Von Hippel-Lindau disease is a rare genetic condition that causes multiple tumors and cysts to grow throughout a person’s lifetime, affecting organs such as the kidneys, brain, spine, eyes, and pancreas. The journey with this disease involves careful monitoring, surgical interventions when needed, and increasingly, innovative medications that can control tumor growth. While living with VHL requires lifelong vigilance and coordinated medical care, advances in treatment are bringing new hope to patients and their families.

What Treatment Options Mean for People with VHL

Managing von Hippel-Lindau disease means addressing a complex challenge: tumors can appear in different organs at different times throughout a person’s life. The main goal of treatment is to prevent these growths from causing serious health problems while preserving organ function as much as possible. Because kidney cancer is the leading cause of death in people with VHL, protecting kidney health becomes especially important.^[1]

Treatment plans need to be highly individualized because each person with VHL experiences the disease differently. Some may develop retinal tumors early in life, while others might first notice problems in their kidneys or adrenal glands. The timing and location of tumors determine what type of treatment is needed and when. Importantly, treatment decisions also depend on tumor size and growth rate, not just their presence. A small, slow-growing tumor might only need monitoring, while a larger or faster-growing one could require immediate action.^[13]

Healthcare for VHL requires a team approach. Patients typically work with specialists in urology, neurosurgery, ophthalmology, genetics, and other fields. This coordination ensures that all potential tumor sites are monitored and that treatments don’t interfere with each other. Regular surveillance throughout life is essential because new tumors can develop at any time.^[4]

Standard Treatment Approaches for VHL Disease

Surgery has traditionally been the cornerstone of VHL treatment. When tumors grow large enough to threaten organ function or risk spreading, surgical removal becomes necessary. The challenge is that people with VHL often require multiple surgeries throughout their lives, and each operation carries risks and requires recovery time. The goal is always to remove tumors while preserving as much healthy tissue as possible.^[1]

For tumors in the brain and spinal cord, called hemangioblastomas, surgery is typically performed when they start causing symptoms such as headaches, balance problems, or weakness. These noncancerous tumors grow from blood vessels and can press on surrounding brain or spinal tissue. Neurosurgeons aim to remove the entire tumor without damaging nearby structures. The timing of surgery is crucial: operating too early might not be necessary, but waiting too long can lead to irreversible nerve damage.^[1]

Eye tumors, specifically retinal hemangioblastomas, require specialized treatment to preserve vision. These growths can appear on the light-sensitive tissue at the back of the eye and may lead to vision loss if untreated. Treatment options include laser therapy, cryotherapy (freezing), or in some cases, surgical removal. The choice depends on the tumor’s size and location. Early detection through regular eye examinations is vital because treating small tumors is much easier and more successful than addressing larger ones that have already caused retinal damage.^[1]

Kidney problems in VHL present a particularly complex challenge. People with this condition often develop both cysts (fluid-filled sacs) and clear cell renal cell carcinoma, a type of kidney cancer. Between 25% and 60% of people with VHL will develop this cancer, making it a leading cause of death in this population. The traditional approach has been to monitor kidney tumors carefully and remove them surgically when they reach about 3 centimeters in size. This timing balances the risk of cancer spreading against the need to preserve kidney function, since repeated surgeries can damage healthy kidney tissue.^[1]

Modern kidney surgery techniques try to save as much healthy tissue as possible. Instead of removing the entire kidney (nephrectomy), surgeons often perform partial nephrectomy, taking out only the tumor and a small margin of surrounding tissue. Alternative approaches include cryoablation, which uses extreme cold to destroy tumor cells, or radiofrequency ablation, which uses heat. These less invasive techniques can be particularly helpful for people with multiple kidney tumors who need repeated treatments.^[13]

