Plexiform Neurofibroma Research Articles

A Case Report of an Isolated Calvarial Defect in the Region of the Lambdoid Suture: A Rare Bone Manifestation of Neurofibromatosis Type 1

The Calvarial bone defects in the lambdoid suture region are a rare bone manifestation of neurofibromatosis type 1. They may be isolated or associated with an adjacent structural lesion, such as a dural ectasia or plexiform neurofibroma. The underlying pathophysiology for the development of these types of skull defects is still unclear. We present the case of a Calvarial defect in the region of the lambdoid suture in a 7-year-old boy with a medical history of neurofibromatosis type 1 who was referred for a brain scan to explore a palpable skull defect in right parieto-occipital region , noticed by his doctor.

Effect of food on selumetinib pharmacokinetics and gastrointestinal tolerability in adolescents with neurofibromatosis type 1-related plexiform neurofibromas.

Selumetinib is approved for the treatment of pediatric patients with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN) in multiple countries, including the USA (≥ 2 years). Until recently, individuals had to take selumetinib twice daily (BID) in a fasted state. This study evaluated the effect of a low-fat meal on selumetinib PK parameters and gastrointestinal (GI) tolerability in adolescent participants with NF1-PN. Eligible participants aged ≥ 12 to< 18 years took 25mg/m2 selumetinib BID with a low-fat meal (T1) for 28 days, followed by a 7-day washout, and then administration in a fasted state (T2) for another 28 days. Primary objectives were to evaluate the effect of a low-fat meal on AUC0-12,ss and GI tolerability after multiple selumetinib doses in T1 versus T2. Key secondary objectives were additional PK parameters and adverse events (AEs). At primary data cut-off, all 24 participants completed T1, and 23 participants completed T2. There were no significant differences in AUC0-12,ss between T1 and T2. In T1 and T2, 29.2% and 33.3% participants, respectively, reported ≥ 1 GI AE. No GI AEs Grade ≥ 3, or serious AEs, or GI AEs resulting in treatment interruptions, discontinuation, or dose reductions were reported in T1 and T2. Dosing selumetinib with a low-fat meal had no clinically relevant impact on selumetinib AUC0-12,ss nor GI tolerability in adolescents with NF1-PN. NCT05101148.

Solitary giant neurofibroma as a retroperitoneal mass: A rare case

Solitary giant neurofibroma as a retroperitoneal mass: A rare case

Orbital Neurogenic Tumors: An Eye Care Service Experience in Turkey

Introduction:This study aimed to evaluate the clinical and pathological features and treatment outcomes of neurogenic tumors developing in the orbit.&#x0D; Materials and Methods: A retrospective study was conducted on the medical records of 23 patients diagnosed with orbital neurogenic tumors between 2008 and 2020 in the ophthalmology clinic. Clinicopathologic features and treatment results of this patient group were evaluated.&#x0D; Results: Twenty-three patients, mean (SD) age 33.34±20.18 (min-max 4-60) years, were included in this study. Median follow-up time was 56.7±42.7 (min-max 9-120) months. At the time of presentation, 15 (65%) patients had proptosis, 8 (35%) patients had strabismus and reduced vision. Histopathologic diagnosis was made after lateral orbitotomy through the skin in 16 patients (69.5%) and medial orbitotomy through the conjunctiva in 4 patients (17.4%). The diagnosis was established clinically in three (13%) cases. Ten patients (43.4%) underwent whole excisional biopsy, nine patients (391.1%) underwent incisional biopsy, and one patient (4.3%) underwent subtotal excisional biopsy. Nine (39.1%) of the orbital neurogenic tumors were diagnosed as meningiomas based on histological and clinical findings, eight (34.8%) as optic nerve gliomas, and the other six (26%) as peripheral nerve origin tumors. Four (44.5%) of the meningiomas originated from the sphenoid wing, and five (55.5%) from the optic nerve sheath. As a treatment modality, external radiotherapy was administered to fifteen patients (65.2%), cyberknife radiosurgery to one patient (4.3%), chemotherapy to one patient (4.3%), and exenteration surgery to one patient (4.3%).&#x0D; Discussion: According to our study, meningioma, optic nerve glioma, and peripheral nerve sheath tumors were the most frequent neurogenic tumors of the orbit. Gliomas and meningiomas of the optic nerve sheath were treated with external radiation. Total excision was performed for schwannoma and solitary neurofibroma among the peripheral nerve sheath tumors, while subtotal excision was performed for infiltrative plexiform neurofibroma. With the treatments applied, survival and the visual prognosis were satisfactory.

