Multiple Primary Paragangliomas in a Pediatric Patient With von Hippel Lindau: A Diagnostic Dilemma.

Pheochromocytoma and paragangliomas (PPGLs) are rare chromaffin cell tumors arising from neural crest tissue. The majority of these tumors are nonmetastatic, with complete cure achieved through surgical resection. PPGLs have been associated with several hereditary cancer syndromes, including von Hippel-Lindau (VHL). We present the case of a 10-year-old patient with VHL and a history of 2 asynchronous pheochromocytomas requiring bilateral adrenalectomies who presented with a new 1.2 cm × 1.3 cm × 1.5 cm nodular structure between the superior pole of the right kidney and the intrahepatic inferior vena cava. The patient was noted to have hypertension but was otherwise asymptomatic. Positron emission tomography-DOTA-(Tyr)3-octreotate revealed a metabolically active retrocrural lymph node. Based on these imaging findings and laboratory studies showing elevated plasma normetanephrine, clinical suspicion was highest for metastatic pheochromocytoma. The patient underwent surgical resection of multiple abdominal tumors. Pathology ultimately favored a diagnosis of multiple primary paragangliomas rather than metastatic disease. With this shift in diagnosis, the patient was managed with surgery alone. One year later, he has no signs of disease recurrence. Long-term surveillance imaging and screening with fractionated plasma metanephrines is indicated to monitor for new tumors in the setting of VHL and 3 prior endocrine tumors.

Renal protective and immunoregulatory effects of Lactobacillus casei strain Shirota in nephropathy-prone mice.

Introduction: The incidence of severe acute kidney injury (AKI) is considerably high worldwide. A previous study showed that gut microbial dysbiosis was a hallmark of AKI in mice. Whether the probiotic Lactobacillus casei strain Shirota (LcS) plays a role in kidney disease, particularly AKI, remains unclear. Methods: To investigate the effects of LcS on kidney injury, tubule-specific conditional von Hippel-Lindau gene-knockout C57BL/6 mice (Vhlhdel/del mice) were supplemented without (Ctrl) or with probiotics (LcS) in Experiment 1, and their lifespan was monitored. Additionally, the Vhlhdel/+ mice were supplemented without (Ctrl and AA) or with probiotics (LcS and LcS + AA) in Experiment 2. Probiotic LcS (1 × 109 colony-forming units) was supplemented once daily. After 4 weeks of LcS supplementation, AA and LcS + AA mice were administered aristolochic acid (AA; 4 mg/kg body weight/day)-containing purified diet for 2 weeks to induce AA nephropathy before sacrifice. Results: Supplementation of LcS significantly prolonged the lifespan of Vhlhdel/del mice, suggesting a potential renal protective effect. AA induced-nephropathy increased not only the indicators of renal dysfunction and injury, including urinary protein and kidney injury molecule (KIM)-1, serum blood urea nitrogen (BUN) and creatinine, but also serum interleukin (IL)-6 levels, renal macrophage infiltrations, and pathological lesions in Vhlhdel/+ mice. LcS supplementation significantly reduced urinary protein and KIM-1 levels, serum BUN and IL-6 levels, and renal M1 macrophages, tissue lesions, and injury scores. We also found that LcS maintained gut integrity under AA induction and increased intestinal lamina propria dendritic cells. Furthermore, LcS significantly reduced pro-inflammatory IL-17A and upregulated anti-inflammatory IL-10 production by immune cells from intestinal Peyer's patches (PP) or mesenteric lymph nodes (MLN), and significantly increased IL-10 and reduced IL-6 production by splenocytes. Conclusion: Prior supplementation with probiotic LcS significantly alleviated the severity of renal injury. This renal protective effect was partially associated with the enhancements of intestinal and systemic anti-inflammatory immune responses, suggesting that LcS-induced immunoregulation might contribute to its renal protective effects.

Belzutifan in Individuals with von Hippel-Lindau Retinal Hemangioblastomas: Institutional Experience and Review of the Literature.

