A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas.

Chordoid glioma (ChG) is a characteristic, slow growing, and well-circumscribed diencephalic tumor, whose mutational landscape is unknown. Here we report the analysis of 16 ChG by whole-exome and RNA-sequencing. We found that 15 ChG harbor the same PRKCA D463H mutation. PRKCA encodes the Protein kinase C (PKC) isozyme alpha (PKCα) and is mutated in a wide range of human cancers. However the hot spot PRKCA D463H mutation was not described in other tumors. PRKCA D463H is strongly associated with the activation of protein translation initiation (EIF2) pathway. PKCαD463H mRNA levels are more abundant than wild-type PKCα transcripts, while PKCαD463H is less stable than the PCKαWT protein. Compared to PCKαWT, the PKCαD463H protein is depleted from the cell membrane. The PKCαD463H mutant enhances proliferation of astrocytes and tanycytes, the cells of origin of ChG. In conclusion, our study identifies the hallmark mutation for chordoid gliomas and provides mechanistic insights on ChG oncogenesis.

Navigation-Guided Endoscopic Intraventricular Injectable Tumor Model: Cadaveric Tumor Resection Model for Neurosurgical Training.

BACKGROUND: Intraventricular tumors present difficult challenges to the neurosurgeon. Neurosurgeons have begun to explore the possibilities of using the endoscope in the radical resection of solid intraventricular lesions. There is a steep learning curve when dealing with such lesions with an endoscope. OBJECTIVE: The aim of this study was to create a laboratory training model for neuroendoscopic surgery of intraventricular lesions guided by the navigation system. We believe this technique is more reliable than the traditional approach using contrast injection with C-arm x-ray guidance. MATERIALS AND METHODS: Five formalin-fixated, latex-injected cadaveric heads were used. The arterial system was injected with red latex through the common carotid arteries, and the venous system was injected with blue latex through the internal jugular veins at the C6 vertebral level. The contrast-enhancing tumor polymer, Stratathane resin ST-504-derived polymer (SRSDP), was injected into the lateral ventricle via Frazier's point under direct endoscopic visualization and real-time neuronavigation guidance. When navigation was used for trajectory planning, the peel-away sheath was registered using a frameless navigational system (BrainLAB, Feldkirchen, Germany). A questionnaire was distributed to all participants in an endoscopic cadaveric course in which the models were used to evaluate the endoscopic tumor model. RESULTS: Neurosurgeons participating in the course performed an endoscopic approach to resect the intraventricular tumor model through an ipsilateral frontal burr hole. The properties of the SRSDP mixture could be manipulated through varying concentrations of the materials used, in order to reach the desired consistency of a nodular solid lesion and possibility for piecemeal resection. The tumor model allowed participants to compare between normal and pathologic endoscopic anatomy in the same cadaveric head. CONCLUSION: This injectable tumor model with the combination of neuroendoscopy and navigation can improve the accuracy of the endoscopic approach and minimize the risk of cadaveric brain specimen damage that in return augments the feeling of lifelike conditions. Using this endoscopic injectable tumor model technique can assist neurosurgeons' preparation for the challenges associated with an endoscopic piecemeal resection of a solid lesion in the lateral or third ventricle.

Intraventricular schwannoma in a child. Literature review and case illustration.

BACKGROUND: Intraventricular schwannoma remains a rare entity in the literature. Controversy exists on the possible pathogenesis of such a tumor within cerebral ventricles. Literature is sparse on tumor characteristics and differences between pediatric and adult patients. CASE REPORT: We present a case of intraventricular schwannoma in a 9-year-old patient presenting with headache, hemiparesis, and focal seizure. Brain CT scan and MRI revealed an intraventricular tumor within left atrium of lateral ventricle. The patient underwent total resection of the tumor via posterior parietal approach. Histopathological exam was in favor of schwannoma. Postoperative brain MRI and MRS showed no recurrence after 18 months. CONCLUSION: Our review of the literature indicates there are some significant differences between pediatric and adult cases in different aspects including gender predominance, intraventricular location, malignant transformation, tendency for recurrence, and surgical outcome. This needs to be taken into account in the literature.

