Angiocentric glioma: a report of nine new cases, including four with atypical histological features.

AIMS: Angiocentric glioma (AG) is a rare, slow-growing tumour of the central nervous system. It is often associated with refractory epilepsy and occurs most commonly in children and young adults. We herein report nine cases of AG, including four with atypical histological findings. METHODS: The clinical data and clinicopathological findings of nine cases with AG histological features were described. RESULTS: All nine patients had a history of refractory epilepsy with a mean history of 4.4 years and a median age of 17.6 years at surgery. The AG lesions were located in the superficial cerebrocortical region. Histological examination of these cases revealed characteristic structural features of AG, including bipolar spindle-shaped cells with an angiocentric growth pattern. However, four cases also exhibited atypical histological features: one had astroblastoma-like characteristics, two had a distinct cystic region with an onion-like structure and myxoid changes, and the other one had a region involving many abnormal neurones reminiscent to ganglioglioma. All were positive for glial fibrillary acidic protein and vimentin. Eight cases were positive for epithelial membrane antigen (EMA), with a dot-like staining pattern. A diffuse D2-40 staining was visible in these cases, with two having similar staining pattern to EMA. All cases were immunonegative for BRAF V600E and isocitrate dehydrogenase-1 R132H mutations. CONCLUSIONS: Our results demonstrate that atypical histological features can be present in AG. A collection of more cases and further molecular analyses are required to confirm our findings.

Progressive myoclonus epilepsy: extraneuronal brown pigment deposition and system neurodegeneration in the brains of Japanese patients with novel SCARB2 mutations.

AIMS: Mutations in the SCARB2 gene cause a rare autosomal recessive disease, progressive myoclonus epilepsy (PME) with or without renal failure, the former also being designated action myoclonus-renal failure syndrome. Although reported cases have been accumulating, only a few have described its neuropathology. We studied two Japanese patients with PME without renal failure, in whom the ages at onset and disease durations were 45 and 20 years, and 14 and 8.5 years respectively. METHODS: Sequencing and restriction analysis of the SCARB2 gene and neuropathological examination with immunohistochemistry were performed. RESULTS: Gene analyses revealed novel homozygous frameshift and nonsense mutations in the SCARB2 gene. Both cases exhibited deposition of brown pigment in the brain, especially the cerebellar and cerebral cortices. Ultrastructurally, the pigment granules were localized in astrocytes. Neuronal loss and gliosis were also evident in the brain, including the pallidoluysian and cerebello-olivary systems. The spinal cord was also affected. Such changes were less severe in one patient with late-onset disease than in the other patient with early-onset disease. In brain and kidney sections, immunostaining with an antibody against the C-terminus of human SCARB2 revealed decreased levels and no expression of the protein respectively. CONCLUSIONS: The frameshift mutation detected in the patient with late-onset disease is a hitherto undescribed, unique type of SCARB2 gene mutation. The present two patients are the first reported to have clearly demonstrated both extraneuronal brown pigment deposition and system neurodegeneration as neuropathological features of PME with SCARB2 mutations.

Cerebral astroblastoma in an adult: an immunohistochemical, ultrastructural and genetic study.

