Search Results (32)

Background/Objectives: Von Hippel–Lindau (VHL) disease is a rare autosomal dominant hereditary disorder. Central nervous system hemangioblastomas are one of the most common tumor types associated with VHL disease. Although these tumors are histologically benign, delayed diagnosis and treatment may result in severe neurological dysfunction, permanent disability, and even death. However, little is known about the experiences of patients with VHL disease. The aim of this study was to gain a better understanding of the illness experiences and psychological responses of patients with VHL disease accompanied by central nervous system hemangioblastomas. Methods: A qualitative study based on a semi-structured guide was conducted. Twelve participants were recruited. Data were collected through face-to-face interviews and analyzed using the constant comparative method. Results: Four themes and their subthemes were identified: 1. powerlessness—unpredictable disease progression and uncontrollable continuity; 2. negative emotional experiences—guilt and self-blame, depression, and low self-esteem; 3. compromise—acceptance of fate, positive outlook, and sense of hope; and 4. persistent worry—worries about family members, anxiety regarding finances and employment, and uncertainty regarding the future. Conclusions: This study identified four major themes in the illness experiences of patients with VHL disease accompanied by central nervous system hemangioblastomas, which provided deep insights into the care needs of individuals with VHL disease. Healthcare providers should develop effective measures to enhance patients’ ability to maintain a good quality of life and confront the future with resilience. Full article

Von Hippel–Lindau disease-associated endolymphatic sac tumors (VHL-associated ELSTs) present diagnostic challenges due to their rarity and nonspecific symptoms. This study describes clinical, pathological and genotypic features to guide treatment. We retrospectively analyzed seven patients with VHL-associated ELSTs. The mean age of otologic symptom [hearing loss (100%) and facial nerve paralysis (85.71%)] onset was 22.43 ± 8.68 years (range: 10–33). Surgical management included trans-labyrinthine and subtotal temporal bone resection approaches. Among three patients with severe preoperative facial nerve dysfunction, two underwent great auricular nerve grafting improved to House–Brackmann grade IV, while one receiving hypoglossal–facial nerve anastomosis reached grade V. Genetic testing identified pathogenic VHL gene missense mutations in three patients. Two female patients demonstrated disease progression during pregnancy. Literature analysis revealed exon-specific patterns: Exon 1 mutations correlated with cerebellar/spinal hemangioblastomas in female patients, while Exon 3 mutations were associated with multisystem tumors. These findings support that VHL-associated ELSTs manifest early with otologic symptoms and demonstrate exon-specific phenotypic patterns. Optimal management requires complete surgical resection, genetic diagnosis, and a multidisciplinary approach to address these complex tumors and achieve favorable outcomes. Full article

Intraoperative ultrasound (IOUS) is an increasingly adopted adjunctive intraoperative visualization method in spinal tumor surgery, offering real-time imaging that improves lesion localization, exposure planning, and resection control. This paper focuses on IOUS findings in rare intradural entities (neuroenteric/respiratory cysts, chronic spinal subdural hematoma, tethered cord/scarring, intradural extramedullary hemangioblastomas, and arachnoid cysts) where evidence remains limited. Across these lesions, IOUS typically depicts cysts as anechoic or hypoechoic cavities with definable walls and occasional septations; CSSDH is also delimited by hypoechoic subdural collections bounded by echogenic membranes; hemangioblastomas, as well as circumscribed, homogeneous nodules often with cystic components; and arachnoid webs/cysts with their boundaries and subtle subarachnoid communications. Doppler and micro-Doppler can delineate feeding and draining vessels in highly vascular tumors, while shear wave elastography provides quantitative stiffness changes that support effective detethering. IOUS complements preoperative MRI, shortens exposure, helps tailor bone and dural openings, and allows immediate assessment of residual disease. Taken together, current data and our experience support IOUS as a safe, cost-effective, and versatile intraoperative tool for rare intradural spinal pathology, while underscoring the need for prospective studies to refine sonographic criteria and validate outcome benefits. Full article

