Epidemiology and economic burden of Von Hippel-Lindau Disease-associated central nervous system hemangioblastomas and pancreatic neuroendocrine tumors in the United States.

BACKGROUND: To date, real-world evidence around the clinical and economic burden related to von Hippel-Lindau (VHL) disease is limited. Therefore, this study characterized the prevalence, healthcare resource utilization (HRU), and economic burden of von Hippel-Lindau-associated central nervous system hemangioblastoma (VHL-CNS-Hb) and pancreatic neuroendocrine tumors (VHL-pNET) in the United States (US). METHODS: Patients with VHL-CNS-Hb or VHL-pNET were identified from Optum's de-identified Clinformatics® Data Mart Database (2007-2020) and matched 1:5 to control patients without VHL disease or CNS-Hb/pNET. Prevalence rates of VHL-CNS-Hb and VHL-pNET (standardized by age and sex) in 2019 were estimated. HRU and healthcare costs (2020 US dollars) were compared between the VHL-CNS-Hb/VHL-pNET and control cohorts. RESULTS: In 2019, US prevalence rates of VHL-CNS-Hb and VHL-pNET were estimated to be 1.12 cases per 100,000 (3,678 patients) and 0.12 cases per 100,000 (389 patients), respectively. Patients with VHL-CNS-Hb (N = 220) had more inpatient, outpatient, and emergency department visits and $49,645 higher annual healthcare costs than controls (N = 1,100). Patients with VHL-pNET (N = 20) had more inpatient and outpatient visits and $56,580 higher annual healthcare costs than controls (N = 100). Costs associated with surgical removal of CNS-Hb and pNET were particularly high. CONCLUSIONS: In this retrospective, claims-based study, both VHL-CNS-Hb and VHL-pNET were associated with substantial HRU and healthcare costs, particularly tumor reduction surgery-related costs. These findings provide important insight for healthcare payers regarding the expected real-world costs that enrollees with VHL-CNS-Hb and VHL-pNET may incur over the course of their disease.

Perioperative Surgical Risks in Patients With Hemangioblastomas: A Retrospective Nationwide Review in Japan.

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.

A meta-analysis of different von Hippel Lindau mutations: are they related to retinal capillary hemangioblastoma?

Retinal capillary hemangioblastomas (RCH) is a benign tumor that represents the initial manifestation in roughly half of Von Hippel Lindau (VHL) patients. They may also occur sporadically without systemic involvement. A first meta-analysis study was investigated to estimate the prevalence of Retinal capillary hemangioblastoma (RCH) in Von Hippel Lindau (VHL) syndrome, and its relation to type and location of mutations in VHL gene. The electronic databases of PubMed, Scopus, Embase, and Google Scholar were utilized to find eligible papers published up to May 2020. Lastly, after the different prevalence of RCH in Europe compared to other continents was noted, we decided to consider European and non-European patients separately. The Random effect model was used to evaluate the relation between developing RCH and types of mutations. The overall prevalence of RCH among VHL patients is about 47%. The prevalence of RCH was significantly higher in Europe in comparison with non-Europeans (p value < 0.001). Overall, the differences between the prevalence of RCH among different mutation types were not statistically significant. However, in Europe, the prevalence of RCH was significantly higher in patients with truncation mutation (p value = 0.007). In Europe, the RCH in VHL patients who had a mutation in exon 2 was significantly lower in comparison with exon 1 (p value = 0.001); but in non-Europeans, the prevalence of RCH in VHL patients that involved exon 2 was significantly higher in comparison with VHL patients with a mutation in exon1 (p value = 0.012). The highest risk of developing RCH was reported among Europeans. Overall, this study showed that the prevalence of RCH in VHL syndrome is not related to type or location of mutations and difference of RCH prevalence is probably depends on other genetic or environmental factor that should be considered in subsequent studies.

Investigation and Management of Apparently Sporadic Central Nervous System Haemangioblastoma for Evidence of Von Hippel-Lindau Disease.

