VHL in the Retina

When capillaries form angiomas, technically called hemangioblastomas, in the retina, they start out extremely small and difficult to see. The capillaries themselves are less than the diameter of a red blood corpuscle, one of the cells that make up the blood.

When angiomas begin, they often grow around the equator or periphery of the retina, far away from the area of central vision. Unlike the equator drawn around the globe of the world, the equator of the eye is vertical. As you stand, draw a circle around your eye from eyebrow to nose and around. The circle you just drew is the equator. To see this area, your ophthalmologist or optometrist must dilate your eye, use high-powered magnifying lenses, and look from side angles. It is more than the usual eye examination (see Figure 4). If there is VHL in your family, be sure to tell your ophthalmologist or optometrist so that he or she will be sure to do this thorough examination and find any small angiomas so that they can be treated in the early stages. A referral to a retinal specialist will be required for treatment of these tumors.

Figure 4: Ophthalmologist exploring the equator of the eye with indirect ophthalmoscope. Illustration by Vincent Giovannuci, O.D.

Not all ophthalmologists and optometrists are familiar with this uncommon disorder. You should look for an eye care professional who is familiar with VHL and qualified to do a thorough dilated examination of the fundus and periphery with an indirect ophthalmoscope.

The objective of treatment is to keep the angioma so small that it does not affect your vision. Treatments generally include laser treatment (light surgery) or cryotherapy (freezing). Leaflets on these treatments are produced by the American Academy of Ophthalmology, and are usually available from your ophthalmologist. Both treatments are trying to keep the angioma from growing.

Sixty percent (60%) of people with VHL have retinal lesions. People as young as 3, and sometimes even younger, can be affected, so screening children is very important. Children who have a positive DNA diagnosis of VHL should be screened for eye lesions beginning at age 1.

New angiomas can occur throughout life so that regular eye exams in affected individuals are important.

Lesions on or near the optic nerve are very difficult to treat successfully. Contact the Alliance for the latest recommendations. Fortunately, they tend to grow slowly.

Generally smaller lesions can be treated more successfully and with fewer complications than larger ones. Leakage or bleeding from angiomas can lead to serious vision damage or retinal detachment, so early treatment and careful management are very important.

VHL in the Brain and Spinal Cord

Angiomas in the brain and spinal cord are also called hemangioblastomas. A cyst inside the spinal cord is called a syrinx. When hemangioblastomas occur, they are generally not treated until symptoms begin to develop or unless they are growing rapidly. With regular visits to a neurologist, on the schedule recommended by your medical team, early signs may be found which may then require further testing usually with CT or MRI. Early signs and symptoms may include back pain, headaches, numbness, dizziness, and weakness or pain in the arms and legs.

Think of it as having a kind of wart on the inside. It’s not a problem to have a wart unless it gets in your way. In these delicate areas, where there is little extra space, the problem is not so much having this wart, but having it exert pressure on brain tissue or the nerves in the spine. It is this pressure, or blockage of the normal flow of spinal fluid, which causes the symptoms. At the same time, some level of risk is associated with surgery to remove lesions of the brain or spinal cord, so the benefits and risks should be considered carefully. Surgery is usually advised after there are symptoms, but before the symptoms become severe.

Some new treatments are being tested. Occasionally, some minimally invasive treatment may be suggested at an early stage to stunt the growth of the tumor and prevent a cyst from forming. The objective, as in the eye, is to keep the lesion so small that it does not become a problem. Stereotactic radiosurgery, sometimes called gamma knife surgery, is a kind of treatment which does not require opening you up. Doctors focus beams of radiation from as many as 201 angles so that a high dose, or “zap” is delivered to a very tiny specific internal area where the beams meet. Some medical centers use stereotactic radiosurgery as a way of containing the growth of VHL brain tumors. You may wish to discuss this option with your medical team. It will not be appropriate in every case. The approach to any brain or spinal hemangioblastoma needs to be discussed carefully with a neurosurgeon informed about VHL. (See next section, Considering Stereotactic Radiosurgery)

Neither approach is always the right one. It depends on the particular tumor, its position and size, and the associated risks of each approach. It is important that you understand thoroughly the options, and that you work with your medical team to arrive at the right choice. Don’t be shy to ask for second opinions. Hemangioblastomas are rare tumors, VHL or not, and few surgeons have a great deal of experience with them. It is helpful both to you and to your neurosurgeon to have multiple opinions on the best approach to your problem.

