Cerebellar Liponeurocytoma, an Unusual Tumor of the Central Nervous System--Ultrastructural Examination.

Cerebellar liponeurocytoma is a rare tumor of the central nervous system which shows neuronal and variable astrocytic differentiation, along with foci of lipomatous differentiation. It is usually located in the cerebellum, and may be mistaken for medulloblastoma with lipidized cells or lipomatous ependymoma. Histopathological examination, supplemented by immunohistochemistry and electron microscopy, is required to distinguish between these entities. This 35-year-old male presented with vomiting and headache for three months, followed by gait imbalance. Neurological examination showed positive cerebellar signs with ataxic gait. Magnetic resonance imaging showed a lesion measuring 4.4 cm× 4.3 cm× 3.9 cm involving the cerebellum. The patient underwent midline suboccipital craniotomy to excise the tumor. Histopathological examination showed a circumscribed, cellular tumor composed of round to polygonal cells with moderate cytoplasm and minimal pleomorphism. Clear intracytoplasmic vacuoles were seen within the tumor cells. These tumor cells were immunopositive for synaptophysin, NSE, and MAP-2, confirming their neurocytic origin. On ultrastructural examination, lipid vacuoles as well as dense-core neurosecretory granules were identified within these neurocytic cells, confirming the diagnosis of liponeurocytoma. No cilia, microvilli, or gap junctions were identified in the tumor cells, ruling out the possibility of lipomatous ependymoma. The differentiation of liponeurocytoma from its morphological mimics is imperative, as their treatment differs drastically. The role of electron microscopy is extremely important in this differential diagnosis.

Atypical teratoid/rhabdoid tumor arising in pleomorphic xanthoastrocytoma: a case report.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly malignant, true rhabdoid tumor in the central nervous system predominantly presenting in young children.AT/RT typically shows rhabdoid cells which can also be seen in other tumors, but it is differentiated from other tumors by the specific genetic alteration involving the SMARCB1 gene. Only a few cases of AT/RT arising in low-grade glioma have been reported. A 13-year-old girl presented with headache, dizziness, nausea and vomiting.A 4.7 cm cerebellar mass was found on MRI.The mass was totally removed. Histologically, the tumor revealed two distinct morphologic appearances: central areas of AT/RT containing rhabdoid cells and sarcomatous component in the background of pleomorphic xanthoastrocytoma(PXA). Immunohistochemically, PXA areas retained nuclear expression of INI-1 and low Ki-67 proliferation index, whereas AT/RT component showed loss of INI-1 nuclear expression and markedly elevated Ki-67 proliferation index. Epithelial membrane antigen (EMA), smooth muscle actin (SMA), and p53 protein were positive only in AT/RT. BRAF V600E mutation was identified in PXA by real-time polymerase chain reaction.We report a rare case of AT/RT arising in PXA which is supposed to progress by inactivation of INI-1 in a pre-existing PXA.

Neuronal differentiation associated with Gli3 expression predicts favorable outcome for patients with medulloblastoma.

Medulloblastoma (MB) is a malignant cerebellar tumor arising in children, and its ontogenesis is regulated by Sonic Hedgehog (Shh) signaling. No data are available regarding the correlation between expression of Gli3, a protein lying downstream of Shh, and neuronal differentiation of MB cells, or the prognostic significance of these features. We re-evaluated the histopathological features of surgical specimens of MB taken from 32 patients, and defined 15 of them as MB with neuronal differentiation (ND), three as MB with both glial and neuronal differentiation (GD), and 14 as differentiation-free (DF) MB. Gli3-immunoreactivity (IR) was evident as a clear circular stain outlining the nuclei of the tumor cells. The difference in the frequency of IR between the ND+GD (94.4%) and DF (0%) groups was significant (P < 0.001). The tumor cells with ND showed IR for both Gli3 and neuronal nuclei. Ultrastructurally, Gli3-IR was observed at the nuclear membrane. The overall survival and event-free survival rates of the patients in the ND group were significantly higher than those in the other groups. The expression profile of Gli3 is of considerable significance, and the association of ND with this feature may be prognostically favorable in patients with MB.