Von Hippel-Lindau (VHL) is a rare genetic disorder caused by mutations in the VHL gene on chromosome 3. The disease is associated with increased incidence of neoplasia. The most common manifestations of the disease are hemangioblastomas of the CNS and spinal cord, followed by renal cell carcinomas (RCC), pancreatic tumors, pheocromocytomas, endolymphatic sac tumors, and broad ligament or epididymal cystadenomas. Due to low incidence of the disease, information about its manifestation and genetic makeup has been slow to be gathered. Herein, we present three patients suffering from VHL, all part of the same family: patient one is the father; patient two is the daughter; and patient three is the nephew of the father, cousin to the daughter. Patients and their samples were investigated by magnetic resonance imaging, immunohistochemistry and genetic testing. Results show a tumor process in the left cerebellar hemisphere of the first patient which was successfully removed. The second patient presents with cervical medullary hemangioblastoma which was also successfully removed. The third patient had a tumor formation located at the craniospinal junction, at the level of the posterior bulb which was also treated. Genetic analysis showed patients one and two presented mutations in the VHL gene, confirming the VHL diagnosis. While the cases presented here follow the general lines for VHL disease, patients are related to each other, present tumors of the nervous system and mutations in the VHL gene, their particularities of presentation and manifestation bring new insights into this rare genetic disease. Full article

Human hemangioblastoma is a benign, slow-growing, highly vascular neoplasm. The tumor most commonly arises in the cerebral hemispheres and cerebellum, where it is more frequently observed in patients with von Hippel–Lindau disease. In veterinary medicine, hemangioblastoma has only been described in the central nervous system of dogs and in the skin of lambs. Our study aimed to characterize the clinical and neuropathological features of five cases of canine spinal cord hemangioblastoma and one case of sciatic nerve localization, and to compare these results with those reported in the veterinary literature. Diagnoses were achieved by neurological examination, neuroimaging, surgery or post-mortem examination, histopathology, and immunohistochemistry. All tumors were composed of numerous, haphazardly arranged capillaries lined by plump endothelium and interstitial fusiform to stellate stromal cells. Immunohistochemically, the stromal cells were strongly immunolabeled with NSE and carbonic anhydrase IX and were negative for von Willebrand factor VIII and inhibin-α. Canine hemangioblastoma exhibits morphological and immunohistochemical features comparable to the human counterpart, although the latter is mostly positive for inhibin-α. Surgery may be effective in cases of intradural-extramedullary and peripheral nerve locations, as in humans. This is the first report of peripheral nerve hemangioblastoma in animals. Full article

Background and Objectives: Here, we report the anatomical and functional outcomes of Pars Plana Vitrectomy (PPV) with feeder vessel ligation, with or without endoresection in cases of retinal detachment (RD) secondary to retinal capillary hemangioblastoma (RCH). Materials and Methods: This retrospective observational study included 12 eyes with RD secondary to RCH. Based on the location of the lesion and the features of the RD, eyes were divided into two groups. Seven eyes with RCH located in Zone 2 or Zone 3, associated with tractional retinal detachment (TRD), underwent PPV with feeder vessel ligation and tumor endoresection. Five eyes, either with RCH in Zone 2 or Zone 3 associated with exudative retinal detachment or with RCH in Zone 1 associated with RD, underwent PPV with feeder vessel ligation alone, without tumor endoresection. Outcome measures included local tumor control, best-corrected visual acuity (BCVA), anatomical success, and rates of complications. Results: RCH regressed completely in 100% of eyes with no evidence of recurrence. The mean follow-up was 4.6 years. In the endoresection group, the mean BCVA was 2.18 ± 0.3 logMAR at baseline and 0.95 ± 0.5 logMAR after surgery (p = 0.018), whereas in the second group, the baseline mean BCVA was 1.33 ± 0.2 logMAR and 1.52 ± 0.7 logMAR postoperatively. In the first group, retinal attachment was achieved in all eyes, whereas in the second group, two eyes presented with persistent RD and proliferative vitreoretinopathy (PVR). No cases of phthisis bulbi or neovascular glaucoma were observed. Conclusions: PPV combined with feeder vessel ligation and endoresection appears to be an effective treatment for TRD secondary to RCH located in Zones 2 and 3, providing satisfactory anatomical and visual outcomes considering the severity of the disease. In cases where tumor location precludes endoresection, PPV with feeder vessel ligation alone may still be a viable option, although the potential risk of PVR could persist. Full article

Background/Objectives: An accurate evaluation of variant actionability is essential in cancer management. In Von Hippel–Lindau Syndrome (VHL), the interpretation of the germline variants is confounded by the presence of non-syndromic component tumors, such as clear cell renal cell carcinoma (ccRCC), hemangioblastoma, pheochromocytoma, and neuroendocrine tumors. These tumors frequently occur sporadically, without any association with VHL syndrome. The presence of these tumors in a patient with a germline VHL variant could lead to inaccurate attribution of these tumors to the germline variant and VHL syndrome. In our previous INT²GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) programs, we demonstrated that integrating tumor-derived and germline evidence offers a comprehensive approach for the accurate assessment of the germline variants in cancer syndromes. Methods/Results: Here, we present a novel INT²GRATE variant evidence framework (VEF) for evaluating the clinical actionability of the germline variants in VHL syndrome, offering an integrated approach that incorporates both constitutional and tumor data. We analyzed 2672 variants in the VHL gene and their associated tumors and clinical evidence to effectively distinguish between constitutional, sporadic, VHL differentials, and VHL allelic genetic conditions. The germline INT²GRATE variants, along with their comprehensive associated evidence, were made accessible in the first open-access INT²GRATE Variant data Portal. Conclusions: This novel and integrated approach to variant assessment and data sharing in hereditary cancer syndromes is essential in the clinical evaluation of genomic variants, advancing precision oncology, and improving patient care. Full article

