Abstract
BACKGROUND: Plexiform neurofibromas (PNs) are histologically benign peripheral nerve sheath tumors associated with neurofibromatosis type 1 (NF1) and often lead to significant morbidity due to growth. Management includes watchful waiting, surgery for partial debulking, and, since recently, systemic treatment with MEK inhibitors. However, due to the scarcity of natural history studies, our understanding of the natural progression of PNs to guide clinicians in deciding in whom and when to intervene is scarce. This study aims to describe the characteristics of NF1 patients with PNs and compare those at high risk for PN progression or experiencing significant morbidity from PN (complex PN) with NF1 patients with PNs of lower complexity. METHODS: In this retrospective cohort study using clinical data from hospital records of NF1 patients with PNs seen at the Sophia Children's Hospital in the Netherlands between 2012 and 2023, we assessed determinants of clinical phenotypes and PN characteristics predictive of outcomes, including PN complexity and the timing of intervention for PN. We assessed the outcomes using logistic regression analysis and Cox regression. RESULTS: Ninety patients with a median age at last evaluation of 15.7 years and a median follow-up duration of 9.8 years were included. Out of 90 individuals with a benign PN, 37 developed plexiform neurofibroma morbidity during follow-up. Older age was (corrected for pathogenic NF1 variant and PN location) significantly associated with plexiform neurofibroma morbidity. Cox regression revealed that craniofacial and trunk PNs were associated with a higher intervention hazard compared to limb PNs. CONCLUSION: Our pilot multivariate approach identified older age and the location of the PN to be mostly associated with a higher chance of plexiform neurofibroma morbidity and higher intervention hazard. This may contribute to decisions regarding in whom and when to initiate treatment in NF1 patients with PNs.