Von Hippel-Lindau Disease Patients Research Articles

MP41-17 GENOTYPE-PHENOTYPE CORRELATIONS AND CLINICAL OUTCOMES OF VON HIPPEL-LINDAU DISEASE PATIENTS WITH LARGE DELETIONS

You have accessJournal of UrologyCME1 Apr 2023MP41-17 GENOTYPE-PHENOTYPE CORRELATIONS AND CLINICAL OUTCOMES OF VON HIPPEL-LINDAU DISEASE PATIENTS WITH LARGE DELETIONS Kenan Zhang and Kan Gong Kenan ZhangKenan Zhang More articles by this author and Kan GongKan Gong More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003279.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Approximately 20-40% of patients with von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary disease, exhibit large deletions (LDs). Few studies have focused on this population. Hence, we aimed to elucidate genotype-phenotype correlations and clinical outcomes in VHL patients with LDs. METHODS: We included 119 VHL patients from 50 unrelated families in whom LDs were detected using traditional and next-generation sequencing methods in this retrospective study. Other germline mutations were confirmed by Sanger sequencing. Genotype-phenotype correlations and survival were analyzed in different groups using Kaplan-Meier and Cox regression. We also evaluated the therapeutic responses to tyrosine kinase inhibitors (TKIs) therapy. RESULTS: The overall penetrance of patients whose age was <60 was 95.2%. Two VHL patients with LDs also carried CHEK2 and FLCN germline mutations. An earlier age of onset of retinal hemangioblastoma was observed in the next generation. The patients with exon 2 deletion of VHL had an earlier onset age of renal cell carcinoma and pancreatic lesions. The risk of renal cell carcinoma was lower in VHL patients with LDs and a BRK1 deletion. The earlier onset age group received a poorer prognosis. Four of 8 (50%) patients showed a partial response to TKIs therapy. CONCLUSIONS: The number of generations and the status of exon 2 could affect onset age of VHL-related manifestation. Onset age was an independent risk factor for overall survival. TKIs therapy was effective for VHL patients with LDs. Our findings would further support clinical surveillance and decision-making processes. Source of Funding: This work was supported by the National High Level Hospital Clinical Research Funding (High Quality Clinical Research Project of Peking University First Hospital, 2022CR75), National Natural Science Foundation of China (No. 82141103; 82172617; 82172665; 81872081), the Scientific Research Seed Fund of Peking University First Hospital (2021SF01), Capital's Funds for Health Improvement and Research (2022-2-4074), and Sino-Russian Mathematics Center. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e562 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kenan Zhang More articles by this author Kan Gong More articles by this author Expand All Advertisement PDF downloadLoading ...

Genotype-phenotype correlations and clinical outcomes of Von Hippel-Lindau disease patients with large deletions

Genotype-phenotype correlations and clinical outcomes of Von Hippel-Lindau disease patients with large deletions

Characterization of Microscopic Multicellular Foci in Grossly Normal Renal Parenchyma of Von Hippel-Lindau Kidney.

Background and Objectives: This study aims to describe the earliest renal lesions in patients with von Hippel-Lindau (VHL) disease, especially the multicellular microscopic pathologic events, to get information into the genesis of renal neoplasms in this condition. Materials and Methods: Multicellular events were identified, and 3dimensional reconstruction was performed in grossly normal kidney parenchyma from VHL disease patients by using H&E-stained slides previously prepared. Results: The lesions were measured and the volume of clusters was calculated. Immunohistochemistry was performed for downstream HIF-target protein carbonic anhydrase 9 (CAIX) as well as CD34 for assessment of angiogenesis. We divided lesions into four types according to lesion height/size. The number of lesions was markedly decreased from lesion 1 (smallest) to lesion 2, then from lesions 2 to 3, and again from lesion 3 to 4. Distribution was highly consistent in the four cases, and the same decrement pattern was seen in all blocks studied. The volumes of clusters were measured and divided into three categories according to their volume. The most frequent pathologic event in VHL kidneys was category 1 (smallest volume), then category 2, and then category 3. Conclusion: We demonstrate that tracking histologic and morphologic changes in 3 dimensions of multicellular microscopic pathologic events enabled us to confirm a protracted sequence of events from smaller to larger cellular amplification events in VHL kidney.

