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Background: The perioperative risk of sporadic hemangioblastomas (HBs) and von Hippel-Lindau disease (VHL)-associated hemangioblastomas (VHL-associated HBs) remains unclear due to the rare prevalence of HB. Therefore, this study aimed to clarify risk factors for better surgical management of patients with HBs., Methods: A retrospective analysis of surgically treated HB patients registered in the Diagnosis Procedure Combination database of Japan, between 2010 and 2015, was performed. Age, sex, sporadic HBs or VHL-associated HBs, medical history, tumor location, hospital case load, postoperative complications, and Barthel index (BI) deterioration were assessed. We also evaluated the outcomes and factors of perioperative BI deterioration., Results: In total, 676 patients with 609 intracranial lesions, 64 spinal lesions, and 3 with both types were eligible. Among them, 618 and 58 patients had sporadic HBs and VHL-associated HBs, respectively. The rates of perioperative BI deterioration were 12.5% and 12.2% for sporadic HBs and VHL-associated HBs, respectively. Perioperative mortality was 1.8% and 0% for sporadic HBs and VHL-associated HBs, respectively. Male sex, old age, high hospital case load, and medical history of diabetes mellitus were significantly associated with perioperative BI deterioration in all cases and sporadic HBs. Only medical history of diabetes mellitus was a significant risk factor for perioperative BI deterioration in VHL-associated HBs., Conclusions: No differences in perioperative BI deterioration rates between sporadic HBs and VHL-associated HBs were found. However, different risk factors for perioperative BI deterioration were identified. Consideration of these risk factors is recommended in all patients undergoing surgery for HB., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Primary optic disc tumors are often a challenge for ophthalmologists. They have very different appearances, and many primary optic disc tumors are associated with syndromic diseases (especially phakomatoses). Because of the rarity of primary optic disc tumors, classification and assessment are often difficult., Material and Methods: A systematic search in the electronic patient files (period 01.01.2015 - 01.06.2022) of the Department of Ophthalmology of the University of Münster Medical Center for patients with primary optic disc tumors was performed. For each tumor entity, exemplary cases were selected, which are presented here in detail. The criteria for the exemplary case selection were a clear diagnosis, the presence of suitable image material and follow-up examinations in our clinic., Results: The search yielded seven cases with three different primary tumor entities in the optic disc region (capillary hemangioblastoma, astrocytic hamartoma and melanocytoma). Four patients were selected as examples and are presented here: two cases for capillary hemangioblastoma (one isolated and the other in the context of Von-Hippel-Lindau syndrome) and one case each for astrocytic hamartoma and melanocytoma). We outline the further diagnosis and the course of the disease and we give an overview of the essential features of the underlying tumors in each case., Conclusion: The knowledge of the different primary tumors of the optic disc is necessary for a correct diagnosis and for the differentiation from malignant processes and optic disc anomalies. In many cases, further interdisciplinary diagnostics are necessary. Multimodal imaging is helpful and a referral to a center for ocular tumors is worth considering., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht./The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary tumour susceptibility disease caused by germline pathogenic variation of the VHL tumour suppressor gene. Affected individuals are at risk of developing multiple malignant and benign tumours in a number of organs.In this report, a male patient in his 20s who presented to the Urologic Oncology Branch at the National Cancer Institute with a clinical diagnosis of VHL was found to have multiple cerebellar haemangioblastomas, bilateral epididymal cysts, multiple pancreatic cysts, and multiple, bilateral renal tumours and cysts. The patient had no family history of VHL and was negative for germline VHL mutation by standard genetic testing. Further genetic analysis demonstrated a germline balanced translocation between chromosomes 1 and 3, t(1;3)(p36.3;p25) with a breakpoint on chromosome 3 within the second intron of the VHL gene. This created a pathogenic germline alteration in VHL by a novel mechanism that was not detectable by standard genetic testing.Karyotype analysis is not commonly performed in existing genetic screening protocols for patients with VHL. Based on this case, protocols should be updated to include karyotype analysis in patients who are clinically diagnosed with VHL but demonstrate no detectable mutation by existing genetic testing., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aims: Retinal haemangioblastomas (RH) remain a major cause of visual impairment in patients with von Hippel-Lindau (VHL) disease. Identification of genotype-phenotype correlation is an important prerequisite for better management, treatment and prognosis., Methods: Retrospective, single-centre cohort study of 200 VHL patients. Genetic data and date of onset of RH, central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renal cell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected. The number and locations of RH were recorded., Results: The first clinical finding occurred at an age of 26 ± 14 years (y) [mean ± SD]. In 91 ± 3% (95% CI 88-94) of the patients, at least one RH occur until the age of 60y. A total of 42 different rare VHL gene variants in 166 patients were detected. A higher age-related incidence of RH, CNSH, ccRCC and PNEN was detected in patients with a truncating variant (TV) compared to patients with a single amino-acid substitution/deletion (AASD) (all p < 0.01), while it is reverse for PPGL (p < 0.01). Patients with a TV showed 0.10 ± 0.15 RH per y during their lifetime compared to 0.05 ± 0.07 in patients with AASD (p < 0.02). The median enucleation/phthisis-free survival time in patients with a TV was 56y (95% CI 50-62) compared to 78y (95% CI 75-81) in patients with AASD (p < 0.02)., Conclusion: Compared to patients with AASD, patients with a TV develop RH, CNSH, ccRCC and PNEN earlier. They experience a higher number of RH and bear a higher risk of enucleation/phthisis. Thus, patients with a TV might be considered for a more intensive ophthalmological monitoring., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

We report the third presentation of an intermixed arteriovenous malformation and hemangioblastoma. The rare occurrence of the diagnostic histologic features of both a neoplasm and vascular malformation in a single lesion is more common in gliomas, as angioglioma, and is termed an 'intermixed' lesion. We review the literature concerning the developmental biology of each lesion, and potential interplay in the formation of an intermixed vascular neoplasm and vascular malformation. The roles of cellular origin, genetic susceptibility, favourable microenvironment, altered local gene expression and key regulatory pathways are reviewed. Our review supports angiography and genetic profiling in intermixed lesions to inform management strategies. Consideration should be given to multimodality therapeutic interventions as required, including microsurgical resection, stereotactic radiosurgery and further research to exploit emerging molecular targets.

Hemangioblastomas of central nervous system are rare and indolent. Twenty-five percent of cases are in association with von Hippel-Lindau disease. Surgery is the standard therapy but un-resectable or recurrent cases need radiation or systemic therapy. Defective von Hippel-Lindau tumor suppressor gene leads to vascular endothelial growth factor overexpression and enhance angiogenesis. Here we report a 19-year-old male, diagnosed at pediatric age, who had retinal and spinal cord hemangioblastomas. He was treated 34 months with bevacizumab, afterwards 12 months with thalidomide and tertiary therapy with pazopanib for 9 months which still goes on. In case of need, radiation and surgical procedures were performed. Vascular endothelial growth factor inhibition continuity is a good therapeutic option, which improves outcomes of von Hippel-Lindau-related hemangioblastomas.

