Tumors of Peripheral Nerve

Incidence and Demographics.

This most common form of schwannoma generally presents in adults with a peak incidence between the third and sixth decades, there being no gender prevalence.

Clinical Manifestations and Localization.

Sites commonly affected include the head and neck, flexor surfaces of the extremities, and spinal as well as cranial nerves, most often of sensory type. Visceral tumors are rare. The same is true of osseous examples. Schwannomas are generally solitary, but multiple schwannomas occur in two disorders: NF2 and schwannomatosis (see Chapter 22 ). Multiple schwannomas affecting primarily the eighth cranial (vestibular branch) nerves bilaterally are pathognomonic of NF2.

Gross Pathology.

In most cases, gross inspection of a schwannoma provides important clues to the diagnosis. In addition to their generally globular shape, the tumors are truly encapsulated and an associated parent nerve is often apparent. The cut surface reveals a subcapsular zone of smooth, slightly dull, homogeneously light tan and firm tissue. This is readily evident in the majority of schwannomas, as are bright yellow areas (aggregates of lipid-laden histiocytes; Fig. 15.14A and B ), hemorrhagic foci, and cystic change ( Fig. 15.14C and D ). Necrosis may be seen, particularly in large examples.

Histopathology.

As a rule, schwannomas begin within single nerve fascicles ( Fig. 15.15 ). Histologic findings in conventional schwannomas include fibrous encapsulation of a largely spindle cell tumor ( Fig. 15.16 ). The compact regions comprise the so-called Antoni A component ( Fig. 15.16A ). Tumor cells and their processes are occasionally arranged in a manner that gives rise to palisaded nuclei ( Verocay bodies; Fig. 15.17A ) or whorls ( Fig. 15.17B ), and a loose-textured (Antoni B) element featuring round nuclei and loose-knit cell processes ( Fig. 15.17C ). This tissue is prone to undergo microcystic change ( Fig. 15.17D ). Thick-walled, hyalinized blood vessels ( Fig. 15.17E ) associated with hemosiderin deposits ( Fig. 15.17F ), as well as collections of foamy histiocytes, are also most frequent in Antoni B tissue. Only occasional schwannomas show myxoid change. Entrapped intratumoral axons are few, often subcapsular, and seen only on special stains. Degenerative atypia in the form of large, hyperchromatic nuclei with smudgy chromatin and lack of nucleoli may be seen ( Fig. 15.18A ), but mitotic figures are lacking or infrequent. Necrosis may also be seen ( Fig. 15.18B ).

Ancillary Diagnostic/Prognostic Studies.

All schwannomas are strongly, uniformly S-100 protein immunoreactive ( Fig. 15.19A ). SOX10 staining is also common ( Fig. 15.19B ) as is collagen IV reactivity ( Fig. 15.19C ). A minority also show patchy GFAP staining. Neurofilament protein-positive axons are scant ( Fig. 15.19D ). The capsule of schwannomas consists of EMA-reactive perineurial cells. Ultrastructurally, the tumor cells show features of well-differentiated Schwann cells, including continuous basal lamina and the formation of long-spacing collagen (“Luse bodies”) ( Fig. 15.20 ).

Differential Diagnosis.

The clinicopathologic distinction of schwannoma from neurofibroma is important. Schwannomas are occasionally NF2 or schwannomatosis associated, globular, eccentric to the remainder of the nerve, encapsulated, variably lipidized (and thus yellow), feature Antoni A and B patterns as well as Verocay bodies, show little or no stromal mucin, contain few mast cells, and rarely undergo malignant change. In contrast, neurofibromas are often NF1 associated and fusiform with respect to the parent nerve; are variably mucoid; show occasional Meissnerian corpuscles or onion bulb–like structures; consist of a wider mix of cells with features of Schwann, perineurial, and intermediate cells; commonly show mast cells; and, when affecting large, deep nerves, have a low but significant capacity for malignant transformation. At the gross level, confusion may also arise with hypervascular tumors, such as hemangioma and paraganglioma. A helpful diagnostic gross feature is the presence of homogeneously light tan, firm tissue. Histologically, the closest mimics of conventional schwannoma are palisaded leiomyoma, palisaded myofibroblastoma of inguinal lymph nodes (PMILN), and gastrointestinal stromal tumor (GIST). Palisaded leiomyoma usually presents in müllerian tissues and is immunoreactive for smooth muscle actin as well as desmin. In contrast to schwannoma, GIST is usually immunoreactive for KIT (CD117) and DOG1.

Treatment and Prognosis.

