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Central neurocytomas are rare central nervous system neoplasms. Since the first description, approximately 500 cases of these tumors have been published to date. Nevertheless, only a limited number of genetic studies on these tumors have been reported. Here we investigated 20 "typical" central neurocytomas using array-based comparative genomic hybridization (array-CGH) with the GenoSensor Array 300. The functional significance of detected chromosomal aberrations harboring potent candidate genes was also examined at the mRNA expression level. Each tumor examined displayed DNA copy-number aberrations (CNAs), and mean number of CNAs per tumor was 38.1 +/- 7.1 (range 19-53). Frequent gains were mapped at 2p24.1-22.1, 10q23.3-26.3, 11q23-25, and 18q21.3-qter. Frequent losses were identified at 1pter-36.3, 1p34.3, 6q13-21, 12q23-qter, 17p13.3, 17q11-23, and 20pter-12.3. There were 10 gained and 23 lost single DNA clones affecting >or=40% of samples tested. mRNA expression levels of 24 selected candidate genes harbored in these imbalanced clones were analyzed. MYCN, PTEN, and OR5BF1 were strongly overexpressed, whereas BIN1, SNRPN, and HRAS were found to be strongly underrepresented at the transcriptional level. Thus these data support that MYCN oncogene gain/overexpression accompanied by reduced expression of BIN1 tumor suppressor may contribute to central neurocytoma tumorigenesis.

We report the case of a 4-year-old girl with a fourth ventricle tumor diagnosed as a cerebellar liponeurocytoma which recurred, showing ependymal differentiation, 14 months after surgery. Magnetic resonance imaging at initial presentation revealed a large mass in the fourth ventricle, and histology showed a neoplasm characterized by a combination of well-differentiated neurocytes and cells resembling adipocytes. The tumor recurrence was histologically identical to the original tumor in some regions, but with fewer adipose-like cells, while other areas presented an endocrine architecture with oligo-like or pleiomorphic cells, and rosette-like arrangements of tumoral cells were seen around the thin vessels, with features similar to cellular ependymoma. The cells in the liponeurocytoma areas expressed synaptophysin, chromogranin A, and epithelial membrane antigen. Glial fibrillary acidic protein was expressed in some dispersed tumoral cells, in lipidized tumoral cells, and in reactive astrocytes. Cytokeratin was focally expressed in the ependymal region of the recurrence. The immunophenotype of our case, with glial, ependymal, and neuronal or neuroendocrine markers, suggest a neurocytoma with lipomatous and ependymal differentiation. This tumor resembled those derived from circumventricular organs. Its localization in the area postrema region led us to hypothesize that it may be derived from this circumventricular organ.

Central neurocytoma is a low-grade neuronal neoplasm that occurs most often within the lateral ventricles. We report the case of a 60-year-old woman who presented with gait problems, headache and memory loss. Preoperative evaluation demonstrated a heterogeneous, hypervascular and partially cystic mass in the left lateral ventricle. Histopathological examination revealed characteristic features of central neurocytoma, including immunoreactivity for synaptophysin, as well as the unusual feature of abundant pigment in the cytoplasm of tumor cells. Special stains revealed iron, consistent with hemosiderin, but found no evidence of melanin or melanosomes. Previous reports of pigmented central neurocytoma have described the presence of lipofuscin or neuromelanin. To our knowledge, the present case represents the first example of pigmented central neurocytoma secondary to hemosiderin deposition.

Distinctive glioneuronal tumors arising within the cerebrum and displaying neuropil-like islands and tumor cells immunoreactive for neuronal and glial antigens have recently been described. We report a similar tumor in the cervico-thoracic region of the spinal cord in a 44-year-old woman that recurred 1 year later with dissemination to the lumbar dura and cauda equina. The tumor was composed of "rosetted" neuropil islands displaying immunoreactivity for synaptophysin, whereas the intervening tumor cells were more fibrillar and immunoreactive for GFAP. The tumor cell nuclei immediately surrounding these neuropil islands were immunoreactive to the newly characterized neuronal marker, anti-Hu. While several cases of neurocytomas have been described in the spinal cord, to the best of our knowledge, this is the first example of a glioneuronal tumor with "rosetted" neuropil islands to be reported in the spinal cord.