Considering Stereotactic Radiosurgery

Stereotactic radiosurgery (SRS) is a non-invasive surgical technique similar to laser surgery, but using beams of radiation instead of light. Machines like the Gamma Knife or Cyberknife or Linear Accelerator are used to perform SRS. This technique can be useful in some cases, especially in the brain. It should still be considered experimental in other tissues. It is very important to approach it as you would any other surgical procedure — with healthy respect, caution, even skepticism. It is better to have the difficult conversation before, rather than after, the treatment.

The best candidate tumor for SRS is less than 2 cm in size, does not have an associated cyst, and is not causing symptoms. It takes as long as two years to see the benefits of SRS treatment, and meanwhile the total mass of the tumor will increase before it begins to shrink. Patients who have symptoms or cysts usually need to have standard surgical resection.

Because SRS works best with small tumors, some of the tumors chosen for treatment might in fact never have grown. Most doctors prefer to wait until the tumor shows some signs of enlarging but without development of a cyst, before considering treatment.

We will appreciate your feedback on this set of questions, so that we can improve it for the next person. We don’t want to alarm you, but we do want to make sure you and your doctor together examine all the possibilities prior to the treatment.

Here are some of the things to watch out for, and the questions to ask:

(1) Get both opinions. We strongly urge you to consult with a physician who is good at BOTH conventional micro-neurosurgery AND stereotactic radiosurgery. It is NOT enough to speak only with a radiation oncologist, or someone who practices only gamma knife. If you can’t find someone who practices both, be sure to talk with someone who is expert in the other method and get that view. In many cases, it is safer to approach a tumor with conventional surgery. You get it out, once and for all, the tissue can be examined under a microscope, and the recovery period is better defined. Of course conventional surgery has its own set of risks and drawbacks, so you need a team of medical professionals who can help you evaluate fairly the pros and cons of both procedures and decide which is better for you in this particular situation at this particular time.

(2) How big is the tumor? Recommendations are NOT to treat a hemangioblastoma larger than 2 centimeters. Size is not the only issue, but it is a very important issue. As Dr. Nauta describes it, it’s a matter of how finely you can focus the beams of radiation. It’s rather like trying to burn a hole with a magnifying glass and sunlight. To make a small hole, you can focus the beam to a small point and use less radiation. To make a bigger hole, you have to cover a larger field, the beam is more weakly concentrated, and you have to use a lot more radiation to do the job. The tumor absorbs more energy and will swell more after the treatment.

(3) Where is it? Once treated, there will be swelling (edema) of the tumor and surrounding tissues. What this means to you is that the treated tumor will get bigger before is gets smaller, and depending how much room there is for it to expand, your symptoms may increase before they get better. What position is the tumor in? When it swells, what symptoms may occur? How will the doctor propose to control the swelling? How can you work in partnership with the medical team to minimize the swelling and get through the swelling period? Note that this period of swelling is not measurable in days but in months. Ask your doctor how long you should expect this swelling period to last.

(4) What are the dangers to surrounding tissues? There is usually some margin of healthy tissue that will be irradiated with a therapeutic dosage. What tissue is within that margin? What would such damage do? If the tumor is in a position where there is fluid beside it, then there is some “margin for error,” but if it is in a critical spot, then its effect on the nearby healthy tissue can be significant.

(5) How many tumors do they propose to treat? What is the sum of the radiation to which you would be subjected? If more than one tumor is to be treated, is it wise to treat them all at this same time? Will the combined swelling of the various tumors cause a dangerous situation? Is it better to treat them one at a time? Pacing the treatment can be critical to managing the post-treatment swelling.

(6) What medication(s) would the doctor propose to use to manage the post-treatment period? Have you taken this medication before? Can they test you for sensitivity to the medication before the treatment, to make sure that you are not likely to have an adverse reaction? The worst problems we have seen from stereotactic radiation involve sensitivities to the medication.

(7) What experience does this team have with treating hemangioblastoma, as opposed to other solid tumors? Hemangioblastomas react differently to radiation treatment. It is important to get someone with experience in treating hemangioblastoma to participate in reviewing the treatment plan prior to the beginning of treatment. If you cannot find someone in your area, we can suggest some sources of second opinions. This should be welcomed by your team, as it is for their protection as much as for your own.

Hearing Changes and VHL

The screening protocol includes a recommendation that you go regularly for an audiometric examination. You should have a “baseline” study to document the state of your hearing, and periodically verify that it has not changed.