Purpose: To provide an update summarizing the biologic pathways governing von Hippel-Lindau (VHL) disease pathogenesis and to provide an overview of systemic manifestations as well as screening recommendations., Methods: A PubMed search of the English language literature was reviewed using the following search terms: von Hippel-Lindau, von Hippel-Lindau disease, and VHL. Of 6,696 publications, the most current and pertinent information related to the pathogenesis and systemic aspects of VHL disease were included in this review., Results: von Hippel-Lindau disease is one of the most frequently occurring multisystem familial cancer syndromes. The disease results from germline mutation in the VHL tumor suppressor gene on the short arm of chromosome 3. Mutation in the VHL gene affects multiple cellular processes including transcriptional regulation, extracellular matrix formation, apoptosis, and, in particular, the cellular adaptive response to hypoxia. As a result, there is widespread development of vascular tumors affecting the retina, brain, and spine, as well as a spectrum of benign and malignant tumors and/or cysts in visceral organs., Conclusion: The ophthalmologist plays a key role in VHL disease diagnosis, as retinal hemangioblastoma is frequently the first disease manifestation. Screening guidelines for individuals with known VHL disease, and those at risk of VHL disease, help to ensure early detection of potentially vision-threatening and life-threatening disease.

Background: The growth rate and natural history of untreated hemangioblastomas remain unclear. This study investigated the natural history of untreated intracranial hemangioblastomas and predictors of tumor growth using volumetric assessment., Method: This study retrospectively enrolled 31 patients with untreated hemangioblastomas between 2004 and 2017 who were followed up for at least 12 months. The 31 patients had a total of 52 hemangioblastomas., Results: The 31 patients included 11 (35.5%) men and 20 (64.5%) women, of mean age 42.5 years. Seventeen (54.8%) patients were genetically diagnosed with Von Hippel-Lindau (VHL) disease. Of the 52 lesions, 33 (63.5%) grew during the follow-up period, whereas 19 (36.5%) remained stable. Overall mean actual growth rate (AGR) was 1.94 cm 3 /year, 2.38 cm 3 /year in the VHL and 1.79 cm 3 /year in the non-VHL group (p = 0.31). Overall mean relative growth rate (RGR) was 21%/year, 26%/year in the VHL and 19%/year in the non-VHL group. Time to 50% treatment probability was 34 months. The 1, 3, 5, and 7-year treatment probabilities were 11.5%, 50.1%, 52.7%, and 73%, respectively. The presence of only symptomatic lesions was significantly predictive of the growth of intracranial hemangioblastoma (odds ratio: 5.0, p = 0.02)., Conclusion: The overall growth rate of intracranial hemangioblastoma was faster than that of other benign intracranial tumors, with symptomatic lesions being the only meaningful predictor of tumor growth. Because of their rapid growth rate and high probability of treatment, a wait and scan management strategy should be carefully applied to intracranial hemangioblastomas.

Introduction: Hemangioblastomas are uncommon tumors of the central nervous system that can be seen in Von Hippel-Lindau (VHL) disease. Despite their benign histology, hemangioblastomas can cause substantial morbidity due to involvement of critical structures. In order to better understand the clinical behavior of spinal cord hemangioblastomas, we have analyzed the clinical, pathologic, radiologic characteristics and management of sporadic and VHL-associated cases at our institution., Methods: We performed a database search to identify all spinal hemangioblastomas at our institution between 1997 and 2016. Tumor characteristics were analyzed for sporadic and VHL-associated tumors separately in order to understand the differences in groups., Results: We included 20 patients with VHL-associated spinal hemangioblastomas, and 22 patients with sporadic spinal hemangioblastomas. VHL-associated patients were significantly younger at time of presentation compared to sporadic patients (p < 0.0025). Thirty-two patients (76.2%) presented with focal weakness, 34 (81.0%) with sensory loss, and 22 (52.4%) with pain. VHL patients were more likely to present with multiple symptoms (p < 0.001). Median follow-up time was 20.9 months, during which 17 tumors recurred. The median recurrence free interval was 44 months. There were no differences in gross total resection rates between sporadic and VHL-associated cases (p = 0.197). VHL-associated cases had a higher rate of repeat surgery for recurrence (14 patients-73.6%) compared to sporadic cases (3 patients-13.6%; p < 0.001)., Conclusion: VHL-associated spinal hemangioblastomas differ from sporadic tumors in terms of age, presenting symptoms, multifocality, and rate of recurrence. Recurrences seem to be unrelated to the extent of resection, indicating the need for life-long follow up for VHL patients.

Von Hippel-Lindau (VHL) disease is an autosomal dominant rare tumor syndrome characterized by high penetrance. VHL mutation carriers develop numerous manifestations in multiple organs during life. The natural course of development of new and growth of existing VHL-related manifestations is still unclear. In this study we aimed to gain insight into the development of subsequent manifestations in VHL disease. We retrospectively scored each new VHL-related manifestation as detected by standard follow-up (retina, central nervous system, kidneys and pancreas, excluding adrenal and endolymfatic sac manifestations) in 75 VHL mutation carriers. The Kaplan-Meier method was used to plot the cumulative proportions of all consecutive manifestations in each organ against age. The cumulative average number of manifestations in all organs during life was calculated by summating these cumulative proportions. Poisson model parameters were used to calculate average time to the detection of consecutive VHL manifestations in each organ. Consecutive VHL-related kidney and retina manifestations during life occur linearly according to Poisson distribution model. The total number of VHL manifestations rises linearly, with an average of seven VHL-related lesions at age 60 years. The incidence of consecutive VHL-related manifestations is constant during life in VHL mutation carriers. Our data is consistent with the notion that somatic inactivation of the remaining allele (Knudson's "two-hit" hypothesis) is the determining factor in developing new VHL-related manifestations.

Hemangioblastomas (HBs) are benign, highly vascular tumors, often characterized by loss of function of the von Hippel-Lindau (vHL) gene. They are the most common central nervous system tumor observed in vHL syndrome. Loss of function of the vHL gene creates a "pseudo-hypoxic" state, causing overactivation of hypoxia-inducible factor (HIF) and vascular endothelial growth factor (VEGF)-related pathways. In some cases, HBs can rapidly increase in size during pregnancy to then present acutely, which most frequently occurs after the 20th gestational week. These changes in size usually occur from enlargement of the cystic component of the HB. Due to their preferred location in the posterior fossa near critical structures as well as along the spinal cord, such cases can present with severe neurological deficits, requiring urgent surgical intervention in a multidisciplinary setting. However, the reasons for this acute flare-up during pregnancy remain poorly understood, as are the reasons why this occurs in only a subset of tumors. Unveiling the etiology for this clinical scenario can affect the treatment of HBs, as it will contribute to the understanding of the pathophysiology of such a transformation from a quiescent lesion to a symptomatic one, not only in the setting of pregnancy. Identifying the correct triggers and the conditions initiating and mediating this switch will enable us to develop preventive medications which should allow us to keep the tumor in its quiescent phase. In this pathophysiological review, we investigate the association between HB growth and pregnancy based on an analysis > 40 such published cases. We suggest that the proangiogenic state of pregnancy is the leading etiology for this striking association, and to support the argument, we discuss its potential impact on HIF overexpression in a non-hypoxic manner through activation of the PI3K/Akt/mTOR pathway by proangiogenic factors. Specifically, we discuss the involvement of placental growth factor (PlGF) and its receptor vascular endothelial growth factor receptor 1 (VEGFR-1) in various pathologic processes that can lead to the formation and growth of peritumoral edema and cysts, which are the primary causes for the development of any symptoms in HB. Both PlGF and VEGFR-1 are expressed at increased levels during pregnancy, and both have been reported as part of various pathological processes, including angiogenesis and tumorigenesis. The unique feature that both do essentially not show any significant negative impact on regular physiological processes makes them attractive therapeutic targets since very little side effects are expected. Further research into the effects of anti-PlGF or anti-VEGFR-1 therapy in HB is therefore recommended.

