[Hypervascular Tumors such as Hemangioblastoma].

Hemangioblastomas are richly vascular tumors. Therefore, visualizing the vascular anatomy of their feeders and drainers is important for planning surgical excision. Preoperative three-dimensional computer graphic(3DCG)images are useful for determining the number, location, and course of their feeders and drainers.

Structural and microvascular changes of the peripapillary retinal nerve fiber layer in Von Hippel-Lindau disease: an OCT and OCT angiography study.

Von Hippel-Lindau (VHL) disease is an autosomal dominant genetic disease caused by VHL gene mutation. Retinal hemangioblastomas (RH) are vascularized tumors and represent the main ocular manifestation of the disease. Histopathologically, RH are composed of capillary vessels and stromal cells, the neoplastic population of the lesion. The origin of these stromal cells remains controversial, even if they are hypothesized to be glial cells. The aim of the present study was to investigate neuronal and microvascular changes of the peripapillary retinal nerve fiber layer, in which glial cells, neurons and capillaries (the radial peripapillary capillary plexus) interact. VHL patients with or without peripheral RH were enrolled and compared to healthy controls. Mean peripapillary retinal nerve fiber layer (pRNFL) thickness was measured by means of optical coherence tomography (OCT). The following vascular parameters of the radial peripapillary capillary plexus were quantified using OCT angiography: Vessel Area Density,Vessel Length Fraction, Vessel Diameter Index and Fractal Dimension. One hundred and nine eyes of 61 patients, and 56 eyes of 28 controls were consecutively studied. Mean pRNFL was significantly thinner in VHL eyes without RH versus eyes with RH and controls. Mean pRNFL thickness did not differ between VHL eyes with RH and controls. All OCTA vascular parameters were reduced in VHL eyes with or without RH versus controls, with significative difference for Vessel Diameter Index. The same OCTA parameters did not significantly differ between VHL eyes with or without RH. In VHL eyes without RH, pRNFL thinning may be the consequence of impaired perfusion of the radial peripapillary capillary plexus, while the increase of pRNFL thickness in VHL eyes with RH may depend on possible activation and proliferation of the other RNFL resident cells, the glial cells.

Hemangioblastoma of the Cerebellopontine Angle Evaluated with Pseudocontinuous Arterial Spin Labeling.

Hemangioblastomas of the cerebellopontine angle (CPA) that emerge extra-axially from the peripheral nervous system are extremely rare. We report a case of hemangioblastoma of the CPA evaluated by pseudocontinuous arterial spin labeling (pCASL). The high rate of tumor blood flow determined using pCASL provided additional useful information for the differential diagnosis of the CPA tumors in this patient.

Insights into retinal hemangioblastoma using ultra widefield imaging.

Purpose: Retinal hemangioblastomas (RHs) are characteristic of von Hippel-Lindau (VHL) disease. Early diagnosis of retinal lesions may aid in systemic diagnosis. Early identification of VHL is life-saving and also prevents vision loss. Fundus fluorescein angiography (FFA) is a useful tool in the diagnosis and management of RHs. The aim of this study is to report FFA features of RH using ultra-widefield (UWF) imaging. Methods: A retrospective cross-sectional study of consecutive patients of RH who underwent UWF FFA at a tertiary eye care center. Images were analyzed and assessed by authors. The main outcome measures were (a) the number and size of RH in each eye and (b) vascular characteristics of the retina. UWF-FFA characteristics in each eye were tabulated. The number of clock hours involved by these characteristics and their correlation with the number and size of RH were analyzed. Results: The study evaluated 24 eyes of 13 patients. The mean age was 28.4 years. The median number of RHs in an eye was 3.5 (range 1-16), and the size of RHs varied from 0.1 to 4 disc diameters. Novel UWF-FFA findings noted in this study were the presence of abnormal capillary network in 22 of 24 eyes (91.7%), capillary leakage in 15 of 24 eyes (62.5%), and capillary telangiectasia in 7 of 24 eyes (29.2%). In addition, feeder arterioles and venules showed bulbous projections in 8 of 24 eyes (33.3%). Conclusion: The UWF-FFA characteristics of RH, which have not been described before, were identified. These add to our understanding of the pathogenesis of the disease and may pave the way for future therapeutic targets.

Posterior Petrosal Transotic Approach for Cerebellopontine Angle Hemangioblastoma: Technical Case Report.

