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Background: Central nervous system hemangioblastomas are the most prevalent manifestation of von Hippel-Lindau (VHL) disease and remain the main cause of mortality. Surgical resection is the primary treatment strategy, but is not always possible, and should be used as restrictively as possible. There is an unmet need for less invasive treatment strategies, such as targeted therapy. Expression of somatostatin receptor 2A (SSTR2A) in VHL-related hemangioblastomas has been described earlier, but the extent of expression in a larger population has yet to be determined. The authors hypothesize that a substantial subset of VHL-related hemangioblastomas show SSTR2A expression, which may serve as a potential new treatment target., Methods: Patients who were surgically treated for a VHL-related hemangioblastoma from 1990 until 2021 at the UMC Utrecht were included. Clinical data was derived from a clinical database. Tissue samples were histopathologically examined with use of hematoxylin and eosin staining, and immunohistochemical analysis of SSTR2A expression was performed., Results: Forty-three tissue samples were obtained from 26 patients. Nine showed strong positivity for SSTR2A expression, whereas 13 showed moderate and 15 sparse expression. Three samples showed no expression of SSTR2A. The distribution showed right-skewedness favoring a strong expression. SSTR2A expression colocalized with endothelial markers and not with stromal cells. Additionally, within-patient variability for SSTR2A expression was described in 14 patients., Conclusion: SSTR2A is expressed in varying degrees in the majority of VHL-related hemangioblastomas. Future treatment with somatostatin analogues or even peptide receptor radionuclide treatment may be considered for SSTR2A-positive cases., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Approximately 60% of hemangioblastomas (HBs) have peritumoral cysts adjacent to the tumor, which can cause neurological deficits due to the mass effect, and the management of cyst formation is a clinical challenge. Vascular mural cells surrounding endothelial cells consist of vascular smooth muscle cells (vSMCs) and pericytes, which are essential elements that support blood vessels and regulate permeability. This study investigated the involvement of mural cells in cyst formation. We analyzed the expression of α-smooth muscle actin (α-SMA), platelet-derived growth factor receptor-beta (PDGFRB), and CD31 in 39 consecutive human cerebellar HBs, 20 of cystic and 19 of solid type. Solid type HBs showed stronger diffuse expression of α-SMA in precapillary arterioles and capillaries within the tumor than cystic type HBs (p = 0.001), whereas there was no difference in PDGFRB and CD31 expression. Detailed observation with immunofluorescence demonstrated that α-SMA was expressed in vascular mural cells surrounding capillaries in the solid rather than in the cystic type. Multivariate analysis including various clinical and pathological factors showed that lower α-SMA expression was significantly correlated with cyst formation (p < 0.001). Our data suggested that vascular mural cells from precapillary arterioles to capillaries expressing α-SMA may be pericytes and play a crucial role in HB cystogenesis., (© 2023. The Author(s), under exclusive licence to The Japan Society of Brain Tumor Pathology.)

Abstract: Sporadic cerebellar hemangioblastomas are rare with majority of these tumors presenting as a part of von Hippel-Lindau syndrome. We demonstrate an unusual case of a symptomatic sporadic cerebellar hemangioblastoma mimicking a meningioma on MRI and 68 Ga-DOTANOC PET imaging., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer disorder caused by a germline mutation in the VHL tumor suppressor gene. Loss of the wild-type allele results in VHL deficiency and the potential formation of cerebellar hemangioblastomas, which resemble embryonic hemangioblast proliferation and differentiation processes. Multiple, microscopic, VHL-deficient precursors, termed developmentally arrested structural elements (DASEs), consistently involve the cerebellar molecular layer in VHL patients, indicating the tumor site of origin. Unlike hemangioblastomas, however, cerebellar DASEs do not express brachyury, a mesodermal marker for hemangioblasts. In this study, neuronal progenitors occupying the molecular layer were investigated as tumor cells of origin. By immunohistochemistry, cerebellar DASEs and hemangioblastomas lacked immunoreactivity with antibody ZIC1 (Zic family member 1), a granule cell progenitor marker with concordance from oligonucleotide RNA expression array analyses. Rather, cerebellar DASEs and hemangioblastomas were immunoreactive with antibody PAX2 (paired box 2), a marker of basket/stellate cell progenitors. VHL cerebellar cortices also revealed PAX2-positive cells in Purkinje and molecular layers, resembling the histological and molecular development of basket/stellate cells in postnatal non-VHL mouse and human cerebella. These data suggest that VHL deficiency can result in the developmental arrest of basket/stellate cells in the human cerebellum and that these PAX2-positive, initiated cells await another insult or signal to form DASEs and eventually, tumors., (Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. 2022.)

Von Hippel-Lindau (VHL) syndrome is a rare inherited cancer disease where the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HBs), CNS-HBs, and clear cell renal cell carcinoma (ccRCC). Since standard therapies in VHL have shown limited response, leaving surgery as the only possible treatment, targeting of the β2-adrenergic receptor (ADRB2) has shown therapeutic antitumor benefits on VHL-retinal HBs (clinical trial), VHL-CNS HBs, and VHL-ccRCC (in vitro and in vivo). In the present study, we wanted to look deep into the effects of the ADRB2 blockers propranolol and ICI-118,551 on two main aspects of cancer progression: (i) the changes on the inflammatory response of ccRCC cells; and (ii) the modulation on the Warburg effect (glycolytic metabolism), concretely, on the expression of genes involved in the cell reactive oxygen species (ROS) balance and levels. Accordingly, in vitro studies with primary VHL-ccRCC and 786-O cells measuring ROS levels, ROS-expression of detoxifying enzymes, and the expression of p65/NF-κB targets by RT-PCR were carried out. Furthermore, histological analyses of ccRCC samples from heterotopic mouse xenografts were performed. The obtained results show that ADRB2 blockade in ccRCC cells reduces the level of oxidative stress and stabilizes the inflammatory response. Thus, these data further support the idea of targeting ADRB2 as a promising strategy for the treatment of VHL and other non-VHL tumors.

Abstract: Hemangioblastoma (HB) is the most common primary intra-axial posterior fossa tumor in adults and is a benign vascular neoplasm. We report the case of a 73-year-old man suffering from biochemical recurrence of prostate cancer where intense overexpression of prostate-specific membrane antigen (PSMA) was observed in HB in a PSMA PET/CT. Overexpression of PSMA in tumor-associated vascular structures has been proposed as an explanation of PSMA ligand uptake in several nonprostatic tumors. Given the pathological nature of HB, this mechanism may explain the intense overexpression of PSMA observed in present case., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Peritumoral cysts are commonly detected in the central nervous system tumors, especially hemangioblastomas (HBs). However, the molecular mechanisms driving their formation and propagation are still unknown. We conducted an integrated lipidomics and transcriptomics analysis on solid and cystic HB samples in order to elucidate the changes in the lipid profile and expression of lipid metabolism-related genes during cyst formation. Transcriptomic analysis revealed differential expression of several genes between the solid and cystic HBs, and those associated with lipid metabolism, such as ADCY4, MGLL, ACOT2, DGKG, SHC1 and LPAR2, were markedly dysregulated in the cystic HBs. The lipidomic analysis further showed a significant reduction in the abundance of triacylglycerol, ceramide, lysophosphatidylcholine and lysophosphatidylethanolamine, and an increase in phosphatidylcholine and phosphatidylethanolamine levels in the cystic HBs. Furthermore, bioinformatics analysis revealed altered lipid biosynthesis, glycerophospholipid metabolism and phospholipase activity in the cystic HBs. Taken together, our findings indicate that cyst formation in HBs is related with aberrant lipid metabolism.

