Progression of atypical extraventricular neurocytoma to anaplastic ganglioglioma.

We report a childhood case of thalamic atypical extraventricular neurocytoma that progressed to highly anaplastic ganglioglioma after 8 years of dormancy after subtotal resection and chemotherapy. The neurocytoma displayed immunoreactivity only for synaptophysin, ß-catenin, S100, and CD56. The ganglioglioma acquired strong immunoreactivity for chromogranin, glial fibrillary acidic protein, neuron-specific enolase, and p53 and showed a very high proliferation rate approaching 50% in some areas. Tumor transformation was associated with overexpression of components of the sonic hedgehog and Wnt developmental signaling pathways, which are known to regulate tumor-initiating cells in malignant brain neoplasms.

Intramedullary gangliogliomas: histopathologic and molecular features of 25 cases.

Gangliogliomas are uncommon glioneuronal tumors, which usually arise in the cerebral hemispheres and occasionally in the brain stem. Gangliogliomas occurring in the spinal cord are extremely rare. In this study, we analyzed the clinical, histopathologic, and molecular features of 25 spinal gangliogliomas. The cases included in our series affected mostly children and young adults (15 males and 10 females; mean age, 20 years; median age, 14 years; age range, 1-72 years) and were predominantly localized in the cervical and thoracic spine. From the clinical point of view (detailed follow-up available for 9 pediatric cases; mean follow-up: 2 years 10 months; range, 3 months to 5 years 10 months), most patients showed stable disease after subtotal resection. Radiotherapy was rarely used as adjuvant treatment. Histologically, gangliogliomas (WHO grade I) (21 cases) showed features largely similar to their supratentorial counterparts. Anaplastic gangliogliomas (World Health Organization grade III) (4 cases) showed features of anaplasia (including high cellularity and increased mitotic and proliferation activity). From a molecular point of view, only 2 tumors (2/19, 11%) harbored a BRAF(V600E) mutation. In conclusion, although spinal gangliogliomas display histologic and clinical features similar to their supratentorial counterparts, they show a relatively low frequency of BRAF(V600E) mutations, alteration otherwise common in hemispheric and brain stem gangliogliomas.

Mixed neuronal-glial tumor in the temporal lobe of an infant: a case report.

BACKGROUND: Tumors that arise in the temporal lobes of infants and spread to the neural system are limited to several diagnoses. Herein, we present an infantile case of a temporal tumor showing neuronal and glial differentiation. CASE PRESENTATION: The patient was a 9-month-old boy with low body weight due to intrauterine growth retardation. At 9 months after birth, he presented partial seizures. Computed tomography scanning revealed a mass (35 * 40 mm) in the left temporal lobe. Isointensity was noted on magnetic resonance T1-weighted images and fluid attenuation inversion recovery images. The tumor was heterogeneously enhanced with gadolinium. Positron emission tomography showed high methionine uptake in the tumor. During surgery, the tumor, which was elastic and soft and bled easily, was gross totally resected. A moderately clear boundary was noted between the tumor and normal brain parenchyma. Histologically, the tumor mainly comprised a ganglioglioma-like portion and short spindle cells at different densities. The former was immunohistochemically positive for some kinds of neuronal markers including synaptophysin. The spindle cells were positive for glial fibrillary acidic protein, but desmoplasia was not observed. DISCUSSION: The tumor contained both neuronal and glial elements; the former were the main constituents of the tumor and included several ganglion-like cells. Because neuronal elements gradually transited to glial cells, a mixed neuronal-glial tumor was diagnosed. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2045126100982604.

First step toward the "fingerprinting" of brain tumors based on synchrotron radiation X-ray fluorescence and multiple discriminant analysis.

Synchrotron-radiation-based X-ray fluorescence was applied to the elemental microimaging of neoplastic tissues in cases of various types of brain tumors. The following cases were studied: glioblastoma multiforme, gemistocytic astrocytoma, oligodendroglioma, anaplastic oligodendroglioma, ganglioglioma, fibrillary astrocytoma, and atypical transitional meningioma. Apart from neoplastic tissue, the analysis included areas of tissue apparently without malignant infiltration. The masses per unit area of P, S, Cl, K, Ca, Fe, Cu, Zn, Br, and Rb were used to construct a diagnostic classifier for brain tumors using multiple discriminant analysis. It was found that S, Cl, Cu, Fe, K, Br, and Zn are the most significant elements in the general discrimination of tumor type. The highest similarity in elemental composition was between atypical transitional meningioma and fibrillary astrocytoma. The smallest differentiation was between glioblastoma multiforme and oligodendroglioma. The mean percentage of correct classifications, estimated according to the a posteriori probabilities procedure, was 99.9%, whereas the mean prediction ability of 87.6% was achieved for ten new cases excluded previously from the model construction. The results showed that multiple discriminant analysis based on elemental composition of tissue may be a potentially valuable method assisting differentiation and/or classification of brain tumors.