BACKGROUND AND IMPORTANCE: Although posterior petrosal approaches are utilized less frequently in many practices today, they continue to provide distinct surgical advantages in carefully selected cases. Here, we report a case of a recurrent cerebellopontine angle (CPA) hemangioblastoma that had failed a prior, more conservative, surgical approach. We provide cadaveric dissections of variations of posterior petrosal approaches to illustrate the advantages of the selected approach. CLINICAL PRESENTATION: A 70-yr-old female presented with a growing left CPA hemangioblastoma. The lesion had undergone a prior subtotal resection from a retrosigmoid approach and subsequent adjuvant radiation treatment. The patient had worsening left facial strength, progressive balance difficulty, and absent left auditory function. Preoperative angiogram demonstrated arterial blood supply from the left anterior inferior cerebellar artery (AICA) that was deemed unsafe for embolization due to significant arteriovenous shunting. A posterior petrosal transotic approach was performed in order to optimize the working angle to the anterior brainstem and afford the ability to occlude the vascular supply from AICA prior to surgical resection of the lesion. CONCLUSION: The posterior petrosal transotic approach offers an improved surgical working angle to the anterior brainstem compared to the translabyrinthine approach. This advantage can be particularly important with vascular tumors that receive blood supply anteriorly, as in this case from AICA, and can improve the safety of the resection.

Use of Intraoperative Indocyanine Green Angiography for Feeder Vessel Ligation and En Bloc Resection of Intramedullary Hemangioblastoma.

BACKGROUND: As vascular tumors, intramedullary hemangioblastomas are associated with significant intraoperative blood loss, making them particularly challenging clinical entities. The use of intraoperative indocyanine green or other fluorescent dyes has previously been described to avoid breaching the tumor capsule, but improved surgical outcomes may result from identifying and ligating the feeder arteries and arterialized draining veins. OBJECTIVE: To describe the use of combined preoperative angiography and intraoperative indocyanine green use for the identification of feeder arteries and arterialized draining veins to decrease blood loss in the resection of intramedullary hemangioblastomas. METHODS: A patient with cervical myelopathy secondary to a large C3 hemangioblastoma and cervicothoracic syrinx underwent a C2-3 laminoplasty with resection of the lesion. To reduce intraoperative blood loss and facilitate safe lesion resection, the vascular architecture of the lesion was defined via preoperative digital subtraction angiography and intraoperative use of indocyanine green. The latter permitted ligation of the major and minor feeding arteries and arterialized veins prior to tumor breach, allowing for facile en bloc resection of the lesion. RESULTS: The lesion was resected en bloc with minimal blood loss (approximately 100 mL) and without intraoperative neuromonitoring signal changes. The patient remained at neurological baseline throughout their stay. CONCLUSION: We present a written and media illustration of a technique for intraoperative indocyanine green use in the en bloc resection of intramedullary hemangioblastoma.

Added Value of Arterial Spin-Labeling MR Imaging for the Differentiation of Cerebellar Hemangioblastoma from Metastasis.

BACKGROUND AND PURPOSE: In adults with only cerebellar masses, hemangioblastoma and metastasis are the 2 most important differential diagnoses. Our aim was to investigate the added value of arterial spin-labeling MR imaging for differentiating hemangioblastoma from metastasis in patients with only cerebellar masses. MATERIALS AND METHODS: This retrospective study included a homogeneous cohort comprising patients with only cerebellar masses, including 16 hemangioblastomas and 14 metastases. All patients underwent enhanced MR imaging, including arterial spin-labeling. First, the presence or absence of a hyperperfused mass was determined. Next, in the hyperperfused mass, relative tumor blood flow (mean blood flow in the tumor divided by blood flow measured in normal-appearing cerebellar tissue) and the size ratio (size in the arterial spin-labeling images divided by size in the postcontrast T1WI) were measured. To validate the arterial spin-labeling findings, 2 observers independently evaluated the conventional MR images and the combined set of arterial spin-labeling images. RESULTS: All patients with hemangioblastomas and half of the patients with metastases presented with a hyperperfused mass (P < .001). The size ratio and relative tumor blood flow were significantly larger for hemangioblastomas than for metastases (P < .001 and P = .039, respectively). The size ratio revealed excellent diagnostic power (area under the curve = 0.991), and the relative tumor blood flow demonstrated moderate diagnostic power (area under the curve = 0.777). The diagnostic accuracy of both observers was significantly improved after the addition of arterial spin-labeling; the area under the curve improved from 0.574 to 0.969 (P < .001) for observer 2 and from 0.683 to 1 (P < .001) for observer 2. CONCLUSIONS: Arterial spin-labeling imaging can aid in distinguishing hemangioblastoma from metastasis in patients with only cerebellar masses.

