Optic nerve and chiasm hemangioblastomas in von Hippel-Lindau disease: report of 12 cases and review of the literature.

Introduction: Optic nerve and chiasm hemangioblastomas are rare tumors, occurring sporadically or in the context of von Hippel-Lindau (VHL) disease. They have only been portrayed in isolated case reports and small cohorts. Their natural history and therapeutic strategies are only scarcely described. To better characterize these rare tumors, we retrospectively analyzed an optic nerve and chiasm hemangioblastoma series of 12 VHL patients. By combining our own experience to a review of all known cases in literature, we intended to create treatment recommendations for optic nerve and chiasm hemangioblastomas in VHL patients. Methods: We reviewed two electronic databases in the hospitals of our senior authors, searching for VHL patients with optic nerve or chiasm hemangioblastomas. Clinical data were summarized. Tumor size and growth rate were measured on contrast enhanced MRI. Comparable data were collected by literature review of all available cases in VHL patients (Pubmed, Trip, Google and Google Scholar). Results: Of 269 VHL patients, 12 had optic nerve or chiasm hemangioblastomas. In 10 of 12 patients, tumors were diagnosed upon annual ophthalmoscopic/MRI screening. Of 8 patients who were asymptomatic at diagnosis, 7 showed absent or very slow annual progression, without developing significant vision impairment. One patient developed moderate vision impairment. Two symptomatic patients suffered from rapid tumor growth and progressive vision impairment. Both underwent late-stage surgery, resulting in incomplete resection and progressive vision impairment. One patient presented with acute vision field loss. A watchful-waiting approach was adopted because the hemangioblastoma was ineligible for vision-sparing surgery. One patient developed progressive vision impairment after watchful waiting. In the literature we found 45 patient cases with 48 hemangioblastomas. Discussion: When optic nerve and chiasm hemangioblastomas are diagnosed, we suggest annual MRI follow-up as long as patients do not develop vision impairment. If tumors grow fast, threaten the contralateral eye, or if patients develop progressive vision deficiency; surgical resection must be considered because neurological impairment is irreversible, and resection of large tumors carries a higher risk of further visual decline.

Expression of Hemangioblast Proteins in von Hippel-Lindau Disease Related Tumors.

Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome that targets a highly selective subset of organs causing specific types of tumors. The biological basis for this principle of organ selectivity and tumor specificity is not well understood. VHL-associated hemangioblastomas share similar molecular and morphological features with embryonic blood and vascular precursor cells. Therefore, we suggest that VHL hemangioblastomas are derived from developmentally arrested hemangioblastic lineage keeping their potential of further differentiation. Due to these common features, it is of major interest to investigate whether VHL-associated tumors other than hemangioblastoma also share these pathways and molecular features. The expression of hemangioblast proteins has not yet been assessed in other VHL-related tumors. To gain a better understanding of VHL tumorigenesis, the expression of hemangioblastic proteins in different VHL-associated tumors was investigated. The expression of embryonic hemangioblast proteins Brachyury and TAL1 (T-cell acute lymphocytic leukemia protein 1) was assessed by immunohistochemistry staining on 75 VHL-related tumors of 51 patients: 47 hemangioblastomas, 13 clear cell renal cell carcinomas, 8 pheochromocytomas, 5 pancreatic neuroendocrine tumors, and 2 extra-adrenal paragangliomas. Brachyury and TAL1 expression was, respectively, observed in 26% and 93% of cerebellar hemangioblastomas, 55% and 95% of spinal hemangioblastomas, 23% and 92% of clear cell renal cell carcinomas, 38% and 88% of pheochromocytomas, 60% and 100% of pancreatic neuroendocrine tumors, and 50% and 100% of paragangliomas. We concluded that the expression of hemangioblast proteins in different VHL-associated tumors indicates a common embryological origin of these lesions. This may also explain the specific topographic distribution of VHL-associated tumors.

Cumulative surgical morbidity in patients with multiple cerebellar and medullary hemangioblastomas.