Place of surgery in the treatment of plexiform nevroma of the face plexiform nevroma of the face: about 09 cases of von recklinghausen disease

Neurofibromatosis 1 (NF1) is the most common neurofibromatosis. It’s a genetic disorder defined by the development of heterogeneous nerve tumors, neurofibromas. 40% of NF1 are revealed by a facial damage. The aim of our work is to present the current knowledge of NF1 and report, from the analysis of clinical cases, surgical indications of plexiform neurofibroma. This is a retrospective study conducted at the department of maxillofacial and aesthetic surgery CHU Mohammed VI Marrakech. Our study included 9 patients with plexiform neurofibroma of the face. The average age was 26.5 years (15 to 36 years). The sex ratio M / F was 1.The neurofibroma was unilateral in all patients. Dysplasia of the sphenoid greater wing was found in 2 patients, causing in a patient a cranial orbit, meningo-encephalocele and pulsatile exophthalmos. 6 patients were operated. And 2 refused. Surgery was iterative with an average of two interventions, and it was to reduce the tumor volume. The aesthetic result was satisfactory and allowed a rehabilitation of patients. There was a recurrence in a patient with a decline of 3 years. Surgery has an important place in the treatment of plexiform neuroma of the face. Its purpose is twofold, aesthetic and functional. It is only palliative because it does not change the evolution of the disease. Two problems arise during surgery: hemorrhagic and invasive nature of these tumors. The resections are often incomplete and intra-tumoral. There is no standardization of the timing and importance of surgery to effector especially in children. The degeneration of neurofibroma in neurofibrosarcoma is a rare but dangerous

An unusual occurrence of abdominal neurofibroma with the neck and orbit plexiform neurofibroma in the pediatric age group

Peripheral nerve sheath tumors, specifically neurofibromas and schwannoma variants, occur both sporadically and in the setting of hereditary conditions, including neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and familial sporadic schwannoma [1]. It is a frequent and polymorphic genetic disorder. The severity is related to the complications. The degeneration of neurofibroma is a very rare complication of neurofibromatosis

FT895 Impairs Mitochondrial Function in Malignant Peripheral Nerve Sheath Tumor Cells.

Neurofibromatosis type 1 (NF1) stands as a prevalent neurocutaneous disorder. Approximately a quarter of NF1 patients experience the development of plexiform neurofibromas, potentially progressing into malignant peripheral nerve sheath tumors (MPNST). FT895, an HDAC11 inhibitor, exhibits potent anti-tumor effects on MPNST cells and enhances the cytotoxicity of cordycepin against MPNST. The study aims to investigate the molecular mechanism underlying FT895's efficacy against MPNST cells. Initially, our study unveiled that FT895 disrupts mitochondrial biogenesis and function. Post-FT895 treatment, reactive oxygen species (ROS) in MPNST notably increased, while mitochondrial DNA copy numbers decreased significantly. Seahorse analysis indicated a considerable decrease in basal, maximal, and ATP-production-coupled respiration following FT895 treatment. Immunostaining highlighted FT895's role in promoting mitochondrial aggregation without triggering mitophagy, possibly due to reduced levels of XBP1, Parkin, and PINK1 proteins. Moreover, the study using CHIP-qPCR analysis revealed a significant reduction in the copy numbers of promoters of the MPV17L2, POLG, TFAM, PINK1, and Parkin genes. The RNA-seq analysis underscored the prominent role of the HIF-1α signaling pathway post-FT895 treatment, aligning with the observed impairment in mitochondrial respiration. In summary, the study pioneers the revelation that FT895 induces mitochondrial respiratory damage in MPNST cells.

Recommendations for assessing appearance concerns related to plexiform and cutaneous neurofibromas in neurofibromatosis 1 clinical trials.

