Diagnosis and Treatment

Your medical team will advise you on the best diagnostic tests to use, and the best course of treatment for the VHL involvement shown by your screening. There are a number of very effective treatments, and more are being discovered.

In addition to physical examination by your doctor, screening will probably involve some combination of magnetic resonance imaging (MRI), computed tomography (CT) scanning, ultrasound scanning, and angiography. The objective is to provide diagnostic pictures of both the blood vessels and soft tissues of your body. This may involve injecting contrast materials, or dyes, into your bloodstream to help the doctors see the blood vessels more clearly in the pictures. Various techniques are also used to determine the density of the tissues being examined, which helps the medical team determine whether it is normal tissue, cyst, or tumor.

Positron Emission Tomography (PET) scanning may be used to determine the activity level of certain kinds of tumors.

Treatments usually involve some kind of surgery to remove potentially malignant tumors before they become harmful to other tissues. Evaluation of a surgical alternative is always a matter of choosing the lesser of two evils. Surgery always has some level of risk, but keeping the angioma or tumor also has its risks. Advances are providing surgical alternatives that are less invasive. You should discuss the relative risks with your medical team.

Even the list of risks that the anesthesiologist reads off before surgery can sound frightening. It is sometimes helpful to say to the doctor, “What odds would you give me of one of those things happening?” Finding out that they are reading a list of things, all of which add up to less than 4%, as opposed to a risk level of 50%, helps to put the risk into perspective. Each of us must examine the relative benefits and risks of a proposed surgery in consultation with our medical teams.

Genetic Research and VHL

DNA (deoxyribonucleic acid) is the biochemical basis of life and of heredity. All of an individual’s characteristics are written in DNA in a kind of code. DNA is assembled into microscopic structures called chromosomes. In the human species there are 46 chromosomes, 23 from the mother and 23 from the father. There are 22 autosomes, numbered 1 to 22, of which each person has a pair (two copies of chromosome 1, two of chromosome 2, etc...) and one pair of the “sex” chromosomes, XX for females and XY for males. On each chromosome are the genes that contain the specific information necessary for the manufacture of proteins. Each gene has two copies, one inherited from the father, and one from the mother. The condition called VHL is caused by a dominant gene, since only one faulty copy of the VHL gene will cause the condition. VHL occurs in both men and women. Each child of a person with VHL is at 50% risk of inheriting the faulty copy of the gene.

The VHL gene is located on the short arm of chromosome 3 at a site called 3p25-p26 (see Figure 10). An international team of scientists identified the precise structure of this gene in 1993. Alterations in the normal structure of this gene are known to result in the condition called VHL.

The VHL gene encodes the formula for a protein whose function seems extremely important in the fundamental process called “transcription” which permits DNA to be transformed into a more simple molecule, RNA, which is used to create the protein.

The normal VHL gene acts as a “tumor-suppressor gene,” whose normal function is to suppress the formation of tumors. In order for a tumor to form, both copies of the VHL gene (the one from the father and the one from the mother) must become inactivated. In an individual who does not have the inherited alteration in the VHL gene, it is necessary for each of these two normal copies of the VHL gene to undergo some change that inactivates the VHL protein and allows a tumor to form. This may take some time, and multiple damaging “hits” to the genes in this cell, before the tumor will form. This explains why when these tumors occur in the general population they are usually single occurrences in a single organ, and the average age of onset of symptomatic kidney cancer in the general population is age 62. Mutation or inactivation of the VHL gene has been found in 85% of the random kidney cancers in the general population studied by the U.S. National Cancer Institute (Duan, 1995). This demonstrates the importance of this gene and the protein it manufactures in every human being.

In the case of people who have inherited one copy of the gene that doesn’t work correctly in the beginning, it is only necessary to deactivate the one remaining copy before a tumor may form. This is a much more likely occurrence, which means that tumors develop more often, at younger ages, and in more organs than in people in the general population. Without preventive action, the average age of onset of symptomatic kidney cancer in people with VHL is age 42. (See Figure 11).

