[A Surgical Case of Anaplastic Ependymoma Involving a Bridging Vein that Drained Directly into the Occipital Sinus].

INTRODUCTION: The draining veins of the brain stem and cerebellum commonly drain into the petrosal vein and sigmoid sinus, and often drain into the marginal sinus in the caudal part of the posterior fossa. Here, we report a rare case of anaplastic ependymoma involving a bridging vein that drained directly into the occipital sinus. CASE DESCRIPTION: A 6-year-old boy was admitted to our hospital with a 1-month history of nausea, headache, and dizziness. Magnetic resonance imaging(MRI)revealed a markedly enhanced fourth ventricular tumor and obstructive hydrocephalus. Surgical removal was performed via a midline suboccipital approach. When opening the dura, we observed a bridging vein that directly connected the brain stem and the tumor with the occipital sinus. Therefore, the Y-shaped dura mater incision was not inverted, and the tumor was totally removed while preserving the draining vein. After the operation, the patient's clinical course was uneventful. The pathological diagnosis was anaplastic ependymoma(WHO grade III). Subsequently, the patient received radiotherapy and was discharged without any neurological deficits 9 weeks after the operation. At 10 months after the initial surgery, the tumor recurred on the fourth ventricle floor. Thus, we performed a second surgical procedure and noted that the bridging vein had regressed. CONCLUSION: We report a rare draining vein that directly connected the brain stem to the occipital sinus. The tumor was removed without sacrificing this vein. Since the draining system of the posterior fossa is sometimes very complicated, we need to pay attention to it during the pre- and intra-operative periods.

Supratentorial extraventricular anaplastic ependymoma in an adult with repeated intratumoral hemorrhage.

We report the case of a 61-year-old man with supratentorial extraventricular anaplastic ependymoma who presented with repeated intratumoral hemorrhage. The patient was admitted with headache. Computed tomography and magnetic resonance imaging showed an enhancing mass with intratumoral hemorrhage in the right temporal lobe. Gross total resection was performed. The tumor was well demarcated from the brain tissue, and showed no continuity with the ventricular system. Histopathological examination revealed the features of anaplastic ependymoma. Therefore, additional radiation therapy and adjuvant chemotherapy were administered. Ten months later, the tumor recurred with hemorrhage in the spinal canal. This case showed rapid malignant progression and repeated intratumoral hemorrhage within a short period of time, both of which are characteristics of anaplastic ependymomas. Close observation of the central nervous system and adjuvant radiotherapy are mandatory, even if the ependymoma presents with repeated intratumoral hemorrhage.

Study of stem cell marker nestin and its correlation with vascular endothelial growth factor and microvascular density in ependymomas.

BACKGROUND: Ependymomas are relatively rare glial tumours, whose pathogenesis is not well elucidated. They are enigmatic tumours that show site-specific differences in their biological behaviour. Recent studies have hypothesized that ependymoma cancer stem cells (CSCs) are derived from radial glia and express stem cell markers such as nestin, which is associated with a poor prognosis. CSCs reside in 'vascular niches', where endothelial cells and molecular signals like vascular endothelial growth factor (VEGF) play an important role in their survival. Studies analysing VEGF expression in ependymomas showed that ependymal vascular proliferation is less sensitive to induction by VEGF, questioning the possible beneficial effect of anti-VEGF therapy in ependymomas. We aimed to study nestin and VEGF immunoexpression in ependymomas, correlate them with clinicopathological parameters and reveal a role for VEGF in ependymomas that extends beyond the context of tumour angiogenesis. METHODS: We analysed 126 cases of ependymomas of different grades and locations for nestin and VEGF immunoexpression. Endothelial cells were labelled with CD34. Vascular patterns and microvascular density was determined. RESULTS: Nestin and VEGF expression in tumour cells were more frequent in supratentorial tumours [89% (33/37) and 65% (24/37) respectively], and were associated with a significantly poor progression-free survival (PFS). VEGF expression did not reveal any correlation with necrosis or bizarre vascular patterns. CONCLUSIONS: Supratentorial location is an independent predictor of a poor PFS. Significant coexpression of nestin and VEGF suggests that latter possibly augments stem cell survival. Thus, anti-VEGF therapy may be a good option in future for nestin immunopositive ependymomas.

