Schwannomas do not have specific imaging characteristics and share some features with neurofibromas. Often, the two lesions cannot be distinguished. MRI is particularly useful for depicting the tumor; a fusiform, ovoid, or dumbbell-shaped tumor located on a large peripheral nerve often can be seen with a low-to-intermediate-intensity T1 signal or a high-intensity T2 signal (Figure 1). Sometimes the nerve of origin can be detected next to the tumor. T2-weighted studies may reveal the nonspecific target sign, which consists of a central target with relatively low signal intensity and a peripheral rim of high signal intensity. The target sign corresponds pathologically to central fibrocollagenous tissue and peripheral myxoid tissue.¹ T1-weighted studies may show the split-fat sign, in which there is a high-signal rim of fat surrounding the tumor. This sign can occur if the tumor originated in an intermuscular location, where there is adipose tissue in the adventitia between muscles³ (Figure 2). A so-called dumbbell lesion may be seen in an enlarging tumor located in the neural foramen or in the internal acoustic meatus, where the tumor has eroded or compressed the adjacent bone.

On ultrasonography, a schwannoma appears as a well-defined hypoechoic mass. On CT, the mass is well defined and hypodense. A so-called ancient schwannoma is a long-standing lesion with advanced degeneration that exhibits calcification, hyalinization, and cystic cavitation; these features can be identified to a varying extent on all imaging modalities⁴ (Figure 3). A heterogeneous appearance with degeneration and cystic cavitation is more likely in schwannoma than in neurofibroma.⁴

A schwannoma usually is tan or white in color, homogenously firm, globoid, and well encapsulated in a nerve sheath, with eccentric growth on the parent nerve (Figure 4). Cut sections show a mixture of gray or white fibrous tissue and bright yellow lipid-rich foci. A schwannoma may have cysts or calcifications. Tumor size varies greatly and usually depends on anatomic location. In the pelvis, schwannomas can reach enormous size and be highly vascular, making them quite challenging to remove.

Schwannomas are composed of Schwann cells, which are spindle shaped with poorly defined eosinophilic cytoplasm and a basophilic nucleus. The cells often assume a teardrop shape. These tumors have two distinct histologic regions. The Antoni A regions are highly ordered and compact collections of Schwann cells arranged in short, intersecting bundles, linear arrays, or sheets. Nuclei tend to palisade around eosinophilic anuclear areas containing cell processes. These stacked arrangements of elongated palisading nuclei are called Verocay bodies (Figure 5). The Antoni B regions are loosely arranged and less cellular because of accumulation of extracellular mucin, which gives the region a myxoid appearance (Figure 6).

The capsule of a schwannoma consists of spindle cells with associated collagen from perineurial and epineurial connective tissue. Common vascular changes are thick-walled, hyalinized vessels with perivascular deposits of hemosiderin. In Antoni B areas, thin-walled vessels surrounded by edematous stroma are common as well. Infiltrates of lymphocytes and plasma cells as well as collections of lipid-laden foamy macrophages are common. Special studies are not required for a typical schwannoma; all variants uniformly stain positive for S100 protein.

Although a conventional schwannoma or neurilemoma is most common, several other types of schwannoma exist. Cellular schwannoma is characterized by Antoni A architecture, high cellularity, and proliferative activity. The cells mainly have a spindle shape. Histologically, a cellular schwannoma can simulate a malignant peripheral nerve sheath tumor, with its high mitotic rate; however, it is benign and does not transform into a malignant peripheral nerve sheath tumor. Usually, a cellular schwannoma occurs in the posterior mediastinum or pelvis. The recurrence rate after incomplete excision can be as high as 40%.⁵

A plexiform schwannoma is characterized by multinodular or wormlike cutaneous tumors. Visceral types can occur but are rare. Histologically, a plexiform schwannoma has typical Schwann cells with more Antoni A areas than Antoni B areas and lacks a thick capsule, especially in the cutaneous type. Recurrence can result from incomplete excision, irregular fingerlike growth, or lack of thick encapsulation. There is no association with neurofibromatosis type I (NF1). The tumors are benign, and, as with cellular schwannomas, a high mitotic index is not prognostically important.