These alterations (or “mutations”) of the VHL gene can now be identified in most people with VHL. The alteration is always the same in members of a single family. Conversely, the precise alteration in the gene will be different from one VHL family to another. More than 500 individual mutations have already been described in the medical literature (Béroud, Worldwide VHL Mutations Database). There is a significant relationship between certain kinds of mutations and the likelihood of pheochromocytomas. Researchers are studying other specific mutations which may be responsible for different aspects of VHL.

In most cases, the alteration in the VHL gene occurred a very long time ago, and the original mutation has been passed down through several generations in a family. VHL in the Black Forest Family in Germany and Pennsylvania has been documented back to the early 1600’s. There are certain people, though, perhaps as many as 20%, who are the first in their family to have an alteration in the VHL gene. Neither parent is affected, and these people have a case of VHL, occurring “de novo,” for the first time. This “new mutation” is caused by a change in the gene in one sperm from the father, or in one egg from the mother, or in the copying of the gene in one of the first stages of division of the embryo. This alteration in the VHL gene can now be passed to future children of this affected person, and necessitates medical screening of these children as well. There are no reliable statistics yet on the rate of new VHL mutations. Currently about 20% of patients are new mutations, and more “de novo” cases of VHL are being identified as awareness of VHL increases.

Progress toward a Cure

It is now possible to do special tests called DNA tests in most families to determine who is and is not at risk. If you don’t have the altered VHL gene, you cannot pass it to your children, and you need not go through further VHL screening tests. Identifying people who are not at risk allows those people to be reassured and spared further worry and testing. DNA testing methods are becoming less expensive and can now find the VHL gene alteration in most families. (See Section 6, Obtaining DNA Testing.)

With the gene identified, there is also increased hope of a cure, or at least of better management for VHL. Already in 2005 we have made great strides in improving diagnosis and treatment of VHL.

We have been working with the scientists and the pharmaceutical companies to come up with a drug that will constrain tumor growth.

If VHL tumors can be kept small or made smaller, we should be able to minimize the amount of surgical intervention required to manage VHL. Meanwhile, though, our best defenses are “early detection and appropriate treatment.” In the near term, this booklet and partnership with your healthcare team will be your best defense.

Remember that the vast improvements in the survivability of prostate and breast cancer have been made without a curing drug — the most important advances have been in early detection and better treatment. The same can be said for VHL.

New research also shows that the VHL gene plays a role in a signaling system that tells the cell how much oxygen is available to it. When the VHL protein is missing, the cell believes — even if it isn’t true — that it is starving for oxygen. So it puts out distress signals to the body, “Help! I need more oxygen!” The body responds by building more blood vessels to bring more blood to bring more oxygen. Thus VHL tumors seem to be a normal self-protective response gone wrong. As we understand the function of the normal VHL protein, we have a better chance of finding a drug that will replace its function and keep tumors from growing.

As part of its function, the VHL protein combines with other proteins in the cell (see Figures 12 and 13). Depending where the genetic alteration occurs, its ability to form connections with these other proteins may be impaired. We are beginning to interpret these differences by studying the relationship between the genotype (the place where the alteration occurs in the gene) and the phenotype (the set of symptoms experienced by these individuals). Researchers have identified four categories of VHL, which may be useful in predicting the relative risk in a family for certain manifestations of VHL. These categories are not absolute; we still recommend screening for all the features of VHL, though the frequency of testing might be varied depending on the results of DNA testing. (See Figure 14).

Researchers still have much laboratory work to do to understand more about what the normal VHL protein does in the body, and what happens when it is defective or absent. Perhaps some day it will be possible to replace it chemically. Some experimental methods in the areas of gene therapy or stem cell therapy may permit replacement or correction of the genetic information. These technologies are still in their infancy.

Figure 13: Pathways in the cell. If the pVHL complex is not functioning properly, then the levels of Hypoxia Inducible Factor (HIF) rise, which in turns allows the overproduction of Vascular Endothelial Growth Factor (VEGF) and Platelet-derived Growth Factor (PDGF) and others. These proteins send out signals to the target cell to stimultate the growth and reproduction of the cell. The signals are received by corresponding “receptors” (like VEGFR and PDGFR in this picture). In order to stop the signal from getting through, drugs may attempt to halt the signal, trap it in transit, or block the receptor. Source: W. G. Kaelin Jr., Dana-Farber Cancer Research Institute. Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6290S-5S.