Tumor vessel biology in pediatric intracranial ependymoma.

OBJECT: This study aimed to characterize the pediatric intracranial ependymoma vasculature in terms of angiogenic activity and maturation status so as to provide indications for the applicability of vessel-targeted therapy in cases of pediatric intracranial ependymoma. METHODS: Tumor samples obtained in patients with ependymomas were immunohistochemically (double) stained for Ki 67/CD34, caspase 3a/CD34, vascular endothelial growth factor (VEGF)-A, -B, -C, -D, collagen Type IV, and smooth muscle actin to determine microvessel density, tumor and endothelial cell proliferation and apoptotic fraction, the relative expression of VEGF family members, and the coverage of the tumor endothelial cells by basal membrane and pericytes. Messenger RNA expression of angiopoietin-1 and -2 was analyzed by real-time reverse transcriptase polymerase chain reaction. These data were compared with those obtained in a glioblastoma series. RESULTS: Despite a low endothelial cell turnover, the microvessel density of ependymomas was similar to that of glioblastomas. In ependymomas the expression of VEGF-A was within the range of the variable expression in glioblastomas. The staining intensities of VEGF-B, -C, and -D in ependymomas were significantly lower (p < 0.001). The expression of angiopoietin-1 was higher in ependymomas than in glioblastomas (p = 0.03), whereas angiopoietin-2 expression was similar. The coverage of tumor endothelial cells with basal membrane and pericytes was more complete in ependymomas (p = 0.009 and p = 0.022, respectively). CONCLUSIONS: The ependymoma vasculature is relatively mature and has little angiogenic activity compared with malignant gliomas. Therefore, the window for vessel normalization as a therapeutic aim might be considered small. However, the status of the tumor vasculature may not be a reliable predictor of treatment effect. Therefore, possible benefits of antiangiogenic treatment cannot be excluded beforehand in patients with ependymomas.

Analysis of blood flow in a third ventricular ependymoma and an olfactory bulb meningioma by using perfusion computed tomography.

Brain perfusion computed tomography (CT) scanning was performed in a mongrel dog and a golden retriever that were diagnosed with third ventricular tumor and olfactory bulb tumor, respectively, by contrast-enhanced CT. The tumors were pathologically diagnosed as ependymoma and meningioma, respectively. Perfusion CT results revealed that the ependymoma in this study had a lower blood flow, higher blood volume, and greater transit time of blood than the adjacent brain tissue. Further, the meningioma in this study had a higher blood flow, higher blood volume, and greater transit time of blood than the adjacent brain tissue. Perfusion CT can potentially be used for the grading of brain tumors and narrowing differential diagnosis, provided the perfusion CT data of animals are accumulated.

Acute paraparesis from hemorrhagic spinal ependymoma: diagnostic dilemma and surgical management. Report of two cases and review of the literature.

Spinal ependymomas are a common type of primary spinal cord neoplasm that frequently occurs in the lumbar spine. The authors report on two patients who presented with acute neurological decline after hemorrhage into ependymomas of the filum terminale. Both were transferred to the authors' institution because of diagnostic uncertainty and a concern about possible intradural vascular abnormalities. Both patients underwent lumbar laminectomies for tumor resection. The pathological finding in each case was myxopapillary ependymoma. Both patients made a significant recovery and were ambulatory and continent at follow-up review. These cases illustrate the rare but clinically significant incidence of acute neurological decline caused by hemorrhagic cauda equina ependymomas, including the potential for delayed diagnosis and treatment.

Morphological analysis of vascular density in ependymomas.