An aged albino male cynomolgus monkey (Macaca fascicularis) more than 35 years old died after showing neurological signs including gait disturbance, trembling, drowsing tendency and a decrease in activity. Neuropathological examination revealed glial fibrillary tangles (GFTs) mainly distributed in the putamen, caudate nucleus, thalamic nuclei, substantia nigra, red nucleus, globus pallidus, trapezoid body, pyramid, pons and medulla oblongata of the brain, and neurofibrillary tangles (NFTs) in the thalamic nuclei. These structures were positively stained by the modified Gallyas-Braak (GB) method and immunostained for tau. The tau-positive argyrophilic GFTs were morphologically classified into four types, as in human cases, i.e., tufts of abnormal fibers (TAFs), thornshaped astrocytes (TSAs), glial coiled bodies (GCBs) and argyrophilic threads (ATs) depending on their GB profiles, and GCBs were the major structures in this case. Some of these structures were also immunoreactive for alpha-synuclein. The glial cells possessing the structures were negative for glial fibrillary acidic protein, a marker for astrocytes, indicating that the argyrophilic GFTs were present in oligodendroglia. In addition, marked neuronal loss and ubiquitin-positive spheroid bodies were observed in the substantia nigra and globus pallidus. According to the characteristic distribution of the argyrophilic structures in neurons and glial cells as well as clinical signs, the monkey might have suffered from a neurodegenerative disease such as progressive supranuclear palsy (PSP). This is the first report of the occurrence of a neurodegenerative disease in a nonhuman animal.

alpha-Synuclein is presynaptic nerve terminal protein and its immunoreactivity has been observed in such neurodegenerative structures as senile plaques of Alzheimer's disease or Lewy bodies of Parkinson's disease. The physiological role of alpha-synuclein is still unknown. It is speculated that alpha-synuclein may be expressed in brain tumors, especially in those showing neuronal differentiation. We examined the immunohistochemical localization of alpha-synuclein in 77 human brain tumors. alpha-Synuclein was widely distributed in the brain tumors showing neuronal differentiation. As a result, positive immunostaining for alpha-synuclein was observed in ganglioglioma, medulloblastoma, neuroblastoma, primitive neuroectodermal tumor, pineocytoma/pineoblastoma, and central neurocytoma. Compared with other neuronal markers, the positive ratio of alpha-synuclein was not as high as synaptophysin, microtubule-associated protein 2, neuron-specific enolase and tau, but it was higher than neurofilament and chromogranin A. The expression of synaptophysin was diffusely observed in the cytoplasm, cellular processes and nucleus in tumors showing neuronal differentiation; however, the expression of alpha-synuclein was predominantly observed in the cytoplasm of the tumors as well as in the cellular processes. On the other hand, non-neuronal brain tumors such as astrocytic tumors or meningiomas were totally negative for alpha-synuclein. In conclusion, the appearance of an alpha-synuclein-positive structure was not limited to neurodegenerative diseases, but could also be detected in neoplastic cells showing neuronal differentiation.

An unusual case of cerebellar neurocytoma with rhabdomyomatous differentiation in a 6-year-old boy is reported. Immunocytochemical and ultrastructural features of the tumour were studied. Abortive synapse formation, the presence of clear vesicles and synaptophysin immunoreactivity of the tumour cells indicated its intermediate neuronal differentiation, while the presence of myoblasts and myotubes and immunolabelling by desmin confirmed the rhabdomyomatous differentiation. In addition, the mesenchymal cells variably expressed neurofilament protein and glial fibrillary acidic protein, suggesting inductive interaction between the neuroectodermal and ectomesenchymal elements and persistence of the pleuripotential nature of the cells along the rhombic area of the brain stem.

To clarify the histogenesis and differentiation potential of central neurocytoma, a pathological investigation of seven tumors from three patients was conducted using immunohistochemistry and ultrastructural analysis in addition to systematic in vitro studies. Six tumors were studied immunohistochemically and five were examined ultrastructurally. All cases that were immunostained were positive for synaptophysin in nuclear-free neuropil islands. In five tumors, a few tumor cells, in addition to reactive astrocytes, were positive for glial fibrillary acidic protein (GFAP). Vimentin staining was also positive in a few tumor cells of five specimens. Neurofilament staining was always negative. All cases for which ultrastructure was examined showed various synaptic abnormalities. Cultured cells were subdivided into three distinct tumor cell types: neuronal cells which stained for neurofilament proteins with neurosecretory granules; small flat undifferentiated cells with a high nuclear-cytoplasmic ratio and scant cytoplasmic organelles; and small round or multipolar astrocytic cells with 10-nm intermediate filaments which stained for GFAP. Our tissue culture studies disclosed that cultured neurocytoma cells form a cellular mosaic similar to subependymal plate layers that are composed of mitotically active cells, neurons and glia.

Recently cases of ganglioneurocytoma and cerebral neurocytoma, very rare variants of central neurocytoma, have been reported. The former is characterized by differentiation toward ganglion cells and the latter by extraventricular origin in the cerebrum, but their existence as distinct clinicopathological entities, is controversial. We report an unusual case of neurocytoma, which arose extraventricularly from the frontal lobe, formed a large cystic lesion and showed ganglioid differentiation, in a 11-year-old girl. Following subtotal tumor resection, she showed a satisfactory clinical course and no evidence of recurrence. This is a very rare case of central neurocytoma-like tumor outside the ventricular system and also of ganglioneurocytoma. This case may provide some insight into the tumorigenesis and widen the clinicopathological concept of neurocytoma.