PD18-04 HAZARD OF DEATH IN VON HIPPEL-LINDAU DISEASE PATIENTS DEPENDS ON GENOTYPE AND ONSET AGE AS WELL AS FIRST AFFECTED LESION

You have accessJournal of UrologyCME1 May 2022PD18-04 HAZARD OF DEATH IN VON HIPPEL-LINDAU DISEASE PATIENTS DEPENDS ON GENOTYPE AND ONSET AGE AS WELL AS FIRST AFFECTED LESION Kaifang Ma, Lin Cai, and Kan Ging Kaifang MaKaifang Ma More articles by this author , Lin CaiLin Cai More articles by this author , and Kan GingKan Ging More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002556.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Historically, von Hippel-Lindau disease (vHL) is characterized by poor survival resulting from multi-organ lesions and higher morbidity. The present study sought to determine the effect of various genetic and clinical factors on survival in patients with vHL. METHODS: In this cohort study, we recruited 768 VHL mutation carriers from 299 vHL families who were retrospectively followed for a total of 30636 person-years. Cox regression models and Kaplan-Meier plot were used to evaluate the effect of genotype, gender, onset age, family history, birth order and first affected lesion on survival. RESULTS: The predicted mean life expectancy for vHL patients was 60 years, and 205 patients died in the study subjects. Individuals with truncated mutation genotype, earlier-onset age and CNS tumour as the first affected lesion had a significantly higher risk of all-cause death, vHL-related death and central nervous system hemangioblastoma-specific death. Male patients had a mortality hazard from renal cell carcinoma that was twice as high as female patients (HR = 1.96, 95%CI: 1.245-3.099, P = 0.005). CONCLUSIONS: The vHL survival study indicated that genotype, onset age, first affected lesion, as well as gender have significant effects on survival. These findings provide a basis for genetic counseling and development of guidelines for vHL surveillance. Source of Funding: This work was financially supported by the National Natural Science Foundation of China (No. 82172617; 82172665; 81872081), the Fundamental Research Funds for the Central Universities (No. BMU2018JI002), and Beijing Key Laboratory of Urogenital diseases (male) molecular diagnosis and treatment center © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e343 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kaifang Ma More articles by this author Lin Cai More articles by this author Kan Ging More articles by this author Expand All Advertisement PDF DownloadLoading ...

PD18-05 CLINICAL CHARACTERISTICS AND RISK FACTORS FOR SURVIVAL IN AFFECTED OFFSPRING OF VON HIPPEL-LINDAU DISEASE PATIENTS

