Fibrolipomatous Hamartoma of the Nerve Arising in the Neck: A Case Report With Review of the Literature and Differential Diagnosis.

We report an unusual case of a fibrolipomatous hamartoma that arose in a nuchal nerve. Typically, fibrolipomatous hamartoma, otherwise known as a neural fibrolipoma or lipomatosis of nerve, arises in the median nerve, brachial plexus, cranial nerves, or plantar nerves. The differential diagnosis is broad and includes benign and malignant spindle cell lesions, such as spindle cell lipoma, perineurioma, and myxoid liposarcoma. We were able to identify the lesion based on the typical histology, including triphasic composition with spindle cell, neural, and adipocytic components and whorled architecture. Because of the atypical location in the neck, detailed immunohistochemical staining was performed. The lesional spindle cells were negative for SMA, CD10, CD68, EMA, S100, PGP9.5, CD34, CD56, and beta-catenin. Colloidal iron stain highlighted marked intralesional mucin deposition. This detailed immunohistochemical profile is a useful diagnostic aid and to our knowledge has not been previously described.

[Sciatic nerve intraneural perineurioma]. / Périneuriome intraneural du nerf sciatique.

Intraneural perineurioma is a benign tumor developed from the perineurium and responsible for localized nerve hypertrophy. This uncommon tumor is characterized by a proliferation of perineural cells with a "pseudo-onion bulb" pattern. We report a sciatic nerve intraneural perineurioma in a 39-year-old patient.

Spontaneous ganglioneuroma possibly originating from the trigeminal ganglion in a B6C3F1 mouse.

In a carcinogenicity study, a neuronal tumor in the cranial cavity was observed in a 110-week-old female B6C3F1 mouse. At necropsy, the tumor was seen at the site of the pituitary gland. Histologically, the tumor consisted of well-differentiated ganglion cells, nerve fiber/neuropil-like elements and ganglion-like cells. The tumor was composed mainly of ganglion-like cells, which were arranged in solid sheets interspersed with thin fibrovascular stroma. Nissl substance was detected at the margin in the cytoplasm of well-differentiated ganglion cells, and nerve fibers were identified by the Kluever-Barrera method. Immunohistochemically, the well-differentiated ganglion cells were positive for S-100, neurofilament protein (NF), neuron-specific enolase (NSE), synaptophysin, and chromogranin A. The nerve fiber/neuropil-like elements were positive for S-100, NF, NSE, and glial fibrillary acidic protein (GFAP), and the ganglion-like cells were strongly positive only for NSE and synaptophysin. On the other hand, there were no pituitary cells, such as prolactin-positive or adrenocorticotropic hormone (ACTH)-positive cells in the tumor tissue. Detailed histopathological examination suggested that the tumor might be a ganglioneuroma arising from the trigeminal ganglion. This report provides additional histopathological evidence of peripheral nerve neoplasms in mice.

[Morphologic and differential diagnosis of sclerosing perineurioma].

The paper discusses morphologic and immunohistochemical characteristics of sclerosing perineurioma. Generally, it is well circumscribed and consists of tiny spindle-shaped plump epitheloid cells embedded in collagenous hyalinized matrix. Immunohistochemically, it was represented by EMA+, S-100, AE1/AE3, CAM 5.2, smooth muscle actin and desmin. Being benign, tumor was identified by differential diagnosis using fibroma of tendon sheath, sclerosing one, glomal tumor, giant cell tumor and sclerosing epitheloid cell sarcoma.

[Morphologic features of reticular (retiform) perineuroma].

The report deals with 8 cases of reticular (retiform) perineuroma, a rare soft-tissue variant of the latter. It presents as a lace-like pattern of long cytoplasmic outgrowths of tumor cell clusters in myxoid or tender collagenized stroma. Despite its potential for infiltrative growth, perineuroma has a benign clinical course.

Extraneural hemangioblastoma: a report of 5 cases.