Endothelial cells by inactivation of VHL gene direct angiogenesis, not vasculogenesis via Twist1 accumulation associated with hemangioblastoma neovascularization.

Inactivation of the VHL tumour suppressor gene is a highly frequent genetic event in the carcinogenesis of central nervous system-(CNS) hemangioblastomas (HBs). The patterning of the similar embryonic vasculogenesis is an increasing concern in HB-neovascularization, and the classic vascular endothelial growth factor (VEGF)-mediated angiogenesis driven by VHL loss-of-function from human endothelium have been questioned. With this regard, we identify a distinct, VHL silencing-driven mechanism in which human vascular endothelial cells by means of increasing cell proliferation and decreasing cell apoptosis, is concomitant with facilitating accumulation of Twist1 protein in vascular endothelial cells in vitro. Importantly, this molecular mechanism is also pinpointed in CNS-HBs, and associated with the process of HB-neovascularization. In contrast with recent studies of HB-neovascularization, these modified cells did not endow with the typical features of vasculogenesis, indicating that this is a common angiogenesis implementing the formation of the vascular network. Taken together, these findings suggest that vasculogenesis and angiogenesis may constitute complementary mechanisms for HB-neovascularization, and could provide a rational recognition of single anti-angiogenic intervention including targeting to the Twist1 signalling for HBs.

Neuroprotective effects respond to cerebral ischemia without susceptibility to HB-tumorigenesis in VHL heterozygous knockout mice.

The von Hippel-Lindau (VHL) tumor suppressor gene plays a prominent role in the development of hemangioblastomas (HBs) within specific regions of the human' central nervous system (CNS). Alterations in VHL gene are rarely observed in the more common features of human VHL-related tumors in animal models, and VHL heterozygous knockout (VHL+/-) mice do not develop HBs. We tested whether VHL heterozygous knockout mice exhibited genetic predisposition to the development of HBs and conferred a selective advantage involving growth of blood vessels to its carrier. No differences were observed between wild-type and VHL+/- mice in development ad reproduction. The heterozygous VHL+/- mice did not develop higher genetic susceptibility to CNS-HBs over their lifetime. Furthermore, this recessive VHL gene heterozygosity is relatively stable. Interestingly, we found these heterozygous VHL+/- mice gained an advantage conferring to angiogenic ability in a particular environment, compared with wild-type mice. The heterozygous VHL+/- mice obviously enhanced hypoxia inducible factor-1 (HIF)-dependent and Twist1 angiogenic mechanism in response to acute cerebral ischemia, resulting in decreased cerebral tissue damage and neuroprotective response through neovascularization. Our findings provide evidence of partial loss function of VHL as a novel precise therapeutic target in acute cerebral ischemia.

Cerebellar hemangioblastoma with perivascular pseudorosette formation and glial differentiation: A case report.

Hemangioblastoma is a well-circumscribed, highly vascular, lipid-rich and low-grade tumor of uncertain histogenesis. Its histopathological features have been well established. Herein, we present a case of cerebellar hemangioblastoma in a 43-year-old woman. Histologically, the tumor was predominantly composed of cellular areas showing eosinophilic or vacuolated stromal cells arranged in nests and sheets. Focally, conventional reticular areas could be seen. Additionally, in some areas, the stromal cells were arranged radially around blood vessels, exhibiting perivascular pseudorosette structures, which were similar mostly to those of ependymomas. Immunohistochemically, the stromal cells markedly showed diffused staining for Vimentin, S-100, CD56, NSE, inhibin-a, podoplanin, alpha-Thalassemia/mental retardation syndrome X and carbonic anhydrase IX, and were negative for cytokeratin, epithelial membrane antigen, oligodendrocyte transcription factor 2, neuronal nuclear antigen, synaptophysin, isocitrate dehydrogenase 1 (R132H), P53 and CD34. Interestingly, the reticular and cellular areas either showed no or individual scattering of the GFAP-positive cells, respectively, while, the perivascular pseudorosette areas strongly and diffusely expressed GFAP. Nuclear mitosis and necrosis were not observed. The MIB-1 antibody labeling index was especially low (about 3%). Based on these findings, the patient was diagnosed with cerebellar hemangioblastoma. In the present case, we documented a distinctive histological appearance of perivascular pseudorosettes in hemangioblastoma and provided the evidence for stromal cells with glial differentiation.