Focal cortical dysplasia type II (malformations of cortical development) aberrantly expresses apoptotic proteins.

bcl-XL, bax, bcl-2, and p53 are apoptotic proteins essential to normal neural development. Aberrant expression of these proteins has been observed in several central nervous system neoplasms. Immunoexpression of these markers is studied in 21 patients with focal cortical dysplasia type II (Taylor-type cortical dysplasia; malformations of cortical development) who had undergone lesionectomy for treatment of pharmacoresistant epilepsy. Paraffin immunohistochemistry using standard methodology was performed on representative sections using antibodies to bcl-XL, bax, bcl-2, and p53. Aberrant expression of bcl-XL, bax, bcl-2, and p53 was observed in the majority of cases, with dysmorphic neurons staining positively for bcl-XL, bax, and bcl-2 in 71%, 76%, and 24% of cases, respectively, and balloon cells staining positively for bcl-XL, bax, and bcl-2 in 89%, 78%, and 17% of cases, respectively. Most cases (86%) showed some expression of p53, with the majority showing expression of p53 most prominently in balloon cells. Previous work has shown gangliogliomas and dysembryoplastic neuroepithelial tumors, both dysplasia-associated neoplasms, to demonstrate aberrant expression of apoptotic markers, suggesting a possible common mechanism of development for these 2 processes in patients in whom they coexist.

Ganglioglioma associated with cerebral cortical dysplasia: an unusual case with extensive leptomeningeal involvement.

Ganglioglioma is a tumor occurring in children and young adults and characterized by a superficial cortical location and biphasic histologic differentiation encompassing neuronal and glial elements. Ganglioglioma may arise anywhere throughout the neuraxis, including the optic nerve, brain stem, pineal gland, cerebellum, cerebrum, and spinal cord; however, the majority of glioneuronal neoplasms involve the temporal lobe. Gangliogliomas may show focal leptomeningeal involvement, but predominant leptomeningeal involvement by gangliogliomas is extremely rare; only 2 cases of ganglioglioma extensively involving the leptomeninges have been reported. In this report, we present an unusual case of a ganglioglioma predominantly present within the leptomeninges of a 15-year-old boy with a history of seizures. Furthermore, the cerebral cortex beneath the tumor showed dysplastic changes. We report a very unusual case of ganglioglioma involving predominantly the cerebral leptomeninges and associated with adjacent cerebral cortical dysplasia. Histologic characteristics and diagnostic pitfalls are discussed.

Glioneuronal tumor with neuropil-like islands (GTNI): a report of 8 cases with chromosome 1p/19q deletion analysis.

Glioneuronal tumor with neuropil-like islands (GTNI) is a rare neoplasm harboring circumscribed loci of neuronal differentiation and diffusely infiltrating astroglial and oligodendrocytelike components. We report 8 previously unpublished examples of GTNI, specifically studied for chromosome 1p and 19q allelic losses. All tumors showed characteristic histologic features and immunoprofile. One primary tumor displayed frankly malignant histology with frequent mitoses, microvascular proliferation, and necrosis. This tumor progressed within months of the initial resection. Three other tumors (2 low-grade and 1 showing only focal microvascular proliferation) recurred at 2 years, 3 years, and 1 year, respectively. All cases were evaluated for 1p/19q allelic losses by standard polymerase chain reaction-based loss of heterozygosity assays. No evidence of 1p/19q losses was found in 7 of 8 tumors. One tumor demonstrated small interstitial deletions at 1p36 (at D1S1612 and D1S513, but not at D1S548 or D1S1592) and a small interstitial deletion at 19q13 (at D19S219 and D19S412, but not at PLA2G4C). The lack of large, whole-arm 1p/19q losses (such as those found in oligodendroglial tumors), aberrant p53 expression, and the predominance of astroglial components may indicate a biologic relationship of the GTNI to diffuse astrocytoma. Although GTNI shares some morphologic features with recently reported cases of oligodendroglioma with neurocytic differentiation, the 2 tumors appear different at the molecular genetic level.

