Undifferentiated perivascular cells in myxoid mesenchymal tumors: an ultrastructural study.

The current WHO classification of soft tissue tumors is based on the lineage of differentiation of the proliferating cells. Since mature mesenchymal cells have a broad phenotypic plasticity it has been considered unnecessary to recur to a hypothetical stem cell to explain the origin of these neoplasms. In spite of this assumption, the target cell of the oncogenic mutations in mesenchymal tumors is still a controversial item. Myxoid mesenchymal tumors constitute a heterogeneous group of neoplasms sharing in an ample mucinous matrix that separates neoplastic cells and facilitates their single submicroscopic study under electron microscopy examination. The authors have studied, by electron microscopy, 74 myxoid mesenchymal tumors, including a large variety of nosologic entities, to assess their madurational gradient. In 43 of 74 cases, a common element has been found: medium-sized cells, with high nucleo-cytoplasmic ratio, lacking lineage specific features, which were arranged around the capillary vessels. In some cases, the authors were able to demonstrate gradual differentiation in these cells, as they moved away from the vessels. These features support the hypothesis that at least some mesenchymal tumors originate from perivascular undifferentiated cells. In addition, the findings might contribute to define both topographic and morphologic characteristics of adult stem mesenchymal cells.

[Perineuriomas and other tumors with perineurial differentiation].

This is a review of the literature on the peripheral nerve sheath tumors with perineural differentiation. The authors provide an overview of the clinicopathological, immunohistochemical, ultrastructural, and genetic features of these neoplasms. Emphasis is laid on various morphological variants of perineurioma (intraneural, retifrm, sclerosing, plexiform, atypical, malignant, etc.) and so-called hybrid tumors (schwannoma-perineurioma, neurofibroma-perineurioma).

Unusual metastasis of malignant aortic body tumor to multiple bones in a dog.

Unusual metastasis of malignant aortic body tumor to multiple bones was detected in a 5-year-old female English Setter dog. Radiographs exhibited an abnormal mass in the base of heart and osteolytic lesions in the bodies of T11 and L2 vertebrates, body of right femur, right proximal humoral epiphysis and infraspinous fossa near to the neck of right scapula. At necropsy, multiple tumor masses of various sizes were observed also in the bones as well as the heart base and tracheobronchial lymph node. Tumor masses of L2 and T11 protruded into the vertebral canal and compressed corresponding sites of spinal cord, leading to paraplegia. Histopathologically, the tumor cells, arranged in sheets or nests, were polyhedral, lightly eosinophilic, finely granular cytoplasm with mostly round to oval nucleus and had scattered bizarre giant cells. Ultrastructural study revealed the characteristic findings that tumor cells contained a large number of small, electron-dense, membrane-limited secretory granules in cytoplasm. This is thought to be an extremely rare case having multiple bone metastases of a malignant aortic body tumor.

Immunolocalization of laminin in neoplasms of the central and peripheral nervous systems.

Laminin is a basement membrane glycoprotein that is expressed in vitro by immature and neoplastic astrocytes. The expression of laminin in vivo was examined immunohistochemically in normal adult brain and 90 neoplasms of the central and peripheral nervous systems. In normal adult brain, laminin was detected in the vasculature, arachnoid, pial-glial membrane, and choroid plexus. The vasculature in all 90 tumors demonstrated intense laminin immunoreactivity. Deposits of laminin were observed at the glioma-mesenchymal junction in several neoplasms, but never between or within neuroepithelial cells. The glial basement membrane often remained intact although surrounded on both sides by invasive glioma or medulloblastoma. However, there was always fragmentation and disruption of the glial membrane in adjacent fields. Laminin expression by tumor cells was observed in 10/10 schwannomas, 9/10 fibroblastic meningiomas, 3/19 nonfibroblastic meningiomas, and 3/6 mixed glioma-sarcomas. Laminin expression in the normal nervous system and in neuroepithelial neoplasms corresponds to regions of recognized basal lamina formation, including the junction between glial and mesenchymal elements. Although invasive gliomas are able to break down the pial-glial basement membrane and gain access to the perivascular or subarachnoid space, this membrane often remains intact late in the invasive process and may represent a partial barrier to tumor invasion. Laminin may be a useful marker for schwannomas, fibroblastic meningiomas, and vascular neoplasms of the nervous system.

Case of the month: January 1998--43 year old male with radicular pain.

A 43-year-old male presented with progressively worsening right lower extremity pain. MRI of the spine showed a discrete intradural, extramedullary, homogeneously enhancing, sausage-shaped mass at L1-L2, noted intraoperatively to expand the filum terminale. Gross, histological, and electron microscopic findings were those of a paraganglioma. The case is used to discuss the differential diagnosis for sausage-shaped tumors of the filum terminale.

Malignant peripheral nerve sheath tumors arising from ganglioneuromas.

Two typical malignant peripheral nerve sheath tumors (PNST) arising in preexisting ganglioneuromas are described. To the best of our knowledge, this association of tumors has not been reported in detail previously. Neither patient had the stigmata nor family history of Von Recklinghausen's neurofibromatosis. In both cases, the ganglioneuromas evolved from more primitive neuroectodermal tumors (one neuroblastoma, one ganglioneuroblastoma) and both patients developed their malignant PNST at previously irradiated sites. Both patients died within 2 years of the diagnosis of their malignant PNST. The origin of these malignant PNSTs from Schwann cells is supported by an ultrastructural analysis of 27 neuroblastomas, ganglioneuroblastomas, and ganglioneuromas.

A case of von Recklinghausen's disease with bilateral pheochromocytoma-malignant peripheral nerve sheath tumors of the adrenal and gastrointestinal autonomic nerve tumors.

A 48-year-old man with neurofibromatosis type 1 presented with chest pain, paroxysmal hypertension, tachycardia, and progressive respiratory insufficiency. Clinical investigation displayed calcified tumors in the anterior mediastinum and pararenal region. Histological examination at autopsy revealed composite tumors consisting of pheochromocytoma and malignant peripheral nerve sheath tumor (MPNST) at two sites: the left adrenal gland and the region surrounding the inferior vena cava, probably corresponding to the right adrenal gland. The MPNST component showed a varied histological appearance, including hyalinized bands with polygonal cells, a cartilaginous and myxoid stroma, a hemangiopericytomatous architecture, and a fibrosarcomatous structure, which suggested osteosarcoma, chondrosarcoma, angiosarcoma, and fibrosarcoma, respectively. In addition, based on the ultrastructural findings, the gastrointestinal tract was involved with mesenchymal tumors showing neurogenic differentiation. These lesions suggest the divergent cellular differentiation of neural crest-derived cells to mesenchymal elements as well as neuroectodermal neoplasms.

CD-34 is expressed by a distinctive cell population in peripheral nerve, nerve sheath tumors, and related lesions.

The pattern of CD-34 antigen (human progenitor cell antigen) immunoreactivity was studied within normal nerve, and a variety of nerve sheath and neuroectodermal tumors. Besides normal nerves, 111 soft tissue tumors were studied, including 17 neurofibromas, 10 neurilemomas, 12 malignant peripheral nerve sheath tumors, 1 melanocytic schwannoma, 21 fibroblastic lesions, 31 fibrohistiocytic lesions, seven neuroectodermal lesions, and 10 miscellaneous tumors. CD-34-positive dendritic cells were consistently identified within the endoneurium of normal nerve, all neurofibromas, dermatofibrosarcomas, and Antoni B (but not Antoni A) areas of neurilemomas. CD-34 was not expressed in the majority (eight of 10 cases) of malignant peripheral nerve sheath tumors. CD-34 was also lacking in all fibroblastic lesions (nodular fasciitis, fibromatosis, keloid, fibrosarcoma) and in neuroectodermal tumors that are not generally considered to show true nerve sheath differentiation (neurotropic melanoma, clear cell sarcoma, neuroepithelioma). We conclude that CD-34 (or a closely related epitope) defines a normally occurring nerve sheath cell that appears to be cytologically and immunophenotypically distinct from a fibroblast and conventional Schwann cell. The antigen can also be localized to benign nerve sheath tumors, but tends to be lost in malignant ones. The consistent presence of CD-34 within all 13 cases of dermatofibrosarcoma protuberans can be used as evidence in support of the view that these lesions are variants of nerve sheath tumors, and distinct from benign fibrous histiocytomas which consistently lack the antigen. Finally, expression of CD-34 by one of three giant cell fibroblastomas reinforces the close relationship between this tumor and dermatofibrosarcoma protuberans.

