Cranial and Spinal Nerve Sheath Tumors

Cranial and Spinal Nerve Sheath Tumors


Clinical Context

A large number of neurosurgical specimens originate outside of the central nervous system (CNS) proper from the perineural cells of the cranial and spinal nerve roots, the vast majority of which are schwannomas. In one large series including patients of all ages, schwannomas were the third most common tumor of the spinal cord area, following meningiomas and ependymomas and constituting more than 20% of all spinal tumors (1). Most patients are middle-aged adults, with no predilection for either sex. Vestibular schwannomas typically present with progressive sensorineural hearing loss (2), and spinal nerve root schwannomas present with local or radicular pain and/or sensory loss (3).

Type 2 neurofibromatosis (NF2), an autosomal dominant tumor predisposition syndrome caused by mutations in the NF2 gene on chromosome 22q, is strongly associated with schwannomas both in and out of the CNS. In addition to bilateral vestibular nerve schwannomas, NF2 patients develop meningiomas and spinal ependymomas. The severity of disease phenotype varies greatly between affected families, but it is more consistent within families and correlates with the type of germline mutation, with deletions and frameshift mutations being more severe than point mutations (4). Most schwannomas are sporadic. Multiplicity, young age, or history of meningioma or spinal ependymoma should raise suspicion for NF2. Schwannomatosis is another inherited condition predisposing to schwannomas, but the patients lack germline NF2 mutations. Some families with isolated schwannomatosis (without meningiomas or spinal ependymomas) have had wild type NF2 and germline mutations in either SMARCB1 (5) or LZTR1 (6), although most cases of schwannomatosis remain unexplained (7).

In spite of the patois moniker “acoustic neuroma,” the vast majority of cerebellopontine angle schwannomas arise from the vestibular component of CN VIII. The dorsal sensory spinal nerve roots are thought to generate most other intradural schwannomas, yet schwannomas can arise anywhere there are peripheral nerves. Intracerebral examples, which are
exceedingly rare, probably develop from minute nerves that travel along blood vessels (8).

Neuroimaging of schwannomas reveals a circumscribed extra-axial tumor with smooth contours compressing its surroundings. When arising within an intervertebral foramen, the tumor bulges from either end, forming a “dumbbell” configuration that is a radiologic signature of schwannoma. Most vestibular schwannomas grow at least partially within the internal auditory canal and protrude into the cerebellopontine angle (9). Gadolinium contrast causes heterogeneous enhancement that is peripheral or ring-shaped in some cases (9,10).

Most vestibular schwannomas grow slowly (0 to 3 mm/year) and can be monitored conservatively for long periods of time (2). When they progress, surgery results in long-term cures for most patients. Unfortunately, surgery incurs a risk of further irreversible hearing loss due to iatrogenic disruption of axons. Stereotactic radiosurgery is a less invasive approach that, although it may be slightly less effective at controlling tumor growth, may be better for preserving hearing (11,12). One large series suggests that observation results in higher quality of life measures than active treatment measures (13). Spinal nerve root schwannomas are similarly indolent and amenable to resection, with generally less serious sensory and motor impairment afterward. Malignant progression of schwannomas is exceedingly rare (14).


Although the vast majority of cases offer little challenge, schwannomas periodically test a pathologist’s vigilance with unfamiliar patterns. Fortunately, schwannomas with unusual histologic patterns are still schwannomas and present with clinical scenarios similar to those with a conventional microscopic appearance. Several schwannoma patterns and variants with unique features are presented separately later.

Several features are consistent among schwannomas regardless of the other elements of histologic pattern; hyalinized blood vessels, collagenous encapsulation, and regionally variable cellularity are present in the vast majority of cases and are excellent adjunct features in recognizing schwannomas with unusual histology. Other elements seen in schwannomas that are less diagnostically helpful include hemosiderin-laden macrophages, “ancient change,” and cystic degeneration. Pseudoepithelialized cystic spaces occasionally form. Recognition of the most common features is the key to diagnosing those few schwannomas with both subtle histology and unusual location or presentation.

Conventional Schwannoma

At low magnification, dense areas (Antoni A) contain cells with irregular elongate nuclei that are arranged in tight fascicles with no clear cell–cell borders, alternating with less cellular areas (Antoni B) composed of loosely arranged cells with hyperchromatic round to oval nuclei (Figure 13-1). The relative amount of Antoni A and B patterns
is variable, and sometimes the two subtly blend and mute the biphasic effect. Periodically, nuclei within Antoni A areas align in ranks, creating stripes of nuclear palisades between belts of fibrillar pink cytoplasm (Figure 13-2). Many vestibular schwannomas are predominantly Antoni A tissue, are relatively hypocellular compared to other locations, and lack nuclear palisading (Figure 13-3). Cells with the characteristic irregular, elongate, club-shaped nuclei also form vague fascicles or whorls in Antoni A areas; their counterparts in Antoni B are far less organized.

FIGURE 13-1 Most schwannomas contain cellular Antoni A and less cellular Antoni B areas.

Cellular Schwannoma

This pattern is probably the most likely to be mistaken for a sarcoma because of its spindle-cell morphology, dense cellularity, and lack of Antoni B tissue or Verocay bodies (Figure 13-4). Additional unusual features such as hyperchromasia, mitosis, necrosis, and pleomorphism led to a malignant initial diagnosis in over a quarter of cases in one large series (15). Only a small number of reported cellular schwannomas have occurred in the intracranial and intraspinal compartments (16,17,18). Cellular schwannomas behave clinically like conventional schwannomas. Distinguishing between cellular schwannoma and malignant peripheral nerve sheath tumor (MPNST) is discussed with the latter entity. Cellular schwannomas express strong and diffuse S100 protein and diffuse SOX10 on immunostaining (19).