Introduction: The systemic HIF-2 alpha inhibitor, belzutifan, has been approved for use in patients with von Hippel-Lindau disease (VHL)-associated renal cell carcinoma, central nervous system (CNS) hemangioblastomas, and pancreatic neuroendocrine tumors. This drug has also shown promise in controlling VHL retinal hemangioblastomas (RHs), but little work has been published on the use of the drug in this setting. Methods: We conducted a retrospective review of patients with VHL-associated RHs followed by the retina service at our institution who were treated with systemic belzutifan. Patient age, gender, genotype, presence of systemic tumors, indication for the drug, initial dose, adjusted dose, side effects, and tumor response were recorded. We also conducted a literature search for all manuscripts describing the effect of belzutifan on VHL-associated ocular tumors. Results: We identified 12 eyes of 7 patients with VHL-associated ocular tumors who were treated with belzutifan at our institution. Of these, 5 eyes of 3 patients had progressing ocular tumors when belzutifan was started. Of the 7 total patients, 2 were treated for renal cell carcinoma, 2 for CNS hemangioblastomas, 2 for RHs, and one for pancreatic neuroendocrine tumors. Initial dose was 120 mg PO daily in 6 patients and 80 mg PO daily in 1 patient. The dose was reduced in all but 1 patient due to side effects. The ocular tumors were controlled in all patients with an average follow-up of 13 months (range 4-24 months). Literature review identified 7 manuscripts that described belzutifan-mediated control of ocular tumors in patients with VHL-associated RHs in 21 patients. Conclusion: The drug belzutifan shows great promise for controlling RHs and preventing vision loss in patients with VHL. Further work needs to address the optimal dose, role of the drug as a neoadjuvant therapy, and long-term efficacy and tolerability of the drug in a larger cohort of patients with ocular tumors.

Dual manifestations: spinal and cerebellar hemangioblastomas indicative of von Hippel-Lindau syndrome.

Hemangioblastomas are rare, benign, and highly vascular tumors of the central nervous system, often associated with von Hippel-Lindau (VHL) syndrome, an autosomal dominant disorder characterized by multiple tumors. We present a case of a 32-year-old male with progressive headaches, visual disturbances, and motor deficits, who was diagnosed with multiple hemangioblastomas in the cervical-thoracic spinal cord and bilateral cerebellum through MRI. Surgical resection and histopathological biopsy confirmed the diagnosis. This case highlights the critical role of MRI in diagnosing and managing VHL-associated hemangioblastomas and underscores the importance of regular imaging for early detection and intervention of new or recurring tumors, optimizing patient outcomes.

Insoluble HIFa protein aggregates by cadmium disrupt hypoxia-prolyl hydroxylase (PHD)-hypoxia inducible factor (HIFa) signaling in renal epithelial (NRK-52E) and interstitial (FAIK3-5) cells.

The kidney is the main organ that senses changes in systemic O2 pressure by hypoxia-PHD-HIFa (HPH) signaling, resulting in adaptive target gene activation, including erythropoietin (EPO). The non-essential transition metal cadmium (Cd) is nephrotoxic and disrupts the renal HPH pathway, which may promote Cd-associated chronic renal disease (CKD). A deeper molecular understanding of Cd interference with renal HPH signaling is missing, and no data with renal cell lines are available. In rat kidney NRK-52E cells, which model the proximal tubule, and murine fibroblastoid atypical interstitial kidney (FAIK3-5) cells, which mimic renal EPO-producing cells, the chemical hypoxia mimetic dimethyloxalylglycine (DMOG; 1 mmol/l) or hypoxia (1% O2) activated HPH signaling. Cd2+ (2.5-20 µmol/l for ≤ 24 h) preferentially induced necrosis (trypan blue uptake) of FAIK3-5 cells at high Cd whereas NRK-52E cells specially developed apoptosis (PARP-1 cleavage) at all Cd concentrations. Cd (12.5 µmol/l) abolished HIFa stabilization and prevented upregulation of target genes (quantitative real-time polymerase chain reaction and immunoblotting) induced by DMOG or hypoxia in both cell lines, which was caused by the formation of insoluble HIFa aggregates. Strikingly, hypoxic preconditioning (1% O2 for 18 h) reduced apoptosis of FAIK3-5 and NRK-52E cells at low Cd concentrations and decreased insoluble HIFa proteins. Hence, drugs mimicking hypoxic preconditioning could reduce CKD induced by chronic low Cd exposure.