Glioneuronal phenotype in a diencephalic pilomyxoid astrocytoma.

We report the presence of divergent populations of cells in a hypothalamic/chiasmatic pilomyxoid astrocytoma of an 11-month-old male, exhibiting differential immunohistochemical localizations for glial fibrillary acidic protein (GFAP) and synaptophysin. The tumor cells were negative for Neu-N and neurofilament protein. Ultrastructurally, the tumor comprised 2 cell types, one with features attributable to a neuronal phenotype alongside cells exhibiting an overt astroglial phenotype. This composite organization was confirmed by confocal microscopy, which revealed 2 distinct, albeit tightly interwoven, populations of GFAP and synaptophysin-labeled tumor cells. Our results indicate that a subset of the so-called pilomyxoid astrocytomas of the hypothalamic/chiasmatic region may represent phenotypically mixed glioneuronal neoplasms distinct from the pilocytic astrocytomas.

Desmoplastic noninfantile ganglioglioma: report of a case.

Desmoplastic infantile ganglioglioma is a rare superficial supratentorial tumor that occurs within the first two years of life. Despite the worrisome radiological and histological appearance, the tumors are often curable following gross total resection. Tumors with similar characteristics are exceedingly rare in the noninfantile population. We present a six-year-old boy with seizures, weakness, and unsteady gait. Radiographic imaging confirmed a very large, solid and cystic mass in the right temporal-parietal region. Pathological examination demonstrated a tumor with severe desmoplasia identical to those reported as "desmoplastic infantile ganglioglioma." This case adds to the limited data available for desmoplastic gangliogliomas in the noninfantile population. It is not clear, yet likely, that the noninfantile form of this neoplasm is biologically similar to the infantile form. It is also unclear whether the desmoplastic noninfantile ganglioglioma has characteristics similar to classical ganglioglioma. This rare case highlights the remarkable versatility of glioneuronal tumors in children.

Desmoplastic infantile ganglioglioma with high proliferation index: report of a case.

Desmoplastic infantile ganglioglioma (DIG) is an uncommon neuroepithelial tumor associated with epilepsy, mostly occurring in the first 2 years of life. Most DIGs carry good prognosis after complete resection, even when a primitive cellular element is present. However a few examples of DIG with histologic anaplasia have recently been reported, and one demonstrated an unusual aggressive behavior. The authors describe herein a DIG with high Ki-67 proliferation index (30%) in a 10-month-old male infant with epilepsy, but with an excellent prognosis after total tumor resection.

Desmoplastic infantile ganglioglioma: a potentially malignant tumor?

Desmoplastic infantile ganglioglioma is a rare intracranial tumor of early childhood with a usually excellent prognosis despite malignant features both radiologically and histologically. We present the case of a desmoplastic infantile ganglioglioma with histologically highly anaplastic features and both intracerebral and pial metastases. After partial resection the tumor was rapidly progressive and new metastases appeared. A combination of vincristine and carboplatinum was used according to the Low Grade Glioma Protocol of the International Society of Pediatric Oncology, with a temporary good response. When histologically characterized by highly anaplastic features, it seems the biologic behavior of this tumor remains uncertain. The aggressive behavior and the responsiveness to chemotherapy in this case may challenge the belief in the benign nature of these rare tumors.

Anaplastic ganglioglioma with sarcomatous component: an immunohistochemical study and molecular analysis of p53 tumor suppressor gene.

The present case report describes a case of ganglioglioma with a distinct sarcomatous component in the left temporal lobe of a 59-year-old Japanese man. Neoplastic neuroglial tissue contained both benign and anaplastic glial components with a MIB-1 labeling index of 0.1% and 12.0%, respectively. Sarcomatous tissue adjacent to the anaplastic glial tissue was dominated by pleomorphic fibroblastic cells with a MIB-1 labeling index of 10.8%. They were immunoreactive for smooth muscle actin, type IV collagen, and alpha 1 antitrypsin, but not for desmin and CD34. Interestingly, some of the sarcomatous cells were double-positive for smooth muscle actin and GFAP. The p53 protein had accumulated in the anaplastic astrocytes and sarcomatous cells, but direct DNA sequencing of PCR products failed to detect any mutation in the p53 gene (from exon 4 to exon 10).

A rosette-forming glioneuronal tumor of the fourth ventricle: infratentorial form of dysembryoplastic neuroepithelial tumor?