Individuals with neurofibromatosis 1 may experience changes in their appearance due to physical manifestations of the disorders and/or treatment sequelae. Appearance concerns related to these physical changes can lead to psychological distress and poorer quality of life. While many neurofibromatosis 1 clinical trials focus on assessing changes in tumor volume, evaluating patients' perspectives on corresponding changes in symptoms such as physical appearance can be key secondary outcomes. We aimed to determine whether any existing patient-reported outcome measures are appropriate for evaluating changes in appearance concerns within neurofibromatosis 1 clinical trials. After updating our previously published systematic review process, we used it to identify and rate existing patient-reported outcome measures related to disfigurement and appearance. Using a systematic literature search and initial triage process, we focused on identifying patient-reported outcome measures that could be used to evaluate changes in appearance concerns in plexiform or cutaneous neurofibroma clinical trials in neurofibromatosis 1. Our revised Patient-Reported Outcome Rating and Acceptance Tool for Endpoints then was used to evaluate each published patient-reported outcome measures in five domains, including (1) respondent characteristics, (2) content validity, (3) scoring format and interpretability, (4) psychometric data, and (5) feasibility. The highest-rated patient-reported outcome measures were then re-reviewed in a side-by-side comparison to generate a final consensus recommendation. Eleven measures assessing appearance concerns were reviewed and rated; no measures were explicitly designed to assess appearance concerns related to neurofibromatosis 1. The FACE-Q Craniofacial Module-Appearance Distress scale was the top-rated measure for potential use in neurofibromatosis 1 clinical trials. Strengths of the measure included that it was rigorously developed, included individuals with neurofibromatosis 1 in the validation sample, was applicable to children and adults, covered item topics deemed important by neurofibromatosis 1 patient representatives, exhibited good psychometric properties, and was feasible for use in neurofibromatosis 1 trials. Limitations included a lack of validation in older adults, no published information regarding sensitivity to change in clinical trials, and limited availability in languages other than English. The Response Evaluation in Neurofibromatosis and Schwannomatosis patient-reported outcome working group currently recommends the FACE-Q Craniofacial Module Appearance Distress scale to evaluate patient-reported changes in appearance concerns in clinical trials for neurofibromatosis 1-related plexiform or cutaneous neurofibromas. Additional research is needed to validate this measure in people with neurofibromatosis 1, including older adults and those with tumors in various body locations, and explore the effects of nontumor manifestations on appearance concerns in people with neurofibromatosis 1 and schwannomatosis.

Spatial Gene-Expression Profiling Unveils Immuno-oncogenic Programs of NF1-Associated Peripheral Nerve Sheath Tumor Progression.

Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) associated with neurofibromatosis type 1 (NF1). Despite similar histologic appearance, these neoplasms exhibit diverse evolutionary trajectories, with a subset progressing to malignant peripheral nerve sheath tumor (MPNST), the leading cause of premature death in individuals with NF1. Malignant transformation of PNF often occurs through the development of atypical neurofibroma (ANF) precursor lesions characterized by distinct histopathologic features and CDKN2A copy-number loss. Although genomic studies have uncovered key driver events promoting tumor progression, the transcriptional changes preceding malignant transformation remain poorly defined. Here we resolve gene-expression profiles in PNST across the neurofibroma-to-MPNST continuum in NF1 patients and mouse models, revealing early molecular features associated with neurofibroma evolution and transformation. Our findings demonstrate that ANF exhibit enhanced signatures of antigen presentation and immune response, which are suppressed as malignant transformation ensues. MPNST further displayed deregulated survival and mitotic fidelity pathways, and targeting key mediators of these pathways, CENPF and BIRC5, disrupted the growth and viability of human MPNST cell lines and primary murine Nf1-Cdkn2a-mutant Schwann cell precursors. Finally, neurofibromas contiguous with MPNST manifested distinct alterations in core oncogenic and immune surveillance programs, suggesting that early molecular events driving disease progression may precede histopathologic evidence of malignancy. If validated prospectively in future studies, these signatures may serve as molecular diagnostic tools to augment conventional histopathologic diagnosis by identifying neurofibromas at high risk of undergoing malignant transformation, facilitating risk-adapted care.

Novel incision to debulk eyelids in a case of Orbital Periorbital Plexiform Neurofibroma (OPPN): A case report