Ependymomas generally show slow growth rate and are associated with a long clinical history. In some cases however the biology of these tumours is considered to be unpredictable on the basis of histologic criteria. Density of microvessels was shown to serve in various malignant neoplasms as a prognostic factor that correlates with increased risk of metastasis and overall free survival. Some data suggest that density of blood vessels may be of prognostic value also in patients with neuroepithelial tumours. The aim of this study was to determinate whether that observation can be applied to ependymomas. The materials included 51 ependymomas G2 and G3 according to the WHO classification. Vasculature was visualized immunohistochemically in paraffin-embedded sections of tumour samples with CD31 and FVIII antibody. Density of blood vessels was calculated using a computed image analyzing system. The data were statistically evaluated. The density of blood vessels in anaplastic (WHO G3) ependymomas was shown to be significantly higher than that in WHO G2 type of the tumour, while there was no statistical difference between subtypes of WHO G2 ependymomas. The results suggest a connection between density of vasculature and the degree of histological malignancy in gliomas of ependymal derivation.

Three-dimensional (3D) reconstruction and quantitative analysis of the microvasculature in medulloblastoma and ependymoma subtypes.

In the World Health Organisation (WHO) classification of tumours of the nervous system, four main histopathological subtypes of medulloblastomas (classic medulloblastoma, desmoplastic medulloblastoma, medulloblastoma with extensive nodularity and advanced neuronal differentiation and large cell/anaplastic medulloblastoma) as well as of ependymal tumours (low-grade ependymoma, anaplastic ependymoma, myxopapillary ependymoma and subependymoma) are recognised. Under the hypothesis that the microvascular architecture of tumours is a reflection of the histopathological subtype, we performed three-dimensional reconstructions of the microvasculature in these subtypes of medulloblastomas and ependymal tumours using computerised image analysis. In addition, we quantitatively assessed three microvascular parameters (number, area, perimeter) in these neoplasms. Three-dimensional reconstructions showed a dense pattern of irregular vessels in classic and large cell medulloblastoma. In desmoplastic medulloblastoma and medulloblastoma with extensive nodularity, the vessels were more unevenly distributed and organised around the nodular areas. Classic medulloblastoma and large cell medulloblastoma had on average the largest vessel area and perimeter. The highest number of vessels was seen in classic medulloblastoma and medulloblastoma with extensive nodularity. Three-dimensional analysis of ependymal tumours showed that low-grade ependymoma had larger but fewer vessels compared to anaplastic ependymoma, while myxopapillary ependymoma had a complex, heterogeneous pattern of vessels and subependymoma few but regular vessels. In ependymal tumours, the highest values for vessel number, vessel area and vessel perimeter were found in anaplastic ependymoma and the lowest values in subependymoma. We conclude that our three-dimensional reconstructions shed unprecedented light on the tumour vasculature in medulloblastomas and ependymal tumours and expect that such reconstructions are helpful tools for further studies on tumour angiogenesis.

Cyclooxygenase-2 (cox-2) expression and angiogenesis in intracranial ependymomas.

AIM: Cyclooxygenase-2 (Cox-2), the inducible key enzyme in the biosynthesis of prostaglandins, appears to play a role in the regulation of progression, invasiveness and angiogenesis of various neoplasms including some glial tumors. Little is known about the role of Cox-2 in angiogenesis and proliferation of ependymomas. We studied Cox-2 expression, Ki-67 labeling index (Ki-67 LI) and microvessel density (MVD) in 30 intracranial ependymomas and analyzed the relationship among these parameters to evaluate their importance in the tumor biology of ependymomas. RESULTS: The mean Ki-67 LI for all tumors ranged from 1 - 50% (mean 9%). Statistically significant difference was present for Ki-67 LI between ependymomas (grade II, WHO) and anaplastic ependymomas (grade III, WHO) (p < 0.001) (mean Ki-67 LI for ependymoma, 2.8%, for anaplastic ependymomas, 15.6%). Anaplastic ependymomas did not demonstrate a greater vascularization than ependymomas, and the MVD values were 84.5 +/- 39.7 for ependymomas, and 90.6 +/- 61.4 for anaplastic ependymomas. Cox-2 immunohistochemical expression was observed in 19 tumors (63%). Although Cox-2 expression was slightly higher in anaplastic ependymomas, it was not statistically significant. No correlation was found between Cox-2 expression and MVD and Ki-67 LI. CONCLUSION: Similar to morphologic and prognostic heterogeneity in ependymomas, Cox-2 expression, MVD and Ki-67 LI also show a great variability. Other factors may be more important for the proliferation and angiogenesis of ependymomas.

