What is von Hippel-Lindau disease?
Von Hippel-Lindau syndrome (VHL) is a hereditary condition associated with tumors arising in multiple organs. VHL-related tumors include hemangioblastomas, which are blood vessel tumors of the brain, spinal cord, and retina. The retinal tumors are also called retinal angiomas, which can lead to blindness if not treated in a timely manner. People with VHL also have an increased risk of developing clear cell renal cell carcinoma (ccRCC), which is a specific type of kidney cancer, as well as a type of tumor in the pancreas known as pancreatic neuroendocrine tumor (pNET). Tumors of the adrenal gland or pheochromocytoma can also develop, with a small number becoming metastatic, meaning they spread to other parts of the body.
Other features of VHL include: kidney cysts, which are closed sacs usually filled with fluid; pancreatic cysts, epididymal cystadenomas, which are tumors near a man’s testicles; broad ligament cystadenomas, which occur near the fallopian tubes in women; and endolymphatic sac tumors (ELST), which are tumors of the inner ear that may cause hearing loss.
What causes VHL?
VHL is a genetic condition. This means that the risk of developing certain types of tumors and other features of VHL can be passed from generation to generation. The gene associated with VHL is also called VHL. Inheriting a deletion or mutation (alteration) in the VHL gene gives a person an increased risk of developing any of the different signs of VHL explained above, called manifestations. Nearly everyone who has VHL syndrome has an identifiable VHL genetic mutation.
How is VHL inherited?
Normally, every cell has 2 copies of each gene: 1 inherited from the mother and 1 inherited from the father. VHL follows an autosomal dominant inheritance pattern, in which inheriting 1 copy of the altered gene will likely result in a mutation of the second (normal) copy of the gene. This puts the individual at risk for developing cancer.
A parent with a gene mutation may pass along a copy of their normal gene or a copy of the gene with the mutation. Therefore, a child who has a parent with a mutation has a 50% chance of inheriting that mutation. A brother, sister, or parent of a person who has a mutation also has a 50% chance of having the same mutation. Up to 10% of individuals with VHL have no family history. This means that these individuals have a de novo mutation and are the first in their family to have this genetic change.
When considering having children, it is advised that a person with VHL discuss future family planning with their partner and make a decision that is the best for them. Some people are more comfortable with the idea of the possible risk of hereditary VHL than others. Some people with VHL feel very worried and anxious about the risk of passing the mutation on. Meeting with a genetic counselor will help you understand all the options available to make the best decision for your family. There are different family planning options available to individuals who have VHL and are considering having children. Some of these options allow someone to have a child unaffected with VHL, and other options simply provide more information about a pregnancy. These options are choices, not a requirement. Many people choose to start a family without doing any genetic or prenatal testing. It is also important to consider that, at this time, there is no clear answer as to whether pregnancy, long term use of hormonal birth control, hormone replacement therapy, or high doses of hormones used for procedures like in vitro fertilization can promote tumor growth for women with VHL.
How common is VHL?
It is estimated that about 1 in 30,000 people has VHL. About 10% of people with VHL do not have any family history of the condition. They have a de novo mutation, meaning a new mutation in the VHL gene not present in their parents.
How is VHL diagnosed?
The only way to diagnose VHL is with genetic testing. Nearly all people with VHL will be found to have a genetic mutation in their VHL gene once tested.
There are no universal guidelines regarding who should be screened for VHL. However, VHL should be suspected when a person has:
Multiple hemangioblastomas of the brain, spinal cord, or eye, or
1 hemangioblastoma and ccRCC, pancreatic cysts, pheochromocytoma, endolymphatic sac tumor, or a epididymal cyst
When a younger person has multiple bilateral ccRCC, meaning cancer in both kidneys
If a person has a family history of VHL, they are suspected of also having VHL if the person has any 1 symptom, such as hemangioblastoma of the brain, spine, or eye, kidney cancer, pancreatic cysts, pheochromocytoma, or endolymphatic sac tumor.
A list of signs and symptoms called VHL Referral Criteria can be found here. Please note that this link takes you to a separate, independent website.
What are the estimated manifestation risks associated with VHL?