Tumors of the adrenal glands, called pheochromocytomas, affect 10% to 20% of people with VHL. These tumors can produce excessive amounts of adrenaline-like hormones, causing dangerous spikes in blood pressure, panic attacks, sweating, and rapid heartbeat. They are particularly risky during surgery, pregnancy, or other stressful situations. Treatment typically involves surgical removal, but doctors first prescribe medications called alpha-blockers to control blood pressure and protect the heart before surgery. When possible, surgeons remove only the tumor, leaving healthy adrenal tissue to continue producing necessary hormones.^[1]

Pancreatic tumors in VHL come in two forms: cysts and neuroendocrine tumors. Cysts are usually harmless and don’t require treatment. Neuroendocrine tumors, which affect 9% to 17% of people with VHL, may need removal if they grow large or cause symptoms. The decision to operate depends on tumor size, growth rate, and whether there are signs of spread. Unlike other VHL tumors, pancreatic cysts rarely cause problems and are often just monitored.^[1]

Side effects from surgery vary depending on the operation’s location and extent. Brain and spinal surgeries can affect coordination, movement, or sensation, though these risks must be weighed against the danger of leaving tumors untreated. Kidney surgeries can gradually reduce kidney function, especially when multiple operations are needed over time. In some cases, people may eventually need dialysis or kidney transplant. Eye surgery risks include bleeding, infection, and in rare cases, loss of vision in the treated eye.^[13]

Breakthrough Treatments Being Tested in Clinical Trials

Research into VHL has led to an understanding of how the disease works at the molecular level, and this knowledge has opened doors to new treatment approaches. Scientists discovered that when the VHL gene is mutated, it causes a buildup of proteins called hypoxia-inducible factors or HIFs. These proteins normally help cells respond to low oxygen levels, but when they accumulate inappropriately, they trigger uncontrolled blood vessel growth and tumor formation. This discovery pointed researchers toward developing drugs that could block HIF activity.^[12]

The most significant breakthrough in VHL treatment came with the development of belzutifan, marketed as Welireg. This drug works by binding directly to a specific HIF protein called HIF-2α, preventing it from promoting tumor growth. For years, scientists believed it was impossible to create drugs that could block transcription factors like HIF-2α, but researchers at the University of Texas Southwestern proved otherwise. They developed a compound that could fit into a pocket in the HIF-2α protein and block its activity. This compound eventually became belzutifan.^[12]

In August 2021, the U.S. Food and Drug Administration approved belzutifan for treating adults with VHL who have kidney cancer, brain or spinal cord hemangioblastomas, or pancreatic neuroendocrine tumors that don’t require immediate surgery. The approval was based on results from Phase 2 clinical trials conducted by researchers at the National Cancer Institute and other centers. These trials showed remarkable results: after 18 months of treatment, nearly half of participants experienced kidney tumor shrinkage of at least 30%. Importantly, the majority of those who responded continued to have shrinking tumors after a year of treatment.^[12]

What makes belzutifan particularly promising is that it doesn’t just affect kidney tumors. In the clinical trials, researchers also saw shrinkage in brain, pancreatic, and even eye tumors. This multi-organ effect is crucial for VHL patients who typically have tumors in multiple locations. The drug is taken as a daily pill, making it far less burdensome than repeated surgeries. For many patients, belzutifan has meant avoiding operations altogether or at least delaying them significantly.^[12]

The side effects of belzutifan are generally manageable, though they require monitoring. The most common side effect is anemia, a decrease in red blood cells that can cause fatigue. This happens because blocking HIF-2α affects the body’s normal response to oxygen levels, which includes red blood cell production. Other side effects can include fatigue, headache, and dizziness. Patients taking belzutifan need regular blood tests to monitor their blood counts and other laboratory values. Despite these side effects, many patients find them preferable to the risks and recovery time associated with surgery.^[13]

Patient experiences with belzutifan have been life-changing. One patient, Justin, had undergone more than a dozen surgeries by his early 30s, following in the footsteps of his father who also had VHL. When new tumors appeared, his doctors at the NIH Clinical Center encouraged him to join a clinical trial testing belzutifan. After starting the medication, his tumors stopped growing, and he hasn’t needed surgery since. The stability the drug provided allowed him to travel internationally, something he couldn’t do during his years of repeated operations and recoveries. He even met his wife during this time.^[15]