Melanotic schwannoma, often mistaken for melanoma, are rare tarlike tumors that lack a grossly defined capsule. Plump spindle-shaped and epithelioid cells are arranged in sheets, lobules, and fascicles and often are accompanied by densely pigmented histiocytes. These
tumors tend to arise from spinal nerves and paraspinal ganglia.⁶ Approximately 10% are malignant, and the presence of macronucleoli or necrosis suggests malignancy. Psammomatous melanotic schwannomas often are associated with the Carney complex, a rare autosomal dominant heritable syndrome that includes cutaneous lentigines, cardiac myxomas, and endocrine neoplasms. Psammoma bodies (small, round calcifications) and cells resembling adipocytes typify these tumors. The diagnosis of this variant is important because of the morbidity associated with cardiac myxoma and the potential for metastasis.

Intraosseous schwannomas are rare benign neoplasms that should be considered in the differential diagnosis of well-defined expansile lytic lesions with sclerotic borders. This is particularly important in middle-aged adults with a mandibular, sacral, or vertebral body mass.

Schwannomatosis is an umbrella term that includes a group of rare syndromes involving multiple schwannomas. Traditionally, schwannomatosis was distinguished from NF2, which denoted patients with germline mutations of the neurofibromin 2 NF2 gene. These patients exhibited bilateral schwannomas of the eighth cranial (vestibulocochlear) nerve and, less frequently, ependymomas, cataracts, and retinal pathology. Although the term neurofibromatosis type II is still commonly used, according to a 2022 study the current nomenclature based on an international consensus favors the term NF2-related schwannomatosis instead of neurofibromatosis type II or NF2, in part to minimize confusion with neurofibromatosis type I.⁷ With new advances in genetics, the classification of schwannomatosis was updated in 2022 to include several entities: NF2-related schwannomatosis, SMARCB1-related schwannomatosis, LZTR1-related schwannomatosis, 22q-related schwannomatosis, and other schwannomatosis. The abbreviated term NF2 in the following text will be used for NF2-related schwannomatosis.

In contrast to NF2-related schwannomatosis, the other schwannomatoses generally do not involve the eighth cranial nerve, but may have occasional meningiomas. They can occur in both familial and sporadic forms. The most common symptom is chronic pain ranging from mild to severe. Based on the tumor location, symptoms can include numbness, weakness, paresthesia, and headache. Classically, the criteria for clinical diagnosis of schwannomatosis (non-NF2 related) are fulfilled if the patient has two or more nonintradermal schwannomas, is older than 30 years, has no evidence of vestibular schwannomas on high-quality MRI, and does not have a known constitutional NF2 mutation.⁸ Alternatively, schwannomatosis can be diagnosed if the patient has a first-degree relative with schwannomatosis and has one or more pathologically confirmed nonvestibular schwannomas, without reference to patient age, MRI findings, or results of NF2 mutation testing. Potential schwannomatosis can be diagnosed without MRI if the patient does not have symptoms of eighth cranial nerve dysfunction, is older than 45 years, has two or more nonintradermal schwannomas, and does not have a known constitutional NF2 mutation.⁹

Schwannomatosis affects men and women equally and becomes symptomatic when the patient is age 20 to 50 years.¹⁰ Patients with schwannomatosis tend to be younger than patients with a solitary schwannoma. The physician therefore should suspect schwannomatosis in a relatively young patient with multiple schwannomas who does not meet the criteria for NF2.¹⁰ The first-appearing symptom is pain from the mass or spinal cord compression.¹⁰ In most instances, schwannomatosis is sporadic; familial schwannomatosis accounts for fewer than 20% of patients.⁷ Areas commonly affected include the spine (74%) and peripheral nerves (89%), whereas cranial nerve schwannomas (mostly trigeminal) are uncommon (8%).¹¹ Because the spine is affected in most patients, MRI of the spine should be part of the routine evaluation. Routine whole-spine MRI imaging is recommended regardless of the location of the symptomatic tumor because schwannomatosis-related schwannomas tend to enlarge and grow into previously healthy nerves.¹⁰