Purpose: This is the first single-institution study of its size to characterize the treatment impact and to address the question of whether hemangioblastoma treatment with Gamma Knife Stereotactic Radiosurgery (GKRS) in both sporadic and VHL patients changes the characteristic saltatory hemangioblastoma growth pattern., Methods: The authors reviewed a single-institution tumor registry to identify patients who had received GKRS for hemangioblastomas between January 1st, 1999, and December 31st, 2017., Results: 15 patients with 101 lesions met search criteria with a median age of first GKRS of 39.2 years (interquartile range [IQR] of 25.7-57.4 years), including 96 VHL and 5 sporadic lesions. The median time from GKRS to last follow-up was 5.4 years (IQR 2.3-11.5 years). 4 lesions (4%) and 3 patients (20%) experienced a local failure. The 1-year, 3-year, and 5-year freedom from new hemangioblastoma formation rates were 97%, 80%, and 46% respectively. Multivariate analysis revealed a reduction in tumor volume after GKRS. Several variables associated with a greater percent reduction in volume from GKRS to last follow-up: non-cystic status (p = .01), no prior craniotomy (p = .04), and follow-up time from GKRS (p < .0001)., Conclusions: GKRS is a successful long-term treatment option for hemangioblastomas changing the clinical course from saltatory growth to reduction in tumor volume. Non-cystic tumors and those without prior craniotomy were associated with a greater percent reduction in volume from GKRS at last follow-up.

Objective: Hemangioblastomas (HBs) are benign vascular tumors of the central nervous system and histologically contain abundant microvessels. Therefore, they clinically exhibit vascular malformation-like characteristics. It has been described that endothelial-to-mesenchymal transition (EndMT) contributes to the pathogenesis of cerebral cavernous malformations. However, it remains unknown whether EndMT contributes to the pathogenesis of central nervous system HBs. The aim of our study was to investigate whether EndMT occurs in central nervous system HBs., Methods: Ten central nervous system HBs were immunohistochemically investigated., Results: Cluster of differentiation (CD) 31 (an endothelial marker) and EndMT markers, such as α-smooth muscle actin (a mesenchymal marker) and CD44 (a mesenchymal stem cell marker), were expressed in the endothelial layer of microvessels in all cases. These findings suggest that endothelial cells (ECs) of microvessels in central nervous system HBs have acquired mesenchymal and stem cell-like characteristics and undergone EndMT. In all cases, both ephrin-B2 and EphB4, which are not detected in adult normal brain vessels, were expressed in the endothelial layer of microvessels. These data suggest that ECs of microvessels in central nervous system HBs are immature or malformed cells and have both arterial and venous characteristics., Conclusions: To our knowledge, this is the first report showing the possibility that EndMT contributes to the pathogenesis of central nervous system HBs. It is likely that ECs of microvessels in central nervous system HBs are immature or malformed cells and have both arterial and venous characteristics. EndMT is expected to be a new therapeutic target in central nervous system HBs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited disorder, characterized by hemangioblastomas of the retina and central nervous system (CNS); renal cysts; clear cell carcinoma; pheochromocytoma (PCC); endolymphatic sac tumors; cystadenomas of the epididymis in males; broad ligament of uterus in females; pancreatic cysts; cystadenomas; and neuroendocrine tumors. We report two cases of VHL disease that presented with PCC as the first manifestation. Further clinical developments during follow-up, hemangioblastoma of CNS in one case and a pancreatic neuroendocrine tumor (PNET) in the second case led to the diagnosis of VHL disease. Genetic analyses of the two cases revealed p.Arg161Gln (c.482G>A) and p.Leu129Pro (c.386T>G) heterozygous missense mutations in the VHL gene, respectively. In children, PCC may be the only and/or initial manifestation of VHL with delayed manifestations of the syndrome in other organs. PNET is a very rare manifestation of VHL disease. To the best of our knowledge, this is only the second reported case presenting with a combination of a PNET and bilateral PCC as components of childhood VHL disease. Pediatric patients diagnosed with PCC should be investigated for genetic causes and especially for VHL.

Importance: von Hippel-Lindau (VHL) disease-associated central nervous system (CNS) lesions include hemangioblastomas and endolymphatic sac tumors (ELSTs), which are associated with significant neurological morbidity and mortality. Recent studies provide critical new biological, diagnostic, and management insights into these tumors., Observations: Biological features, natural history, clinical findings, and management strategies of VHL disease-associated CNS tumors are reviewed. The VHL disease results from a germline mutation of the VHL gene (located on the short arm of chromosome 3), a tumor suppressor that encodes for the VHL protein. Whereas VHL disease is associated with visceral manifestations, CNS lesions are the most common source of morbidity and mortality. Craniospinal hemangioblastomas are almost entirely (99%) found in the cerebellum, brainstem, and spinal cord. These tumors arise from multipotent hemangioblasts. Peritumoral cysts frequently underlie the clinical findings associated with hemangioblastomas (>90% of symptomatic tumors). Prospective natural history studies demonstrate that CNS hemangioblastomas typically grow in a saltatory pattern. Due to this unpredictable growth pattern, surgical resection is reserved for symptomatic lesions, as many tumors do not become symptomatic. Recent studies indicate that VHL disease-associated ELSTs cause audiovestibular morbidity (hearing loss, tinnitus, and vertigo) via 3 mechanisms-otic capsule invasion, intralabyrinthine hemorrhage, and endolymphatic hydrops. Specialized magnetic resonance imaging techniques have been defined to elucidate each of these mechanisms, even when a tumor mass is not identified on imaging. Endolymphatic sac tumors cause audiovestibular morbidity unrelated to size or progression, and resection is now recommended at initial discovery of a tumor mass or a tumor-associated mechanism of morbidity., Conclusions and Relevance: New insights into the development, pathobiological origin, natural history, and long-term outcomes of VHL disease-associated CNS tumors have redefined their management and treatment indications and potentially provide new targeted therapeutic strategies. Resection is reserved for symptomatic hemangioblastomas, but early resection of newly detected ELSTs is now recommended.

Purpose: To study the use of ultra-widefield fluorescein angiography (UWF FA) in the detection and management of retinal capillary hemangioblastomas in patients with von Hippel-Lindau disease., Methods: This is a retrospective study of patients with von Hippel-Lindau disease who underwent UWF FA using the Optos camera at a single center from June 2009 to May 2015. The clinical use of UWF FA was reviewed, and the number of hemangioblastomas identified on UWF FA was compared with ophthalmoscopy and a simulated seven standard field (7SF) FA montage., Results: Twenty eyes of 10 patients were identified. Only 33% of lesions seen on UWF FA were also found on ophthalmoscopy, and 88% of lesions visualized on UWF FA were located outside the 7SF overlay. In 5 eyes that had gaze steering, 18% of lesions could be visualized only on gaze-steered images. For the 14 eyes with data available, 6 had procedures recommended and 8 eyes observed based on data from UWF FA. One of 20 eyes had a lesion on ophthalmoscopy that was missed by imaging., Conclusion: Ultra-widefield FA using the Optos camera is helpful for the evaluation and management of patients with von Hippel-Lindau disease. The UWF FA with gaze steering appears to detect more hemangioblastomas than ophthalmoscopy and conventional angiography.