Introduction: Central nervous system hemangioblastoma is a benign tumor associated with or without von Hippel-Lindau (VHL) disease which is an autosomal dominant hereditary disease that results from a germline mutation in the VHL gene. A main axis of signaling pathways in central nervous system hemangioblastoma is VHL-HIF signaling pathway. Here, we propose an alternative VHL-JAK-STAT signaling pathway in hemangioblastoma and discuss the role., Methods: Using MACS method, Scl + hemangioblast-like cells were isolated from multipotent nestin-expressing stem cells. Then, ubiquitination of JAK2 in those cells and immunoprecipitation between JAK2 and VHL were examined. Then, expressions of JAK2 and STAT3 in those cells and expressions of VHL-associated hemangioblastoma tissues were examined. In addition, the VHL genes of patients bearing hemangioblastoma were analyzed., Results: JAK2 and STAT3 in Scl + hemangioblast-like cells were ubiquitinated after VHL- expression vector was transferred to those cells. Expressions of JAK2 and STAT3 in those cells were well recognized before the transfer, but those disappeared after the transfer. Expressions of both JAK2 and STAT3 in hemangioblastoma tissues were well shown. The VHL gene analysis revealed that patients bearing hemangioblastoma carried missense mutations in 5, small deletions in 2, large deletions in 4, and nonsense mutation in 1 CONCLUSIONS: VHL-JAK-STAT signaling pathway might play an important role in proliferation, angiogenesis, and maintenance of stem-cell-nature in hemangioblastoma as an alternative signaling pathway to supplement VHL-HIF signaling pathway.

Brain metastases from renal cell carcinoma (RCC) are associated with significant morbidity and mortality. However, there are only few large series in the pathology literature specifically analyzing the clinicopathologic and immunohistochemical features in comparison with primary brain tumors with clear cell features. We identified 34 cases of metastatic RCC to the brain from the Urologic Pathology and Neuropathology files of 2 institutions between 2000 and 2018. Mean patient age at diagnosis of primary RCC was 59 years (range: 37 to 82 y). The mean size of 34 primary RCC was 7.9 cm (range: 2.5 to 19.5 cm). Twenty of 34 (59%) cases of brain metastases had primary RCC categorized as pT3. Brain imaging showed a solitary, well circumscribed, enhancing lesion in 18 of 34 (53%) patients and multifocal lesions in 16 of 34 (47%) patients. The mean size of metastatic RCC to the brain was 2.3 cm (range: 0.3 to 5.5 cm). Fifteen of 34 (44%) cases had isolated brain metastases and 19 of 34 (56%) cases had concomitant extracerebral metastases. The histologic subtypes were clear cell RCC 29 of 34 (85%) cases, RCC unclassified 4 of 34 (12%) cases, and papillary RCC 1 of 34 (3%) cases. We also included primary brain tumors with clear cell features including hemangioblastoma (30 cases), microcystic meningioma (11 cases), and clear cell meningioma (3 cases). The utility of an immunohistochemical panel that includes PAX8, carbonic anhydrase IX, SST2Ra, and inhibin is very useful in the distinction of these entities in a subset of patients.

Von Hippel-Lindau (Vhl) protein inhibits hypoxia-inducible factor (Hif), yet its deletion in murine retina does not cause the extensive angiogenesis expected with Hif induction. The mechanism is unclear. Here we show that retinoblastoma tumor suppressor (Rb1) constrains expression of Hif target genes in the Vhl-/- retina. Deleting Rb1 induced extensive retinal neovascularization and autophagic ablation of photoreceptors in the Vhl-/- retina. RNA-sequencing, ChIP, and reporter assays showed Rb1 recruitment to and repression of certain Hif target genes. Activating Rb1 by deleting cyclin D1 induced a partial defect in the retinal superficial vascular plexus. Unexpectedly, removing Vhl suppressed retinoblastoma formation in murine Rb1/Rbl1-deficient retina but generated subretinal vascular growths resembling retinal angiomatous proliferation (RAP) and retinal capillary hemangioblastoma (RCH). Most stromal cells in the RAP/RCH-like lesions were Sox9+, suggesting a Müller glia origin, and expressed Lgals3, a marker of human brain hemangioblastoma. Thus, the Rb family limit Hif target gene expression in the Vhl-/- retina, and removing this inhibitory signal generates new models for RAP and RCH.

One of the major consequences of the lack of a functional VHL protein in von Hippel-Lindau disease, a rare cancer, is the constitutive activation of the HIF pathway. This activation ends up in the generation of Central Nervous System (CNS) Hemangioblastomas among other tumours along the lifespan of the patient. Nowadays, only surgery has been proven efficient as therapy since the systemic attempts have failed. Propranolol, a non-specific β1-and β2-adrenergic receptor antagonist, was recently designated as the first therapeutic (orphan) drug for VHL disease. Nevertheless, its β1 affinity provokes the decrease in blood pressure, being not recommended for low or regular blood pressure VHL patients. In order to overcome the β1-drawback, the properties of a high specific β2-adrenergic receptor blocker named ICI-118,551 have been studied. ICI-118,551 was able to decrease Hemangioblastomas cell viability in a specific manner, by triggering apoptosis. Moreover, ICI-118,551 also impaired the nuclear internalization of HIF-1α in Hemangioblastomas and hypoxic primary endothelial cells, reducing significantly the activation of HIF-target genes and halting the tumour-related angiogenic processes. In this work, we demonstrate the therapeutical properties of ICI-118,551 in VHL-derived CNS-Hemangioblastoma primary cultures, becoming a promising drug for VHL disease and other HIF-related diseases.