OBJECTIVE: Patients affected with von Hippel-Lindau disease often develop multiple hemangioblastomas in the cerebellum and spinal cord. Timing of surgical intervention is difficult and depends largely on the anticipated surgical morbidity. However, data regarding surgical outcome after multiple cerebellar and medullary surgeries are scarce. Our objective was to evaluate cumulative surgical morbidity in patients operated on multiple cerebellar and medullary hemangioblastomas and to deduce recommendations for treatment. METHODS: We performed a retrospective analysis for a consecutive cohort of von Hippel-Lindau patients with surgical treatment of at least two cerebellar and/or medullary hemangioblastomas. Pre- and postoperative functional grades were reviewed in patients' files and compared by Modified Ranking Scale (cerebellar surgeries) or by Modified McCormick Score (medullary surgeries). RESULTS: Thirty-six patients were surgically treated for at least two cerebellar hemangioblastomas (12 patients), at least two medullary hemangioblastomas (19 patients) or at least two hemangioblastomas in both locations (5 patients). Fourthy-eight cerebellar and 80 medullary procedures were performed in total. On average, multiple cerebellar surgeries caused no clinical deterioration, whereas multiple medullary surgeries led to a slight cumulative deterioration of postoperative functional grades. The severity of this deterioration did not correlate to the number of performed medullary surgeries. CONCLUSION: Resection of multiple cerebellar hemangioblastomas is not associated with cumulative morbidity. Although there is a certain cumulative surgical morbidity caused by medullary surgeries, its extent does not increase with the number of performed surgeries. Microsurgical removal of asymptomatic tumors with radiographic progression can also be considered for patients with multiple tumors and previous surgeries.

Von Hippel-Lindau Disease: Current Challenges and Future Prospects.

Understanding of molecular mechanisms of tumor growth has an increasing impact on the development of diagnostics and targeted therapy of human neoplasia. In this review, we summarize the current knowledge on molecular mechanisms and their clinical implications in von Hippel-Lindau (VHL) disease. This autosomal dominant tumor syndrome usually manifests in young adulthood and predisposes affected patients to the development of benign and malignant tumors of different organ systems mainly including the nervous system and internal organs. A consequent screening and timely preventive treatment of lesions are crucial for patients affected by VHL disease. Surgical indications and treatment have been evaluated and optimized over many years. In the last decade, pharmacological therapies have been evolving, but are largely still at an experimental stage. Effective pharmacological therapy as well as detection of biomarkers is based on the understanding of the molecular basis of disease. The molecular basis of von Hippel-Lindau disease is the loss of function of the VHL protein and subsequent accumulation of hypoxia-inducible factor with downstream effects on cellular metabolism and differentiation. Organs affected by VHL disease may develop frank tumors. More characteristically, however, they reveal multiple separate microscopic foci of neoplastic cell proliferation. The exact mechanisms of tumorigenesis in VHL disease are, however, still not entirely understood and knowledge on biomarkers and targeted therapy is scarce.

Hemangioblastoma and von Hippel-Lindau disease: genetic background, spectrum of disease, and neurosurgical treatment.