The genetic basis of schwannomas is complex, and it is important to note that different genes affect different clinical subsets. Mutations in the NF2 gene at position 22q12.2 appear to be the basis of sporadic schwannomas and NF2 but not familial schwannomatosis.¹² This tumor-suppressor gene codes for moesin-ezrin-radixin-like protein (MERLIN; also called schwannomin or neurofibromin 2), a cell membrane-associated protein that links the cell membrane and the cytoskeleton and functions in intracellular signaling pathways. The mutations decrease the synthesis of MERLIN. The NF2 gene follows the two-hit hypothesis: the mutation must affect both alleles that code for MERLIN protein to reduce its expression sufficiently to cause tumor formation.¹³

The molecular basis of schwannomatosis appears to involve a variety of different genetic mechanisms. The SMARCB1 tumor-suppressor gene and its product, the integrase interactor 1 (INI1) protein, are involved in approximately 50% of familial schwannomatosis. Interestingly, mutation of SMARCB1 is infrequent in sporadic schwannomas. Of the remaining patients with schwannomatosis and without mutation in SMARCB1, most carry a mutation in LZTR1.² Familial schwannomatosis and sporadic schwannomas also differ in their patterns of INI1 staining.^14,15 The calcineurin-binding
protein 1 (CABIN1) gene, adjacent to the NF2 gene on chromosome 22, has been implicated in the pathogenesis of both NF2 and schwannomatosis.¹⁶

Excision of a schwannoma usually can spare the parent nerve because the tumor is separable from the underlying nerve fibers. The excision usually is performed over the nerve parallel to the fascicles so that the mass can be almost extruded. The encapsulation of the tumor facilitates the excision. For tumors that originate from a nonexpendable nerve, after exposure, the tumor will be stimulated with a stimulating electrode and the muscle activity will be recorded by a sensor. If response is recorded, it means the nerve of origin is a motor nerve. In this case, if a nerve bundle is identified on the surface of the tumor, an incision is made along the bundle and the tumor will be enucleated. If no nerve bundle is identified, electrical stimuli will be applied to identify which part of the tumor surface has no motor response, and then an incision is made over the unresponsive area to enucleate the tumor.

However, if there is no response to the electrical stimulation, it means the nerve of origin is expected to be a sensory or sympathetic nerve. In this case, if a nerve bundle is identified on the surface of the tumor, an incision is made along the bundle and the tumor will be enucleated. If no nerve bundle is identified, because electrical stimulation will not be helpful, incision will be made over the most swollen area of the tumor to cut the part that likely has the least amount of fibers. If the nerve bundles are tangled in the tumor, piecemeal resection is used to avoid maximum nerve injury.¹⁷ In these cases, despite the risk of incomplete removal, recurrence or progression is unusual.¹ Management of schwannomatosis follows the same principles. Many experts surgically treat only symptomatic tumors or those that are enlarged at follow-up.¹⁰

Nonsurgical options are limited. Radiation has limited use because of the risk of malignant transformation in NF2-deficient schwannomas.¹⁸ The efficacy of chemotherapy drugs has been limited and transient.¹⁹ Schwannomas are appropriate targets for gene therapy, because of their homogenous Schwann-lineage cellular composition, slow growth, and mitotic index. In this process, a tissue-specific transgene that is capable of selectively killing schwannoma tumor cells is delivered into the tumor. There are a few preclinical schwannoma gene therapy studies. By using the Schwann-lineage cell specific promoter, P0, intratumoral injection of a herpes simplex virus 1 amplicon vector expressing caspase 1²⁰ or intratumoral injection of an adeno-associated virus 1 vector for delivery of an N-terminal fragment of gasdermin-D as a transgene will prevent transgene expression in neurons and will selectively kill the schwannoma tumor cells.²¹