An ultrastructural study of the histogenesis of haemangioblastoma.

Seven cases of cerebellar haemangioblastoma, not associated with von Hippel-Lindau disease (sporadic haemangioblastomas), were studied by light and electron transmission microscopy. Morphological features that might provide information about the histogenesis of the tumour were examined. The ultrastructural data indicate both the common ancestry of the different cytotypes that make up the tumour, and the mesenchymal origin of the elements present, which were also documented by their capacity to synthesise lipid droplets in the cytoplasm (a process of lipidization similar to that of pre-adipocytes).

An immunohistochemical and electron microscopic study of atypical teratoid/rhabdoid tumor.

We report two infant cases with atypical teratoid/rhabdoid tumor (AT/RT) located in the cerebellar vermis and spinal cord. MRI showed the tumors were isointense on T1-weighted images and mixed intensity of isointense and slight high intensity on T2-weighted images. Postcontrast MRI demonstrated clear margin of tumor and heterogeneous strong enhancement. It was difficult to differentiate the tumor from medulloblastoma by hematoxylin and eosin staining. However, immunohistochemical staining showed that these tumor cells react positively for cytokeratin, smooth muscle actin (SMA), and epithelial membrane antigen (EMA) and helped us with the differentiation. Electron microscopic study has confirmed the presence of mesenchymal components, such as filaments and desmosome junctions in the rhabdoid cells, but no neuronal components. The tumors rapidly increased in size, showing high MIB-1 index, and the prognosis was gave.

Medulloblastoma demonstrating multipotent differentiation: case report.

We report a 6-year-old boy who presented with a medulloblastoma demonstrating classic, myoblastic, neuronal, glial, and melanotic differentiation and manifesting as severe morning headache. Magnetic resonance imaging revealed a mass lesion with cystic components in the cerebellar vermis. He underwent suboccipital craniotomy and total resection of the tumor. The specimen consisted of three morphologically distinct components. The first component consisted of densely packed cells with round-to-oval highly hyperchromatic nuclei surrounded by scanty cytoplasm. Immunohistochemical staining revealed diffuse expression of neurofilament protein and focal expression of desmin and myoglobin. The second component consisted of long spindle-shaped cells with elongated nuclei and eosinophilic cytoplasm. Immunohistochemical staining revealed diffuse expression of neurofilament protein, desmin, and myoglobin. The third component consisted of cells with small, densely hyperchromatic nuclei and scanty cytoplasm in a fine fibrillary background. Mature ganglion cells and melanotic tumor cells were also observed. Immunohistochemical staining revealed diffuse expression of synaptophysin and neurofilament protein, and focal expression of glial fibrillary acidic protein, S-100 protein, desmin, and myoglobin. The diagnosis was medulloblastoma with myoblastic, neuronal, astrocytic, and melanotic differentiation. Medulloblastoma demonstrating multipotent differentiation is rare, but the features observed in this case support the idea that medulloblastoma originates from multipotent stem cells.

Evaluation of poly (glycerol-adipate) nanoparticle uptake in an in vitro 3-D brain tumor co-culture model.

Despite the inherent problems associated with in vivo animal models of tumor growth and metastases, many of the current in vitro brain tumor models also do not accurately mimic tumor-host brain interactions. Therefore, there is a need to develop such co-culture models to study tumor biology and, importantly, the efficacy of drug delivery systems targeting the brain. So far, few investigations of this nature have been published. In this paper we describe the development of a new model system and its application to drug delivery assessment. For our new model, a co-culture of DAOY cell brain tumor aggregates and organo-typic brain slices was developed. Initially, the DAOY aggregates attached to cerebellum slices and invaded as a unit. Single cells in the periphery of the aggregate detached from the DAOY aggregates and gradually replaced normal brain cells. This invasive behavior of DAOY cells toward organotypic cerebellum slices shows a similar pattern to that seen in vivo. After validation of the co-culture model using transmission electron microscopy, nanoparticle (NP) uptake was then evaluated. Confocal micrographs illustrated that DAOY cells in this co-culture model took up most of the NPs, but few NPs were distributed into brain cells. This finding corresponded with results of NP uptake in DAOY and brain aggregates reported elsewhere.