Usefulness of high-resolution 3D multifusion medical imaging for preoperative planning in patients with posterior fossa hemangioblastoma: technical note.

Successful resection of hemangioblastoma depends on preoperative assessment of the precise locations of feeding arteries and draining veins. Simultaneous 3D visualization of feeding arteries, draining veins, and surrounding structures is needed. The present study evaluated the usefulness of high-resolution 3D multifusion medical imaging (hr-3DMMI) for preoperative planning of hemangioblastoma. The hr-3DMMI combined MRI, MR angiography, thin-slice CT, and 3D rotated angiography. Surface rendering was mainly used for the creation of hr-3DMMI using multiple thresholds to create 3D models, and processing took approximately 3-5 hours. This hr-3DMMI technique was used in 5 patients for preoperative planning and the imaging findings were compared with the operative findings. Hr-3DMMI could simulate the whole 3D tumor as a unique sphere and show the precise penetration points of both feeding arteries and draining veins with the same spatial relationships as the original tumor. All feeding arteries and draining veins were found intraoperatively at the same position as estimated preoperatively, and were occluded as planned preoperatively. This hr-3DMMI technique could demonstrate the precise locations of feeding arteries and draining veins preoperatively and estimate the appropriate route for resection of the tumor. Hr-3DMMI is expected to be a very useful support tool for surgery of hemangioblastoma.

CD41 and CD45 expression marks the angioformative initiation of neovascularisation in human haemangioblastoma.

The initiation and formation of haemangioblastoma (HB) neovascularisation remain unknown, with concomitant controversy on its cytological origin. We detected HB-derived specific haematopoietic progenitors identified by surface expression of CD41 and CD45, which are similar to human embryonic vasculogenesis. CD41/CD45 cells expressed mesodermal markers, including SCL, Flk1 and c-kit. CD41 also seemed to appear before CD45 on haematopoietic progenitors. In vitro analysis showed that the CD41(+)/CD45 subpopulation gave rise to occasional primitive erythroid activity and endothelial marker expression. Meanwhile, kinetic investigation of the CD41(+)/CD45(+) subpopulation showed that some molecules, including SCL, Flk1 and c-kit, were involved in vascular formation. The CD45(+)/c-kit(+) population that lacked primitive haematopoiesis came from CD41(+) cells. Acquisition of CD45 expression by the haematopoietic progenitors was associated with advanced differentiation towards the vascular cell lineage. Taken together, the present data suggested that CD41 and CD45 expression marked the onset of HB neovascularisation and the stepwise development of the angioformative period. Our findings provide new insights into the mechanisms of HB neovascularisation and the underlying therapeutic targets of anti-vascular treatment.

Visualization of vascular structure of spinal hemangioblastoma using intraoperative indocyanine green videoangiography and temporary feeder occlusion.

BACKGROUND AND PURPOSE: To more safely resect pathological lesions during spinal vascular lesion surgery, it is most important to understand local abnormal hemodynamics in detail. New devices or techniques that make out intraoperative local hemodynamics have been awaited. To introduce a resourceful method, we present a case of spinal hemangioblastoma for which temporary arterial occlusion during near-infrared intraoperative indocyanine green (ICG) videoangiography gives useful assessment of the main and minor feeders easily. METHODS: A 36-year-old female suffered progressive paresthesia of both lower extremities for 12 months and gait disturbance for 2 weeks. A neurological examination revealed T10 myelopathy. Magnetic resonance imaging (MRI) of the thoracic spine showed an intramedullary tumor at the T8 level and severe spinal cord edema with a flow void in the extended dorsal spinal veins. Spinal angiography showed a hemangioblastoma at the T8 level, with two main feeders and minor feeders. RESULTS: She underwent total resection of the tumor by a posterior approach. During the intraoperative ICG videoangiography, temporary arterial occlusion of the two main feeders and FLOW(®)800 analysis enabled clear understanding of the vasculature, especially of the two minor feeders. At the 9-month follow-up, her neurological manifestation was partially resolved, and post-operative MRI showed total removal of the tumor and disappearance of the spinal cord edema. CONCLUSIONS: Temporary clipping of the main feeders during intraoperative ICG videoangiography is very useful for easily determining the minor feeding arteries, and helpful for maintaining normal perfusion of the spinal cord in spinal hemangioblastoma surgery. Furthermore, the FLOW 800 analysis, especially the false color-coded variation, increased our understanding of the hemodynamics.