You and your family can help to move the progress of VHL research forward by contributing samples of blood and tumor tissue to any local research projects you can.

For example, there are a number of efforts to identify biomarkers. These markers, found in blood or urine, would indicate the level of tumor activity in the body without expensive scans. In order to find such biomarkers, they need samples of blood and urine from a large number of people with VHL. Please help whenever you can.

When surgery is planned, call the VHL Tissue Bank and register to donate the tissue your surgeon will be removing. The Bank will arrange for tissue collection with your surgeon. Remember that tissue not recovered within 24 hours cannot be used for research. (See Section 10, Tissue Bank, for the donor registration form.)

When clinical trials are announced, please read the announcement to determine whether the drug offered might be appropriate to your particular circumstances. Please consider participating in trials when they are right for you. Your top priority should always be to do what is best for your present and long-term health.

News of the current state of genetic research on VHL is carried in the VHL Family Forum.

The VHL Family Alliance works to encourage research on von Hippel-Lindau through the Research Database, the VHL Tissue Bank, the VHL Fund for Cancer Research, and the VHLFA Research Grants program. (See Membership Information.) Please help to sustain these efforts.

There is no magic pill — yet! — that will make VHL go away. VHL is a lifelong challenge. It is less demanding of your attention than something like diabetes — you don’t have to check your blood sugar multiple times a day or change every aspect of your diet — but you do need to put the right level of attention onto monitoring it, keeping your mind, body, and spirit strong, and keeping this issue in perspective in the whole of your life.

It is important to take care of your general level of health. If you make sure that you are in good health, then the challenges VHL throws your way will be easier to deal with. Eat right, don’t smoke, exercise, drive carefully, and don’t hide behind alcohol or drugs. Eat less red meat, and eat a diet based more on vegetable sources (see Figure 15). Watch for cancer-prevention tips in the press for ideas on how to keep your body’s own natural defenses strong against the forces that cause cancer by causing genes to become deactivated. This area is being closely studied, and reliable information is only beginning to emerge.

Figure 15: Health Eating Pyramid. Source: Harvard School of Public Health, as quoted in Willett, Eat, Drink, and Be Healthy, 2001

One of the greatest known risk factors for any medical condition is smoking. Studies on kidney tumors in the general population indicate that patients who smoke, especially men, have more tumors than those who don’t, and that those tumors grow more rapidly. If you do need to have surgery, people who smoke are at higher risk for a number of post-operative complications.

There is no evidence to indicate that VHL patients should limit their physical activities in any way, except for short periods following treatments. Certain kinds of brain, spinal, or eye tumors, may be aggravated by doing a lot of heavy straining, like bench-pressing 200 pound weights so that the veins in your forehead stand out, pumping your exercising heart rate beyond your recommended limits, or going through the hardest parts of labor in childbirth. Check with your doctor to determine your own exercise tolerance. Moderate exercise, however, is good for everyone.

Some families with VHL are experimenting with cancer-prevention diets and avoidance of growth hormone (fed to cattle and chickens in some countries) in an attempt to soften the course of the disease. Scientists are beginning to learn more about the ability of some vegetables (notably fermented soy products and cruciferous vegetables like cabbage) to retard the growth of new blood vessels. Green tea may enhance the immune system. Genistein (an isoflavone found in soy) has been shown to slow the growth of vascular tumors of the eye.

If you are interested in adding this approach to your total health plan, information is available from the VHL Family Alliance or through the many cancer-prevention channels, including www.vhl.org/nutrition. Ask at your medical center for recommendations on nutrition for cancer prevention (See Figure 16).