Astroblastoma is a rare glial tumor of unknown origin, usually affecting the cerebral hemispheres of children and young adults. Here we report an unusual cerebral tumor in a 60-year-old woman. On MRI, the tumor appeared as a well circumscribed lesion in the left frontal lobe. Histopathologically, it was composed of rounded eosinophilic cells, and was divisible into two areas. One area was characterized by a collection of GFAP-positive cells around sclerotic blood vessels (astroblastic pseudorosettes and perivascular hyalinization), and had a Ki-67 labeling index of 2.8%. However, the other area was highly cellular, showing many GFAP-negative cells often with a rhabdoid appearance, mitoses and a Ki-67 index of 15.7%. Thus, a final diagnosis of malignant astroblastoma was made. In both areas of the tumor, nearly all the cells were positive for epithelial membrane antigen, and many were positive for oligodendrocyte transcription factor 2 (Olig2). Focal expression of cytokeratin was also evident. With regard to genetic markers, the tumor cells were positive for INI1 and negative for mutant IDH1. The p53 labeling index was <1%. Ultrastructurally, the presence of intra- and intercellular lumina with microvilli was a feature. DNA examination of IDH1/2 and TP53 showed no mutations. In conclusion, although ependymal features were evident ultrastructurally in the present tumor, the immunohistochemical expression pattern of Olig2 was that of diffuse astrocytoma. On the other hand, the absence of mutations in both IDH1/2 and TP53 suggested that the present tumor was not a purely astrocytic neoplasm. Further studies, including molecular and genetic analyses, will provide insight into the histogenesis of astroblastoma.

Chordoid glioma of the third ventricle: four cases including one case with papillary features.

Chordoid glioma is a rare, slowly growing tumor of the CNS, which is always located in the third ventricle of adults. Chordoid glioma has classic histological features consisting of clusters and cords of epithelioid tumor cells embedded within a mucinous stroma with rich lymphoplasmacytic infiltrate. The important distinctive immunohistochemical feature of this neoplasm is strong and diffuse reactivity for GFAP. Here, we report four cases of chordoid glioma that occupied the anterior portion of the third ventricle or suprasellar region. These four cases were all adult females with almost typical clinical, radiological, histologic and immunohistochemical characteristics of chordoid glioma. However, in one case there was an unusual histologic finding with regard to the papillary region. In this region, elongated tumor cells were observed radiating toward a central vessel to form characteristic papillary structures. Immunohistochemically, three cases showed strong reactivity for GFAP, and one exhibited weak reactivity. All cases were focally positive for epithelial membrane antigen, CD34 and D2-40, but negative for neurofilament protein (NFP). Several ultrastructural investigations have supported the ependymal origin of chordoid glioma. In some cases of immunoreactivity for NFP, some authors have supposed that chordoid glioma originates from a multipotential stem cell with glial and neuronal cell differentiation. With regard to the present four cases with immunoreactivity for D2-40 (an ependymal marker) and CD34 (undifferentiated neural precursors) and based on previously published data, we considered that the majority of chordoid gliomas had an ependymal origin, and that a small minority might have originated from a multipotential stem cell having ependymal and neuronal cell differentiation.

Periventricular nodular heterotopia functionally couples with the overlying hippocampus.

Patients with periventricular nodular heterotopia (PVNH) often have severe epilepsy. However, it is unclear how the heterotopia contributes to epileptogenesis. Recently, electrophysiologic studies using intraoperative depth electrodes have indicated that interaction between the heterotopia and overlying cortex is crucial for seizure onset. We performed an in vitro physiologic study using slices of resected brain from a 22-year-old man with PVNH, who manifested medically refractory mesial temporal lobe epilepsy. Preoperative evaluation indicated that the right mesial temporal structure and PVNH were the epileptogenic focus. The resected tissue was immediately immersed in cold artificial cerebrospinal fluid, and then slices of the brain tissue including the heterotopic nodules and overlying hippocampus were prepared. We electrically stimulated the incubated slices, and the elicited neural activities were analyzed as changes in the flavoprotein fluorescence signals. When we stimulated either the heterotopic nodule or the overlying hippocampus, clear functional coupling of neural activities between these structures was observed. The coupling response evoked by stimulation of the subiculum and developing within the heterotopic nodule was enhanced by application of bicuculline. Therefore, activities of the hippocampus and the nodule are closely correlated.

Primary lateral sclerosis: upper-motor-predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration--immunohistochemical and biochemical analyses of TDP-43.