If you sense changes in your hearing, or other indications of inner ear problems, you should follow up with a neurotologist. MRI or CT of the Internal Auditory Canal should be used to check for an Endolymphatic Sac Tumor (ELST), which may occur in about 15% of people with VHL.

The ELST tumor forms in the endolymphatic sac, or in the temporal bone, behind the ear. The endolymphatic duct runs from the inner ear to the back surface of the petrous bone and ends beneath the dura at the boundary of the brain as a flattened expansion, the endolymphatic sac. (See Figure 5.) This tiny structure is filled with fluid (called endolymph) and has a delicate system of pressure regulation that is responsible for one’s sense of balance and equilibrium. Menière’s disease is another condition that is caused by a disturbance in this area, and ELST’s are often misdiagnosed as Menière’s disease.

Figure 5. The inner ear, showing the endolymphatic sac (ELS). The endolymphatic duct runs from the inner ear to the back surface of the petrous bone and ends beneath the dura at the boundary of the brain as a flattened expansion, the endolymphatic sac. In the inset, you can see that the ELS is right up against the dura, the fibrous membrane that covers the brain. The bony structure is the petrous bone. Fluid accumulation (called hydrops) may explain the Menière’s-like symptoms (hearing loss, tinnitus, and vertigo) in patients with ELST. Hydrops may result from blockage of the reabsorption of endolymph in the endolymphatic sac, inflammation in response to hemorrhage, or excessive production of fluid by the tumor. Fluid production is typical also of other VHL tumors. Illustration courtesy of Dr. Lonser, U.S. NIH. As published in the VHL Family Forum, 12:2, September 2004.

People report hearing changes which range from subtle changes in the “texture” of the hearing to profound hearing loss. Other symptoms may include hearing loss, tinnitus (ringing in the ears), dizziness, a fullness in the ears, or a weakness or slackness in the nerve that runs through the cheek of your face. Hearing loss may occur gradually over a period of 3-6 months or longer, or in some cases it may occur suddenly.

Once hearing is lost it is very difficult to regain. Here again, it is very important to watch for early symptoms and address the problem carefully in order to preserve hearing. If there is a loss of hearing, swift action will be needed if there is to be any hope of restoring it.

Once an ELST is visible on an MRI, surgery should be considered. Careful surgical removal of the ELST will stop further damage, and can be done without damaging hearing or balance. This delicate microsurgery usually requires teamwork between a neurosurgeon and a neurotologist in a practice that does a lot of inner ear surgery. Call the VHL Family Alliance for assistance in locating a surgeon familiar with this problem.

VHL and your Reproductive Health

People with VHL should follow the cancer-preventive precautions and self-examinations recommended for everyone. Just because you have VHL does not exempt you from other conditions that occur in the general population. Follow the normal guidelines for breast and testicular self-examinations and take good care of your reproductive health.

There is one notable occurrence in men that is associated with VHL: epididymal cystadenomas may occur in as many as 50% of men with VHL in some families. Similarly, women with VHL may have cystadenomas of the broad ligament near the fallopian tube, the embryological counterpart to the epididymis. Both are almost always harmless, although they may sometimes cause pain.

For Men

The epididymis is a small coiled conduit that lies above and behind the testicle, in the scrotum, on the path to the vas deferens, the tube that carries the sperm from the testicle to the prostate gland. The epididymis is as long as the testicle, lying in a flattened C shape against one side of the testicle. It’s a complex tubular system that gathers the sperm and stores them until they are needed. It’s a little like the coil on the back of an air conditioner, where the condensation takes place (see Figure 6). After having been stored in the epididymis, sperm then move through the vas deferens to the prostate, where they are mixed with seminal fluid from the seminal vesicles and move through the prostate into the urethra during ejaculation.

A small number of cysts are found in the epididymis of about one-fourth of men in the general population. By themselves, cysts are not an occasion for concern and are not even particularly noteworthy. However one specific type of cyst is significant in VHL. A cystadenoma is a benign tumor with one or more cysts inside it, having more density than a simple cyst. Papillary cystadenomas of the epididymis are a rare occurrence in the general population. These cysts can occur on one or both testes. When they occur on both sides, they almost always mean a definite diagnosis of VHL. They range in size from 1 to 5 centimeters (0.3 to 1.7 inches). The man may feel a “pebble” in the scrotum, but they are usually not painful and do not continue to enlarge.

