Over the past decades, the stepwise progression from plexiform neurofibroma via precursor lesions to malignant peripheral nerve sheath tumor (MPNST) has been extensively characterized at the molecular level, revealing several key genetic drivers. Yet many questions remain unanswered. Where do we currently stand, and how does this translate into diagnostics and clinical practice?

Background: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with early metastasis and poor therapeutic response. They commonly arise in neurofibromatosis type 1 (NF1) predisposed populations, particularly young adults. MPNST develops through sequential progression from plexiform neurofibroma (PNF) to atypical neurofibroma (ANF) to MPNST. Intratumoral regions within MPNST often histologically resemble these precursor states, providing a framework to study tumor evolution and identify therapeutic drivers.

Methods: We procured 12 MPNST tumors and microdissected histologically benign-like, premalignant-like, and malignant-like regions to capture the intratumoral heterogeneity. We applied an integrated multi-omics approach combining histopathology, DNA methylation profiling, targeted DNA panel sequencing (TDS), and single-nucleus RNA sequencing (snRNA-seq) to investigate tumor evolution.

Results: TDS identified pathogenic variants in TP53, SUZ12, and EED in several cases, already detectable in premalignant-like regions. Methylation-derived copy number variation (CNV) analysis revealed progressively increasing CNV burden as well as progressive loss of CDKN2A from benign-like to malignant-like regions. snRNA-seq showed MPNST to be predominantly composed of Schwann-like and Mesenchymal-like tumor cells with distinct subprograms, including patient-specific populations enriched in malignant-like samples. Trajectory analysis identified a Schwann-to-Mesenchymal transition as the central evolutionary axis, with dedifferentiation-associated branching at both schwann and mesenchymal states. Gene set enrichment analysis revealed increased proliferative and mesenchymal transition programs alongside reduced immune and inflammatory signaling during progression.

Conclusion: Our preliminary data suggest that MPNST progression is driven by early genomic alterations, increasing genomic instability, and transcriptional reprogramming along a Schwann-to-Mesenchymal axis. Malignant programs emerge early in precursor-like regions, highlighting early molecular events as potential therapeutic targets.

Background: Plexiform neurofibromas (PN) occur in approximately half of patients with neurofibromatosis type 1 (NF1) and may progress to malignant peripheral nerve sheath tumors (MPNST). Translational research combining clinical data with molecular biomarkers may improve early detection and treatment strategies for these complications. We describe the development of a nationwide, longitudinal natural history study (LNHS) and biobank in the Netherlands and report exploratory biomarker studies.
Methods: A consortium has been established within a pilot team of five centres in the NF1 expertise network, supported by standardised agreements for data and material sharing. The database contains observational data from outpatient clinics based on the EU-PEARL LNHS protocol and ERN-GENTURIS registry. Its modular design initially focuses on PN/MPNST, with potential for expansion. The biobank starts with blood collection and will be extended with tissue samples. Centres unable to provide biomaterials may still contribute clinical data.
Results: Data and blood collection commenced in early 2026 at Erasmus University Medical Center and has been gradually expanded throughout the consortium. Several exploratory biomarker studies are ongoing. microRNA analyses are being performed in plasma from 27 trametinib-treated patients (14 responders, 13 stable disease). Circulating tumor DNA analysis is ongoing in 10 PN and 10 MPNST patients. Proteomic analysis will be applied to 47 paired PN–MPNST tissue samples. Preliminary results will be presented at the conference.
Conclusion: This multicenter collaboration demonstrates the feasibility of establishing a prospective cohort for validation of clinical predictors and biomarkers. It may serve as a blueprint for broader European collaboration and improvement in NF1 care.

Background
Atypical neurofibromas (ANF), specifically ANNUBP and low-grade (lg)- MPNSTs), pose challenges in determining the optimal surgical approach. The relationship between subtotal resection and its impact on recurrence rates, metastasis and survival is ill-defined. This raises questions regarding the necessity of radical resection, particularly when such an approach may result in permanent neurological deficits. The present retrospective study aims to clarify the impact of surgical margin on local recurrence and survival outcomes in patients diagnosed with borderline neurofibromatous lesions.
Methods
We conducted a retrospective analysis of patients diagnosed with neurofibromas with atypia and/or hypercellularity (NF a/h), ANF, and lg-MPNSTs, who underwent surgical interventions between 2000 and 2020 in two sarcoma centers. Data was collected on histopathology, surgical margins, and tumor characteristics, which were correlated with local recurrence rates and survival outcomes.
Results
A total of 86 patients met the inclusion criteria, with a mean age of 39 years (SD 18). At 10 years, the disease-specific survival (DSS) was 100%, 100% and 96% for NF a/h, ANF, lg-MPNST, respectively. During a mean follow-up period of 4.4 years, local recurrence was observed in 27 patients (37%), while one patient (0.8%) developed distant metastasis. There was no statistically significant difference in recurrence rates or DSS between patients undergoing subtotal and total resection in all subgroups.
Conclusion
The results suggest that radical resection may be unwarranted, as it does not reduce recurrence rate or improve survival. These findings highlight the essential importance of choosing nerve-sparing resection in borderline neurofibromatous lesions when radical resection could lead to neurological deficits.

Background: Atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBPs) were first described in 2016 and are recognized precursor lesions to malignant peripheral nerve sheath tumours (MPNSTs). Although increasing awareness has improved detection, optimal management and long-term outcomes remain incompletely defined. We report our 10-year institutional experience with ANNUBP in a dedicated multidisciplinary NF1 service.
Methods: We performed a retrospective review of patients diagnosed with ANNUBP between 2016 and 2025. Clinical presentation, imaging characteristics, pathology findings, treatment strategies, and oncological outcomes were analysed. Pre-operative diagnosis was established through multidisciplinary review incorporating clinical examination, MRI and FDG-PET imaging. Definitive diagnosis was confirmed through histopathological assessment.
Results: A total of 23 patients with 26 ANNUBPs were identified. Median age at diagnosis was 28 years (range 7-60 years). Pain and interval growth were the most common indications for investigation. Twenty (83%) patients had cutaneous lesions while 5 (17%) had non-cutaneous lesions. All patients underwent pre-operative MRI. Surgical resection was undertaken in all patients. Histopathology consistently demonstrated atypia and hypercellularity without definitive features of MPNST. After a median follow-up of 23 months (range3-92months), one patients had died from unknown causes. All other patients are still under active follow up.
Conclusions: ANNUBP represents a clinically important intermediate stage in NF1-associated malignant transformation. Early recognition through dedicated surveillance pathways and multidisciplinary assessment facilitates timely intervention before progression to MPNST. Our 10-year experience supports surgical resection as an effective management strategy for selected patients and highlights the importance of long-term follow-up within specialist NF1 centres.