Hemangioblastoma is a morphologically distinctive tumor that can occur sporadically or in association with von Hippel-Lindau disease, and which involves the central nervous system in the majority of the cases. Rare occurrences of hemangioblastoma in peripheral nerves and extraneural tissues have been reported. The histogenesis of this tumor remains uncertain. Various cell lineages such as vascular, glial, neural, fibrohistiocytic, and smooth muscle/myofibroblastic have been proposed for the so-called stromal cells, which are thought to represent the neoplastic component of these lesions. We report on 5 cases of hemangioblastoma arising in extraneural tissues. Two of the tumors were located in the presacral region, and one each in the maxilla, kidney, and adrenal glands. All 5 cases were morphologically indistinguishable from central nervous system hemangioblastoma. The existence of these cases suggests that the "stromal" cells of hemangioblastoma can demonstrate a variety of mature specific lineages, such as smooth muscle/myofibroblastic, or neuroendocrine, depending on the location and possibly the microenvironment.

Oncolytic herpes simplex virus therapy for peripheral nerve tumors.

Oncolytic viruses are one of many emerging cancer therapies. The surgical management of peripheral nerve tumors carries an inherent risk of damaging the nerves involved and so the search for novel therapies with reduced risk of morbidity continues. In this review the authors discuss the use of oncolytic herpes simplex virus (HSV) in the treatment of peripheral nerve tumors. Herpes simplex virus has a number of characteristics that make it a useful oncolytic vector, including its large, sequenced genome that can accommodate multiple transgenes, its lack of insertional mutagenesis, its ability to infect a wide array of cell types in various species, and the availability of well-established antiviral therapies to treat it. The efficacy of oncolytic HSV therapy against schwannomas and malignant peripheral nerve sheath tumors has been studied in multiple experimental models both in vitro and in vivo. The virus utilizes cell pathways unique to tumors to enhance its oncolytic efficacy, preferentially and effectively targeting and destroying peripheral nerve tumor cells without harming normal cells. This effect is augmented by transgenes expressing antiangiogenic factors, such as dominant-negative fibroblast growth factor receptor and platelet factor 4, and displays synergy with chemotherapy. Different oncolytic HSV vectors have been tested, including hrR3, G207, and G47D. In addition, new animal models have been developed to test the efficacy of oncolytic HSV therapy in peripheral nerve tumors. The safety of oncolytic HSV is well established and has been tested in nonhuman primates and in human clinical trials.

Retroperitoneal schwannomas: diagnostic and therapeutic implications.

AIMS AND BACKGROUND: Schwannomas are a rare group of soft-tissue tumors that are derived from the peripheral nerve sheath and rarely develop in the retroperitoneum. METHODS AND STUDY DESIGN: We reviewed the clinicopathological features of 4 patients referred to our unit between October 1999 and March 2004 who on radiological examination were diagnosed with pancreatic, adrenal, psoas and retroperitoneal fat tissue tumors and subsequently underwent surgical treatment. RESULTS: The preoperative diagnosis was incorrect in all cases. At time of surgery, we found a mass probably arising from the adrenal gland in 2 patients, a lesion originating from the femoral nerve in 1 patient, and a retroperitoneal mass without a clear site of origin in 1 patient. Pathological evaluation revealed schwannomas in all cases, with no signs of malignancy. Complete surgical excision was performed in all patients without any major postoperative complications. At the time of writing all patients are alive with no evidence of local or distant recurrence. CONCLUSIONS: Radical surgical excision is considered the best treatment for these neoplasms, resulting in a very good longterm prognosis.

Is clear cell sarcoma a malignant form of psammomatous melanotic schwannoma? Case report.

The authors present a case of clear cell sarcoma (CCS) in which the tumor originated in the S-1 nerve root and had been previously diagnosed as psammomatous melanotic schwannoma (PMS). This is the third case of a spinal nerve root origin for CCS reported in the English-language literature. The similar histogenesis of CCS and malignant melanoma supports the hypothesis that biological agents or immunotherapy are potentially important areas of investigation. The patient underwent S1-3 laminectomy and gross-total resection of the mass lesion. The border of the resection was extended 1 cm distal to the tumor margin. The postoperative period was uneventful. The new histopathological diagnosis was CCS (malignant melanoma of soft tissue). Despite total resection, the patient returned with disseminated disease at the 18-month follow-up visit. His follow-up magnetic resonance image of the lumbar spine revealed sacral L5-S3 involvement of the vertebral bodies along with disseminated cauda equina seeding. A CCS originating from peripheral nerves is quite rare. The histopathological and immunohistochemical appearance of CCSs resembles those of PMSs. Surgery should be the first choice of treatment.