: Plexiform neurofibroma with neurofibromatosis 1 is a autosomal dominant condition and a relatively rare condition. It is also termed as Von Recklinghausen disease. PN involving the structures like eyelid, orbit, periorbital and facial structures are labelled as orbital-periorbital PN(OPPN). These are slowly progressing lesions and are present since birth but increase in size during childhood and are locally infiltrating in nature.: To describe a lid incision to simultaneously debulk both upper and lower eyelid, preserving the vascularity in a case of Orbital Periorbital Plexiform Neurofibroma (OPPN).: We report a case of 22 year male who presented with a disfiguring swelling of right side of face since childhood. After thorough clinical and radiological evaluation it was diagnosed to be a OPPN. Staged debulking was planned and after stage 1 debulking, tissue was sent for HPE which revealed overgrowth of peripheral nerve components and connective tissue dermis showing infiltrating tumour composed of oval to spindle cells with pleomorphic nuclei and moderate cytoplasm. Staged debulking with lid reduction surgery was performed.: Neurofibroma is a rare entity with plexiform neurofibroma occurring in 5-15% of patients. OPPN infiltrates locally without respecting the anatomical planes but follows the trigeminal nerve distribution usually. Indications for debulking procedure are usually the disfigurement and optimal timing is also not certain because the extent and rate of growth cannot be predicted.: The facial appearance and outcome in patients with OPPN can be significantly improved through lid reduction surgery.

Genotype-phenotype correlations of neurofibromatosis type 1: a cross-sectional study from a large Chinese cohort.

Neurofibromatosis type 1 (NF1) is a highly heterogeneous autosomal genetic disorder characterized by a broad spectrum of clinical and molecular manifestations. The correlations between genotype and phenotype in NF1 remain elusive. This study aimed to elucidate genotype-phenotype associations in a large Chinese cohort of NF1 patients. We included NF1 patients from our center who underwent genetic testing for NF1 variants and systemic examination. Genotype-phenotype correlation analyses were performed, focusing on variation types and involved neurofibromin domains. A total of 195 patients were enrolled, comprising 105 males and 90 females, with a median age of 18years. Truncating variants, single amino acid variations, and splicing variants accounted for 139/195 (71.3%), 23/195 (11.8%), and 33/195 (16.9%), respectively. Patients with splicing variants exhibited a significantly higher prevalence of spinal plexiform neurofibromas (spinal PNF) than those with truncating variants (76.4% vs. 51.8%; p = 0.022). Variations affecting the PKC domain were associated with higher rates of cutaneous neurofibromas (CNF) (100% vs. 64.9%, p < 0.001), Lisch nodules (100% vs. 61.2%, p < 0.001), plexiform neurofibromas (PNF) (100% vs. 95.7%, p = 0.009), and psychiatric disorders (11.8% vs. 1.6%, p = 0.042). Patients with mutations in the CSRD had an elevated risk of secondary primary malignancies (11.6% vs. 2.8%, p = 0.015). GRD involvement might enhance the risk of Lisch nodules (76.9% vs. 53.7%, p = 0.044). Variations in the Sec14-PH domain were correlated with a higher rate of CNF (76.8% vs. 58.6%, p = 0.014). Additionally, we found that the p.R1748* variants carry a high risk of malignancy. Our study suggested some novel genotype-phenotype correlations within a Chinese cohort, providing innovative insights into this complex field that may contribute to genetic counseling, risk stratification, and clinical management for the NF1 population.

Drug Responses in Plexiform Neurofibroma Type I (PNF1) Cell Lines Using High-Throughput Data and Combined Effectiveness and Potency.

Background: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germline NF1 gene mutations that predispose patients to developing plexiform neurofibromas, which are benign but often disfiguring tumors of the peripheral nerve sheath induced by loss of heterozygosity at the NF1 locus. These can progress to malignant peripheral nerve sheath tumors (MPNSTs). There are no approved drug treatments for adults with NF1-related inoperable plexiform neurofibromas, and only one drug (selumetinib), which is an FDA-approved targeted therapy for the treatment of symptomatic pediatric plexiform neurofibromas, highlighting the need for additional drug screening and development. In high-throughput screening, the effectiveness of drugs against cell lines is often assessed by measuring in vitro potency (AC50) or the area under the curve (AUC). However, the variability of dose-response curves across drugs and cell lines and the frequency of partial effectiveness suggest that these measures alone fail to provide a full picture of overall efficacy. Methods: Using concentration-response data, we combined response effectiveness (EFF) and potency (AC50) into (a) a score characterizing the effect of a compound on a single cell line, S = log[EFF/AC50], and (b) a relative score, ΔS, characterizing the relative difference between a reference (e.g., non-tumor) and test (tumor) cell line. ΔS was applied to data from high-throughput screening (HTS) of a drug panel tested on NF1-/- tumor cells, using immortalized non-tumor NF1+/- cells as a reference. Results: We identified drugs with sensitivity, targeting expected pathways, such as MAPK-ERK and PI3K-AKT, as well as serotonin-related targets, among others. The ΔS technique used here, in tandem with a supplemental ΔS web tool, simplifies HTS analysis and may provide a springboard for further investigations into drug response in NF1-related cancers. The tool may also prove useful for drug development in a variety of other cancers.