The genetic differences between types 1 and 2 in von Hippel-Lindau syndrome: comprehensive meta-analysis.

BACKGROUND: Patients with von Hippel-Lindau (VHL) disease are at risk of developing tumors in the eye, brain, kidney, adrenal gland, and other organs based on their gene mutations. The VHL tumor suppressor gene contains pathogenic variants responsible for these events. This meta-analysis aims to investigate the genetic differences among the various types of VHL syndrome and their correlation with the location of mutations (exons and domains) in the VHL gene. METHOD: Papers eligible for publication until September 2023 were identified using the electronic databases of PubMed, Google Scholar, Scopus, and EMBASE. The Random Effect model was utilized to evaluate the genetic differences between type 1 and type 2 VHL syndromes. RESULTS: The prevalence of missense mutations (MSs) was found to be 58.9% in type 1, while it was 88.1% in type 2. Interestingly, the probability of observing MSs in type 1 was 0.42 times lower compared to type 2. The mutation hotspots of the VHL gene were R167Q/W, Y98H, R238W, and S65L, respectively. Although type 2 had a high presentation of Y98H and R238W, it did not have a higher S65L than type 1. The analysis demonstrated a statistically significant higher prevalence of truncated mutations (PTMs) in type 1. Among type 1, large/complete deletions (L/C DELs) were found in 16.9% of cases, whereas in type 2 only 3.7%. This difference was statistically significant with a p-value < 0.001. Overall, the probability of identifying mutations in domain 2 compared to domain 1 was found to be 2.13 times higher in type 1 (p-value < 0.001). Furthermore, the probability of detecting exon 1 in comparison with observing exon 2 in type 1 was 2.11 times higher than type 2 and revealed a statistically significant result (p-value < 0.001). The detection of exon 2 was 2.18 times higher in type 1 (p-value < 0.001). In addition, the likelihood of discovering exon 2 compared with others was significantly lower in type 1 compared with type 2 VHL (OR = 0.63, p-value = 0.015). CONCLUSIONS: We have revealed a comprehensive genetic difference between types 1 and 2 of VHL syndrome. The significant differences in MS, PTMs, L/C DELs, and the location of the mutations between type 1 and type 2 VHL patients in the Asian, European, and American populations emphasize the genetic heterogeneity of the syndrome. These findings may pave the way for the diagnosis, treatment, and further investigation of the mechanisms behind this complex genetic disorder.

Clinical T1a Renal Cell Carcinoma with Solitary Diaphragmatic Metastasis in a Patient with von Hippel-Lindau Disease.

We report the case of a 38-year-old man with two von Hippel-Lindau disease-associated T1a renal cell carcinomas (RCCs) (<2 cm in diameter) which developed into a 2.5-cm solitary diaphragmatic metastatic tumor. After diagnosis using percutaneous biopsy, the diaphragmatic metastasis and two RCCs were treated by laparoscopic resection and percutaneous cryoablation, respectively. One year after treatment, the patient survived without local recurrence or distant metastasis. This report describes a rare case of RCC metastasis in VHL disease and its treatment.

Surgical Outcomes in Patients with Endolymphatic Sac Tumors: A Single-Center Experience of 29 Patients.

OBJECTIVE: To analyze the clinical features and surgical outcomes of patients with endolymphatic sac tumors (ELSTs). STUDY DESIGN: Single institution retrospective cohort study. METHODS: The clinical data of 29 patients with 30 ELSTs who underwent surgery were retrospectively reviewed. Information on patient demographics, tumor size and grade, intraoperative blood loss volume, hearing and facial nerve outcomes, and follow-up data was collected and analyzed. RESULTS: The main symptoms were hearing loss in 26 ELSTs (86.7%) and tinnitus in 17 (56.7%). Twenty-four (80%) ELSTs were in advanced stages (Grade III). The median tumor volume was 6.35 cm3. The median intraoperative blood loss volume was 300 mL. Facial nerve function was well preserved in 21 patients. Among all patients with Grade III tumors, 12 patients underwent tension-free anterior facial nerve rerouting, and 11 patients (91.7%) maintained good facial nerve function postoperatively (HB I and HB II). Only one patient exhibited permanent vocal cord paralysis, and no patients experienced cerebrospinal fluid (CSF) leakage postoperatively. Gross total resection was achieved in 22 patients (73.3%), 5 patients (16.7%) experienced tumor recurrence, and 3 (10%) had residual tumors. CONCLUSIONS: Most ELSTs tend to be diagnosed in the advanced stage. Tension-free anterior facial nerve rerouting could maximally preserve facial nerve function. The intraoperative blood loss volume was associated with tumor size and stage. Tumor recurrence tends to occur at the posterior edge of the petrosal bone, internal auditory canal, and surface of the posterior fossa. Given the relatively high recurrence rate of ELSTs, long-term follow-up is recommended. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Neurosurgical Implications of Targeting Hypoxia-Inducible Factor 2α in Hemangioblastomas with Belzutifan.

