Myosin XVA expression in the pituitary and in other neuroendocrine tissues and tumors.

The myosin superfamily of molecular motor proteins includes conventional myosins and several classes of unconventional myosins. Recent studies have characterized the human and mouse unconventional myosin XVA, which has a role in the formation and/or maintenance of the unique actin-rich structures of inner ear sensory hair cells. Myosin XVA is also highly expressed in human anterior pituitary cells. In this study we examined the distribution of myosin XVA protein and mRNA in normal and neoplastic human pituitaries and other neuroendocrine cells and tumors. Myosin XVA was expressed in all types of normal anterior pituitary cells and pituitary tumors and in other neuroendocrine cells and tumors including those of the adrenal medulla, parathyroid, and pancreatic islets. Most nonneuroendocrine tissues examined including liver cells were negative for myosin XVA protein and mRNA, although the distal and proximal tubules of normal kidneys showed moderate immunoreactivity for myosin XVA. Ultrastructural immunohistochemistry localized myosin XVA in association with secretory granules of human anterior pituitary cells and human pituitary tumors. These data suggest that in neuroendocrine cells myosin XVA may have a role in secretory granule movement and/or secretion.

Jejunal stromal tumor with skeinoid fibers or myenteric plexoma: a case report.

Small intestinal stromal tumors with 'skeinoid fibers' are uncommon stromal tumors with an associated controversial histogenesis. Although their microscopic appearance is suggestive of a smooth muscle nature, they lack specific smooth muscle features, as evident by electron microscopy and immunohistochemistry. They also appear to lack features of neurogenic origin because they fall to react with neural/neuroendocrine markers such as S-100 protein, neuron-specific enolase and chromogranin. It is interesting, nonetheless, to note that the ultrastructural examination of these tumors may show structures reminiscent of neural differentiation, such as cytoplasmic projections, containing occasional membrane-bound, dense-core, neurosecretory-type granules, which mimick the long cytoplasmic processes seen in tumors of neural origin. Moreover, the association of these tumors with Von Recklinghausen's neurofibromatosis, as well as the presence of 'skeinoid fibers' in proven neurogenic spindle cell neoplasms such as gastrointestinal autonomic nerve tumors and schwannomas, suggests that these tumors might also be neurogenic in origin and enhances the diagnostic value of 'skeinoid fibers' as a possible ultrastructural marker of neural differentiation. Thus, light microscopic evaluation is clearly insufficient to accurately diagnose these tumors and to determine their histogenesis, electron microscopic and immunohistochemical studies being necessary. In this article the histogenesis of small intestinal stromal tumors with 'skeinoid fibers', regarding a jejunal neoplasm in a 63-year-old patient, is reviewed. The light microscopic, immunohistochemical and ultrastructural features are described and compared with findings usually seen in all those stromal tumors which may raise a differential diagnosis, such as smooth muscle stromal tumors, gastrointestinal autonomic nerve tumors, schwannomas, paragangliomas and fibrosarcomas.

Gastrointestinal autonomic nerve tumor: a common type of gastrointestinal stromal neoplasm.

Seven of 15 gastrointestinal stromal tumors from the author's file were classified as plexosarcomas when examined by electron microscopy and immunohistochemistry. Electron microscopy was essential for the diagnosis.

Intermediate filaments in the nervous system: implications in cancer.

In this review, we describe the different intermediate filament (IF) proteins, their assembly into IFs, the functions of IFs and their relation to disease with a particular emphasis on the intermediate filaments expressed in the nervous system. In the mammalian nervous system, seven intermediate filament proteins are known to be expressed in neurons or neuroblasts. These include the three neurofilament triplet proteins, which are present in both central and peripheral neurons; alpha-internexin, which is the first neuronal intermediate filament protein expressed in the developing mammalian nervous system and present primarily in CNS neurons in the adult nervous system; peripherin, which is most abundant in the PNS; vimentin, which is expressed in neuronal progenitor cells along with nestin, as well as in a few adult neurons. In contrast to these neuron-specific IF proteins, the glial fibrillary acidic protein (GFAP) is glial specific and expressed in mature astrocytes. Vimentin and nestin are also expressed in glial progenitor cells and vimentin is expressed along with GFAP in some mature astrocytes. As a whole, the expression of IF proteins is tissue specific and developmentally regulated. As a result, IF proteins are good markers for determining the cell origin and differentiation status of tumor cells. For example, peripherin is expressed in neuroblastomas, GFAP in astrocytomas and neurofilaments in tumors of neuronal origin. However, tumor cells may express IF patterns which are irrelevant to their cell origin. Therefore, one has to be very careful in using IF patterns as sole indicators of cell origin and differentiation status of tumors.

Nuclear morphometry and DNA densitometry of human gliomas by image analysis.