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.

Malignant peripheral nerve sheath tumor of the pleura with epithelial and rhabdomyoblastic differentiation: report of a case clinically simulating mesothelioma.

A primary malignant peripheral nerve sheath tumor (MPNST) of the pleura that clinically mimicked a malignant mesothelioma in a 57-year-old man is described. Histologically, the tumor had features similar to those described in cases of the so-called epithelioid MPNST. A unique finding in this case was the demonstration of keratin expression in the epithelioid component of the tumor, as well as the presence of rhabdomyoblasts. This is the first example of an MPNST with heterologous elements arising in the pleura. Immunohistochemical and ultrastructural studies were important in differentiating this tumor from other malignancies with sarcomatoid and epithelioid features involving the pleura.

A new human malignant peripheral nerve sheath tumour-cell line, HS-sch-2, harbouring p53 point mutation.

Only a few human malignant peripheral nerve sheath tumour (MPNST)-cell lines have been reported, and their characteristics have not been fully established. In this study, we established a new human cell line, HS-Sch-2, from an MPNST of the ordinary type which arose in a 54-year-old woman without von Recklinghausen's disease. This cell line was characterized by chromosome analysis, immunohistochemistry, ultrastructural examination, and direct sequencing of the p53 gene. The HS-Sch-2 cells have grown for more than 48 months in vitro, and exhibited hypotriploid karyotypes with complex chromosome abnormalities lacking a specific pattern. Histological features of the heterotranplanted nude mouse tumours were essentially the same as those of the original MPNST, with positive reactions for S-100 protein and neuron-specific enolase but not for epithelial membrane antigen, fibronectin or CD34. Ultrastructural examination in vivo revealed intricate interdigitation of long cytoplasmic processes and basal lamina-like structures. In addition, direct sequencing of the p53 gene detected a point mutation from CGT to CAT at codon 273 in exon 8. This HS-Sch-2 cell line, which exhibits distinctive morphological characteristics of MPNST and a p53 point mutation, will be useful for biological and pathological investigations of MPNST.

Cauda equina tumor with ependymal and paraganglionic differentiation.

We describe the case of a 31-year-old woman who was first treated for a pigmented choroid plexus papilloma of the fourth ventricle. Ten year later, she developed a new tumor in the region of the cauda equina. This second neoplasm contained areas of papillary ependymoma that displayed phosphotungstic acid hematoxylin-positive glial fibers and immunoreactivity for glial fibrillary acidic and S-100 proteins. Areas of ependymoma merged with others that displayed the appearance of a paraganglioma, including lobules and nests of chief cells immunoreactive for neuron-specific enolase, synaptophysin, chromogranin, and serotonin. Satellite cells, but not chief cells, stained for glial fibrillary acidic and S-100 proteins. Electron microscopy showed features of both ependymal and paraganglionic differentiation, including intercellular lumina with microvilli, junctional complexes, cell processes with closely packed filaments, and dense core granules. Our case represents a rare example of a cauda equina neoplasm with simultaneous ependymal and paraganglionic differentiation. To our knowledge, this is the first described example of a tumor of this region showing features of both ependymoma and paraganglioma.

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.

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.

Radiation-associated synovial sarcoma.

We describe a case of synovial sarcoma occurring in a 36 year-old woman, 8 years after radiation therapy for Hodgkin's disease. The tumor showed histological, immunohistochemical, ultrastructural, and molecular features diagnostic of synovial sarcoma. To our knowledge, this is the first report of a fully documented case of radiation associated synovial sarcoma.