Conventional schwannomas are benign tumors that can be cured by complete resection. When incompletely excised, they occasionally recur and become clinically symptomatic. Recurrences are more frequent in so-called “giant sacral schwannomas,” which are often subtotally resected, as well as in the setting of NF2. Effective surgical treatment of schwannomas needs to include within the resection specimen, the entering and exiting nerve fascicle, which can often be separated from the parent nerve. This permits preservation of neurologic function, even when tumors are large. There is no compelling evidence that schwannomas undergo accelerated growth during pregnancy, and as such, surgery can typically be delayed until after delivery. The exceptionally rare occurrence of malignant transformation in conventional schwannoma is discussed later in the chapter.

Demographics, Clinical Manifestations, and Localization.

This is a variant of schwannoma with a female predominance and a site predilection for the posterior mediastinum and pelvis. Craniospinal and cutaneous nerves may also be affected. About 4% occur in the setting of NF1. Cellular schwannomas are benign and should neither be considered a MPNST precursor nor mistaken for MPNST.

Gross Pathology.

Grossly, cellular schwannomas are ovoid but more solid than the conventional variant, usually having a relatively uniform, firm, tan cut surface ( Fig. 15.21 ) with only occasional white and yellow patches. If hemorrhage is present, it is usually focal, perhaps related to prior biopsy. Furthermore, there is usually no gross evidence of necrosis. Some examples are plexiform/multinodular (discussion to come). Bone erosion may be seen, especially in paraspinal cases.

Histopathology.

Like conventional schwannoma, cellular schwannomas are encapsulated ( Fig. 15.22A ) and exhibit vascular hyalinization ( Fig. 15.22B ), but are composed predominantly or exclusively of Antoni A type tissue without well-formed Verocay bodies. They consist mostly of spindle cells closely arrayed in fascicles ( Fig. 15.22C ), a storiform arrangement, or in a nonspecific pattern. Cellular whorls are a notable but inconstant finding. Lymphoid aggregates are often seen in or beneath the capsule ( Fig. 15.22D ) as are intratumoral collections of lipid-laden histiocytes. The spindle cells possess eosinophilic cytoplasm. Nuclei generally show minor pleomorphism and hyperchromasia. Mitoses usually are easily found ( Fig. 15.22C ). Microfoci of necrosis may be seen but are typically nonpalisading in nature ( Fig. 15.23 ). Intratumoral nerve fibers, quite dispersed due to tumor volume, are few and generally subcapsular. The immunohistochemical ( Fig. 15.24 ) and ultrastructural features are those of a well-differentiated schwannoma.

Differential Diagnosis.

Much has been written about the differential diagnosis of cellular schwannoma. In brief, the two tumors with which it is most often confused are (1) benign and low-grade malignant smooth muscle tumors, and (2) malignant peripheral nerve sheath tumor (MPNST). Although there are subtle cytologic differences between cellular schwannomas and smooth muscle tumors, a few simple observations aid in this distinction. Smooth muscle tumors are typically unencapsulated, whereas cellular schwannomas feature a capsule and are invariably strongly and diffusely reactive for S-100 protein, but immunonegative for muscle markers.

Far more troubling for pathologists are the histologic similarities of cellular schwannoma to MPNST. Cellular schwannomas are usually globular, encapsulated tumors whereas MPNSTs are fusiform or globoid in configuration and are pseudo-encapsulated, the latter consisting of infiltrated surrounding tissue. Antoni A tissue predominates in cellular schwannoma by definition, the cells being arranged in fascicles or whorls; hyperchromasia and nuclear pleomorphism are generally mild. Hyalinized blood vessels and subcapsular lymphoid deposits are also common features. In contrast, MPNSTs are composed of spindle cells showing greater hyperchromasia and nuclear atypia. Whereas cellular schwannomas show only microscopic foci of necrosis, MPNSTs often show grossly obvious necrosis, which is often palisading in type. Schwannomas typically feature relatively low mitotic counts (<4 per 10 HPF), whereas MPNSTs far exceed that number. Cellular schwannomas are composed of a uniform cell population of Schwann cells, but MPNSTs may feature considerable cytologic variation. Cellular schwannomas are diffusely positive for S-100 protein and SOX10; podoplanin (D2-40) expression is also a feature. In contrast, MPNSTs show only minor reactivity for Schwann cell markers. S-100 protein is the most frequently expressed marker, but even with the inclusion of multiple other Schwann cell markers, only 50% to 65% of MPNSTs show some degree of labeling. Recently described features that favor the diagnosis of MPNST over cellular schwannoma include neurofibromin and H3K27 trimethylation loss. Lastly, cellular schwannomas may show significant bone erosion but do not metastasize. Instead, MPNSTs destroy surrounding soft tissue, permeate bone, and frequently metastasize. Surprising clinical and operative associations include: (a) the rare occurrence of cellular schwannoma in a patient with NF1, and (b) the even rarer finding of concurrent and separate cellular schwannoma and MPNST.

Treatment and Prognosis.