Objectives: Assessing a posterior fossa tumour in an adult can be challenging. Metastasis, haemangioblastoma, ependymal tumours, and medulloblastoma are the most common diagnostic possibilities. Our aim was to evaluate the contribution of magnetic resonance spectroscopy (MRS) in the diagnosis of these entities., Methods: We retrospectively evaluated 56 consecutive patients with a posterior fossa tumour and histological diagnosis of ependymal tumour, medulloblastoma, haemangioblastoma, and metastasis in which good-quality spectra at short (TE 30 ms) or/and intermediate (TE, 136 ms) TE were available. Spectra were compared using the Mann-Whitney U non-parametric test in order to select the spectral datapoints and the intensity ratios that showed significant differences between groups of lesions. Performance of these datapoints and their ratios were assessed with ROC curves., Results: The most characteristic signatures on spectroscopy were high choline (Cho) in medulloblastoma (p < 0.001), high myoinositol (mIns) in ependymal tumours (p < 0.05), and high lipids (LIP) in haemangioblastoma (p < 0.01) and metastasis (p < 0.01). Selected ratios between normalised intensity signals of resonances provided accuracy values between 79 and 95% for pairwise comparisons. Intensity ratio NI 3.21ppm/3.55ppm provided satisfactory discrimination between medulloblastoma and ependymal tumours (accuracy, 92%), ratio NI 2.11ppm/1.10ppm discriminated ependymal tumours from haemangioblastoma (accuracy, 94%), ratio NI 3.21ppm/1.13ppm discriminated haemangioblastoma from medulloblastoma (accuracy, 95%), and ratio NI 1.28ppm/2.02pmm discriminated haemangioblastoma from metastasis (accuracy, 83%)., Conclusions: MRS may improve the non-invasive diagnosis of posterior fossa tumours in adults., Key Points: • High choline suggests a medulloblastoma in a posterior fossa tumour. • High myoinositol suggests an ependymal lesion in a posterior fossa tumour. • High lipids suggest a metastasis or a haemangioblastoma in a posterior fossa tumour.

Von Hippel-Lindau disease is an inherited syndrome associated with several benign and malignant tumors such as central nervous system (CNS) hemangioblastoma. Herein, we report a known case of A Von Hippel-Lindau patient with a cerebral hemangioblastoma who was referred for further evaluation because of recent paraparesis. F-FDG PET/CT showed no focal uptake in the thoracic spine, which demonstrated increased Ga DOTATATE activity, owing to overexpression of somatostatin receptors, suggesting spinal cord hemangioblastoma. This case report indicates the significant role of Ga-labeled somatostatin receptor analogs in the diagnosis of hemangioblastoma.

Hemangioblastoma is composed of neoplastic stromal cells and a prominent capillary network. To date, the identity of stromal cells remains unclear. Mesenchymal stem cells can give rise to committed vascular progenitor cells, and ephrin-B2/EphB4 and Notch signaling have crucial roles in these steps. The aim of our study was to elucidate that stromal cells of central nervous system hemangioblastomas have mesenchymal stem cell-derived vascular progenitor cell properties. Ten hemangioblastomas were investigated immunohistochemically. CD44, a mesenchymal stem cell marker, was detected in stromal cells of all cases, suggesting that stromal cells have mesenchymal stem cell-like properties. Neither CD31 nor α-SMA was expressed in stromal cells, suggesting that stromal cells have not acquired differentiated vascular cell properties. Both ephrin-B2 and EphB4, immature vascular cell markers, were detected in stromal cells of all cases. Jagged1, Notch1, and Hesr2/Hey2, which are known to be detected in both immature endothelial cells and mural cells, were expressed in stromal cells of all cases. Notch3, which is known to be detected in differentiating mural cells, was also expressed in all cases. These results suggest that stromal cells also have vascular progenitor cell properties. In conclusion, stromal cells of hemangioblastomas exhibit mesenchymal stem cell-derived vascular progenitor cell properties.

Rationale: Hemangioblastoma is a rare tumor of the central nervous system (CNS). It is usually observed in patients with von-Hippel Lindau (VHL). The peak age for hemangioblastoma is between 20 and 50 years of age with very few cases over 65 or below 18 years of age., Patient Concerns: We report a female with a rare VHL mutation (c.337C>T) who was diagnosed with multifocal CNS hemangioblastoma at a very young age., Diagnosis: At 17-years of age, she presented with obstructive hydrocephalus due to large cystic cerebellar mass. Imaging showed multiple lesions resembling drop metastases throughout her spinal cord. Immunohistochemistry of the resected tumor confirmed the pathological diagnosis of hemangioblastoma (World Health Organization Grade 1)., Interventions and Outcome: She was treated with multi-stage resection of her primary and drop- metastasis like disease. She presented six months later with retinal hemangioblastoma while her other lesions were stable. She presented with multiple CNS and eye hemangioblastomas after failing to follow up for 2 years. Subsequently, Everolimus was started to treat her systemic disease., Lessons: The unique feature of our case is the presence of multiple drop-metastases like spinal lesions, which has not been reported in the literature to be associated with hemangioblastoma.

Purpose: The aim of this study was to assess whether dynamic PET with 11 C-methionine (MET) (MET-PET) is useful in the diagnosis of brain tumors., Methods: One hundred sixty patients with brain tumors (139 gliomas, 9 meningiomas, 4 hemangioblastomas and 8 primary central nervous system lymphomas [PCNSL]) underwent dynamic MET-PET with a 3-dimensional acquisition mode, and the maximum tumor MET-standardized uptake value (MET-SUV) was measured consecutively to construct a time-activity curve (TAC). Furthermore, receiver operating characteristic (ROC) curves were generated from the time-to-peak (TTP) and the slope of the curve in the late phase (SLOPE)., Results: The TAC patterns of MET-SUVs (MET-TACs) could be divided into four characteristic types when MET dynamics were analyzed by dividing the MET-TAC into three phases. MET-SUVs were significantly higher in early and late phases in glioblastoma compared to anaplastic astrocytoma, diffuse astrocytoma and the normal frontal cortex (P < 0.05). The SLOPE in the late phase was significantly lower in tumors that included an oligodendroglial component compared to astrocytic tumors (P < 0.001). When we set the cutoff of the SLOPE in the late phase to - 0.04 h -1 for the differentiation of tumors that included an oligodendroglial component from astrocytic tumors, the diagnostic accuracy was 74.2% sensitivity and 64.9% specificity. The area under the ROC curve was 0.731., Conclusions: The results of this study show that quantification of the MET-TAC for each brain tumor identified by a dynamic MET-PET study could be helpful in the non-invasive discrimination of brain tumor subtypes, in particular gliomas.

The inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene plays a crucial role in the development of hemangioblastomas (HBs) within the human central nervous system (CNS). However, both the cytological origin and the evolutionary process of HBs (including neovascularization) remain controversial, and anti-angiogenesis for VHL-HBs, based on classic HB angiogenesis, have produced disappointing results in clinical trials. One major obstacle to the successful clinical translation of anti-vascular treatment is the lack of a thorough understanding of neovascularization in this vascular tumor. In this article, we present a comprehensive procedure to evaluate in vitro whether classic tumor angiogenesis exists in HBs, as well as its role in HBs. With this procedure, researchers can accurately understand the complexity of HB neovascularization and identify the function of this common form of angiogenesis in HBs. These protocols can be used to evaluate the most promising anti-vascular therapy for tumors, which has high translational potential either for tumors treatment or for aiding in the optimization of the anti-angiogenic treatment for HBs in future translations. The results highlight the complexity of HB neovascularization and suggest that this common form angiogenesis is only a complementary mechanism in HB neovascularization.