Development of a semi-automatic segmentation technique based on mean magnetic resonance imaging intensity thresholding for volumetric quantification of plexiform neurofibromas

Rationale and objectivesPlexiform neurofibromas (PNs) are peripheral nerve tumors that occur in 25–50 % of patients with neurofibromatosis type 1. PNs may have complex, diffused, and irregular shapes. The objective of this work was to develop a volumetric quantification method for PNs as clinical assessment is currently based on unidimensional measurement. Materials and methodsA semi-automatic segmentation technique based on mean magnetic resonance imaging (MRI) intensity thresholding (SSTMean) was developed and compared to a similar and previously published technique based on minimum image intensity thresholding (SSTMini). The performance (volume and computation time) of the two techniques was compared to manual tracings of 15 tumors of different locations, shapes, and sizes. Performance was also assessed using different MRI sequences. Reproducibility was assessed by inter-observer analysis. ResultsWhen compared to manual tracing, quantification performed with SSTMean was not significantly different (mean difference: 1.2 %), while volumes computed by SSTMini were significantly different (p < .0001, mean difference: 13.4 %). Volumes quantified by SSTMean were also significantly different than the ones assessed by SSTMini (p < .0001). Using SSTMean, volumes quantified with short TI inversion recovery, T1-, and T2-weighted imaging were not significantly different. Computation times used by SSTMean and SSTMini were significantly lower than for manual segmentation (p < .0001). The highest difference measured by two users was 8 cm3. ConclusionOur method showed accuracy compared to a current gold standard (manual tracing) and reproducibility between users. The refined segmentation threshold and the possibility to define multiple regions-of-interest to initiate segmentation may have contributed to its performance. The versatility and speed of our method may prove useful to better monitor volumetric changes in lesions of patients enrolled in clinical trials to assessing response to therapy.

Plexiform Neurofibroma: Case Report

Plexiform neurofibroma (PNF) is a benign nerve tumor, most often developing in the cephalic region. It is usually considered pathognomonic for neurofibromatosis type 1 (NF1) or Von Recklinghausen disease. We report the case of a patient treated in our training for plexiform neurofibroma on NF1. This is a 28-year-old patient, without any particular ATCD, who consulted for a left scalpo-fronto-palpebral subcutaneous swelling that had been present for 12 years, causing major aesthetic discomfort. Furthermore, it presented numerous (&gt; 6) café au lait spots greater than 15mm in diameter. The patient underwent excision of the left scalpo-fronto-palpebral tumor under general anesthesia with direct closure. The pathological examination confirmed the diagnosis of plexiform neurofibroma. The postoperative course was simple and the result satisfactory. Surgical excision remains the only treatment for plexiform neurofibomas in Von Recklinghausen disease.

Impact of neurofibromatosis type 1 with plexiform neurofibromas on the health-related quality of life and work productivity of adult patients and caregivers in the UK: a cross-sectional survey

BackgroundPlexiform neurofibromas (PN) are complex, benign nerve-sheath tumours that occur in 30–50% of patients with neurofibromatosis type 1 (NF1), a rare, genetic disorder. PN are associated with substantial, heterogeneous morbidities that impact health-related quality of life (HRQoL), including affecting motor function and causing pain, though HRQoL and work productivity data are scarce. This UK cross-sectional study explored HRQoL and work productivity in adult patients with NF1 PN and caregivers of paediatric patients.MethodsAdult patients and caregivers of paediatric patients self-enrolled in an online survey (March–April 2021). Outcomes included EQ-5D-5L, PROMIS® GH and INF1-QOL (adult patients only), and EQ-5D-5L, CarerQol and WPAI (caregivers only). Utilities were estimated from EQ-5D-5L responses using the UK crosswalk value set. Linear regression models explored univariable associations between adult patient characteristics and HRQoL.ResultsMean (± standard deviation) EQ-5D utility in adult patients with NF1 PN was 0.65 (± 0.29; n = 35; age-/sex-matched norm: 0.89 [± 0.04]). Moderate–extreme pain/discomfort and anxiety/depression were reported by 14/35 (40.0%) and 18/35 (51.4%) patients, respectively. Mean PROMIS® GH physical and mental health scores were 43.6 (± 9.19) and 41.7 (± 11.5; n = 35; matched norm: 50.0 [± 10.0]). Mean INF1-QOL score was 11.03 (± 6.02; n = 33). Chronic itching, at least one symptom, at least one comorbidity, PN location at extremities (arms/legs) and pain were associated with worse HRQoL scores.Mean caregiver EQ-5D utility was 0.72 (± 0.24; n = 8; age-/sex-matched norm: 0.88 [± 0.03]). Moderate pain/discomfort and moderate–severe anxiety/depression were reported by 4/8 (50.0%) and 2/8 (25.0%) caregivers, respectively. Mean CarerQol score was 69.3 (± 13.9; n = 8). Mean WPAI regular activity productivity loss was 36.3% (± 31.6%; n = 8).ConclusionsNF1 PN worsens adult patient and caregiver HRQoL compared to the general population, notably affecting pain and discomfort, anxiety and depression and caregiver productivity.

