Continuing Education Activity

Neurofibromas are the most common peripheral nerve sheath tumor and are often found either by patients or during routine skin exams. These lesions appear as soft, skin-colored papules or small subcutaneous nodules. There are three main types of neurofibromas: localized, diffuse, and plexiform. The majority of neurofibromas are sporadically-occurring and localized and have an extremely low risk of malignant transformation. However, the plexiform type is pathognomonic for neurofibromatosis type 1 and carries an increased risk of malignant transformation. This activity reviews the evaluation and management of neurofibromas and highlights the role of the interprofessional team in managing affected patients.

Objectives:

• Describe the appearance of a neurofibroma.
• Explain how to counsel a patient with multiple cutaneous neurofibromas or a plexiform neurofibroma.
• Identify management considerations for patients presenting with neurofibromas.
• Explain the importance of collaboration and communication amongst the interprofessional team to improve outcomes for patients affected by neurofibromas.

Introduction

Neurofibromas are the most prevalent benign peripheral nerve sheath tumor. Often appearing as a soft, skin-colored papule or small subcutaneous nodule, they arise from endoneurium and the connective tissues of peripheral nerve sheaths. Neurofibromas are comprised of Schwann cells, fibroblasts, perineural cells, and mast cells in a variably myxoid background.[1] A mutation in the NF1 gene causes neurofibromas. There are three main types of neurofibromas: localized (most common), diffuse, and plexiform. Although the majority of neurofibromas occur sporadically and have an extremely low risk of malignant transformation, the plexiform type is pathognomonic for neurofibromatosis type 1 (NF 1). It carries an increased risk of malignant transformation.[2] The complete excision of the lesion is curative.

Etiology

Approximately 90% of cases occur sporadically, while the remaining cases are associated with neurofibromatosis type 1 or 2.[3][2]

Epidemiology

Neurofibromas are the most common tumor of the peripheral nerve sheath, affecting men and women equally, without racial or ethnic predilection. Age of onset is highly variable; however, localized lesions most commonly occur in adults aged 20 to 40 years. The diffuse and plexiform types occur more frequently in children, with the plexiform type rarely occurring after age 5.[4]

Pathophysiology

In both sporadic and syndromic cases, neurofibromas are a result of a deletion in the NF1 gene. In sporadic cases, only the lesional cells carry the NF1 mutation. In syndromic cases, neurofibromas are the result of a germline mutation in NF1, encoding the tumor suppressor protein neurofibromin, on chromosome 17q11.2.[5][6]

Histopathology

Macroscopic: Often an unencapsulated, well-circumscribed, grey-tan firm mass. Typically ovoid or fusiform, with a pale gelatinous cut surface. Usually, no areas of degeneration, necrosis, or hemorrhage are grossly identified. There may be transected nerve fibers attached to the mass forming portion of the lesion.[7] The plexiform type is often large, with multiple tortuous nerve fascicles, grossly described as a "bag of worms."

Microscopic Exam Histologic Features [8][7]

• Loose and haphazard spindled cells with poorly defined cell borders
• Background of myxoid to pale pink collagenous matrix
  • Coarse collagen bundles are present and often described as “shredded carrots.”
• Low to moderate cellularity
• Mast cells commonly found within the lesion
• Small, hyperchromatic, wavy nuclei, resembling “diving dolphins,” sometimes with nuclear enlargement and smudgy chromatin
• Nuclei may also be described as “buckled” or “comma-shaped.”
• Rarely, may encounter multinucleated giant cells
• Absent to minimal mitoses
• May also occur within the nerve (intraneural localized neurofibroma) 

Localized Type[2][7]

• Well circumscribed lesion in the dermis or subcutaneous tissue 
  • Dermal lesions typically unencapsulated with a "grenz zone" of uninvolved dermis between lesion and epidermis
  • Subcutaneous lesions often have a true capsule

Diffuse Type[9]

• Poorly defined, expansile proliferation around adnexal structures, extending into the subcutaneous tissue and infiltrating adipose
• May entrap nerves or be intraneural (intraneural diffuse neurofibroma)
• Characteristic pseudomeissnerian corpuscles, comprised of fibrillary and whorled Schwann cells

Plexiform Type[10] 