They may arise during the teen-age years or later in life. It is not unusual for them to occur for the first time in the forties. They can be removed if they are annoying, but removing them is much the same operation as a vasectomy and may result in the disabling of the delivery of sperm from the operated side.

They do not interfere with sexual function. In most cases the only “problem” associated with cystadenomas is the minor annoyance of knowing it is there. Occasionally, depending on their position, cystadenomas may block the delivery of sperm and cause infertility. However this is a very rare occurrence. If a cystadenoma is painful, you should definitely check with a doctor, since on rare occasions they can become inflamed and then rupture.

The best way to keep track of them is to do a Testicular Self-Exam (TSE) monthly, as recommended for cancer prevention. Testicular cancer is NOT associated with VHL, but is a risk for all men in the general population. A TSE helps you become familiar with the size and shape of any epididymal cystadenomas, and make sure there are no unusual bumps or lumps in the testicles.

• Check yourself right after a hot shower. The skin of the scrotum is then relaxed and soft.
• Become familiar with the normal size, shape, and weight of your testicles.
• Using both hands, gently roll each testicle between your fingers.
• Identify the epididymis. This is a rope-like structure on the top and back of each testicle. This structure is NOT an abnormal lump, but epididymal cystadenomas may occur in this structure. Note their size and shape, and keep a record for comparison in the future.
• Be on the alert for a tiny lump under the skin, in front or along the sides of either testicle. A lump may remind you of a piece of uncooked rice or a small cooked pea.
• Report any swelling to your health care provider.

If you have lumps or swellings, it does not necessarily mean that you have testicular cancer, but you must be checked by your healthcare provider.

For Women

A corresponding tumor occurs in women, called an Adnexal Papillary Cystadenoma of Probable Mesonephric Origin (APMO). A cystadenoma is a benign tumor with one or more cysts inside it, having more density than a simple cyst. Papillary cystadenoma of the broad ligament are a rare occurrence in the general population.

The broad ligament is a folded sheet of tissue that drapes over the uterus, fallopian tubes and the ovaries. (See Figure 7.) Cells in this area are from the same origin in the development of the embryo as the epididymis in males.

Cysts in this area are very common in the general population. However if an “unusual” cyst or tumor is seen in the area of the broad ligament or fallopian tubes, a cystadenoma associated with VHL should be considered. Ask your doctor to do a careful differential diagnosis, to prevent over-treatment of benign tumors.

Please report tumors of the broad ligament or fallopian tube to the VHL Family Alliance research database to help increase our knowledge. Until more is known about this VHL associated tumor, the reviewing pathologist may call these tumors by another name such as “papillary tumors of low malignant potential.”

Pregnancy and VHL

Women with VHL should take special precautions when considering pregnancy. Research seems to indicate that pregnancy does not promote accelerated tumor growth, but it also does not halt tumor growth. All the changes in your body can mask symptoms and signs of tumors, so it is important to know what’s going on before those changes begin.

- Your blood volume will double during pregnancy. If you have a hemangioblastoma in the brain or spinal cord or retina, this increased blood flow may expand the tumor at least for a period of time during the pregnancy. Some women have reported worsening of symptoms during the pregnancy, followed by a lessening of symptoms after delivery. In some cases, the expansion took mild or non-existent symptoms and expanded them to a critical level.

- The weight of the fetus will add strain to your spinal column. Depending on what tumors are already present in the spinal cord, this additional stress may cause a worsening of symptoms.

- The additional fluids will put increased load on your kidneys. You need to make sure that your kidney function is normal so that your kidneys will serve you and your baby well.

- The stress of pregnancy and delivery can trigger a pheochromocytoma. (See next section, VHL in the Adrenal Glands.) Be very sure to get checked — and re-checked — for a pheo during the pregnancy, to avoid complications in this area.

If you are considering getting pregnant, or if you have already become pregnant, have a thorough check-up. Identify any tumors you may already have. Discuss with your doctor what might happen if these tumors should grow during pregnancy. Since it is preferable not to use tests that involve radiation while you are pregnant for fear of harming the baby, it is best if you can do the testing in advance and know what your risk factors are. Hopefully the tumors will not grow, but if they do, here are some things you should know:

• What symptoms should you watch for?
• Would the consequences possibly have a serious impact on your own health?
• How could it affect the fetus?

