Schwannomatosis

Schwannomas are benign tumors of the nervous system originating in the neural sheath. Most commonly, schwannomas occur as solitary encapsulated subcutaneous tumors in an otherwise normal individual. More rarely they are multiple or arise from other points along the peripheral nervous system, including cranial nerves, spinal roots, the brachial and lumbar-sacral plexus, or major peripheral nerves. Previous designations for schwannomas included neurinoma and neurilemmoma, although schwannoma is now the preferred terminology. ^[1]

Several syndromes are associated with an increased frequency of schwannomas, the best known of which are the neurofibromatoses. The hallmark tumor of neurofibromatosis 2 (NF2) is the vestibular schwannoma (previously known as the acoustic neuroma). Over 95% of individuals inheriting NF2 will eventually develop bilateral vestibular schwannomas. ^[2] At least two-thirds of patients with NF2 develop schwannomas in other locations, especially subcutaneously, ^[3] and in NF2-affected children, development of subcutaneous tumors may precede the development of vestibular schwannomas. ^[4] NF2 is also associated with an increased frequency of meningioma, ependymoma, and astrocytoma in addition to a number of ophthalmologic abnormalities. ^[3,5] The hallmark tumor of neurofibromatosis 1 (NF1) is the neurofibroma, an entity histologically distinct from the schwannoma. ^[1] Although schwannoma is a criteria for the diagnosis of NF1, ^[6] its occurrence in NF1 is rare. ^[7]

Recent reports suggest that some patients develop multiple schwannomas without other stigmata of NF1 or NF2 and that schwannomatosis may thus be regarded as a distinct clinical entity. ^[8,9] Many of these reports were made before the NIH consensus statement on neurofibromatosis and included individuals who would now be considered to have NF2 because of the presence of vestibular schwannoma. ^[6] The purpose of this study was to analyze a group of individuals with multiple schwannomas without vestibular schwannoma to determine whether there is clinical overlap with NF1 or NF2 and to further define the clinical, pathologic, and genetic characteristics of schwannomatosis.

Methods.

The criteria for inclusion in this study were multiple pathologically defined schwannomas of any portion of the nervous system without vestibular schwannoma diagnostic of NF2. When more than one individual in a family was found to meet these criteria, only the proband was included in the present study. Eleven individuals were personally examined by one of the authors (M.M. or M.P.S.) in the neurofibromatosis clinic at the Massachusetts General Hospital. In addition, three individuals were referred to us by outside practitioners with a diagnosis of multiple schwannomas. All patients underwent gadolinium-enhanced cranial MRI with specific attention to the possibility of vestibular schwannoma or other intracranial tumor. For each patient we reviewed the medical, surgical, radiologic, and pathologic records of the patient, with specific attention to age of onset, location of tumors, other stigmata of NF1 or NF2, results of ophthalmologic evaluation, and family history. Histologic review was conducted of all available surgical specimens. To the best of our knowledge, none of these patients have been previously reported in the literature.

Case reports.

Patient 2.

A 48-year-old woman (patient 11 in Table 1) noted a tender mass of the arm in her early 30s. At age 35 she had three tumors removed from her right wrist and hand that were given a pathologic diagnosis of subcutaneous neurilemmoma. Further tumors developed over the right forearm that were exquisitely painful with even minor trauma. An MRI obtained of the forearm revealed multiple tumors along the course of the radial nerve Figure 2. Surgical exploration of the right forearm revealed at least 11 distinct tumors, pathologically schwannomas. Subsequently to surgery she had some weakness of the thumb extensor as well as decreased sensation over the distal dorsum of the right thumb; however, she has much less pain. Physical examination revealed no other cutaneous tumors and no evidence of NF1 or NF2. A neurologic examination was otherwise normal.

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Figure 2. T₂-weighted MR imaging of the right forearm in patient 11. Multiple masses appear along the course of the radial nerve (arrows).

The patient has a history of smoking 1.5 packs per day for 15 years. There is no history of other toxin or radiation exposure. There is no family history of neurofibromatosis, skin tumors, or nervous system tumors in the patient's parents, siblings, or children. An MRI of the brain and cervical spine done with contrast enhancement revealed no abnormalities.

Results.