Eleven cases of a distinctive tumor of the posterior fossa are described. The patients (age range 12-59 years) presented with headache and/or ataxia. Neuroimaging revealed a relatively discrete, focally enhancing mass(es) primarily involving the aqueduct, fourth ventricle, and cerebellar vermis. Hydrocephalus was present in seven cases, and two lesions were multicentric. In two cases a significant increase in tumor size was documented. Gross total or subtotal resections were achieved in 10 cases. One patient underwent biopsy alone and another received postoperative irradiation. Histologically, two components were identified in all cases. One consisted of neurocytes forming neurocytic and/or perivascular pseudorosettes in a fibrillary, partly microcystic matrix. The second, astrocytic component resembled pilocytic astrocytoma in 10 cases and consisted of fibrillated spindle cells with oval nuclei associated with occasional Rosenthal fibers, granular bodies, glomeruloid capillaries, and microcalcifications. Regionally, this component was more diffuse and patternless, consisting of sheets of round to oval, oligodendrocyte-like cells. Rare ganglion cells were seen in four cases. The rosettes were consistently synaptophysin and MAP-2 immunoreactive, whereas the spindle cells were positive for S-100 protein and glial fibrillary acidic protein. Overall, atypia was minimal; no mitoses were found, and Ki67 labeling indices were low. Ultrastructurally, the neurocytic cells featured processes containing microtubules and occasional dense core granules. Mature synapses were found in one of the four cases studied. Although the histologic features of this unique tumor superficially resemble those of dysembryoplastic neuroepithelial tumor, rosette formation by neuronal cells, the frequent presence of a pilocytic astrocytoma component, and the growing nature of the lesion argue against that diagnosis, as does occasional multifocality.

Immunophenotype of pleomorphic xanthoastrocytoma.

Pleomorphic xanthoastrocytoma (PXA) is an uncommon tumor, often seizure-associated and occurring in the temporal lobe of young adults. Although its cells are considered astrocytic in nature, recent studies suggest the presence of neuronal differentiation and a possible relationship to glioneuronal neoplasms. We immunostained 40 cases of PXA, including two composite PXA-gangliogliomas (PXA-GG), with a panel of glial (glial fibrillary acidic protein, S-100 protein) and neuronal markers (class III beta-tubulin, synaptophysin, neurofilament proteins, MAP2, and chromogranin A). Conventional PXAs demonstrated immunoreactivity for glial fibrillary acidic protein (100% of cases), S-100 protein (100%), class III beta-tubulin (73%), synaptophysin (38%), NF proteins (18 and 8%), and MAP2 (8%). Chromogranin A stain was absent in all conventional PXA cases. Neoplastic ganglion cells in both PXA-GGs stained with class III beta-tubulin, synaptophysin, and chromogranin A. Ultrastructural studies, performed in nine cases, demonstrated neuronal features including microtubules, dense core granules, and/or clear vesicles largely limited to cell processes (two PXAs) and in the cytoplasm (PXA component of one PXA-GG). Although the essential nature of PXA is clearly and uniformly glial, the significance of the limited neuronal differentiation is unclear, as it is the relationship between conventional PXA and PXA-GG. We found no evidence that the former is a precursor of the latter.

Cytologic features of desmoplastic infantile ganglioglioma: a report of two cases.

BACKGROUND: Desmoplastic infantile ganglioglioma (DIG) is a rare intracranial tumor of infancy, characterized by solid and cystic components, voluminous size and supratentorial location. Although its histologic features have been reported, there has been no cytologic description of the tumor. Cytologic findings on imprint and aspirated material from two cases of histologically verified DIG are discussed. CASES: A 12-month-old male with cutis marmorata telangiectatica congenita and a 44-month-old female with episodes of spasm were referred to our center. Radiologic examination revealed a large, cystic, supratentorial mass in both patients. The mass was surgically removed, and histology revealed prominent desmoplasia with a mixture of astroglial and neuronal cells. Cytologic findings on imprint material and the needle aspirates taken from the cystic area of the tumor revealed a few isolated or sheetlike arrangements of small cells positive for glial fibrillary acidic protein and a few large cells with abundant cytoplasm and prominent nucleoli, positive for neuronal marker. CONCLUSION: Although distinction between ganglioglioma and DIG may be difficult by cytology alone, with the characteristic clinical presentation and radiologic findings, the possibility of DIG should be kept in mind when the specimens contain both astroglial and neuronal elements.