Objective: Hemangioblastomas with enhanced cyst walls represent a rare radiologic presentation of hemangioblastomas with poor understandings. We aimed to summarize the clinical and radiologic features, important differential diagnosis, surgical strategy, and clinical outcome of this rare entity., Methods: From June 2008 to March 2017, 12 patients with cystic hemangioblastomas presenting with enhanced wall thickness on MRI were treated in our department. The clinical presentations, radiologic investigations, surgical treatment, neurologic outcome, and recurrence rate were evaluated. Important preoperative differential diagnosis and surgical strategy of this entity were discussed., Results: Twelve patients with cystic hemangioblastomas presenting with an enhanced cyst wall on magnetic resonance imaging were analyzed retrospectively. There were 5 male and 7 female subjects, with a mean age of 41.4 years (range, 13-78 years) and an average duration of symptoms before diagnosis of 2.23 months (range, 0.5-8.0 months). Radiologically, enhancement of both tumoral nodule and cyst were observed in 8 patients, while pure ring-enhanced cyst without typical tumoral nodule was found in 4 patients. Histopathologic examination confirmed the diagnosis of hemangioblastomas, and the enhanced cyst wall and mural nodule shared the same histopathologic pattern. Postoperative complications occurred in only 1 patient with postoperative cerebellar hemorrhage. During follow-up, 8 patients achieved favorable neurologic outcomes (Karnofsky score: 100) without recurrence; however, 4 patients experienced local tumor recurrence after the initial surgery., Conclusions: Hemangioblastomas with enhanced cyst wall possess distinctive radiologic features, and they are frequently misdiagnosed preoperatively. Favorable tumor control can be achieved only when gross total resection of both the tumor nodule and cyst wall are performed. Close follow-up is necessary because of the high recurrence rate in this subset of hemangioblastomas., (Copyright © 2017. Published by Elsevier Inc.)

The autosomal dominant von Hippel-Lindau disease (vHL) is associated with a lifelong risk of tumor development, especially retinal and CNS hemangioblastomas, pheochromocytoma, and renal cell carcinoma. Knowledge of paediatric vHL development is limited, and current surveillance guidelines are based on expert opinions. We aimed to describe the course of vHL development in children and adolescents, focusing on age at first manifestation, manifestation frequencies, and types. The prevalence of vHL diagnosis as well as manifestations in childhood were evaluated based on 99 patients, who had started surveillance before 18 years: 37 Danish patients from the national vHL research database and 62 international patients reported in 15 articles. Overall, 70% (69 of 99) developed manifestations before 18 years (median age at first manifestation: 12 years (range: 6-17 years)). Thirty per cent (30 of 99) had developed more than one manifestation type; the most frequent were retinal (34%) and CNS (30%) hemangioblastomas. Among the 37 Danish patients, 85% (97 of 116) of their tumors were asymptomatic. Vision outcome is significantly improved in hemangioblastomas that are treated while still asymptomatic. We agree with current guidelines that retinal surveillance be performed from birth. The patients had their first CNS hemangioblastomas at the median ages of 13-14 years (range: 6-17 years). Further, 11% (4 of 37) of the Danish patients had CNS surgery in their teenage years. Although the cohort is too small to make definite conclusions about specific initiation ages, regular CNS surveillance from vHL patients' teenage years seems clinically relevant., (© 2017 Wiley Periodicals, Inc.)

Background: Pediatric hemangioblastomas are rare, and the clinical features, timing of surgical intervention, optimal treatment, and clinical outcomes are still unclear., Methods: We performed a retrospective study of all patients with CNS hemangioblastomas who were treated at West China Hospital from January 2003 to March 2015. Patients under the age of 16 years were included in the study. The medical records of these patients were reviewed and statistically analyzed., Results: Twenty-five children (15 females and ten males, [mean age 12.6 ± 4.7 years, range 1-16 years]) presented with hemangioblastomas. Tumors were detected in the cerebellum, brainstem, and spinal cord in 40, 28, and 32% of patients, respectively. Sixteen children (64%) had VHL syndrome. The most frequent symptoms were those related to increased intracranial pressure. The mean duration of symptoms was 1.5 ± 2.1 months. Preoperative hydrocephalus was noted in 11 children (44%). Gross total resection was achieved in all children. Clinical symptoms improved in 19 children (76%), unchanged in four children (16%), and aggravated in two children (8%), respectively. The mean follow-up was 44.5 ± 32.3 months. Five patients (20%) experienced disease progression. Using univariate analysis, both tumor-associated cysts (P = 0.027) and VHL disease (P = 0.032) were significantly related to postoperative outcomes., Conclusions: Pediatric hemangioblastomas have many different clinical features compared with adult cases. A high degree of suspicion for VHL disease should be raised in pediatric hemangioblastomas. Despite many challenges involved, surgical outcomes for pediatric hemangioblastomas are favorable. Lifelong follow-up is mandatory to detect the disease progression.

Objectives: Hemangioblastomas in the cerebellopontine angle (CPA) are uncommon and have rarely been reported. They may be easily misdiagnosed because of the atypical location and clinical and imaging features. The present study aimed to characterize clinical and radiologic features, treatment strategies, and outcomes in these rare lesions and to investigate various factors that may affect postoperative outcomes., Methods: The medical records of patients with CPA hemangioblastomas who underwent surgery from 2003-2016 at the West China Hospital were reviewed retrospectively and statistically analyzed., Results: Twenty-three patients (14 males and 9 females) presented with CPA hemangioblastomas. Eight patients (34.8%) had von Hippel-Lindau (VHL) syndrome. Gross total resection was achieved in 22 patients (95.6%). The mean follow-up was 45.1 ± 36.2 months (range 3-144 months). After surgery, the symptoms improved in 18 cases (78.3%), remained unchanged in 3 cases (13%), and were aggravated in 2 cases (8.7%). Four patients showed local recurrence during follow-up (17.4%). Patients with cystic hemangioblastomas had a better neurologic improvement (P = 0.041) compared with patients with solid tumors. Furthermore, patients with maximal diameter of tumors >3 cm (P = 0.035) or solid tumors (P = 0.018) showed a higher incidence of postoperative complications. The local recurrence was correlated with VHL disease (P = 0.027)., Conclusions: Although hemangioblastomas of the CPA are challenging lesions to treat surgically, they can be removed safely when these lesions are appropriately diagnosed and treated. Patients with VHL disease are more likely to have a local recurrence. A regular follow-up is recommended to detect the local and distant recurrence, even if the clinical course is benign and the tumor is totally resected., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To report the occurrence of fibrovascular proliferation (FVP) in the retina in von Hippel-lindau (VHl) patients and its association with prior treatment., Design: A retrospective study., Methods: A retrospective study of 101 VHL patients. Fundus photos were available for 28 patients. FVP was classified into peripheral and posterior pole., Results: All 28 patients had retinal capillary hemangioblastomas (RCH) in 1 or both eyes; 15 patients were found to have FVP (group A), whereas 13 patients did not (group B). Mean age of patients in group A was 35 ± 11.3 years and 36.6 ± 13.8 in group B (P = 0.74). In group A, 27 eyes had RCH; 21 (77.77%) had FVP. In group B, 19 eyes had RCH. The number of treated eyes was significantly higher in group A (81.48%) than group B (42.1%) (P = 0.007). In group A, FVP was noted in the posterior pole in 9 eyes, in the periphery in 5 eyes, and 7 eyes developed both posterior pole and peripheral FVP., Conclusions: FVP can occur in the peripheral retina and in the posterior pole. There is a significant association between prior treatment of RCH and the occurrence of FVP., (Copyright 2017 Asia-Pacific Academy of Ophthalmology.)