You have accessJournal of UrologyCME1 May 2022PD18-05 CLINICAL CHARACTERISTICS AND RISK FACTORS FOR SURVIVAL IN AFFECTED OFFSPRING OF VON HIPPEL-LINDAU DISEASE PATIENTS Kenan Zhang, Cai Lin, Wuping Yang, Kan Gong, and Yawei Xu Kenan ZhangKenan Zhang More articles by this author , Cai LinCai Lin More articles by this author , Wuping YangWuping Yang More articles by this author , Kan GongKan Gong More articles by this author , and Yawei XuYawei Xu More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002556.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Von Hippel-Lindau (VHL) disease is an autosomal dominant genetic tumor syndrome with poor prognosis. The clinical manifestation was found to be more serious in affected offspring of VHL patients, but the risk factors and survival for them has never been reported before. We aimed to explore how these patients were influenced by genetic and clinical factors. METHODS: In this retrospective study, we collected 372 affected offspring of VHL patients from 118 unrelated VHL families. Patients were stratified into different groups based on sets of variables. The age-related risk, overall survival and central nervous system haemangioblastoma (CHB)-specific survival were analyzed between different groups using Kaplan-Meier survival analysis and Cox regression analysis. RESULTS: The estimated median life expectancy and median onset age for affected offspring of VHL patients was 66 years and 28 years respectively. The later generation and patients with mutations in exon 3 had an earlier onset age. The first presenting symptom was the only independent risk factor influencing overall survival and CHB-specific survival. Patients that the first presenting symptom is CNS significantly had a lower life expectancy both in overall survival and CHB-specific survival analysis. CONCLUSIONS: This study indicated that affected offspring of VHL patients with CNS as the first presenting symptom was an independent risk factor for overall survival and CHB-specific survival, which is helpful to clinical decision-making and generate a more precise surveillance protocol. Source of Funding: This study was granted by the ethical committee of Peking University First Hospital (2021KY336, Beijing, China). Each participant provided signed informed consent before participate in the present study and all patients understood the process and possible consequences © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e344 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kenan Zhang More articles by this author Cai Lin More articles by this author Wuping Yang More articles by this author Kan Gong More articles by this author Yawei Xu More articles by this author Expand All Advertisement PDF DownloadLoading ...

A1108 - Hazard of death in von Hippel-Lindau disease patients depends on genotype and onset age as well as first affected lesion

A1108 - Hazard of death in von Hippel-Lindau disease patients depends on genotype and onset age as well as first affected lesion

Clinical characteristics and risk factors for survival in affected offspring of von Hippel-Lindau disease patients

BackgroundVon Hippel-Lindau (VHL) disease is an autosomal dominant genetic tumour syndrome with poor prognosis. The clinical manifestation was found to be more serious in affected offspring of patients with VHL...

Abstract PL03-02: (Re)emerging principles of cancer therapy

Abstract It is likely that some of the mutations that occur late during evolution, whether passenger mutations or passenger mutations, are likely only tolerated (let alone advantageous to the cancer cell) because of the mutations that preceded them. If so, targeting mutations that occur early during tumor evolution should selectively kill cancer cells by unmasking the otherwise deleterious effects of subsequent mutations. There are now many precision cancer drugs that target such early mutations, including EGFR inhibitors for lung cancer, c-Kit mutations for GI stromal tumors, and B-Raf inhibitors for B-Raf mutant melanomas. Inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL) is an early event in kidney cancer. Inactivated proteins can sometimes be tackled by exploiting epistatic relationships or synthetic lethality. For example, pVHL suppresses the HIF2 transcription factor, which in turn regulates VEGF. VEGF inhibitors are now mainstays of kidney cancer treatment. HIF2 was viewed as “undruggable”, but undruggable proteins can sometimes be targeted by allosteric modulators or degraders. A first-in-class allosteric HIF2 inhibitor has advanced to phase 3 trials based on promising early data. Most cancer drugs work better in the frontline setting, and a recent study of previously untreated von Hippel-Lindau disease patients strongly suggests this will be true for the HIF2 inhibitor. Combination therapy will be required to cure most cancer. It is tempting to combine drugs that have interdependent actions in an attempt to achieve synergy, but this increases the risk of cross-resistance. The classical way to prevent resistance is to combine drugs that have distinct mechanisms of action (to minimize toxicity and cross-resistance). In this regard, immunotherapy has emerged as a powerful modality to treat cancer cells, and complements therapies aimed at inducing cancer cell death. Both kidney cancer and melanomas are highly immunogenic and can respond to immune checkpoint blockade, yet kidney cancer has a much lower mutational burden than melanoma. Recent work suggests that kidney cancers promiscuously express endogenous retroviruses, which might serve as a source of neoantigens. If true, it might be possible to pharmacologically enhance ERV expression to augment immunotherapy. Citation Format: William George Kaelin. (Re)emerging principles of cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr PL03-02.