Diagnostic and biological implications of mel-CAM expression in mesenchymal neoplasms.

Mel-CAM (previously MUC18) is an integral membrane glycoprotein involved in heterophilic intercellular adhesions. Mel-CAM is expressed specifically in certain normal mesenchymal tissues, including smooth muscle, endothelium, and Schwann cells. As a member of the immunoglobulin supergene family of cell adhesion molecules (CAMs), Mel-CAM may play a pivotal role in the normal differentiation and functional activity of these tissues. To determine the distribution of Mel-CAM in mesenchymal neoplasms and to investigate its potential role as a factor in tumor progression, we evaluated a spectrum of mesenchymal neoplasms by immunohistochemistry using a Mel-CAM-specific polyclonal antibody on formalin-fixed tissues. Mel-CAM positivity was observed in 5 (100%) of 5 leiomyomas, 29 (91%) of 32 leiomyosarcomas, 5 (100%) of 5 hemangiomas, 5 (100%) of 5 angiosarcomas, 3 (100%) of 3 Kaposi's sarcomas, 8 (100%) of 8 schwannomas, 10 (100%) of 10 neurofibromas, 0 (0%) of 8 malignant peripheral nerve sheath tumors, 2 (15%) of 13 malignant fibrous histiocytomas, 0 (0%) of 8 fibrosarcomas, 0 (0%) of 7 synovial sarcomas, and 0 (0%) of 6 liposarcomas. These results show that Mel-CAM is expressed consistently in neoplasms of smooth muscle and vascular origin, and that immunostaining for Mel-CAM may serve as a useful adjunct in differentiating leiomyosarcomas, angiosarcomas, and Kaposi's sarcomas from other spindle cell neoplasms. Furthermore, the observation that Mel-CAM is expressed consistently in schwannomas and neurofibromas but not in malignant peripheral nerve sheath tumors implicates Mel-CAM as a potential modulator of malignant transformation in peripheral nerve tumors.

Low-grade small round cell tumor of the cauda equina with EWSR1-WT1 fusion and indolent clinical course.

We report a case of a longstanding, large tumor involving spinal nerve roots of the cauda equina. The tumor showed small round cells arranged in nests and cords and immunophenotypic features of a glomus tumor, along with infrequent mitoses and a low Ki-67 labeling index, but exhibited some rosette-like structures, with focal CD99 and Neu-N expression. Subsequent molecular analysis showed the presence of an EWSR1-WT1 gene fusion by fluorescence in situ hybridization, which was confirmed by reverse- transcriptase polymerase chain reaction. To our knowledge, this is the first case reported with EWSR1-WT1 fusion in a small round blue cell tumor with smooth muscle differentiation and an indolent course.

Schwannoma (neurilemoma) with malignant transformation. A rare, distinctive peripheral nerve tumor.

Malignant transformation of a schwannoma (neurilemoma) is an exceedingly rare event. We describe two cases with such change and review the reported purported examples. The tumors in our patients involved a finger and pelvis. Sex, age, and clinical follow-up were available for only the second case, involving a 31-year-old man who died with recurrent and metastatic tumor. Seven acceptable cases were found in the literature. Analysis of the nine cases of schwannoma with malignant transformation showed no sex predilection, but revealed a tumor differing significantly from conventional malignant peripheral nerve sheath tumors. The mean age (56 years) was two decades older, no patient had neurofibromatosis, in four cases there was a years-long history of an antecedent mass, and in none of the cases was the malignant component an interlacing, fasciculated spindle-cell tumor. Rather, the malignant component was commonly purely epithelioid (seven of nine cases). In the two other cases, cells of the malignant component had neuroepithelial features. The prognosis for patients with schwannomas undergoing malignant change is poor. Five of eight patients with follow-up (62%) died of disease with either residual (one patient) or metastatic tumor (four patients).

Florid vascular proliferation associated with neural and neuroendocrine neoplasms. A diagnostic clue and potential pitfall.