von Hippel-Lindau (VHL) disease is an autosomal-dominant tumor predisposition syndrome characterized by the development of highly vascularized tumors and cysts. LOH of the VHL gene results in aberrant upregulation of hypoxia-inducible factors (HIF) and has been associated with tumor formation. Hemangioblastomas of the central nervous system and retina represent the most prevalent VHL-associated tumors, but no VHL animal model has reproduced retinal capillary hemangioblastomas (RCH), the hallmark lesion of ocular VHL. Here we report our work in developing a murine model of VHL-associated RCH by conditionally inactivating Vhl in a hemangioblast population using a Scl -Cre-ERT2 transgenic mouse line. In transgenic mice carrying the conditional allele and the Scl -Cre-ERT2 allele, 64% exhibited various retinal vascular anomalies following tamoxifen induction. Affected Vhl -mutant mice demonstrated retinal vascular lesions associated with prominent vasculature, anomalous capillary networks, hemorrhage, exudates, and localized fibrosis. Histologic analyses showed RCH-like lesions characterized by tortuous, dilated vasculature surrounded by "tumorlet" cell cluster and isolated foamy stromal cells, which are typically associated with RCH. Fluorescein angiography suggested increased vascular permeability of the irregular retinal vasculature and hemangioblastoma-like lesions. Vhl deletion was detected in "tumorlet" cells via microdissection. Our findings provide a phenotypic recapitulation of VHL-associated RCH in a murine model that may be useful to study RCH pathogenesis and therapeutics aimed at treating ocular VHL. Significance: This study describes a model that phenotypically recapitulates a form of retinal pathogenesis that is driven by genetic loss of the VHL tumor suppressor, providing a useful tool for its study and therapeutic intervention. Cancer Res; 78(5); 1266-74. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Objective: Brain arteriovenous malformations (AVMs) are the most common cause of nontraumatic intracerebral hemorrhage in young adults. The genesis of brain AVM remains enigmatic. We investigated microRNA (miRNA) expression and its contribution to the pathogenesis of brain AVMs., Methods: We used a large-scale miRNA analysis of 16 samples including AVMs, hemangioblastoma, and controls to identify a distinct AVM miRNA signature. AVM smooth muscle cells (AVMSMCs) were isolated and identified by flow cytometry and immunohistochemistry, and candidate miRNAs were then tested in these cells. Migration, tube formation, and CCK-8-induced proliferation assays were used to test the effect of the miRNAs on phenotypic properties of AVMSMCs. A quantitative proteomics approach was used to identify protein expression changes in AVMSMCs treated with miRNA mimics., Results: A distinct AVM miRNA signature comprising a large portion of lowly expressed miRNAs was identified. Among these miRNAs, miR-137 and miR-195* levels were significantly decreased in AVMs and constituent AVMSMCs. Experimentally elevating the level of these microRNAs inhibited AVMSMC migration, tube formation, and survival in vitro and the formation of vascular rings in vivo. Proteomics showed the protein expression signature of AVMSMCs and identified downstream proteins regulated by miR-137 and miR-195* that were key signaling proteins involved in vessel development., Interpretation: Our results indicate that miR-137 and miR-195* act as vasculogenic suppressors in AVMs by altering phenotypic properties of AVMSMCs, and that the absence of miR-137 and miR-195* expression leads to abnormal vasculogenesis. Ann Neurol 2017;82:371-384., (© 2017 American Neurological Association.)

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.

Retinal hemangioblastomas are highly vascular benign tumors that can be encountered either sporadically or within the von Hippel-Lindau (VHL) syndrome. We report a case of a VHL patient with retinal hemangioblastoma who underwent PET/CT scans using F-FDG and Ga-DOTATATE. The tumor showed low-level F-FDG and increased Ga-DOTATATE activity, suggesting cell-surface overexpression of somatostatin receptors. The presented case indicates the clinical applications of somatostatin receptor imaging with Ga-DOTA-conjugated peptides in detection and follow-up of VHL manifestations, screening of asymptomatic gene carriers, and in diagnosis of sporadic retinal hemangioblastomas, which may have similar features on MRI with other retinal tumors.

Purpose: This study aimed to determine the expression of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and endothelial tyrosine kinase receptor (Tie-2) in central nervous system (CNS) hemangioblastomas (HBs) and explore the correlation with peritumoral cyst formation., Method: A total of 22 paraffin-embedded specimens derived from 11 cyst-associated and 11 solid solitary CNS HBs were collected for streptavidin-peroxidase immunohistochemical staining. The expression levels of Ang-1, Ang-2 and Tie-2 in cystic and solid HBs were estimated and compared according to the integrated optical density (IOD) of staining in the sections. To further confirm the differential expression of Ang-1 and Ang-2 between cystic and solid HBs, an additional 9 frozen specimens from 5 cyst-associated and 4 solid solitary HBs were collected for Western blot analysis. Clinical histories and radiological records of the patients were reviewed retrospectively., Results: Compared to normal cerebellum tissue, Ang-1, Ang-2 and Tie-2 were prominently overexpressed in both the stromal cells and endothelial cells of CNS HBs. The expression of Ang-2 and the ratio of Ang-2/Ang-1 in the cystic group were significantly higher than those in the solid group. The intensity of Ang-2 expression in the cystic group was negatively correlated with age. There was no correlation between the expression level of the proteins and sex, tumor location, tumor volume or cyst volume., Conclusions: Ang/Tie signaling is upregulated in HBs and is likely associated with the process of intense vascularization and cyst formation. Higher Ang-2 levels and a higher Ang-2/Ang-1 ratio may contribute to cyst formation by increasing the vascular permeability. The decrease in Ang-2 expression with advanced age in cystic-associated HBs may be associated with the reduced growth rate of peritumoral cysts among elderly patients. Ang-2 shows great potential as an effective therapeutic target of symptomatic CNS HBs associated with cysts., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Hemangioblastoma (HB) is mainly located in the brain and the spinal cord. The tumor is composed of two major components, namely neoplastic stromal cells and abundant microvessels. Thus, hyper-vascularization is the hallmark of this tumor. Despite the identification of germline and/or epigenetic mutations of Von Hippel Lindau (VHL) gene as an important pathogenic mechanism of HB, little is known about the molecular signaling involved in this highly vascularized tumor. The present study investigated the key players of multiple angiogenic signaling pathways including VEGF/VEGFR2, EphB4/EphrinB2, SDF1α/CXCR4 and Notch/Dll4 pathways in surgical specimens of 22 HB. The expression of key angiogenic factors was detected by RT 2 -PCR and Western blot. Immunofluorescent staining revealed the cellular localization of these proteins. We demonstrated a massive upregulation of mRNA levels of VEGF and VEGFR2, CXCR4 and SDF1α, EphB4 and EphrinB2, as well as the main components of Dll4-Notch signaling in HB. An increase in the protein expression of VEGF, CXCR4 and the core-components of Dll4-Notch signaling was associated with an activation of Akt and Erk1/2 and accompanied by an elevated expression of PCNA. Immuofluorescent staining revealed the expression of VEGF and CXCR4 in endothelial cells as well as in tumor cells. Dll4 protein was predominantly found in tumor cells, whereas EphB4 immunoreactivity was exclusively detected in endothelial cells. We conclude that multiple key angiogenic pathways were activated in HB, which may synergistically contribute to the abundant vascularization in this tumor. Identification of these aberrant pathways provides potential targets for a possible future application of anti-angiogenic therapy for this tumor, particularly when a total surgical resection becomes difficult due to the localization or multiplicity of the tumor., (© 2016 Japanese Society of Neuropathology.)