Purpose: Intramedullary spinal cord tumors (IMSCTs) account for 2–8% of all primary CNS tumors, with ependymal tumors astrocytic tumors and hemangioblastoma being the most prevalent. Due to scarcity of large-scale studies, we aim to provide insights into the long-term neurological and functional outcomes following their resection. Methods: A single-center study where retrospective review of all patients’ medical records with IMSCT resection between October 2001 and March 2023 was conducted. Data on demographic characteristics, clinical presentations, and surgical outcomes were collected and analyzed. Results: This study included 253 patients (57.7% male) with a mean age of 36.2 ± 19. The cohort comprised ependymal tumors (45.1%), astrocytic tumors (35.6%), hemangioblastoma (11.1%), and miscellaneous tumors (n = 21; 8.3%). Differences were observed in age at surgery (p < 0.001) and mortality (p = 0.002) across tumor types. Gross total resection was more frequently achieved in hemangioblastoma (96.4%) and ependymal tumors (82.5%) compared to astrocytic tumors (55.6%) (p < 0.001). Long-term postoperative improvements were significant, with reductions in numbness from 74.7% to 52.2%, pain from 42.2% to 25.7%, and bladder incontinence from 23.7% to 11.6%, particularly in ependymal tumors and astrocytic tumors. Kaplan–Meier analysis showed that patients with ependymal tumors had the highest overall survival rates (94.8% at 5 years, 86.7% at 10 years, 76.3% at 15 years, and 65.4% at 20 years) compared to hemangioblastoma (88.7% at 5 and 10 years, and 53.2% at 15 years) and astrocytic tumors (67.8% at 5 years, 58.1% at 10 and 15 years) (p = 0.001). Conclusions: This study highlights the differences in survival and long-term functional outcomes among patients with IMSCTs based on tumor histology and grade. Full article

Background: Von Hippel-Lindau (VHL) disease, a hereditary cancer syndrome, is characterized by mutations in the VHL gene, which result in the stabilization of hypoxia-inducible factors (HIF)-1α and -2α, ultimately leading to the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system (CNS-HBs). The standard treatment for these brain tumors is neurosurgical resection. However, multiple surgeries are often necessary due to tumor recurrence, which increases the risk of neurological sequelae. Thus, elucidation of the proliferative behavior of hemangioblastomas (with the aim of identifying biomarkers associated with tumor progression) and the development of pharmacological therapies could reduce the need for repeated surgical interventions and provide alternative treatment options for unresectable CNS-HBs. Belzutifan (Welireg™), a selective HIF-2α inhibitor and the only FDA-approved non-surgical option, has shown limited efficacy in CNS-HBs, highlighting the need for alternative therapeutic strategies. Results: In this study, primary cell cultures were successfully established from CNS-HB tissue samples of VHL patients, achieving a 75% success rate. These cultures were predominantly composed of stromal cells and pericytes. The proliferative patterns of patient-derived HB cell cultures significantly correlated with tumor burden and recurrence in VHL patients. Furthermore, flow cytometry, reverse transcription-PCR, and Western blot analyses revealed marked overexpression of both HIF-1α and HIF-2α isoforms in primary HB cells. In addition, evaluation of the therapeutic potential of acriflavine, a dual HIF-1α/HIF-2α inhibitor, demonstrated reduced HB cells viability, induced G2/M cell cycle arrest, and predominantly triggered necrotic cell death in patient-derived HB cultures. Conclusions: These results suggest that the in vitro proliferative dynamics of HB cell cultures may reflect clinical characteristics associated with CNS-HB progression, potentially serving as indicators to predict tumor development in patients with VHL. Furthermore, our findings support the simultaneous targeting of both HIF-1α and HIF-2α isoforms as a promising non-invasive therapeutic strategy. Full article