Haemangioblastomas are rare, highly vascularised tumours that typically occur in the cerebellum, brain stem and spinal cord. Up to a third of individuals with a haemangioblastoma will have von Hippel-Lindau (VHL) disease. Individuals with haemangioblastoma and underlying VHL disease present, on average, at a younger age and frequently have a personal or family history of VHL disease-related tumours (e.g., retinal or central nervous system (CNS) haemangioblastomas, renal cell carcinoma, phaeochromocytoma). However, a subset present an apparently sporadic haemangioblastoma without other features of VHL disease. To detect such individuals, it has been recommended that genetic testing and clinical/radiological assessment for VHL disease should be offered to patients with a haemangioblastoma. To assess "real-world" clinical practice, we undertook a national survey of clinical genetics centres. All participating centres responded that they would offer genetic testing and a comprehensive assessment (ophthalmological examination and CNS and abdominal imaging) to a patient presenting with a CNS haemangioblastoma. However, for individuals who tested negative, there was variability in practice with regard to the need for continued follow-up. We then reviewed the results of follow-up surveillance in 91 such individuals seen at four centres. The risk of developing a potential VHL-related tumour (haemangioblastoma or RCC) was estimated at 10.8% at 10 years follow-up. The risks of developing a recurrent haemangioblastoma were higher in those who presented <40 years of age. In the light of these and previous findings, we propose an age-stratified protocol for surveillance of VHL-related tumours in individuals with apparently isolated haemangioblastoma.

Impact of Pancreatic Neuroendocrine Tumor on Mortality in Patients With von Hippel-Lindau Disease.

OBJECTIVE: The main causes for morbidity and mortality in von Hippel-Lindau (VHL) disease are central nervous system hemangioblastoma and clear cell renal cell carcinoma, but the effect of VHL-related pancreatic neuroendocrine tumors (PNET) on patient outcome is unclear. We assessed the impact of PNET diagnosis in patients with VHL on all-cause mortality (ACM) risk. METHODS: We used the Surveillance, Epidemiology, and End Results database. Of 16 344 patients, 170 had VHL based on clinical diagnostic criteria, and 510 patients had PNET (91 VHL-related and 419 sporadic). RESULTS: Survival analysis demonstrated a lower ACM among patients with VHL-related PNET compared to patients with sporadic PNET (log-rank test, P = .011). Among patients with VHL, ACM risk was higher with vs without PNET (P = .029). The subgroup analysis revealed a higher ACM risk with metastatic PNET (sporadic P = .0031 and VHL-related P = .08) and a similar trend for PNET diameter ≥3 cm (P = .06 and P = 0.1 in sporadic and VHL-related PNET, respectively). In a multivariable analysis of patients with VHL, diagnosis with PNET by itself was associated with a trend of lower risk for ACM, while presence of metastatic PNET was independently associated with increased ACM risk. CONCLUSION: Diagnosis with PNET is not associated with a higher ACM risk in VHL by itself. The independent association of advanced PNET stage with higher mortality risk emphasizes the importance of active surveillance for detecting high-risk PNET at an early stage to allow timely intervention.

Genotype-phenotype correlation in von Hippel-Lindau disease.

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.

Sporadic Solid/Cystic Hemangioblastomas in the Cerebellum: Retrospective Study of More Than Ten Years of Experience in a Single Center.

