Peripheral nerve sheath neoplasms

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Peripheral nerve sheath neoplasms

Neoplasms derived from cells that surround peripheral nerves may present with central nervous system (CNS) symptoms and signs when they arise at a proximal site. The three main groups of these nerve sheath neoplasms are schwannomas (neurilemmomas), neurofibromas, and malignant peripheral nerve sheath tumors (MPNSTs; neurofibrosarcomas). Nearly all cranial nerve sheath tumors and most peripheral nerve sheath tumors in the spinal canal are schwannomas. All three groups show an association with neurofibromatosis (NF).

GENETICS OF NEUROFIBROMATOSIS TYPE 1 (NF1)

The NF1 gene is on chromosome 17q11.

NF1 shows autosomal dominant inheritance with almost complete penetrance.

The prevalence of NF1 is approximately 1:3000. About 50% of cases represent new mutations.

The NF1 gene product is neurofibromin, which is a guanosine triphosphatase-activating protein that influences cell proliferation and differentiation, and is abundant in Schwann cells and neurons.

SCHWANNOMAS

Schwannomas are slowly growing neoplasms composed of Schwann cells. Solitary schwannomas with effects on the CNS occur on cranial (Table 42.1, Fig. 42.1) and spinal nerve roots; rarely they are found in the substance of the brain or spinal cord. Melanotic schwannomas have a predilection for spinal nerve roots. The plexiform schwannoma is rare and occurs in the skin. Unlike the plexiform neurofibroma, it is not associated with NF.

Table 42.1

The commonest neoplasm of the cerebellopontine angle is a schwannoma of the vestibulocochlear nerve

Cerebellopontine angle neoplasm	%
Schwannoma	85
Meningioma	10
Others (cholesteatoma, glioma, medulloblastoma, metastatic carcinoma, paraganglioma, hemangioma, AT/RT)	5

42.1 Vestibulocochlear nerve schwannomas.
(a) A partly cystic schwannoma in the cerebellopontine angle indents the brain stem. Flattened fascicles of vestibulocochlear nerve run over the surface of the neoplasm. (b) A schwannoma sits at the mouth of the internal auditory meatus. (c) A hemorrhage occupies part of this schwannoma, which has caused compression and distortion of the brain stem.

MACROSCOPIC APPEARANCES

Schwannomas are composed of nodular rubbery tissue, which has a variegated cut surface. Yellow and gray areas may be interspersed with hemorrhagic foci or cysts. The neoplasm has a capsule and the nerve from which the schwannoma arises may be splayed over the surface of the neoplasm (Figs 42.2, 42.3).

42.2 The relationship of neurofibroma and schwannoma to associated nerve.
The neurofibroma incorporates axons, but the schwannoma displaces normal elements of the nerve to one side (see Fig. 42.3).

42.3 The relationship between schwannoma and peripheral nerve.
(a) A cystic schwannoma arising from the eighth nerve (arrow) distorts the brain stem. The tumor has been hemisected to reveal its multicystic architecture. (b) An antibody to neurofilament protein labels axons in a nerve alongside a schwannoma.

MICROSCOPIC APPEARANCES

Two histologic patterns predominate (Figs 42.4–42.6):

42.4 Schwannoma.
Adjacent Antoni A (right) and B (left) areas.

42.5 Schwannoma.
Abundant pericellular reticulin in an Antoni A area. Section adjacent to that in Figure 42.4.

42.6 Schwannoma.
Fascicles of spindle-shaped cells are interrupted by small myxoid areas. Note the small blood vessel with a markedly thickened wall.

Antoni A areas, in which spindle-shaped cells with rod-shaped nuclei and dense pericellular reticulin are arranged in compact intertwining fascicles.

Antoni B areas, in which stellate or spindle-shaped cells with smaller, more hyperchromatic nuclei, tenuous cytoplasmic processes, and scanty surrounding reticulin are loosely arranged in a myxoid stroma.