Of these 14 patients with multiple schwannomas, there were 8 women and 6 men. Age of onset ranged from 11 to 52 years. One patient reported that tumors appeared after trauma to an involved limb; an additional patient noted an increase in size of her existing tumors during pregnancy. Two patients were exposed to industrial chemicals. No other associations were made with trauma, endogenous or exogenous hormones, or toxin exposure. No patient was found to have intradermal tumors or plaques as has been reported in NF2 patients ^[2] or Japanese neurilemmomatosis patients. ^[8] Nine of 14 patients had peripheral tumors visible by examination; these tumors were defined as deep to the dermis because the skin could be moved over them. Initial symptoms of peripheral nerve and subcutaneous tumors were primarily pain, which often became disabling. These tumors were consistently described as causing shooting pain or dysesthesia in extremities with minimal trauma. In seven patients, schwannomas were found on both spinal nerve roots and peripheral nerves. All patients with known spinal root tumors had neurologic symptoms of cord compression; however, not all neurologically normal patients underwent imaging of the spinal cord, leaving the possibility that some asymptomatic spinal tumors may have been missed. Cranial nerve involvement was seen in only one patient.

Anatomic localization was marked in three patients in whom disease was limited to peripheral nerve in a single extremity (left leg in one and right arm in two). In one patient, diffuse involvement of peripheral nerve, brachial plexus, and spinal nerve roots was completely limited to the left side of the body. One patient had tumors limited to the head and neck, and one patient had tumors limited to the spine.

No patient in this group was found to have other stigmata of NF1 ^[6] by examination, including cafe au lait macules, freckling, macrocephaly, or developmental disability. Detailed ophthalmologic examination, including slit lamp examination, was carried out in seven patients with no evidence of Lisch nodules, posterior lenticular opacity, or retinal abnormalities; a single patient was found to have senile cataract at age 72. No patient gave a history of any other NF-associated tumor such as neurofibroma, meningioma, ependymoma, or astrocytoma. Two patients had a history of unexplained nonprogressive high-frequency hearing loss. A single patient had a syndrome of unexplained weight loss.

Imaging studies revealed discreet, enhancing, well-circumscribed tumors in the limbs Figure 1 and Figure 2. Spinal tumors typically carried a ``dumbbell'' appearance. Cranial imaging was done in all 14 patients, and in no patient was abnormal enhancement seen along the eighth cranial nerve nor were tumors suggestive of meningioma seen in any case. In two patients, scattered T₂ hyperintense foci of unknown etiology were seen in the subcortical white matter.

Only one individual (patient 8 in Table 1) gave a positive family history of schwannoma. This patient's sister (not included in Table 1) had onset of pain and weakness of the left arm at age 39 and was found to have four spinal tumors, two of which were pathologically proven to be schwannomas. She had no stigmata of NF1 or NF2 or other tumors by physical examination. The father of this patient was said to have had a tumor removed from his skin in his 60s; however, he is now deceased and no pathologic details are available. No other family member of this patient is known to be affected. No other patient gave a history of skin, brain, or spinal cord tumors or neurofibromatosis in a first-degree relative. Nine individuals had a total of 18 unaffected children.

Nine patients underwent surgical removal of subcutaneous tumors because of pain. In most cases, patients had relief of pain after surgery; however, in several cases tumors recurred. Six patients underwent laminectomy for partial or total removal of dumbbell tumors of spinal nerve roots. Five of six had improvement in neurologic status after laminectomy; however, one patient had recurrence of tumor with progressive disability. The clinical characteristics of all 14 patients are summarized in Table 1.

All surgically removed tumor specimens from these patients had been given a diagnosis of schwannoma or, in older cases, neurilemmoma. Pathologic review was done by one of the authors (M.P.S.) on 11 specimens from nine patients. In all 11 cases schwannomas arose from either spinal root or deep peripheral nerves; none were intradermal. Gross examination was similar in all cases with soft, solid, pale yellow nodules. In one case (patient 5 in Table 1), the nodule was grossly encapsulated with a whorled appearance on cut surface.