Figure 16: The Art of Conscious Living “When we are able to mobilize our inner resources to face our problems artfully, we find we are usually able to orient ourselves in such a way that we can use the pressure of the problem itself to propel us through it, just as a sailor can position a sail to make the best use of the pressure of the wind to propel the boat. You can’t sail straight into the wind, and if you only know how to sail with the wind at your back, you will only go where the wind blows you. But if you know how to use the wind energy and are patient you can sometimes get where you want to go. You can still be in control. . . We all accept that no one controls the weather. Good sailors learn to read it carefully and respect its power. They will avoid storms if possible, but when caught in one, they know when to take down the sails, batten down the hatches, drop anchor, and ride things out, controlling what is controllable and letting go of the rest. . . . Developing skill in facing and effectively handling the various “weather conditions” in your life is what we mean by the art of conscious living.” — Jon Kabat-Zinn, Ph.D., Director of the Stress Reduction Clinic at the University of Massachusetts Medical Center, Worcester, Massachusetts. As quoted from his book, Full Catastrophe Living: Using the Wisdom of your Body and Mind to Face Stress, Pain and Illness, p. 3. (Delta Books, New York, 1990).

There is growing evidence that prolonged inflammation may have some influence on the course of diseases such as cancer, Alzheimer’s and heart disease. Dr. Weil recommends a diet rich in omega-3 fatty acids (walnuts, freshly ground flaxseed and oily fishes are good sources). Extra-virgin olive oil is preferred over sunflower, corn, and safflower oils. Use natural anti-inflammatory spices like ginger and turmeric.

VHL is a chronic disease. While it may not affect your life on a day-to-day basis, every once in a while it will jump into first place, demanding your attention. If you work with your medical team to monitor it on a regular basis, you will be able to maintain greater control over the situation and manage the interruptions that it may cause in your life. By keeping up with a regular program of medical check-ups, you can reduce your worry of the unknown.

The Healthy Eating Pyramid

The Healthy Eating Pyramid from the Harvard School of Public Health (see Figure 15) is a proposed revision of the classic Food Guide Pyramid developed by the U.S. Department of Agriculture. It incorporates the new learning about nutrition and cancer prevention. The Healthy Eating Pyramid sits on a foundation of daily exercise and weight control. Why? These two related elements strongly influence your chances of staying healthy. They also affect what and how you eat and how your food affects you. The other bricks of the Healthy Eating Pyramid include:

Whole Grain Foods (at most meals). The body needs carbohydrates mainly for energy. The best sources of carbohydrates are whole grains such as oatmeal, whole-wheat bread, and brown rice. They deliver the outer (bran) and inner (germ) layers along with energy-rich starch. The body can’t digest whole grains as quickly as it can highly processed carbohydrates such as white flour. This keeps blood sugar and insulin levels from rising, then falling, too quickly. Better control of blood sugar and insulin can keep hunger at bay and may prevent the development of type 2 diabetes.

Plant Oils. Surprised that the Healthy Eating Pyramid puts some fats near the base, indicating they are okay to eat? Although this recommendation seems to go against conventional wisdom, it’s exactly in line with the evidence and with common eating habits. The average American gets one third or more of his or her daily calories from fats, so placing them near the foundation of the pyramid makes sense. Note, though, that it specifically mentions plant oils, not all types of fat. Good sources of healthy unsaturated fats include olive, canola, soy, corn, sunflower, peanut, and other vegetable oils, as well as fatty fish such as salmon. These healthy fats not only improve cholesterol levels (when eaten in place of highly processed carbohydrates) but can also protect the heart from sudden and potentially deadly rhythm problems.

Vegetables (in abundance) and Fruits (2 to 3 times). A diet rich in fruits and vegetables can decrease the chances of having a heart attack or stroke; protect against a variety of cancers; lower blood pressure; help you avoid the painful intestinal ailment called diverticulitis; guard against cataract and macular degeneration; and add variety to your diet and wake up your palate.

Fish, Poultry, and Eggs (0 to 2 times). These are important sources of protein. A wealth of research suggests that eating fish can reduce the risk of heart disease. Chicken and turkey are also good sources of protein and can be low in saturated fat. Eggs, which have long been demonized because they contain fairly high levels of cholesterol, aren’t as bad as they’re cracked up to be. In fact, an egg is a much better breakfast than a doughnut cooked in an oil rich in trans fats or a bagel made from refined flour.

Nuts and Legumes (1 to 3 times). Nuts and legumes are excellent sources of protein, fiber, vitamins, and minerals. Legumes include black beans, navy beans, garbanzos, and other beans that are usually sold dried. Many kinds of nuts contain healthy fats, and packages of some varieties (almonds, walnuts, pecans, peanuts, hazelnuts, and pistachios) can now even carry a label saying they’re good for your heart.