GENETIC ASPECTS OF NERVE SHEATH NEOPLASMS

MPNSTs and NF1

30–50% of MPNSTs are associated with NF1.

For NF1 patients, the lifetime risk of developing an MPNST is approximately 2%.

Approximately 5–10% of plexiform neurofibromas in patients with NF1 progress to MPNST.

Schwannomas and NF2

Patients with NF2 may have bilateral vestibular schwannomas.

Sporadic schwannomas frequently show NF2 gene mutation plus allelic loss in the other chromosome (22q).

Carney’s complex

This autosomal dominant syndrome comprises melanotic schwannomas, spotty pigmentation, cardiac or skin myxomas, and endocrine overactivity (Cushing syndrome or acromegaly).

Most cases are caused by mutations in the cAMP-dependent protein kinase A type I-alpha regulatory subunit (PRKAR1A), on chromosome 17q23-q24; in some families the syndrome is linked to chromosome 2p16.

GENETICS OF NEUROFIBROMATOSIS TYPE 2 (NF2)

The NF2 gene is on chromosome 22q12.

NF2 shows autosomal dominant inheritance with high penetrance.

About 50% of cases represent new mutations.

The prevalence of NF2 is approximately 1:40 000.

The NF2 gene product is merlin (or schwannomin), which is associated with membrane and cytoskeletal structures (it binds to actin).

NF2

Neoplasms associated with NF2

Meningiomas (may be multiple).

(Plexiform neurofibromas are not found in NF2, and malignant progression of associated nerve sheath neoplasms is very rare.)

Clinical criteria for NF2

One of the following four clinical presentations is needed to fulfil current diagnostic criteria for NF2:

Bilateral vestibular schwannomas.

First-degree relative with NF2 plus one vestibular nerve schwannoma.

First-degree relative with NF2 plus two of the following:

• posterior subcapsular lens opacity.

Two of the following:

• unilateral vestibular nerve schwannoma

• multiple meningiomas

• multiple schwannomas

• glioma

• neurofibroma

• posterior subcapsular lens opacity

• cerebral calcification.

There may be conspicuous palisading of nuclei. Verocay bodies are a characteristic feature (Fig. 42.7). Thickened blood vessels with hyaline walls and clumps of hemosiderin-laden or foamy macrophages are common findings (Fig. 42.8). Mitoses, if present, are sparse.

42.7 Verocay body.
This consists of sequential nuclear palisades separated by an anuclear area.

42.8 Schwannoma.
Hyaline paucicellular tissue surrounds blood vessels in a schwannoma.

A small proportion of schwannomas contains melanin (Fig. 42.9), and melanotic schwannomas may contain epithelioid cells.

42.9 Melanotic schwannoma.

The presence of cells with misshapen hyperchromatic nuclei in many otherwise cytologically bland schwannomas is thought to be a manifestation of degenerative (or ‘ancient’) change (Fig. 42.10).

42.10 Nuclear hyperchromasia and pleomorphism in a schwannoma.
(a,b) These are common findings in schwannomas and, if there are no mitoses, are thought to be degenerative.

Cellular schwannomas rarely affect the CNS (Fig. 42.11). They show a marked preponderance of Antoni A areas that contain cells with a high nuclear:cytoplasmic ratio. Mitotic figures are evident. Xanthomatous foci may be seen. The cellular schwannoma can be distinguished from MPNSTs by its circumscribed shape and fibrous capsule, hyalinized blood vessels, and small but distinct myxoid areas.

42.11 Cellular schwannoma.
A high nuclear:cytoplasmic ratio and scattered mitoses are present in some areas, but this neoplasm retains the architectural pattern of a schwannoma with Antoni A and B areas, and contains thick-walled blood vessels.

CEREBELLOPONTINE ANGLE (CPA) NEOPLASMS

Schwannomas make up the vast majority of CPA neoplasms (see Table 42.1), but two other CPA neoplasms (fibroblastic meningioma and astrocytoma of the brain stem or cerebellum) may be confused with schwannomas. Histologic features that distinguish these neoplasms include:

The reticulin pattern. The reticulin in a fibroblastic meningioma can be extensive, but rarely surrounds each cell to produce the dense pattern seen in schwannomas.