Chordoid gliomas of the third ventricle share TTF-1 expression with organum vasculosum of the lamina terminalis.

Chordoid glioma of the third ventricle (CG3V) is a rare tumor developing in a stereotyped localization. It has been related to the circumventricular organ of the lamina terminalis, in the anterior part of the third ventricle, but its oncogenesis is poorly understood. TTF-1 transcription factor is involved in the development and adult physiology of the ventral forebrain. We studied the histopathologic and immunohistochemical features of a multicentric series of 17 cases of CG3V. We described additional histologic patterns (solid, fibrosing, and fusiform) to the typical chordoid pattern. TTF-1 was constantly expressed in CG3V, as in developing and adult lamina terminalis. The anti-TTF-1 SPT24 clone was more sensitive than the 8G7G3/1 clone. No mutation of IDH1 R132, IDH2 R172, or BRAF V600 codons was found. We showed TTF-1 as a useful marker for the diagnosis of CG3V and the understanding of its oncogenesis.

Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model.

BACKGROUND: Combining anti-angiogenesis agents with cytotoxic agents for the treatment of malignant gliomas may affect the cytotoxic drug distribution by normalizing the blood-brain barrier (BBB). This study examines the intratumoral concentration of temozolomide (TMZ) in the presence and absence of the pan-VEGF receptor tyrosine kinase inhibitor, cediranib. METHODS: Seven nude rats bearing U87 intracerebral gliomas had a microdialysis probe centered within the tumor. Ten-days after tumor implantation, TMZ (50 mg/kg) was given orally. The extracellular fluid (ECF) concentrations of TMZ within the tumor were assessed via microdialysis for 6 h following TMZ administration. Cediranib (6 mg/kg) was then given orally, and 12 h later, TMZ was re-administered with subsequent microdialysis collection. A subset of animals also underwent functional MRI to assess angiogenesis in vivo at post-inoculation days 12 and 21, before and after the cediranib treatment. RESULTS: After dosing of oral TMZ only, ECF-TMZ mean-C(max) and area under the concentration curve(AUC(0-∞)) within the tumor were 0.59 µg/mL and 1.82 µg h/mL, respectively. Post-cediranib, ECF-TMZ mean-C(max) and AUC(0-∞) were 0.83 µg/mL and 3.72 ± 0.61 µg h/mL within the tumor, respectively. This represented a 1.4-fold (p = 0.3) and 2.0-fold (p = 0.06) increase in the ECF-TMZ C(max) and AUC(0-∞), respectively, after cediranib administration. In vivo MRI measurements of the various vascular parameters were consistent with a BBB "normalization" profile following cediranib treatment. CONCLUSIONS: In the U87 intracerebral glioma model, within the first day of administration of cediranib, the intratumoral concentrations of TMZ in tumor ECF were slightly, but not statistically significantly, increased when compared to the treatment of TMZ alone with radiographic evidence of a normalized BBB.

Embryonal tumor with abundant neuropil and true rosettes with melanotic (retinal) differentiation.

Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a rare variant of central nervous system primitive neuroectodermal tumor occurring exclusively in the pediatric population. We report a unique case of a 6-month male child presenting with a large intraventricular lesion. Histological examination revealed a tumor composed of primitive neuroectodermal cells in dense aggregates, interspersed by hypocellular areas containing small round cells widely dispersed in neuropil-like material. Few ependymal and occasional ependymoblastic rosettes were appreciated. Focal melanotic neuroepithelium recapitulating retinal differentiation was also seen. Documentation of such cases may expand the neuroectodermal differentiation spectrum of ETANTR.

Molecular characterization of circumventricular organs and third ventricle ependyma in the rat: potential markers for periventricular tumors.