OBJECTIVE: To highlight the neurosurgical implications of the hypoxia-inducible factor-2α- targeting agent belzutifan in the management of both von-Hippel Lindau (VHL)-associated and sporadic hemangioblastomas (HBLs). METHODS: The literature was queried for VHL, HBLs, and belzutifan. A summary of recent uses of belzutifan and currently ongoing clinical trials that are investigating the use of belzutifan in the treatment of HBLs is presented. RESULTS: VHL disease occurs as a result of germline mutations in the VHL tumor suppressor gene on chromosome 3p25-p26, leading to growth of benign and malignant tumors such as HBLs. The possibility of intermittent growth in HBLs indicates that it is important to avoid hasty surgical interventions. Belzutifan is the first nonsurgical food and drug administration-approved treatment for VHL disease-related tumors that may delay or circumvent the need for surgery or radiation therapy by inhibiting HIF-2α, an important component of cellular hypoxic response. There is limited real-world experience of belzutifan in patients with HBLs as a primary indication, though there are 2 phase II clinical trials investigating the use of belzutifan in the treatment of HBLs. CONCLUSIONS: There is limited experience regarding the use of belzutifan for CNS hemangioblastoma. While its application has been limited to a small group of clinical cases, it has exhibited significant efficacy in reducing the size and consequences of HBLs. Based on the promising outcomes observed in individual patient experiences and ongoing clinical trials, we infer that further exploration and integration of belzutifan into neurosurgical treatment plans for both sporadic and VHL-associated HBLs are warranted.

Unusual Presentation of Von Hippel-Lindau Syndrome With Gastric Variceal Bleeding.

Gastric varices are most commonly a complication of portal hypertension or splenic vein thrombosis (SVT). The presence of gastric varices due to portal hypertension is significantly less than the prevalence of esophageal varices. SVT is a known complication of pancreatitis due to inflammation or compression of the splenic vein coursing along the posterior surface of the pancreas. Occlusion of the splenic vein leads to left-sided portal hypertension. Left-sided portal hypertension results in the development of collateral vessels that bypass the splenic vein by connecting with the short gastric veins. The associated increased pressure within the gastric vessels results in gastric varices. Gastric varices due to SVT may occur in the absence of or be disproportionate to esophageal varices. We report an interesting case of gastrointestinal bleeding from gastric varices related to cirrhosis secondary to metabolic dysfunction-associated steatohepatitis and SVT secondary to chronic pancreatitis due to pancreatic neuroendocrine tumor (NET) in a patient diagnosed with von Hippel-Lindau (VHL) syndrome.

Advances in Molecular Mechanisms of Kidney Disease: Integrating Renal Tumorigenesis of Hereditary Cancer Syndrome.

Renal cell carcinoma (RCC) comprises various histologically distinct subtypes, each characterized by specific genetic alterations, necessitating individualized management and treatment strategies for each subtype. An exhaustive search of the PubMed database was conducted without any filters or restrictions. Inclusion criteria encompassed original English articles focusing on molecular mechanisms of kidney cancer. On the other hand, all non-original articles and articles published in any language other than English were excluded. Hereditary kidney cancer represents 5-8% of all kidney cancer cases and is associated with syndromes such as von Hippel-Lindau syndrome, Birt-Hogg-Dubè syndrome, succinate dehydrogenase-deficient renal cell cancer syndrome, tuberous sclerosis complex, hereditary papillary renal cell carcinoma, fumarate hydratase deficiency syndrome, BAP1 tumor predisposition syndrome, and other uncommon hereditary cancer syndromes. These conditions are characterized by distinct genetic mutations and related extra-renal symptoms. The majority of renal cell carcinoma predispositions stem from loss-of-function mutations in tumor suppressor genes. These mutations promote malignant advancement through the somatic inactivation of the remaining allele. This review aims to elucidate the main molecular mechanisms underlying the pathophysiology of major syndromes associated with renal cell carcinoma. By providing a comprehensive overview, it aims to facilitate early diagnosis and to highlight the principal therapeutic options available.

