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JAMA Dermatology Mar 2024
Topics: Humans; Child; Neurofibromatosis 1; Neurofibroma, Plexiform; Cafe-au-Lait Spots; Benzimidazoles
PubMed: 38198164
DOI: 10.1001/jamadermatol.2023.5338 -
Clinical Cancer Research : An Official... Mar 2024Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) associated with neurofibromatosis type 1 (NF1). Despite similar histologic appearance,...
PURPOSE
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.
EXPERIMENTAL DESIGN
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.
RESULTS
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.
CONCLUSIONS
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.
Topics: Animals; Humans; Mice; Gene Expression Profiling; Nerve Sheath Neoplasms; Neurofibroma; Neurofibromatosis 1; Neurofibrosarcoma
PubMed: 38127282
DOI: 10.1158/1078-0432.CCR-23-2548 -
Indian Journal of Otolaryngology and... Sep 2023Ganglioneuromas (GNs) are slow-growing, benign tumors arising from Schwann cells, gangliocytes, and neuronal tissues. We report a rare intraparotid ganglioneuroma in a...
Ganglioneuromas (GNs) are slow-growing, benign tumors arising from Schwann cells, gangliocytes, and neuronal tissues. We report a rare intraparotid ganglioneuroma in a 42-year-old female presented with a parotid mass. The onset of the lesion dated back to 2021, but the growth was remarkable only in November 2022. The FNA suggested a plexiform neurofibroma. The post-surgical microscopic examination of the excised lesion revealed neoplastic large, rounded cells with abundant, finely granular eosinophilic cytoplasm and a large, eccentric nucleus with a prominent nucleolus as well as fasciculated, with an elongated cytoplasm with fine fibrillar extensions. No mitosis or tumor necrosis was observed. The periphery of the tumor showed perineural entrapment. The immunohistochemical staining for S100 protein, synaptophysin, and chromogranin A were positive. However, the neoplastic cells showed no immunoreactivity for cytokeratin (CK5/6, CK7, AE1/AE3), epithelial membrane antigen, HMB45, Melan A, CD30, CD117 and p40. The case was signed out as mature intraparotid ganglioneuroma. The treatment of choice was surgical resection without adjuvant radiotherapy. No recurrence or post-surgical complications were hitherto reported. To the best of our knowledge, this is the first reported case of intraparotid ganglioneuroma. Caution should be taken not to diagnose this benign neoplasm as a metastasis (e.g. metastatic neuroblastoma) or to request unnecessary overtreatment (e.g., postoperative chemotherapy and radiotherapy).
PubMed: 37636636
DOI: 10.1007/s12070-023-03800-7 -
Expert Review of Neurotherapeutics Apr 2024Neurofibromatosis type 1 (NF1) is a rare neurogenetic disorder characterized by multiple organ system involvement and a predisposition to benign and malignant tumor... (Review)
Review
INTRODUCTION
Neurofibromatosis type 1 (NF1) is a rare neurogenetic disorder characterized by multiple organ system involvement and a predisposition to benign and malignant tumor development. With revised NF1 clinical criteria and the availability of germline genetic testing, there is now an opportunity to render an early diagnosis, expedite medical surveillance, and initiate treatment in a prompt and targeted manner.
AREAS COVERED
The authors review the spectrum of medical problems associated with NF1, focusing specifically on children and young adults. The age-dependent appearance of NF1-associated features is highlighted, and the currently accepted medical treatments are discussed. Additionally, future directions for optimizing the care of this unique population of children are outlined.
EXPERT OPINION
The appearance of NF1-related medical problems is age dependent, requiring surveillance for those features most likely to occur at any given age during childhood. As such, we advocate a life stage-focused screening approach beginning in infancy and continuing through the transition to adult care. With early detection, it becomes possible to promptly institute therapies and reduce patient morbidity. Importantly, with continued advancement in our understanding of disease pathogenesis, future improvements in the care of children with NF1 might incorporate improved risk assessments and more personalized molecularly targeted treatments.
Topics: Child; Young Adult; Humans; Adolescent; Neurofibromatosis 1; Genetic Testing
PubMed: 38406862
DOI: 10.1080/14737175.2024.2324117 -
Cancers Dec 2023: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germline gene mutations that predispose patients to developing plexiform...