Cellular schwannomas are benign but capable of recurrence when incompletely excised. This is particularly true of proximal tumors involving the spinal nerves extending into the spinal canal, sacral tumors, and intracranial examples. In such instances, fully 30% to 40% recur. There have been no reports of a cellular schwannoma metastasizing.

Incidence, Demographics, Clinical Manifestations, and Localization.

Roughly 5% of all schwannomas are multinodular or plexiform and of either conventional or cellular subtype. In a large study, head and neck (23%) and skin (15%) were found to be most often affected. Deep-seated examples are uncommon, favor females, tend to be syndrome unassociated, and often show their plexiform nodular feature radiographically ( Fig. 15.25 ). Prior to its recognition two decades ago, examples were regarded as plexiform neurofibromas or as MPNSTs arising in the same. A frequent feature, most notably in cutaneous examples, is lack of encapsulation. The same is not true of large soft tissue examples. Although there is no association with NF1, superficially situated tumors occur in NF2 and in schwannomatosis, each accounting for approximately 5% of all cases.

Gross Pathology.

Plexiform schwannomas vary in size. Their plexiform multinodular nature may not be grossly evident in small cutaneous tumors, but is obvious in sizable, soft tissue lesions ( Fig. 15.26 ). Only occasionally do they show the entwining “worms” appearance of plexiform neurofibroma. The same is true of rare visceral examples. As in conventional schwannomas, patchy yellow discoloration may be seen on the cut surface of larger tumors.

Histopathology.

Microscopic sections show contorted profiles of affected tumor consisting of compact, elongate neoplastic Schwann cells, more Antoni A than B in pattern ( Fig. 15.27A ). Epithelioid cytology is rarely encountered. Occasional mitoses may be seen. Hyalinized blood vessels are usually limited to larger examples. As a rule, lymphoid aggregates and clusters of lipid-laden histiocytes are absent. The tumor is uniformly S-100 protein positive ( Fig. 15.27B ) and shows pericellular collagen IV staining. In small tumors, entrapped axons are few or absent on neurofilament protein stain but are more readily seen in larger examples. The fascicles of affected nerves are surrounded by residual EMA-immunoreactive perineurium.

Differential Diagnosis.

Some cellular childhood examples of this tumor may mimic MPNST, but should not be considered malignant. Although such tumors may recur locally, both their immunohistochemistry and lack of metastatic potential argue in favor of their status as cellular schwannoma subtypes. Emphasis has been placed on the presence of four or more mitoses/10 HPF in many cases, but some studies have not found mitotic activity to be prognostically important when evaluating plexiform or cellular schwannomas. Local recurrence is a problem that may be attributed to failure to achieve a total resection, due either to lack of encapsulation or to irregular tumor contours in the form of finger-like protrusions.

Plexiform schwannomas must also be distinguished from plexiform neurofibromas, palisaded encapsulated neuroma (PEN), and neurotropic melanoma. Plexiform neurofibromas are far less cellular, contain more mucinous matrix, and show fewer S-100 protein staining cells. In contrast to plexiform schwannoma, PENs contain more numerous axons as seen on neurofilament protein immunostain and often demonstrate a nerve twig entering on their deep aspect. Like most plexiform schwannomas, neurotropic melanomas occur in the skin and subcutaneous tissue. Given profound differences in prognosis, it is of utmost importance to distinguish the two. Neurotropic melanoma favors the head and neck and is often associated with an overlying lentigo-type in situ melanoma. Both tumors involve nerves, but plexiform schwannomas form a mass pushing the distorted, remnant parent nerve to one side, such that residual normal nerve is often difficult to identify. In contrast, in neurotropic melanoma, nerve fibers are often readily identified. Neurotropic melanomas primarily occupy the epineurium and encase as well as invade the perineurium to form distinctive, concentric rings surrounding intact endoneurium. Additionally, neurotropic melanomas have nuclei that are larger, more irregular in shape, and more often markedly hyperchromatic. Lastly, neurotropic melanoma is commonly associated with prominent desmoplasia, whereas plexiform schwannoma is not. Although S-100 protein immunoreactivity is seen, staining for HMB-45 is often lacking in desmoplastic melanoma.

Treatment and Prognosis.

Plexiform schwannomas must be interpreted as benign neoplasms. As mentioned, however, a small proportion of incompletely excised tumors do recur.

Incidence, Demographics, Clinical Manifestations, and Localization.

The term melanotic schwannoma is likely a misnomer, and most now consider this tumor to be a unique diagnostic entity, rather than merely a histologic variant of schwannoma. This very uncommon, clinicopathologically and genetically unique tumor has a predilection for posterior spinal nerves and their ganglia. Autonomic nerves may also be affected. Its peak incidence is in the fourth decade, and in contrast to schwannomas a subset of these tumors metastasize. In a recent study of 40 cases, local recurrences and metastases developed in 35% and 44% of cases, respectively. The authors therefore proposed the designation of malignant melanotic schwannian tumors, given the substantial number of cases with more aggressive biology, in contrast to schwannoma.