Primary lateral sclerosis (PLS) is clinically defined as a disorder selectively affecting the upper motor neuron (UMN) system. However, recently it has also been considered that PLS is heterogeneous in its clinical presentation. To elucidate the association of PLS, or disorders mimicking PLS, with 43-kDa TAR DNA-binding protein (TDP-43) abnormality, we examined two adult patients with motor neuron disease, which clinically was limited almost entirely to the UMN system, and was followed by progressive frontotemporal atrophy. In the present study, the distribution and severity, and biochemical profile of phosphorylated TDP-43 (pTDP-43) in the brains and spinal cords were examined immunohistochemically and biochemically. Pathologically, in both cases, frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) was evident, with the most severe degeneration in the motor cortex. An important feature in both cases was the presence of Bunina bodies and/or ubiquitin inclusions, albeit very rarely, in the well preserved lower motor neurons. The amygdala and neostriatum were also affected. pTDP-43 immunohistochemistry revealed the presence of many positively stained neuronal cytoplamic inclusions (NCIs) and dystrophic neurites/neuropil threads in the affected frontotemporal cortex and subcortical gray matter. By contrast, such pTDP-43 lesions, including NCIs, were observed in only a few lower motor neurons. pTDP-43 immunoblotting revealed that fragments of ∼25-kDa were present in the cortices, but not in the spinal cord in both cases. Genetically, neither of the patients had any mutation in the TDP-43 gene. In conclusion, we consider that although PLS may be a clinically significant disease entity, at autopsy, the majority of such clinical cases would present as upper-motor-predominant amyotrophic lateral sclerosis with FTLD-TDP.

Epidermoid cyst involving the medial temporal lobe: surgical pathologic features of the epileptogenic lesion.

Epidermoid cysts in the middle fossa are rare and may involve the temporal lobe and lateral ventricle. Affected patients often suffer from seizures, but the pathomechanisms underlying the epileptogenic lesions have remained unclear. Here we report the surgical pathological features of the hippocampus in a 31-year-old woman with mesial temporal lobe epilepsy (mTLE), in whom an epidermoid cyst involving the right basal cistern and inferior horn of the lateral ventricle was evident. The ictal electrocorticogram indicated seizure onset at the parahippocampal gyrus. An anterior temporal lobectomy and amygdalohippocampectomy were performed. Histologically, the hippocampus showed marked atrophy with severe loss of pyramidal neurons in the cornu Ammonis subfields and granule cell loss in the dentate gyrus. At the ventricular surface of the hippocampus, there were small granulomatous lesions with spicularly anchored keratin substance. These features indicated multiple and chronic stab wounds by the cyst contents and consequent local inflammatory responses within the parenchyma. The predisposition to adhesion between the tumor and hippocampus may have caused neurons to develop abnormal irritability to certain chemical mediators present in the cyst. Epileptogenicity involving the atrophic hippocampus and medial temporal lobes nearby may have developed in association with these processes. This case appears to provide information that is useful for surgical planning in patients with mTLE and epidermoid cysts involving the medial temporal lobe.

Spatiotemporal dynamics of epileptiform propagations: imaging of human brain slices.

Seizure activities often originate from a localized region of the cerebral cortex and spread across large areas of the brain. The properties of these spreading abnormal discharges may account for clinical phenotypes in epilepsy patients, although the manner of their propagation and the underlying mechanisms are not well understood. In the present study we performed flavoprotein fluorescence imaging of cortical brain slices surgically resected from patients with partial epilepsy caused by various symptomatic lesions. Elicited neural activities in the epileptogenic tissue spread horizontally over the cortex momentarily, but those in control tissue taken from patients with brain tumors who had no history of epilepsy demonstrated only localized responses. Characteristically, the epileptiform propagation comprised early and late phases. When the stimulus intensity was changed gradually, the early phase showed an all-or-none behavior, whereas the late phase showed a gradual increase in the response. Moreover, the two phases were propagated through different cortical layers, suggesting that they are derived from distinct neural circuits. Morphological investigation revealed the presence of hypertrophic neurons and loss of dendritic spines, which might participate in the aberrant activities observed by flavoprotein fluorescence imaging. These findings indicate that synchronized activities of the early phase may play a key role in spreading abnormal discharges in human cortical epilepsies.