Immunohistochemistry. Most astrocytomas are GFAP-positive, but schwannomas are infrequently GFAP-positive. Schwannomas, but not meningiomas, label uniformly for S-100 protein.

Ultrastructural examination. Schwannomas have a pericellular basal lamina (unlike most astrocytic, melanocytic and meningothelial neoplasms) and lack both the densely packed bundles of intermediate filaments that are seen in many astrocytic neoplasms and the desmosomes of meningiomas.

The term schwannosis refers to a reactive, usually ectopic, proliferation of Schwann cells. In the CNS it has a predilection for the dorsal root entry zone and perivascular spaces in the spinal cord or brain stem. Schwannosis is usually related to previous focal injury, but may occur in association with a schwannoma of the dorsal nerve root.

Immunohistochemically, schwannomas label with antibodies to S-100 and vimentin. Immunoreactivity for glial fibrillary acidic protein (GFAP) is occasionally convincing. Melanotic variants label with S-100 and HMB-45 antibodies. Schwannomas have a pericellular basal lamina, and this differentiates them from melanocytic neoplasms. The cellular schwannoma shows widespread and strong S-100 immunoreactivity.

Malignant progression of a schwannoma is extremely rare, but has occurred in some melanotic schwannomas of the sympathetic chain.

NEUROFIBROMAS

Neurofibromas may be:

dermal, producing a nodular lesion in the skin

intraneural, occurring as solitary or plexiform tumors.

They rarely affect the CNS, and then usually in the context of NF (Fig. 42.12). Involvement of a plexus or large nerve trunks by plexiform neurofibromas is pathognomonic of NF1. In contrast, the rare plexiform schwannoma that occurs mainly in the skin is not associated with NF1. Neurofibromas grow slowly and arise within the endoneurium. They consist largely of Schwann cells, but fibroblasts and pericytes are also significant components.

42.12 Neurofibromatosis type 1.
Multiple thoracolumbar (a) and cervical root (b) nerve sheath tumors in a patient with NF1.

MACROSCOPIC APPEARANCES

Solitary intraneural neurofibromas are usually oval, gray or tan-colored neoplasms with a smooth shiny surface covered by a delicate pseudocapsule. Neurofibromas are not cystic and do not contain the xanthomatous areas seen in schwannomas. Solitary neurofibromas incorporate and expand the nerve from which they arise, whereas schwannomas grow away from the edge of the nerve (see Fig. 42.2).

Plexiform neurofibromas expand several nerves in a plexus or fascicles in a nerve trunk (Fig. 42.13). Irregular swellings give the nerve trunks the appearance of a ginger root.

42.13 Plexiform neurofibroma.
(a) Intraoperative exposure of swollen nerve trunks that form part of a plexiform neurofibroma. (b) Histology of a plexiform neurofibroma reveals diffuse infiltration of multiple adjacent fascicles by neoplastic cells.

MICROSCOPIC APPEARANCES

Neurofibromas are circumscribed, but not encapsulated. Their wavy spindle-shaped cells lie in a mucoid matrix or between bundles of collagen (Fig. 42.14). Many cells have nuclei with a serpentine form.

42.14 Neurofibroma.
(a,b) This nerve sheath tumor is composed of haphazardly arranged cells with wavy nuclei and variable amounts of cytoplasm. Scattered lymphocytes are also present in this case.

Immunohistochemical and ultrastructural studies suggest that neurofibromas are composed of several types of cell: fibroblasts and pericytes are mixed with Schwann cells, and mast cells may be scattered through the neoplasm. Neoplastic cells infiltrate nerve fascicles rather than displacing them (Fig. 42.15).

42.15 Neurofibroma.
Axons in the infiltrated nerve are immunolabeled with an antibody to neurofilaments. The axons are widely separated by the neoplastic cells.