Circumventricular organs (CVOs) are specialized ventricular structures around the third and fourth ventricles of the brain. In humans, these structures are present during the fetal period and some become vestigial after birth. Some of these organs, such as the pineal gland (PG), subcommissural organ (SCO), and organum vasculosum of the lamina terminalis, might be the sites of origin of periventricular tumors, notably pineal parenchymal tumors, papillary tumor of the pineal region and chordoid glioma. In contrast to the situation in humans, CVOs are present in the adult rat and can be dissected by laser capture microdissection (LCM). In this study, we used LCM and microarrays to analyze the transcriptomes of three CVOs, the SCO, the subfornical organ (SFO), and the PG and the third ventricle ependyma in the adult rat, in order to better characterize these organs at the molecular level. Several genes were expressed only, or mainly, in one of these structures, for example, Erbb2 and Col11a1 in the ependyma, Epcam and Claudin-3 (CLDN3) in the SCO, Ren1 and Slc22a3 in the SFO and Tph, Aanat and Asmt in the PG. The expression of these genes in periventricular tumors should be examined as evidence for a possible origin from the CVOs. Furthermore, we performed an immunohistochemical study of CLDN3, a membrane protein involved in forming cellular tight junctions and found that CLDN3 expression was restricted to the apical pole of ependymocytes in the SCO. This microarray study provides new evidence regarding the possible origin of some rare periventricular tumors.

MIB-1 labeling index predicts recurrence in intraventricular central neurocytomas.

Despite the relatively low-grade of most central neurocytomas (CN), evidence suggests the existence of an aggressive subset with a propensity for recurrence. Recent studies have found the MIB-1 labeling index to be a prognostic indicator in CN. Here we review our experience with CN to analyze the relationships between extent of resection, adjuvant therapy, tumor histology, and clinical outcomes based on aggressive histology, as defined by MIB-1 labeling. A retrospective review was performed on histologically proven CN surgically resected from 1993 to 2009 at the University of California at San Francisco. Recurrence rates were analyzed using the Kaplan-Meier method with respect to MIB-1 labeling and extent of resection. All MIB-1 labeling indices were analyzed. A total of 18 patients were identified with a mean age of 30 years (range 17-58 years) and median follow-up of 40 months (5-173 months). The treatments were: gross total resection (GTR) alone (17% of patients), subtotal resection (STR) alone (50% of patients), STR plus radiotherapy (XRT: external beam or stereotactic radiosurgery: 28% of patients), or STR plus chemotherapy (5% of patients). The extent of resection and a MIB-1 labeling index >4% was predictive of recurrence (p<0.01). In the 33% of the patients in whom the tumor recurred, all had STR with MIB-1 labeling >4% with median time to recurrence of 23.5 months. The 2-year and 4-year recurrence rates in patients with MIB-1 labeling >4% were 50% and 75% respectively. No patient with a MIB-1 labeling index <4% who received STR alone had a recurrence. Thus, in patients with CN who were treated with STR, histology demonstrating a MIB-1 labeling index >4% can be a clinically useful prognostic indicator and can help guide adjuvant treatment.

Primary supratentorial atypical teratoid/rhabdoid tumor in children: a report of two cases.

Atypical teratoid/rhabdoid tumor is a highly malignant tumor of the central nervous system, usually occurring in the posterior fossa in infants and young children. Supratentorial example is relatively rare, especially with involvement of the cerebral ventricle system. Herein, we reported 2 cases of atypical teratoid/rhabdoid tumor located in the septum pellucidum within the lateral and third ventricles and right parietooccipital region, respectively. Histopathologically, both of the tumors were composed of rhabdoid tumor cells and mesenchymal components, without primitive neuroectodermal tumor or epithelial differentiation. Immunohistochemical staining showed that these tumor cells reacted positively for vimentin, S-100 protein, synaptophysin, and neuron-specific enolase. Only 1 case was found to be epithelial membrane antigen reactive. The tumor cells lacked nuclear expression of INI1. These cases emphasize that atypical teratoid/rhabdoid tumor should be also considered in the list of differential diagnosis, even when these rhabdoid tumor cells do not arise in the predilection sites.

Proton MR spectroscopy of central neurocytoma using short and long echo time: new proofs for the existence of glycine and glutamate.