In particular, get a thorough test for a pheochromocytoma (“pheo” (say FEE-oh) for short). It is critically important that you be tested for a pheo before planning a pregnancy, or as soon as you are pregnant, and especially before going through the birthing process.

Discuss these risk factors fully with your partner as well before making the decision. This is a joint decision. You might be willing to risk it, but is your partner willing to put you at risk? Discussing it prior to pregnancy is much better than living with the anger or guilt that can arise from walking blindly into a risky situation.

If you are already pregnant, tell your obstetrician and connect him or her with other members of your medical team. Watch for symptoms and report any symptoms to the doctor. Vomiting and headaches will take more watching than for most pregnant women, since these can also be signs of brain and spinal tumors. Don’t ignore them or discount them, particularly if they are excessive or persistent. A little morning sickness is normal; the amount of vomiting is variable within a pregnancy and you should always check with your medical team on whether there is cause for concern. Don’t panic; talk with your doctors.

Approximately 2-3 months after the baby is born, have another thorough check-up to evaluate any changes in your own health.

VHL in the Adrenal Glands

The adrenal glands are approximately 3 x 2 x 2 cm (1 inch long) perched on top of each of the kidneys. (See Figure 8.) VHL may be associated with a kind of tumor of the adrenal glands called a pheochromocytoma, (“pheo”). These tumors occur more frequently in some families than in others. In families that have adrenal involvement, they are quite common. They are rarely malignant among people with VHL (3%). Detected early, they are not difficult to deal with, but they are potentially lethal if not treated because of the damage they can cause to the heart and blood vessels and the potential for dangerously high blood pressure occurring during stresses such as surgery, accidents, or childbirth.

Figure 8. Kidney, pancreas, and adrenal glands. The figure shows the relative positions of these organs. Illustration by Gerhard Spirzer, from Kahle et al, Color Atlas, 2:141.

Pheos produce so-called “stress hormones” (noradrenaline and adrenaline) that your body uses to gain speed and strength in an emergency. The pheo secretes excessive amounts of these stress hormones into the bloodstream. The primary symptom is high or variable blood pressure, especially spiking blood pressure, that puts strain on your heart and vascular system and can cause heart attack or stroke. Patients may notice headache, increased cold perspiration, irregular or rapid heartbeat, or what feels like a panic attack, fear, anxiety or sometimes rage.

New research indicates that adrenal tumors are as much as four times more common among people with VHL than previously thought, and that traditional blood and urine tests alone are inadequate to find most pheos. It is recommended that all people with VHL be screened for pheos. Usually an initial test is done with blood and urine tests, and if additional information is required, or if there are symptoms of pheo but the blood and urine tests are negative, imaging tests or PET scanning may be used. It is particularly important to be checked for a pheo prior to any surgery, pregnancy, or childbirth. If a pheo is present, complications may be avoided by blocking off the effects of stress hormones with drugs, beginning about seven days before the procedure.

The accuracy of the urine and blood tests for pheochromocytoma activity will be determined in large part by your own cooperation in preparing for the test. Even if no instructions are provided, you should avoid smoking, alcohol, and caffeine for at least four hours before the test. Be sure to tell your doctor and the technician if you are taking any anti-depressant medication. You might want to prepare a list of all the medications you are taking, and discuss this list with the doctor before the test. Where other instructions are given, they may differ from center to center, sometimes due to different methods of analysis. Follow any instructions carefully to avoid a false reading. See Preparing for Pheo Testing in Section 5.

If these chemical tests indicate the presence of a pheo, but it cannot easily be located on CT or MRI, an MIBG or PET scan may be recommended. These tests help to localize, or locate, a pheo, even if it is outside the adrenal gland. When they are outside, they are sometimes called paragangliomas. They may occur anywhere on the sympathetic nervous system, anywhere along a line drawn from your groin to your ear lobe. Multiple tests may be needed to find them.

If surgery is required, the standard of care these days is partial adrenalectomy. Studies have shown that keeping even a small amount of the cortex of the adrenal gland will make it much easier for you to manage after surgery. Even if you still have another healthy gland, remember that there may be another pheo in the future that could put that second gland at risk, so your goal should be to keep a portion of each gland working for you.

In recent years the “key hole” operating technique (laparoscopy) is being used to treat pheos. Laparoscopic partial adrenalectomy is now possible in most cases. With this technique there is less risk of infection, and the recovery is much faster. Refer your doctor especially to the articles by Walther et al in Section 8, References.