Introduction: Hemangioblastomas (HBs) are benign, highly vascular tumors that can be found intracranially or in the spinal region, representing around 2–15% of primary intramedullary tumors. They can occur sporadically or in association with Von Hipple–Lindau (VHL) disease. Despite recent of advancement of nonsurgical treatments, complete surgical resection remains the gold standard of care for the spinal HBs. Materials and Methods: We conducted an international multicenter retrospective analysis of adult patients surgically treated for spinal HBs in four European referral centers between January 2000 and September 2024, with a minimum post-operative follow-up duration of 6 months. Patients’ sex and age at surgical intervention, clinical presentation, and duration symptoms prior to clinical diagnosis were identified. The pre- and post-operative neurological status at 1 and 6 months and at the last visit was assessed using the modified McCormick score (MCS). The extent of surgical resection was divided into gross total resection (GTR) and subtotal resection (STR). Finally, post-operative complications were inspected as well, namely cerebrospinal fluid leaks, infections, hemorrhages and post-operative spinal stability. Results: A total of 35 patients were included in the cohort, with an age median of 52 years (34.5–60) and a slight male predominance (21/35, i.e., 60%). The median follow-up period was 37.5 months (12–75). More than half were located in the cervical region, making it the most common (54.3%). Syrinxes were observed in 23 cases (72%), and HBs were more commonly intramedullary (80%). GTR was achievable in around 88% of cases. Post-operative complications were observed in nine patients (25.7%). Nearly half of patients were discharged into rehabilitations centers (48.5%). Tumor recurrence was seen in 10.3% only. At the last follow-up, an excellent overall post-operative neurological status (positive ∆ McCormick) was observed in most of patients (88%) and was found to be associated with a relatively younger age group. Tumor location and presence of syrinxes did not show any statistical significance regarding clinical outcome. In patients having benefited from intra-operative monitoring, only D-wave changes showed statistical significance regarding post-operative outcome (p < 0.05). Conclusions: A large majority of patients operated for a spinal HB demonstrated favorable outcome after surgery, with unchanged or improved neurological status. Advanced age could have an impact on the post-operative neurological outcome. Other factors such as tumor size, location, and the presence of syrinx did not seem to significantly impact the neurological outcome. Finally, the surgery of these vascular lesions with no possibility of debulking or piece-meal removal and requiring “en bloc” resection is technically demanding and should be performed by experienced teams in spine and spinal cord surgery only. Full article

von Hippel–Lindau syndrome (VHLS) is a hereditary cancer syndrome with CNS hemangioblastomas, clear cell renal carcinoma, pheochromocytoma, retinal angiomas, and a number of other manifestations. VHLS is caused by a mutation in the VHL gene and is inherited in an autosomal dominant manner. However, some cases of VHLS develop de novo, and among them, there are rare patients with a mosaic form of the disease. Genetic testing in mosaic patients is prone to false-negative results due to the low copy number of a mutant allele in DNA isolated from the blood. We describe a case of molecular genetic diagnostics of VHLS in a 39-year-old patient using various methods, including mutation analysis in asynchronous primary tumors and repeated DNA analysis from blood using NGS with high coverage for the mutant position. As a result, the patient was diagnosed with a mosaic form of VHLS caused by the variant c.481C>T (p.Arg161Ter), the proportion of which in the blood DNA was 2%. We also summarized the literature data on the mosaic form of VHLS: the severity of clinical manifestations, the features of differential diagnostics of VHLS with a negative result of routine molecular genetic VHL testing, and specific options of active surveillance and treatment for mutation carriers. Full article

Purpose: To delineate the genotype and phenotype of RH in a Chinese cohort. Methods: A group of 51 Chinese probands with RH across 76 eyes was assembled and underwent complete retinal imaging examinations. Sanger sequencing and universal primer quantitative fluorescent multiplex–polymerase chain reaction (UPQFM-PCR) were employed for mutation detection in the coding region of the Von Hippel–Lindal (VHL) gene. For frequency calculation, our series was combined with three large cohorts of East Asian descent through a literature review. Results: The Von Hippel–Lindal (VHL) syndrome was excluded in fifteen patients (median age: 32.00 years) with unilateral solitary RH. Thirty-six patients of younger ages (median: 22.00 years, p = 0.008, Mann–Whitney test) conformed to the diagnostic criteria of the VHL syndrome, and thirty-four patients were genetically confirmed. There were four novel variants identified in the VHL gene. Codons 167, 161 and 86 exhibited a mutation occurrence of more than 5% after pooling with literature data, and the large genomic deletion demonstrated a frequency of 17.65%. The RHs were classified as “extrapapillary”, “juxtapapillary” and “mixed” types in 53, 7 and 5 eyes, respectively. Almost all extrapapillary RH lesions were found in the peripheral retina. Hemangioblastomas in the central nervous system (CNS) were observed in 25 out of 31 kindreds (80.65%) with full systemic evaluation data. Conclusions: VHL-associated RH might exhibit earlier onset than non-VHL RH. Large genomic deletions were observed at a notably high frequency in the Chinese series with VHL-associated RH, which might be associated with East Asian ethnicity background. RH could potentially serve as an early indicator of CNS hemangioblastoma. Full article

