Peripheral nerve sheath tumors are common neoplasms, with classic identifiable features, but on occasion, they are diagnostically challenging. Although well-defined subtypes of peripheral nerve sheath tumors were described early in the history of surgical pathology, controversies regarding the classification and grading of these tumors persist. Advances in molecular biology have provided new insights into the nature of the various peripheral nerve sheath tumors, and have begun to suggest novel targeted therapeutic approaches. In this review, we discuss current concepts and problematic areas in the pathology of peripheral nerve sheath tumors. Diagnostic criteria and differential diagnosis for the major categories of nerve sheath tumors are proposed, including neurofibroma, schwannoma, and perineurioma. Diagnostically challenging variants, including plexiform, cellular and melanotic schwannomas are highlighted. A subset of these affects the childhood population, and has historically been interpreted as malignant, although current evidence and outcome data suggest they represent benign entities. The growing current literature and the author's experience with difficult to classify borderline or “hybrid tumors” are discussed and illustrated. Some of these classification gray zones occur with frequency in the gastrointestinal tract, an anatomical compartment that must always be entertained when examining these neoplasms. Other growing recent areas of interest include the heterogeneous group of pseudoneoplastic lesions involving peripheral nerve composed of mature adipose tissue and/or skeletal muscle, such as the enigmatic neuromuscular choristoma. Malignant peripheral nerve sheath tumors (MPNST) represent a diagnostically controversial group; difficulties in grading and guidelines to separate “atypical neurofibroma” from MPNST are provided. There is an increasing literature of MPNST mimics which neuropathologists must be aware of, including synovial sarcoma and ossifying fibromyxoid tumor. Finally, we discuss entities that are lacking from the section on cranial and paraspinal nerves in the current WHO classification, and that may warrant inclusion in future classifications. In summary, although the diagnosis and classification of most conventional peripheral nerve sheath tumors are relatively straightforward for the experienced observer, yet borderline and difficult-to-classify neoplasms continue to be problematic. In the current review, we attempt to provide some useful guidelines for the surgical neuropathologist to help navigate these persistent, challenging problems.

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Pathology of Peripheral Nerve Sheath Tumors: Diagnostic Overview and Update on Selected Diagnostic Problems

The frequency and morphological spectrum of gastrointestinal peripheral nerve sheath tumors (PNSTs) from consecutive case material has not been studied in the c-KIT era. We reviewed all mesenchymal gastrointestinal (GI) lesions at our departments according to current diagnostic criteria. PNSTs formed the third commonest group of mesenchymal GI tumors with a lower frequency (< or =5%) compared to gastrointestinal stromal tumors (GISTs; approximately 50%) and smooth muscle neoplasms ( approximately 30%). Granular cell tumors (GCTs; n = 31) and schwannomas (n = 22) were the most common types of PNSTs encountered. Rare tumors included neurofibromatosis 1 (NF1)-associated PNSTs (n = 5) and gastric perineurioma (n = 1). Thirteen schwannomas (including also some recent cases) were initially diagnosed as GIST, leiomyoma, or neurofibroma. Unusual histological variants included sigmoid GCT with prominent lipomatous component (n = 1), reticular-microcystic schwannoma of small (n = 1) and large (n = 1) bowel, NF1-associated gastric schwannoma (the first case to date), and psammomatous melanotic colonic schwannoma unrelated to Carney complex (n = 1). PNSTs coexisted with GIST in four patients (three had definite NF1). In conclusion, PNSTs of the GI tract are rare uniformly benign neoplasms that may show schwannian, perineurial, fibroblastic, or mixed differentiation. Most of them (92%) occurred sporadically unassociated with NF1 or NF2. Gastrointestinal PNSTs are still underrecognized by general pathologists. Awareness of their diverse morphology will help to avoid confusing them with smooth muscle neoplasms and GIST that they may closely mimic.

Peripheral nerve sheath tumors of the gastrointestinal tract: a multicenter study of 58 patients including NF1-associated gastric schwannoma and unusual morphologic variants.

Schwannomas are benign peripheral nerve sheath tumors believed to be composed purely of cells with ultrastructural features of Schwann cells; these tumors are believed to develop eccentrically from the surface of nerves and not to contain axons, other than immediately beneath the capsule. This concept has recently been disputed in cases associated with neurofibromatosis type 2. The usual presence of intratumoral axons in neurofibromas is said to allow easy distinction from schwannomas. Eighty sporadic schwannomas (20 conventional, 20 cellular, 20 ancient, 10 gastric, and 10 plexiform) were retrieved from the authors' files. Hematoxylin-and-eosin stained slides were reviewed, diagnoses were confirmed and all tumors were stained for S-100 protein and neurofilament protein (NFP). The amount (rare, focal, multifocal, and diffuse) and distribution (central and/or peripheral) of axons within the tumors were analyzed. All tumors were strongly and diffusely positive for S-100 protein (nuclear and cytoplasmic staining). NFP-positive axons were identified in 11 of 20 (55%) conventional schwannomas (2 rare, 4 focal, 3 multifocal, and 2 diffuse; 5 central, 4 peripheral, and 2 central and peripheral) and in 15 of 20 (75%) cellular schwannomas (3 rare, 6 focal, and 6 multifocal; 12 central, 1 peripheral, and 2 central and peripheral). Of the 20 ancient schwannomas, 7 cases (35%) showed intratumoral axons, highlighted by NFP immunostaining (1 rare, 4 focal, 1 multifocal, and 1 diffuse; 4 peripheral, 2 central, and 1 central and peripheral). Most cases of gastric schwannoma showed no evidence of intratumoral axons; 9 cases (90%) were negative for NFP and only 1 case (10%) was positive (focal and central). Seven of 10 cases (70%) of plexiform schwannomas were negative for NFP, whereas only 3 cases (30%) showed positive axons (2 multifocal and 1 focal; 3 central). The unexpected but quite frequent presence of intratumoral axons in schwannomas argues against conventional views of these lesions' pathogenesis as an eccentric encapsulated lesion and raises the possibility that a more diverse cell population, perhaps more closely resembling neurofibromas, may constitute these neoplasms. Although NFP-positive axons were most often present in the conventional and cellular variants of schwannoma, their presence was also observed in a minority of ancient, gastric and plexiform schwannomas. Differentiation between neurofibroma and schwannoma in cases with overlapping cytoarchitectural features should not be based solely on the presence or absence of NFP-positive axons within a given tumor.