VHL in the Kidneys

The kidneys are organs about 12 cm (4 inches) long in the abdominal cavity, or about the size of your fist. (See Figure 8.) VHL in the kidney may cause cysts or tumors. It is common for any adult in the general population to have an occasional kidney cyst. VHL cysts are usually multiple, but the presence of one or more simple cysts is not a problem in itself. It is also possible for tumors to form in the kidney that are renal cell carcinomas (RCC), one kind of kidney cancer, formerly known as hypernephroma.

There are generally no specific physical signs to help find problems early. It is critically important to begin monitoring the kidneys long before any obvious physical symptoms or signs occur. The kidneys continue to function while these structural changes are occurring, without physical symptoms, and with normal urine tests.

Think of it as having a mole on your skin, except that you cannot see that it is growing. When it is very small there may be no cause for alarm. When the mole begins to grow or change in suspicious ways your doctor would recommend that it be removed.

Similarly, when a kidney tumor is quite large when discovered, or if it changes shape, or its size or rate of growth becomes suspicious, your medical team may recommend surgery. Not all kidney tumors require immediate surgery. Based on characteristics such as density, size, shape, and location, they will recommend either a time to repeat the imaging tests or surgical resection (removal of the tumor). Once they emerge, VHL kidney tumors are like Renal Cell Carcinoma in the general population. The biggest difference is that in VHL, we have the opportunity to find them earlier than most people who have sporadic kidney cancer. That gives us much better options for dealing with them early, keeping that kidney working for you, and avoiding the worst consequences of cancer. Knowing that someone with VHL is at risk for RCC, the tumors can be found at much earlier stages. If you wait for symptoms, the tumor will usually be at a much later and more dangerous stage when it is found.

Opinions differ on the right time to operate, but there is widespread agreement on this general approach. In VHL, a person with kidney involvement typically has a series of tumors on both kidneys over the course of several decades. Clearly one cannot remove every little tumor, since that would be too many surgeries for the person, and especially for this small organ, to endure. The goal is to maintain the patient’s own kidney function throughout his or her lifetime, to minimize the number of surgeries and yet remove tumors before they metastasize and cause the cancer to grow in other organs. The tricky part is to choose the right moment to operate — not too early and not too late.

The objective is to track the progression of the cells from harmless to a later point, but before they become capable of spreading. If you think of a dandelion, it begins as a bud, becomes a rather pretty yellow flower, turns white, and one day the white seedlings are carried off on the wind to seed the lawn. If you pick the yellow flowers, the seeds are not mature and cannot spread. The cells have to mature to the point where they know how to seed the lawn.

That is the point we are trying to find for cancer tumors as well. Cancer researchers have identified a series of distinct stages that the cells go through before they are even capable of metastasizing.

It would be nice if there were some easy blood or urine test — some biomarker — to check on the cell progression, but there is no such test at this time. What the clinical research has shown, though, is that the size of a solid tumor is one relatively crude but fairly reliable sign of its progress.

Biopsies are usually not called for in this case, since with a diagnosis of VHL one is pretty certain what the structure will contain. There will be cancer cells even in very small tumors. The question is: what is their level of progression?

Cysts are generally not considered sufficient cause for an operation. There will be a small seedling of a tumor in the wall of the cyst, and it will be important to watch the size of that tumor, not of the cyst itself.

The consensus from the Freiburg (Germany) meeting (1994) was to recommend surgery only when the largest tumor is larger than 3 cm. This recommendation was verified by a multi-center study under Dr. Andrew Novick (Steinbach, 1995) and all the VHL study teams worldwide now concur with this guideline. So far there are only three verified reports of metastasis from tumors smaller than 4 cm, all of which were greater than 3 cm.

In watching your kidneys, your medical team is working to evaluate whether you have cysts or solid tumors. You will need tests such as ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). The doctors will watch the tissue density, the position of the tumors, their size and rate of growth. Each of these diagnostic methods gives them a different kind of information. Depending on where the tumors are located and your own medical history, your team will recommend the methods that provide the best detailed information with the least risk to you.

It is important that you understand in as much detail as you wish the medical findings that your medical team is concerned about, and that you participate with them in determining the right timing and treatment. Don’t be shy to get a second opinion. The distinction between a cyst and a tumor can be debatable depending on the clarity of the image and the experience of the radiologist who reviews the VHL tumors. Our experience has shown that even among experts there can be differences of opinion. This is an area where the perspective of one or more physicians with significant experience in VHL can make a world of difference. Films or compact discs (CDs) can easily be sent to a consulting physician far away, even in another country. Contact the VHL Family Alliance for assistance in locating an expert who can assist you.