BACKGROUND: Solid/cystic hemangioblastomas are rare, and they lack a systematic description. We clarify the epidemiology, clinical features, imaging characteristics, and surgical outcomes of sporadic solid/cystic hemangioblastomas in the cerebellum. METHODS: A total of 75 patients with sporadic hemangioblastomas from 2006 to 2018 were enrolled in this retrospective study and divided into solid (26/75), cystic (40/75), and solid/cystic (9/75) groups according to the imaging findings. All patients underwent microsurgical resection and had a definite 31 pathologic diagnosis. RESULTS: The age at diagnosis in the solid/cystic group was the highest among the 3 groups (P < 0.05). The solid/cystic group showed the shortest symptom duration (P < 0.05), which was related to obvious peritumoral brain edema (P < 0.05). The combination of computed tomography angiography and magnetic resonance imaging helped with the differential diagnosis. The solid/cystic group showed the lowest rate of gross total resection (P < 0.05) as a result of the obscure brain-tumor interface, and the guidance of intraoperative ultrasonography helped with the microsurgical procedures to a certain extent. Patients in the solid/cystic group showed greater intraoperative blood loss (P < 0.05), a lower ratio of symptom improvement (P < 0.05), and a longer mean hospital stay (P < 0.05) than did patients in the cystic group. CONCLUSIONS: Cerebellar sporadic solid/cystic hemangioblastomas are rare and usually affect elderly people. The combination of computed tomography angiography and magnetic resonance imaging may improve the preoperative diagnosis. Solid/cystic hemangioblastomas showed the lowest rate of gross total resection as a result of the obscure brain-tumor interface.

A rare condition: Spontaneous subarachnoid haemorrhage due to spinal hemangioblastoma: Report of 2 cases and review of the literature.

INTRODUCTION: Subarachnoid haemorrhage (SAH), secondary to spinal hemangioblastoma (HBL), is extremely rare, with only a few case reports to date. We report the experience of our reference centre for spinal tumours and Von Hippel-Lindau (VHL) disease in patients with spinal HBL presenting with SAH. We further performed a systematic review of the literature. METHODS: We report two cases. A systematic search was performed using the PubMed, Embase and Cochrane databases, with no limit for publication date. Inclusion criteria were: patients with HBL presenting with SAH, with or without VHL. The systematic review retrieved only 10 studies, including 16 patients. RESULTS: In our centre, the first case concerned radicular HBL at D12 level, presenting with spinal and brain SAH. The patient underwent uneventful microsurgical en bloc resection. Postoperative course was normal. The second case concerned HBL with SAH at the cervico-medullary junction, with rapidly fatal course. The systematic review revealed female predominance, at a median age of 40 years, with HBL predominantly located at cervical level, common preoperative symptoms being headache and signs of meningeal irritation. CONCLUSIONS: In conclusion, spinal HBL is an extremely rare cause of SAH. The systematic review found putative risk factors: female gender, age 40-50 years, cervical location, and median size 2cm. Diagnosis can be difficult when presentation mimics intracerebral SAH. We advocate early surgical removal. The risk of rapidly fatal course, in case of major haemorrhage, needs to be borne in mind.

Novel genetic characterisation and phenotype correlation in von Hippel-Lindau (VHL) disease based on the Elongin C binding site: a large retrospective study.

BACKGROUND: Von Hippel-Lindau (VHL) disease is an autosomal dominant genetic tumour syndrome resulting from mutations in the VHL gene lineage, and its prognosis is generally poor. This study aimed to provide a more valuable genotype-phenotype correlation based on the Elongin C binding site in VHL disease. METHODS: This study included 553 patients (194 families) who were diagnosed with VHL disease in our centre from September 2010 to February 2019. According to the type of gene mutation, the patients were divided into the Elongin C binding site missense mutation (EM) group, the non-Elongin C binding site missense mutation (nEM) group and the truncation mutation (TR) group. We analysed and compared the age-related tumour risk and prognosis of the three groups. RESULTS: A total of 14 new intragenic mutations were found in this cohort. The age-related risk of central nervous system haemangioblastoma (CHB) and pancreatic tumour in the EM group was lower than in the combined nEM-TR group, while the corresponding risk of pheochromocytoma (PHEO) was higher. Additionally, the prognoses of EM and nEM-TR were analysed. The median survival period in the EM group was longer than that in the nEM-TR group, and both the total survival and the CHB-specific survival of the EM group were better than those of the nEM-TR group. CONCLUSION: In conclusion, our study demonstrated that the EM was an independent risk factor for PHEO. The EM is also an independent protective factor for CHB age-related risk, overall survival and CHB-specific survival in VHL disease. This modified genotype-phenotype correlation integrates gene mutation, the Elongin B binding site, and phenotypic diversity and provides a reference for clinical diagnosis.

