Plexiform NeurofibromaEdit

Plexiform neurofibroma is a distinctive variant of benign nerve sheath tumors that predominantly arises in the setting of neurofibromatosis type 1 (neurofibromatosis type 1). Unlike focal neurofibromas, plexiform neurofibromas (PNs) grow as diffuse, tortuous networks along major nerves and nerve plexuses, often involving large regions of the body. They can be present at birth or become evident in childhood and adolescence, and they contribute a substantial portion of the disease burden in NF1, including cosmetic concerns, functional impairment, and, in a minority of cases, risk of malignant transformation. The management of PN requires multidisciplinary care because of the diffuse growth pattern and potential impacts on nerves, limbs, and vital structures.

This article reviews the biology, clinical features, diagnosis, and management of plexiform neurofibromas, with emphasis on how clinicians balance risks and benefits in treating a condition that is intimately tied to the broader syndrome of NF1. The discussion includes the genetic and molecular underpinnings that drive PN development, the role of imaging and pathology in diagnosis, and current and emerging treatment options, such as targeted therapies that seek to curb tumor growth while preserving function. See also discussions of neurofibromatosis type 1 and related tumors, including malignant peripheral nerve sheath tumor.

Overview

Plexiform neurofibromas are composed of a mixture of cell types present in NF1-associated tumors, including Schwann cells, fibroblasts, mast cells, and other supporting elements, all embedded within a myxoid to fibrous stroma. The defining feature is a growth pattern that tracks along derived nerves and can involve multiple nerve trunks, giving rise to a “bag of worms” sensation on palpation in some cases. PNs are typically associated with loss-of-function mutations in the NF1 gene, which encodes neurofibromin, a negative regulator of the Ras signaling pathway. Loss of neurofibromin function leads to uncontrolled cell proliferation and abnormal nerve-tissue growth via downstream effectors in the MAPK signaling cascade.

Plexiform neurofibromas are most commonly seen in individuals with NF1 but are not exclusive to any single population. The spectrum of NF1 manifestations is broad, and PN represents one of the most challenging aspects of the disease due to its diffuse nature and potential for progression. For background on the broader genetic context, see neurofibromatosis type 1 and neurofibromin.

Clinical presentation

Onset and growth: PNs can be present at birth or develop in early childhood, with growth often accelerating during puberty or in adulthood depending on hormonal influences and overall disease activity.
Distribution: PNs commonly involve the trunk, face, limbs, and pelvis, sometimes encasing major nerve plexuses (e.g., the brachial, lumbosacral, or sciatic plexuses), which can complicate surgical management and functional outcomes.
Symptoms and impact: Patients may experience disfigurement, pain, neuropathic symptoms, or functional impairment due to mass effect or nerve involvement. In some cases, PNs are associated with cosmetic concerns and psychosocial impact, underscoring the value of multidisciplinary care and support services.
Malignant transformation: A minority of plexiform neurofibromas undergo malignant transformation to malignant peripheral nerve sheath tumor (malignant peripheral nerve sheath tumor), a development that carries a worse prognosis and calls for vigilant imaging and biopsy when suspicious changes arise (e.g., rapid growth, new pain, or neurological deficit). See also MPNST.

Genetics and pathogenesis

NF1 gene and Ras signaling: The NF1 gene encodes neurofibromin, a Ras-GTPase activating protein. Loss of neurofibromin leads to upregulated Ras signaling and increased cell proliferation within the nerve sheath. This molecular cascade underlies PN development in most patients with NF1. For more on the genetic basis, see neurofibromatosis type 1 and RAS signaling.
Cellular composition: PNs arise from Schwann cells and associated stromal elements within nerves. Their diffuse, infiltrative nature reflects the complex microenvironment of NF1-associated tumors.
Variability and penetrance: Not all individuals with NF1 develop PNs, and among those who do, the severity and pattern of PN growth vary considerably, contributing to a spectrum of clinical experiences.

Diagnosis

Imaging: Magnetic resonance imaging (magnetic resonance imaging) is the primary modality for characterizing PN anatomy, extent, and relationship to nearby structures. MRI helps delineate diffusion along nerve plexuses and assess involvement of critical compartments. Sometimes, imaging features raise concern for malignant change, prompting further evaluation with functional imaging or biopsy. See also MRI.
Evaluation and biopsy: When imaging or clinical features suggest progression or malignant transformation, tissue biopsy and histopathological examination are used to distinguish PN from MPNST and to guide management. See also biopsy.
Associated NF1 features: The diagnosis of PN is often considered in the context of the broader NF1 phenotype, which may include café-au-lait macules, axillary/inguinal freckling, iris Lisch nodules, and other neurocutaneous findings. See cafe-au-lait spots and Lisch nodules for related NF1 features.

Management

Observational approach: In cases where PN is stable and not causing functional impairment or rapid growth, careful monitoring with periodic imaging and clinical assessment is a common approach, given the risks associated with surgical intervention in diffusely involved nerves.
Surgical considerations: When feasible, debulking or excisional procedures may relieve mass effect or improve function, but complete resection is often not possible without risking significant nerve injury. Surgical planning frequently involves a multidisciplinary team, including surgeons, radiologists, and neurologists, to balance tumor control with preservation of neurologic function. See surgery.
Targeted therapies: A notable advancement in PN management is the use of targeted therapies that act on the Ras-MAPK pathway. MEK inhibitors, such as selumetinib, have demonstrated activity in pediatric patients with inoperable PN and are part of evolving treatment paradigms for selected patients. Ongoing trials continue to refine which patients benefit most and how these therapies are best integrated with surgery and surveillance. See also MEK inhibitors.
Other therapies and trials: Beyond MEK inhibitors, clinical trials explore combinations, alternative targets, and optimization of dosing to maximize tumor control while minimizing adverse effects. See clinical trials and neurofibromatosis type 1 research initiatives.
Surveillance: Regular follow-up, including periodic imaging and functional assessments, is important to detect changes that might signal progression or malignant transformation. See also surveillance.

Prognosis and clinical course

Disease burden: The impact of PN on quality of life can be substantial due to pain, disfigurement, and the potential for functional impairment, especially when tumors involve major nerves or areas critical for movement and sensation.
Malignant transformation risk: The risk of PN evolving into MPNST is a central concern in NF1 management. Early recognition of suspicious changes—such as rapid growth, new or worsening pain, or neurologic deficit—is crucial for timely intervention. See MPNST.
Long-term outlook: With advances in imaging, surgical technique, and targeted therapies, outcomes for many individuals with PN have improved, though management remains complex and highly individualized. See also neurofibromatosis type 1.

Controversies and debates

Timing of intervention: There is ongoing debate about when to operate on PN, given the diffuse involvement and potential for neurologic compromise. Proponents of early debulking emphasize relief of symptoms and prevention of disfigurement, while proponents of a more conservative approach stress nerve preservation and the risks of incomplete resection.
Role of targeted therapies: The approval and use of MEK inhibitors represent a shift in management, especially for inoperable PN. Questions remain about long-term outcomes, optimal duration of therapy, cost, access, and how best to integrate drug treatment with surgical and observation strategies.
Surveillance intensity: Guidelines for imaging frequency and modalities vary, reflecting differences in tumor behavior, age at presentation, and risk of malignant transformation. Balancing early detection with resource use and patient burden is a practical consideration in clinical decision-making.
Access and equity: As with many complex NF1-related therapies, access to specialized care, advanced imaging, and targeted treatments can be uneven across regions and health systems, raising debates about how to ensure equitable care for all patients with PN.