RATIONALE AND OBJECTIVES: Central neurocytomas (CNCs) are rare benign tumors typically located in the lateral ventricle of the central nervous system. The authors report five patients with CNCs and review 16 previously published studies that included 52 patients with CNCs to explore the magnetic resonance spectroscopic features of CNCs. MATERIALS AND METHODS: Five patients with CNCs were retrospectively reviewed. They were examined using point-resolved spectroscopic series with short and/or long echo times. The integrals of choline, creatine, and the 3.55-ppm peak were determined using Magnetic Resonance User Interface software, and the metabolite ratios relative to creatine were obtained. In two cases, T2 relaxation times of choline and the metabolite resonance at 3.55 ppm were calculated using data points acquired with different echo times and an exponential decay model. RESULTS: Consistent with previously published studies, all five patients showed highly increased choline and reduced N-acetylaspartate and creatine. Four patients in the present study and 35 in published data demonstrated prominent peaks at 3.55 ppm, which were assigned to glycine because of its relaxation pattern and long T2 relaxation time. In addition, increased in vivo glutamate and glutamine was also confirmed in three patients examined with short echo times. Alanine and lactate peaks were observed in three and two patients, respectively. CONCLUSIONS: The present study shows that the 3.55-ppm peak characteristic of CNC should be assigned to glycine according to its T2 relaxation time. Besides increased glycine and choline, the presence of glutamate or glutamine, which appears on series with short echo times, may further confirm the diagnosis of CNC.

F-18 FDG avid primary CNS lymphoma located in the ventricles.

Primary malignant lymphoma is a non-Hodgkin lymphoma which occurs in the brain in the absence of systemic involvement. A 63-year-old woman presented to emergency service, complaining of sudden onset vomiting and dizziness. She was unconscious when she was admitted to the hospital. She had no complain, until a week ago when she experienced a headache nonresponding to analgesic. Preliminary diagnosis was cerebrovascular hemorrhage or intracranial mass. Magnetic resonance imaging and PET/CT yielded a mass filling all ventricles. Histopathology of the mass matched with malignant lymphoma located in the ventricles.

A clinicopathological, immunohistochemical and neuroradiological study of eight patients with central neurocytoma.

Central neurocytomas are low-grade tumors of neuronal origin located in the lateral ventricle that present predominantly with raised intracranial pressure. In this retrospective study, we investigated the clinical, radiological, histopathological and immunohistochemical features of eight patients (seven males and one female; age range 16-61 years; mean=35.1 years) with neurocytoma. Raised intracranial pressure was the most common presenting feature. In addition, one patient presented with marked visual deterioration and one presented with a visual field defect. All lesions were located in the lateral ventricle (right lateral ventricle: four patients, left lateral ventricle: three patients, both ventricles: one patients). Radiology showed marked intratumoral calcification in two patients. Total microsurgical excision was achieved in seven patients. Histopathology showed sheets of monotonously small-to-medium-sized neoplastic cells with uniform round-to-oval nuclei and inconspicuous nucleoli. Immunohistochemistry was positive for synaptophysin and neuron-specific enolase (NSE) in all tumors, and glial fibrillary acidic protein was focally positive in two patients. One patient had lipomatous differentiation within the tumor. No recurrence was noted in any of our patients until the last follow-up; however, there were two deaths in our series.

Synaptophysin negative central neurocytoma.

BACKGROUND: Central neurocytoma is a rare primary brain tumour, mostly localised in the lateral ventricles in relation to the foramen of Monro. OBJECTIVES: To report a case of a rare central neurocytoma with a complete loss of Synaptophysin expression and provide the differential diagnosis. METHODS AND RESULTS: We describe a case of a 34-year old man with a headache, unsteady gait and dim vision. MRI demonstrated a tumorous expansion localised in both lateral ventricles. The patient underwent a subtotal resection. Histology showed a picture consistent with central neurocytoma, but tumour was completely negative for Synaptophysin. We describe our approach in such a diagnostically difficult case. CONCLUSIONS: In the rare case of Synaptophysin-negative central neurocytoma, its neuronal differentiation should be substantiated by electron-microscopic examination. Unfortunately in the routine work, biopsy samples are usually fixed in formalin fixative which does not preserve ultrastructure well. In such situations, an accurate diagnosis is disputable and based on careful assessment of the histological features, exclusion of tumours with similar morphology and detailed correlation with MRI pictures (Fig. 4, Ref. 6). Full Text (Free, PDF) www.bmj.sk.

Intraventricular gliosarcoma: unusual location of an uncommon tumor.