alpha(v)beta(3) Integrin in central nervous system tumors.

alpha(v)beta(3) Is an integrin specifically expressed in endothelial cells of newly forming blood vessels. Integrin-mediated angiogenesis is hypothesized to play a central role in the development and the progression of central nervous system neoplasms. Accordingly, it is considered a potential target for antiangiogenic therapy. In the current study, we compare the expression of alpha(v)beta(3) in ependymomas, oligodendrogliomas, pilocytic astrocytomas, medulloblastomas, and vestibular schwannomas (acoustic neuromas). Samples of 5 tumors of each of the 5 tumor types were harvested surgically and frozen. After the pathological diagnosis was confirmed, immunohistochemistry was performed using an anti- alpha(v)beta(3) monoclonal antibody (LM609). The expression of alpha(v)beta(3) was assessed using a 4-tiered (0-3) grading scheme reflecting the percentage of positively staining vessels. All vestibular schwannomas demonstrated strong (grade 3) alpha(v)beta(3) expression. The expression was uniformly prominent in Antoni B regions of the tumors. Of 5 ependymomas, 4 demonstrated uniformly strong alpha(v)beta(3). Oligodendrogliomas, medulloblastomas, and pilocytic astrocytomas demonstrated more variable alpha(v)beta(3). alpha(v)beta(3) may contribute significantly to angiogenesis in vestibular schwannomas and ependymomas. Despite the high vascular density of oligodendrogliomas, pilocytic astrocytomas, and medulloblastomas, these tumors had variable moderate alpha(v)beta(3) expression. This discrepancy suggests temporal and/or regional variability in the angiogenesis in these types of tumor. This study provides the first demonstration of alpha(v)beta(3) expression in vestibular schwannomas, medulloblastomas, and pilocytic astrocytomas.

Spontaneous hemorrhage of a spinal ependymoma: a rare cause of acute cauda equina syndrome: a case report.

STUDY DESIGN: An interesting case of spontaneous bleeding from an ependymoma of the filum terminale is presented. OBJECTIVES: To document a rare case of rapid neurologic deterioration as a consequence of spinal tumoral hemorrhage and to highlight important issues regarding tumor histologic subtype and the impact of anticoagulation that have emerged from an illuminating review of the literature. SUMMARY OF BACKGROUND DATA: To our knowledge, there have been only 8 reported cases of hemorrhage from an ependymoma of the filum terminale or conus medullaris causing acute cauda equina syndrome. Bleeding is described in the pathology texts as being a consequence of the vascular architecture of the myxopapillary subtype and so postulated to be more common in this group. Anticoagulation is recognized to increase the frequency of tumoral bleeding, but no studies report its effect of severity of clinical presentation. METHODS: We report the case of a 57-year-old woman who developed nontraumatic acute cauda equina syndrome, including sphincter compromise. She underwent a lumbosacral laminectomy for evacuation of a hematoma, at which stage a filum terminale ependymoma was excised. Histopathologic analysis demonstrated it to be of a nonmyxopapillary subtype. RESULTS: The patient demonstrated gradual improvement of the neurologic deficit. At 12-month follow-up, her saddle area sensory deficit has resolved, her right lower limb is much stronger allowing her to walk long distances, and she is successfully performing intermittent self-catheterization of her bladder. CONCLUSIONS: The possibility of an underlying tumor should always be borne in mind so that adequate preoperative planning can be undertaken. The presence of the myxopapillary subtype should not prevent a clinician from excluding other reasons for hemorrhage, and counseling when reinstituting anticoagulation must include warning against a worse prognosis from any future hemorrhage.

Brain surface ependymoma with repeated episodes of intratumoral hemorrhage--case report.