In 48 patients with gliomas in whom complete clinical follow-up was obtained, DNA ploidy was evaluated by using formalin-fixed paraffin-embedded tissues and by means of image analysis. The mean DNA indices, determined by averaging DNA indices of all tumor cells in a tumor, were mainly affected by mean DNA indices of the nuclei of SG2M phase tumor cell (including S phase and G2M phase cells) (SG2M DNA indices) and that mean DNA indices correlated with the SG2M phase fraction. The SG2M DNA indices and the percentage of tumor cells with S phase and G2M phase were higher in high grade gliomas including anaplastic glioma and glioblastoma multiforme than in low grade gliomas. Patients with G2M-hypertetraploid tumors demonstrated a shorter time to tumor progression than those with G2M-tetraploid in high grade glioma. Morphometrically, the nuclei of SG2M phase glioma cells were larger and more deformity than those of G0G1 phase (including G0 phase and G1 phase cells) cells. The G2M-hypertetraploid tumors were highly malignant and demonstrated large nuclei, greater nuclear deformity, and a higher proliferative potential. The G2M-tetraploid gliomas demonstrated a shorter time to tumor progression in cases whose the SG2M fraction was large. In contrast, G2M-hypotetraploid gliomas revealed an insignificant trend towards a longer time to tumor progression than those associated with tetraploid and hypertetraploid gliomas. We emphasize herein the prognostic importance of the SG2M phase cell, as well as other proliferation indices.

AgNOR content and PCNA expression in transplanted malignant neurinoma in rats.

Malignant neurinomas can be induced in BD IX rats by transplacental application of ethylnitroso-urea during pregnancy. Tumors develop in the offspring in trigeminal and spinal nerves and can be easily transplanted upon rats of the same strain. During the first passages a considerable shortening of subsequent induction periods takes place. Concurrently, silver stained Nucleolar Organizer Regions (AgNORs) increase in number and other measured AgNOR parameters change in a similar way. The number of cells that express the proliferation marker PCNA equally becomes more frequent during the first subcutaneously transplanted generations. There is high correlation between AgNOR parameters, number of PCNA expressing cells, induction times and passage. It is concluded that the first generations of the transplantation model of these tumors can be used to test the validity of proliferation indicators. Our results show further that AgNORs in fact belong to the group of markers of proliferation.

Is polar spongioblastoma a tumor entity?

The distribution of cells in a parallel fashion with palisades of nuclei is common in neuroepithelial tumors. The authors have selected 16 such tumors from their series for study, as examples of different neuroepithelial oncotypes containing palisades of nuclei: three ependymomas, three hemispheric pilocytic astrocytomas, three oligodendrogliomas, three medulloblastomas, three cerebellar astrocytomas, and one central neuroblastoma. In two additional tumors, affecting a 12-year-old girl and a 51-year-old woman, this feature was present in the entire surgical specimen and the diagnosis was consistent with a polar spongioblastoma. This diagnosis applies in the literature to rate tumors of childhood and adolescence, both malignant and with embryonal features. In one specimen, a clear ependymomatous feature was found in a remote area of the tumor and in the other there were ultrastructural characteristics of neuroblastoma. Nuclear palisades can be found as local architectural features in many neuroepithelial tumors. The rare tumors diagnosed as polar spongioblastoma, according to published criteria, correspond to ependymomas and neuroblastomas. Polar spongioblastoma does not exist as a tumor entity.

Neuroendocrine carcinoma of the stomach with extensive somatostatin immunoreactivity.

Upper gastrointestinal tract neuroendocrine tumors producing predominantly somatostatin have thus far been described only in the duodenum; their characteristic features include the frequent presence of psammoma bodies (psammomatous somatostinomas), and the association with von Recklinghausen's neurofibromatosis. Gastric neuroendocrine tumors, on the other hand, tend to display immunoreactivity to serotonin but may include small subpopulations producing gastrin, motilin, pancreatic polypeptide, and somatostatin. In this report we describe a neuroendocrine carcinoma of the stomach with rapidly fatal outcome, displaying neurosecretory granules by electron microscopy and immunoreactivity to pan-neuroendocrine markers, ie, chromogranin and neuron-specific enolase. The only neuroendocrine regulatory peptide detected in the tumor was somatostatin, identified by immunohistochemistry in the majority of neoplastic cells. In contrast with duodenal somatostinomas, there were no psammoma bodies and no demonstrable association with von Recklinghausen's neurofibromatosis. To our knowledge this appears to be the first report of a malignant neuroendocrine tumor with diffuse somatostatin immunoreactivity.

Expression and ligand-binding function of the integrin alpha 4 beta 1 (VLA-4) on neural-crest-derived tumor cell lines.