We report the light microscopic and immunohistochemical features of vascular proliferations associated with 26 extracranial neural and neuroendocrine neoplasms including esthesioneuroblastoma, neuroblastoma/ganglioneuroblastoma, the primitive neural component of immature teratoma, mediastinal teratoma, primitive neuroectodermal tumor, intra-abdominal desmoplastic small cell tumor, Merkel cell carcinoma of the skin, and thyroid medullary carcinoma. These vascular proliferations were similar to those associated with high-grade glial neoplasms and were characterized by tufts of vessels with a glomeruloid configuration or by long cords of vessels. Immunohistochemical evaluation documented the presence of endothelial cells, perithelial cells, and basement membrane components within the foci of proliferating vessels. We propose that these vascular proliferations represent a characteristic feature of the neuroendocrine/neural neoplastic phenotype and that they possibly arise as the result of angiogenic factors produced by the neoplastic cells. The presence of these distinctive vascular lesions in the stroma of a poorly differentiated neoplasm should alert the pathologist to the possibility of the neoplasm being of a neural or neuroendocrine nature.

Perineurial malignant peripheral nerve sheath tumor (MPNST): a clinicopathologic, immunohistochemical, and ultrastructural study of seven cases.

Most malignant peripheral nerve sheath tumors (MPNST) are schwannian in nature. The pathologic features of MPNST with perineurial cell differentiation remain to be characterized. To determine the clinicopathologic, immunohistochemical, and ultrastructural characteristics of perineurial MPNST, 121 MPNST from the Mayo Clinic Tissue Registry were examined. Of these 23 spindle cell tumors with long processes disposed in whorls or storiform patterns, features typical of perineurioma, were studied. On the basis of immunohistochemistry (epithelial membrane antigen+/S-100-), 5 perineurial MPNST were identified among 23 tumors selected. These and two previously characterized perineurial MPNST are the subject of this study. None of seven tumors was associated with NF-1. Patients included five males and two females ranging in age from 11 to 83 years (mean, 45.7 years). The tumors measured 1.5 to 30 cm (mean, 9.1 cm) and arose in the extremities (two), trunk (two), face (one), mediastinum (one), and retroperitoneum (one). Only one tumor was nerve associated (phrenic nerve). All tumors were surgically removed. No encapsulation or neurofibroma components were noted. Necrosis was seen in three lesions. Four tumors were classified as high-grade malignant and three as low grade. Mitotic indices varied from 1 to 85/10 high-power fields (median, 16). Immunoreactivities included epithelial membrane antigen (100%), vimentin (100%), Leu-7 (57%), and CD34 (14%). Stains for S-100 protein, muscle markers, and cytokeratin were nonreactive. Ultrastructurally, perineurial-like cells were noted in three tumors and cells intermediate between perineurial and Schwann cells in one. Four tumors recurred and two metastasized; no deaths of disease were noted at follow-ups of 28 to 98 months (mean, 66.9). In conclusion, 4% of MPNST show perineurial cell differentiation. An NF-1 association has yet to be described. Nerve involvement is infrequent. Their immunophenotype (epithelial membrane antigen+/S-100-) frequently indicates ultrastructural perineurial differentiation. The prognosis of perineural MPNST appears to be more favorable than that of conventional MPNST.

Multiple familial gastrointestinal autonomic nerve tumors and small intestinal neuronal dysplasia.

Multiple small intestinal stromal tumors were removed from mother and natural daughter within 15 months of each other. Both had long histories of recurrent iron deficiency anemia and upper gastrointestinal bleeding. Light microscopy revealed that the tumors had arisen in conjunction with diffuse hyperplasia/ dysplasia of Auerbach's myenteric plexus. Immunohistochemistry generally did not show myogenic or paraganglionic phenotypes; CD34 was positive in most tumors. Electron microscopy confirmed the association with the abnormal Auerbach's plexus and showed the structure of gastrointestinal autonomic nerve tumors (GANTs). These findings provide information as to the origin and evolution of GANTs, and also have implications for the clinical management of these tumors which appear to occur more frequently than previously thought.

Gangliosides and neutral glycolipids in ependymal, neuronal and primitive neuroectodermal tumors.

