Schwannoma

A schwannoma, also known as a neurilemoma, is a common benign tumor composed of neoplastic Schwann cells, the cells responsible for myelinating peripheral nerves. Schwannomas primarily develop in the peripheral nervous system, though they can affect cranial nerves, such as the vestibular nerve. Multiple schwannomas are a feature of neurofibromatosis type 2 (NF2) and schwannomatosis. (Schwannomatosis is a rare genetic disorder distinct from neurofibromatosis types 1 and 2, associated with the development of multiple schwannomas). Schwannomas associated with NF2 typically present before the age of 30, while those associated with schwannomatosis usually manifests in adulthood. Bilateral vestibular schwannomas are a hallmark of NF2.

Epidemiology

Approximately 90% of schwannomas occur as solitary lesions, with the remaining 10% associated with genetic conditions such as neurofibromatosis type 2 (NF2) or schwannomatosis. Schwannomas affect men and women equally and can develop at any age, though their peak incidence is between the third and sixth decades of life. These tumors are typically small and slow growing, arising from the Schwann cells of peripheral nerves. They tend to remain connected to the nerve sheath eccentrically, displacing rather than infiltrating the nerve fibers.

Schwannomas can develop anywhere Schwann cells are present, including nerve branches in muscles and nerve roots in the pelvis or spine. The most common locations are the head and neck (especially the vestibular nerve), flexor surfaces of the extremities, and the posterior mediastinum. While exact prevalence data are limited, schwannomas are considered relatively rare in the general population.

Malignant transformation of schwannomas is extremely rare, occurring in fewer than 1% of cases.

Clinical Features

Schwannomas are slow-growing tumors that are often asymptomatic or discovered incidentally via imaging. When visible or palpable, they may appear as a spindle-shaped (fusiform) swelling along the course of a nerve. Importantly, schwannomas develop beside the intact nerve fascicles (bundles of nerve fibers), rather than within or entangling the nerve fibers themselves. This characteristic growth pattern often allows the tumor to be surgically separated from the nerve with minimal or no damage.

Patients may experience symptoms related to the affected nerve, including radiating pain along the nerve’s distribution, paresthesias (abnormal sensations such as tingling, numbness, or ‘pins and needles’) in the area supplied by the nerve, and a positive Tinel’s sign, where tapping over the tumor site causes radiating pain or tingling along the course of the nerve. Despite these symptoms, function in adjacent, uninvolved portions of the nerve is typically preserved.

In some cases, larger tumors may cause additional local symptoms due to pressure on surrounding structures, potentially leading to more significant discomfort or functional impairment. However, many schwannomas remain asymptomatic throughout their course, especially when they are small or located in areas where they do not compress sensitive structures.

Radiographic Features

On magnetic resonance imaging (MRI), schwannomas typically demonstrate low signal intensity on T1-weighted sequences and high signal intensity on T2-weighted sequences, with diffuse enhancement following gadolinium contrast. These characteristics reflect the tumor’s cellular composition, with Antoni A areas (high cellularity) and Antoni B areas (less cellular, myxoid regions).

When present in larger peripheral nerves, schwannomas may show the “string sign” on sagittal or coronal MRI (Figure 1), where the normal nerve is visible entering and exiting the tumor at its proximal and distal poles. Approximately 20% of schwannomas exhibit the “target sign” on T2-weighted images, characterized by a central low-intensity area surrounded by a hyperintense rim. This pattern reflects the compact Antoni A tissue in the center and the less cellular Antoni B tissue in the periphery. However, the “target sign” is not pathognomonic for schwannomas, as it can also appear in neurofibromas and other tumors.

Schwannomas may originate from small nerve twigs within a muscle, which can make identifying the nerve of origin challenging, especially in larger tumors. This can sometimes lead to confusion with other soft tissue tumors on imaging. While MRI is the gold standard for schwannoma imaging, ultrasound can also be useful for superficial lesions, where schwannomas typically appear as well-defined, hypoechoic masses with posterior acoustic enhancement.

It is important to note that although imaging findings are suggestive, they are not definitively diagnostic. Biopsy or excision with histopathological examination remains essential for confirming the diagnosis and differentiating schwannomas from other nerve sheath tumors and from other tumors that may occur adjacent to nerves.