Screening saves sight: An unusual case of type-1 neurofibromatosis

Neurofibromatosis (NF), described by von Recklinghausen in 1882, consists of at least two distinct disorders: NF1 (von Recklinghausen's or peripheral neurofibromatosis) and NF2, formerly known as 'central neurofibromatosis." The prevalence of NF is approximately 1 in 4,000, and of NF2, 1 in 50,000. Neurofibromatosis type 1 is a multisystemic neurocutaneous disorder with an autosomal dominant hereditary pattern. Ocular manifestations include plexiform neurofibroma of eyelid, Lisch nodules in iris, optic nerve glioma, glaucoma, sphenoid wing dysplasia. Retinal and choroidal involvement are encountered less frequently. Unusual ocular findings include multiple choroidal nevi, combined hamartoma, choroidal Schwannoma, choroidal melanoma and vaso proliferative retinal tumors.Here we report a case of an 18 year old girl diagnosed with neurofibromatosis type 1 who on routine ocular examination was found to have high myopia in both eyes and on fundus examination had a macula ‘on’ inferior retinal detachment with retinal hole in right eye. Inferior retinal detachment is rarely reported in neurofibromatosis type 1. This case emphasizes the importance of conducting ocular examination even in asymptomatic patients with neurofibromatosis, so that early detection and treatment can prevent vision loss secondary to retinal detachment.

ANGI-07. GLIOBLASTOMA WITH BONY METASTATIC DISEASE IN A PATIENT WITH NEUROFIBROMATOSIS TYPE 1: A CASE REPORT

Abstract Neurofibromatosis Type 1 (NF1) is an autosomal dominant tumor predisposition syndrome causing diffuse neurofibromas, plexiform neurofibromas, and in a minority of patients malignant peripheral nerve sheath tumors (MPNST) and gliomas. Gliomas from NF1 typically present early in life and can be grade 1-4, with higher grades less frequent. Malignant gliomas associated with NF1 have a different molecular landscape compared to sporadic gliomas. Extracranial spread of gliomas is extremely rare for reasons unknown, but renal transplants from gliomas patients have resulted in clonal gliomas in organ recipients. We present here the first reported case of extracranial metastases of GBM to bone in a 21 year old male with NF1. At the age of 18, he was diagnosed with a high-grade astrocytoma consistent with GBM (IDH wildtype, MGMT unmethylated). This was 2 years following a diagnosis of a right neck plexiform neurofibroma. His GBM was initially treated with six cycles of temozolomide. Following temozolomide he underwent another resection (1.5 years after initial surgery) due to tumor recurrence. Resection was followed by proton radiation therapy and selumetinib, a MEK inhibitor approved for treatment of plexiform neurofibromas in NF1. The selumetinib did reduce his plexiform neurofibroma, but did not have an apparent effect on his GBM. Selumetinib was stopped five months after initiation due to increased tumor burden and he began lomustine, followed by bevacizumab and etoposide at next recurrence. About 2.5 years after his initial GBM diagnosis, he had low back pain and imaging showed multiple sites of bony metastases. Pathology confirmed extracranial spread of GBM.