Purpose: The evaluation of long-term results of vitreoretinal surgery and retinal capillary hemangioblastoma (RCH) resection in patients with complicated retinal detachment (RD) secondary to RCHs., Methods: Twelve eyes of 12 patients were operated on with vitreoretinal surgery, including occlusion of afferent and efferent feeder vessels with endodiathermy and endolaser photocoagulation, and subsequent resection of RCHs. The long-term anatomical and visual outcomes were retrospectively evaluated., Results: Total exudative RD was detected in six eyes and subtotal exudative RD was found in the remaining six eyes. A tractional component was present in eight eyes, and four eyes had pure exudative RD. Laser treatment had been previously applied to four eyes but vitreoretinal surgery was the primary treatment in eight eyes. A total of 19 RCHs were resected. The quadrant location of RCHs was superior temporal in six, superior nasal in five, inferior nasal in five, and inferior temporal in three. The dimensions of the RCHs ranged between 1 and 4 disk diameters (DD) (1-DD in 1 eye, 1.5-DD in 3, 2-DD in 10, 2.5-DD in 3, 3-DD in 1, and 4-DD in 1). Preoperative mean logarithm of the minimum angle of resolution visual acuity was 1.9 ± 1.0 (3.0-0.7) (20/1,588 ± 20/200 [20/20,000-20/100]). Silicone oil and C3F8 was applied to four and eight eyes, respectively. The median postoperative follow-up was 30.5 (18-48) months. Single operation and final anatomical success was obtained in 9 and 11 eyes, respectively. Mean logarithm of the minimum angle of resolution visual acuity in the postoperative 18th month and at the final visit were 1.05 ± 0.8 (3.0-0.2) (20/224 ± 20/125 [20/20,000-20/32]) and 0.96 ± 0.8 (3.0-0.2) (20/182 ± 20/125 [20/20,000-20/32]), respectively. New RCHs occurred in eight eyes. Rubeosis iridis was not present in any of the eyes., Conclusion: Promising anatomical and visual outcomes were obtained after vitreoretinal surgery and resection of RCHs in eyes with complicated RD secondary to RCH. However, life-long follow-up is needed to recognize recurrent RD seen even in the early period or recurrences of RCHs seen in the long-term period.

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.

Background: von Hippel-Lindau (VHL) disease is a rare hereditary tumor syndrome caused by VHL gene mutations that is characterized by heterogeneous phenotypes such as benign/malignant tumors of the central nervous system, retina, kidney, adrenal gland, and pancreas. The genotype-phenotype correlation has not been well characterized in the Korean population so far. Therefore, this study aimed to evaluate the VHL mutation spectrum and genotype-phenotype correlations in Korean VHL patients., Methods: Thirteen unrelated subjects with VHL mutations were included. Direct sequencing and multiplex ligation-dependent probe amplification were performed. Consequently, the clinical manifestations and family histories of the subjects were evaluated., Results: We identified 10 different VHL mutations. The c.160&#95;161delAT frameshift mutation was novel. Missense mutations clustered in 2 domains (α domain in exon 1; β domain in exon 3). The most frequently observed mutation was c.208G > A (p.Glu70Lys). Milder phenotypes were observed in subjects with de novo mutations. Age-specific risk for CNS hemangioblastoma was significantly higher in subjects carrying missense mutations within the HIF-α binding site (P < 0.05)., Conclusions: This study provides insight into the genotype-phenotype correlation in that amino acid substitutions in the HIF-α binding site may predispose patients to age-related risks of CNS hemangioblastoma.

Object: Intramedullary hemangioblastomas are rare lesions. They can be related to von Hippel-Lindau syndrome or they may be sporadic. This study describes surgical treatment for this infrequent tumor., Methods: Twelve consecutive patients received surgery to remove sporadic or von Hippel-Lindau syndrome-associated intramedullary hemangioblastomas. Patients were evaluated at four time points: before treatment, on postoperative day one, on the day of discharge, and at a follow-up examination., Results: The patients showed good preoperative neurological status. The cohort had a slight female predominance. All tumors spanned at least one spinal segment. In all cases, total tumor removal was achieved, and a good outcome was obtained. None of the following factors had a significant effect on outcome: age, sex, tumor size, the presence of a syrinx, or the presence of von Hippel-Lindau syndrome., Conclusions: The surgical removal of intramedullary hemangioblastomas resulted in satisfactory long-term functional outcomes. The best results were obtained before neurological symptoms occurred. Thus, we suggest that surgery should be considered for managing asymptomatic, surgically accessible, space-occupying lesions in sIH group, and isolated, space-occupying lesions in vHLS-IH group., (Copyright © 2016 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Hemangioblastoma of the central nervous system occurs as sporadic tumors or as a part of von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary tumor syndrome caused by a germline mutation in the VHL tumor suppressor gene. We screened a Chinese family with VHL for mutations in the VHL gene and evaluated a genetic test for diagnosing VHL disease and clinical screening of family members. DNA extracted from the peripheral blood of all live members and from tissue of deceased family members with VHL disease was amplified by polymerase chain reaction to 3 VHL gene exons. Mutations in the amplification products were compared against the Human Gene Mutation Database. The involvement of multiple organs among the kindred with VHL disease was confirmed by medical history and radiography. Of the 12 members of the 4-generation family, 5 were diagnosed with VHL disease. Patient age at the initial diagnosis was 26-36 years (mean = 31 years). The mean time was 15 (11-19 months) from symptom appearance to the first patient visit to the hospital. Sequence analysis revealed that the frameshift mutation 327del C (p.Gly39Alafs*26) in exon 1 affected all family members, but not the healthy individuals or 16 unrelated controls. Members without gene mutation showed no clinical manifestation of VHL disease. We detected a conserved novel frameshift mutation in the VHL gene of the family members that contributes to VHL. DNA analysis of VHL is advantageous for VHL diagnosis. We developed a quick and reliable method for VHL diagnosis.