: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germline 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 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. : 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, = log[EFF/AC50], and (b) a relative score, , characterizing the relative difference between a reference (e.g., non-tumor) and test (tumor) cell line. was applied to data from high-throughput screening (HTS) of a drug panel tested on tumor cells, using immortalized non-tumor cells as a reference. : We identified drugs with sensitivity, targeting expected pathways, such as MAPK-ERK and PI3K-AKT, as well as serotonin-related targets, among others. The technique used here, in tandem with a supplemental 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.
PubMed: 38136356
DOI: 10.3390/cancers15245811 -
The Laryngoscope Oct 2023To characterize otologic and audiologic manifestations in our NF1 cohort and explore the relationship between otologic and audiologic findings in a subset of patients...
OBJECTIVES
To characterize otologic and audiologic manifestations in our NF1 cohort and explore the relationship between otologic and audiologic findings in a subset of patients with ear-related plexiform neurofibromas (PNs).
METHODS
Audiologic and otologic clinical evaluations were conducted on 102 patients with NF1 in a natural history study (5-45 years; M = 14.4 years; Mdn = 14). Testing included pure tone and speech audiometry, middle ear function, neurodiagnostic auditory brainstem response (ABR), auditory processing, and MRIs of the head and neck region. Patients referred to this study had an overall higher incidence and burden of PNs than the overall NF1 population.
RESULTS
The majority of subjects in this cohort had normal hearing sensitivity (81%) and normal middle ear function (78%). Nineteen participants had hearing loss that ranged in degree from mild to profound, with the majority in the mild range. Hearing loss was twice as likely to be conductive than sensorineural. In patients with ear-related PNs (n = 12), hearing loss was predominantly conductive (60%). Seventy-five percent of ears with PNs had atypical tympanometric tracings that could not be characterized by the classic categories. In all 20 patients with a PN in the temporal bone, the ear canal was affected, and the PNs often extended to the surrounding soft tissue regions.
CONCLUSIONS
People with NF1-related PNs in the temporal bone and adjacent skull base should have audiometric and otologic monitoring. Addressing hearing concerns should be part of routine clinical evaluations in patients with NF1. Magnetic resonance imaging (MRI) should be performed in patients with NF1 who have hearing loss.
LEVEL OF EVIDENCE
3 Laryngoscope, 133:2770-2778, 2023.
Topics: Humans; Child; Young Adult; Neurofibromatosis 1; Neurofibroma, Plexiform; Audiometry; Hearing; Hearing Loss; Deafness
PubMed: 36583617
DOI: 10.1002/lary.30522 -
Journal of Medical Genetics Jan 2024Differential diagnosis between and ) is crucial as treatment and surveillance differ. We report the case of a girl with a clinical diagnosis of sporadic NF1 who...
Differential diagnosis between and ) is crucial as treatment and surveillance differ. We report the case of a girl with a clinical diagnosis of sporadic NF1 who developed a glioblastoma. Immunohistochemistry for MMR proteins identified PMS2 loss in tumour and normal cells and WES showed the tumour had an ultra-hypermutated phenotype, supporting the diagnosis of CMMRD. Germline analyses identified two variants (one pathogenic variant and one classified as variant(s) of unknown significance) in the gene and subsequent functional assays on blood lymphocytes confirmed the diagnosis of CMMRD. The large plexiform neurofibroma of the thigh and the freckling were however more compatible with NF1. Indeed, a PV (variant allele frequencies of 20%, 3% and 9% and in blood, skin and saliva samples, respectively) was identified confirming a mosaicism for NF1. Retrospective analysis of a French cohort identified NF1 mosaicism in blood DNA in 2 out of 22 patients with CMMRD, underlining the existence of early postzygotic PV of gene in patients with CMMRD whose tumours have been frequently reported to exhibit somatic mutations. It highlights the potential role of this pathway in the pathogenesis of CMMRD-associated gliomas and argues in favour of testing MEK inhibitors in this context.
Topics: Female; Humans; Neurofibromatosis 1; Mosaicism; Retrospective Studies; Mismatch Repair Endonuclease PMS2; Neoplastic Syndromes, Hereditary; Brain Neoplasms; Colorectal Neoplasms; DNA Mismatch Repair
PubMed: 37775264
DOI: 10.1136/jmg-2023-109235 -
Journal of Neurology May 2024The approval of selumetinib in patients with neurofibromatosis type 1(NF1) and inoperable plexiform neurofibromas (PN) has reshaped the landscape of clinical management... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The approval of selumetinib in patients with neurofibromatosis type 1(NF1) and inoperable plexiform neurofibromas (PN) has reshaped the landscape of clinical management of the disease, and further comprehensive evaluation of the drug's efficacy and safety is needed.