von Hippel-Lindau (VHL) patients develop multiple central nervous system hemangioblastomas (HB). Some HBs become symptomatic with exponential growth or cyst formation following long periods of quiescence. Understanding the factors underlying growth in hemangioblastoma may lead to better strategies to arrest or prevent tumor growth. In 5 VHL patients, we resected quiescent hemangioblastomas (Q-HB) that were en-route during surgical access to symptomatic hemangioblastomas (S-HB), for matched tumor analysis. Quantitative reverse transcriptase analysis demonstrated a 2-fold increase in EPO expression in all S-HB, while 4/5 showed either Hypoxia Inducible Factor-1α or 2α upregulation. Additionally, all S-HB had increased phosphorylated erythropoietin (EPO) receptor and phosphorylated STAT-5 relative to matched Q-HB, with increased phosphorylated JAK-2 largely confined to the stromal cells in clusters within the tumors. These findings suggest that Q-HB to S-HB conversion may be associated with an erythropoietin-signaling loop. Furthermore, we found that EPO is detectable in cyst fluid from S-HB (n = 14), while absent in CSF (n = 1). Additionally, S-HB presentation or S-HB resection does not result in discernible change in serum EPO or hemoglobin (n = 60). These observations suggest that the altered erythropoietin signaling is focal and suggests that studying modulation of erythropoietin receptor pathway may lead to strategies in preventing HB growth.

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.

Central nervous system hemangioblastomas (CNS-HBs) occur sporadically or as a component of von Hippel-Lindau-VHL syndrome. CNS-HBs share some molecular similarities with pheochromocytomas/paragangliomas (PPGLs) and renal cell carcinomas (RCCs). Recently, hypoxia-inducible factors, particularly somatic HIF2A mutations, have been found to play an important role in the pathogenesis of PPGLs. Somatic mutations in HIF2A have been reported in PPGLs associated with polycythemia, which have been reported to also be present in patients with RCCs and HBs. However, whether CNS-HBs is associated with the presence of a HIF2A mutation is currently uknown. We analyzed somatic HIF2A and VHL mutations in a series of 28 sporadic CNS-HBs. We also investigated the expression of HIF target proteins and hypoxia-associated factor (HAF). Two sporadic CNS-HBs were found to have somatic HIF2A mutations. One tumor had 2 HIF2A missense mutations, one of which was previously described in a PPGL (c.1121 T>A, F374Y). The second patient had coexistence of somatic truncated mutations (c.1669 C>T, Q557*) in HIF2A together with a VHL mutation. Neither of the two patients had polycythemia at the time of diagnosis. We demonstrate that the novel truncated mutation in HIF2A (Q557*) affects HIF-2α prolyl hydroxylation with its reduced ubiquitination but intact transcriptional activity, resulting in an activating effect. Both CNS-HB samples showed positive expression of VEGFR2/CA9/Glut1 and HAF. Our data support the unique central role of the VHL/HIF-2α signaling pathway in the molecular pathogenesis of CNS-HBs and show for the first time the presence of HIF2A mutations in sporadic HB.

Introduction: Intramedullary tumors account for 2-4% of all CNS neoplasms. Surgical resection is challenging because of aggravated neurological impairment in up to 64% of patients. We analyzed a consecutive series of patients with intramedullary tumors and focused on the extent of resection, functional outcome, and tumor recurrence., Methods: 53 patients (23 women and 30 men; mean age 46.3 years) were included who had undergone microsurgical resection for intramedullary spinal tumors. We reviewed the patient records for tumor size, edema, intratumoral hemorrhage, consistency, midline detection, resection method, extent of resection, histopathology, and recurrence. Outcome was measured by the Karnofsky Score (KPI), the McCormick score (MCS), and the Medical Research Council Neurological Performance Score (MRC-NPS)., Results: The most frequent diagnosis was ependymoma (37.7%), lymphoma (13.2%) and astrocytoma (11.3%). The majority of tumors were located in the thoracic spine (62.2%). Gross total resection was achieved in 73.6% and most successful in patients with ependymal histology (p<0.01). Tumor recurrence - observed in 11.3% - was significantly associated with age >65 years, astrocytic histology, higher tumor grades, and higher Ki-67 labeling. At follow-up, MCS and MRC-NPS showed significantly better results than prior to resection (p<0.001), and pain and sensory deficits had improved in 67.9% and 64.2% of patients, respectively. Microsurgical resection improved the neurological status significantly. Pain and sensory deficits showed higher improvement rates than paresis and vegetative dysfunction., Conclusion: Our data help identify patients at risk of tumor recurrence and classify the course of postoperative neurological performance., (Copyright © 2015 Elsevier B.V. All rights reserved.)

To date, 13 cases of sporadic renal hemangioblastoma have been reported. In this article, we report such a case that might cause the diagnostic pitfall. A 37-year-old Japanese was found to have a renal mass by periodic medical check-up. He underwent radical nephrectomy. Macroscopically, the tumor was well-defined without fibrous capsule and the cut surface of the tumor exhibited light brown to gray-tan color without hemorrhage or necrosis. Microscopically, the tumor was made up of large polygonal to short spindle cells with eosinophilic cytoplasm with occasional vacuolization and abundant arborizing capillary network. Immunohistochemically, neoplastic cells showed diffuse positivity for inhibin-alpha, S-100 protein, vimentin, CA9, PAX2 and PAX8, but negativity for cytokeratin CAM5.2, alpha smooth muscle actin, Melanosome, Melan A, TFE3 and cathepsin K. In genetic analyses, this tumor showed no changes of VHL gene mutation, hypermethylation and loss of heterozygosity of chromosome 3p. Additionally, G-band karyotype and array comparative genomic hybridization studies showed a normal chromosome. In conclusion, the positivity for CA9, PAX2 and PAX8 in sporadic renal hemangioblastoma may cause the critical diagnostic pitfall in the differential diagnosis from clear cell renal cell carcinoma. Pathologists need to pay attention to systemic evaluation including macroscopic, microscopic and immunohistochemical findings. In some cases, molecular genetic study may be necessary.

