Neurofibroma

Neurofibroma is a common benign peripheral nerve sheath tumor that affects both children and adults. Unlike a schwannoma, which is encapsulated and arises exclusively from Schwann cells, a neurofibroma is unencapsulated and derives from various intraneural support cells, including Schwann cells, fibroblasts, endothelial cells, and glandular elements. It grows centrally within a nerve and can cause axon entanglement due to its involvement with the endoneurium, the innermost layer of connective tissue surrounding individual nerve fibers.

Ninety percent of neurofibromas are solitary, de novo lesions and are not associated with neurofibromatosis, which is a genetic disorder characterized by multiple neurofibromas and other tumors. Neurofibromas have two subtypes: dermal and plexiform. The dermal subtype arises from peripheral nerves, may be either cutaneous or located deep within soft tissue or muscle, and carries a lower risk of malignancy. The plexiform subtype arises from multiple nerves or fascicles, grows more extensively, and requires monitoring for malignant transformation.

Epidemiology

Neurofibromas are most commonly diagnosed in patients between 20 and 30 years of age and affect both genders equally. These tumors can increase in size and carry a risk of malignant transformation over time, particularly when associated with neurofibromatosis type 1 (NF-1) or during periods of hormonal change, such as pregnancy or puberty. The plexiform subtype is present in up to 40% of patients with neurofibromas and is most frequently seen in the pediatric population.

Clinical Features

Neurofibromas typically present as palpable, painless, cutaneous lesions. These lesions are usually firm, mobile, and less than 2 cm in diameter. A key characteristic is the “buttonhole sign,” in which palpation causes the lesion to retract into the skin. Most patients are primarily concerned with the cosmetic appearance of the lesion, although some may also report pain, pruritus, or paresthesia.

Intramuscular neurofibromas can develop from either a major nerve (where the nerve is easily visualized) or smaller nerve twigs (where the nerve may be difficult or impossible to identify). These lesions may result in more significant functional impairment due to their deeper location within muscle tissue.

The plexiform subtype presents as a poorly defined lesion, often referred to as a “bag of worms” because of its increased vascularity and complex involvement of nerve structures. The plexiform subtype can be more challenging to diagnose clinically and often requires imaging studies and biopsy for accurate evaluation. Plexiform neurofibromas can grow to substantial sizes and may cause more severe symptoms due to their extensive involvement of nerve structures.

Radiologic Features

While plain radiographs may reveal soft-tissue shadows in large neurofibromas, they are often normal or non-specific for smaller lesions. Magnetic resonance imaging (MRI) is the preferred imaging modality due to its superior soft tissue contrast and ability to delineate the tumor’s relationship with surrounding structures. On MRI, neurofibromas typically appear isointense to muscle on T1-weighted sequences and hyperintense on T2-weighted fat-suppressed sequences.

As peripheral nerve sheath tumors, neurofibromas share several characteristic MRI features with schwannomas:

Split fat sign: A thin margin of displaced fat surrounds the tumor and the associated nerve (Figure 1).
String sign: The entering and exiting nerve may be visualized on T1 coronal or sagittal sequences (Figure 2).
Target sign: On T2-weighted sequences, the tumor displays a hypointense (darker) center with a hyperintense periphery, due to central fibrosis surrounded by myxoid tissue (Figure 3).

Figure 1: Coronal T1 MRI of the thigh demonstrating a neurofibroma arising centrally within a nerve. The “split fat sign” can be appreciated both proximally and distally.

Figure 2: Coronal T1 MRI of the upper arm demonstrating a neurofibroma of the median nerve, with the “string sign” of the exiting nerve extending distally from the tumor.

Figure 3: Axial T2 fat-saturated MRI of the knee demonstrating a neurofibroma in the posterior knee. The “target sign” can be appreciated, with dark signal centrally and brighter signal in the periphery.

It is important to note that these signs may not be present in every case, and their absence does not rule out the diagnosis of neurofibroma. Even when present, these signs are suggestive but not diagnostic of this lesion. Contrast enhancement is typically heterogeneous, which can help differentiate neurofibromas from other soft tissue tumors, although a definitive diagnosis still requires biopsy for histologic confirmation.

While neurofibromas are typically centrally located within the nerve, and schwannomas are eccentrically located, distinguishing between the two can be challenging on MRI, especially when the nerve or tumor is small.

Positron emission tomography-computed tomography (PET-CT) is useful for detecting malignant transformation of neurofibromas, particularly in patients with neurofibromatosis type 1 (NF-1). These patients have an increased risk of developing malignant peripheral nerve sheath tumors (MPNST) with a roughly 10% risk per lifetime, which require prompt intervention. In cases demonstrating tumor growth with or without pain, malignant transformation should be considered, and biopsy may be necessary to establish a definitive diagnosis.

Pathology

Gross Pathology

Neurofibromas typically appear as firm, fusiform masses with a translucent gray color. They grow along the length of the nerve, and the nerve can often be seen entering and exiting the tumor from either side, reflecting its central location within the nerve. The plexiform subtype has a distinctive gross appearance, often described as a “bag of worms” due to the presence of multiple, intertwined, hypertrophic nerve fascicles and dilated blood vessels. Plexiform neurofibromas are usually poorly circumscribed and infiltrate surrounding tissues.

