What are the management and treatment options for a patient with a history of Von Hippel-Lindau (VHL) Disease?

From the Guidelines

Management of Von Hippel-Lindau (VHL) disease requires a comprehensive, multidisciplinary approach focused on surveillance, surgical intervention, and targeted therapies, with a strong emphasis on preventing complications through early detection and intervention before lesions cause irreversible damage or malignant transformation. The approach should include regular screening with MRI of the brain and spine every 1-2 years, annual abdominal imaging (MRI or CT), annual ophthalmologic examination, and audiometry evaluations every 2-3 years 1. For patients with VHL-associated renal cell carcinoma (RCC), belzutifan, a novel hypoxia-inducible factor 2a transcription factor inhibitor, is recommended for patients who do not require immediate surgery, given its overall response rate of 64% and reduction in the need for subsequent intervention 1. Key aspects of management include:

• CNS hemangioblastomas: surgical resection for symptomatic lesions or those showing significant growth, while asymptomatic stable lesions may be monitored
• Renal cell carcinomas: nephron-sparing surgery when tumors reach 3 cm in diameter, and targeted therapies such as belzutifan or tyrosine kinase inhibitors like sunitinib for metastatic disease
• Pheochromocytomas: preoperative alpha-blockade with medications like phenoxybenzamine followed by surgical resection
• Pancreatic neuroendocrine tumors: resection when they reach 2-3 cm or show concerning features
• Retinal hemangioblastomas: treatment with laser photocoagulation or cryotherapy for peripheral lesions, while endolymphatic sac tumors may require surgical removal
• Genetic counseling and psychological support are essential for patients and families to cope with this lifelong condition 1. It is crucial for patients to be managed by a multidisciplinary team with experience in VHL disease, whenever possible, to ensure comprehensive care and access to genetic testing 1.

From the Research

Management and Treatment Options for Von Hippel-Lindau Disease

• The management of Von Hippel-Lindau (VHL) disease involves a multidisciplinary approach, including regular surveillance and treatment of associated tumors and cysts 2.
• Surveillance should be initiated in childhood and include regular examination of the retina, CNS, inner ear, kidneys, neuroendocrine glands, and pancreas 2, 3.
• Treatment of VHL manifestations should be planned to optimize the chance of cure, without unnecessary sequelae, and most manifestations are currently treated by surgery 2.
• However, belzutifan, a drug 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 2.

Hemangioblastoma Diagnosis and Surveillance

• Hemangioblastomas are a frequent underlying cause of neurological morbidity and death in patients with VHL disease, and unified evidence-based surveillance recommendations have been established 4.
• The International VHL Surveillance Guidelines Consortium recommends that clinical evaluation (yearly) be used as the primary screening tool for hemangioblastomas in VHL, and screening be performed between the ages of 11 and 65 years, or with the onset of symptoms 4.
• Baseline MRI should be first performed at the age of 11 years or after identification of neurological symptoms or signs, and continue every 2 years 4.

Role of Hemangioblastoma in VHL Disease

• Hemangioblastoma plays a major role in the unfavorable overall survival of VHL disease patients, and the involvement of central nervous system hemangioblastoma (CHB) and retinal hemangioblastoma (RA) are independent risk factors for overall survival 5.
• The involvement of renal cell carcinoma (RCC) is not a significant risk factor for overall survival, and only RA is a risk factor for CHB-specific survival 5.

Treatment of Hemangioblastomas

• Indication for surgery remains personalized and should be approved by an experienced VHL board, but neurological symptoms, rapid tumor growth, or critically large tumor/cyst sizes are the key indications to remove hemangioblastomas 3.
• Modern neurosurgical techniques should encompass microsurgery, neuronavigation, intraoperative neuromonitoring, fluorescein dye-based intraoperative angiography, intraoperative ultrasound, and minimally invasive approaches, preceded in selected cases by endovascular embolization 3.
• Small retinal tumors of the peripheral retina can be treated by laser coagulation, larger tumors by cryocoagulation or brachytherapy 3.