Hemangioblasts are capable of differentiation into vascular structures and blood. Patients with von Hippel-Lindau (VHL) disease develop hemangioblastomas which are composed of VHL-deficient tumor cells with protracted hemangioblastic differentiation potential. In a subset of these tumors, hemangioblastic differentiation is characterized by different stages of red blood cell formation. It has remained controversial, however, whether VHL-deficient hemangioblastic cells are similarly capable of differentiating into vascular cells and functioning vascular structures in vivo. By histologic, immunohistologic and microdissection-based genetic analysis of 60 VHL disease-associated hemangioblastomas, we re-examined the controversial question whether VHL-deficient neoplastic hemangioblastic cells are capable of vascular differentiation (vasculogenesis). In most tumors (n=47), there was no evidence of either vasculogenesis or hematopoiesis; tumor cells were either scattered between reactive angiogenetic vascular structures or arranged in solid clusters. A subset of tumors (n=13), however, revealed vaculogenetic structures that were composed of cuboidal or flat cells and frequently contained red blood cell precursors or mature red blood cells. Microdissection-based deletion analysis of epithelial cells confirmed them to be VHL-deficient tumor cells. Immunohistochemistry for CD31 was consistently negative in these structures, and no evidence could be obtained for connectivity with reactive vasculature. We demonstrate that hemangioblastic differentiation capacity of VHL-deficient hemangioblastic cells includes not only erythropoiesis, but also differentiation into primitive vasculogenetic structures. Tumor cells, however, do not appear to have the potential of terminal differentiation into mature and functional vascular structures., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Peritumoral cyst formation is commonly associated with hemangioblastomas of the central nervous system. Results of a proteomic profiling of hemangioblastoma cyst fluid suggested that cyst formation, whether intratumoral or peritumoral, is a consequence of vascular leakage because protein profiles of cyst fluid and blood serum were similar. To the best of our knowledge, this is the first report of in vivo and ex vivo magnetic resonance spectroscopy analyses of hemangioblastoma cyst fluid that investigates on the mechanism leading to peritumoral cyst formation.

Brachyury is a transcription factor which is required for posterior mesoderm formation and differentiation as well as for notochord development during embryogenesis. Due to its expression in the neoplastic cells of chordoma, a malignant tumour deriving from notochordal remnants, but not in tumors showing a similar histology, brachyury has been proposed as a diagnostic marker of this neoplasia. Though commonly considered a hallmark of chordoma, the expression of brachyury has been also documented in the stromal cells of hemangioblastoma (HBL), a slow growing tumor which may involve the central nervous system (CNS) and, rarely, the kidney. Herein we review the role of brachyury immunohistochemical detection in the identification and differential diagnosis of chordoma and HBL towards histological mimickers and suggest that brachyury is added to the panel of immunohistochemical markers for the recognition of HBL in routinary practice, principally in unusual sites.

Introduction: Hemangioblastomas occur as sporadic or as von Hippel-Lindau syndrome (VHL) associated tumors. In both settings, activation of the VHL-HIF-1 (hypoxia induced factor) pathway is thought to be important in tumor biology., Material and Methods: We performed immunohistochemical studies on 23 hemangioblastomas, 13 meningiomas and 4 hemangiopericytomas to evaluate expression of the VHL-HIF-1 regulated proteins vascular endothelial growth factor (VEGF), carbonic anhydrase IX (CAIX) and hypoxia inducible gene 2 (HIG-2)., Results: Hemangioblastomas showed significantly higher expression of CAIX and VEGF than the other tested tumors. They showed strong membranous expression of CAIX in a pattern identical to that observed in clear cell renal cell carcinomas (CCRCC). Interestingly, hemangioblastomas lacked significant reactivity for HIG-2., Conclusions: The VHL-HIF-1 regulated genes VEGF and CAIX are expressed in hemangioblastomas but significant HIG-2 expression is not observed. Carbonic anhydrase IX staining in particular may be a helpful marker of hemangioblastomas but does not aid in the distinction from CCRCC.

Objective: To investigate the clinicopathological characteristics of sporadic renal hemangioblastoma., Methods: Two cases of sporadic renal hemangioblastoma were studied by histological and immunohistochemical staining, along with review of the literature., Results: Both cases were presented with a renal mass during annual physical examination with an age of 40 and 45 years, respectively. The lesions located in the middle portion of the kidney with a sharp tumor border. Histopathologically, the tumors were characterized by two major components: capillary and stromal cells. Immunohistochemically, the stromal cells were positive for vimentin, NSE, S-100 protein and inhibin-α, and negative for CK, HMB45, Melan A, EMA, CD56 and syn. Both tumors showed a very low level of Ki-67 labeling. The endothelial cells were positive for CD34., Conclusion: Sporadic renal hemangioblastoma is a rare benign neoplasm, the diagnosis of which is based on the characteristic follicular architecture and an exclusion of other carcinomas of the kidney.

Hemangioblastoma is a benign, morphologically distinctive neoplasm of disputed histogenesis that typically occurs in the central nervous system either in the setting of von Hippel-Lindau disease or more often sporadically. Extraneural hemangioblastoma is exceptional and raises a challenging differential diagnosis. Herein, we report a primary renal hemangioblastoma occurring in 51-year-old woman without stigmata of von Hippel-Lindau disease. Histologically, the tumor was composed of sheets of polygonal epithelioid stromal cells with ample pale or eosinophilic, vacuolated cytoplasm in an arborizing capillary network. Tumor cells showed variable nuclear pleomorphism, intranuclear cytoplasmic invaginations, scattered hyaline globules, and psammoma-like calcifications. Some areas showed branching hemangiopericytoma-like vessels with tumor cells radiating from the wall, while other areas were edematous and hyalinized with sparse stromal cells and abundant reticular vessels. Immunohistochemically, the tumor cells reacted strongly and diffusely with antibodies to PAX8, CD10, α-inhibin, S100 protein, neuron-specific enolase, and vimentin, and they showed focal positivity with antibodies to epithelial membrane antigen and AE1/AE3. Tumor cells were negative for CK7, CK8/18, RCC antigen, synaptophysin, chromogranin, c-kit, D2-40, HMB45, melan-A, cathepsin K, SMA, desmin, CD31, CD34, and estrogen and progesterone receptors. Positive immunoreactivity for PAX8 is unexpected and contrasts to central nervous system (CNS) hemangioblastomas, which are essentially always negative for PAX8. This novel finding adds support to the hypothesis that the immunoprofile of extraneural hemangioblastoma varies with site of origin, perhaps as a result of tumor cell lineage and retention of organ-specific markers or acquisition of site-specific antigens due to local factors., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Von Hippel-Lindau Disease (VHL) is an autosomal dominant inherited systemic cancer syndrome that gives rise to cystic and highly vascularized tumors in many organs, including the eye. Recent studies have contributed to the understanding of VHL pathophysiology, genetics, and the role of the VHL protein. This article reviews recent studies on VHL clinical findings, genetics and tumorigenesis., Methods: Literature review of articles on VHL genetics with correlation to clinical findings., Results: Genotype-phenotype correlation studies show that patients with a complete deletion mutation of the VHL gene, relative to participants with a missense or protein-truncating mutation, had better visual acuity and decreased tumorigenesis incidence of retinal hemangioblastomas. It has also been documented that higher levels of vascular endothelial growth factor (VEGF), hypoxia induced factor (HIF), and ubiquitin are found in ocular hemangioblastomas. The stromal foamy vacuolated cells seem to be the true tumor cells of the disease acting on the surrounding endothelial cells in ocular hemangioblastomas. Tumor cells and ocular lesions have shown increased levels of Erythropoietin (Epo), Epo receptor (EpoR), and CD133. Also, CXCR4, a CXC chemokine receptor, is expressed in retinal VHL hemangioblastomas. Recent studies suggest that the VHL mutation alone may not be sufficient to develop VHL-associated neoplasms. Studies suggest that targeting various proteins along with anti-angiogenesis molecules may be a better therapeutic approach than targeting VEGF alone., Conclusion: Understanding of the mechanisms and genetics underlying VHL and its associated retinal hemangioblastomas has increased substantially in recent years. This knowledge suggests that future advances may include better identification of individuals at higher risk of vision loss and the development of novel individualized therapies.