Low grade malignant peripheral nerve sheath tumour: varied cytological and histological patterns.

BACKGROUND: A small number of malignant peripheral nerve sheath tumours (MPNSTs) are low grade, and the nature of these low grade tumours has never been systematically assessed. AIMS: To describe the clinicopathological, immunohistochemical, and ultrastructural features of low grade MPNST and to discuss the main differential diagnoses. METHODS: Four cases of low grade MPNST were studied, including one coexistent with neurofibromatosis type 1. The tumours were analysed with respect to nuclear atypia, cellularity, nuclear enlargement, hyperchromasia, mitotic rate, and necrosis. Immunohistochemistry was performed by standard techniques, and an ultrastructural study was performed on one tumour. RESULTS: The ages of the patients ranged from 32 to 72 years (mean, 58). Two were male and two were female. Three tumours occurred in the deep tissue, including one in the retroperitoneum, and one was located in the dermal and subcutaneous tissue. The maximum diameters of the tumours ranged from 3.5 to 8.0 cm. Microscopically, all tumours showed moderate hypercellularity, an increased nuclear to cytoplasmic ratio, and hyperchromasia, but exhibited varied growth patterns, including those that were atypical neurofibroma-like, low grade fibromyxoid sarcoma-like, low grade epithelioid, and haemangiopericytoma-like. All tumours showed immunoreactivity for S-100 protein and vimentin. CONCLUSIONS: These findings suggest that careful clinical and histological evaluation, along with S-100 protein immunostaining, are essential for the accurate diagnosis of low grade MPNST.

Neuroma formation and numbers of axons in a rat model of experimental peripheral neuropathy.

Two weeks following chronic partial constriction of rat sciatic nerve, the perineurium was disrupted and a neuroma had formed at the constriction site in all nerves (n = 5). Axon counts demonstrated an 84-99% and a 62-84% decrease in myelinated and unmyelinated axons respectively, distal to the lesion. Distally, the majority of surviving myelinated axons had diameters of less than 5.0 microns. There was considerable disparity in fiber loss from animal to animal, but similar behavioral changes were demonstrated by all animals. These results are discussed with reference to previously published data and possible mechanisms underlying the behavioral manifestations of this neuropathy model.

Perineurioma: a benign peripheral nerve tumor.

A unique benign peripheral nerve tumor, called a perineurioma, is described in this report. Light and electron microscopy and immunohistochemistry indicate that this tumor was derived from the perineurial cell. We discuss the ultrastructure, histogenesis, and management of this neoplasm.

Comparative study of neuroma formation in the rat sciatic nerve after CO2 laser and scalpel neurectomy.

Recent reports have suggested that peripheral neurectomy with the CO2 laser may be effective in preventing subsequent neuroma formation. To study this question further, we performed bilateral sciatic nerve sections in 31 rats using a steel scalpel on one nerve and a CO2 laser on the opposite side. The animals were killed 30 days after neurectomy and specimens were removed for gross observation, light microscopy, and electron microscopy. Axon composition studies were carried out in selected animals and axon diameter histograms were prepared. Well-formed neuromas were present in nerves transected by both the scalpel and the CO2 laser. The scalpel neuromas were characterized by a greater degree of interfascicular collagen deposition and perineurial cell proliferation. Laser neuromas demonstrated less perineurial compartmentalization and scar tissue formation. In addition, a foreign body reaction with multinucleated giant cells surrounding carbonaceous debris was seen that was not present in the scalpel neuromas. Analysis of axon composition studies revealed that both neuromas had a greater density of axons and a higher percentage of small diameter myelinated and unmyelinated axons as compared to control nerves. Laser neuromas had more axons per unit area than scalpel neuromas, but the percentage composition of axons was very similar in the two groups. We could find no evidence in the rat sciatic nerve model that CO2 laser neurectomy is less likely to result in neuroma formation than is conventional scalpel neurectomy.