Comprehensive characterization of a Canadian cohort of von Hippel-Lindau disease patients.

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or ß-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.

[Retinal hemangioblastoma: Treatment strategy and long-term follow-up in a retrospective cohort]. / Hémangioblastomes rétiniens : stratégie thérapeutique et suivi à long terme dans une cohorte rétrospective.

INTRODUCTION: Retinal hemangioblastoma (RH) is a benign vascular tumor frequently associated with Von Hippel-Lindau disease (VHL). Tumor growth of RH may lead to deterioration of visual acuity, which can be difficult to treat. Early diagnosis may reduce complication rate and side effects of treatment. The present retrospective study evaluates the long-term follow-up and complications of RH treatment as a function of the therapeutic strategy used. MATERIALS AND METHODS: The study included patients with RH, followed at Croix Rousse university hospital, Lyon between 2010 and 2017. The following clinical features were recorded : age at diagnosis, presenting symptom, presence of VHL disease, treatments used, post-therapeutic complications and visual outcomes. RESULTS: Seven eyes of five patients were included in our study. Eighty percent of the patients had a mutation in the VHL gene. Four eyes (57%) were treated with laser photocoagulation and three eyes (43%) were treated with cryotherapy. The mean duration of follow-up was 35 months. One of the eyes treated using laser photocoagulation was complicated by an early epiretinal membrane with no visual consequence. Of the eyes treated by cryoapplication, one was complicated by a vitreous hemorrhage, and another by a rhegmatogenous retinal detachment, both of which resulted in a decrease in visual acuity. CONCLUSION: The long-term outcome for patients treated for RH was relatively good. Complications were strongly correlated with the initial size of the vascular tumor. Early diagnosis seems to improve visual outcomes. Ophthalmologic monitoring should be part of the systemic, multidisciplinary management.

Hemangioblastomas of the Posterior Cranial Fossa in Adults: Demographics, Clinical, Morphologic, Pathologic, Surgical Features, and Outcomes. A Systematic Review.

BACKGROUND: Posterior cranial fossa (PCF) hemangioblastomas are benign, highly vascularized, and well-differentiated tumors with well-described histopathologic features. Although relatively rare, this tumor is the most prevalent primary tumor of the cerebellum in adults. OBJECTIVE: Because the demographics of patients with such a tumor (as well as the clinical, morphologic, pathologic, surgical features, and outcomes) are not fully understood, we systematized characteristic patient and tumor features. METHODS: We undertook a systematic review of the English-language literature in PubMed for PCF hemangioblastomas in adults published in the past 31 years. We analyzed geographic distribution and year of publication of articles; demographic data of patients; presenting symptoms and clinical signs; tumor location and morphology; histopathologic features, extent of tumor resection, perioperative blood loss, and postoperative complications; length of hospital stay; and outcomes. RESULTS: We reviewed 207 articles describing 1759 infratentorial hemangioblastomas in a cohort of 1515 adult patients. We found female predominance in patients with Von Hippel-Lindau disease (VHLD) compared with male predominance in the general patient group. Symptoms of intracranial hypertension were more common in the VHLD group compared with the general group of patients. The cerebellar location was more common in the VHLD group and solid (parenchymatous) tumor was the most common type. Most patients underwent total resection but rate of resection did not differ between the general and VHLD groups. Most patients had a favorable outcome. CONCLUSIONS: The literature of adult PCF hemangioblastomas is limited and general surgical experience with such tumors is scarce because of their rarity. Rates of postoperative complications and mortality remain higher than expected. However, prognosis and surgical outcomes are generally favorable. Nevertheless, surgery of adult PCF hemangioblastomas is a demanding and challenging task.

Retinal hemangioblastoma: prevalence, incidence and frequency of underlying von Hippel-Lindau disease.

