What is a plexiform neurofibroma?

What is a Plexiform Neurofibroma?

A plexiform neurofibroma is a complex benign nerve sheath tumor that follows multiple nerve branches or fascicles, typically diagnosed in early childhood, occurring in approximately 50% of patients with neurofibromatosis type 1 (NF1), and carries significant risk for malignant transformation, functional deficits, and disfigurement. 1, 2

Key Distinguishing Features

Plexiform neurofibromas differ fundamentally from other neurofibromas in several critical ways:

• Growth pattern: PNs grow along multiple nerve branches with a reticular pattern that does not respect tissue borders, involving several nerve fascicles simultaneously 1, 3
• Timing of onset: Most PNs are congenital or diagnosed in early childhood, with highest risk of growth occurring before age 8 years 1, 4, 2
• Malignant potential: Unlike discrete dermal or subcutaneous neurofibromas which have no risk of malignant transformation, PNs carry a 10% lifetime risk of transforming into malignant peripheral nerve sheath tumors (MPNSTs) 1, 3

Cellular Composition and Pathogenesis

The tumor arises from loss of neurofibromin function due to NF1 gene mutations on chromosome 17q11.2, leading to dysregulated Ras signaling and uncontrolled cell proliferation. 1

• PNs are composed of neoplastic Schwann cells (which lack NF1 gene expression), fibroblasts, perineural cells, and mast cells 1
• Activated Ras triggers a cascade involving Raf and MAPK pathways that drive increased cell proliferation 1
• The tumor microenvironment contributes through Schwann cell secretion of kit ligand, which recruits mast cells and promotes abnormal growth 1
• Additional growth factors including EGFR, PDGFR, and VEGF may contribute to PN development and progression 1

Clinical Manifestations and Morbidity

PNs cause substantial morbidity through three primary mechanisms: disfigurement, functional impairment, and vision loss (when involving orbital-periorbital structures). 1, 2

• Appearance-related morbidity: Proptosis, ptosis, and facial disfigurement lead to social embarrassment and decreased self-esteem 1
• Visual complications: Orbital-periorbital PNs (OPPNs) cause vision loss through deprivational or anisometropic amblyopia and glaucoma 1, 2
• Functional deficits: PNs can cause neurologic deficits depending on their location and size 1
• Pain: Progressive severe pain is a warning sign for potential malignant transformation 4

Association with NF1

While PNs are most commonly associated with NF1, isolated cases without NF1 do occur, though they are extremely rare:

• Approximately 50% of NF1 patients develop PNs during their lifetime 2
• NF1 is an autosomal dominant disorder occurring in approximately 1:3,500 births, with 50% of cases due to sporadic mutations 1, 2
• Isolated PNs without NF1 represent very rare observations, with only scattered case reports in the literature 5, 3

Critical Warning Signs for Malignant Transformation

Monitor closely for signs suggesting transformation to atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP) or MPNST: 4, 6

• Progressive severe pain that is new or unexplained 4
• Changes in tumor volume or rapid growth 4
• New or worsening neurologic symptoms 4
• FDG-PET SUVmax ≥3.5 or decreased apparent diffusion coefficient on MRI warrant biopsy 6

Molecular Features of Progression

When PNs progress toward malignancy, specific molecular alterations occur that can be detected through molecular profiling: 1, 6

• CDKN2A/B homozygous deletion indicates ANNUBP 1, 6
• SUZ12, EED, or TP53 inactivating mutations indicate MPNST 1, 6
• Significant aneuploidy suggests MPNST 1, 6

Treatment Landscape

The treatment paradigm has shifted dramatically with FDA approval of the MEK inhibitor selumetinib for symptomatic, inoperable PNs in children aged 2 years and older. 4, 7

• Selumetinib produces clinically meaningful tumor shrinkage (≥20% volume reduction) and functional improvement 4
• Surgery remains an option for resectable tumors causing visual decline, progressive growth, functional deficits, or progressive disfigurement 4
• Trametinib can serve as an alternative MEK inhibitor when selumetinib is unavailable 4
• Early intervention with selumetinib may prevent progression and facial disfigurement in children with established but small OPPNs 4

Common Pitfall

Do not confuse discrete neurofibromas (dermal or subcutaneous) with plexiform neurofibromas—they have fundamentally different natural histories and malignant potential. Discrete neurofibromas typically appear in the second decade of life, remain small, have no malignant potential, and rarely cause neurologic deficits, whereas PNs present in early childhood, grow along multiple nerve branches, carry 10% lifetime risk of malignant transformation, and frequently cause significant morbidity. 1, 2