Hypertrophy of hippocampal end folium neurons in patients with mesial temporal lobe epilepsy.

Hypertrophic and dysmorphic neurons have been identified in the hippocampal end folium of patients with mesial temporal lobe epilepsy (mTLE). No data are available regarding the correlation between these cellular alterations and the severity of hippocampal sclerosis (HS), and the significance of this phenomenon has been unclear. We evaluated both the perikaryon and nuclear areas of residual neurons in the hippocampal end folium of 47 patients with mTLE, seven with lesional neocortical temporal lobe epilepsy (LTLE), and 10 controls without seizure episodes. According to the severity of neuron loss in the end folium, we defined mTLE cases showing slight (<10%) or no, moderate (10-50%) and severe (>50%) loss as groups A, B and C, respectively. We also performed immunohistochemistry with antibodies against heat shock protein 70 and the phosphorylated epitope of neurofilament. In both mTLE and LTLE cases, the perikaryon and nuclear areas of the end folium neurons were significantly greater than those in the controls (P < 0.0001), and those in mTLE were significantly greater than those in LTLE. There were no differences in areas between groups A and B, but the areas in group C were significantly greater than those of both groups A and B. Neurons with large, bizarre morphology were labeled with both antibodies. Neuronal hypertrophy is evident in patients with epilepsy, and appears to advance gradually as the hippocampal sclerosis becomes more severe. This alteration may be a consequence of cellular stress incurred by neurons.

Balloon cells in the dentate gyrus in hippocampal sclerosis associated with non-herpetic acute limbic encephalitis.

The presence of balloon cells, a pathognomonic cellular feature of focal cortical dysplasia type IIB, in a background of hippocampal sclerosis is rare. Here we report the surgical pathologic features of the hippocampus resected from a 32-year-old woman with mesial temporal lobe epilepsy and a precipitating history of non-herpetic acute limbic encephalitis. Histologically, the resected specimen showed features of hippocampal sclerosis with granule cell dispersion. Characteristically, many balloon cells, immunoreactive for nestin, vimentin, glial fibrillary acidic protein (GFAP), GFAP-delta and CD34, were observed in the molecular and granule cell layers of the dentate gyrus. In the present case hippocampal sclerosis was an apparently acquired alteration, rather than a result of maldevelopment. The appearance of balloon cells raises questions regarding their origin and morphogenesis.

Neurocutaneous melanosis: surgical pathological features of an apparently hamartomatous lesion in the amygdala.

Neurocutaneous melanosis (NCM) is a rare, congenital phakomatosis characterized by the presence of congenital melanocytic nevi and a benign or malignant pigmented cell tumor of the leptomeninges of the CNS. Here the authors report the surgical pathological features of a lesion in the left amygdala in a 10-year-old girl with giant congenital pigmented nevi and mesial temporal lobe epilepsy. The lesion exhibited high intensity on T1-weighted MR images and low intensity to isointensity on T2-weighted images. A left anterior temporal lobectomy and hippocampectomy were performed. Histologically, the lesion was composed of melanin-containing polygonal cells arranged in solid alveolar or multiple lobular patterns. Immunohistochemically, the cells were immunoreactive for HMB45, S100 protein, and vimentin, the profiles being consistent with those of melanocytes. Bundles of astrocytic processes surrounded the nests of melanocytes. Melanin-containing and dysmorphic neurons were also scattered near the nests. In the temporal neocortex adjacent to the amygdaloid melanocytic lesion, cortical dysplasia with cortical laminar disorganization was evident. Based on the histopathological features, the parenchymal lesion appeared to be hamartomatous in nature rather than a neoplasm, involving aberrant migration of melanocytes into the developing neuroepithelial tissue. This case appears to represent an unusual CNS manifestation of NCM.

Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, Parkinsonism, and motor neuron disease: a distinct clinicopathological and biochemical disease entity.

Tau is the pathological protein in several neurodegenerative disorders classified as frontotemporal lobar degeneration (FTLD), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). We report an unusual tauopathy in three Japanese patients presenting with Parkinsonism and motor neuron disease (neuroimaging revealed frontotemporal cerebral atrophy in two patients who were examined). At autopsy, all cases showed FTLD with the most severe neuronal loss and gliosis evident in the premotor and precentral gyri. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. In the spinal cord, loss of anterior horn cells and degeneration of the corticospinal tract were evident. In addition, the affected regions exhibited neuronal cytoplasmic inclusions resembling neurofibrillary tangles. Immunostaining using antibodies against hyperphosphorylated tau and 4-repeat tau revealed widespread occurrence of neuronal and glial cytoplasmic inclusions in the central nervous system; the astrocytic tau lesions were unique, and different in morphology from astrocytic plaques in CBD, or tufted astrocytes in PSP. However, immunoblotting of frozen brain samples available in two cases revealed predominantly 4R tau, with the approximately 37-kDa and 33-kDa low-molecular mass tau fragments characteristic of CBD and PSP, respectively. No mutations were found in the tau gene in either of the two cases. Based on these clinicopathological, biochemical, and genetic findings, we consider that the present three patients form a distinct 4R tauopathy associated with sporadic FTLD.

Intraventricular pleomorphic xanthoastrocytoma with anaplastic features.

Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic tumor that usually occurs in the superficial cerebral hemispheres of children and young adults and has a relatively favorable prognosis. We report an unusual case of supratentorial, intraventricular tumor in a 52-year-old man. The tumor was composed of pleomorphic cells, including giant cells, most of which were multinucleated, and small cells. In addition, frequent xanthic changes in the cytoplasm of the tumor cells, and widespread reticulin deposits and lymphocytic infiltrates in the stroma were characteristic features. Large areas of necrosis were also evident. However, mitotic figures were rare (1-2 mitoses per 10 high-power fields). Many tumor cells were positive for GFAP, and a number were positive for neurofilament protein and synaptophysin, indicating their neuronal differentiation. In addition, occasional tumor cells were positive for CD34. p53 protein was entirely negative in the tumor cells. In diagnosing this tumor histopathologically, differentiation between PXA and giant cell glioblastoma (GCG), a rare variant of glioblastoma, was problematic. However, considering the overall histopathological picture, a final diagnosis of PXA with anaplastic features was made. The present case indicates that PXA can occur as an intraventricular tumor, and suggests that in some instances, it would be very difficult to differentiate PXA and GCG histopathologically.

Alzheimer's disease: report of two autopsy cases with a clinical diagnosis of corticobasal degeneration.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Corticobasal degeneration (CBD) is a rare neurodegenerative disease affecting adults, being characterized clinically by a combination of extrapyramidal signs and focal cortical syndromes. In both diseases, tau deposits are a characteristic neuropathological feature. We report two new patients with autopsy-proven AD, in whom clinical diagnoses of CBD were made during life. The ages of the patients at onset were 52 and 67 years, and the disease durations were 9 and 15 years, respectively. At autopsy, both cases exhibited marked cortical atrophy with evident neuronal loss in the convex areas of the frontal and parietal lobes. Immunohistochemically, AT8-positive neurofibrillary tangles (NFTs) and Abeta-positive senile plaques (SPs) were widespread and abundant in the cerebral cortex (Alzheimer pathology stage VI/C of Braak and Braak), leading us to the final pathological diagnosis of AD. No tau lesions suggestive of CBD were observed, and the deep gray matter areas, including the substantia nigra, were unremarkable (exceptionally, only mild neuronal loss was noted in the putamen in case 2). These findings further strengthen the idea that in AD, neurodegeneration with tau and Abeta deposits may begin in the fronto-parietal neocortical areas, which are often preferentially affected in CBD, earlier than, or as early as the medial temporal lobe, and that extrapyramidal signs, such as rigidity and tremor, can occur in the absence of neuronal loss in the basal ganglia and substantia nigra.