BACKGROUND AND AIMS: We aimed to determine the frequency of von Hippel-Lindau disease (vHL) as the underlying cause of retinal hemangioblastoma and to estimate retinal hemangioblastoma incidence and prevalence in a national cohort study. METHODS: Through the national patient register and vHL research database, we identified 81 patients diagnosed with a retinal hemangioblastoma in Denmark between 1977 and 2014. Consent was obtained for 54 living and 10 deceased patients with retinal hemangioblastoma. For each participant, we collected medical records and family information. Almost all (63 of 64) participants were or had previously been tested for mutations in the VHL gene. RESULTS: Overall, 84% of the participants (54 of the 64) had vHL. Compared with the non-vHL patients, the vHL patients had their first retinal hemangioblastoma at a younger age (22.5 vs 40 years), and were more likely to have an asymptomatic first hemangioblastoma (80% vs 20%). Overall, 76% (41 of 54) of the vHL patients had a family history of vHL, while none of the patients without vHL did. Despite the rarity of the disease, on average more than eight new tumours are diagnosed each year due to multiple tumour development in vHL patients. The estimated prevalence of patients with retinal hemangioblastoma was up to 1 in 73 080 individuals. CONCLUSION: In the first national study in which almost all participants were genetically tested, vHL was the underlying cause of retinal hemangioblastoma in 84% of cases; more often than previously reported. We recommend that genetic and clinical vHL screening should be performed in all patients with retinal hemangioblastoma.

von Hippel-Lindau development in children and adolescents.

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.

Epidemiology and clinical characteristics of hemangioblastomas in the elderly: An update.

Hemangioblastomas are benign tumors, derived from "stromal" cells of unclear origin. While previously thought to be a rare entity in elderly patients, we had previously reported a case series of six elderly patients (aged over 65years at diagnosis) diagnosed with hemangioblastoma in our 12year experience. Here, we report a followup series, describing eight additional cases of hemangioblastomas diagnosed in elderly patients (out of 26 in subjects over age 18). Seven of the eight cases were sporadic, and one case was suspicious for being associated with the von Hippel-Lindau (VHL) syndrome. All eight cases had presented with symptoms related to compression, and surgical resection resulted in good clinical outcomes. Combined with our previous report, 14/103 (13.6%) of the hemangioblastomas diagnosed in a 15-year period in a single hospital were present in elderly patients, suggesting that the prevalence in elderly patients of hemangioblastomas is higher than previously expected.

Spinal cord hemangioblastomas: significance of intraoperative neurophysiological monitoring for resection and long-term outcome.