INTRODUCTION: Hemangioblastomas are rare, histologically benign, highly vascularized tumors of the brain, the spinal cord, and the retina, occurring sporadically or associated with the autosomal dominant inherited von Hippel-Lindau (VHL) disease. Children or adults with VHL disease have one of > 300 known germline mutations of the VHL gene located on chromosome 3. They are prone to develop hemangioblastomas, extremely rarely starting at age 6, rarely at age 12-18, and, typically and almost all, as adults. There is a plethora of VHL-associated tumors and cysts, mainly in the kidney, pancreas, adrenals, reproductive organs, and central nervous system. Due to a lack of causal treatment, alleviation of symptoms and prevention of permanent neurological deficits as well as malignant transformation are the main task. Paucity of data and the nonlinear course of tumor progression make management of pediatric VHL patients with hemangioblastomas challenging. METHODS: The Freiburg surveillance protocol was developed by combining data from the literature and our experience of examinations of > 300 VHL patients per year at our university VHL center. RESULTS: Key recommendations are to start screening of patients at risk by funduscopy with dilated pupils for retinal tumors with admission to school and with MRI of the brain and spinal cord at age 14, then continue biannually until age 18, with emergency MRI in case of neurological symptoms. Indication for surgery remains personalized and should be approved by an experienced VHL board, but we regard neurological symptoms, rapid tumor growth, or critically large tumor/cyst sizes as the key indications to remove hemangioblastomas. Since repeated surgery on hemangioblastomas in VHL patients is not rare, modern neurosurgical techniques should encompass microsurgery, neuronavigation, intraoperative neuromonitoring, fluorescein dye-based intraoperative angiography, intraoperative ultrasound, and minimally invasive approaches, preceded in selected cases by endovascular embolization. Highly specialized neurosurgeons are able to achieve a very low risk of permanent morbidity for the removal of hemangioblastomas from the cerebellum and spinal cord. Small retinal tumors of the peripheral retina can be treated by laser coagulation, larger tumors by cryocoagulation or brachytherapy. CONCLUSION: We consider management at experienced VHL centers mandatory and careful surveillance and monitoring of asymptomatic lesions are required to prevent unnecessary operations and minimize morbidity.

Predictors of dopamine agonist resistance in prolactinoma patients.

BACKGROUND: Surgical resection of prolactinomas resistant to dopamine agonists is frequently incomplete due to fibrotic changes of the tumour under pharmacological therapy. In order to identify a subgroup of patients who may benefit from early surgery, we thought to investigate possible predictive factors of pharmacological resistance of prolactinomas to dopamine agonists. METHODS: We retrospectively analyzed a database of a Belgian tertiary reference center for patients with pituitary tumours from 2014 to 2016. The groups of interest were patients with dopamine agonist responsive and resistant prolactinomas. The possible predictive factors, including MRI findings, endocrinological parameters, response of tumour and patient factors for dopamine agonist resistance were investigated. RESULTS: We included 69 patients of whom 52 were women (75,4%) and 17 were men (24,6%). Rate of dopamine agonist resistance was 15.9%. We identified four significant predictors of dopamine agonist resistance: male gender, a large tumour volume, prolonged time to prolactin normalization and presence of a cystic, hemorrhagic and/or necrotic component. In addition, symptoms due to mass effect, high baseline prolactin level and a high contrast capture on MRI are factors that can be taken into consideration. CONCLUSION: We identified predictive factors for pharmacological resistance and developed a scoring system for patient specific prediction of resistance to dopamine agonists. This scoring system may have impact on the timing and decision of surgery in prolactinoma patients after further prospective evaluation.

Minimally invasive resection of spinal hemangioblastoma: feasibility and clinical results in a series of 18 patients.

OBJECTIVE: Hemangioblastomas are benign, highly vascularized tumors that can occur sporadically or as part of von Hippel-Lindau (VHL) disease. Traditionally, spinal hemangioblastomas have been surgically treated via an open approach. In recent years, however, minimally invasive techniques using tubular retractors have been increasingly applied in spine surgery. Such procedures involve less tissue trauma but are also particularly demanding for the surgeon, especially in cases of highly vascular tumors such as hemangioblastomas. The object of this study was to evaluate the safety and efficacy of minimally invasive resection of selected spinal hemangioblastomas. METHODS: The authors conducted a retrospective single-center study of all patients who, between January 2010 and January 2018, had been operated on for spinal hemangioblastoma via a minimally invasive approach performed at the surgeon's discretion. The surgical technique is described and the pre- and postoperative neurological and imaging results were analyzed descriptively. The primary outcome was the postoperative compared to preoperative neurological condition (McCormick grade). The secondary outcomes were the extent of tumor resection and postoperative complications. RESULTS: Eighteen patients, 12 female and 6 male, harboring a total of 19 spinal hemangioblastomas underwent surgery in the study period. Seventeen patients had stable neurological findings with stable or improved McCormick grades (94.5%) at a mean of 4.3 months after surgery. One (5.5%) of the 18 patients developed progressive neurological symptoms with a worsened McCormick grade that did not improve in the long-term follow-up. Sixteen of the 18 patients had VHL disease, whereas 2 patients had sporadic spinal hemangioblastomas. In all patients, postoperative MRI showed complete resection of the tumors. No other surgery-related perioperative or postoperative complications were recorded. CONCLUSIONS: A minimally invasive approach for the resection of selected spinal hemangioblastomas is safe and allows complete tumor resection with good clinical results in experienced hands.