Human neural-crest-derived tumor cell lines, including three neuroblastomas, an astrocytoma, a glioblastoma, a rhabdomyosarcoma and a melanoma were screened for the expression of the integrin alpha 4 beta 1 (VLA-4). The neuroblastomas IMR-32 and SK-N-SH, the astrocytoma 131-INI, the glioblastoma Fogerty and the rhabdomyosarcoma TE-671 expressed alpha 4 beta 1 as determined by cytofluorometry and immunoprecipitation. Another neuroblastoma line, LA-N-1, did not express alpha 4 beta 1. Analysis of immunoprecipitated alpha 4 beta 1 showed that the alpha 4 subunit from the various cell types differed in relative molecular weight (M(r)). The variability in the observed M(r) could be accounted for by differences in the levels of N-linked glycosylation. The observed variability in M(r) did not appear to affect function since intact cells and solubilized alpha 4 beta 1 bound to a synthetic peptide identical in sequence to the CS-1 region of the alternatively spliced IIICS domain of fibronectin, a known alpha 4 beta 1 ligand.

Glioneurofibroma: renaming the pediatric "gliofibroma": a neoplasm composed of Schwann cells and astrocytes.

Three children had central nervous system tumors with histologic and ultrastructural features corresponding to those of tumors previously described as "gliofibromas." These features, which include a composite appearance with glial and mesenchymal elements, with glial fibrillary acidic protein (GFAP)-containing and GFAP-immunonegative cells, diffuse S-100 immunoreactivity, and basal lamina wrapping processes of both cell types, suggest that the "mesenchymal" cells are Schwann cells, not fibroblasts. We therefore propose to rename this entity "glioneurofibroma." The clinical behavior of these lesions is uncertain but is more often indolent or benign.

Induction of K-channel expression in a neuroblastoma cell line.

Whole-cell currents were examined in mouse neuroblastoma cells of the N2AB-1 line. In standard culture medium, N2AB-1 cells exhibited large voltage-dependent Na currents but no discernible K currents. Treatment of N2AB-1 cells with either dimethylsulfoxide (DMSO) in low-serum medium or with retinoic acid (RA) caused the expression of delayed rectifier K currents. Currents from two types of K channel with single channel slope conductances of 15.0 pS and 6.4 pS were observed in outside-out patches from cells of both treatment groups. Thus, while N2AB-1 cells did not exhibit K currents under standard culture conditions, they did possess the gene(s) encoding K channels. The treatments caused other changes that were not directly linked to K-channel expression. RA treatment caused neurite extension in most, but not all, N2AB-1 cells; however, all RA-treated cells, including those without neurites, expressed K currents. RA treatment did not suppress cell division or cause hypertrophy. In contrast, treatment with DMSO/low serum suppressed cell division and caused cellular hypertrophy, but did not cause long neurites to form. Thus, the regulation of K channels was not coupled in a simple fashion to properties that have been associated with a differentiated neuronal phenotype: neurite elaboration, changes in cell size, and inhibition of cell division. These results suggest that N2AB-1 cells may be a good model system for investigating the processes regulating K-channel expression.

Intraspinal neurothekeoma (nerve sheath myxoma). A report of two cases.

Neurothekeomas (nerve sheath myxomas) are rare benign cutaneous tumors. The authors describe two spinal intradural cases that show histologic, immunohistochemical, and electron microscopic features identical to their cutaneous counterparts. The authors' findings suggest histogenesis from Schwann's cells or undifferentiated nerve sheath precursor cells. Neurothekeomas in unusual locations should be differentiated from myxoid neurofibromas, perineuriomas, and soft tissue myxomas.

Spontaneous multidrug transport in human glioma cells is regulated by transforming growth factors type beta.

The multidrug transporting cell membrane molecule P-glycoprotein can be spontaneously expressed in human glioma cells. Transcripts of mdr genes were detected in glial tumor cells by polymerase chain reaction and Northern blotting, expression of P-glycoprotein was analyzed by immunocytochemistry and functional activity by cytofluorometry of fluorescent probe transport. In vitro treatment of glioma cells with vincristine induced coordinate over-expression of both mdr1 and mdr3 genes associated with very high P-glycoprotein-mediated multidrug transport, resistant to the inhibitory activity of chemosensitizers like verapamil. The physiological modulators of multidrug transport are as yet unknown. We therefore initiated a screening program to analyze the effects of cytokines on multidrug transport. We observed, that transforming growth factors (TGF)-beta 1, -beta 2, and -beta 1.2-but not the related bone morphogenetic protein (BMP) 2--inhibited multidrug transport. Interestingly, BMP 2 antagonized the TGF-beta induced inhibition of multidrug transport.

Chordomas with malignant spindle cell components. A DNA flow cytometric and immunohistochemical study with histogenetic implications.