Ex vivo pediatric brain tumors express Fas (CD95) and FasL (CD95L) and are resistant to apoptosis induction.

Fas (APO-1/CD95/TNFRSF6) is a member of the tumor necrosis/nerve growth factor receptor family that signals apoptotic cell death in sensitive cells. Expression of Fas and its agonistic ligand (FasL/TNFSF6) was investigated in ex vivo pediatric brain tumor specimens of various histologic types. Fas expression was identified in all of the 18 tumors analyzed by flow cytometry and immunohistochemistry. FasL expression was identified in most of the 13 tumors analyzed by both Western analysis and immunohistochemistry. Nine of these tumor specimens were treated with either the agonistic anti-Fas antibody (APO-1) in combination with protein A or FasL in short-term cytotoxicity assays. Sensitivity to apoptosis induced by the topoisomerase II inhibitor, etoposide, was also assessed. Despite the presence of Fas, all the specimens analyzed demonstrated a high degree of resistance to Fas-mediated apoptosis. These 9 specimens also showed a high degree of resistance to etoposide. Only 2 of the 9 specimens were susceptible to etoposide-induced cell death, whereas only 3 were sensitive to Fas-mediated apoptosis. One brain tumor was sensitive to both Fas ligation and etoposide treatment. This contrasted with the high degree of susceptibility to both etoposide- and Fas-induced apoptosis observed in the reference Jurkat cell line. The results suggest that Fas expression may be a general feature of tumors of the CNS and that a significant degree of resistance to Fas-mediated apoptosis may exist in ex vivo pediatric brain tumor specimens.

Glioneuronal tumor with neuropil-like islands.

Mixed glioneuronal neoplasms are relatively uncommon tumors in the central nervous system. Recently, an unusual glioneuronal tumor arising in adults marked histologically by neuropil-like islands was described. We present a similar case arising in a 23-year-old woman who presented with headaches and seizures and on imaging studies was noted to have a frontal-temporal lobe mass. The patient underwent partial resection of the tumor, which histologically resembled anaplastic astrocytoma, and received a course of radiation therapy and chemotherapy. Increasing seizure frequency and expanding size on neuroimaging prompted a re-excision of the tumor. The second resection was marked by islands of tissue resembling gray matter with slightly atypical neuronal and glial cells situated in the white matter. These islands stained positively with synaptophysin and did not stain with glial fibrillary acid protein. Mild vascular proliferation and moderate nuclear pleomorphism also characterized the tumor. Areas of necrosis were not noted. A MIB-1 labeling index of 18.1% was noted. P53 immunoreactivity was observed in approximately 40% of tumor cell nuclei. This lesion is felt to represent a clinically aggressive glioneuronal neoplasm with an unusual and distinctive histologic phenotype. HUM PATHOL 31:1435-1438.

Class III beta-tubulin immunoreactive intranuclear inclusions in human ependymomas and gangliogliomas.

We have observed intranuclear inclusion bodies immunoreactive for the cytoskeletal protein class III beta tubulin (C3betaT) in neurons and ependymal cells of post-mortem human brain. The relationship of these inclusions, detected by light microscopy, to the intranuclear rodlets described by the classical microscopists is unknown. The present study was conducted to determine whether these proteinaceous inclusions (C3betaT-NIIs) exist in the neoplastic counterparts of these cell types. Immunohistochemical staining for C3betaT revealed intensely stained, predominantly rod-shaped intranuclear inclusions in a variable proportion of tumor cells in five of ten ependymomas. In addition, C3betaT-NIIs were encountered in less than 1% of neuronal cells in two of five gangliogliomas. This study represents the first report of tubulin-containing intranuclear inclusions in brain tumors. The functional significance of these inclusions in normal human brain and in cerebral neuroepithelial neoplasms remains to be determined.

Desmoplastic infantile ganglioglioma.

We present the clinical, anatomic, and laboratory findings in a 4-month-old child with desmosplastic infantile ganglioglioma. Microtubule-associated protein-2 (AP18) and neuron-specific B-tubulin (TUJ-1) were more sensitive in detecting immature neural elements than synaptophysin. Despite the immature neuroblastic component, focal intermediate proliferation indices, microinvasion, presence of secondary features (extension into Virchow Robin spaces, perineuronal satellitosis), and subtotal resection, the child has done well, with striking improvement of the magnetic resonance imaging (MRI) image, head size improvement, no tumor recurrence, and minimal neurological deficits.