Pathology

Schwannomas typically present as well-encapsulated, white to yellowish tumors (Figure 2). One of their key features is their ability to be easily separated from surrounding nerve fascicles, reflecting their growth alongside the nerve rather than within it. Microscopically, schwannomas exhibit a biphasic pattern, characterized by two distinct tissue types: densely cellular regions composed of tightly packed spindle cells arranged in intersecting bundles (Antoni A areas) and less cellular regions (Antoni B areas) (Figure 3). The Antoni B areas contain loosely arranged cells within a myxoid matrix, giving them a relatively “barren” appearance compared to Antoni A areas.

A pathognomonic feature of schwannomas, particularly in Antoni A areas, is the presence of Verocay bodies. These structures consist of two rows of aligned nuclei in a palisading formation surrounded by acellular eosinophilic zones. The presence of Verocay bodies helps differentiate schwannomas from other peripheral nerve sheath tumors.

“Ancient change” may occur in longstanding schwannomas which have outgrown their blood supply and degenerated (without malignant transformation). These changes include the presence of nuclear atypia and pleomorphism, very low mitotic activity, an increase in Antony A hypocellular areas, and fibrosis including thick-walled blood vessels.

Schwannomas show strong, diffuse positivity for S100 protein in both the cell nuclei and cytoplasm, confirming their Schwann cell origin. SOX10 is another immunohistochemical marker that may aid in diagnosis.

The most common cytogenetic abnormality in schwannomas is the complete or partial loss of chromosome 22, where the NF2 gene is located (chromosome 22q12). This genetic mutation plays a significant role in the development of schwannomas, particularly in cases associated with neurofibromatosis type 2 (NF2).

Differential Diagnosis

The primary differential diagnoses to consider are neurofibroma and synovial sarcoma, which can also be painful and grow adjacent to a nerve. Schwannomas and neurofibromas are both types of benign nerve tumors, but they have some key differences. Schwannomas originate solely from Schwann cells, which produce the myelin sheath around nerves. Schwannomas typically grow as a distinct mass that pushes the nerve aside, compressing it externally. Schwannomas are usually solitary tumors whereas neurofibromas can be solitary or multiple. Schwannomas are characteristic of neurofibromatosis type 2 whereas neurofibromas are typically associated with neurofibromatosis type 1 (NF1). Schwannomas are generally amenable to surgical excision as they do not intertwine with nerve fibers. Also, schwannomas rarely become malignant.

Disease Course: Treatment and Prognosis

Asymptomatic, histologically verified schwannomas can be observed. They have a very low likelihood (<1%) of malignant transformation, even if continued growth is noted. Marginal excision is performed for symptomatic lesions. For schwannomas that are associated or continuous with larger peripheral nerves, the epineurium is incised to reveal the schwannoma and adjacent nerve fascicles, from which the tumor is carefully peeled and excised. Recurrence is rare.

A needle biopsy should be considered for any painful or growing mass, even if it appears close to or within a peripheral nerve.  Some consideration is needed here, however, in light of the low but real incidence of nerve injury associated with needle biopsy of a tumor intimately associated with a major nerve.  Considering this, in cases that look to be a benign schwannoma by imaging, and which have a positive Tinel sign; it is reasonable to perform a primary excision and a frozen section analysis in order to prevent possible nerve injury from the needle biopsy. Large schwannomas are often biopsied given the concern for malignancy, while small malignant tumors can be mistaken for schwannomas. Thus, a biopsy prior to excision can be valuable even if a schwannoma is suspected.

Key Test Topics

• Schwannomas in a large nerve may present with a string sign on MRI where the normal nerve is seen entering and exiting the proximal and distal poles of the tumor.
• Clinically, symptomatic schwannomas can present as a painful soft-tissue mass with a positive Tinel’s sign
• On pathology, schwannomas present with a biphasic pattern of Antoni A (densely packed spindle cells) and Antoni B areas (loosely packed cells in a myxoid background), Verocay bodies (rows of palisading nuclei in the Antoni A areas), thick walled capillaries and strong S100 positivity.