Decisions about when to operate and the extent of the procedure need to be made by the entire team, especially including the patient, with full disclosure of all information. All points of view, the location of the tumor, the patient’s level of stamina and health, and even the possible desire of the patient to be free of the tumor, all play a role.

In cases where the last remaining kidney must be removed, VHL patients have been proven to be good candidates for kidney transplant. (See Goldfarb, 1997.) VHL tumors grow from abnormalities within the cells of the kidney itself. Since the new kidney has the donor’s genetic structure and two healthy copies of the VHL gene, it is not at risk for VHL tumors.

VHL in the Pancreas

The pancreas is an organ extending from left to right in the upper abdomen, in the back, lying directly behind and against the stomach and the small intestine. (See Figure 8.) It consists of two glandular parts: one produces secretions which are essential in digestion, which flows by way of the large pancreatic duct together with bile produced by the liver into the upper part of the digestive tract. The other part is formed by the islet cells, in which hormones such as insulin are formed, which regulates the blood sugar level.

Pancreatic lesions are generally considered to be the least symptomatic among the lesions of von Hippel-Lindau disease. Families report a number of subtle symptoms, though, which may be caused by pancreatic cysts.

Three types of lesions may be found commonly in the pancreas:
• cysts
• serous microcystic adenomas, or “cystadenomas”
• islet cell tumors, or pancreatic neuroendocrine tumors (PNET)

Pancreatic cysts may be found in a large number of people with VHL, with wide variation among families. The frequency of pancreatic cysts ranges from 0% in two large families to 93% in others. Many cysts, even very large ones, may be present without causing symptoms, and no treatment is required. In some cases, enlarged cysts may press against the stomach and cause discomfort. Surgical drainage of a large cyst may provide relief.

Tumors may occur in the pancreas. Serous microcystic adenomas, benign tumors, are the most common. These generally need not be removed unless they are causing obstructions to the normal flow of fluids and enzymes.

Your medical team may request additional tests to detect abnormal hormonal function. Depending on their size, type and location, VHL cysts and tumors of the pancreas can cause functional problems as well as structural problems. Cysts and tumors may block one or more of the ducts that carry essential fluids from one organ to another. Blockage of the delivery of insulin may cause digestive problems or diabetes. Insulin or digestive enzymes may need to be prescribed to maintain health. An endocrinologist can assist you and your medical team in the evaluation and management of VHL tumors of the pancreas.

In rare cases, the pancreas may become so replaced with multiple small cysts that it becomes nonfunctional, which may result in fatty stools and diarrhea. Symptoms may be relieved with pancreatic enzyme replacement. On rare occasions, insulin-dependent diabetes may result. If lesions obstruct the bile ducts, there may be jaundice, pain, inflammation or infection. Jaundice is when the skin and urine become yellow, and the stools become quite pale. Pain is your body’s signal to you that there is something wrong that requires attention; seek medical help immediately, as pancreatitis is a serious condition requiring medical attention.

The most worrisome pancreatic issue is solid tumors, not cysts, arising within the islet cells of the pancreas, which may be pancreatic neuroendocrine tumors (PNET). They can cause bile duct obstructions, and can even metastasize or spread to the liver or bone. The location of the tumor is important in deciding when to operate. A small tumor that is growing rapidly next to an important structure in the head of the pancreas may need early surgery, or a larger tumor in the tail of the pancreas might be able to be monitored. The type of surgery also varies with the location. It may be possible to simply remove small tumors, or portions of the pancreas may need to be removed. A surgeon with expertise in pancreatic neuroendocrine tumors is important in helping you decide on the best course of action.

The general guideline is to remove pancreatic neuroendocrine tumors greater than 3 cm in the body or tail of the pancreas, or greater than 2 cm in the head of the pancreas. Laparoscopy is often possible for removal of these tumors.

Figure 9: Dandelions demonstrate that cells need to mature to a certain point before they know how to send out seeds and plant more tumors in other places. We need not pull up every green one, but it is important to pick them while they are yellow. To manage VHL, you and your medical team will work out the right balance between avoiding metastatic cancer and maintaining healthy organs.

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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