Study Design: Marjolin's ulcer is a squamous cell carcinoma that develops in posttraumatic scars and chronic wounds. Suspicion of such lesions should be raised in chronic wounds demonstrating characteristic changes. We have reported the peculiar phenomenon of malignant transformation of chronic pressure sores that occurred in a paraplegic patient., Objectives: The aim of this study was to cover the extensive defects by a last resort reconstructive option., Setting: Department of Plastic and Reconstructive Surgery, Università Politecnica delle Marche, Ancona, Italy., Methods and Results: A 40-year-old paraplegic man, with multiple hemangioblastomas of the brain and spinal cord due to Von Hippel Lindau syndrome developed pressure ulcers with unstable healing over the sacral, trochanteric, bilateral, and ischiatic areas after 15 years from neurosurgery. The biopsy result showed an invasive squamous carcinoma. Carcinomas in pressure sores are highly aggressive, and they need to be treated more radically. In our case we opted for a demolitive surgical treatment including musculocutaneous rotational flap harvested from total left thigh to cover the extensive defects. The limb was previously disarticulated., Conclusion: In Marjolin's ulcer, multiple biopsies are the first-line modality for the early diagnosis as they are a safe method with high rate of accuracy. First-line treatment is surgery consisting of radical excision with lymph node dissection, if they are involved. Adjuvant radiation therapy may be used in selected patients. Management of massive pelvic defects can be a challenging problem. The pedicled lower limb flap offers a technique that can be considered as a last resort procedure for extensive defects where other options are insufficient or not available anymore. In our case the patient is disease-free after 2 years of follow-up.

Von Hippel-Lindau (VHL) disease is an autosomal dominant multiorgan tumor syndrome caused by a germline mutation in the VHL gene. Characteristic tumors include CNS hemangioblastomas (HBs), endolymphatic sac tumors, renal cell carcinomas, pheochromocytomas, and pancreatic neuroendocrine tumors. Sporadic VHL disease with a de novo germline mutation is rare. The authors describe a case of multiple CNS HBs in a patient with a heterozygous de novo germline mutation at c.239G>T [p.S80I] of VHL. This is the first known case of a sporadic de novo germline mutation of VHL at c.239G>T. Clinicians should continue to consider VHL disease in patients presenting with sporadic CNS HBs, including those without a family history, to confirm or exclude additional VHL-associated visceral lesions.

Introduction: Central nervous system (CNS) hemangioblastomas (HGB) are rare vascular tumors. The goal of this study was to analyze their epidemiology, treatment and prognosis in association with von Hippel-Lindau (VHL) disease., Methods: We retrospectively reviewed a series of patients treated in our department for a CNS HGB with VHL disease between 1996 and 2008. We analyzed pre- and postoperative clinical and radiological characteristics, number of visceral lesions (fundoscopy, abdomino-pelvian CT, metanephrines), clinical course (modified Rankin Scale and McCormick scale) and late prognosis (Kaplan-Meier survival curves)., Results: We studied 19 cases (sex-ratio 0.9, mean age 36). The mean time to diagnosis was 61days. The main symptom was intracranial hypertension for cerebellar lesions (7/15) and a sensitive-motor deficit for medulla oblongata (2/5) or spinal lesions (5/11). Preferred locations were cerebellum (15/31), often nodulo-cystic appearance, followed by spinal cord (11/31), frequently coming with adjacent syringomyelia. Multiple locations and visceral lesions were found in two-third of the cases. Surgical removal was complete in more than three-quarter of the cases. Mean follow-up duration was 9years. Postoperative mortality rate was 16%. In cerebellar and medulla oblongata locations together, final mRS was ≤1 in 17 of the 20 cases. In spinal cord locations, final McCormick score was ≤2 in all the cases. After delayed follow-up, about two-third of patients experienced recurrence or new progressive CNS lesions., Conclusion: HGB are rare CNS tumors. VHL disease should be considered when an HGB is diagnosed before 30, is located at the spinal cord, comes with multiple other CNS lesions or with typical peripheral lesions. Microsurgical removal is the gold standard treatment and can offer good functional results., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

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.

Hemangioblastoma is a rare tumor of uncertain histotype that typically arises in the cerebellum, quite often in the setting of Von Hippel-Lindau syndrome (VHL). Exceptional cases of hemangioblastoma arising outside the central nervous system have been reported, but little is known about their clinicopathologic and immunohistochemical features. Twenty-two cases of hemangioblastoma arising at peripheral sites were identified in consultation files. Clinical, morphologic, and immunohistochemical features were evaluated. Outcome data were obtained from referring pathologists. Twelve patients were female and 10 male; the median age was 58 years (range, 27 to 79 y). All the tumors were solitary (except 1) and arose in spinal nerve roots (12), kidney (3), intestine (2), orbit (1), forearm (1), peritoneum (1), periadrenal soft tissue (1), and flank (1). Five patients had VHL; another 5 had lesions suggestive of VHL. One patient had tuberous sclerosis. The median tumor size was 4 cm (range, 1.3 to 15 cm). Most tumors were well circumscribed; 6 were poorly marginated-3 eroded the adjacent bone and 1 extended into the pleura. All tumors were composed of an admixed population of plump spindle cells and microvacuolated cells with palely eosinophilic or clear cytoplasm, which often mimicked lipoblasts or renal cell carcinoma. In 5 cases the microvacuolated cells were scant. Spindle cell nuclei were hyperchromatic or vesicular with inconspicuous nucleoli. Four tumors showed marked nuclear pleomorphism. Mitotic activity was low (range, 0 to 2/10 HPF). All tumors had a complex capillary network, with admixed larger thin-walled or thick-walled vessels in a solid and often lobular growth pattern, similar to central nervous system hemangioblastoma. In 9 cases the larger vessels showed a branching hemangiopericytoma-like pattern. No necrosis or lymphovascular invasion was identified. Tumor cells expressed inhibin in 95% (20/21), neuron-specific enolase in 79% (15/19), and S100 protein in 65% (13/20); they also expressed GLUT1 (7/10, mostly weak), SMA (4/5), epithelial membrane antigen (2/8, focal), PAX8 (1/10), and desmin (1/4). Brachyury was consistently negative (0/19), as were keratin, HMB-45, melan-A, and GFAP. CD31 and CD34 highlighted tumor vasculature. Follow-up information was available for 17 patients (range, 5 to 117 mo; median 36 mo). Three patients had locally persistent disease after incomplete resection. True local recurrence or distant metastasis has not been identified in any patient so far. One patient died of metastatic renal cell carcinoma. Peripheral hemangioblastoma is rare, often associated with VHL syndrome, and may mimic some malignant tumors. The immunohistochemical profile can aid diagnosis. Unresectable cases may be locally aggressive, but complete excision appears to be curative. Recognition of this tumor may identify patients in whom testing for VHL syndrome is warranted.

Background: Intramedullary hemangioblastomas are rare benign tumors, occurring sporadically or in von Hippel- Lindau disease., Methods: We describe our local surgical experience with intramedullary hemangioblastomas. Clinical, imaging and surgical data from five consecutive hemangioblastoma cases identified from a series of 59 patients with intramedullary tumors treated between 2003-2009 are reviewed., Results: The mean age of the patients was 39.6 years (range 21- 56). All of them were symptomatic and two patients had von Hippel-Lindau disease with associated posterior fossa hemangioblastomas. All tumors were preoperatively diagnosed as hemangioblastomas based on magnetic resonance findings. All patients underwent surgery with complete removal of the tumor in 4 cases and a partial removal in a case with extension towards the anterior part of the cord. Good neurological outcome was noted in four cases while in the fifth, complicated with a significant intraoperative hemorrhage, a fully reversible aggravation of neurological status occurred., Conclusions: Spinal cord hemangioblastomas are surgically curable tumors. Microsurgical complete resection is the standard of care and can be performed with good neurological outcome in most of the cases. Ventral tumor location and important intraoperative bleeding are associated with less optimal outcome., (Celsius.)

