Schwannomas (also known as neuromas, neurinomas "of Verocay" and neurilemmomas) are benign, well-encapsulated, slow-growing nerve sheath tumors composed exclusively of Schwann cells derived from the neural crest. The tumor can originate from any myelinated central or peripheral nerve with Schwann cells. The World Health Organization classifies schwannoma as a grade I benign tumor. Schwannomas are solitary in 90% of the cases. Multiple tumors in the same patient should bring attention to syndromic associations (neurofibromatosis type 2, schwannomatosis, and Carney complex).
Approximately 90% of the schwannomas are sporadic. Schwannomas occurring in specific syndromes (neurofibromatosis type 2, schwannomatosis, and Carney complex) may have a possible genetic etiology, not only in the syndromic schwannoma but in sporadic cases. Neurofibromatosis type 2 accounts for 3% of the syndromic schwannomas, while schwannomatosis for 2%, and meningiomatosis with or without neurofibromatosis type 2 in 5%.
Genetic studies show that the NF2 gene on chromosome 22 plays an essential role in sporadic and syndromic schwannoma development. The NF2 gene encodes for the merlin protein (schwannomin). Specific gene mutations in the NF2 gene cause the inactivation of the gene, thus preventing the formation of the merlin protein. Inactivation of both alleles of the NF2 gene is observed in most schwannomas. Carney complex may have a loss of PRKAR1A expression.
Spinal schwannomas can have SMARCB1 mutations and inactivation.
Of all nerve sheath tumors, schwannoma is the most common in approximately 89% of the cases. About 60% of the benign schwannomas are vestibular schwannomas. Schwannomas usually affect persons between the ages of 50 to 60. No sex or racial predilection is recognized. Tumors are generally located in the upper limbs, followed by the head, the trunk, and flexor surfaces of the lower extremities. Other locations include the posterior mediastinum, retroperitoneum, spinal roots, bone, gastrointestinal tract, pancreas, liver, thyroid, adrenal glands, and lymph nodes.
The Central Brain Tumor Registry of the United States shows that non−malignant nerve sheath tumors account for 8.6% of all central nervous system tumors reported, with no gender predominance, but a higher incidence in whites. The median age at diagnosis is 56 years. The incidence is 4.4 to 5.23 cases per 100,000 adults/year; in children and adolescents, it is 0.44 cases per 100,000/year. The incidence of malignant nerve sheath tumors is 0.03 cases per 100,000/year.
The incidence of vestibular schwannomas in the USA is 1.2 cases per 100,000/year. The median age of patients is 55 years. Similar rates occur among males and females, but higher in whites than in nonwhites. In Denmark, vestibular schwannomas have an incidence of 3.4 cases per 100,000/year with a mean age at diagnosis of 60 years. Other reported incidences for vestibular schwannomas varied between 1.8 to 2.6 cases per 100,000/year.
Spinal schwannoma incidence is 0.24 cases per 100,000/year. Spinal schwannomas are more common in white males, usually affecting persons between the ages of 65 and 74.
Although rare, it is important to acknowledge the existence of primary malignant tumors of this cell type as their histology is distinct from schwannomas. Malignant transformation may show malignant epithelioid cells, which occur even without neurofibromatosis.
Classic Schwannoma: This is an encapsulated tumor with two distinct histological regions. Antoni A tissue shows hypercellular spindle cells, sometimes palisade around eosinophilic areas (Verocay bodies). Immunostain is positive for S100 protein staining. Antoni B tissue shows a hypocellular myxomatous pattern with a background of loose connective tissue. Cyst, hemorrhage, and fatty degeneration may be present. Calcifications and mitotic figures are rare.
Cellular schwannoma: It is a relatively uncommon, but significant variant of schwannoma. It is located principally in the paravertebral region. It shows compact hypercellular areas composed entirely of Antoni A areas and devoid of Verocay bodies. Cellular schwannoma prompts consideration of malignancy due to its high cellularity, increased mitotic activity, fascicular growth pattern, and occasional locally destructive character. Clues that aid in the diagnosis include the presence of histiocyte aggregates and high expression of pericellular collagen IV. The diffuse expression of S100 protein is uncommon in spindled malignant peripheral nerve sheath tumors (MPNST), which should point toward cellular schwannoma if present. Cytokeratin immunoreactivity may manifest in some cellular schwannomas and may indicate cross-reactivity with glial fibrillary acid protein. It is important to note that cellular schwannoma is characterized by weak expression of desmin, smooth muscle actin, CD117, and DOG1.
Despite their high cellularity, cellular schwannomas do not have the malignant potential and do not metastasize. Local recurrence varies and may be higher compared to classic schwannomas. This recurrence relates partially to the location considering the propensity for deep anatomic regions not always amenable to gross total resection. However, recurrent lesions have slow growth. Mitotic activity, most of the time, does not exceed 5 per 10 high power fields. Mitotic activity, above 10 per 10 high power fields, may occur in rare instances. If other diagnostic features of cellular schwannoma are present, the proliferative action is still compatible with a benign diagnosis.
Plexiform schwannoma: This variant occurs in subcutaneous or cutaneous superficial locations and is defined by a pattern of growth that may be considered plexiform. Plexiform schwannoma has an association with schwannomatosis, NF2, and other schwannoma predisposing syndromes. These tumors may not be as circumscribed as a classic schwannoma, and a capsule might even be absent. They involve multiple fascicles. The tumors have an Antoni A pattern. Neurofilament protein immunoreactive axons are present within the lesion.