The role of inflammatory reactions in brain tumors is still unclear. In particular, there is little information about the participation of the microglia/macrophage cell system. We therefore investigated 72 surgical biopsy samples of brain tumors (astrocytoma, glioblastoma, oligodendroglioma, ependymoma, medulloblastoma, cerebral lymphoma, gangliocytoma, neurocytoma and germinoma) and the brains of eight cases with malignant gliomas that came to autopsy, using immunohistochemical markers for the monocyte/macrophage lineage (Ki-M1P, HLA-DR, KP1, My4, My7, Ki-M1, Ki-M6, EBM 11). These markers allowed us to characterize four subtypes of the microglia/macrophage cell system: ramified microglia, ameboid microglia, perivascular microglia and brain macrophages. Among the different tumors, glioblastomas and anaplastic gliomas showed the largest number of mixed cell populations, which consisted of macro-phages and ramified and ameboid microglia. In glial tumors of low malignancy fewer, predominantly ameboid, microglia were found. Neuronal tumors showed only a mild increase of microglia. Cerebral lymphomas contained macrophages diffusely distributed within the tumor center, while activated microglia were prominent at the border zone and in the adjacent brain tissue. The autopsy cases were used to study the morphometric distribution of microglia/macrophages. There was a significant increase of microglia/macrophages within the tumor, but no differences were seen between central and peripheral tumor areas. The non-neoplastic gray and white matter contained more microglial cells than controls. We conclude that the distribution pattern of ameboid and ramified microglial cells and macrophages is distinct in most of the investigated tumor types, underlining the complex immunological function of the microglia/macrophage cell system.

Central neurocytoma is a rare brain tumor composed of small round synaptophysin-positive cells, suggesting a neuronal origin of these tumor cells. Glial properties are inferred, however, from the observation that the tumor cells exhibit a strong morphological similarity to oligodendroglioma cells and show an astrocytic differentiation in vitro. To test for neuronal or glial physiological properties, we studied cultured neurocytoma cells derived from a surgical specimen from a 44-year-old man, employing the patch-clamp technique. Early primary cultures were composed of morphologically unique bi- or multipolar cells which were positive for synaptophysin and negative for the astrocyte marker glial fibrillary acidic protein. In the majority of these cells, whole-cell membrane current recordings revealed physiological properties of neurons, i.e., a high density of Na+ currents, the capacity to generate action potentials, and the expression of inotropic neurotransmitter receptors. Metabotropic neurotransmitter receptors could be demonstrated by Ca2+ imaging techniques. The remaining bi- or multipolar cells and almost all cells in later culture stages and in vitro passage lacked these neuronal properties and showed physiological features characteristic of glial cells. We conclude that the major population of neurocytoma cells shows physiological properties of neurons and that with time in culture this population is replaced by electrically passive cells.

We have identified two central neurocytomas which contained cells co-expressing glial fibrillary acidic protein and synaptophysin defined by double-label immunostaining. Dual-positive cells were mostly polygonal in shape and with a morphological appearance similar to that of reactive astrocytes. This distinct morphology could be used to distinguish cells expressing glial fibrillary acidic protein from cells with round and clear cytoplasm which did not express glial fibrillary acidic protein and which composed the majority of the tumor. Samples containing polygonal cells were selected for electron microscopy from toluidine blue-stained semithin sections. Ultrastructural findings were similar in both neurocytomas, with both being composed predominantly of round cells with clear cytoplasm corresponding to the clear cells identified by light microscopy. Dense-core vesicles and clear vesicles were frequently observed in the cell processes. Apart from these clear cells, polygonal cells with electron-dense cytoplasm were noted. Paralleling the result of double immunostaining, these polygonal cells contained both dense-core vesicles and intermediate, presumably glial filaments. Microtubules and lipofuscin granules were also observed. These results suggest that cells expressing glial fibrillary acidic protein in central neurocytoma include tumor cells with both neuronal and glial characteristics.

We report a case of spinal cord neurocytoma in a 67-year-old man who had experienced a progressive numbness of the left foot during the previous 4 years. Magnetic resonance imaging showed a well-defined intramedullary tumor located at the T10-T11 level. The pathological examination revealed histological characteristics described in neurocytomas. The tumor cells showed a uniform small nucleus and clear or slightly eosinophilic cytoplasm with frequent perinuclear halos, resembling the picture of oligodendroglioma. Some tumor cells exhibited mature ganglion cell appearance. Electron microscopy showed cells with microtubules and dense-core vesicles in their cytoplasm and cytoplasmic process. Immunohistochemically, the majority of tumor cells expressed synaptophysin and neuron-specific enolase. We conclude that this tumor is an exceptional case of neurocytoma located in the spinal cord, and consider that the term neurocytoma can be applied to tumors with neuronal differentiation intermediate between neuroblastoma and ganglioneuroma, even if arising in CNS outside of the intracranial ventricular system.