Cytologic pleomorphism and nuclear hyperchromasia may be degenerative, but such changes should be regarded with suspicion in neurofibromas. These cytologic features indicate anaplasia if there are mitoses (even a few) or if they are seen in a neurofibroma from a patient with NF1. Anaplasia tends to become more extensive in successive biopsies from recurrent neoplasms, marking their progression to MPNSTs.

Neurofibromas are immunoreactive for vimentin, but S-100 immunoreactivity is patchy, reflecting the scattered distribution of Schwann cells (Fig. 42.16).

42.16 Neurofibroma.
The neoplastic Schwann cells are immunolabeled with an antibody to S-100 protein.

MALIGNANT NERVE SHEATH TUMORS

MPNSTs that affect the CNS usually arise close to the spinal cord, from the cervical or brachial plexuses. Intracranial examples have been reported, and most commonly arise from the trigeminal nerve. Malignant transformation of plexiform neurofibromas in patients with NF1 is heralded by rapid enlargement, increasing neurologic deficit, and pain. Mutations of TP53 and homozygous deletions of CDKN2A are associated with progression of neurofibromas to MPNSTs, implicating the p53 or pRb regulatory pathways in this malignant transformation.

DIFFERENTIAL DIAGNOSIS OF MPNST

Various malignant spindle-cell neoplasms can mimic the cytological and immunohistochemical features of MPNST.

Some monophasic synovial sarcomas (~20%) are focally immunopositive for S-100, but most also express cytokeratins and EMA. MPNSTs are immunonegative for cytokeratins, but may show foci of EMA immunoreactivity (perineurial differentiation). Nearly all synovial sarcomas harbor a t(X,18), which can be demonstrated by iFISH.

Leiomyosarcomas usually express smooth muscle actin, while MPNSTs are immunonegative for this antigen.

Fibrosarcomas, which usually demonstrate more stromal collagen than MPNSTs, also do not express S-100.

Spindle-cell malignant melanomas (MMs) can be difficult to distinguish from MPNSTs; both have a similar neuroectodermal histogenesis and express S-100. MMs are expected to express S-100, HMB-45 and melan-A more readily than MPNSTs. The epithelioid variant of MPNST, which closely resembles MM, shows widespread reactivity for S-100, but is immunonegative for HMB-45 and melan-A.

MACROSCOPIC APPEARANCES

MPNSTs infiltrate and expand nerve trunks, producing fusiform swellings, and may invade surrounding soft tissues, resulting in a poorly defined border. They may contain areas of necrosis and hemorrhage.

MICROSCOPIC APPEARANCES

Fascicular and storiform patterns are typical. The nuclear:cytoplasmic ratio is high and mitotic figures are easily found (Fig. 42.17). Nuclear palisading is infrequent. Foci of necrosis are often evident. The waviness of the cell nuclei may be maintained, at least in some parts of the tumor.

42.17 MPNST.
(a) A higher nuclear:cytoplasmic ratio and mitotic count than in a schwannoma are found in this neoplasm. (b) Cytologic pleomorphism and micronecrosis are additional features. (c) The growth fraction, as indicated by Ki-67 immunoreactivity, is high.

About 10% of MPNSTs show heterologous differentiation. Exhibiting varying degrees of differentiation/cytologic malignancy, mesenchymal tissues – skeletal muscle (triton tumor), bone, and cartilage – may be present (Fig. 42.18).

42.18 Triton tumor.
This variant of MPNST is characterized by a rhabdomyosarcomatous element. This manifests as large cells with deeply eosinophilic cytoplasm (a), in which cross-striations may occasionally be seen. These cells are immunoreactive for myoglobin (b).

Epithelial differentiation may result in the formation of clusters of glands (Fig. 42.19). An epithelioid variant accounting for 5% of cases and consisting of strings or nests of round cells with prominent nucleoli can be mistaken for a carcinoma or malignant melanoma (Fig. 42.20). Very occasionally, MPNSTs contain melanin, and rarely an MPNST may arise from a melanotic schwannoma.