A focused 35-minute whole body MRI screening protocol for patients with von Hippel-Lindau disease.

BACKGROUND: Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumor syndrome. Affected patients develop central nervous system hemangioblastomas and abdominal tumors, among other lesions. Patients undergo an annual clinical screening program including separate magnetic resonance imaging (MRI) of the brain, whole spine and abdomen. Consequently, patients are repeatedly subjected to time-consuming and expensive MRI scans, performed with cumulative Gadolinium injections. We report our experience with a 35-min whole body MRI screening protocol, specifically designed for detection of VHL-associated lesions. METHODS: We designed an MRI protocol dedicated to the typical characteristics of VHL-associated lesions in different imaging sequences, within the time frame of 35 min. Blank imaging of the abdomen is carried out first, followed by abdominal sequences with Gadolinium contrast. Next, the full spine is examined, followed by imaging of the brain. A single dose of contrast used for abdominal imaging is sufficient for further highlighting of spine- and brain lesions, thus limiting the Gadolinium dosage. We used 1.5 Tesla equipment, dealing with fewer artifacts compared to a 3 Tesla system for spine- and abdominal imaging, while preserving acceptable quality for central nervous system images. In addition, imaging on a 1.5 Tesla scanner is slightly faster. RESULTS: From January 2016 to November 2018, we performed 38 whole body screening MRIs in 18 VHL patients; looking for the most common types of VHL lesions in the abdomen, spine, and brain, both for new lesions and follow-up. The one-step approach MRI examinations lead to 6 surgical interventions for clinically significant or symptomatic hemangioblastomas in the brain and spine. One renal cell carcinoma was treated with radiofrequency ablation. In comparison with previous conventional MRI scans of the same patients, all lesions were visible with the focused protocol. CONCLUSIONS: Annual screening in VHL disease can be done in a rapid, safe and sensitive way by using a dedicated whole body MRI protocol; saving MRI examination time and limiting Gadolinium dose.

Polyglobulia in patients with hemangioblastomas is related to tumor size but not to serum erythropoietin.

BACKGROUND: Hemangioblastomas are associated with elevated hemoglobin (Hb) levels (polyglobulia), which is associated with a higher risk for cerebral stroke, cardiac infarction and pulmonary embolism. The pathomechanism of polyglobulia remains unclear and different theories have been postulated. Among those are elevated serum erythropoietin (EPO) levels caused by secretion of the tumor or associated tumor cyst. METHODS: To elucidate the pathomechanism, we systematically investigated the relation between polyglobulia, serum EPO level, size of the solid tumor and associated cyst in hemangioblastomas. We prospectively evaluated hemoglobin and EPO levels in a series of 33 consecutive patients operated on hemangioblastomas in our center. We measured the size of the solid tumor and associated cyst in magnetic resonance imaging. Statistical evaluations were performed using the Fisher's exact test and student's t-test. RESULTS: As a result five patients had elevated hemoglobin levels. Only one of these had an elevated serum EPO level. Of 26 patients with normal hemoglobin levels, 4 patients had elevated EPO levels.Patients with low or normal hemoglobin levels (84%) had an average tumor size of 0.8 cm3, which differed significantly from patients with elevated hemoglobin levels (16%), who had an average solid tumor size of 8.0 cm3 (p < 0.05). We did not observe a significant correlation between EPO levels or polyglobulia and associated cysts. CONCLUSIONS: We therefore conclude that in contrast to previous case reports and interpretations, our data show no correlation between polyglobulia and EPO levels or associated cysts in patients with hemangioblastomas. In fact, it is the size of the solid tumor that correlates with polyglobulia.The study was retrospectively registered in the German Clinical Trial Registry on 10 July 2014; Trial registration: DRKS00006310.