OBJECTIVE Spinal cord hemangioblastomas are rare benign tumors developing either sporadically or as part of von Hippel-Lindau (VHL) disease. Generally, resection is the treatment of choice. However, the significance of intraoperative neurophysiological monitoring (IONM) for resection and postoperative outcome is still controversial. The authors analyzed the surgical and clinical courses of patients who had undergone resection of spinal cord hemangioblastoma, with special attention to preoperative imaging, the use of IONM, and short- and long-term outcomes. METHODS A series of 24 patients (male/female 1:1, lesion sporadic/associated with VHL 2.4:1) who had undergone 26 operations for the resection of 27 spinal cord hemangioblastomas was analyzed. All patients had undergone pre- and postoperative contrast-enhanced MRI. In all cases, microsurgical tumor removal had been performed under continuous IONM of both somatosensory and transcranial motor evoked potentials as well as electromyographic recording. Clinical characteristics, imaging findings, and operative records were retrospectively analyzed. Outcome parameters included short- and long-term status as regards sensorimotor deficits and a questionnaire on general performance, patient satisfaction, and Oswestry Disability Index (ODI) at the end of the follow-up period. The impact of IONM findings on postoperative deficits and outcome parameters as well as risk factors affecting functional prognosis was statistically assessed. RESULTS Preoperative symptoms (mean duration 16.2 ± 22.0 months) included sensory changes (100.0%), pain (66.7%), spinal ataxia (66.7%), motor deficit (41.7%), and bladder/bowel dysfunction (12.5%). Average age at the first operation was 36.8 ± 12.8 years. Most tumors (21 intramedullary, 6 intra- and/or extramedullary) were located dorsally (92.6%) and cervically (77.8%) and were accompanied by peritumoral edema and/or syringomyelia (81.5%). Tumor resection was achieved via laminectomy for 15 tumors, hemilaminectomy for 5, laminoplasty for 6, and interlaminar approach for 1. Gross-total resection was accomplished for 26 tumors (96.3%) with no local tumor recurrence during follow-up. Intraoperative neurophysiological monitoring was nonpathological in 11 operations (42.3%) and pathological in 15 (57.7%). Patients with nonpathological IONM had significantly fewer new sensorimotor deficits (p = 0.005). Long-term follow-up evaluation (mean 7.9 ± 4.0 years postoperatively, 7 patients lost to follow-up) revealed a stable or improved McCormick myelopathy grade in 88.2% of the patients, and 88.2% reported a stable or improved overall outcome according to Odom's criteria. Long-term general performance was excellent with 88.2% having a WHO/Eastern Cooperative Oncology Group (ECOG) Performance Status grade ≤ 1, 76.5% a Karnofsky Performance Scale score ≥ 80, and 70.6% a Barthel Index (BI) of 100. The mean ODI (11.4% ± 12.5%) indicated only minimal disability. There was a significant correlation between pathological IONM findings and a worse long-term status according to the BI and ODI (p = 0.011 and 0.024, respectively). Additionally, VHL disease was a risk factor affecting functional prognosis (p = 0.044). CONCLUSIONS Microsurgical removal of spinal cord hemangioblastomas with IONM facilitates a satisfying long-term outcome for patients. Nonpathological IONM findings are associated with a lower risk of new sensorimotor deficits and correlate with a better overall long-term outcome. von Hippel-Lindau disease is a risk factor for a worse long-term prognosis.

Incidence and Prognosis of Spinal Hemangioblastoma: A Surveillance Epidemiology and End Results Study.

OBJECTIVE: Intradural spinal hemangioblastoma are infrequent, vascular, pathologically benign tumors occurring either sporadically or in association with von Hippel-Lindau disease along the neural axis. Described in fewer than 1,000 cases, literature is variable with respect to epidemiological factors associated with spinal hemangioblastoma and their treatment. The objective of this study was to evaluate the epidemiology of intradural spinal hemangioblastoma with the Surveillance, Epidemiology and End Results (SEER) database while also presenting an illustrative case. METHODS: The SEER database was queried for cases of spinal hemangioblastoma between 2000 and 2010 with the use of SEER*Stat software. Incidence was evaluated as a function of age, sex and race. Survival was evaluated with the Cox proportionate hazards ratio using IBM SPSS software evaluating age, sex, location, treatment modality, pathology and number of primaries (p = 0.05). Descriptive statistics of the same factors were also calculated. The case of a 43-year-old patient with a surgical upper cervical intramedullary hemangioblastoma is also presented. RESULTS: In the data set between 2000 and 2010, there were 133 cases with an age-adjusted incidence of 0.014 (0.012-0.017) per 100,000 to the standard USA population. Hemangioblastoma was the tenth most common intradural spinal tumor type representing 2.1% (133 of 6,156) of all spinal tumors. There was no difference in incidence between men and women with an female:male rate ratio of 1.05 (0.73-1.50) with p = 0.86. The average age of patients was 48.0 (45.2-50.9) years, and a lower incidence was noted in patients <15 years compared to all other age groups (p < 0.05). There was no difference in incidence amongst the different races. Treatment included surgical resection in 106 (79.7%) cases, radiation with surgery in 7 (5.3%) cases, and radiation alone was used in only 1 (0.8%) case, and no treatment was performed in 17 (12.8%) cases. Mortality was noted in 12 (9%) cases, and median survival of 27.5 months (range 1-66 months) over the 10-year period. Mortality was attributable to the malignancy in 3 (2%) cases. There was no statistically significant different in Cox hazard ratios for mortality for sex, race, treatment modality, pathology or number of primaries. CONCLUSIONS: Spinal hemangioblastoma represent a small fraction of primary intradural spinal tumors, and this study did not identify any difference in incidence between genders. Surgical treatment alone was the most common treatment modality. Overall prognosis is good, with 9% observed mortality over the 10-year period, with 2% mortality attributable to the malignancy.