The authors studied four chordomas with malignant spindle cell components (SCs) and 12 conventional chordomas (CCs) by DNA flow cytometry using paraffin-embedded tissue. In addition, immunohistochemical stains for a variety of epithelial and mesenchymal markers were performed. The four SCs contained areas histologically identical to conventional chordomas, as well as a high-grade malignant spindle cell component. All four (100%) SCs had an aneuploid-multiploid DNA content. Of interest, the conventional chordoma areas in these tumors had DNA contents different from those containing the high-grade malignant spindle cells. In contrast, only three (27%) of the 11 conventional chordomas with analyzable histograms had an aneuploid-multiploid DNA content. Immunohistochemical studies performed on the four SCs showed the high-grade malignant spindle cells to stain strongly for vimentin and weakly for cytokeratin, S-100 protein, and epithelial membrane antigen (EMA), whereas the areas of conventional chordoma in these same neoplasms stained moderately for vimentin and S-100 protein, and strongly for cytokeratin and EMA. In two cases, the staining for EMA and cytokeratin highlighted a gradual transition between the areas of conventional chordoma and the spindle cell areas. The immunohistochemical staining pattern of the 12 conventional chordomas was similar to that seen in the conventional chordoma components of the four chordomas with malignant spindle cell components. These results suggest that: 1) aneuploidy is more common in SCs than in CCs, and 2) some SCs are multipotential neoplasms in which the neoplastic cells are capable of differentiation along both epithelial and mesenchymal pathways.

Morphology of experimental tumors of the sympathetic nervous system.

The morphology of experimental tumors of the sympathetic nervous system in rabbits and hamsters induced by administration of nitrose compounds and the use of modifying factors were studied. The tumors were localized in the mediastinum, retroperitoneal space, adrenals and kidneys. A predominant involvement of the female animals was observed. Histological, histochemical and electron microscopic studies of 33 tumors of the sympathetic nervous system were carried out. By their degree of maturity the tumors were classified as ganglioneuromas, ganglioneuroblastomas and neuroblastomas. By their structure the experimental tumors were similar to the analogous neoplasias of man.

Epithelioid malignant schwannoma. A case report.

A case of epithelioid malignant schwannoma (EMS) is reported. The tumor arose in the left radial nerve at the axillary fossa of a 65-year-old male. A few months after resection of the primary axillary tumor, several intrapulmonary metastases appeared. Microscopically, the primary tumor showed highly cellular areas of polygonal or rounded cells, resembling lymphoma or melanoma, while the metastatic tumors revealed cord formation or rows, resembling carcinoma. Immunohistochemical studies showed that some of these tumor cells contained S-100 protein. Ultrastructurally, these tumor cells revealed delicate cytoplasmic projections, which contained bundles of microfilaments. However, the tumor cells did not have melanosomes. Varying amounts of basal lamina material surrounded the tumor cells. From the above features, we obtained a correct diagnosis of EMS.

Membranous changes in primary malignant CNS lymphomas.

Ultrastructural studies of 17 primary malignant CNS lymphomas revealed 6 tumors with abnormal intracytoplasmic and/or intranuclear membranous structures, most frequently associated with the endoplasmic reticulum or perinuclear envelope. In most cases, tubuloreticular inclusions and paired cisternae were present. Less frequent were accumulation of microtubules, concentric lamellar bodies, and rod-like or paracrystalline intranuclear inclusions. The specificity and significance of these membranous structures remain questionable because of their frequent occurrence in a variety of normal and pathological conditions. Some of these changes may be considered as cellular reactions to viral infections, others may indicate cellular activity or degeneration.

[Morphology and histogenesis of paraganglioma]. / Morfologiia i gistogenez paragangliomy.

Histological and ultrastructural studies were performed to examine 6 paragangliomas of various sites: carotid glomus, aortic body, sympathetic chain, and stomach. Five of the tumors in question had a histological structure typical of a paraganglioma. The gastric tumor was distinguished by being similar to a pheochromocytoma. With regard to the degree of infiltrative growth, the paragangliomas of the sympathetic chain and stomach were regarded as malignant. The ultrastructures of the paragangliomas examined were found to be of the same type. In all the neoplasms, tumor cells had signs of neuroendocrine and neurogenous differentiations that were characteristic of the ultrastructural organization of postganglionic neurons in the autonomic nervous system. The neurogenous differentiation was evidenced by cytoplasmic portions that are structurally similar to rough-surface endoplasmic reticulum, which is pertaining to Nissl's bodies; neurofilaments that form concentric structures containing neuroendocrine granules such as fibrous or Pick's bodies; intracytoplasmic cilia; specialized cytoplasmic processes of two types: axons and dendrites; partially reduced intercellular contacts, such as axosomatic and axodendritic synapses; sustentacular cells (sustenocytes). In the neoplasms evaluated as malignant, the neurogenous differential signs were more pronounced by reducing the number of neurosecretory granules, which might, apparently, serve as an ultrastructural criterion for establishing the degree of paraganglioma malignancy.