Contemporary Management of Renal Cell Carcinoma: A Review for General Practitioners in Oncology.

Renal cell carcinoma accounts for a significant proportion of cancer diagnoses in Canadians. Over the past several years, the management of renal cell cancers has undergone rapid changes in all prognostic risk categories, resulting in improved oncologic outcomes. Novel strategies for metastatic disease make use of the synergy between checkpoints and angiogenesis inhibition. Moreover, combination checkpoint inhibition has demonstrated durable efficacy in some patients. Adjuvant immunotherapy has recently shown a survival benefit for the first time in select cases. Significant efforts are underway to explore new compounds or combinations for later-line diseases, such as inhibitors of hypoxia-inducible factors and radiolabeled biomolecules targeting tumor antigens within the neoplastic microenvironment for precise payload delivery. In this manuscript, we provide a comprehensive review of the available data addressing key therapeutic areas pertaining to systemic therapy for metastatic and localized disease, review the most relevant prognostic tools, describe local therapies and management of CNS disease, and discuss practice-changing trials currently underway. Finally, we focus on some of the practical aspects for general practitioners in oncology caring for patients with renal cell carcinoma.

Clear Cell Renal Cell Carcinoma: Characterizing the Phenotype of Von Hippel-Lindau Mutation Using MRI.

BACKGROUND: The von Hippel-Lindau (VHL) mutation is an important alteration in clear cell renal cell carcinoma (ccRCC); however, its imaging phenotype remains unclear. PURPOSE: To investigate whether MRI features can reflect the VHL mutation status. STUDY TYPE: Retrospective. FIELD STRENGTH/SEQUENCE: 3 T/fast spin echo T2-weighted, spin-echo echo planar diffusion-weighted, gradient recalled echo T1-weighted, gradient recalled echo chemical-shift T1-weighted, and contrast-enhanced gradient recalled echo T1-weighted sequences. POPULATION: One hundred five patients with ccRCC who underwent preoperative contrast-enhanced MRI and subsequent genomic sequencing: 59 consecutive patients from our institution (38 [64.41%] with VHL mutations) formed a training cohort, and 46 from The Cancer Genome Atlas (TCGA) database (24 [52.17%] with VHL mutations) formed an independent test cohort. ASSESSMENT: Two radiologists, with 23 and 33 years of experience respectively, jointly evaluated the semantic MRI features of the primary lesion in ccRCCs to propose potential features related to VHL mutations in both cohorts. Three additional readers, with 5, 7, and 10 years of experience respectively, independently reviewed all lesions to assess the interobserver agreement of MRI features. A VHL mutational likelihood score (VHL-MULIS) system was constructed using the training cohort and validated using the independent test cohort. STATISTICAL TESTS: Fisher's test or chi-square test, t-test or Mann-Whitney U test, logistic regression, Cohen's kappa (κ), area under the receiver operating characteristic curve (AUC). A two-sided P value <0.05 was considered statistically significant. RESULTS: In both the local and public cohorts, T2-weighted signal intensity and presence of microscopic fat from primary lesions were significantly associated with VHL mutation status. The VHL-MULIS incorporated maximum diameter, T2-weighted signal intensity, and presence of microscopic fat in the training cohort and demonstrated promising diagnostic ability (AUC, 0.82; sensitivity, 0.79; specificity, 0.82) and substantial interobserver agreement (κ, 0.787) in the test cohort. DATA CONCLUSION: The VHL mutation exhibited a distinct MRI phenotype. Integrating multiple semantic MRI features has potential to reflect the mutation status in patients with ccRCC. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

The Discovery of a Specific CKIP-1 Ligand for the Potential Treatment of Disuse Osteoporosis.

