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Handbook of Clinical Neurology 2015von Hippel-Lindau (VHL) disease is an inheritable condition with an incidence of 1 in 36000 live births. Individuals with VHL develop benign and malignant tumors... (Review)
Review
von Hippel-Lindau (VHL) disease is an inheritable condition with an incidence of 1 in 36000 live births. Individuals with VHL develop benign and malignant tumors including retinal and central nervous system hemangioblastomas, clear cell renal cell carcinomas (RCC), pheochromocytomas, pancreatic neuroendocrine tumors and endolymphatic sac tumors (ELSTs). VHL is caused by germline loss of function of the VHL gene on one allele at chromosome 3p25-26. A somatic "second hit" event leads to the loss of the other allele and tumor formation. Loss of VHL function in cells leads to increased expression and stabilization of hypoxia inducible factor (HIF). VHL protein/HIF pathway has been implicated in tumorigenesis for hemangioblastomas, RCC and other VHL tumors. Clinical examination, imaging, and genetic testing for VHL mutations confirm VHL disease. Management of VHL disease largely consists of surgical resection of symptomatic tumors (hemangioblastomas), tumors prone to metastasize (RCC larger than 3cm), or tumors causing hormonal symptoms (pheochromocytomas). Despite advances in early diagnosis and management of VHL disease, life expectancy for VHL patients remains low at 40-52 years. Secondary effects from VHL manifestations are mitigated by routine surveillance and early detection. In this chapter, we summarize the current state of knowledge in VHL disease.
Topics: Hemangioblastoma; Humans; von Hippel-Lindau Disease
PubMed: 26564077
DOI: 10.1016/B978-0-444-62702-5.00010-X -
The New England Journal of Medicine Nov 2021Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to gene inactivation and constitutive activation of the transcription...
BACKGROUND
Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α).
METHODS
In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan.
RESULTS
After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl).
CONCLUSIONS
Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).
Topics: Adult; Age of Onset; Aged; Anemia; Antineoplastic Agents; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Renal Cell; Disease Progression; Fatigue; Female; Follow-Up Studies; Hemangioblastoma; Humans; Indenes; Kidney Neoplasms; Male; Middle Aged; Neoplasms, Multiple Primary; Neuroendocrine Tumors; Pancreatic Neoplasms; von Hippel-Lindau Disease
PubMed: 34818478
DOI: 10.1056/NEJMoa2103425 -
European Journal of Medical Genetics Aug 2022von Hippel Lindau disease (vHL) is caused by a hereditary predisposition to multiple neoplasms, especially hemangioblastomas in the retina and CNS, renal cell carcinomas...
von Hippel Lindau disease (vHL) is caused by a hereditary predisposition to multiple neoplasms, especially hemangioblastomas in the retina and CNS, renal cell carcinomas (RCC), pheochromocytomas, neuroendocrine pancreatic tumours (PNET) and endolymphatic sac tumours. Evidence based approaches are needed to ensure an optimal clinical care, while minimizing the burden for the patients and their families. This guideline is based on evidence from the international vHL literature and extensive research of geno- and phenotypic characteristics, disease progression and surveillance effect in the national Danish vHL cohort. We included the views and preferences of the Danish vHL patients, ensured consensus among Danish experts and compared with international recommendations. RECOMMENDATIONS: vHL can be diagnosed on clinical criteria, only; however, in most cases the diagnosis can be supported by identification of a pathogenic or likely pathogenic variant in VHL. Surveillance should be initiated in childhood in persons with, or at risk of, vHL, and include regular examination of the retina, CNS, inner ear, kidneys, neuroendocrine glands, and pancreas. Treatment of vHL manifestations should be planned to optimize the chance of cure, without unnecessary sequelae. Most manifestations are currently treated by surgery. However, belzutifan, that targets HIF-2α was recently approved by the U.S. Food and Drug Administration (FDA) for adult patients with vHL-associated RCC, CNS hemangioblastomas, or PNETs, not requiring immediate surgery. Diagnostics, surveillance, and treatment of vHL can be undertaken successfully by experts collaborating in multidisciplinary teams. Systematic registration, collaboration with patient organisations, and research are fundamental for the continuous improvement of clinical care and optimization of outcome with minimal patient inconvenience.
Topics: Adult; Carcinoma, Renal Cell; Genetic Predisposition to Disease; Hemangioblastoma; Humans; Kidney Neoplasms; von Hippel-Lindau Disease
PubMed: 35709961
DOI: 10.1016/j.ejmg.2022.104538 -
Clinical Cancer Research : An Official... Nov 2022On August 13, 2021, the FDA approved belzutifan (WELIREG, Merck), a first-in-class hypoxia-inducible factor (HIF) inhibitor for adult patients with von Hippel-Lindau...
