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Review
. 2021 Feb 16;88(3):443-456.
doi: 10.1093/neuros/nyab021.

Diagnostic Pathology of Tumors of Peripheral Nerve

Sarra M Belakhoua  1   2 , Fausto J Rodriguez  1   3   4
Affiliations
Review

Diagnostic Pathology of Tumors of Peripheral Nerve

Sarra M Belakhoua et al. Neurosurgery. .

Abstract

Neoplasms of the peripheral nervous system represent a heterogenous group with a wide spectrum of morphological features and biological potential. They range from benign and curable by complete excision (schwannoma and soft tissue perineurioma) to benign but potentially aggressive at the local level (plexiform neurofibroma) to the highly malignant (malignant peripheral nerve sheath tumors [MPNST]). In this review, we discuss the diagnostic and pathologic features of common peripheral nerve sheath tumors, particularly those that may be encountered in the intracranial compartment or in the spine and paraspinal region. The discussion will cover schwannoma, neurofibroma, atypical neurofibromatous neoplasms of uncertain biological potential, intraneural and soft tissue perineurioma, hybrid nerve sheath tumors, MPNST, and the recently renamed enigmatic tumor, malignant melanotic nerve sheath tumor, formerly referred to as melanotic schwannoma. We also discuss the diagnostic relevance of these neoplasms to specific genetic and familial syndromes of nerve, including neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis. In addition, we discuss updates in our understanding of the molecular alterations that represent key drivers of these neoplasms, including neurofibromatosis type 1 and type 2, SMARCB1, LZTR1, and PRKAR1A loss, as well as the acquisition of CDKN2A/B mutations and alterations in the polycomb repressor complex members (SUZ12 and EED) in the malignant progression to MPNST. In summary, this review covers practical aspects of pathologic diagnosis with updates relevant to neurosurgical practice.

Keywords: LZTR1; NF1; NF2; PRKAR1A; SMARCB1; MPNST; Neurofibroma; Neurofibromatosis; Schwann cell; Schwannoma; Schwannomatosis.