[Focal cortical dysplasia with refractory epilepsy: clinicopathologic study of 38 cases].

OBJECTIVE: To investigate the clinicopathologic features of focal cortical dysplasia (FCD) in patients with refractory epilepsy. METHODS: The clinical, radiologic and pathologic features of 38 cases of FCD receiving surgical treatment in 2005 were reviewed retrospectively. RESULTS: The mean age of disease onset was 9.2 years. The disease lasted for 11.9 years on average and often presented as complex partial seizure. Radiologic examination revealed hippocampal sclerosis, or abnormal signals in the grey matter in 21 cases. According to Palmini's classification system, the following pathologic subgroups were identified: FCD type IA (3/38), FCD type IB (20/38), FCD type IIA (5/38) and FCD type IIB (5/38). The remaining 5 cases were classified as mild cortical dysplasia. Topographically, FCD type II was often seen in the extratemporal region (8/10), predominantly in the frontal lobe (5/8). Dual pathology was identified only in cases with FCD type IB. Immunohistochemical study showed that the giant neurons, immature neurons and dysmorphic neurons were strongly positive for NeuN. A small number of balloon cells expressed nestin. CONCLUSIONS: FCD is a common cause of refractory epilepsy. FCD type IB is the predominant pathologic subtype. Associated hippocampal sclerosis is sometimes seen. Clinicopathologic differences between FCD type I and FCD type II are observed.

[Expression and diagnostic significance of OCT4, CD117 and CD30 in germ cell tumors].

OBJECTIVE: To study the immunohistochemical expression of OCT4, CD117 and CD30 in germ cell tumors and to assess their diagnostic value. METHODS: Immunohistochemical study for OCT4 was performed on formalin-fixed, paraffin-embedded tissues of 63 cases of germ cell tumors, including seminoma (21), dysgerminoma (7), germinoma (8), embryonal carcinoma (8), yolk sac tumor (6), mature teratoma (10) and immature teratoma (3), as well as 25 cases of non-germ cell tumors, including granulosa cell tumor (8), clear cell adenocarcinoma (4), Leydig's cell tumor (5), diffuse large B-cell lymphoma (4) and malignant melanoma (4). Besides, the expression of CD117 and CD30 in all germ cell tumors was studied. RESULTS: All cases of seminoma and germinoma, 6/7 cases of dysgerminoma and 7/8 cases of embryonal carcinoma were positive for OCT4, with strong nuclear staining. All other germ cell tumors and non-germ cell tumors were negative for OCT4, except for 1 case of yolk sac tumor and 1 case of clear cell adenocarcinoma which showed weak staining. Positive membranous expression of CD117 was demonstrated in 19/21(90.5%) seminoma, 5/7 dysgerminoma and 7/8 germinoma. Focal weak membranous staining was also noted in 1 case of yolk sac tumor. The melanocytes in teratoma were also positive for CD117. All cases of embryonal carcinoma were negative. On the other hand, positive membranous expression of CD30 were demonstrated in 6/8 embryonal carcinoma. One case of germinoma and 1 case of yolk sac tumor showed weak cytoplasmic positivity. All cases of seminoma and dysgerminoma, 7/8 germinoma and all cases of teratoma were negative for CD30. CONCLUSIONS: OCT4 is a sensitive and relatively specific marker for diagnosing seminoma, dysgerminoma, germinoma and embryonal carcinoma. CD117 and CD30 immunostains, when used in combination, represent valuable tools for distinguishing embryonal carcinoma and seminoma, dysgerminoma, germinoma.