Histologic and histogenetic investigations of intracranial hemangioblastomas.

BACKGROUND: The aim of this study was to elucidate the histologic characteristics and the histogenesis of intracranial HBs. METHODS: Specimens from 40 patients with HBs were verified surgically and pathologically at the Huashan Hospital Department of Neurosurgery (Fudan University, Shanghai, China). All sections were immunohistochemically stained. In addition, fresh specimens were examined by electron microscopy in 3 cases and cells were cultured in 10. RESULTS: Hemangioblastomas were composed of endothelial cells, pericytes, and stromal cells. Vimentin was expressed in all 3 cell types of HB. CD34 was expressed in endothelial cells, and SMA was expressed in pericytes. Telomerase was expressed in stromal cells. Chromogranin A, CD68, and CD117 showed a negative reaction in HBs. Vascular endothelial growth factor showed a positive reaction in stromal cells, and Flt-1 showed a positive reaction in endothelial cells. There was no difference in immunohistochemical staining between specimens from cystic HBs and those from solid HBs. Three cell types had individual ultrastructural characteristics. Stromal cells represented a heterogeneity of abnormally differentiating mesenchymal cells in cell culture. CONCLUSIONS: Hemangioblastomas may originate from the mesenchyme. Stromal cells are the real tumor components of HBs although they represent a heterogeneity.

Morphophenotype of medulloblastoma in children and adults. The size of nuclei.

OBJECTIVE: Uniform cells with round, regular nuclei characterize the typical histologic aspect of medulloblastoma. Enlargement of nuclei distinguishes the large-cell medulloblastoma variant and is associated with a poor prognosis in pediatric medulloblastomas. The aim of the present study was to compare the size of nuclei between pediatric and adult medulloblastomas by a morphometric analysis. MATERIAL AND METHODS: In 79 neurosurgical specimens of cerebellar medulloblastomas, the maximum nuclear diameter of the largest nuclei was measured. Measurements were performed with a digital-image analysis system. The measure of the maximum diameter was chosen in order to reduce the split cell error. RESULTS: The difference between the mean values in children and adults was statistically significant (p = 0,001). The distribution of maximum values measured in each case had two distinct peaks in the two age groups, in 3.5% of adult cases and in more than 30% of pediatric cases the maximum nuclear size was superior to 12 microm. CONCLUSIONS: The present results show that nuclei of tumor cells in pediatric medulloblastomas are larger than those in adult medulloblastomas and confirm that the phenotype of medulloblastoma is different in the two age groups. Distinct genetic events can, thus, underlie medulloblastoma in childhood and adult age, the prognostic role of genetic variables can differ by age.

Capillary hemangioblastoma of soft tissue: report of a case and review of the literature.

Capillary hemangioblastoma (CH) is a tumor of unknown histogenesis that arises primarily in the posterior cranial fossa, either as a sporadic event or in association with von Hippel-Lindau disease. To date, only 6 examples of a tumor with morphological features of CH arising in the somatic soft tissues have been documented in case reports and small series, and 3 of these tumors were associated with a peripheral nerve. Herein, we report a case of CH arising in the gastrocnemius muscle and not associated with a peripheral nerve in a 53-year-old woman with no clinical stigmata or family history of von Hippel-Lindau disease.

Stromal cells in hemangioblastoma: neuroectodermal differentiation and morphological similarities to ependymoma.