Histopathology

Under the microscope, neurofibromas display a characteristic “shredded carrot” appearance, consisting of numerous elongated, wavy fibroblasts with dark-staining nuclei interspersed between strands of collagen and mucoid material (Figure 4). The tumor is composed of varying proportions of cells, myxoid matrix, and collagen fibers. Neurofibromas are typically hypocellular and grow in a disorganized pattern. Unlike schwannomas, they lack Antoni A (densely cellular) and Antoni B (loosely cellular) regions. The cellular composition includes Schwann cells, fibroblasts, perineurial-like cells, and mast cells. Localized neurofibromas are well-circumscribed and typically involve a single nerve fascicle, while diffuse neurofibromas are ill-defined, often involving multiple fascicles and infiltrating surrounding tissues. Plexiform neurofibromas are usually associated with neurofibromatosis type 1 (NF-1) and have the potential for malignant transformation.

Figure 4: H&E stain of neurofibroma, demonstrating elongated, wavy fibroblasts in a hypocellular myxoid matrix with wispy collagen fibers. (Image courtesy of Dr. Gord Zhu)

Immunohistochemical staining aids in diagnosing neurofibromas and distinguishing them from other peripheral nerve sheath tumors. Neurofibromas typically show moderate to strong positive staining for S100 protein (a Schwann cell marker); positive staining for CD34, particularly in fibroblastic cells; and negative staining for epithelial membrane antigen (EMA). In contrast, schwannomas show strong, diffuse S100 positivity. The combination of these staining patterns, along with the characteristic histological features, helps establish the diagnosis of neurofibroma.

Differential Diagnosis

The primary differential diagnosis for neurofibroma is schwannoma. Differentiating neurofibromas from schwannomas can be challenging, particularly in small lesions. However, in larger lesions, their relative positions within the nerve can aid in differentiation: schwannomas tend to be eccentric, while neurofibromas are centrally located. Other conditions to consider in the differential diagnosis include lipomas, fibromas, sarcomas, ganglion cysts, and other benign or malignant soft tissue tumors. The clinical presentation, including the presence of associated syndromes like neurofibromatosis type 1 (NF-1), plays a key role in narrowing the differential.

In patients with NF-1, there should be a high index of suspicion for malignant peripheral nerve sheath tumor (MPNST) formation if the lesion shows rapid growth or increasing symptoms. MPNST can arise de novo or from malignant degeneration of a pre-existing neurofibroma, and approximately 50% of MPNST cases are associated with NF-1. Imaging features suggestive of malignant transformation include rapid growth, heterogeneous enhancement, perilesional edema, and invasion of surrounding structures. FDG-PET imaging can be useful in assessing malignant transformation, particularly in the context of NF-1.

Disease Course: Treatment and Prognosis

Neurofibromas generally have a low risk of malignant transformation, except when associated with neurofibromatosis type 1 (NF-1) in which case the risk of malignant transformation throughout life is on the order of 10%. Management is typically guided by the presence of symptoms. Small, asymptomatic tumors can often be managed with observation and serial MRI monitoring once a histologic diagnosis is confirmed. Symptomatic tumors can be treated with marginal excision but this surgery risks damage of the underlying nerve. Since neurofibromas grow centrally within the nerve, surgery may necessitate sacrificing part or all of the affected nerve, potentially leading to neurological deficits. For tumors involving large motor nerves, nerve grafting or nonoperative management, including pain management and physical therapy, may be considered to avoid loss of function.

Recurrence after surgical excision is extremely rare, which contributes to a generally favorable prognosis for most patients with neurofibromas. However, the risk of neurological deficits following surgery should be carefully discussed with patients prior to treatment.

In patients with NF-1, approximately 10% of neurofibromas, particularly those of the plexiform subtype, undergo malignant transformation into malignant peripheral nerve sheath tumors (MPNST). As a result, patients with plexiform neurofibromas should be evaluated for NF-1 and have their tumors routinely monitored. Imaging or biopsy should be promptly performed in cases of pain or rapid tumor growth to assess for malignant transformation. FDG-PET imaging can also be useful in assessing malignant transformation, particularly in NF-1 patients.

For cases that undergo malignant transformation to MPNST, the prognosis is generally poor with 5-year survival rates ranging from 35-50%. Early detection and aggressive treatment, including surgical resection, potential radiation therapy and possible adjuvant chemotherapy, are crucial in these cases.

It is important to note that neurofibromas, especially when visible, can have significant psychological impacts on patients. Psychological support and counseling should be considered as part of the comprehensive care for this disease. Additionally, genetic counseling is recommended for patients with multiple neurofibromas or suspected NF-1, as this can have implications for family planning and long-term management.

Key Test Topics

MRI demonstrates a mass centrally located within a nerve as opposed to schwannomas which tend to be peripheral.
Neurofibromas lack the Antoni A and B components of schwannomas and usually display a characteristic “shredded carrot” appearance, consisting of numerous elongated, wavy fibroblasts with dark-staining nuclei interspersed between strands of collagen and mucoid material.
Patients with NF-1 or plexiform neurofibromas are at risk of malignant transformation which presents as pain or rapid growth of the mass.

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