A 70-year-old woman presented with a rare brain surface ependymoma with repeated intratumoral hemorrhage. She was admitted with progressive dementia. Two years earlier, a diagnosis of subcortical hematoma in the right frontal lobe had been made following a fall. On admission, magnetic resonance imaging showed a huge right frontal mass lesion with multiple hemorrhagic cysts. She underwent gross total resection. The tumor was located on the surface of the frontal lobe, and was sharply demarcated from the surrounding brain tissue with no attachment to the ventricular wall. The histological features were consistent with an ependymoma forming perivascular pseudorosettes. Immunohistochemistry showed positive staining for glial fibrillary acidic protein. Electron microscopy showed microvilli and zonula adherens. This case demonstrates the natural course of malignant progression of ectopic ependymomas. Ependymoma should be included in the differential diagnosis of tumors associated with repeated subcortical hematomas, even if located on the brain surface and distant from ventricles.

Expression of vascular endothelial growth factor and its receptors in the anaplastic progression of astrocytoma, oligodendroglioma, and ependymoma.

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible angiogenic factor, which is known to be upregulated in most cases of glioblastoma multiforme (GBM). The expression of VEGF and its receptors in ependymomas, oligodendrogliomas, and particularly the expression during anaplastic progression of these three types of gliomas has not been studied extensively. Fifty-six gliomas, consisting of 10 ependymomas, 12 oligodendrogliomas, 3 anaplastic oligodendrogliomas, 6 astrocytomas grade II, 5 anaplastic astrocytomas, and 20 glioblastoma multiformes, were investigated for VEGF and receptor expression using in situ hybridization (ISH) and reverse transcription polymerase chain reaction (RT-PCR). Results showed that VEGF was moderately to strongly expressed in 8 of 10 ependymomas and in all anaplastic oligodendrogliomas and glioblastoma multiforme cases. These tumors displayed similar degrees of extensive necrosis and vascular proliferation, with VEGF expression consistently seen in tumor cells around necrotic areas. The VEGF expression, although present at a lower level, also was shown in 4 of 12 oligodendrogliomas, in 3 of 6 astrocytomas grade II, and in 2 of 5 anaplastic astrocytomas, with a regional rather than diffuse pattern of positive result. The findings from the in situ hybridization study correlated with the expression index, as determined by reverse transcription polymerase chain reaction. Expression of VEGF was correlated significantly with vascular proliferation (p < 10(-5)) and necrosis (p < 10(-5)), as well as with microvessel density (p = 0.002, rs = 0.41). The VEGF receptors, kinase domain region (KDR) and Fms-like-tyrosine kinase (Flt-1), also were upregulated in the tumor vasculature of glioblastoma multiforme, anaplastic oligodendrogliomas, and ependymomas with necrosis, whereas the astrocytomas grade II, anaplastic astrocytomas, and oligodendroglioma tumors tended to express a weak to nondetectable signal. Anaplastic progression in all three types of gliomas is heralded by the occurrence of small zones of VEGF-expressing cells and early vascular proliferation, followed by an accelerated phase of angiogenesis closely associated with VEGF induction around areas of necrosis and with the expression of VEGF receptors in the tumor vasculature.

The use of hyperventilation in contrast-enhanced MR of brain tumors.

Angiographic studies have demonstrated improved visibility of glial tumors after hyperventilation. The present study was undertaken to determine whether hyperventilation would change the MR enhancement characteristics of various glial tumors. Eighteen patients were studied twice: once with standard contrast-enhanced MR imaging and again with standard imaging plus hyperventilation. After hyperventilation, six low-grade astrocytomas showed no change and three showed a small decrease in relative enhancement (<10%). The ependymomas showed a 10% to 13% increase in the degree of enhancement, but no change in the area of enhancement. All the anaplastic astrocytomas showed an increase in the degree of enhancement (mean, 38%). Three of the anaplastic astrocytomas showed new foci of enhancement that were not seen on the nonhyperventilation study. Hyperventilation appears to be an inexpensive and safe method for increasing the conspicuity of abnormal areas of the blood-brain barrier.