Hemangioblastomas of the retina, central nervous system, and kidney are observed in patients with mutations in the von Hippel-Lindau (VHL) tumor suppressor gene. Mutations in the VHL lead to constitutive activation of hypoxia-inducible-factor (HIF) pathway. HIF-mediated expression of pro-angiogenic genes causes extensive pathological neovascularization in hemangioblastomas. A number of studies have shown coexistence of pro-angiogenic and stem cell markers in 'tumorlet-like stromal cells' in the retinal and optic nerve hemangioblastomas, leading to suggestions that hemangioblastomas originate from developmentally arrested stem cells or embryonic progenitors. Since recent studies have shown that the HIF pathway also plays a role in the maintenance/de-differentiation of normal and cancerous stem cells, we evaluated the role of the HIF pathway in the expression of stem cell markers in VHL-/- renal cell carcinoma cells under normoxia or VHL+/+ retinal pigment epithelial cells under hypoxia. Here we show that the expression of stem cell markers in hemangioblastomas is due to activation of the HIF pathway. Further, we show that honokiol, digoxin, and doxorubicin, three recently identified HIF inhibitors from natural sources, blocks the expression of stem cell markers. Our results show the mechanism for the cytological origin of neoplastic stromal cells in hemangioblastomas, and suggest that inhibition of the HIF pathway is an attractive strategy for the treatment of hemangioblastomas., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Hemangioblastoma (HB), a rare neoplasm of uncertain histogenesis, is characterized histologically by the presence of vacuolated; lipid-containing cells 'stromal cells' and a well developed, fine capillary network. Stromal cells are the neoplastic component of this tumor. Five-um sections were stained using streptavidin- biotin immunoperoxidase and immunofluorescent techniques. The stromal cells were uniformly "HIF-1α, Galectin-3, VEGF, VEGFR, WT-1, and bcl2," positive. Endothelial cells but not stromal cells were uniformly immunoreactive to CD31. Co-localization of HIF-1α with galectin-3 and VEGF as well as galectin-3 with VEGF in stromal cells is confirmed by immunofluorescent technique. In conclusion, the development of HB is multi-factorial and the expression of galectin-3 correlates with the expression of HIF-1α and VEGF. Galectin-3 can be used as a marker for the diagnosis of HB as well as it can be a valuable candidate for future targeting immunotherapy.

We present the first documented case of hemangioblastoma located in the left colon. A 75-year-old woman undergoing adjuvant chemotherapy for breast cancer experienced rectal bleeding. Colonoscopy revealed a roundish mass covered with normal mucosa in the sigmoid colon. Endoscopic ultrasound showed an isoechoic lesion originating from the third layer of the intestinal wall; underlying layers were normal. Endoscopic ultrasound features were not suggestive of either cancer or malignant stromal tumor. Left hemicolectomy was subsequently performed due to repeated episodes of lower gastrointestinal bleeding. Grossly, a circumscribed submucosal yellowish nodule (13 mm) was observed, which was not attached to any peripheral nerve. Histologically, the lesion was composed of large, atypical cells traversed by a network of blood vessels. Immunohistochemically, the cells showed positivity for inhibin and NSE and weak positivity for S-100. A diagnosis of hemangioblastoma was made. This case highlights that hemangioblastoma of the gastrointestinal tract can also occur.

The authors report 2 cases of an apparently unpublished stromal tumor of the lung characterized by a predominantly endobronchial growth pattern and benign-appearing clear cells. Both tumors were discovered incidentally in adult patients during routine workups for other medical reasons and treated with lobectomy. On gross inspection there was no evidence of infiltration of the adjacent lung tissue. Microscopically, both lesions featured monotonous oval-shaped to spindle-shaped cells growing in a vaguely nested pattern. The cytoplasm was slightly vacuolated or granular. In 1 case there was a variable admixture with mature fat. Immunohistochemistry was negative for markers of epithelial and stromal differentiation except for vimentin. A focal reaction for CD34 was seen in 1 case. No mutation of coding sequence of VHL gene was seen in one case. Medical follow-up at 1 year was negative for tumor recurrence or metastases. The broad differential diagnosis within the spectrum of stromal lung tumor is discussed. Owing to distinctive microscopic features such as the nesting of clear cells within a vascularized background, both tumors appeared similar to hemangioblastoma, although the expected immunohistochemical profile of the latter was not fully expressed. Because of pattern of growth seen in both lesions we believe that the appellation of endobronchial, hemangioblastoma-like clear cell stromal tumor may be provisionally designed.

Hemangioblastoma of the kidney is a rare, newly recognized tumor with morphological features similar to its cerebellar counterpart. There have been only 4 cases reported in the literature in English, all of them occurring in middle-aged to elderly patients. Here, we report a case of renal hemangioblastoma in a young adult without clinical evidence of von Hippel-Lindau disease. The tumor was composed of polygonal cells with mildly eosinophilic to clear cytoplasm and a rich vascular network. Immunohistochemical staining revealed a typical profile (positivity for α-inhibin, neuron-specific enolase and S100; negative results for epithelial membrane antigen, HMB-45, and Melan-A), which confirmed the diagnosis. Despite the similarity to renal-cell carcinoma in morphology, hemangioblastoma of the kidney is clinically indolent. Correct recognition of this pathological entity is important to avoid overdiagnosis and unnecessary clinical treatment.

We present here an intriguing case of sporadic renal haemangioblastoma occurring in a 61-year-old male. The tumor consisted of nests of polygonal cells and abundant capillary networks. The neoplastic cells generally showed abundant eosinophilic cytoplasm and prominent eccentric nuclei, resembling the rhabdoid cells. Pronounced intranuclear cytoplasmic pseudoinclusions were another significant feature seen. NSE, a-inhibin and S100 were positive in tumor cells and particularly, focal CD10 expressions were observed. This is possibly the first reported case of a haemangioblastoma showing a rhabdoid phenotype and CD10 immunopositivity. Malignant rhabdoid tumor and renal cell carcinoma with rhabdoid features were probably the most challenging mimics need to be differentiated. The result of focal CD10 staining in our case may further lead to confusion with renal cell carcinoma. To avoid misdiagnosis, more considerations should be attached to the rare neoplasm., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1068858553657049.