The Controversial Nosology of Benign Nerve Sheath Tumors: Neurofilament Protein Staining Demonstrates Intratumoral Axons in Many Sporadic Schwannomas

The authors report a small case series of hybrid nerve sheath tumors occurring in the setting of type 1 neurofibromatosis. Four lesions were benign and consisted of plexiform neurofibromas with considerable areas of perineuriomatous differentiation in patients with type 1 neurofibromatosis. In these lesions, biphasic (Schwannian and perineuriomatous) differentiation was apparent on immunohistochemistry, with the perineuriomatous areas staining for epithelial membrane antigen, glut-1, and claudin-1 and being negative for S-100 protein. Three patients were members of a single family, with a history of various malignant neoplasms. Included in the series is 1 hybrid lesion in which neurofibromatous and perineuriomatous areas were clearly visible on hematoxylin- and eosin-stained slides. The lesion was unique in that it manifested malignant change in the S-100 protein-positive component, which was classified as malignant peripheral nerve sheath tumor. The malignant component showed areas with an epithelioid cell morphology.

Hybrid peripheral nerve sheath tumors, including a malignant variant in type 1 neurofibromatosis.

Soft tissue neoplasms with features of both schwannoma and perineurioma (hybrid schwannoma-perineurioma) have been increasingly recognized in recent years. To date, only a single case of this entity has been documented in the gastrointestinal tract (sigmoid colon). We herein describe 2 new cases of this entity. For comparison, we reevaluated 12 classic gastrointestinal schwannomas for the perineurial cell component. The 2 hybrid schwannoma-perineuriomas were detected incidentally in the gastric antrum and the vermiform appendix in a 50-year-old woman and a 17-year-old man during surgery for gastric GIST and appendicitis-like symptoms, respectively. None of the patients had neurofibromatosis 1 or 2. Patients were alive with no evidence of recurrence or new tumors at 8 and 12 months, respectively. The tumors measured 1.2 cm and 1.5 cm in size. Histologically, they showed prominent storiform, lamellar, and fascicular patterns. Notably, both lacked peripheral lymphoid cuffs and the trabecular pattern of gastrointestinal schwannomas. Both tumors coexpressed protein S100 (≥80%), CD34 (80%), and the perineurial cell markers (20% to 40% of tumor cells). The perineurial cell component formed alternating fascicles with S100-positive cells throughout the neoplasm. Reevaluation of 12 classic gastrointestinal schwannomas showed isolated claudin-1/epithelial membrane antigen-positive cells. However, 4 schwannomas (33%) strongly expressed glucose transporter-1 in most of the tumor cells indicating its limited specificity in this setting. Compared with gastrointestinal schwannomas, CD34 expression was stronger and more diffuse in hybrid schwannoma-perineuriomas. We conclude that hybrid schwannoma-perineuriomas are distinct from gastrointestinal schwannoma, both histologically and immunohistochemically.

Hybrid schwannoma-perineurioma of the gastrointestinal tract: a clinicopathologic study of 2 cases and reappraisal of perineurial cells in gastrointestinal schwannomas.

Gastrointestinal schwannoma (GIS) is a distinctive and extremely rare lesion showing some differences from conventional soft tissue schwannoma and some similarities with common soft tissue neurofibroma. Soft tissue neurofibromas and schwannomas differ by contents of specific types of nerve sheath cells, such as Schwann cells, perineurial cells and CD34+ cells. To compare GIS with these soft tissue lesions, eight cases of typical GIS were studied immunohistochemically to evaluate their nerve sheath cell types. Epithelial membrane antigen (EMA) and claudin-1 as perineurial cell markers, and neurofilament protein as a marker for intratumoral axons were used. In addition, the tumors were stained for cytokeratin, CD117 (C-KIT), alpha-muscle specific actin, S100 protein and CD34. EMA- and claudin-positive cells were seen in 2 (25%) and one lesion, respectively, thus resembling cellular composition of neurofibroma. Intratumoral neurofilament protein positive axons otherwise typical of neurofibroma were found inside 4 tumors (50%). CD34 positivity was found in 6 tumors (75%) and often revealed a diffuse pattern as seen in neurofibroma and not a zonal pattern as described in schwannomas. These results show that GIS has some features that are more typical for neurofibroma than for conventional schwannoma. In surgical pathology practice, a finding of intratumoral axons and positivity for claudin-1 and especially for EMA should not preclude diagnosis of GIS.

L Sokol

Papers

Perineurial cells and nerve axons in gastrointestinal schwannomas: a similarity with neurofibromas. An immunohistochemical study of eight cases