Neutral glycolipid and ganglioside compositions were determined on 11 ependymal tumors, 12 medulloblastomas, 6 other neuronal tumors of the brain, 4 peripheral neuroblastomas, 1 cerebral primitive neuroectodermal tumor (PNET), and 1 PNET of the thoracic wall. Within the group of tumors that can demonstrate neuronal phenotypes, there was an association between the degree of neuronal differentiation usually demonstrated by these tumors and the proportions of both GD1a and 1b-pathway gangliosides. The amount of globoside also correlated with the amount of 1b pathway gangliosides. Patients with medulloblastomas whose 1b gangliosides made up over 15% of the total gangliosides survived longer that those with lower proportions of 1b gangliosides. The only gangliosides in the choroid plexus papilloma were GM3 and GD1a, but other ependymal tumors had significant amounts of GD1b and its metabolic precursors. Ependymoma and anaplastic ependymoma had similar neutral glycolipid compositions, which were different from subependymoma, which lacked ceramide monohexoside and ceramide dihexoside. These differences in glycolipid compositions suggest that there may be fundamental biological differences between these types of ependymal tumors.

Gastrointestinal autonomic nerve tumor: further observations regarding an ultrastructural and immunohistochemical analysis of six cases.

Gastrointestinal autonomic nerve tumor (GANT) is a specialized form of stromal neoplasm whose ultrastructural features support a myenteric plexus derivation and provide the basis for its diagnosis. GANT actual frequency, relationship to skeinoid fibers, and CD34 expression status are some of the controversial aspects of this entity. Out of 14 gastrointestinal stromal tumors gathered during a 1-year period, six (42%) instances were diagnosed as GANT by electron microscopic study of at least five ultrathin sections per case. Additionally, GANTs were immunohistochemically investigated with a panel of nine antibodies including CD34. Ultrastructurally, every GANT case showed diagnostic findings and evidence of skeinoid fibers, whereas immunohistochemically all except one were CD34 positive. Immunoreactivity for neuron-specific enolase, synaptophysin, and vimentin was a common occurrence as well. In conclusion, GANT seems to be more frequent than hitherto recognized, skenoid fibers are a regular feature of GANT, and a positive CD34 immunoreaction does not discriminate between GANT and other non-smooth muscle, non-schwannian neoplasms.

Hepatocyte growth factor and c-MET in benign and malignant peripheral nerve sheath tumors.

Hepatocyte growth factor (HGF), secreted by mesenchymal cells, has pleiotropic biological activities on several cell types. HGF and its receptor, the c-met proto-oncogene product (c-MET) have been implicated in the genesis and progression of several carcinomas and sarcomas. It has been suggested that MET/HGF autocrine signaling may contribute to tumorigenesis in sarcomas. HGF has been recently found to be a mitogen for rat Schwann cells and to be present in neurofibromas in NF1 patients. In this investigation, we assessed the immunoreactive patterns of HGF and MET in benign and malignant peripheral nerve sheath tumors (PNST) using archival formalin-fixed tissue. The standard avidin-biotin-peroxidase method was used. All benign tumors were negative with HGF. Eight cases of MPNST were positive with both HGF and MET. In some malignant PNST, positivity with both ligand and the receptor may be indicative of an autocrine mediated signal transduction and may implicate HGF/MET in tumor progression. Immunoreactivity with MET was strikingly greater in MPNST in contrast to benign PNST; this finding may prove to be helpful in distinguishing some histologically low-grade MPNST from cellular and atypical benign PNST.

Malignant peripheral nerve sheath tumors: an immunohistochemical study in relation to ultrastructural features.

The constituent cells in malignant peripheral nerve sheath tumors were examined by studying the expression of immunohistochemical markers for Schwann cells and perineurial cells in relation to ultrastructural features in 12 malignant peripheral nerve sheath tumors. Ultrastructural studies demonstrated mixed proliferation of Schwann cells, perineurial cells, fibroblastic cells, and primitive cells in many malignant peripheral nerve sheath tumors. Expression of S-100 protein was well correlated with Schwann cell-like differentiation of tumor cells. However, Leu-7 and epithelial membrane antigen, which have been considered to be specific to Schwann cells and perineurial cells, respectively, were common to Schwann cells, perineurial cells, and primitive cells. The common immunophenotypic expression suggests a close relationship among these cell types. The unusual expression of cytokeratin could be explained by the plasticity of intermediate filament expression.