Posterior approach for anteriorly located cervical spinal cord hemangioblastomas: technical note.

The surgical management of anteriorly located spinal cord hemangioblastomas remains a challenge. Different approaches have been published, of which the anterior approach seems to be the most obvious and commonly used. A posterior approach might be more suitable in certain patients, especially in cases of cystic hemangioblastomas. The authors present 3 cases of anterior spinal hemangioblastomas, which were all resected via a posterior approach. The authors discuss the rationale for choosing this approach and explain the technique in detail.

Central nervous system gadolinium accumulation in patients undergoing periodical contrast MRI screening for hereditary tumor syndromes.

BACKGROUND: Patients with hereditary tumor syndromes undergo periodical magnetic resonance imaging (MRI) screening with Gadolinium contrast. Gadolinium accumulation has recently been described in the central nervous system after repeated administrations. The prevalence and rate of accumulation in different subgroups of patients are unknown. Neither are the mechanism nor clinical impact. This may cause uncertainty about the screening. To explore the prevalence and rate of Gadolinium accumulation in different subgroups, we retrospectively analyzed MRIs of patients with von Hippel-Lindau disease (VHL) and Tuberous Sclerosis Complex (TSC). METHODS: We determined the prevalence and rate of accumulation in the dentate nucleus and globus pallidus on unenhanced T1-weighted MRI from VHL and TSC patients. We compared the signal intensities of these regions to the signal intensity of the pons. We evaluated the impact of number of MRIs, kidney function and liver function on Gadolinium accumulation. RESULTS: Twenty eight VHL patients and 24 TSC patients were included. The prevalence of accumulation in the dentate nucleus and globus pallidus increased linearly according to number of Gadolinium enhanced MRIs and was higher in the VHL group (100%). A significant linear correlation between number of MRIs and increased signal intensity was observed in the VHL group. CONCLUSIONS: Gadolinium accumulation occurs in almost all patients undergoing contrast MRI screening after >5 MRIs. We advocate a screening protocol for patients with hereditary tumor syndromes that minimizes the Gadolinium dose. This can be accomplished by using a single administration to simultaneously screen for brain, spine and/or abdominal lesions, using an MRI protocol focused on either VHL- or TSC-specific lesions. Higher prevalence and rate of accumulation in VHL patients may be explained by the typical vascular leakage accompanying central nervous system hemangioblastomas.

International multicentre validation of the arteriovenous malformation-related intracerebral haemorrhage (AVICH) score.

OBJECTIVE: The recently published arteriovenous malformation-related intracerebral haemorrhage (AVICH) score showed better outcome prediction for patients with arteriovenous malformation (AVM)-related intracerebral haemorrhage (ICH) than other AVM or ICH scores. Here we present the results of a multicentre, external validation of the AVICH score. METHODS: All participating centres (n=11) provided anonymous data on 325 patients to form the Spetzler-Martin (SM) grade, the supplemented SM (sSM) grade, the ICH score and the AVICH score. Modified Rankin score (mRS) at last follow-up (mean 25.6 months) was dichotomized into favourable (mRS 0-2, n=210) and unfavourable (mRS 3-6;n=115). Univariate and AUROC analyses were performed to validate the AVICH score. RESULTS: Except nidus structure and AVM size, all single parameters forming the SM, sSM, ICH and AVICH score and the scores itself were significantly different between both outcome groups in the univariate analysis. The AVICH score was confirmed to be the highest predictive outcome score with an AUROC of 0.765 compared with 0.705 for the ICH score and 0.682 for the sSM grade. CONCLUSION: The multicentre-validated AVICH score predicts clinical outcome superior to pre-existing scores. We suggest the routine use of this score for future clinical outcome prediction and in clinical research. TRIAL REGISTRATION NUMBER: NCT02920645.

Outcome of Surgical or Endovascular Treatment of Giant Intracranial Aneurysms, with Emphasis on Age, Aneurysm Location, and Unruptured Aneuryms--A Systematic Review and Meta-Analysis.