New von Hippel-Lindau manifestations develop at the same or decreased rates in pregnancy.

OBJECTIVE: In a national retrospective cohort study, we aimed to determine the effect of pregnancy on new von Hippel-Lindau (vHL) tumor development during pregnancy and at 1, 3, and 5 years after conception. METHODS: We included 52 VHL mutation carriers (26 men and 26 women) with 581 manifestations diagnosed throughout their lifetimes. We analyzed age-dependent manifestation rates using Poisson regression. We compared the women's rates in intervals where they had been pregnant with their age-matched nonpregnant intervals. We investigated possible long-term effects using pregnancy intervals of increasing lengths of 1, 3, and 5 years after conception. Furthermore, we compared age-related manifestation rates for women and men. RESULTS: From birth to the participants' current age, 581 manifestations were diagnosed; mean age was 37.5 years (range 2-64 years). Seventeen women had completed 30 pregnancies. Manifestation rates in women's pregnant intervals were lower compared with their age-matched nonpregnant intervals (1 year: hazard ratio [HR] = 0.439, 95% confidence interval [CI] 0.131-1.474, p = 0.18; 3 years: HR = 0.412, 95% CI 0.214-0.796, p = 0.0083; and 5 years: HR = 0.450, 95% CI 0.136-1.489, p = 0.19). Men and women had similar manifestation rates, both increasing from their 20s. CONCLUSIONS: Pregnancy does not aggravate vHL tumor development, and we neither discourage pregnancy in VHL mutation carriers nor recommend intensified surveillance during pregnancy. The pregnancy effect is not due to concurrence of a naturally milder tumor development in women's fertile ages, as the rate of new tumor development increases for both men and women from 20 years of age, even more in men than in women.

Feasibility of a novel diagnostic chart of intramedullary spinal cord tumors in magnetic resonance imaging.

STUDY DESIGN: Retrospective chart review. OBJECTIVES: Each type of intramedullary spinal cord tumor (IMSCT) has specific anatomical and pathological features visible on magnetic resonance (MR) imaging. The purpose of this study was to investigate the accuracy of preoperative IMSCT diagnosis using our diagnostic chart of tumor-specific MR imaging findings. SETTING: Hamamatsu, Japan. METHODS: From 2009 to 2013, 28 consecutive patients with IMSCT who underwent surgery in our university hospital were included in this study. There were 17 men and 11 women with an average age of 49 years (12-81). The pathological diagnoses were hemangioblastoma (12), ependymoma (11), astrocytoma (4) and squamous cell carcinoma (1). Tumor-specific MR imaging findings were as follows: ependymoma ((a) spinal cord swelling, (b) contrast effect with necrosis, (c) tumor in the center of the spinal cord), hemangioblastoma ((a) spinal cord swelling, (b) homogeneous contrast effect) and astrocytoma ((a) spinal cord swelling, (b) contrast effect is either, (c) eccentric tumor). Based on these features, we generated a diagnostic chart to investigate the MR imaging diagnosis accuracy for IMSCTs. RESULTS: The accuracy of preoperative diagnosis was 89% (25/28 cases). Correct diagnoses were made in 100% of hemangioblastomas (12/12 cases), 90% of ependymomas (9/11 cases) and 100% of astrocytomas (4/4 cases). CONCLUSIONS: Different types of IMSCTs exhibit unique MR imaging characteristics. These features can be used to preoperatively diagnose IMSCTs with high accuracy.

[Epidemiology, treatment and follow-up of central nervous system hemangioblastomas in von Hippel-Lindau disease]. / Épidémiologie, traitement et suivi des hémangioblastomes du système nerveux central dans le cadre de la maladie de von Hippel-Lindau.

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.