Plexiform Schwannoma

Occasionally, schwannomas grow in a complex or multinodular pattern that simulates the configuration of a plexiform neurofibroma. Most cases arise in the skin and subcutis of the trunk. Unlike the strong association between plexiform neurofibroma and NF1, this lesion is not a pathognomonic indicator of NF2 and occurs sporadically in many cases (20,21).

FIGURE 13-2 Nuclei align in palisades to form Verocay bodies in classic schwannomas.

Epithelioid and “Neuroblastoma-Like” Schwannoma

FIGURE 13-3 Many vestibular schwannomas are Antoni A predominant and relatively hypocellular with increased degenerative nuclear pleomorphism.

Rarely, schwannomas lose their spindle-cell morphology and grow as sheets of small cells (Figure 13-5), which even more rarely arrange in rosette-like structures reminiscent of neuroblastoma. Some cases have shown malignant behavior, although most follow a benign course (22,23). Epithelioid morphology can also be seen focally in otherwise unremarkable schwannomas. In the spine, another cellular epithelioid neoplasm that also stains strongly for
S100 protein is ependymoma, which would be distinguished from schwannoma by strong and diffuse immunostaining for glial fibrillary acidic protein (GFAP). One large series of epithelioid schwannomas showed a majority to have loss of SMARCB1/INI1 immunostaining, which is usually noted in malignant tumors, although they had excellent outcomes, with no metastasis and only one recurrence (24).

FIGURE 13-4 Cellular schwannomas resemble malignant peripheral nerve sheath tumor, with long fascicles of spindled cells and no Verocay bodies or Antoni B tissue.

FIGURE 13-5 Epithelioid, neuroblastoma-like schwannomas are densely cellular with round cells but may contain residual areas of more classic schwannoma.

FIGURE 13-6 Myxoid, signet-ring-like change can be seen focally in schwannomas, but rarely involves the entire lesion, as in this case.

Myxoid Schwannoma

This pattern is distinctly uncommon and has an appearance almost unrecognizable as schwannoma (Figure 13-6). Basophilic pools of mucin compress the nuclei to one side, causing a “signet-ring” appearance that may cause concern for more aggressive neoplasms (25). Unlike adenocarcinomas with similar cytomorphology, these myxoidschwannomas are tightly coherent and well circumscribed. Immunohistochemically, these lesions retain the characteristic of strong and diffuse S100 immunostainingand meshwork of laminin and collagen IV staining of other schwannomas.


Schwannomas virtually always react strongly and diffusely with S100 protein immunostaining and in an intercellular latticework pattern for type IV collagen and laminin. Although not entirely specific, strong S100 protein staining is important supporting evidence of schwannoma, without which the diagnosis is tenuous. Type IV collagen and laminin can be useful in differentiating schwannomas from fibroblastic and myofibroblastic tumors. The strength and wide distribution of S100 protein and collagen IV staining in schwannomas is rarely seen in other tumor types. The transcription factor SOX10 is sensitive for identifying schwannomas, being expressed in almost all cases, but is also expressed in melanomas and myoepithelial tumors, among others (26). Ki-67/MIB1 proliferation indices are highly variable and do not predict the behavior of schwannomas. Many schwannomas also express GFAP to varying degrees (27).

Differential Diagnosis

Considerable overlap between neurofibromas and schwannomas can be seen histologically; indeed, hybrid schwannoma/neurofibromas are well documented (28). In the classic view, neurofibromas grow within nerves and incorporate axons to expand the nerve in a fusiform, concentric fashion, whereas schwannomas grow from the surface of nerves and do not incorporate axons, forming an eccentric, circumscribed mass. Immunohistochemistry for neurofilament is a good method for highlighting entrapped axons, but this method has recently been challenged (29). Neurofibromas also generally lack the distinct fascicles and hyalinized blood vessels of schwannomas. In any event, it is entirely acceptable to call a tumor with features of both tumors a “hybridschwannoma/neurofibroma,” particularly in the setting of a patient with neurofibromatosis of either type, in which context such lesions are more common (28).

FIGURE 13-7 Schwannomas break into mesh-like fragments of fascicles that form “windows” in crush preparations, a feature that distinguishes them from meningiomas.

Especially in the cerebellopontine angle, where schwannomas often contain little Antoni B tissue, fibrous meningiomas should always be included in the differential diagnosis. Intraoperatively, crush preparations clearly differentiate the two, with schwannomas breaking into mesh-like fragments with punched-out “windows” between intact fascicles and minimal single-cell dispersion in the background (Figure 13-7). The free ends of the fascicles also appear cleanly snapped off, with few or no shaggy ends. Elongate fascicles within tissue fragments display the signature irregular, club-shaped nuclei (Figure 13-8). Fibrous meningiomas fragment into smaller pieces on crush preparations with greater shedding of individual tumor cells and more ragged edges and ends of fragments. Psammoma
bodies should not generally be seen in schwannomas. Immunohistochemistry for epithelial membrane antigen (EMA) will show membranous staining in meningiomas and only occasional focal or faint staining in schwannomas. S100 protein staining is often present in meningiomas but rarely to the degree seen in schwannomas.

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Oct 22, 2018 | Posted by in NEUROLOGY | Comments Off on Cranial and Spinal Nerve Sheath Tumors
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