summary Neurofibromas are benign peripheral nerve sheath tumors most commonly associated with neurofibromatosis. The condition usually presents in patients with neurofibromatosis with cutaneous lesions, as well as lesions near the brain, spinal cord and parotid glands. Diagnosis is made with clinical history, physical exam, and MRI with and without contrast. Treatment is observation for asymptomatic lesions. Surgical excision is indicated for symptomatic lesions. Epidemiology Demographics sporadic neurofibromas age 20-40 years Neurofibromatosis (NF1) age < 20 Anatomic location sporadic neurofibromas peripheral PNS tumors of the extremities Neurofibromatosis (NF1) tendency to be found near spinal cord/brain (CNS) and uncommon locations (parotid glands, tongue) Etiology Cell types fibroblasts (predominant cell) nonmyelinating Schwann cells cell of origin, arises from this cell perineural cells differentiate from Schwannoma, which involves Schwann cell alone Molecular biology arise in nonmyelinating Schwann cells with biallelic inactivation of NF1 tumor-suppressor gene loss of expression of protein neurofibromin neurofibromin negatively regulates RAS-mediated pathway loss of neurofibromin leads to increased RAS activity affects RAS-dependent MAPK activity which is essential for osteoclast function and survival rapid hyperplasia of nonmyelinating Schwann cells into neurofibromas after NF1 inactivation recruits perineural cells, fibroblasts, mast cells, endothelial cells Classification Subtypes of neurofibroma Origin Description Associations Onset Malignancy Dermal Arise from single peripheral nerve Fusiform swelling of nerve 90% sporadic, 10% arise in NF1 At puberty Do not become malignant Plexiform Arise from multiple nerve bundles "Bag of worms" (tortuous enlargement of nerves) Pathognomic of NF1 Early childhood 10% become malignant (MPNST) Types of Schwann cells Axons Disease process Myelinating Covers large-diameter PNS axons with myelin Nonmyelinating Covers small-diameter PNS axons with cytoplastic processes Responsible for neurofibromatosis Presentation Symptoms asymptomatic stinging, itching, pain, disfiguration Physical exam reduced sensation cutaneous lesions can "button hole" through skin defect using finger pressure signs of neurofibromatosis (2 of 7) (NIH criteria) 2 or more neurofibromas, or 1 plexiform neurofibroma axillary or groin freckling (Crowe's sign) 6 or more coast of California cafe-au-lait spots 5mm diameter in prepubertal >15mm diameter in postpubertal sphenoid wing dysplasia or thinning of long bone cortex (anterolateral tibial bowing) 2 or more Lisch nodules (iris hamartomas) on slit lamp optic glioma 1st degree relative with NF1 associated with NF1 dystrophic kyphoscoliosis rib penciling intraspinal neurofibromas and dumbbell lesions dural ectasia meningiomas Imaging MRI with and without contrast findings differentiate Schwannoma from neurofibroma Schwannoma are found ECCENTRIC to the nerve fibers Solitary neurofibromas are found CENTRAL to the nerve fibers nerve continuity sign fusiform tumor in continuity with the neurovascular bundle split fat sign fusiform tumor surrounded by a thin margin of fat because the mass within the neurovascular bundle enlarges and displaces the adjacent intramuscular fat target sign lesion of high signal intensity peripherally and low signal centrally (on coronal STIR) PET-CT Histology Characteristics cells hypocellular predominantly fibroblasts mixed Schwann cells, mast cells, lymphocytes elongated, wavy nuclei stroma rich wire-like collagen fiber network may be myxoid distorted structures resembling Pacini or Meissner corpuscles variable S100 staining Differential MPNST (malignant peripheral nerve sheath tumor or neurofibrosarcoma) 5% of patients with NF, 10-25% lifetime risk symptoms include painful, enlarging soft tissue mass usually from plexiform neurofibroma 10% of plexiform neurofibromas transform into MPNST associated with loss of expression of CDKN2A or TP53 genes in non-myelinating Schwann cells (that also have biallelic inactivation of NF1) poor prognosis widespread metastasis high rate of local recurrence Schwannoma Wilms tumor Melanoma Leukemia Rhabdomyosarcoma Pheochromocytoma Treatment Nonoperative observe if asymptomatic Operative surgical excision if symptomatic may require nerve grafting