Hemangioblastomas (HBs) are rare indolent vascular tumors that may occur sporadically or in association with von Hippel-Lindau (VHL) disease. Total neurosurgical resection is the standard upfront approach providing long-term tumor control. At time of tumor recurrence, second surgery, radiosurgery or radiotherapy are the main therapeutic strategies. Limited information is available on the role of pharmacological strategies. Anti-angiogenic agents, particularly multitarget tyrosine kinase inhibitors (semaxanib, sunitinib, vatalanib), thalidomide and interferon alfa-2a are currently the most widely studied strategies to prolonge disease stability. Salvage therapy with anti-angiogenetic drugs may be of benefit in some patients who are not suitable for surgery, radiosurgery or radiotherapy, with progressive or recurrent hemangioblastoma especially those located in retina, since anti-angiogenetic therapy may delay tumor progression. This strategy warrants prospective evaluation in a clinical trial., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Patients with von Hippel-Lindau disease carry a germline mutation of the Von Hippel-Lindau (VHL) tumor-suppressor gene. We discuss the molecular consequences of loss of VHL gene function and their impact on the nervous system. Dysfunction of the VHL protein causes accumulation and activation of hypoxia inducible factor (HIF) which can be demonstrated in earliest stages of tumorigenesis and is followed by expression of VEGF, erythropoietin, nitric oxide synthase and glucose transporter 1 in VHL-deficient tumor cells. HIF-independent functions of VHL, epigenetic inactivation of VHL, pVHL proteostasis, and links between loss of VHL function and developmental arrest are also described. A most intriguing feature in VHL disease is the occurrence of primary hemangioblastic tumors in the nervous system, the origin of which has not yet been entirely clarified, and current hypotheses are discussed. Endolymphatic sac tumors may extend into the brain, but originally arise from proliferation of endolymphatic duct/sac epithelium; the exact nature of the proliferating epithelial cell, however, also has remained unclear, as well as the question why tumors almost consistently develop in the intraosseous portion of the endolymphatic sac/duct only. The epitheloid clear cell morphology of both advanced hemangioblastoma and renal clear cell carcinoma can make the differential diagnosis challenging, recent developments in immunohistochemical differentiation are discussed. Finally, metastasis to brain may not only be caused by renal carcinoma, but may derive from VHL disease-associated pheochromocytoma/paraganglioma, or pancreatic neuroendocrine tumor.

We report a 41-year-old man who presented with low back pain, lower extremity paresthesia, urinary retention and constipation. Magnetic resonance imaging showed a vascular intradural-extramedullary lesion at the second lumbar vertebral level. His medical history revealed that he had undergone surgery for a cerebellar hemangioblastoma 5 years ago. The patient underwent a spinal operation and a vascular tumor was removed from filum terminale. Pathologic examination of the tumor revealed a hemangioblastoma. Hemangioblastomas may occur sporadically or in association with von Hippel-Lindau disease. In the second case, they are often multiple and accompanied by cerebellar and brainstem lesions. The hemangioblastomas reported in the conus medullaris or in the extramedullary compartment adjacent to the conus medullaris are rare, tumors of the cauda equina are uncommon, and lesions of the filum terminale are extremely rare. We report a patient with von Hippel-Lindau disease having filum terminale hemangioblastoma and discuss the diagnosis, pathogenesis and treatment of hemangioblastoma.

Purpose: Standard treatment of asymptomatic spinal cord hemangioblastoma in von Hippel-Lindau (VHL) disease has yet to be established. The purpose of this study was to propose guidelines for the treatment of asymptomatic spinal cord hemangioblastomas in VHL disease., Materials and Methods: VHL disease patients treated for spinal cord hemangioblastomas between 1999 and 2009 were included. All spinal cord hemangioblastomas were divided into three groups: Group 1, asymptomatic tumors at initial diagnosis followed with serial imaging studies; Group 2, asymptomatic tumors at initial diagnosis that were subsequently resected; and Group 3, symptomatic tumors at initial diagnosis, all of which were resected., Results: We identified 24 spinal cord hemangioblastomas in 12 patients. Groups 1, 2 and 3 comprised 13, 4 and 7 tumors, respectively. Group 1 exhibited a smaller tumor volume (257.1 mm³) and syrinx size (0.8 vertebral columns) than those of Group 2 (1304.5 mm³, 3.3 vertebral columns) and Group 3 (1787.4 mm³, 6.1 vertebral columns). No difference in tumor volume or syrinx size was observed between Groups 2 and 3. Five tumors in Group 1 were resected during follow-up because symptoms had developed or the tumor had significantly grown. Finally, among 17 asymptomatic tumors at the initial diagnosis, nine tumors were resected. Only one tumor of these nine tumors resulted in neurological deficits, while five of seven symptomatic tumors caused neurological deficits., Conclusion: Selective resection of asymptomatic tumors before they cause neurological deficits might bring about better outcomes.

We describe the microscopic findings of a clinically unsuspected retinal hemangioblastoma in an eye removed for pain and blindness. Although the patient was otherwise in good health, further investigation revealed von Hippel-Lindau (VHL) disease. Retinal hemangioblastomas are small benign tumors than can be easily overlooked in histological examination of an eye. Awareness of the context in which retinal hemangioblastoma can be found may be the most important factor in recognizing this lesion microscopically., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

Patients with von Hippel-Lindau (VHL) syndrome with diffuse CNS hemangioblastomas have morbidity related to their disease and require a lifetime of surgical resections. Ninety-seven percent of tumors progress, and 5-year surgery rates are 20%-60%. Stereotactic radiosurgery and fractionated radiotherapy have had limited success. For the first time, we have used infratentorial craniospinal radiation therapy (ICSRT) for VHL patients with CNS hemangioblastomas. Consecutive VHL patients treated at the National Institutes of Health with radiographic evidence of hemangioblastomas were included if they received ICSRT. Patients underwent neurologic examinations and imaging at 3- to 12-month intervals. Seven patients with 84 hemangioblastomas met eligibility criteria. ICSRT was commonly administered to 43.2 Gy in 24 fractions. Mean pre-ICSRT tumor volume was 5.48 cm(3). At a mean follow-up of 73.8 months, mean post-ICSRT tumor volume was 6.87 cm(3), and 91 tumors were identified. Complete radiographic resolution was achieved in 17.9% of lesions. Although many patients were no longer optimal surgical candidates, only 4 surgeries were needed for symptomatic lesions after ICSRT, compared with 33 prior. Acute toxicity was mild and no patient developed grade ≥1 late spinal cord toxicity according to the criteria of the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer, despite the high dose that the entire spinal cord received. Clinical and radiographic stability or resolution was demonstrated in the majority of tumors. Tumor growth rate in this study was less than reported in natural history studies, and the rate of surgical intervention was reduced. ICSRT was well tolerated, can decrease hemangioblastoma growth rate, and is a potential therapeutic option for VHL patients that warrants further investigation.