Intramedullary primary spinal cord tumors are rare in adults and their classification has recently evolved. Their treatment most frequently relies on maximal safe surgical resection. Herein, we review, in light of the WHO 2021 classification of central nervous system tumors, the knowledge regarding the role of radiotherapy and systemic treatments in spinal ependymomas, spinal astrocytomas (pilocytic astrocytoma, diffuse astrocytoma, spinal glioblastoma IDH wildtype, diffuse midline glioma H3-K27M altered, and high-grade astrocytoma with piloid features), neuro-glial tumors (ganglioglioma and diffuse leptomeningeal glioneuronal tumor), and hemangioblastomas. In spinal ependymomas, radiotherapy is recommended for incompletely resected grade 2 tumors, grade 3 tumors, and recurrent tumors not amenable to re-surgery. Chemotherapy is used in recurrent cases. In spinal astrocytomas, radiotherapy is recommended for incompletely resected grade 2 astrocytomas and grade 3 or 4 tumors as well as recurrent tumors. Chemotherapy is indicated for newly diagnosed high-grade astrocytomas and recurrent cases. In hemangioblastomas not amenable to surgery, radiotherapy is an effective alternative option. Targeted therapies are playing an increasingly important role in the management of some intramedullary primary spinal cord tumor subtypes. BRAF and/or MEK inhibitors have demonstrated efficacy in pilocytic astrocytomas and glioneuronal tumors, belzutifan in von Hippel–Lindau-related hemangioblastomas, and promising results have been reported with ONC201 in diffuse midline glioma H3-K27M altered. Full article

Background: Cystic, sporadic hemangioblastomas (HBLs) represent a unique, therapeutically challenging subset of central nervous system tumors, mainly due to their unpredictable growth patterns and potential for symptomatic progression. This study aims to explore the complexities surrounding the diagnosis, treatment, and long-term management of these lesions. Methods: A comprehensive literature review was performed, and a detailed case study of a 56-year-old patient with a cystic, sporadic cerebellar HBL was produced. Results: The case highlights the multiphasic growth pattern typical of cystic, sporadic HBLs, characterized by periods of dormancy and subsequent rapid expansion. An initial surgical intervention offered temporary control. Tumor recurrence, mainly through cystic enlargement, was treated by SRS. A subsequent recurrence, again caused by cystic growth, eventually led to the patient’s death. The intricacies of treatment modalities, focusing on the transition from surgical resection to stereotactic radiosurgery (SRS) upon recurrence, are discussed. Parameters indicating impending tumor growth, coupled with symptomatic advances, are also explored. Conclusions: The management of cystic, sporadic cerebellar HBLs requires a strategic approach that can be informed by radiological characteristics and tumoral behavior. This study underscores the importance of a proactive, individualized management plan and suggests guidelines that could inform clinical decision making. Full article

The aim was to identify predictors of progression in a series of patients managed for an intracranial hemangioblastoma, in order to guide the postoperative follow-up modalities. The characteristics of 81 patients managed for an intracranial hemangioblastoma between January 2000 and October 2022 were retrospectively analyzed. The mean age at diagnosis was of 48 ± 16 years. Eleven (14%) patients had von Hippel–Lindau disease. The most frequent tumor location was the cerebellar hemispheres (n = 51, 65%) and 11 (14%) patients had multicentric hemangioblastomas. A gross total resection was achieved in 75 (93%) patients. Eighteen (22%) patients had a local progression, with a median progression-free survival of 56 months 95% CI [1;240]. Eleven (14%) patients had a distant progression (new hemangioblastoma and/or growth of an already known hemangioblastoma). Local progression was more frequent in younger patients (39 ± 14 years vs. 51 ± 16 years; p = 0.005), and those with von Hippel–Lindau disease (n = 8, 44% vs. n = 3, 5%, p < 0.0001), multiple cerebral locations (n = 3, 17% vs. n = 2, 3%, p = 0.02), and partial tumoral resection (n = 4, 18% vs. n = 1, 2%, p = 0.0006). Therefore, it is advisable to propose a postoperative follow-up for at least 10 years, and longer if at least one predictor of progression is present. Full article