METHODS
Original articles reporting on the efficacy and safety of elumetinib in patients with NF1 were comprehensively searched in the Pubmed database, Embase database, Cochrane Library, and Web of Science database and screened for inclusion of studies that met the criteria. We pooled the objective response rate (ORR), disease control rate (DCR), disease progression rate (DPR), and the rate of improvement in PN-related complications using meta-analysis. The incidence of drug-related adverse events was also statistically analyzed.
RESULTS
This study included 10 clinical trials involving 268 patients. The pooled ORR was 68.0% (95% CI 58.0-77.3%), the DCR was 96.8% (95% CI 90.8-99.7%) and the DPR was only 1.4% (95% CI 0-4.3%). The pooled improvement rate was 75.3% (95% CI 56.2-90.9%) for pain and 77.8% (95% CI 63.1-92.5%) for motor disorders. Most adverse events were mild, with the most common being gastrointestinal reactions (diarrhea: 62.5%; vomiting: 54.5%).
CONCLUSION
Our study demonstrates that selumetinib is effective in patients with NF1 and PN, significantly improving the serious complications associated with PN as well as having tolerable toxicities. Our findings help to increase clinicians' confidence in applying selumetinib and promote the clinical adoption and benefit of the new drug.
Topics: Humans; Neurofibroma, Plexiform; Neurofibromatosis 1; Benzimidazoles; Protein Kinase Inhibitors
PubMed: 38502338
DOI: 10.1007/s00415-024-12301-8 -
Acta Neuropathologica Communications Sep 2023Plexiform neurofibroma (PN) is a leading cause of morbidity in children with the genetic condition Neurofibromatosis Type 1 (NF1), often disfiguring or threatening vital...
Plexiform neurofibroma (PN) is a leading cause of morbidity in children with the genetic condition Neurofibromatosis Type 1 (NF1), often disfiguring or threatening vital structures. During formation of PN, a complex tumor microenvironment (TME) develops, with recruitment of neoplastic and non-neoplastic cell types being critical for growth and progression. Due to the cohesive cellularity of PN, single-cell RNA-sequencing is difficult and may result in a loss of detection of critical cellular subpopulations. To bypass this barrier, we performed single-nuclei RNA-sequencing (snRNA-seq) on 8 frozen PN samples, and integrated this with spatial transcriptomics (ST) in 4 PN samples and immunohistochemistry to provide morphological context to transcriptomic data. SnRNA-seq analysis definitively charted the heterogeneous cellular subpopulations in the PN TME, with the predominant fraction being fibroblast subtypes. PN showed a remarkable amount of inter-sample homogeneity regarding cellular subpopulation proportions despite being resected from a variety of anatomical locations. ST analysis identified distinct cellular subpopulations which were annotated using snRNA-seq data and correlated with histological features. Schwann cell/fibroblast interactions were identified by receptor/ligand interaction analysis demonstrating a high probability of Neurexin 1/Neuroligin 1 (NRXN1/NLGN1) receptor-ligand cross-talk predicted between fibroblasts and non-myelinated Schwann cells (NM-SC) and subtypes, respectively. We observed aberrant expression of NRXN1 and NLGN1 in our PN snRNA-seq data compared to a normal mouse sciatic nerve single-cell RNA-seq dataset. This pathway has never been described in PN and may indicate a clear and direct communication pathway between putative NM-SC cells of origin and surrounding fibroblasts, potentially driving disease progression. SnRNA-seq integrated with spatial transcriptomics advances our understanding of the complex cellular heterogeneity of PN TME and identify potential novel communication pathways that may drive disease progression, a finding that could provide translational therapy options for patients with these devastating tumors of childhood and early adulthood.
Topics: Child; Humans; Mice; Animals; Adult; Neurofibromatosis 1; Neurofibroma, Plexiform; Transcriptome; Ligands; RNA, Small Nuclear; Disease Progression; RNA; Tumor Microenvironment
PubMed: 37770931
DOI: 10.1186/s40478-023-01639-1 -
Hand Surgery & Rehabilitation Dec 2023Plexiform neurofibroma is a benign peripheral nerve-sheath tumor, rarely involving major nerves of the extremities. In the literature, there are no clear treatment...
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.
Topics: Male; Humans; Middle Aged; Child; Neurofibroma, Plexiform; Median Nerve; Hamartoma; Carpal Tunnel Syndrome; Peripheral Nervous System Neoplasms; Upper Extremity
PubMed: 37714515
DOI: 10.1016/j.hansur.2023.08.007