Another drug that has shown promise in VHL treatment is pazopanib, which was originally developed for advanced kidney cancer. While not specifically approved for VHL, it has been used in some cases, particularly for kidney tumors. Pazopanib works differently from belzutifan: it blocks several different proteins involved in blood vessel growth and tumor cell division, including proteins that are activated by HIF. This broader mechanism means it can affect tumor growth through multiple pathways.^[13]

Researchers continue to study belzutifan in ongoing clinical trials to better understand its long-term effects and optimal use. Some studies are examining whether the drug can prevent new tumors from forming, not just shrink existing ones. Others are looking at combining belzutifan with surgery to see if this approach might be better than either treatment alone. Scientists are also investigating whether belzutifan might be effective for other VHL-associated tumors, such as those in the inner ear.^[12]

The mechanism behind why VHL causes kidney cancer specifically has been a focus of research. Scientists found that kidney cells are particularly dependent on proper VHL protein function. When the VHL gene is mutated, kidney cells accumulate HIF proteins that drive the formation of new blood vessels and promote cell growth. These processes are normally tightly controlled, but in VHL, they become dysregulated, leading to cancer. Understanding this mechanism has helped researchers identify not just HIF-2α as a target, but potentially other molecules in the same pathway that could be blocked by future drugs.^[2]

Clinical trials for VHL are conducted at specialized centers with expertise in this rare disease. In the United States, the National Cancer Institute has been a leader in VHL research, conducting natural history studies that follow patients over many years to understand how the disease progresses. These studies have been crucial for determining the best times to intervene with treatment. The VHL Alliance maintains a list of Clinical Care Centers where patients can receive expert, coordinated care and potentially participate in research studies.^[16]

Eligibility for clinical trials typically requires a confirmed diagnosis of VHL, either through genetic testing showing a VHL gene mutation or through clinical criteria (specific patterns of tumors). Some trials accept patients with any VHL-associated tumor, while others focus on specific tumor types. Phase 1 trials focus primarily on safety and determining the right dose of a new treatment. Phase 2 trials test whether the treatment works and continue to monitor safety. Phase 3 trials compare the new treatment to current standard treatments to see which is better.^[13]

Most Common Treatment Methods

• Surgical removal of tumors
  • Neurosurgery for brain and spinal cord hemangioblastomas to prevent nerve damage and relieve symptoms like headaches or weakness
  • Partial nephrectomy to remove kidney tumors while preserving as much healthy kidney tissue as possible
  • Adrenalectomy (preferably partial) to remove pheochromocytomas while maintaining hormone production
  • Eye surgery, laser therapy, or cryotherapy for retinal hemangioblastomas to preserve vision
  • Removal of pancreatic neuroendocrine tumors when they grow large or cause symptoms
• Targeted drug therapy
  • Belzutifan (Welireg), an HIF-2α inhibitor taken daily as a pill to shrink kidney cancer, brain/spinal hemangioblastomas, and pancreatic neuroendocrine tumors in VHL patients who don’t need immediate surgery
  • Pazopanib for advanced kidney cancer, blocking multiple proteins involved in tumor growth and blood vessel formation
• Minimally invasive tumor destruction
  • Cryoablation using extreme cold to freeze and destroy kidney tumors without removing tissue
  • Radiofrequency ablation using heat energy to eliminate kidney tumors, especially useful for patients needing multiple treatments
• Surveillance and monitoring
  • Annual eye examinations starting in early childhood to detect retinal tumors before vision loss
  • Brain and spine MRI imaging every two years starting at age 15 to find hemangioblastomas
  • Abdominal imaging (CT or MRI) to monitor kidneys, pancreas, and adrenal glands for cysts and tumors
  • Blood tests to check for hormones produced by pheochromocytomas
  • Hearing tests every two years to detect inner ear tumors early