Histologic evaluation of all specimens demonstrated interlacing bundles of fusiform cells with thick-walled blood vessels. Verocay bodies were particularly prominent in one case of a lumbar root schwannoma Figure 3 A. Two tumors (a brachial plexus tumor from patient 6 and a lumbar spine schwannoma from patient 3 in Table 1) revealed marked nodularity, a pattern frequently encountered in vestibular schwannomas from patients with NF2 Figure 3 B. ^[10] Other regions of these tumors exhibited a plexiform pattern with distinct bundles of schwannoma separated by stroma within a single lesion Figure 3 C. Previous authors observed that schwannomas with a plexiform pattern may have an increased potential for invasion beyond the perineurium into adjacent tissue. ^[11] The clinical course of patient 6 supports that observation with erosion of vertebral bodies and invasion into lung parenchyma. Histologic review of these patients did not demonstrate increased mitotic activity or necrosis. One patient did have conspicuous chronic inflammation and occasional mitotic figures in association with hematoma (patient 2 in Table 1, Figure 3 D). Finally, one patient showed clearly anatomically distinct schwannomas arising from branches of the radial nerve in the forearm, supporting the radiographic and surgical impression in this patient (patient 11 in Table 1 and Figure 2).

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Figure 3. Typical pathology of schwannoma specimens encountered in this report. (A) Typical Antoni A and Antoni B tissue is seen. Photomicrograph courtesy of Dr. David Louis (Neuropathology Department, Massachusetts General Hospital). (B) Marked nodularity seen in a spinal schwannoma in patient 3. (Reproduced from reference 40 with permission of the publisher.) (C) Plexiform pathology as also seen in a spinal schwannoma from patient 3. This pattern is in contrast to that seen in B in which there is no intervening stroma. (D) Mild chronic inflammatory infiltrate seen in patient 2.

Discussion.

This study describes our experience with 14 patients with multiple schwannomas. This group includes individuals with both spinal root and peripheral nerve schwannomas; however, intradermal tumors reported by Shishiba et al. ^[8] were not present. The primary symptoms related by these patients included disabling pain and neurologic disability related to cord compression. None of our patients had other manifestations of NF1. We also found no other manifestations of NF2 in this population, including meningioma, ependymoma, or ocular abnormalities such as cataract. Unlike both NF1 and NF2, which are autosomal dominant diseases with full or nearly full penetrance, there was a paucity of familiar occurrence.

Detailed pathologic review of these cases revealed typical features of schwannomas. ^[12] The significance of occasionally different patterns (nodular, plexiform, and multiple discreet tumors on a single nerve) is unclear, but they may represent different pathomolecular processes.

There have been several other reports of patients with multiple schwannomas in the literature variously described as multiple neurilemmomas (or neurilemmomas), agminated neurilemmomas, multiple schwannomas, neurilemmomatosis, or schwannomatosis. Many of these reports describe patients with highly localized disease of the peripheral nerve Table 2 reminiscent of patients 9, 10, and 11 in Table 1. In two patients, ^[13] the tumors were intradermal and were confused with a granulomatous dermatitis. Most patients presented with pain and became asymptomatic after surgical removal of their tumors. In two cases, ^[14,15] the onset of tumor formation was related to local trauma; in an additional case, the tumors appeared 6 months after local surgery. ^[16]

Some case reports of patients with multiple schwannomas without clear anatomic localization were reported before the NIH consensus statement ^[6] and include patients who would now be classified as having NF2. For example, Shishiba et al. ^[8] reviewed the clinical characteristics of four of their own cases and 29 cases previously reported in the Japanese literature who had multiple cutaneous schwannomas without NF1. At least 15 of the patients reviewed had eight cranial nerve schwannomas but not all underwent cranial imaging, leaving the true frequency of NF2 in this study unclear. Age of onset in this study ranged from birth to 41 years with 10 women and 23 men and no familial occurrences. All patients described in this work ^[8] were of Japanese origin and had intradermal lesions (often in addition to other lesions), a location that is otherwise rare outside of NF2. It is unclear whether this is a bias in reporting or a pathology peculiar to persons of Japanese extraction. Purcell and Dixon ^[9] also reported on two patients said to have schwannomatosis, but the first patient would now be recognized to have NF2.

