A 15-year-old boy presents with a progressive hyperpigmented patch on his thigh that first appeared several years ago. The patient does not report any pain related to the lesion, but he notes that it feels like a “bag of worms” when palpated. Physical examination reveals multiple café au lait spots on his trunk and axillary freckling. Biopsy of the patch is performed, and the results show peripheral nerve overgrowth and invasion into connective tissue.
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Plexiform neurofibromas are a subtype of nerve tumors generally associated with the multisystem genetic disorder, neurofibromatosis type 1 (NF1). Due to a lack of consensus, the National Institutes of Health developed the following criteria in 1987 to aid in the diagnosis of this autosomal-dominant disorder1:
- At least 6 café au lait spots measuring >5 mm in diameter in children or >15 mm across in adolescents and adults
- At least 2 neurofibromas or 1 plexiform neurofibroma
- Freckling in the area of the armpit or the groin
- At least 2 growths on the iris (Lisch nodules or iris hamartomas)
- Optic nerve glioma
- Abnormal growth of the spine, the sphenoid bone, or the tibia
- A parent, sibling, or child with NF1
The presence of plexiform neurofibromas can serve as a diagnostic criterion for NF1; however, isolated plexiform neurofibromas can occur in the absence of NF1.2
Almost all patients diagnosed with NF1 will go on to develop neurofibromas. Cutaneous neurofibromas are benign tumors, but patients who develop plexiform neurofibroma have a 5% lifetime risk of malignant transformation.3,4 The lesions present early in life and are thought to be congenital defects.3 They can cause significant disfigurement and life-threatening complications involving neurologic, orthopedic, orbital, and airway structures. Therefore, patients should be monitored carefully for any growth or pattern changes in a preexisting plexiform neurofibroma that may indicate possible malignant transformation.
In general, a neurofibroma is a benign peripheral nerve sheath tumor composed of Schwann cells, fibroblasts, perineurial cells, and mast cells.5 Plexiform neurofibromas arise from multiple nerves in the trunk or extremities and follow the distribution of the involved peripheral nerves, producing large infiltrative masses.4 These growths can vary in severity from no skin involvement to severe facial disfigurement or elephantiasis with limb hypertrophy.6 They occur in up to 30% of cases of NF1 and commonly involve the orbit, face, neck, back, chest, and abdomen.7
Clinically, a plexiform neurofibroma presents as a diffuse, possibly hyperpigmented overgrowth of skin and soft tissue, often with a deep invasion of nerves and subcutaneous tissue. These bulging and deforming masses are described as feeling like “bags of worms” due to their involvement of connective tissue and skin folds.7 The involved nerves may become irregularly thickened and grow into a distorted, tortuous structure.
Histologically, the lesion will have a loose myxoid background with low cellularity. There are often areas of collagen bundles, which have a “shredded carrot” appearance microscopically.8 The loss of both copies of the NF1 gene in Schwann cells is consistently implicated in the invasive and angiogenic pathogenesis of plexiform neurofibromas.3 The product of the NF1 gene, neurofibromin, functions as a GTPase-activating protein, which inhibits Ras GTPase activity.8
Tumors that are symptomatic and diagnosed at an earlier age are associated with poor prognosis. A study focused on plexiform neurofibroma outcomes in pediatric patients found that patients with symptomatic plexiform neurofibromas have significantly higher mortality rates compared with those with asymptomatic disease.9 In addition, younger patients were found to have the most rapid growth rate of plexiform neurofibromas in another study with a median participant age of 8.3 years.10
A significant concern for plexiform neurofibromas is their potential to transform into malignant peripheral nerve sheath tumors (MPNSTs). These highly malignant tumors are locally invasive with multiple recurrences and eventual metastatic spread.8 This malignant progression occurs in 2% to 16% of cases.7 Plexiform neurofibromas can also compress the spinal cord or airway and cause significant bone erosion.11 Although there are no reliable tests to screen for an MPNST, these tumors often present as a painful expansion of an existing plexiform neurofibroma, hardening of the tumor, and weakness or numbness in an affected arm or leg.12 Magnetic resonance imaging and positron emission tomography imaging with fluorodeoxyglucose may be useful in distinguishing MPNST from benign plexiform neurofibromas in patients with NF1.13
Previously, plexiform neurofibromas were thought to be pathognomonic for NF1, but recent studies have shown that plexiform neurofibromas can be an isolated finding.2 The diagnosis of plexiform neurofibroma is made clinically, and management often involves a multidisciplinary team consisting of a physician, neurologist, surgeon, ophthalmologist, and geneticist.14 Other differential diagnoses for plexiform neurofibroma include neurocutaneous melanosis, congenital smooth muscle hamartoma, Klippel-Trenaunay-Weber syndrome, Proteus syndrome, lipoma, lipomatosis, and neurofibroma.15
The mainstay of treatment for a plexiform neurofibroma includes surgery for symptomatic relief, although its vascularity and intraneural spread make complete excision difficult.11 Once malignant transformation has taken place, chemotherapy can be administered. Radiation is generally not suggested for the treatment of plexiform neurofibromas, as this could promote malignant transformation.16
Unlike schwannomas, it is not possible to separate the lesion from the nerve in plexiform neurofibromas.8 For unresectable, symptomatic cases, good results have been reported with administration of interferon alfa.17 Genetic counseling should be offered to patients to assess family risk, to look for other possible conditions, and whenever the diagnosis is unclear.10 Therapy should be aimed at resecting deforming masses and cancerous tissue when malignant transformation has occurred.7 However, even in the setting of complete excision, approximately 20% of cases reoccur.18
The patient in this case met diagnostic criteria for NF1 and underwent genetic testing as part of his future family planning. There were no concerning features of his plexiform neurofibroma, so no treatment was necessary.
Alexandria Brown, BS, and Eleanor Johnson, BA, are medical students at Baylor College of Medicine in Houston, Texas, and Christopher Rizk, MD, is a certified dermatologist at Elite Dermatology in Houston, Texas.
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