BACKGROUND: Designing treatment strategies for unruptured giant intracranial aneurysms (GIA) is difficult as evidence of large clinical trials is lacking. We examined the outcome following surgical or endovascular GIA treatment focusing on patient age, GIA location and unruptured GIA. METHODS: Medline and Embase were searched for studies reporting on GIA treatment outcome published after January 2000. We calculated the proportion of good outcome (PGO) for all included GIA and for unruptured GIA by meta-analysis using a random effects model. RESULTS: We included 54 studies containing 64 study populations with 1,269 GIA at a median follow-up time (FU-T) of 26.4 months (95% CI 10.8-42.0). PGO was 80.9% (77.4-84.4) in the analysis of all GIA compared to 81.2% (75.3-86.1) in the separate analysis of unruptured GIA. For each year added to patient age, PGO decreased by 0.8%, both for all GIA and unruptured GIA. For all GIA, surgical treatment resulted in a PGO of 80.3% (95% CI 76.0-84.6) compared to 84.2% (78.5-89.8, p = 0.27) after endovascular treatment. In unruptured GIA, PGO was 79.7% (95% CI 71.5-87.8) after surgical treatment and 84.9% (79.1-90.7, p = 0.54) after endovascular treatment. PGO was lower in high quality studies and in studies presenting aggregate instead of individual patient data. In unruptured GIA, the OR for good treatment outcome was 5.2 (95% CI 2.0-13.0) at the internal carotid artery compared to 0.1 (0.1-0.3, p < 0.1) in the posterior circulation. Patient sex, FU-T and prevalence of ruptured GIA were not associated with PGO. CONCLUSIONS: We found that the chances of good outcome after surgical or endovascular GIA treatment mainly depend on patient age and aneurysm location rather than on the type of treatment conducted. Our analysis may inform future research on GIA.

Characterization of endolymphatic sac tumors and von Hippel-Lindau disease in the International Endolymphatic Sac Tumor Registry.

BACKGROUND: Endolymphatic sac tumors (ELSTs) are, with a prevalence of up to 16%, a component of von Hippel-Lindau (VHL) disease. Data from international registries regarding heritable fraction and characteristics, germline VHL mutation frequency, and prevalence are lacking. METHODS: Systematic registration of ELSTs from international centers of otorhinolaryngology and from multidisciplinary VHL centers' registries was performed. Molecular genetic analyses of the VHL gene were offered to all patients. RESULTS: Our population-based registry comprised 93 patients with ELST and 1789 patients with VHL. The prevalence of VHL germline mutations in apparently sporadic ELSTs was 39%. The prevalence of ELSTs in patients with VHL was 3.6%. ELST was the initial manifestation in 32% of patients with VHL-ELST. CONCLUSION: Prevalence of ELST in VHL disease is much lower compared to the literature. VHL-associated ELSTs can be the first presentation of the syndrome and mimic sporadic tumors, thus emphasizing the need of molecular testing in all presentations of ELST. © 2015 Wiley Periodicals, Inc. Head Neck 38: 673-679, 2016.

VHL-deficient vasculogenesis in hemangioblastoma.

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.

Associations of collagen type I α2 polymorphisms with the presence of intracranial aneurysms in patients from Germany.

OBJECTIVE: Subarachnoid hemorrhage from ruptured intracranial aneurysms is associated with a severe prognosis. Preventive treatment of unruptured intracranial aneurysms is possible and recommended. However, the identification of risk patients by genetic analyses is not possible because of lack of candidate genes. Collagen type I α2 (COL1A2) has been associated with the presence of aneurysms in patients from Japan, China, and Korea. In this study, we investigate whether COL1A2 is a possible aneurysm candidate gene in the German population. METHODS: Patients admitted with intracranial aneurysms to our department and collaborating departments were enrolled. Three single-nucleotide polymorphisms (SNPs) of the COL1A2 gene, namely rs42524 in exon 28, rs1800238 in exon 32, and rs2621215 in intron 46 were investigated using restriction enzymes and sequencing. HapMap data were used for comparison of allelic frequencies with the normal population by χ2 test to identify significant associations between genotypes and the presence of aneurysms. RESULTS: Two hundred sixty-nine patients were enrolled into the study. There was a significant correlation with the presence of aneurysms for the GC allele of the SNP rs42524 in exon 28 (P = .02). The other polymorphisms did not show significant correlations. CONCLUSIONS: The COL1A2 gene is associated with intracranial aneurysms in a subset of the German population. However, it is not responsible for the majority of aneurysms, and further candidate genes need to be identified to develop sensitive genetic screening for patients at risk.