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Figures

FIGURE 1.
FIGURE 1.
Microanatomy of peripheral nerve. The peripheral nerve is composed of epineurium surrounding individual units (fascicles, in light green). The various nerve sheath tumors share phenotypic properties with the non-neoplastic cell components illustrated, predominantly with Schwann cells. Perineurial cells form the perineurium surrounding individual fascicles and have phenotypic overlap with the neoplastic cells of perineurioma. A variety of mesenchymal cells populate the epineurium, and although rare, there is a wide morphological and biological variation in the group of soft tissue neoplasms that may also involve the peripheral nerve as a primary site. Note that the phenotypic overlap of neoplasms with non-neoplastic cell counterparts does not imply that the latter are the cell of origin for the related neoplasms. In experimental models, cells of origin tend to be stem cell/progenitor cell precursors.
FIGURE 2.
FIGURE 2.
Summary of molecular genetic pathogenesis of nerve sheath tumors. Tumor syndromes of nerve usually develop secondary to germline mutations in several key tumor suppressor genes: NF1, NF2, SMARCB1, or LZTR1 (schwannomatosis) and PRKAR1A (MMNST, in Carney complex). In the context of NF1, mutations associated with tumor progression include CDKN2A (p16) in atypical neurofibroma/ANNUBP and alterations in members of the PRC 2 (SUZ12 or EED).
FIGURE 3.
FIGURE 3.
Schwannoma. A, The vestibular branch of cranial nerve VIII is the main intracranial site of origin of schwannoma. B, Antoni A areas are compact and may contain characteristic palisades known as Verocay bodies. C, Antoni B patterns are composed of loose tissue with variable histiocytic infiltrates. Cellular schwannoma is a specific variant that is particularly prone to be mistaken for malignancy. D, Mitotic figures may be encountered (arrow). E, Plexiform neurofibromas are composed of multinodular aggregates of predominantly Antoni A tissue. F, Epithelioid schwannomas are rare, composed of plump cells with prominent nuclei and nucleoli. Strong expression of mature Schwann cell markers is typical of all schwannomas, including S100 G and SOX10 H. I, Patchy loss or a “mosaic” pattern of INI1/SMARCB1 immunostaining is typical of syndrome-associated (NF2 and schwannomatosis) schwannomas.
FIGURE 4.
FIGURE 4.
A, Neurofibroma. Multiple neurofibromas involving cervical nerve roots in a patient with NF1. Neurofibromas are composed of wavy nuclei, somewhat smaller than those of schwannoma, with associated delicate collagen B and variable myxoid stroma C. D, Plexiform neurofibromas are typical NF1-associated tumors and form multiple tortuous nodules, reflecting multifasicular involvement best appreciated at low power. E, Diffuse neurofibromas may be infiltrating, frequently entrapping adnexal structures (arrow) and containing characteristic pseudomeissnerian corpuscles (asterisks). Massive soft tissue neurofibromas are typically enormous neoplasms, developing exclusively in NF1 patients. F, A cellular, but benign, round cell component is frequent (arrows). G, Neurofibromas frequently involve the dorsal roots in NF1 patients. Infiltration of dorsal root ganglia should not be mistaken for ganglion cell differentiation. The designation ANNUBP is usually reserved for the identification of some worrisome histologic features in small biopsies from NF1 patients but not meeting criteria for malignancy. H, This example demonstrates hypercellularity and nuclear enlargement. I, NFP immunostain is useful in highlighting underlying axons in the substance of neurofibromas (arrow).
FIGURE 5.
FIGURE 5.
Perineurioma. A, Intraneural perineurioma is a benign nerve sheath tumor characterized by the formation of pseudo-onion bulbs composed of neoplastic perineurial cells best appreciated on cross sections. B, Longitudinal sections may appear hypercellular, but the neoplasms are uniformly benign. Soft tissue perineuriomas form solid masses typically unassociated with major nerves. C, A storiform pattern is typical. EMA expression is typical of all perineurioma subtypes D, although it may be weak or focal.
FIGURE 6.
FIGURE 6.
Hybrid nerve sheath tumors. It is increasingly recognized that a subset of benign nerve sheath tumors may contain components of more than 1 tumor type. A, Hybrid schwannoma-perineurioma is the most frequent hybrid nerve sheath tumor. B, Schwannoma-neurofibroma usually takes the form of schwannian nodules (asterisk) in a plexiform neurofibroma background. Hybrid neurofibroma-perineurioma with neurofibroma C and perineurioma D components highlighted by S100 E and EMA immunostains F, respectively.
FIGURE 7.
FIGURE 7.
MMNSTs. A, MMNSTs are distinctive nerve sheath neoplasms with conspicuous pigmentation that frequently involve nerve roots, ganglia (arrows indicating entrapped ganglion cells) and autonomic nerves. The tumors may be composed of epithelioid cells with macronucloli forming nests B or spindle cells C. D, Areas of decreased pigmentation may be encountered. E, NFP helps in outlining the axons in the presumed parent nerve. F, Collagen IV may be useful in outlining basal lamina deposition, a feature of Schwann cells.
FIGURE 8.
FIGURE 8.
MPNSTs. MPNST are usually high-grade neoplasms that may arise in a neurofibroma precursor (asterisks) A and are characterized by hypercellularity/nuclear atypia B and frequent necrosis C. D, Epithelioid MPNST is a distinctive subset characterized by neoplastic cells with large nuclei with macronucleoli. MPNST developing in a pre-existing neurofibroma (asterisks) E and displaying low-grade histology, including lesser cell density and rare mitotic figures (arrow) F. MPNSTs typically have decreased expression of mature Schwann cell markers, including S100 G and SOX10 H, and in fact may be completely negative. Loss of H3K27 trimethylation (H3K27me3) is a relatively specific feature. I, Retained positivity in underlying endothelial cells is a useful internal positive control (arrows).
FIGURE 9.
FIGURE 9.
Miscellaneous tumors of peripheral nerve. A variety of soft tissue neoplasms may develop in association with a major nerve or nerve root. A, Lipoma of cranial nerve VIII with associated entrapped ganglion cells (arrow). Synovial sarcoma is a malignant difficult mimic of nerve sheath tumors when arising primarily in nerve. B, The distinction may require molecular testing. C, Smooth muscle tumors may also involve peripheral nerve occasionally. D, This example developed in an immunosuppressed patient and was EBV associated (in Situ hybridization study for EBV encoded ribonucleic acid). Diffuse large B-cell lymphoma may present as a peripheral nerve infiltrate overriding axons E, and is typically outlined by CD20 immunostain F.
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