The histogenesis of stromal cells in hemangioblastoma is inconclusive despite a long-term controversy. An immunohistochemical and ultrastructural study was conducted for 17 cases of cerebellar hemangioblastoma. A wide range of immunohistological markers, targeting epithelial, mesenchymal, endothelial and neuroectodermal tissues, was used. In all cases, the microscopic hallmark characterizing hemangioblastomas, that is, lipid-containing stromal cells and a fine capillary network, known as a reticular variant, was noted. Stromal cells showed a variable immunoreactivity for neuroectodermal markers, such as S-100 protein, CD56, CD57, CD99, and neuron-specific enolase. This result, in conjunction with the absence of immunoreactivity for epithelial, mesenchymal, and endothelial markers, likely suggests neuroectodermal differentiation of stromal cells. In three cases, another component, known as a cellular variant, where epithelioid tumor cells were arranged in nests encircled by capillaries and/or in pseudorosette-like structures, was noted. Glial fibrillary acidic protein-immunoreactivity, which was totally absent in cases only showing the reticular pattern, was noted in two of them, suggesting a distinctive sign of glial differentiation in a proportion of hemangioblastomas. Ultrastructurally, microvilli-like projections in intracytoplasmic vacuoles were demonstrated in stromal cells. This result, taken together with the neuroectodermal hypothesis of stromal cells, suggests that hemangioblastomas may occasionally exhibit morphological similarities to ependymomas.

Low-grade glial tumor with features of astroblastoma in a dog.

A 12-year-old, neutered, male Belgian Malinois/Great Dane cross dog presented with a 5-month history of weakness and lack of endurance followed by acute onset of rear limb ataxia. At autopsy, a 9 x 16 mm, multilobular, firm, white to tan, expansile mass was found in the cerebellum. Mild dilatation of the lateral ventricles was also noted. Histologically, there was a well-demarcated glial neoplasm composed of medium-sized astrocytic elements that had homogeneous cytoplasm, sometimes with globular eosinophilic inclusions, irregular peripherally located nuclei with a single nucleolus, and short cytoplasmic processes. Prominent perivascular pseudorosettes with cellular processes in contact with blood vessels were present. Some blood vessels exhibited hyalinized walls. Mitotic figures were not observed. Immunohistochemically, neoplastic cells expressed glial fibrillary acidic protein and vimentin. These features are consistent with an astroblastoma. This is the first clinicopathologic correlation and detailed description of a low-grade glial tumor with features of astroblastoma in a dog.

A non-infantile case of desmoplastic infantile astrocytoma.

CASE REPORT: We describe a very rare non-infantile case of desmoplastic infantile astrocytoma (DIA). A 9-year-old boy presented with motor weakness and sensory disturbance in his right upper and lower limbs. CT and MRI showed a contrast-enhanced large cystic tumor in the left sensorimotor area. We successfully resected the entire tumor. Its histopathological features were typical of DIA. OUTCOME: The patient's neurological symptoms improved postoperatively. Neither radiotherapy nor chemotherapy was used postoperatively. The patient developed normally and had been doing well for 12 months after surgery without tumor recurrence.

Testing the "Go or Grow" hypothesis in human medulloblastoma cell lines in two and three dimensions.

OBJECTIVE: The "Go or Grow" hypothesis proposes that cell division and cell migration are temporally exclusive events and that tumor cells defer cell division to migrate. The purpose of this study was to assess the Go or Grow hypothesis using medulloblastoma cell lines in directional migration and invasion assays in monolayer and three-dimensional cultures. METHODS: Time-lapse videomicroscopy was used to continually monitor the directional migration, invasion, and mitosis of individual cells. The mitotic activity observed by time-lapse videomicroscopy was compared with staining for the proliferating cell nuclear antigen Ki-67. RESULTS: A positive correlation exists between the migratory/invasive and mitotic activities of the four medulloblastoma cell lines studied. Within individual cell lines, however, migration and invasion distances are not influenced by the number of cell divisions. Time-lapse videomicroscopy and Ki-67 staining revealed similar trends in mitotic activity between migrating and nonmigrating cells within cell lines. Analysis of cell velocities before, after, and between cell divisions revealed an increase in cell velocity after cell divisions. CONCLUSION: In the models studied, four medulloblastoma cell lines do not defer cell proliferation for migration across an uncoated surface or invasion of a Type I collagen matrix, contrary to the Go or Grow hypothesis. Migrating and invading cells continue to proliferate and migrate/invade a cell line-dependent distance irrespective of the number of divisions that take place. These findings emphasize the need to evaluate the effect of future therapies on both biological events and, if possible, to identify intracellular signaling proteins that negatively regulate medulloblastoma migration/invasion and proliferation.