Renal cancer in von Hippel-Lindau disease and related syndromes.

Sporadic and hereditary forms of renal cell carcinoma (RCC), von Hippel-Lindau (VHL) disease and the familial paraganglioma syndromes are closely related in terms of their clinical, molecular, and genetic aspects. Most RCCs occur sporadically and the heritable fraction of RCC is estimated to be just 2-4%. An understanding of the molecular genetic basis, the disease-specific and gene-specific biology and the clinical characteristics of these cancer syndromes is of utmost importance for effective genetic diagnosis and appropriate treatment. In addition, such insight will improve our understanding of sporadic RCCs. To date, 10 different heritable RCC syndromes have been described. VHL syndrome is the oldest known hereditary RCC syndrome. Similar to VHL disease, phaeochromocytoma is a major manifestation of the paraganglioma syndromes types 1, 3 and 4 in which RCCs have been reported. These syndromes are therefore regarded as VHL-related disorders and are included in this Review. Multifocal tumours, bilateral occurrence, a young age at diagnosis and/or family history are clinical red flags suggestive of hereditary disease and should trigger referral for genetic and molecular analysis. The identification of an underlying genetic alteration enables gene-specific risk assessment and opens up the possibility of a tailored follow-up strategy and specific surveillance protocols as the basis of effective preventive medicine. The important goals of preventive medicine are to increase the life expectancy of affected patients and to improve their quality of life. The study of seemingly rare hereditary syndromes and their susceptibility genes has consistently revealed clues regarding the aetiology and pathogenesis of these diseases, and can aid diagnosis and the development of therapeutics for patients affected by much more common sporadic counterparts.

Autosomal dominant polycystic kidney disease: prevalence of renal neoplasias in surgical kidney specimens.

BACKGROUND: The role of autosomal dominant polycystic kidney disease (ADPKD) as a risk factor for renal cell carcinoma (RCC) is still under discussion. Data on prevalence of RCC in ADPKD are limited, especially on a large population scale. The aim of this study was to analyze the prevalence of RCC in ADPKD kidneys and characterize the clinical features of this coincidence. METHODS: Based on our histopathological registry for ADPKD and the Else Kröner-Fresenius Registry, we retrospectively reviewed malignant and benign renal lesions in patients with ADPKD who had undergone renal surgery from 1988 to 2011. RESULTS: 240 ADPKD patients underwent 301 renal surgeries. Mean age at surgery was 54 years. Overall, 16 malignant and 11 benign lesions were analyzed in 301 kidneys (5.3%; 3.7%), meaning that 12/240 (5%; 1:20) patients presented with malignant renal lesions. 66.7% (8/12) of these patients had undergone dialysis prior to surgery. We found 10/16 (63%) papillary RCC, 5/16 (31%) clear cell RCC, and 1/16 (6%) papillary noninvasive urothelial cancer. Regarding all renal lesions, 6/17 (35.3%) patients had more than one histological finding in their kidneys. In 2 cases, metachronous metastases were removed. Mean follow-up was 66.7 months. CONCLUSION: Kidney-related prevalence of RCC in ADPKD kidneys was surprisingly high. Whether or not this is due to chronic dialysis or due to the underlying disease is still speculative. Like other cystic renal diseases with an increased risk for RCC, the attending physician should be aware of the malignant potential of ADPKD, especially with concomitant dialysis.

Nervous system involvement in von Hippel-Lindau disease: pathology and mechanisms.

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.