On August 13, 2021, the FDA approved belzutifan (WELIREG, Merck), a first-in-class hypoxia-inducible factor (HIF) inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. The FDA granted approval based on the clinically meaningful effects on overall response rate (ORR) observed in patients enrolled in Study MK-6482-004. All 61 patients had VHL-associated RCC; some also had CNS hemangioblastomas and/or pNET. For VHL disease-associated RCC, ORR was 49% [95% confidence interval (CI), 36-62], median duration of response (DoR) was not reached, 56% of responders had DoR ≥12 months, and median time to response was 8 months. Twenty-four patients had measurable CNS hemangioblastomas with an ORR of 63% (95% CI, 41-81), and 12 patients had measurable pNET with an ORR of 83% (95% CI, 52-98). For these tumors, median DoR was not reached, with 73% and 50% of patients having response durations ≥12 months for CNS hemangioblastomas and pNET, respectively. The most common adverse reactions, including laboratory abnormalities, reported in ≥20% were anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Belzutifan can render some hormonal contraceptives ineffective and can cause embryo-fetal harm during pregnancy. This article summarizes the data and the FDA thought process supporting traditional approval of belzutifan for this indication.
Topics: Adult; Humans; Pregnancy; Female; von Hippel-Lindau Disease; Hemangioblastoma; Carcinoma, Renal Cell; Central Nervous System Neoplasms; Antineoplastic Agents; Kidney Neoplasms; Neuroectodermal Tumors, Primitive
PubMed: 35727604
DOI: 10.1158/1078-0432.CCR-22-1054 -
Journal of Cancer Research and... 2021Retinal hemangioblastomas are one of the most common and early manifestations of Von Hippel-Lindau disease. Early detection is the key in their management. When left...
Retinal hemangioblastomas are one of the most common and early manifestations of Von Hippel-Lindau disease. Early detection is the key in their management. When left untreated, these benign neoplasms may continue to grow and result in scleral infiltration and extraocular extension warranting enucleation of the globe.
Topics: Adult; Cerebellar Neoplasms; Combined Modality Therapy; Female; Fungi; Hemangioblastoma; Humans; Prognosis; Retinal Neoplasms; Scleral Diseases
PubMed: 33723171
DOI: 10.4103/jcrt.JCRT_718_18 -
Journal of Craniovertebral Junction &... 2016Spinal nerve root hemangioblastomas present mostly as intradural-extradurally. Purely extradural spinal nerve root hemangioblastoma is a very rare entity. In this study,... (Review)
Review
Spinal nerve root hemangioblastomas present mostly as intradural-extradurally. Purely extradural spinal nerve root hemangioblastoma is a very rare entity. In this study, we aimed to analyze epidemiological perspectives of purely extradural spinal nerve root hemangioblastomas presented in English medical literature in addition to our own exemplary case. PubMed/MEDLINE was searched using the terms "hemangioblastoma," "extradural," "spinal," and "nerve root." Demographical variables of age, gender, concomitant presence of von Hippel-Lindau (VHL) disease; spinal imaging and/or intraoperative findings for tumor location were surveyed from retrieved articles. There are 38 patients with purely extradural spinal nerve root hemangioblastoma. The median age is 45 years (range = 24-72 years). Female:male ratio is 0.6. Spinal levels for purely extradural spinal nerve root hemangioblastomas, in order of decreasing frequency, are thoracic (48.6%), cervical (13.5%), lumbar (13.5%), lumbosacral (10.8%), sacral (8.1%), and thoracolumbar (5.4%). Concomitant presence of VHL disease is 45%. Purely extradural spinal nerve root hemangioblastomas are very rare and can be confused with other more common extradural spinal cord tumors. Concomitant presence of VHL disease is observed in less than half of the patients with purely extradural spinal nerve root hemangioblastomas. Surgery is the first-line treatment in these tumors.
PubMed: 27891027
DOI: 10.4103/0974-8237.193255 -
Retina (Philadelphia, Pa.) Dec 2019To review the current state of diagnosis and management of retinal hemangioblastoma and retinal vascular proliferation arising from von Hippel-Lindau (VHL) disease. (Review)
Review
PURPOSE
To review the current state of diagnosis and management of retinal hemangioblastoma and retinal vascular proliferation arising from von Hippel-Lindau (VHL) disease.