Bone homeostasis relies on the delicate balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. The casein kinase 2 interacting protein-1 (CKIP-1), a specific CK2α subunit-interacting protein, has been documented as one of the crucial negative regulators of bone formation. CKIP-1 siRNA therapy has constraints that limit its use in clinical applications. Therefore, it is necessary to explore effective targeting strategies for CKIP-1. In this study, we observed an upregulation of CKIP-1 protein expression in the microgravity environment, while its ubiquitination levels decreased. We further investigated the interaction between CKIP-1 and VHL and found that VHL enhanced CKIP-1 degradation through the ubiquitylation-proteasome system (UPS). Additionally, we discovered a small molecule ligand, named C77, through DNA-encoded library (DEL) screening, which binds to CKIP-1 both in vivo and in vitro, as confirmed by Surface Plasmon Resonance (SPR) and the Cellular Thermal shift assay (CETSA), respectively. Our findings demonstrated the potential of VHL and C77 as guiding factors in the development of CKIP-1-based Proteolysis-Targeting Chimeras (PROTACs), which could be future therapeutic interventions in disuse osteoporosis.

Innovative solutions? Belzutifan therapy for hemangioblastomas in Von Hippel-Lindau disease: A systematic review and single-arm meta-analysis.

BACKGROUND: Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder that predisposes patients to develop multiple cysts and tumors, such as hemangioblastomas (HBs) and clear cell renal cell carcinoma (ccRCC), due to mutations in the VHL tumor suppressor gene. While treatment of HBs varies based on their characteristics and has improved patient survival, it still involves high morbidity and mortality, leading to ongoing debates and studies to refine therapy strategies. Recent developments include the emergence of Belzutifan, a novel inhibitor targeting hypoxia-inducible factor 2α (HIF-2α), which has shown promising results in ongoing trials, particularly for patients not immediately requiring surgery. METHODS: This systematic review and meta-analysis aimed to comprehensively evaluate the efficacy and safety of Belzutifan for treating HBs associated with VHL disease. Search was conducted across Medline, Embase, Cochrane, and Web of Science databases. Statistical Analysis was performed, with proportions and 95 % confidence intervals. Statistical analyses were carried out using R Studio. RESULTS: Ten studies were selected, comprising 553 patients. The population mean age was 40 (24-65), and 50 % of the population was formed by males. In terms of proportion, 6 analyses were performed: Disease Stability of 31 % [95 %CI:14 %-47 %; I2 = 2 %]; Disease Progression of 2 %[95 %CI:0 %-9 %; I2 = 0 %]; Partial Response of 75 % [95 %CI:54 %-96 %; I2 = 58 %]. Complete response of 1 % [95 %CI:0 %-7 %; I2 = 0 %];and Side effects, anemia 81 % rate [95 % CI:54 %-100 %; I2 = 94 %], and fatigue rate of 79 % [95 % CI:54 %-100 %;I2 = 94 %]. CONCLUSION: Results indicate that Belzutifan effectively stabilizes disease, reduces tumor progression, and achieves significant therapeutic responses, although side effects like anemia and fatigue were noted.

Trigeminal nerve hemangioblastoma in the setting of undiagnosed von Hippel-Lindau disease: illustrative case.

BACKGROUND: Von Hippel-Lindau disease (VHL) is an autosomal dominant tumor predisposition syndrome caused by mutations in the VHL gene. Patients with VHL are predisposed to developing numerous neoplasms, including central nervous system hemangioblastomas that typically arise within the cerebellum, brainstem, or spinal cord. The authors present the unusual case of a 69-year-old patient with a hemangioblastoma of the trigeminal nerve as his initial presentation of VHL. OBSERVATIONS: A 69-year-old male presented with progressive right-sided V3 paresthesias, gait disturbance, and diplopia. Magnetic resonance imaging demonstrated an enhancing 0.5-cm nodule within the right trigeminal nerve and an associated peritumoral cyst exerting mass effect on the cerebral peduncle. Neural axis imaging demonstrated pia-based enhancing lesions concerning for multiple spinal hemangioblastomas. The patient underwent an uncomplicated retrosigmoid craniotomy for trigeminal nerve hemangioblastoma resection. The patient had postoperative improvement in his gait, diplopia, and facial paresthesias. Genetic testing revealed that the patient was heterozygous for a pathological mutation in the VHL gene. LESSONS: Hemangioblastomas in adults over 50 years of age should prompt a workup for VHL. Recognizing that cranial nerves are a possible site of hemangioblastoma occurrence is important for neurosurgeons and radiologists alike. Resection of cranial nerve hemangioblastomas is technically challenging but can lead to symptom improvement for patients. https://thejns.org/doi/10.3171/CASE24149.

