common genetic diseases. Bone and soft tissue manifestations are common disease manifestations. STANDARD RADIOLOGICAL PROCEDURE AND EVALUATION: The standard radiological procedure is magnetic resonance imaging (MRI). All macroscopic disease manifestations can be diagnosed radiologically and observed during the course. Specific complications such as plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNST) in NF1 are readily visible on MRI. Differentiation of plexiform neurofibromas and MPNST is uncertain and requires follow-up. RECOMMENDATION FOR PRACTICE: MRI is the most important procedure for the investigation of soft tissue and bone manifestations of NF1 and TS.

Trametinib therapy for children with neurofibromatosis type 1 and life-threatening plexiform neurofibroma or treatment-refractory low-grade glioma.

PURPOSE: To describe a series of children with extensive PNF or treatment refractory PLGG treated on a compassionate basis with trametinib. METHODS: We report on six patients with NF-1 treated with trametinib on a compassionate basis at British Columbia Children's Hospital since 2017. Data were collected retrospectively from the patient record. RAPNO and volumetric criteria were used to evaluate the response of intracranial and extracranial lesions, respectively. RESULTS: Subjects were 21 months to 14 years old at the time of initiation of trametinib therapy and 3/6 subjects are male. Duration of therapy was 4-28 months at the time of this report. All patients had partial response or were stable on analysis. Two patients with life-threatening PNF had a partial radiographic response in tandem with significant clinical improvement and developmental catch up. One subject discontinued therapy after 6 months due to paronychia and inadequate response. The most common adverse effect (AE) was grade 1-2 paronychia or dermatitis in 5/6 patients. There were no grade 3 or 4 AEs. At the time of this report, five patients remain on therapy. CONCLUSION: Trametinib is an effective therapy for advanced PNF and refractory PLGG in patients with NF-1 and is well tolerated in children. Further data and clinical trials are required to assess tolerance, efficacy and durability of response, and length of treatment required in such patients.

Trametinib for orbital plexiform neurofibromas in young children with neurofibromatosis type 1.

INTRODUCTION: Plexiform neurofibromas (PNF) in neurofibromatosis type 1 (NF1) are usually diagnosed in childhood and can grow rapidly during this period. In 10% of patients, PNF involve the orbital-periorbital area and may cause visual problems including glaucoma, visual loss from amblyopia (deprivational, strabismic, or refractive), optic nerve compression, or keratopathy. Ptosis, proptosis, and facial disfigurement lead to social problems and decreased self-esteem. Complete surgical removal involves significant risks and mutilation, and regrowth after debulking is not uncommon. Inhibitors of the RAS/MAPK pathway have recently been investigated for their activity in PNF. We administered the oral MEK inhibitor trametinib to five young children with NF1 and PNF of the orbital area, with visual compromise and progressive tumor growth; and followed them clinically and by volumetric MRI. METHODS: Treatment was initiated at a mean age of 26.8 months (SD ± 12.8) and continued for a median 28 months (range 16-51). Doses were 0.025 mg/kg/day for children aged > 6 years and 0.032 mg/kg/day for those aged < 6 years. RESULTS: Volumetric MRI measurements showed a reduction of 2.9-33% at 1 year after treatment initiation, with maximal reductions of 44% and 49% in two patients, at 44 and 36 months, respectively. No change in visual function was recorded during treatment. One child reported decreased orbital pain after 2 weeks; and another, with involvement of the masseters, had increased ability to chew food. Toxicities were mostly to skin and nails, grades 1-2. CONCLUSIONS: Trametinib can decrease tumor size in some young children with orbital PNF and may prevent progressive disfigurement.

Selumetinib side effects in children treated for plexiform neurofibromas: first case reports of peripheral edema and hair color change.

BACKGROUND: Plexiform neurofibromas (PNs) are congenital tumors that affect around 50 % of the subjects with neurofibromatosis type 1. Despite being histologically benign, PNs can grow rapidly, especially in the pediatric age, and cause severe morbidities. In the past, various therapeutic approaches have been proposed to treat these masses, none of which obtained valuable results. Selumetinib, an inhibitor of mitogen-activated protein kinase (MEK) 1 and 2, has been the first molecule to demonstrate the ability of tackling the growth of PNs. The drug's most common side effects, which usually are mild or moderate, include gastrointestinal symptoms (diarrhea, abdominal pain), dermatologic manifestations (maculo-papular and acneiform rash, paronychia, mucositis), and various laboratory test abnormalities (elevation of creatine kinase and aminotransferase). CASES PRESENTATION: We report two previously undescribed adverse events in pediatric patients: peripheral edema and hair color change. The first case of peripheral edema occurred in a 7-year-old boy affected by a severe form of NF1, after two years of treatment with selumetinib at the standard dose (25 mg/m2twice a day). The edema involved the right leg, and the patient did not complain of pain. The second case of peripheral edema occurred in a 12-year-old girl after six months of therapy with selumetinib at the standard dose, involving her lower left leg. The patient initially complained of pain in that area, but it gradually and spontaneously resolved. In both patients, all the radiological exams, including lymphoscintigraphy, pelvic and abdominal ultrasound, and doppler ultrasound of the affected limb, as well as blood tests, revealed no abnormalities. Hair color change appeared in a 4-year-old boy after six months of therapy at the standard dose. The boy's hair, whose natural color was dark blonde, became lighter in some areas. Despite the appearance of these side effects, all the patients and their families decided to continue the treatment with selumetinib, in considerations of its clinical benefits. CONCLUSIONS: Since the use of selumetinib to treat plexiform neurofibromas is increasing in the pediatric population, clinicians should be aware of its side effects, so to decide whether continuing the treatment, reducing the dose or even interrupting it, when appropriate.