CNSC-04. DIAGNOSIS AND TREATMENT OF PERIPHERAL AND CRANIAL NERVE TUMORS WITH EXPERT RECOMMENDATIONS: AN EUROPEAN NETWORK FOR RARE CANCERS (EURACAN) INITIATIVE

Abstract BACKGROUND The 2021 WHO classification of the CNS Tumors identifies as “Peripheral nerve sheath tumors” (PNST) some entities with specific clinical and anatomical characteristics, histological and molecular markers, imaging findings, and aggressiveness. Material and methods. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is particularly low due to the rarity, and drawn recommendations accordingly. RESULTS Tumor diagnosis is primarily based on hematoxylin and eosin-stained sections and immunohistochemistry. Molecular analysis is not essential to establish the histological nature of these tumors, although genetic analyses on DNA extracted from PNST (neurofibromas/schwannomas) is required to diagnose mosaic forms of NF1 and SPS. MRI is the gold-standard to delineate the extension with respect to adjacent structures. Gross-total resection is the first choice, and can be curative in benign lesions; however, the extent of resection must be balanced with preservation of nerve functioning. Radiotherapy can be omitted in benign tumors after complete resection and in NF-related tumors, due to the theoretic risk of secondary malignancies in a tumor-suppressor syndrome. Systemic therapy should be considered in incomplete resected plexiform neurofibromas/MPNSTs. MEK inhibitor selumetinib can be used in NF1 children ≥2 years with inoperable/symptomatic plexiform neurofibromas, while anthracycline-based treatment is the first choice for unresectable/locally advanced/metastatic MPNST. Clinical trials on other MEK1-2 inhibitors alone or in combination with mTOR inhibitors are under investigation in plexiform neurofibromas and MPNST, respectively. CONCLUSIONS Given the heterogeneity and rarity of these tumors, there is a paucity of well-powered clinical trials, thus it is not possible to generate evidence-based treatment recommendations for non-surgical modalities. However, some clinical trials have been reported on targeted therapies in plexiform neurofibromas of NF1 patients or in heterogenous cohorts of soft-tissue tumors, including MPNSTs, with initial data of efficacy that need to be further investigated.

EPCO-04. SPATIAL TRANSCRIPTOMIC ANALYSIS OF MALIGNANT PERIPHERAL NERVE SHEATH TUMORS REVEALS THERAPEUTICALLY TARGETABLE MOLECULAR SIGNATURES IN REGIONS UNDERGOING HISTOPATHOLOGIC TRANSFORMATION

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) evolve from plexiform neurofibromas (pNF) in patients with neurofibromatosis type-1 (NF-1) yet the cellular and transcriptomic mechanisms underlying this transformation remain unclear. Here, we perform spatial gene expression profiling on fifteen MPNSTs to correlate histologic observations with transcriptomic programs and identify mechanisms underlying malignant transformation. METHODS: Fifteen MPNSTs, including tumors with a histopathologically defined transition zone between adjacent low-grade and high-grade areas (n=3), were retrospectively identified. Spatial transcriptomic profiling was performed using Visium followed by downstream processing with SpaceRanger, Seurat, Harmony, and monocle. RESULTS: 50,807 unique spatial transcriptomes were distributed across 17 unique clusters, of which 12 were enriched for tumor cells and 5 for non-tumor microenvironment cells based on histologic evaluation, unsupervised cell-type assignment, marker gene expression, and cell signature gene sets. Transcriptomic clusters in low-grade areas were enriched for genes regulating mononuclear cell migration and cell-cell adhesion, while high-grade regions were enriched for Ras/Raf/MEK/ERK target genes, anti-apoptotic programs, and extracellular matrix reorganization genes. Trajectory inference beginning in low grade regions revealed spatially organized molecular signatures of malignant transformation enriched for cell cycle progression within histopathologically homogeneous regions. Moreover, the intermediate transformation zone between low-grade neurofibromatous and high-grade MPNST histopathologic regions was marked by loss of cell differentiation genes and increased cell cycle progression. CONCLUSIONS: Spatial transcriptomic analysis elucidates the cellular and gene expression patterns underlying progression from pNF to MPNST. Distinct cell populations exist across low-grade, transformation zone, and high-grade regions in MPNSTs highlighted by alterations in Ras/Raf/MEK/ERK signaling, cell differentiation and cell cycle programs, shedding light on targets for combinatorial molecular therapy to decrease the risk of malignant transformation and serving as a biomarker of aggressive peripheral nerve tumors to complement conventional histopathology.

Giant plexiform neurofibroma of the eyelid

Giant plexiform neurofibroma of the eyelid