# Peripheral Nerve Tumors: Schwannomas and Neurofibromas

## Introduction

Peripheral nerve sheath tumors encompass a spectrum of benign and malignant neoplasms arising from the cellular components of peripheral nerves. Schwannomas and neurofibromas are the most common benign peripheral nerve sheath tumors, and their distinction has critical surgical and prognostic implications. Understanding the relationship between these tumors and hereditary syndromes such as neurofibromatosis types 1 and 2 and schwannomatosis is essential for neurosurgical management.

## Schwannomas

### Pathology and Biology

Schwannomas arise from Schwann cells and are encapsulated, well-circumscribed tumors. They are eccentrically located on the nerve, with nerve fascicles displaced but not infiltrated by the tumor. Histologically, Antoni A tissue is highly cellular with nuclear palisading forming Verocay bodies, while Antoni B tissue is loosely organized with myxoid stroma. Schwannomas are strongly and diffusely positive for S-100 protein on immunohistochemistry. Most are sporadic and solitary; multiple schwannomas suggest NF2 or schwannomatosis.

### Clinical Presentation

Schwannomas present as slow-growing, palpable masses along a peripheral nerve. The Tinel sign is elicited by percussion over the mass, producing distal paresthesias. Pain may be present, but neurological deficit is uncommon in small tumors. The most common locations include the flexor surfaces of extremities, spinal nerve roots as intradural extramedullary tumors, and the cerebellopontine angle as vestibular schwannomas.

### Surgical Management

Intracapsular enucleation is the primary surgical technique, as the tumor can typically be shelled out from the nerve with preservation of fascicles. The capsule is incised longitudinally, and uninvolved fascicles are identified and preserved. Intraoperative nerve stimulation identifies functional fascicles entering the tumor. Usually one or two fascicles enter the tumor and are sacrificed while the remainder are preserved. The recurrence rate is less than 5 percent for complete excision, though long-term follow-up is recommended. Observation is appropriate for asymptomatic, small tumors.

## Neurofibromas

### Pathology and Biology

Neurofibromas arise from multiple cell types including Schwann cells, fibroblasts, perineurial cells, and mast cells. Unlike schwannomas, they are not encapsulated, and nerve fascicles are intimately intertwined within the tumor. Immunohistochemistry shows S-100 positivity that is weaker than in schwannomas, with CD34 positivity in some components. Three types are recognized: localized or intraneural neurofibromas produce fusiform enlargement of a single nerve segment; diffuse neurofibromas form plaque-like subcutaneous growths; and plexiform neurofibromas involve multiple nerve fascicles and branches, growing along the nerve like a bag of worms and are pathognomonic for NF1.

### Clinical Presentation

Neurofibromas present as painless, soft, compressible masses. The buttonhole sign describes invagination of cutaneous neurofibromas into subcutaneous tissue when pressed. Plexiform neurofibromas may cause disfigurement, pain, and functional impairment. Neurological deficit is more common than with schwannomas due to the fascicular involvement inherent to these tumors.

### Surgical Considerations

Resection of neurofibromas is more challenging than schwannoma surgery due to fascicular infiltration. Complete excision often requires sacrifice of involved fascicles, resulting in neurological deficit. Surgery is indicated for symptomatic tumors, progressive growth, or suspected malignant transformation. Plexiform neurofibromas may require debulking for functional or cosmetic reasons, though complete resection is rarely possible. Selumetinib, a MEK inhibitor, is FDA-approved for symptomatic, inoperable plexiform neurofibromas in NF1 patients aged 2 years and older.

## Hereditary Syndromes

### Neurofibromatosis Type 1 (NF1)

NF1 is an autosomal dominant disorder caused by mutation of the NF1 gene on chromosome 17, which encodes neurofibromin, a RAS-GAP protein. The incidence is 1 in 3,000 with 50 percent representing de novo mutations. Revised diagnostic criteria from 2021 require two or more of the following: six or more cafe-au-lait macules, two or more neurofibromas or one plexiform neurofibroma, axillary or inguinal freckling, optic pathway glioma, Lisch nodules, osseous lesions, a first-degree relative with NF1, or a pathogenic NF1 variant. The lifetime risk of malignant peripheral nerve sheath tumor is 8 to 13 percent in NF1 patients, arising most commonly from plexiform neurofibromas. Warning signs of malignant transformation include rapid growth, new pain, an enlarging hard mass, and new neurological deficit.

### Neurofibromatosis Type 2 (NF2)

NF2 is an autosomal dominant disorder caused by mutation of the NF2 gene on chromosome 22, which encodes merlin, a tumor suppressor protein. The hallmark is bilateral vestibular schwannomas. NF2 is also associated with meningiomas, spinal schwannomas, and ependymomas. Peripheral schwannomas are common and usually multiple. Management centers on hearing preservation and tumor control.

### Schwannomatosis

Schwannomatosis has been recently reclassified and is associated with SMARCB1 or LZTR1 mutations. Patients develop multiple schwannomas without vestibular schwannomas, which distinguishes the condition from NF2. Chronic pain is the dominant symptom and is often disproportionate to tumor burden. Meningiomas may occur but are less common than in NF2.

| Feature | Schwannoma | Neurofibroma |
|---------|-----------|--------------|
| Capsule | Encapsulated | Non-encapsulated |
| Nerve relationship | Eccentric, displaces fascicles | Infiltrates fascicles |
| Cell of origin | Schwann cells only | Multiple (Schwann, fibroblast, perineurial) |
| S-100 staining | Strong, diffuse | Weaker, focal |
| Surgery | Intracapsular enucleation; fascicle preservation | Fascicle sacrifice often required |
| Recurrence | <5% | Higher; incomplete excision common |
| Malignant potential | Very rare | 8-13% in NF1 (plexiform) |
| Syndrome association | NF2, Schwannomatosis | NF1 |

## Malignant Peripheral Nerve Sheath Tumors (MPNSTs)

MPNSTs are aggressive sarcomas arising from peripheral nerves or preexisting neurofibromas. Approximately 50 percent occur in NF1 patients and 50 percent are sporadic. They present as rapidly enlarging, painful masses with neurological deficit. Imaging reveals heterogeneous enhancement on MRI, and FDG-PET avidity with SUV greater than 3.5 helps distinguish malignant tumors from benign neurofibromas. Treatment consists of wide surgical resection with negative margins, adjuvant radiation therapy, and chemotherapy for metastatic disease. The 5-year survival is 35 to 50 percent and is worse in NF1-associated tumors.

## Imaging

MRI is the modality of choice for peripheral nerve tumors. Schwannomas appear well-circumscribed and eccentric to the nerve with heterogeneous enhancement and a target sign on T2 characterized by central low signal and peripheral high signal. Neurofibromas are fusiform and central within the nerve, and the target sign may also be present. Features concerning for malignancy include size greater than 5 centimeters, heterogeneous enhancement, perilesional edema, and irregular margins. Ultrasound is useful for superficial tumors and guides biopsy. PET-CT helps distinguish benign from malignant lesions in NF1 patients.

## Clinical Pearls

Schwannomas are encapsulated and eccentric to the nerve, allowing intracapsular enucleation with fascicle preservation, whereas neurofibromas are infiltrative, making complete excision without neurological deficit difficult. Plexiform neurofibromas are pathognomonic for NF1 and carry an 8 to 13 percent lifetime risk of malignant transformation to MPNST. Rapid growth, new pain, or new neurological deficit in a known neurofibroma should prompt urgent evaluation for MPNST with MRI and PET-CT. Bilateral vestibular schwannomas are the hallmark of NF2, while multiple non-vestibular schwannomas without vestibular involvement suggest schwannomatosis. Intraoperative nerve stimulation is essential during schwannoma resection to identify and preserve functional fascicles.

## References
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3. Guha D, Davidson B, Nadi M, et al. Management of peripheral nerve sheath tumors: 17 years of experience. J Neurosurg. 2018;128(4):1163-1170.
4. Kim DH, Murovic JA, Tiel RL, et al. A series of 397 peripheral neural sheath tumors. J Neurosurg. 2005;102(2):246-255.