Dairy or Calcium Supplement (1 to 2 times). Building bone and keeping it strong takes calcium, vitamin D, exercise, and a whole lot more. Dairy products have traditionally been the main source of calcium. But there are other healthy ways to get calcium than from milk and cheese, which can contain a lot of saturated fat. Three glasses of whole milk, for example, contains as much saturated fat as 13 strips of cooked bacon. If you enjoy dairy foods, try to stick with no-fat or low-fat products. If you don’t like dairy products, calcium supplements offer an easy and inexpensive way to get your daily calcium.

Red Meat and Butter (Use Sparingly): These sit at the top of the Healthy Eating Pyramid because they contain lots of saturated fat. If you eat red meat every day, switching to fish or chicken several times a week can improve cholesterol levels. So can switching from butter to olive oil.

White Rice, White Bread, Potatoes, Pasta, and Sweets (Use Sparingly): Why are these staples at the top, rather than the bottom, of the Healthy Eating Pyramid? They can cause fast and furious increases in blood sugar that can lead to weight gain, diabetes, heart disease, and other chronic disorders. Whole-grain carbohydrates cause slower, steadier increases in blood sugar that don’t overwhelm the body’s ability to handle this much needed but potentially dangerous nutrient.

Multiple Vitamin: A daily multivitamin, multimineral supplement offers a kind of nutritional backup. While it can’t in any way replace healthy eating, or make up for unhealthy eating, it can fill in the nutrient holes that may sometimes affect even the most careful eaters. You don’t need an expensive name-brand or designer vitamin. A standard, store-brand, RDA-level one is fine. Look for one that meets the requirements of the USP (U.S. Pharmacopeia), or another organization that sets standards for drugs and supplements.

Alcohol (in moderation): Scores of studies suggest that having an alcoholic drink a day lowers the risk of heart disease. Moderation is clearly important, since alcohol has risks as well as benefits. For men, a good balance point is 1 to 2 drinks a day. For women, it’s at most one drink a day.

Pyramid and discussion adapted from Willett, Eat, Drink, and Be Healthy, 2001

Living with Knowing

Having a chronic disease is a stressful experience. It’s easy to say you should think of a brain tumor as a wart, but it’s easier said than done. No one can completely avoid stress; it’s an essential part of living. We encourage you to incorporate into your life a stress management program that works for you. There are many different kinds — sports, yoga, prayer, meditation — it doesn’t matter which one you choose as long as you do it.

Put some attention onto stress management on a regular basis. Ask your medical team for a referral to a stress management program, or visit your local bookstore and find a book that you feel will be meaningful to you. Consider one by Benson, Kabat-Zinn, Borysenko, David Burns, Albert Ellis, or another of the many physicians who are now using stress-reduction as a way of softening the course of chronic illness. The VHL Family Alliance maintains a list of suggested readings on stress management that have been found to be medically beneficial. (See Section, Some Suggestions for Reading, below.)

Assertiveness training can help you reduce your anxiety and improve your effectiveness in dealing with doctors and complex situations.

A chronic disease can put strain on the best of marriages. Don’t be shy to ask for help or counseling. You are not alone. It is not your fault. VHL is not a punishment, it is a disease.

Husbands, wives, parents, and children will all feel the strain in different ways. Affected people have the very real mental and physical pressures of the disease and its treatments and effects. It is normal to go through denial, anger, and a whole range of fragile emotions. It is normal to feel more needful, and to be angry when your family doesn’t automatically understand your needs. It is important to talk with your family about how you are feeling. You’re not burdening them; you are giving them the privilege of participating with you. It is less stressful on everyone when you are partners in dealing with VHL.

Unaffected members of the family will feel their own strains, anger and guilt. Unaffected children may be angry that the affected child gets all the attention, or may feel guilty that they were spared. Affected or not, children often harbor unspoken fears for themselves or for their parents, which may come out as misbehavior or school performance issues. Schools often have social workers or psychologists who can be called upon to assist children, and in some areas there are support groups for children whose families are affected by cancer or chronic illness.
Finding out you have VHL is a traumatic event, which quite naturally results in normal, unpleasant reactions. It is normal to feel anger, and it is important to work through those feelings to a place where you can turn that negative energy into constructive action to protect yourself and others in your family.