Abstract 4708: Comprehensive analysis of 71 VHL germline deletions and rearrangements

Abstract An estimated 35% of von Hippel-Lindau (VHL) disease patients possess a gross germline deletion of one, two, or all three exons of VHL. In this study, 71 germline deletions have been extensively characterized, including 59 partial deletions (PD) and 12 complete VHL deletions (CD). VHL patients possessing germline VHL deletions were enrolled on an IRB-approved protocol. An Agilent custom high-definition comparative genomic hybridization array (aCGH) including 21 probes within the VHL gene at an average probe density of 2 probes per kb was used to map most VHL deletions; 4 patients were evaluated using CLIA-approved VHL deletion/duplication analysis. Primers were designed adjacent to the estimated deletion boundaries, and the breakpoints were mapped by Sanger bidirectional sequencing. Fifty eight deletions (55 PD and 3 CD) have been mapped to the exact breakpoint. Nearly all (55 of 58) deletions involve Alu repeats at both breakpoints. Several novel observations have been made in this cohort, including two cases that have complex rearrangements involving both deletion and inversion, two cases that have inserted extra Alu-like sequences, three cases that involve breakpoints in Alu repeats situated in opposite orientations, and a “hotspot” PD of exon 3 involving the same pair of Alu repeats that is observed in 12 families. In conclusion, this is the largest study to date of germline deletions in VHL patients. Deletions almost always involve Alu repeats, which are enriched in and near the VHL gene. In two cases, both a deletion and an inversion are observed, implying that it may be possible for an inversion to occur in the absence of deletion. Citation Format: Cathy D. Vocke, Christopher J. Ricketts, Laura S. Schmidt, Mark W. Ball, James Peterson, Lindsay A. Middelton, W Marston Linehan. Comprehensive analysis of 71 VHL germline deletions and rearrangements [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4708.

Growth characteristics and therapeutic decision markers in von Hippel-Lindau disease patients with renal cell carcinoma

BackgroundVon Hippel-Lindau (VHL) disease is a multi-systemic hereditary disease associated with several benign and malignant tumor entities, including clear cell renal cell carcinoma (ccRCC). Since ccRCCs grow slowly, nephron sparing surgery is typically performed at a tumor diameter of 3–4 cm before the tumor metastasizes. However, in the case of recurrent disease, repeated surgical intervention can impair renal function. Therefore, it is crucial to optimize the timing for surgical interventions through a better understanding of the growth kinetics of ccRCCs in VHL. We investigated tumor growth kinetics and modern volumetric assessment to guide future therapeutic decisions.ResultsThe prevalence of ccRCC was 28% in a cohort of 510 VHL patients. Of 144 patients with ccRCC, 41 were followed with serial imaging which identified 102 renal tumors, which exhibited heterogeneous growth kinetics. ccRCCs grew at an average absolute growth rate of 0.287 cm/year, an average relative growth rate [(lnV1-lnV0)/(t1-t0)] of 0.42% and an average volume doubling time of 27.15 months. Women had a faster relative growth rate than men. Age and specific mutations did not influence tumor growth. Because of the tumor heterogeneity, we developed an additional cut-off volume of 40 cm3 for surgical intervention.ConclusionsTumor heterogeneity and differences in growth kinetics is suggestive of a state of transient tumor dormancy in ccRCCs of VHL patients. The relative growth rate has not been previously described in other studies. Volumetric assessment as an additional parameter for surgical intervention could be a useful clinical tool and needs further investigation.

Hemangioblastoma Instead of Renal Cell Carcinoma Plays a Major Role in the Unfavorable Overall Survival of Von Hippel-Lindau Disease Patients.

Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome characterized by poor survival. The effect of the involvement of each organ on survival remains unclear. Our study aimed to study the effect of the involvement of each organ on survival in VHL disease patients. We retrospectively analyzed 336 patients from 125 families. The onset age was compared between different groups using Mann-Whitney U test and Kruskal-Wallis test. Univariate and multivariate time-dependent Cox regression analyses were conducted to evaluate how survival was influenced by the involvement of each organ. The median survival time for VHL disease patients was 66 years. The onset age was earlier in the central nervous system (CNS) group than in the abdominal group. The involvement of central nervous system hemangioblastoma (CHB) and retinal hemangioblastoma (RA) were independent risk factors for overall survival. The involvement of renal cell carcinoma (RCC) was not a significant risk factor for overall survival. Only RA was a risk factor for CHB-specific survival. This study analyzed the relationship between organ involvement and survival of VHL patients. This may help guide future genetic counseling and clinical decision-making.

Pilot study of dovitinib in patients with von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is an autosomal dominant disease occurring in 1 in 35,000 births and leads to an increased risk of a phenotypically diverse array of tumor types including, but not limited to, clear cell renal cell carcinoma (ccRCC) and hemangioblastomas (HBs). Previous studies of patients with VHL disease treated with the tyrosine kinase inhibitor (TKI) sunitinib did not show clinical response in HBs. Interestingly, VHL-related HBs displayed increased fibroblast growth factor receptor 3 (FGFR3) protein expression when compared to VHL-related ccRCCs. Therefore, in this pilot study, we assessed the safety and efficacy profile of TKI 258 (dovitinib), a multi-tyrosine kinase inhibitor of VEGF receptor and fibroblast growth factor (FGF), in patients with VHL disease who had measureable HBs. The trial was stopped after six patients enrolled after the toxicity stopping rule was triggered. With regards to safety, 6/6 subjects had at least one adverse event (AE). Best response in 6/6 subjects was stable disease (SD) in HBs. While the negative safety and efficacy results of this pilot study do not favor the use of dovitinib for the treatment of asymptomatic HBs in VHL disease patients, further investigation into alternative scheduling and other FGFR inhibitors for the treatment of HBs in VHL disease patients is warranted given the promising pre-clinical and molecular data.

VHL Inactivation in Precancerous Kidney Cells Induces an Inflammatory Response via ER Stress-Activated IRE1α Signaling.

Mutations and epigenetic inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) are major causes of clear-cell renal cell carcinoma (ccRCC) that may originate from chronic inflammation. However, the role of VHL loss of function in the development of ccRCC via inflammation remains poorly understood. VHL-mutant cells exhibit metabolic abnormalities that can cause chronic endoplasmic reticulum (ER) stress and unfolded protein response. We hypothesize that unresolved ER stress induces the inflammatory responses observed in ccRCC. ER stress markers including BiP and XBP1s were significantly increased in cultured and primary VHL loss-of-function kidney cells. In epithelial cells, the kinase activity of IRE1α was required for the induction of NF-κB and JNK and for the recruitment of macrophages. IRE1α kinase activity was also important for the development of fibrotic phenotype in conditional Vhlh knockout mice. Our results offer insights into the therapeutic potential against ccRCC development by relieving metabolic stress. Such cancer prevention strategy may be critical for high-risk cohorts such as the familial VHL disease patients. Cancer Res; 77(13); 3406-16. ©2017 AACR.

Development of Database and Genomic Medicine for von Hippel-Lindau Disease in Japan.

von Hippel-Lindau (VHL) disease is a hereditary tumor disease in which tumors develop in multiple organs, not only as hemangioblastomas (HBs) in the central nervous system, but also as kidney tumors, pheochromocytomas, and so on. Much about the epidemiology of VHL disease remained unknown until fairly recently in Japan, leading to calls for the establishment of a VHL disease epidemiological database in Japanese. To elucidate its epidemiology in Japan, the Japanese Ministry of Health, Labour and Welfare created the VHL Disease Study Group, which was put in charge of carrying out a nationwide epidemiological survey. The survey found close to 400 Japanese VHL disease patients throughout the country. Based on those results, the VHL Disease Study Group created the VHL Disease Treatment Guideline and also a severity classification. It is thought that the prognosis of VHL disease patients can be improved by performing genetic diagnosis and careful follow-up. Accordingly, the University of Tokyo Hospital put in place an in-hospital system for implementing genomic medicine for VHL disease based on genetic diagnosis. For that system, it was especially important to establish (I) accurate genetic diagnostic techniques, (II) genetic counseling capabilities for the patients and their families, and (III) a system of cooperation among multiple departments, including urology departments, and so on. Further elucidation of the epidemiology and the development of genomic medicine are needed to improve the treatment results of VHL disease in Japan.