Other reports of multiple schwannomas include those of Daras et al., ^[17] who reported a single individual with at least eight spinal schwannomas on thoracic, lumbar, and sacral nerve roots reminiscent of our patient 12. This 27-year-old woman had no evidence of intracranial tumors by MRI and no other stigmata of NF1 or NF2. Vaquero et al. ^[18] and Doi et al. ^[19] reported on two patients with multiple intracranial schwannomas. The patient of Doi et al. ^[19] most likely had NF1 with malignant metastases from a thoracic tumor. Lindboe and Nordal ^[20] reported a puzzling association of spastic paraparesis with autopsy-proven degeneration of the lateral corticospinal tracts along with multiple cauda equina schwannomas seemingly asymptomatic during life. Oda et al. ^[21] reported a similarly puzzling and perhaps serendipitous association in a 54-year-old man with three schwannomas who developed a thymoma-associated myasthenia gravis.

Multiple schwannomas in a child is a difficult clinical problem because the appearance of peripheral schwannoma may precede that of vestibular schwannomas in patients known to have NF2. ^[4] Although most of our patients were beyond the average age of presentation of vestibular schwannoma in NF2 patients, ^[22] our younger patients may eventually develop vestibular tumors. The case reported by Prevoo and Starink ^[23] illustrates this difficulty in a 4-year-old boy with multiple skin schwannomas and subcapsular posterior polar cataract. When present, a positive family history is very helpful in such cases, such as that reported in Sasaki and Nakajima ^[24] of a 5-year-old with multiple skin schwannomas whose father had bilateral vestibular schwannoma.

Three patients with multiple schwannomas have been reported who also had multiple meningiomas. Patient 2 of Purcell and Dixon, ^[9] who had at least two dermal schwannomas and a ``plaque'' reminiscent of NF2, ^[2] also had at least four spinal tumors and two intracranial meningiomas. This patient was said to be free of eighth cranial nerve tumors on the basis of a contrast-enhanced CT, although she did have diminished hearing in the right ear of unexplained cause. A similar patient, described by Murata et al., ^[25] was a severely affected child with numerous dermal tumors, bilateral brachial plexus tumors, cataracts, and at least three spinal tumors. Bilateral cerebellopontine angle tumors were present by MRI, but at least one proved to be a meningioma. Rongioletti et al. ^[26] reported a third case of a 19-year-old woman with four skin tumors and meningiomas of the left orbit and cerebellopontine angle; no spinal imaging was reported. In these three cases, the dermal tumors were said to show the relative rare pathology of plexiform schwannoma. ^[11] Because meningioma and schwannoma may intermix in at the cerebellar pontine angle in patients with NF2, ^[10] the second two patients ^[25,26] may have had eighth nerve schwannomas not seen pathologically because of sampling. The relationship of these patients to NF2 remains speculative. A table summarizing features of these and other ^[27,28] nonlocalized cases of multiple schwannomas is available from the National Auxiliary Publications Service.

Although this body of information strongly supports the concept that schwannomatosis is a distinct clinical entity, its pathophysiological basis remains unclear. Patients with highly localized disease (patients 9, 10, and 11 in Table 1 and those in Table 2) may harbor so-called ``segmental'' mutation of the NF2 gene or other schwannoma-related genes. Alternatively, they may have suffered a single early transforming event with local noncontiguous spread of tumors such as that postulated for patients with multiple meningiomas without family history. ^[29] Those persons with more generalized disease may carry a tumor suppressor gene syndrome as their phenotype is similar to more common tumor suppressor syndromes ^[30] in which inherited germline inactivation of a single copy of a tumor suppressor gene is followed by development of multiple tumors in susceptible tissues when the second copy of the gene is inactivated by random somatic mutations acquired during DNA replication. Candidates include variant forms of inactivation of both the NF1 ^[31,32] and the NF2 ^[33,34] transcript. Indeed, a recent report ^[35] implicates the NF2 transcript in a small number of patients with multiple intradermal tumors. Because of the lack of phenotypic overlap with these syndromes, a third locus-related schwannoma development must also be considered in our patients. Finally, any hypothesis regarding the pathogenetics of this disorder must also take into account the surprising lack of family history in these patients. Molecular genetic analysis of these patients and tumor material from them will be invaluable in distinguishing between these possibilities.

Note.

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Acknowledgments

We thank the patients and families who contributed to this study and Drs. Mark Edgar and Andrew Rosenberg for expert pathologic consultation.