Plexiform schwannomas that originate in deep anatomic lesions are more problematic. The anatomic locations may be within soft tissues or principal peripheral nerves. They may demonstrate high mitotic activity and cellularity and may not be easily distinguishable from MPNST. Although their potential for malignancy is negligible, these tumors may have a relatively high local recurrence, occurring in approximately 50% of the cases.
Melanotic schwannoma: This subtype of schwannoma may be described as a distinctive, rare, potentially malignant neoplasm that presents with epithelioid cells and melanin accumulated in neoplastic cells and melanophages. Usually arises around the spinal nerve roots. It is positive for MelanA, and sometimes to glial fibrillary acidic protein and neurofilament protein.
Schwannomas grow slowly and may exist for years without any symptom manifestation. Schwannomas can present in various locations, which explains the variations in clinical presentations. Tenderness is felt when palpating the mass. Neurologic symptoms may show if the tumor is large. Approximately, there is a 5-year delay between symptoms and diagnosis.
Schwannomas in the extremities may present as an asymptomatic mass, mild pain in the area, or paresthesia due to pressure on the parent nerve. Sciatic nerve schwannomas can mimic disk herniation with low back pain with radiation down the leg. Schwannoma that involves the C7 nerve root, can produce thoracic outlet syndrome. A schwannoma in the ankle or the wrist can present as tarsal tunnel syndrome or carpal tunnel syndrome. The presentation of distal symptoms can be due to a lesion in a proximal nerve. Schwannoma may trigger a physiological deficit due to local pressure on the originating nerve.
Vestibular schwannomas usually present with decreased hearing, tinnitus, and imbalance. Rarely, a patient will show facial nerve palsy. Trigeminal schwannoma cause numbness or pain in the trigeminal nerve distribution. It the tumor is located at a specific root (V1, V2, or V3), pain and numbness are at the corresponding anatomical area of the face.
Plain radiography is usually not specific. Intraosseous schwannoma typically has a benign appearance. Bone foramina in the spine can be expanded. Chordomas, giant cell tumors, and chondroblastomas are part of the differential diagnoses for schwannomas. Bone destruction is usually present with these lesions, especially when the sacrum is involved.
Magnetic resonance imaging (MRI) and computed tomographic (CT) scan are among special studies to consider, but MRI is preferred. The MRI usually shows an oval or round mass with an isointense or hypointense signal on T1-weighted images and a hyperintense, heterogeneous signal on T2-weighted images. The lesion enhances uniformly with gadolinium contrast. A target sign (central area of hypointensity with a peripheral T2 signal hyperintensity) is the most specific sign of a peripheral nerve sheath tumor but is not specific for a schwannoma.
Ultrasound can be used to detect schwannomas under the skin and can be useful during surgery.
Resection in a problematic case may result in a significant physiological deficit; thus, it is preferred to leave these benign lesions under close observation. There is an increasing trend in observation of vestibular schwannomas, with fewer patients offered an initial surgery in recent years. Yearly brain MRI assesses the rate of tumor growth.
Tumor biopsy should be a consideration after confirming a nerve tumor on relevant imaging tests or nerve biopsy in case of aggressive peripheral neuropathy mimicking large nerve tumors. Schwannomas respond positively to local resection. Schwannomas do not infiltrate the nerve of origin; therefore, they usually are separated from it. Marginal excision of the lesion is done, though the nerves are not affected. If the surgeon suspects that complete resection would cause a permanent neurologic deficit, they might call for an intralesional resection or stereotactic radiosurgery. Trigeminal schwannomas in the pterygopalatine fossa or infratemporal fossa benefit more from endoscopic endonasal approaches. Surgery on vestibular schwannomas uses the retrosigmoid, middle fossa, or translabyrinthine approach depending on the size of the tumor, the location, and the experience of the surgeon.
Stereotactic radiosurgery becomes necessary if the growing tumor is near vital blood vessels or nerves. Hearing preservation and tumor control show excellent results with treatment. More than 75% of the patients retain serviceable hearing. The radiation dose to the central cochlea should be less than 4.2 Gy.
Prognosis is excellent. Recurrence after total resection is uncommon. Malignant changes may occur in long-standing schwannomas, although this is rarely reported. The malignant changes mostly occur in patients that have an underlying neurofibromatosis. Prognosis also depends on the size, location of the tumor, and underlying conditions.
Most of the complications occur post-surgically. The occurrence of postoperative complications is significantly higher in younger patients, large tumor size, deep location of the tumor, and tumors originating from the ulnar nerve.
Frequently reported complications:
Schwannoma typically has a benign course; however, in rare cases, it can undergo malignant transformation. Patients should be encouraged to follow-up with the neurosurgeon, peripheral nerve surgeon, or radiation oncology to discuss the management plans regularly. Frequent CT/MRI monitoring is necessary to assess the tumor size in those tumors under observation.
Due to schwannoma's benign nature, prompt diagnosis and treatment are necessary in suspected cases. An interprofessional team approach will improve patient outcomes. The interprofessional group should include a neurosurgeon, peripheral nerve surgeon, and radiation oncologist. Collaboration, shared decision-making, and communication are crucial elements for a good outcome.
Due to the implication of a nerve with the possibility of injury, some patients require physical therapy to rehabilitate their face or the extremity affected.
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