Coexistence of brain tumors of different pathologies is rare, and the majority of the cases were related to genetic disorders or secondary tumors occurring after radiotherapy. A 73-year-old man was introduced to the outpatient department suffering from severe nausea and vertigo. Magnetic resonance imaging showed a cystic tumor in the left cerebellar hemisphere and another lesion in the sella turcica. There was no evident family history of von Hippel-Lindau (VHL) disease, and the systemic investigation failed to detect any other tumors or signs of VHL disease. Treatment was performed in two stages, and he was discharged with remaining slight ataxic gait. The diagnoses were cerebellar hemangioblastoma and pituitary null cell adenoma. Additional immunohistochemical investigation using VHL disease gene-related protein in both tumors showed minute granular positive staining in the cytoplasm of stromal cells in the former, and diffuse and strong granular cytoplasmic positive staining in the latter. Further analysis is required to confirm the true implication of the VHL gene mutation, and the possible involvement of VHL gene-related protein in the pathogenesis of these coexisting tumors.

Background: Von Hippel-Lindau (VHL) disease induces vascular neoplasms in multiple organs. We evaluated the safety and efficacy of sunitinib in VHL patients and examined the expression of candidate receptors in archived tissue., Methods: Patients with VHL were given four cycles of 50 mg sunitinib daily for 28 days, followed by 14 days off. Primary end point was toxicity. Modified RECIST were used for efficacy assessment. We evaluated 20 archival renal cell carcinomas (RCCs) and 20 hemangioblastomas (HBs) for biomarker expression levels using laser-scanning cytometry (LSC)., Results: Fifteen patients were treated. Grade 3 toxicity included fatigue in five patients. Dose reductions were needed in 10 patients. Eighteen RCC and 21 HB lesions were evaluable. Six of the RCCs (33%) responded partially, versus none of the HBs (P = 0.014). LSC revealed that mean levels of phosphorylated vascular endothelial growth factor receptor-2 were lower in HB than in RCC endothelium (P = 0.003) and mean phosphorylated fibroblast growth factor receptor substrate-2 (pFRS2) levels were higher in HB (P = 0.003)., Conclusions: Sunitinib treatment in VHL patients showed acceptable toxicity. Significant response was observed in RCC but not in HB. Greater expression of pFRS2 in HB tissue than in RCC raises the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with HB.

The cytological origin of hemangioblastomas (HBs) is controversial possibly owing to limitation in the framework of normal vascular development. Our previous study reported that SSEA1 (stage-specific embryonic antigen-1) cells had the potential of HB-like structure formation in vitro cellular models. Here, we characterized primary proliferating tumor-initiating cells (TICs) and their neoplasmtic transformation. Neural stem cell marker SSEA1 and its lineage-related genes were demonstrated; no embryonic and mesenchymal stem cell markers were detected whereas their lineage-related genes in part were activated. Immunohistochemistry showed that the proliferating marker was preferentially expressed in SSEA1 cells. There was significant difference in the percentage of SSEA1 cells (SSEA1+/Ki67+ cells) between inherited and sporadic HBs although the tumor proliferative index (Ki67+ cells/ all cells) did not reach statistical significance between the two groups. Further, corresponding to the morphological changes of nucleolus in number and size, these highly proliferating SSEA1 cells demonstrated coexpression of either D2-40 or the mesodermal marker Scl (stem cell leukemia), brachyury, and Flk-1 (vascular endothelial growth factor-2), respectively, indicative of the neoplasmtic transformation into the stromal or vascular cells. The present data suggest that HBs might derive from neoplastic transformation of neural stem cells/progenitors. Such findings also provide new insights into the biology of HBs and the definition of TICs in situ, as well as the mechanisms of tumor neovascularization.

Object: Central nervous system hemangioblastomas are the most common manifestation of von Hippel-Lindau (VHL) disease, an autosomal dominant tumor suppressor syndrome that results in loss of VHL protein function and continuous upregulation of hypoxia-inducible factors. These tumors are composed of neoplastic stromal cells and abundant vasculature. Stromal cells express markers consistent with multipotent embryonically arrested hemangioblasts, which are precursors for hematopoietic and vascular lineages. Notch receptors are transmembrane signaling molecules that regulate multiple developmental processes including hematopoiesis and vasculogenesis. To investigate the importance of notch signaling in the development of VHL disease-associated CNS hemangioblastomas, the authors examined the presence of the four notch receptors and downstream notch effectors in this setting., Methods: The authors used surgical specimens obtained from confirmed VHL-associated hemangioblastomas. Immunohistochemical analysis for the four notch receptors and the downstream effectors was performed on formalin-fixed paraffin-embedded sections. Western blot analysis for HES1 was performed on frozen specimens., Results: All four notch receptors are present in hemangioblastomas. NOTCH1 and NOTCH4 receptors were widely and prominently expressed in both the stromal and vascular cells, NOTCH2 receptor expression was limited to primarily stromal cells, and NOTCH3 receptor expression was limited to vascular cells. All 4 receptors displayed a nuclear presence. Immunohistochemical analysis also demonstrated that downstream notch effectors, HES1 and HES5, were uniformly expressed in tumor stromal and vascular cells, but HES3, HEY1, and HEY2 were not. Strong HES1 expression was confirmed by Western blot analysis., Conclusions: The presence of all four notch receptors and downstream effector molecules suggests that the notch signaling pathway plays a critical role in the maintenance of the undifferentiated pluripotent phenotype of these tumors and in the associated vascular response. Moreover, the prominent expression of notch receptors in VHL-associated CNS hemangioblastomas reveals a new and possibly potent therapeutic target.

There is increasing evidence that suggests that knockout of tumor-suppressor gene function causes developmental arrest and protraction of cellular differentiation. In the peripheral nervous system of patients with the tumor-suppressor gene disorder, von Hippel-Lindau disease, we have demonstrated developmentally arrested structural elements composed of hemangioblast progenitor cells. Some developmentally arrested structural elements progress to a frank tumor, hemangioblastoma. However, in von Hippel-Lindau disease, hemangioblastomas are frequently observed in the cerebellum, suggesting an origin in the central nervous system. We performed a structural and topographic analysis of cerebellar tissues obtained from von Hippel-Lindau disease patients to identify and characterize developmentally arrested structural elements in the central nervous system. We examined the entire cerebella of five tumor-free von Hippel-Lindau disease patients and of three non-von Hippel-Lindau disease controls. In all, 9 cerebellar developmentally arrested structural elements were detected and topographically mapped in 385 blocks of von Hippel-Lindau disease cerebella. No developmentally arrested structural elements were seen in 214 blocks from control cerebella. Developmentally arrested structural elements are composed of poorly differentiated cells that express hypoxia-inducible factor (HIF)2α, but not HIF1α or brachyury, and preferentially involve the molecular layer of the dorsum cerebelli. For the first time, we identify and characterize developmentally arrested structural elements in the central nervous system of von Hippel-Lindau patients. We provide evidence that developmentally arrested structural elements in the cerebellum are composed of developmentally arrested hemangioblast progenitor cells in the molecular layer of the dorsum cerebelli.