Tumor derived vasculogenesis in von Hippel-Lindau disease-associated tumors.

von Hippel-Lindau disease (VHL) patients develop highly vascular tumors, including central nervous system hemangioblastomas. It has been hypothesized that the vascular nature of these tumors is the product of reactive angiogenesis. However, recent data indicate that VHL-associated hemangioblastoma neoplastic cells originate from embryologically-arrested hemangioblasts capable of blood and endothelial cell differentiation. To determine the origin of tumor vasculature in VHL-associated hemangioblastomas, we analyzed the vascular elements in tumors from VHL patients. We demonstrate that isolated vascular structures and blood vessels within VHL-associated hemangioblastomas are a result of tumor-derived vasculogenesis. Further, similar to hemangioblastomas, we demonstrate that other VHL-associated lesions possess vascular tissue of tumor origin and that tumor-derived endothelial cells emerge within implanted VHL deficient UMRC6 RCC murine xenografts. These findings further establish the embryologic, developmentally arrested, hemangioblast as the tumor cell of origin for VHL-associated hemangioblastomas and indicate that it is also the progenitor cell for other VHL-associated tumors.

Usefulness of tumor blood flow imaging by intraoperative indocyanine green videoangiography in hemangioblastoma surgery.

OBJECTIVE: Hemangioblastomas remain a surgical challenge because of their arteriovenous malformation-like character. Recently, indocyanine green (ICG) videoangiography has been applied to neurosurgical vascular surgery. The aim of this study was to evaluate the usefulness of tumor blood flow imaging by intraoperative ICG videoangiography in surgery for hemangioblastomas. METHODS: Twenty intraoperative ICG videoangiography procedures were performed in 12 patients with hemangioblastomas. Seven lesions were located in the cerebellum, two lesions were in the medulla oblongata, and three lesions were in the spinal cord. RESULTS: Ten procedures were performed before or during dissection, and 10 procedures were performed after tumor resection. ICG videoangiography could provide dynamic images of blood flow in the tumor and its related vessels under surgical view. Interpretation of these dynamic images of tumor blood flow was useful for discrimination of transit feeders (feeders en passage) and also for estimation of unexposed feeders covered with brain parenchyma. Postresection ICG videoangiography could confirm complete tumor resection and normalized blood flow in surrounding vessels. CONCLUSIONS: In surgery for hemangioblastomas, careful interpretation of dynamic ICG images can provide useful information on transit feeders and unexposed hidden vessels that cannot be directly visualized by ICG.

Use of near-infrared indocyanine videoangiography and Flow 800 in the resectioning of a spinal cord haemangioblastoma.

Haemangioblastomas are hypervascularized tumours. Their surgical management requires a complete resectioning and a prompt handling of the vascular inlets and outlets. The use of intraoperative indocyanine green video angiography (ICG-VAG) depicts the precise vascular pattern for the surgeon. Its use is safe and easy, and the procedure can be repeated during the operation. Here we present a case of spinal haemangioblastoma treated with the aid of intraoperative ICG-VAG and the Flow 800 software. The use of the Flow 800 allowed the surgeon to detect, at a glance, minimal changes in the vascular supply during the dissection. The colour-coded images generated by the Flow 800 increase the ICG-CAG sensitivity, improving the capability to detect changes in vascular patterns.

Intra-extradural dumbbell-shaped hemangioblastoma manifesting as subarachnoid hemorrhage in the cauda equina.

A 56-year-old man presented with a rare intra-extradural dumbbell-shaped hemangioblastoma in the lumbar spine associated with von Hippel-Lindau (VHL) disease manifesting as subarachnoid hemorrhage. The tumor, which was exiting at the right L2-3 intervertebral foramen, was removed successfully by total facetectomy and posterior spinal fusion at the L2-3 segment. Nine years later, a recurrent tumor due to VHL was also totally removed with minimal neurological complications. Accurate diagnosis of this vascular-rich lesion is essential for developing an adequate surgical strategy. The dumbbell-shaped tumor requires total facetectomy and spinal reconstruction, and care should be taken to preserve the entire nerve root origin by only identifying the affected nerve fascicles at the origin, if possible. Postoperative adhesion must be minimized for second surgery in patients with genetic disease such as VHL, who are likely to suffer recurrence.

Cerebellar hemangioblastoma supplied by persistent hypoglossal artery.

The authors report a unique case of an intramedullary cerebellar hemangioblastoma that was supplied by a persistent hypoglossal artery. In this case, recognition of the persistent hypoglossal artery through angiographic imaging was crucial in identifying tumor blood supply and in guiding the decision to perform a craniotomy without tumor embolization.