Characterization of spinal hemangioblastomas in patients with and without von Hippel-Lindau, and YAP expression.

INTRODUCTION: Hemangioblastoma (HB) is a benign tumor of the central nervous system, associated with von Hippel-Lindau disease (VHL), or sporadic. The aim of this study was to compare and examine the clinical-pathological profile of patients with spinal hemangioblastoma and YAP expression. METHODS: A retrospective, descriptive, comparative study. All patients who underwent surgery for spinal HB between 2016 and 2023 were included. Clinical and radiological data were collected and analyzed. An immunohistochemistry panel including NeuN, neurofilaments (NF), and YAP-1, was performed. RESULTS: Nine patients were studied, six women and three men. Four patients had previously diagnosed VHL. The tumor location included: four cervical (44.44%), two thoracic (22.22%), two pontine with cervical extension (22.22%) and one patient with two lesions, one cervical and one thoracic (11.11%). Non-significant clinical differences were identified between VHL and sporadic patients. Imaging evidenced seven extramedullary and three intramedullary tumors. Histologically, intra-tumoral and perivascular axonal tracts were observed in all cases. One third of the tumors (two with VHL and one sporadic) presented extramedullary hematopoiesis. Seven cases (77.8%) expressed nuclear YAP (three with VHL and four sporadic HBs). The surgical outcome was good and only one patient with VHL undergoing subtotal resection had recurrence. CONCLUSIONS: Spinal HBs can be associated with VHL or be sporadic. To the best of our knowledge, this is the first study to describe YAP expression in HB. It is important to investigate the involvement of the Hippo pathway in HBs as a possible therapeutic target.

Comprehensive treatment of von Hippel-Lindau disease: A case report.

von Hippel-Lindau (VHL) disease is a rare autosomal dominant multiorgan disease characterized by several benign and malignant tumors rich in vascular, as well as cysts in other organs. A great clinical treatment strategy is significantly warranted for good prognosis of patients with VHL disease. Herein, we reported a case of a 45-year-old woman diagnosed with VHL disease with spinal hemangioblastoma (HB) and clear cell renal cell carcinoma (ccRCC). Four years after the resection of the right kidney, a recurrent RCC in the right kidney and a malignant lesion in the left kidney were observed. This patient was started on sorafenib (800 mg, daily) and tislelizumab (200 mg per 3 weeks). After 6 months of treatment, the size of renal cell carcinoma was dramatically reduced and renal function improved. More importantly, she achieved partial response during the whole treatment. Microscopically, intramedullary masses resection was done and the HB in T4-5 thoracic spinal was removed. Neurologic symptoms such as numbness and pain were remarkably alleviated. Additionally, tislelizumab-induced elevation in liver transaminase levels and hypothyroidism were revered by hepatoprotector and levothyroxine, respectively. In short, comprehensive treatment strategies may benefit patients with VHL disease, especially with HB and ccRCC.

Cauda equina myxopapillary ependymoma in von Hippel-Lindau disease: A case report.

Background: Patients affected by Von Hippel-Lindau (VHL) are prone to develop central nervous system neoplasms such as hemangioblastomas (HBs). Myxopapillary ependymoma (MPE) is not commonly associated with VHL disease. Case Description: We present the first case of a VHL patient affected by simultaneous silent cauda equina MPE and a symptomatic conus medullaris HB. The patient was first operated for systemic tumors and followed for asymptomatic HBs. Simple surveillance was maintained until neurological symptoms appeared. Regular follow-up demonstrated objective growth of the cystic conus medullaris tumor while the cauda equina lesion remained stable. Surgery was performed to avoid further neurological worsening. Histopathological examination showed conus medullaris HB and a nearby cauda equina MPE. Conclusion: Simultaneous spinal HBs and isolated MPE may exceptionally occur in VHL patients.