Cerebellar central liponeurocytoma.

Cerebellar liponeurocytoma is a rare, benign neuroepithelial tumor that occurs exclusively in the cerebellum of adults. Its salient histological features include advanced neuronal/neurocytic differentiation, focal vacuolated cells resembling mature adipose cells, low mitotic activity, and lack of endothelial proliferation and/or necrosis. The morphological appearance of this neoplasm can be confused with that of oligodendroglioma, neurocytoma, ependymoma, medulloblastoma, hemangioblastoma, metastatic renal cell carcinoma, and other clear cell carcinomas. Its full biological potential and histological features, however, have not been fully exploited due to the rarity of this tumor. The authors describe a case with clinical, imaging, histological, immunohistochemical, and ultrastructural features.

Ultrastructural spectrum of medulloblastoma with immunocytochemical correlations.

Electron microscopy was used to examine 72 cases of medulloblastoma to better characterize the ultrastructural spectrum of this tumor. Twenty-four cases showed prominent neural differentiation. Twenty-three cases showed minimal (21) or no (2) recognizable neural differentiation, and the remainder of the cases (25) showed intermediate differentiation. All 42 cases tested stained for neuron-specific enolase, 28 for synaptophysin, and 12 for neurofilament protein. All cases showed strong reactivity for glial fibrillary acidic protein (GFAP) within reactive astrocytes. Three cases showed reactivity for GFAP within tumor cells. Medulloblastoma exhibits a broad spectrum of neural differentiation, with nearly all cases showing at least some degree of this change, and it universally exhibits participation of reactive astrocytes which can create a potential for diagnostic confusion.

Cerebellar liponeurocytoma: immunohistochemical and ultrastructural study of a case.

The clinical, histopathological, and ultrastructural features of a cerebellar liponeurocytoma are reported. The tumor, a 3-cm mass localized in the right cerebellar hemisphere, was resected from a 61-year-old man clinically presenting with symptoms of intracranial hypertension. The lesion was composed of small, in some areas closely packed, medulloblastoma-like cells with prominent areas of lipidization phenomena. Moreover, mitoses, cellular atypia, and numerous vascular structures were focally observed. Glial and neuronal differentiation was immunohistochemically noted (glial fibrillary acidic protein, synaptophysin, neurofilaments, and neuron-specific enolase positivity). The p53 oncoprotein was detected in the majority of neoplastic cells and a moderate proliferation activity, evaluated by Mib-1 antibody, was focally appreciated. Ultrastructural study did not show evident neuritic processes, synapses, or dense core neuroendocrine granules. This cerebellar tumor previously called lipidized medulloblastoma and recently renamed cerebellar liponeurocytoma is considered an adult neoplasm with excellent prognosis histologically presenting prominent lipidized areas and, at the immunohistochemical and ultrastructural level, both glial and neuronal differentiation. The present study provides the first description of a less differentiated and histologically more aggressive form of this unusual tumor.

Cerebellar neuroblastoma in an infant.

A cerebellar neoplasm in an 8-month-old boy is reported. While this tumour was composed of small cells and had regions resembling desmoplastic medulloblastoma, it showed ultrastructural neuronal characteristics including bundles of microtubules in the cell processes, numerous synaptic vesicles, and occasional abortive or complete synapses. These characteristic features warranted the diagnosis of a neuroblastoma of the cerebellum. The nature of this rare intraparenchymal tumour in infants is also briefly discussed.