A method for quantitative measurement of cerebral vascular permeability using X-ray CT and iodinated contrast medium.

Cerebral vascular permeability is an important consideration in treatment for intracranial tumours. We have developed a new method to measure the cerebral vascular permeability quantitatively using a conventional X-ray CT scanner and iodinated contrast medium. We have already applied our method in 50 cases of intracranial tumour and 5 cases, which establish the methodology, are demonstrated. Dynamic CT scanning of a section including the tumour and the superior sagittal sinus was performed over 40 min after bolus injection of contrast medium, and 25 images were acquired. Our theoretical model of contrast enhancement was applied to analyse time-density curves, and the following parameters were obtained: Ki (inward flux constant), Kb (backward flux constant), Vp (vascular plasma volume), and lambda (extracellular fluid space volume). Furthermore, functional maps were generated from parameters for each pixel. Changes in intra-arterial iodine concentration, required in our model, were measured from CT numbers in the superior sagittal sinus. We have investigated several aspects of our method. Histological findings in surgical specimens of intracranial tumours agreed well with the parameters obtained by our method. Vp was verified quantitatively by single photon emission computed tomography. Our method was shown to be reproducible. These results show that the parameters are useful for assessing tumours and in planning chemotherapy. Our method, which employs no special equipment, is readily available at any institution.

Local blood flow changes in malignant brain tumours under induced hypertension.

Changes in tumour blood flow under an induced hypertensive state were examined in malignant brain tumours to know if the precondition for the effectiveness of induced hypertensive chemotherapy--relative increase in tumour blood flow--are fulfilled. Tumour blood flow was measured under both a resting and an induced hypertensive state in 12 patients with various malignant brain tumours (6 gliomas, 6 metastatic brain tumours) using xenon-enhanced computed tomography. The blood pressure was elevated 40% above the systemic blood pressure of the resting state by the infusion of angiotensin II. Tumour blood flow increased 30% on average above the normal brain tissue blood flow after the induction of an induced hypertensive state (p < 0.05). The tumour blood flow increased in 11 cases of malignant tumours, but decreased in one case with massive brain oedema after induced hypertension. The increase in blood flow was higher in hypervascular tumours and less in hypovascular tumours. Therefore, induced hypertensive chemotherapy probably will be more effective in hypervascular malignant brain tumours with small mass effects.

Hypertrophic retromedullary venous drainage in spinal cord tumours: MR visualisation.

Pseudoangiomatous dilatation of retromedullary veins at myelography was noted in three cases of intramedullary spinal cord tumours. This concerned two haemangioblastomas at levels Th8 and L1, respectively, and an ependymoma of the conus terminalis. MRI accurately demonstrated the tumoural mass, together with the enlarged and tortuous draining perimedullary veins. In patients with dilated vascular shadows on myelography, MRI should be performed before medullary angiography to differentiate between spinal vascular malformations and intramedullary tumours with enlarged draining veins.

[Electron microscopic observations of blood vessels in ependymoma].

The findings of an ultrastructural study of the blood vessels and their surrounding structures in ependymoma are demonstrated. Six surgically removed cases of ependymoma are investigated. The lumen of the blood vessels, especially in vascular rosettes is often wider than those of normal brain capillaries. The endothelial cells are structurally varied, but sometimes attenuated in many areas. Also, they often have several fenestrations. Moreover, they have increased pinocytotic vesicles and filaments, and contain occasional Weibel-Palade bodies, multivesicular bodies and other cytoplasmic organelles. The perivascular space is often wide, especially in intraspinal ependymoma, and filled with multiple layers of basal laminae permeated by electron, dense fluids. There are also collagenous fibers and Luse bodies. Basal lamina covering tumor cell surfaces is more distinct than other basal laminae. The tumor cells facing the blood vessel interestingly show structures similar to those of astrocytic vascular feet. The fenestration in the endothelial cells probably has an important role in the increased vascular permeability of ependymoma.