Gross Pathology.

Melanotic schwannomas are usually solitary and ovoid, but a multifocal nodular presentation may be seen, in which case the tumor is often malignant. The tumors generally are covered entirely or in large part by a thin fibrous membrane; their cut surface varies from gray to pitch black and often has the feel of dried tar ( Fig. 15.29 ). Nearby bone may be eroded, but intraosseous examples are quite rare.

Histopathology and Genetics.

Most melanotic schwannomas are characterized by plump spindle and epithelioid cells ( Fig. 15.30 ). Nonetheless, considerable histologic variation may be seen. The cells are disposed in lobules, nests, sheets, and/or somewhat fascicular arrangements ( Fig. 15.30A and B ), and have indistinct cell borders, thus yielding a syncytial appearance. Melanin pigmentation is variable as is cytoplasmic volume ( Fig. 15.30A–C ). Nuclei are round to ovoid with delicate chromatin and small nucleoli. Melanocytic markers such as HMB-45, Melan-A (MART-1), and tyrosinase are positive. Ultrastructural studies show variably pigmented melanosomes. Coarse chromatin and prominent, “violaceous” nucleoli in association with numerous mitoses and necrosis are suggestive of malignancy. Melanotic schwannomas arising from paraspinal ganglia may contain residual ganglion cells.

About 45% of the melanotic schwannomas contain psammoma bodies ( Fig. 15.31A ); termed “ psammomatous melanotic schwannomas (PMS),” such tumors often also feature lipoma-like fat accumulation ( Fig. 15.31B ). This variant of melanotic schwannoma is more often associated with Carney complex, although the reported frequency of the association is highly variable (see also Chapter 22 ). The mean age of complex-affected patients is 22 years, a full decade younger than for those with non-syndromic melanotic schwannomas. Components of the disorder include lentiginous pigmentation; blue nevi; myxomas of heart, skin, or breast; congenital osteochondromyxoma; and endocrine overactivity (variably due to pigmented nodular adrenocortical hyperplasia producing Cushing syndrome, large cell Sertoli cell tumors of testis associated with sexual precocity, or pituitary adenoma, typically acromegaly associated). A complex tumor with myoid, neuroendocrine, and perineurial features has also been described in this setting.

Half of Carney complex patients have mutations of the PRKAR1A tumor suppressor gene, located on 17q 22-24 and encoding for the type 1 alpha regulatory subunit of cAMP-dependent protein kinase A (PKA). Loss of heterozygosity for this gene locus has been found in associated tumors. Loss of expression of the PRKAR1A protein, the Carney complex–associated tumor suppressor gene product, has been observed in melanotic schwannoma and is not limited to Carney complex–associated neoplasms ( Fig. 15.32A ).

Differential Diagnosis.

The differential diagnosis of melanotic schwannoma includes malignant melanoma (both primary meningeal and metastatic) and meningeal melanocytoma, all of which express melanocytic markers including SOX10 ( Fig. 15.32B ). In contrast to melanoma, the cells of melanotic schwannoma are often disposed in lobules or clusters, some collagen IV delineated ( Fig. 15.32C ), and generally bland with only slight cytologic atypia and often syncytial cytology of cells. Melanomas do not feature psammoma bodies or adipose-like cells. The same is true of melanocytomas, which originate from leptomeninges, often feature whorling, lack atypia, but may exhibit perilobular basal lamina formation. Additionally, primary leptomeningeal melanomas follow a similar genetic progression as that of blue nevi–associated melanomas and uveal melanomas, more commonly displaying GNAQ or GNA11 mutations, often followed by loss of BAP1 expression.

Clinical Manifestations and Localization.

In contrast to intraneural neurofibromas occurring at deep sites, cutaneous neurofibromas are mainly extraneural proliferations. Nonetheless, they no doubt originate from small nerves residing in dermal and/or subcutaneous tissue.

Localized cutaneous neurofibromas elevate the skin as soft, hemispheric to pedunculated lesions having no particular distribution. Painless, freely movable, and ranging in size up to 2 cm, the vast majority of the localized type are solitary and sporadic, occurring in 20- to 30-year-old patients (see Fig. 15.33A ). On the other hand, when multiple, they are a key feature of NF1, becoming particularly evident at puberty ( Fig. 15.33B ). In later life, NF1-associated tumors may be innumerable.

In contrast to localized lesions, diffuse cutaneous neurofibromas are uncommon. Plaque-like, they form cutaneous and often subcutaneous lesions, frequently in the head and neck region of children or young adults ( Fig. 15.34 ). An association with NF1 is seen in only about 10%.