Background: Central nervous system (CNS) hemangioblastomas are a benign condition, which can be permanently cured by complete surgical removal. However, the vascular nature of these lesions and difficulties in localizing the tumors account for operative morbidity and recurrence. Power Doppler flow sonography has been proven useful during surgical removal of other vascular lesions., Objective: To evaluate the usefulness of Power Doppler flow sonography for hemangioblastoma., Methods: We used the SonoWand Invite (Sonowand AS, Trondheim, Norway) intraoperative navigation system in a consecutive series of hemangioblastomas operated on at our institution. Patients with von Hippel-Lindau (VHL) disease as well as sporadic hemangioblastomas were included., Results: The system was used on n = 64 consecutive hemangioblastomas operated on at our institution from 2007 to 2009. The tumors were localized in the cerebellum (n = 26), spinal cord (n = 27), brainstem (n = 10), and supratentorial (n = 1). In VHL disease was diagnosed 53 patients, and germline mutations of the VHL tumor suppressor gene were identified in 98%. Average tumor size was 1782 mm and 45% of the tumors were cystic. Forty-two of 64 tumors could be localized by grayscale sonography. All tumors were visible on power Doppler flow sonography. However, in 40 cases, only the pathological vessels and not the solid tumor itself enhanced on power Doppler. Postoperative MRI follow-up revealed remnant/recurrent tumors in 2 cases., Conclusion: Power Doppler flow sonography is a sensitive intraoperative tool to guide the surgical approach and resection and provides reliable resection control in surgery of CNS hemangioblastoma.

The autosomal dominantly inherited disorder von Hippel-Lindau disease (VHL) is caused by germline mutations in the VHL tumour suppressor gene (TSG). VHL mutations predispose to the development of a variety of tumours (most commonly retinal and central nervous system haemangioblastomas, clear cell renal carcinoma and phaeochromocytomas). Here, we review the clinical and genetic features of VHL disease, briefly review the molecular pathogenesis and outline clinical management and tumour surveillance strategies.

Von Hippel-Lindau disease (VHL) comprises a series of complicated clinical manifestations. We hereby report one unique case of VHL with a natural history that mimics acute myelitis. MRI and biopsy in this patient showed multiple solid hemangioblastomas of the central nervous system and kidney. This study further confirmed that VHL is of highly clinical, imaging, and pathological heterogeneity. Diagnosis for VHL should be based on combination of clinical, radiological, pathological, and genetic data.

A third case of corpus callosum hemangioblastoma (HB) is presented. With no preoperative embolization, surgery was uneventful and the postoperative course was excellent. Based on the literature, we attempted to clarify the histogenesis of HB and to explain why they are exceptional in the supratentorial region in contrast to the posterior cranial fossa. The VHL gene is expressed particularly in Purkinje cells of the cerebellum, but this expression is also possible in supratentorial structures. Its mutation leads to developmental arrest of angioblasts that become potentially neoplastic cells. These CD133-positive pluripotent neoplastic angioblasts, similar to stem cells, may be immature HB in the brain. They also express VEGF, coexpress Epo/EpoR, and are capable of differentiation into primitive vascular structures. This coexpression may not only mediate developmental stagnation, but may also induce HB proliferation. Therefore, HB tumorigenesis may be initiated during embryogenesis and may originate from angiomesenchyma because of the expression of three cell types (stromal cells, pericytes, and endothelial cells) in vimentin. Their capacity for proliferation and differentiation in HB depends on the microenvironment., (Copyright © 2009 Elsevier Masson SAS. All rights reserved.)

We report a rare case of a woman with bilateral papillary cystadenomata of the broad ligament with von Hippel-Lindau disease (VHL) (other manifestations: capillary hemangioblastomas of the spinal cord). Patient surveillance is important, because in the course of VHL-associated tumors malignant lesions may arise that are relevant for the prognosis.

Object: Spinal cord hemangioblastomas are a common protean manifestation of von Hippel-Lindau (VHL) disease and can be associated with significant morbidity. To better define expected outcome and optimal management of these tumors in the context of this neoplasia syndrome, the authors analyzed the findings from patients with VHL disease who underwent resection of spinal cord hemangioblastomas., Methods: Consecutive patients with VHL disease who underwent surgery for spinal cord hemangioblastomas with > 6 months follow-up were included in the study. Serial clinical examinations, functional scores, imaging findings, and operative records were analyzed., Results: One hundred eight patients (57 male, 51 female) underwent 156 operations for resection of 218 spinal cord hemangioblastomas. One hundred forty-six operations (94%) were performed for symptom-producing tumors. The most common presenting symptoms included hypesthesia (64% of resections), hyperreflexia (57%), dysesthesia (43%), and weakness (36%). Mean follow-up was 7.0 +/- 5.0 years (range 0.5-20.9 years). Complete resection was achieved for 217 tumors (99.5%). At 6-months follow-up, patients were stable or improved after 149 operations (96%) and worse after 7 operations (4%). Ventral tumors (OR 15.66, 95% CI 2.54-96.45; p = 0.003) or completely intramedullary tumors (OR 10.74, 95% CI 2.07-55.66; p = 0.005) were associated with an increased risk of postoperative worsening. The proportion of patients remaining functionally stable at 2, 5, 10, and 15 years' follow-up was 93, 86, 78, and 78%. Long-term functional decline was caused by extensive VHL-associated CNS disease (6 patients), VHL-associated visceral disease (1 patient), or non-VHL disease (2 patients)., Conclusions: Resection of symptomatic spinal cord hemangioblastomas is a safe and effective means of preserving neurological function in patients with VHL disease. Tumor location (ventral or completely intramedullary) can be used to assess functional risk associated with surgery. Long-term decline in neurological function is usually caused by VHL-associated disease progression.

To determine the effectiveness of stereotactic radiosurgery (SRS) treatment to central nervous system (CNS) hemangioblastomas in von Hippel-Lindau disease (VHL), we analyzed long-term results in VHL patients treated with SRS. Patients were enrolled in a prospective VHL natural history study, undergoing SRS treatment of CNS hemangioblastomas. Treatment regimens, serial clinical evaluations, and longitudinal imaging data were analyzed. Twenty VHL patients (10 males and 10 females) underwent SRS treatment of 44 CNS hemangioblastomas (39 cerebellar and 5 brainstem). Mean (+/-SD) age at treatment was 37.5 +/- 12.0 years (range: 13-67). Mean follow-up was 8.5 +/- 3.2 years (range: 3.0-17.6 years). All patients were alive at last follow-up. Mean treated tumor volume was 0.5 +/- 0.7 cm(3) (range: 0.01-3.6 cm(3)). Mean prescription dose was 18.9 Gy (range: 12-24 Gy) at the tumor margin. Local control rate at 2, 5, 10, and 15 years after SRS treatment was 91%, 83%, 61%, and 51%, respectively. Univariate analysis did not identify variables associated (P > .05) with worse tumor control at last follow-up. Thirty-three percent of SRS-treated small (<1.0 cm diameter), asymptomatic tumors progressed over a long-term follow-up. There were no long-term adverse radiation effects. Although SRS treatment of hemangioblastomas in VHL has a low risk for adverse radiation effects, it is associated with diminishing control over a long-term follow-up. These results indicate that SRS should not be used to prophylactically treat asymptomatic tumors and should be reserved for the treatment of tumors that are not surgically resectable.