Gliosarcomas are uncommon variants of glioblastoma bearing the histological hallmark of two distinct tumor components (high grade glial and sarcomatous). They share similarities with glioblastomas as far as clinico-epidemiological and prognostic factors are concerned. They are commonly cortically-surfacing lesions occurring mostly in the supratentorial compartment. Intraventricular location of a gliosarcoma is very uncommon and reported only once before. We report one such case where the lesion was subependymal and protruded into the ventricle giving the appearance of a truly intraventricluar tumor. We discuss this case and review the relevant literature.

Pigmented ependymoma with signet-ring cells and Rosenthal fibers: a rare variant of ependymoma.

We report a rare case of ependymoma with vacuolar features, signet cells, pigmentation and numerous Rosenthal fibers arising in the fourth ventricle of a 35-year-old woman. The tumor was composed of cells with cytoplasmic vacuoles, signet cells and clear cells. The clear cells were compactly arranged resembling oligodendroglioma. Pseudovascular and ependymal rosettes were observed only in focal areas. Additionally, some tumor cells contained brown cytoplasmic pigment, which was histochemically compatible with lipofuscin and neuromelanin. On immunohistochemical examination, the tumor cells were positive for S100, glial fibrillary acidic protein and vimentin, and negative for synaptophysin, cytokeratin, neurofilament and HMB45. Epithelial membrane antigen staining showed dot-like and small vesicular reactivity. The case is presented to increase familiarity with these extraordinary variants of ependymoma.

Subependymomas of the lateral ventricle: tumor recurrence correlated with increased Ki-67 labeling index.

Subependymomas of the lateral ventricles are rare tumors. We present two patients with subependymomas of the lateral ventricle, who underwent gross total resection of the tumor via transcallosal approach. The patient, with increased Ki-67 labeling index had recurrence of tumor two years after the initial operation. We emphasize at the risk of recurrence which is probably correlated with Ki-67 labeling index.

Cystic papillary meningioma with subarachnoid dissemination: a case report and review of the literature.

Meningiomas usually present as benign tumors corresponding to WHO grade I. The development of the papillary variant of meningiomas with cyst formation in the central nervous system is extremely rare. We report a case of cystic papillary meningioma in a young female occurring in the lateral ventricle with invasion of brain parenchyma and dissemination of subarachnoid space. The tumor exhibits a marked peritumoral cyst, with contrast enhancement on magnetic resonance imaging (MRI) in accordance with type 2 of Zee's classification of cystic meningioma. Histologically, the tumor displays a classical perivascular pseudopapillary pattern with focal necrosis and subarachnoid space dissemination. Tumor cells are diffusely positive for epithelial membrane antigen (EMA) and vimentin, but lack immunoreactivity for cytokeratin (CK) and glial fibrillary acidic protein (GFAP). MIB-1 labeling is high, accounting for 5% of tumor focally. A diagnosis of primary intraventricular cystic papillary meningioma with subarachnoid space dissemination (WHO grade III) was made. To our knowledge, there is no report describing the radiological and histological characteristics of cystic papillary meningioma presenting in the lateral ventricle. In addition, the biological behavior and the clinical outcome of this tumor are also discussed.

In vivo proton magnetic resonance spectroscopy of intraventricular tumours of the brain.

The aim of this study was to assess the usefulness of proton MR spectroscopy in the diagnosis of intraventricular tumours. Fifty-two intraventricular tumours pertaining to 16 different tumour types were derived from our database. All cases had single-voxel proton MR spectroscopy performed at TE at both 30 and 136 ms at 1.5 T. The Mann-Whitney U test was used to search for the most discriminative datapoints each tumour type. Characteristic trends were found for some groups: high Glx and Ala in meningiomas (p < 0.001 and p < 0.01, respectively), high mobile lipids in metastasis (p < 0.001), high Cho in PNET (p < 0.001), high mI + Gly in ependymoma (p < 0.001), high NAC (p < 0.01) in the absence of the normal brain parenchyma pattern in colloid cysts, and high mI/Gly and Ala in central neurocytoma. Proton MR spectroscopy provides additional metabolic information that could be useful in the diagnosis of intraventricular brain tumors.