Beta-2-glycoprotein-1 and alpha-1-antitrypsin as urinary markers of renal cancer in von Hippel–Lindau patients

Context: Von Hippel–Lindau disease (VHLD) is a rare inherited neoplastic syndrome. Among all the VHLD-associated tumors, clear cell renal cell carcinoma (ccRCC) is the major cause of death.Objective: The aim of this paper is the discovery of new non-invasive biomarker for the monitoring of VHLD patients.Materials and methods: We compared the urinary proteome of VHLD patients, ccRCC patients and healthy volunteers.Results: Among all differentially expressed proteins, alpha-1-antitrypsin (A1AT) and APOH (beta-2-glycoprotein-1) are strongly over-abundant only in the urine of VHLD patients with a history of ccRCC.Discussion and conclusion: A1AT and APOH could be promising non-invasive biomarkers.

137 Somatostatin Receptor Expression on VHL-Associated Hemangioblastomas Offers Novel Therapeutic Target

INTRODUCTION:Up to 80% of von Hippel-Lindau disease (VHL) patients develop central nervous system hemangioblastomas (HBs) during the disease course. Treatment of choice for symptomatic HBs remains surgery. VHL-related HBs show avid DOTATATE uptake on PET imaging, suggesting the presence of somatosta

Advanced renal cell carcinoma associated with von Hippel-Lindau disease: A case report and review of the literature.

The autosomal dominant hereditary disorder von Hippel-Lindau (VHL) disease is caused by a germline mutation in the VHL gene. The symptoms of VHL include hemangioblastoma of the central nervous system, retinal angiomas, visceral tumors and multiple visceral cysts. However, advanced renal cell carcinoma (RCC) occurs in few VHL patients at initial diagnosis; in addition, sporadic VHL disease with de novo germline mutation is rare. The current study reports the clinical case of a 33-year-old Asian male patient diagnosed with advanced bilateral multicentric renal carcinomas. The patient underwent radical nephrectomy with embolectomy of the right kidney for treatment of T3b-stage RCC and laparoscopic nephron-sparing surgery of the left kidney. Sunitinib was administered following histological diagnosis and during follow-up. Genetic analysis revealed a missense mutation, c.194C>G (p.Ser65Trp). In addition, genetic analysis of the patient's parents and brothers, who were unaffected, confirmed a diagnosis of de novo VHL disease. To the best of our knowledge, the present study reports the first known case of a sporadic de novo germline mutation of VHL at c.194C>G. Current understanding of the molecular genetics and pathophysiology of VHL disease, as well as developments in surgical and target therapies for RCC have advanced in recent years; however, early detection through genetic screening and regular clinical surveillance of VHL disease patients and their families continues to be the primary basis for managing the disease.

Spectrum of magnetic resonance imaging findings in pancreatic and other abdominal manifestations of Von Hippel-Lindau disease in a series of 23 patients: a pictorial review.