METHODS
A review of the literature was performed. Consensus was reached among authors regarding current practice, with reference to published data where possible.
RESULTS
von Hippel-Lindau disease and its ocular manifestations are relatively rare, and there is limited evidence in the literature on which to base management. There was consensus on core principles, including 1) recognition and diagnosis of von Hippel-Lindau disease when present, with appropriate referral for care of this potentially lethal systemic condition; 2) regular ophthalmic evaluation for individuals with von Hippel-Lindau disease, to identify and offer timely treatment for new or active retinal hemangioblastomas; 3) ablative treatment of retinal hemangioblastomas that can be safely destroyed, to lower risk of vision loss; 4) observation or consideration of nonablative treatments for retinal hemangioblastomas that cannot be safely destroyed; and 5) observation of asymptomatic retinal vascular proliferation, with consideration of vitrectomy for lesions exerting effects on vision.
CONCLUSION
Ocular outcomes can be gratifying in many cases with appropriate management. Improved understanding of the molecular basis for the disease creates an opportunity for rational design of better therapies.
Topics: Hemangioblastoma; Humans; Retinal Neoplasms; Retinal Vessels; von Hippel-Lindau Disease
PubMed: 31259811
DOI: 10.1097/IAE.0000000000002572 -
Journal of Craniovertebral Junction &... 2022Spinal cervical extradural and intra-extradural hemangioblastomas are exceptional, with only nine reported cases. This study reviews the diagnostic and surgical problems...
Spinal cervical extradural and intra-extradural hemangioblastomas are exceptional, with only nine reported cases. This study reviews the diagnostic and surgical problems of this rare entity. Two female patients, aged 80 years and 25 years, respectively, one with Von Hippel-Lindau disease (VHLD), experienced brachial pain and weakness. On magnetic resonance imaging, a dumbbell intra-extraspinal hemangioblastoma was evidenced. The surgical resection through posterior laminectomy resulted in clinical remission of brachial pain and weakness. The magnetic resonance aspect of a dumbbell lesion suggests a neurogenic tumor; the correct preoperative diagnosis is possible in individuals with VHLD. The surgical problems include high tumor vascularity, vertebral artery control, and nerve root preservation. However, the surgical excision results in clinical remission.
PubMed: 35837434
DOI: 10.4103/jcvjs.jcvjs_146_21 -
Medicine Nov 2022This study aimed to evaluate the diagnostic performance of dynamic susceptibility contrast (DSC) perfusion magnetic resonance imaging and apparent diffusion coefficient...
This study aimed to evaluate the diagnostic performance of dynamic susceptibility contrast (DSC) perfusion magnetic resonance imaging and apparent diffusion coefficient (ADC) for differentiating common posterior fossa tumors, pilocytic astrocytoma (PA), medulloblastoma (MB), and hemangioblastoma (HB). Between January 2016 and April 2022, we enrolled 23 (median age, 7 years [range, 2-26]; 12 female), 13 (10 years [1-24]; 3 female), and 12 (43 years [23-73]; 7 female) patients with PA, MB, and HB, respectively. Normalized relative cerebral blood volume and flow (nrCBV and nrCBF) and normalized mean ADC (nADCmean) were calculated from volume-of-interest and statistically compared. nADCmean was significantly higher in PA than in MB (PA: median, 2.2 [range, 1.59-2.65] vs MB: 0.93 [0.70-1.37], P < .001). nrCBF was significantly higher in HB than in PA and MB (PA: 1.10 [0.54-2.26] vs MB: 1.62 [0.93-3.16] vs HB: 7.83 [2.75-20.1], all P < .001). nrCBV was significantly different between all 3 tumor types (PA: 0.89 [0.34-2.28] vs MB: 1.69 [0.93-4.23] vs HB: 8.48 [4.59-16.3], P = .008 for PA vs MB; P < .001 for PA vs HB and MB vs HB). All tumors were successfully differentiated using an algorithmic approach with a threshold value of 4.58 for nrCBV and subsequent threshold value of 1.38 for nADCmean. DSC parameters and nADCmean were significantly different between PA, MB, and HB. An algorithmic approach combining nrCBV and nADCmean may be useful for differentiating these tumor types.
Topics: Humans; Female; Child; Medulloblastoma; Hemangioblastoma; Retrospective Studies; Diagnosis, Differential; Astrocytoma; Magnetic Resonance Imaging; Diffusion Magnetic Resonance Imaging; Perfusion; Cerebellar Neoplasms; Brain Neoplasms
PubMed: 36343086
DOI: 10.1097/MD.0000000000031708