With patience, understanding, and the assistance of your medical and spiritual advisers and friends, your family will survive this challenge and thrive.

Family Support

It also helps to talk with someone who is on the same journey. Join a family support program, such as the VHL Family Alliance. Pick up the phone and call, if only just to talk for a while, or join the online support group. Other families with VHL like yours are there to listen and to share their own experiences, which may help you gain a different perspective on the problem. Listen and learn, or join in the conversation. Participate in local support group meetings.

Think of it as an old-fashioned barn-raising (see Figure 17). One person, even one couple, can’t raise a barn alone. The community, though, can come together and do it in a few days, pooling their skills and experiences and making the task easier. Each member of the group benefits in turn from the community effort.

It can be frightening to reach out, but it is much worse to be alone. Besides, we need to hear from you. It is through sharing information that this organization was born. It is through sharing our experiences, and putting that information together with the expertise of the caring physicians and researchers who are also working on VHL, that we are learning the keys to improving diagnosis, treatment, and quality of life for everyone with VHL.

Some Suggestions for Reading

• Robert E. Alberti, et al., Your Perfect Right: Assertiveness and Equality in your Life and Relationships (8th edition, 2001)
• Herbert Benson, M.D., Timeless Healing: The Power and Biology of Belief (1996)
• Joan Borysenko, Ph.D., Minding the Body, Mending the Mind (1987)
• Jeffrey Brantley, M.D., Calming the Anxious Mind (2003)
• David Burns, Feeling Good: The New Mood Therapy (1999)
• Albert Ellis, A Guide to Rational Living (1975)
• John A. Gottman, Ph.D. and Jean DeClaire, The Relationship Cure (2001)
• Jerome Groopman, M.D., The Anatomy of Hope: How People Prevail in the Face of Illness (2003)
• Jerome Groopman, Second Opinions: Stories of Intuition and Choice in the Changing World of Medicine (2000)
• Jon Kabat-Zinn, Full Catastrophe Living: Using the Wisdom of your Body and Mind to Face Stress, Pain, and Illness (1990)
• Harold S. Kushner, When Bad Things Happen to Good People (1981)
• Robert D. Putnam, Better Together: Restoring the American Community (2003)

Questions to Ask the Doctor

With early detection and appropriate treatment, von Hippel-Lindau disease has a better prognosis, or outcome, than many other tumor conditions and cancers. But any diagnosis of serious illness can be frightening, and it’s natural to have concerns about medical tests, treatments, insurance, and doctors’ bills.

Patients have many important questions to ask about VHL, and their medical team is the best place to start to look for answers. Most people want to know exactly what kind of involvement they have, how it can be treated, and how successful the treatment is likely to be. Get a second, or even a third opinion if you wish. The following are some questions that patients may want to ask their physician:

• Should I change my normal activities?
• How often are checkups needed?
• What symptoms should I watch for?
• If you are told what size a tumor is (e.g. 2 cm.), ask what that means.
• At what point do I need to worry about this tumor?
• What are the danger signals we are watching for?
• What kinds of treatment are available?
• What are the risks or side effects of treatment?
• What are the odds of those risks happening?
• What are the risks of no treatment?
• Is there a less invasive treatment I should consider?
• Can abdominal surgery be done laparoscopically?
• What other health professionals do I need on my medical team to ensure that we have checked for all the probable features of VHL?
• What can I do to assist doctors in learning more about VHL?
• How experienced are you in dealing with VHL?
• Where can I consult specialists who are experienced with VHL?
• Who will be the main person responsible for looking after my medical interests and coordinating communication among my specialists?
• Is there a research project I can participate in?
• Is there a clinical trial that would be appropriate for me?

Reminder Calendar

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VHL Family Alliance
2001 Beacon St, Suite 208, Boston, MA 02135-7787 USA
Tel: +1 800 767-4845 or +1 617 277-5667; Fax: +1 858-712-8712
http://www.vhl.org; E-mail: info@vhl.org