• Multiple intertwined hypertrophic nerve fascicles 
• Serpentine pattern with multiple nodules
• May have predominantly myxoid or edematous background with thick collagen fibers
• May have atypia (nuclear enlargement, hyperchromasia) related to the degenerative change

Variants Most Commonly Associated With Localized Type And Less Commonly Diffuse Type Neurofibromas[11][12][13][14][15][16][17][18]

• Cellular: Increased cellularity, with or without atypia, no significant increase in mitotic activity
• Pigmented: Histologically and immunohistochemically shows melanin production
• Atypical/Bizarre: Hyperchromatic, pleomorphic, atypical nuclei with degenerative change, arranged in a distinct lamellar pattern
• Epithelioid: Cohesive nests of epithelioid tumor cells
• Granular cell: Contains granular cells, eosinophilic and similar in appearance to those comprising granular cell tumors
• Lipomatous: Diffusely scattered adipocytes, intrinsic to the tumor
• Dendritic cell: Dendritic cell morphology with pseudorosettes
• Hybrid neurofibroma/schwannoma: Nodules resembling schwannoma within a typical neurofibroma

Immunohistochemical Evaluation[8][13][19]

• S100 (+) in Schwann cells (approximately 50% of tumor cells)
• CD34 (+) in spindled fibroblasts with distinct “fingerprint” immunopositivity.
  • The “fingerprint” is due to positive staining between whorled collagen bundles, resembling a human fingerprint - this “fingerprint,” if present in greater than 60% of the lesion, is useful in diagnosing neurofibroma and distinguishing neurofibroma from early desmoplastic melanoma
• EMA (+) in occasional perineural cells
• Myelin basic protein (+)
• Neurofilament protein (+) in intratumoral axons
• Acid mucopolysaccharides (+) in mucinous stroma

History and Physical

Patients with neurofibromas are often asymptomatic; however, irritation, mild pruritus, pain, or paresthesia, can occur. The presentation may vary by type of neurofibroma, but the most common chief complaint is cosmetic appearance.[20]

Localized lesions commonly present as a painless skin-colored or violaceous papule, nodule, or subcutaneous mass. Solitary lesions are typically less than 2 cm and have a characteristic “buttonhole sign,” where on palpation, the lesion retracts into the subcutis and reappears on the release of pressure. Localized neurofibromas can occur anywhere on the body, with a predilection for the trunk, head/neck, and extremities.[21] Lesions are often thought to be nevi or acrochordons clinically.

Diffuse neurofibromas most commonly present on the head/neck as ill-defined, indurated plaques with thickened skin. Mild numbness or tingling may occur if the lesion is large.[22]

Plexiform neurofibromas most commonly occur on the head/neck, trunk, and extremities. They surround multiple nerve fascicles and can grow to be large. If superficial, they commonly present as a skin-colored or hyperpigmented nodular swelling. Deeper lesions arising from spinal nerve roots may become highly irregular and tortuous. Deep lesions may present with pain, numbness, paresthesias, mass effect, and sequelae of spinal nerve compression.[21]

Evaluation

Evaluation of solitary superficial lesions is often by physical exam and/or excisional biopsy with microscopic examination. Larger lesions require biopsy and/or additional imaging by CT/MRI to assess the extent of involvement and plan for surgical excision.[23][24]

Treatment / Management

For most cases, complete surgical excision is the preferred treatment, with local recurrence extremely rare. There are currently no alternative therapies for cutaneous neurofibromas.[25]

In rare cases of diffuse or plexiform neurofibromas where complete surgical excision is not possible, lesions are often totally resected for cosmetic or symptomatic relief. These patients require monitoring to watch for rapid growth or recurrence at the discretion of the clinical providers. Interferon-alpha has been studied as an adjunct therapy for plexiform neurofibromas, with variable results.[26][21]

Differential Diagnosis

Malignant peripheral nerve sheath tumor: An aggressive neurogenic neoplasm arising from peripheral nerve or pre-existing nerve sheath tumor, including neurofibromas. Approximately 50% of cases are associated with NF1. A history of rapid growth in a prior stable neurofibroma is suspicious.  Histologically there may be areas of admixed neurofibroma. The malignant portion will show increased cellularity, mitoses, and necrosis. Immunohistochemistry: S100 focally positive in approximately 50% of tumors.[7][27] Epithelioid MPNST can be negative for INI-1, about 30% of the time.

Schwannoma: A benign peripheral nerve sheath tumor comprised predominantly of Schwann cells. Associated with somatic and germline mutations in NF2. Histologically often more cellular, circumscribed, with Verocay bodies and Antoni A and B areas. Immunohistochemistry: Diffuse, uniform staining with S100.[28]

Perineuroma: A rare, benign mesenchymal tumor comprised of perineural cells. No definitive association with neurofibromatosis. Immunohistochemistry: EMA(+), Claudin-1(+), GLUT1(+) S100(-), CD34(+/-).[29]

Dermatofibroma: A benign proliferation of fibroblasts and histiocytes within the dermis. Often presents as an indurated papule. Immunohistochemistry: FXIIIA(+), CD163(+), CD68(+), CD34(-).[30]

Dermatofibrosarcoma protuberans: A low-grade fibroblastic sarcoma affecting the dermis and subcutis, with COL1A1-PDGFB gene fusion. This lesion is locally aggressive with a high rate of recurrence (50%) and increased risk of progression and metastasis. Immunohistochemistry: Diffuse CD34(+), S100(-), FXIIIA(-).[30]

Superficial leiomyoma: A benign dermal smooth muscle neoplasm, often arising from arrector pili (pilo-leiomyoma). Immunohistochemistry: SMA(+), MSA(+), Desmin (+).[31]

Neurotized melanocytic nevus: A benign nevus with melanocytic nests and loose neurotized stroma. Immunohistochemistry: Melanocytic markers(+).

Ganglioneuroma: A benign tumor of neural crest origin, comprised of ganglion cells arising from nerves. Most commonly found in the posterior mediastinum and retroperitoneum. Immunohistochemistry: S100 protein stains Schwann cells and synaptophysin stains ganglion cells. 

Plexiform fibrohistiocytic tumor: An infiltrative mesenchymal neoplasm, most commonly at the dermal-subcutaneous junction, comprised of fibroblasts and histiocytes. Immunohistochemistry: SMA(+), S100 protein (-).[32]

Desmoplastic melanoma: An invasive melanoma that often resembles a dermal scar. Frequently there is an associated melanoma in-situ. Often large at diagnosis, there can be peripheral lymphoid aggregates and cytologic atypia. Immunohistochemistry: S100 and SOX10 (+).[33][34]

Prognosis

All types of neurofibromas are benign. Local recurrence is extremely rare complete excision of the lesion, and the risk of malignant transformation is exceedingly low; however, malignant transformation affects approximately 10% of patients with NF1.[35][36] NF1 should be considered for any patient presenting with a plexiform neurofibroma. Plexiform types are also the most common precursor to malignant peripheral nerve sheath tumors.  Patients with multiple localized neurofibromas should also be candidates for further neurofibromatosis testing.[37][38]

Complications

The complications related to localized neurofibromas are mild and typically related to surgical excision of the lesion: pain, bleeding, scarring, and local infection. In plexiform lesions, complications arise from the inherent risks of surgery, and in rare cases, the inability to surgically remove the entire lesion. In patients with NF1 and persistent lesions, there is an increased risk of malignant transformation to malignant peripheral nerve sheath tumors.[35][36]

Deterrence and Patient Education

There are no definitive risk factors for sporadic neurofibromas that develop in the absence of NF1. In the setting of multiple localized, diffuse, or plexiform neurofibromas, café au lait macules, intertriginous freckling, optic glioma, Lisch nodules, or skeletal dysplasias, neurofibromatosis should also merit diagnostic consideration.[39][38]

Enhancing Healthcare Team Outcomes

Appropriate diagnosis and treatment of neurofibromas depend on the collaborative efforts of an interprofessional healthcare team. It is crucial for the clinician to communicate history and physical exam findings to the pathologist, and for the pathologist to communicate diagnosis and pertinent details to the clinician, primary care provider, and nurse practitioner, and nursing staff. An accurate history and physical, diagnosis, and interprofessional communication ensure the best outcome for the patient.[3] As plexiform neurofibroma is associated with NF1, care should be taken to communicate that fact to clinicians if rendering this diagnosis. Similarly, it is best to not render this diagnosis lightly without an appropriate clinical and gross description of the lesion. Dermatology and plastic surgery nurses assist with surgery, arranging for follow up, and educating patients and their families. [Level 5]