Von Hippel Lindau disease is a rare autosomal dominantly inherited multisystem disorder characterized by development of benign and malignant tumors. The abdominal manifestation of the syndrome are protean. Magnetic resonance plays an important role in identification of abdominal abnormalities and follow-up of lesions. To describe magnetic resonance imaging findings and patterns of pancreatic and other principal abdominal manifestations in a series of von Hippel-Lindau (VHL) disease patients and to review literature. We retrospectively reviewed abdominal magnetic resonance studies performed in 23 patients (10 males, 13 females) diagnosed of VHL. In all examined patients abdominal involvement was present. The pancreatic imaging findings detected were: unilocular cystic lesions (6/23: 26.1%); serous cystadenomas (11/23: 47.8%), including diffuse lesions (8/23: 34.8%); solid neuroendocrine tumors (8/23: 34.8%); cystic neuroendocrine tumors (1/23: 4.3%). The renal findings detected were: simple renal cysts (18/23: 78.3%); complex renal cysts (13/23: 56.5%), including benign lesions (10/23: 43.5%) and malignant lesions (3/23: 13.0%); renal carcinomas (11/23: 47.8%) and 5 of these (45.5%) were multiple and bilateral. Five patients (21.7%) presented pheochromocytoma (4 of these were bilateral; 80.0%) and 1 patient (4.3%) presented cystadenoma of the epididymis. In VHL disease patients, magnetic resonance imaging plays an essential role in the identification of pancreatic and other abdominal lesions, in their follow-up, in the screening of asymptomatic gene carriers, and in their long-term surveillance.

O5.10 * 5-ALA FLUORESCENCE GUIDED RESECTION OF HEMANGIOBLASTOMAS - IS IT USEFUL WITH CONVENTIONAL SURGICAL TOOLS?

BACKGROUND: The use of 5-aminolevulinic acid (5-ALA) for fluorescent guided malignant glioma surgery has proved to be useful to ensure a complete resection and thus, a best survival result. One report has described its usefulness for the detection of hemangioblastoma fragments at the cyst wall after apparently complete tumor resection. Von Hippel-Lindau disease patients suffer from many CNS hemangioblastomas, requiring multiple surgical procedures for resection of tumors, many times obscured because distorted structures and dense gliotic scars. MATERIAL AND METHODS: In order to test the eventual utility of 5-ALA fluorescent guided surgery in multiple hemangioblastomas, we have performed surgical procedures in two VHL patients for resection of multiple hemangioblastomas. After patient consent and approval by the Ethical Committee, 5-ALA was administered as oral dose 20 mg/kg 3 hours before anesthesia induction. A surgical microscope modified for Protoporphyrin IX (PpIX)fluorescence guidance, and frameless neuronavigation were used for the surgical procedure. After neuronavigated location and microsurgical dissection of tumors, some involved in dense scars, surgical field visualization was performed alternating standard light illumination and violet-blue light mode, to excite PpIX and collect fluorescence by visualization in surgical oculars and registration on a color camera. RESULTS: Both VHL patients had been previously subjected to surgical procedures for resection of previous posterior fossa tumors. In one case, resection of 7 cerebellar and brainstem tumors was planned on neuronavegator after MRI images, and performed; postsurgical MRI showed a one residual tumor, unnoticed during the surgical procedure because dense scarring tissue. In the second patient, 4 tumors were planned for resection, 3 in cerebellum and 1 in brainstem, and all of them were found and resected. In no case red remitted fluorescence was observed during the location, dissection or resection of tumors. Histopathology analysis proved that all 11 tumors were typical hemangioblastomas. One small area with pink remitted fluorescence in the surgical bed of a tumor proved to be just gliosis without tumor cells. CONCLUSIONS: In the present cases, 5-ALA fluorescent guided surgery for multiple hemangioblastoma resections has not been of utility with the regular surgical armamentarium, instead of the above mentioned experience from one author. The different system for fluorescence evaluation (adapted surgical microscope visualization versus spectroscopy adapted probe system and digitized evaluation) could explain the different results. Other studies are necessary to confirm the results with regular surgical armamentarium, and to explore ancillary tools for detection of localization and extension of CNS tumors under fluorescent conditions during surgical procedures.

De novo VHL germline mutation detected in a patient with mild clinical phenotype of von Hippel-Lindau disease

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.