Retinal hemangioblastomas: about 60%
Cerebellar hemangioblastomas: 44% to 72%
Kidney cancer/ccRCC: 25% to 60%
Epididymal cystadenomas: 25% of 60% of males with VHL
Spinal cord hemangioblastomas: 13% to 50%
Endolymphatic sac tumors (ELSTs): 10% to 25%
Brain stem hemangioblastomas: 10% to 25%
Pheochromocytomas/paragangliomas: 10% to 20%
Pancreatic neuroendocrine tumors: 9% to 17%
Broad ligament cystadenomas: about 10% of females with VHL
Would the treatment of kidney cancer change if I have VHL? (updated 09/2021)
In general, treatment for kidney cancer is similar regardless of whether a patient has VHL. However, there is some evidence about specific VHL considerations regarding surgery. For a person with VHL and kidney cancer, surgery for a kidney tumor is generally considered when the largest tumor reaches 3 centimeters (cm) in size. Preserving the kidney’s function with the intent of preventing or delaying dialysis is an important part of the current surgical approach to VHL, and surgeons generally try to remove kidney tumors while trying to leave as much normal kidney behind as possible (called nephron sparing surgery or partial nephrectomy). This is generally done with enucleative resection, taking zero margins as the tumor capsule is separated from the surrounding adjaent parenchyma. Similarly, the main treatment for tumors arising in other organs is also surgery, which is done when the tumor reaches a specific size or causes symptoms.
For individuals with metastatic kidney cancer, treatment options using systemic therapy with medication are similar to those for patients with ccRCC unrelated to VHL, including tyrosine kinase inhibitors (TKIs) and checkpoint inhibitors (PD-1/PD-L1 and CTLA-4). Researchers are also actively investigating the use of systemic medications earlier in the disease stage when patients cannot have surgery.
There is one approved treatment for people with VHL disease and associated RCC, central nervous system (CNS) hemangioblastoma, or pNET that does not require immediate surgery. Belzutifan (Welireg) is a medication taken by mouth (orally) that targets hypoxia-inducible factor-2 alpha (HIF2a). In people with VHL disease as well as most forms of non-hereditary ccRCC, HIF2a activates more than 100 critical targets that contribute to tumor growth. A recent study (NCT03401788) included 61 people with VHL-associated tumors, mostly in the kidney, that did not need surgery right away. In this study, 27.2% of the kidney tumors responded to the treatment. However, the treatment stopped or stabilized more than 80% of cancerous lesions in the kidney. CNS hemangiomas and pNETs also responded to this medication. The researchers found that belzutifan had manageable side effects, and more than 95% of the study participants have remained on this medication for more than 1 year at the time of approval.
What are the suggested screening guidelines for VHL?
Screening for new tumors or active surveillance for known tumors are both very important aspects of VHL care. If tumors are found early, there is a much better chance that treatment will be successful. There are clear recommendations on the frequency and type of screening that should be performed. As VHL manifestations can vary, recommendations for a person's medical surveillance will change over their lifetime. These recommendations are expected to change over time as more information is made available and new technologies are developed specific to VHL. It is important to talk with your health care team about appropriate screening tests.
Learn more about the screening recommendations to detect early disease manifestations on the VHL Alliance website, which is a separate organization.
Questions to ask the health care team
If you are concerned about your risk for developing cancer, talk with your health care team. It can be helpful to bring someone along to your appointments to take notes. Consider asking your health care team the following questions:
What is my risk of developing kidney cancer?
What is my risk of developing other types of cancer?
What can I do to reduce my risk of cancer?
What are my options for cancer screening?
When is surgery needed to remove tumors?
If you are concerned about your family history and think your family may have VHL, consider asking the following questions:
Does my family history increase my risk of developing kidney cancer or other types of tumors?
Does my family history suggest the need for a cancer risk assessment?
Will you refer me to a genetic counselor or other genetics specialist?
Should I consider genetic testing?
What to Expect When You Meet With a Genetic Counselor
Collecting Your Family Cancer History
Sharing Genetic Test Results with Your Family
MyVHL: Patient Natural History Study
National Cancer Institute: Genetics of Kidney Cancer
To find a genetic counselor in your area, ask your health care team or visit the following website: