Report from the Dutch Symposium

Ordering Information -- Sessions on Audio or Video Tape"

The 6th International Symposium on MEN and VHL was held at Leewenhorst Congress Center outside the sleepy seaside village of Nordwijkerhoud on the North Sea near Leiden, Holland. Gillian Houlders from England, Chris Hendrickx from Belgium, and I represented the VHL Family Alliance. We met with several members of the Dutch VHL support group, with Jeannette Bos-Mol, chairman of the group, and Joke Jansen-Schillhorn van Veen, a volunteer who organizes support groups for various conditions for Dr. Lips.

Chart 1. Where did the attendees come from?   The majority (71%) were from European countries.  40% were radiologists, 26% were clinicians.

Convening the meeting, Dr. Cornelius J. M. Lips of the University Hospital at Utrecht reminded us that it was a good place to study the molecular causes of disease because the ground glass lenses that brought the modern microscope to full power were invented in the 17th century by Antonie van Leeuwenhoek, a Dutch microscopist, in nearby Leiden. Dr. Lips’ genetic research began with a study of sickle cell anemia in 1975. Studying cancer is even more complex than other molecular diseases because it is a combination of promoters, inhibitors, breakdowns, repairs, and failures to repair. Just when you think you understand its cause, you realize there is yet another effect.

The easy genetics have been done -- the mapping and isolation of the highly penetrant susceptibility genes. The emphasis in genetics is now shifting from the study of inheritance to the cell biology, the functional analysis of genes, and the detection of less common susceptibility genes. We are realizing that there is a stronger influence of the environment and other modifiers. Using techniques from epidemiology, we can determine what candidate genes might be involved.

Dr. J. Aiden Carney, a pathologist, proposed that VHL might be classified as a multiple endocrine neoplasia (MEN). "Neoplasia" is a new growth, or tumor, arising from a single cell with a genetic flaw. MEN syndrome diseases include those which have tumors of 2 or more endocrine organs and some non-endocrine tumors as well, but the endocrine tumors dominate. MEN and VHL are both included in a loose classification of diseases called phakomatoses. This classification, described by a Dutch scientist van der Hoeve in 1925, include ones which have small spots or patches on the skin, endocrine and other tumors, and other congenital malformations.

Dr. Maartje Los [228] talked about her studies of level of vascular endothelial growth factor (VEGF) in various tissues of people with VHL. The purpose of her study was to determine the nature of angiogenesis (development of new blood vessels) in VHL. Angiogenic factors (those which lead to the development of new blood vessels, or hemangiomas) are hypoxia (when there is too little oxygen, the body builds more blood vessels to bring more blood to bring more oxygen), tissue injury (where increased blood flow is needed for repairs), and vascular endothelial growth factor (VEGF). Thus the VHL protein is up-regulating an angiogenic factor and down-regulating an inhibitor of angiogenesis.

They tested ocular fluid of VHL patients for VEGF, IL-8, ET-1, and bFGF. As a control group, they used cataract patients with normal retinas. They found much higher levels at much earlier ages in VHL patients.

There were high levels of VEGF in renal cyst fluid, much higher than in blood. In blood and in urine, levels of VEGF, bFGF, and IL-8 were the same as the age-matched control group. Therefore it does seem that the VHL gene might be regulating VEGF expression in living tissues.

The urine samples used in this test were donated by members of the VHL Family Alliance to Dr. Emil Voest while he was at the Dana Farber Cancer Research Institute in Boston in 1994.

Dr. D. Wittebol-Post [257] described her research on hemangioblastomas of the retina. In the past people were sometimes diagnosed with "von Hippel’s disease." We do not know how many of these people had VHL versus sporadic retinal hemangioblastoma, but presumably most of them had VHL. She and Dr. Richard agreed that multiple retinal hemangioblastomas are sufficient for a diagnosis of VHL. From the point of view of a pathologist, the retinal angiomas are identical to cerebellar hemangioblastomas, though they do not develop cysts. In peripheral tumors, treatment is generally successful. Treatment of angiomas in the central part of the vision is the most tricky, since the treatment itself can cause some damage to surrounding tissue and thus to the vision.

Dr. Gunter Janetscchek [259] presented his experience with laparoscopic surgery for VHL which has previously been reported (VHLFF, March 1997). He and Dr. Neumann have now had long-term experience with partial adrenalectomy and find that this is a very good course to take, as it avoids or at least delays putting people on replacement therapy. Dr. Jane Green of Canada agreed that long-term replacement therapy sometimes causes problems. In her group of patients there is a higher rate of recurrence than in the German experience so she feels that in some families there may be a greater need for careful follow-up, but she agreed with the conservative approach even so. Dr. Neumann follows patients by watching blood pressure, symptoms, and appearance of micro-nodules on MRI.

Dr. Gerd Kempermann [260] spoke about ELST. The cells from ELST look very much like those from thyroid, so ELST was often mistaken for metastasis from thyroid. It is only in the last 10 years that people have begun to understand ELST. Interestingly, the first patient described by Dr. von Hippel had an ear tumor. In the literature there are only 10 cases cited, but Dr. Oldfield’s retrospective analysis identified a significantly higher number.

Whenever ELST is found on both sides, one should consider a genetic cause. It is important and often not easy to distinguish ELST from other similar kinds of tumors. It is often wrongly identified as a metastasis from thyroid, lung, breast, or kidney, or as a paraganglioma, or ceruminal gland tumor, or salivary choristoma, or plexus papilloma, or meningioma. Confirmed carcinoma of the temporal bone is very rare, and should be questioned as a misdiagnosis. Dr. Richard has 20 cases of ELST in France, 18 of which are VHL. Dr. Kempermann concluded that in cases of hearing impairment in VHL patients, ELST should be considered as the cause. CT scan or MRI in VHL patients should include the cerebello-pontine angle and the apex of the petrous bone.

Dr. Stéphane Richard [258] of Paris described the structure of hemangioblastoma of the central nervous system. There are many VEGF receptors and high concentrations of VEGF have been found around hemangioblastomas. Secondary polycythemia was found in 20% of the cases of intratentorial hemangioblastoma. In the experience of the French study, 61% of those with seemingly sporadic hemangioblastoma of the cerebellum under age 20 were in fact VHL; 50% of those under 30, and the percentages decrease with patient age. In cases of spinal hemangioblastoma, the percentages were even higher: 93% of those under 20, and 86% of those under 30 proved to be VHL. He concluded that all patients with sporadic hemangioblastoma, especially in the spine, should be investigated for VHL.

Dr. Dieter Schmidt [368] of Freiburg presented his series of ophthalmology patients with VHL. He uses fluorescein to determine which is the artery and which is the vein, and whether there is a connection between the two, in order to plan treatment so as not to compromise the blood supply to the retina. He prefers early laser-photocoagulation, though he has seen a number of untreated patients and followed the microangiomas as long as 6 years without seeing change.

Dr. Hartmut Neumann [124] of Freiburg described his work on genotype/phenotype correlation in VHL -- among people with a specific point mutation (genotype), what differences are seen in their symptoms and the course of the disease (phenotype)? The most dramatic differences are seen in the "505 mutations" (where pheos are very prevalent and kidney cancer is rare) and in the Hawaii family (where kidney cancer is very prevalent and pheos are very rare). There is an urgent need for international cooperation to compile data.

Dr. Eamonn Maher [125] of Birmingham, England, described his study of DNA testing in VHL. Mutations have been detected in 132 families (an 80% success rate) and family members who are shown not to be gene carriers can be released from regular screening. In families in whom a mutation is not detected DNA linkage studies can be used to predict carrier status in most cases. The type of VHL mutation can be used to predict the risk of pheochromocytoma with certain "missense" mutations resulting in a high risk. Screening programs can then be adjusted appropriately. A few VHL mutations may predispose to pheochromocytoma only, with no other features of VHL disease. The type of VHL mutation did not appear to determine the severity of eye involvement, but Dr. Maher reported that there was evidence that additional genetic or environmental modifying effects are involved. This means that it is not possible to accurately predict the severity of eye involvement knowing the type of VHL gene mutation. DNA analysis can be useful in cases where a clinical diagnosis of VHL disease is uncertain.

Dr. William Kaelin [126] presented his work on understanding the function of the VHL protein which has previously been reported (VHLFF, June 1997). His team has identified a new function of VHL in regulating the fibronectin matrix assembly. The consequences of this function are not yet understood. He is not yet considering environmental factors, but is looking at the possible effects of modifier genes.

Dr. David Goldfarb [127] of Cleveland reported the experience of the Cleveland Clinic and associated centers in the multi-center study of VHL kidney tumors which has previously been reported (VHLFF, June 1995). Subsequently, they have undertaken to look at the long-term survival rates of people treated with nephron-sparing surgery, with radical nephrectomy, and with renal transplants. His conclusion is that for low-grade tumors, removal of the tumors while conserving the organ is the best course of action. They found that tumors could be removed in the body, and that ex vivo ("bench") surgery was not necessary. Very few of the patients in his series had high stage disease. People with radical nephrectomy had poorer survival rates, probably also because these were the most advanced tumors. Eventually almost all patients had another tumor, but most went at least 5-8 years without need for additional surgical intervention. His team uses a goal of maintaining renal function without compromising long-term survival. They do close radiographic follow-up (every six months) and have found a very small risk of metastasis with this strategy.

Among the small number of patients who did eventually lose all kidney function, transplantation proved to be very successful. If the transplant lasts at least three years, it is cheaper than dialysis. There was some concern that immune suppression might lead to additional tumors. To study this question, they followed 32 VHL transplant recipients, 23 men and 9 women, and a control group of non-VHL related transplant patients matched by age and sex and donor, over a 48 month period. They found no significant differences between the outcomes of these two groups. They conclude that for most patients with VHL, there is no need for a waiting period between nephrectomy and transplant if the tumors in the kidney were of low stage. If there are high stage tumors, a two year waiting period is advised. The majority of VHL patients will fall into the low stage category. Live kidney donors are preferred for transplantation, but in VHL families it is important to do DNA testing on the donor to ensure that the donor kidney is not affected. When technically feasible, renal sparing surgery is the preferred approach.

At the end of the meeting an electronic voting method was used to collate the participants’ opinions on some questions. This voting is not final by any means, but was an interesting polling of their opinions. 40% of those present were radiologists, 26% were clinicians. See also Chart 1.

28% of the attendees had less than 5 years experience, 16% had 5-10 years experience, 36% had 10-20 years experience. Most of the questions concerned MEN, but the following questions applied to VHL.

"At what age do you recommend DNA analysis for VHL?" The consensus among those who responded was to test between ages 1 and 5 (see Chart 2). In the discussion that followed, several doctors explained that in some countries, there are efforts to create laws to prevent parents from making decisions about DNA testing of minor children unless there is material benefit to the health of the child from obtaining this information before the child is of age to choose. The intention of this question was to determine the age at which knowing this information would most benefit the child. Dr. Neumann said that in his experience most people want their children tested at 1-5 years, and he feels that this is medically important because he has some children with serious eye problems younger than age 5.

Chart 2. Opinion poll questions: "At what age do you recommend DNA analysis for VHL?" Since clinical exams begin at age 3-5, the consensus (44%) was 1-5 years.

"Should we try to protect individuals carrying mutated tumor susceptibility genes from radiation or other mutagenic exposure?" This question was poorly worded, and the voting results were unclear. From the discussion it was clear that especially for children and asymptomatic individuals of any age, the majority of those present prefer to avoid testing methods that involve radiation whenever possible, but where needed to provide clarifying information about a particular issue, the use of CT annually is warranted and agreed.

The next question was to determine whether physicians are pursuing cases of seemingly sporadic (random) tumors in the general population that can occur in these syndromes. "Are you performing DNA analysis in patients with apparently sporadic MEN1, MEN2, or VHL-like tumors?" 89% said yes, 11% said no. In the discussion, Dr. Richard said he felt that in patients with no history of genetic illness in the family, where the tumor is supposedly "sporadic" (random in the general population), if the patient is younger than 20 and has tumors in more than one organ, he feels that the patient should definitely be tested for VHL or MEN. He has seen as many as 25% of sporadic hemangioblastoma and 85% of cases of seemingly sporadic retinal angiomas prove to be VHL, and unless DNA testing is done, the patient will go undiagnosed.

"Who should deliver the results of DNA testing?" Overwhelmingly, those present felt that the attending internist or endocrinologist should deliver the news. Most of these people were from MEN, where the patient has a close ongoing relationship with the endocrinologist, which undoubtedly influenced the results. Joyce Graff stated that among the families she hears more stories of badly delivered news among internists, urologists, neurologists, etc., than among geneticists and genetic counselors. From the family perspective she would argue for genetics personnel to deliver the news. Genetics professionals are aware of and should be governed by ethical principles, such as not making directive statements about the opinion of the physician as to whether or not this person should have children. If internists and other clinicians are going to deliver this news, they need some training in sensitivity to the ethics and non-clinical issues involved.

"Most pheochromocytomas grow slowly and screening procedures are expensive. MRI may be more sensitive than measurement of catecholamines and metabolites [urine & blood tests]. Which frequency of screening do you prefer?" (see Chart 3.)

Chart 3. Testing for pheochromocytoma

There was consensus that patients should be followed annually, with only 6% saying that they test only when there are symptoms. Most do blood and urine testing (38%), but only 12% routinely do MRIs. 38% recommend MRI only if these chemical levels are increased in blood or urine. In the discussion, one speaker said that in 20 years he has not seen a patient who has gotten into trouble without elevated catecholamines. MRIs are expensive, and there are attempts to ration the use of expensive procedures. Dr. Neumann said that catecholamines are less sensitive, so he uses MRI, and watches blood pressure and other symptoms as well. He had one patient who died of a pheo at age 5 in the 1960’s. Another said that he has seen patients with normal catecholamines who had a perceptible pheo.

"If one adrenal is affected, what is your advice about the opposite normal one?" (see Chart 4). There was consensus not to remove an unaffected adrenal gland in the hopes of preventing a future pheo. However, those present were sharply divided over whether to remove the entire affected adrenal gland, or only the medulla. In the discussion, one physician said that he has personally been very reluctant to do a partial adrenalectomy and leave some tissue that might form another tumor. One said that he felt one could remove the entire medulla and leave the adrenal cortex; another felt it was impossible to remove every scrap of the medulla. Dr. Robert Gagel said that in the experience of the M.D. Anderson Center in Houston in following 15 partial adrenalectomies over a 25-30 year period there were only three recurrences.

Chart 4. How much of the adrenal gland to remove?

In sum, it was an excellent meeting, Dr. & Mrs. Lips were wonderful hosts, and it always good to see the doctors putting their heads together over some of the more difficult issues. This group of leading experts on VHL is a warm and caring group of highly skilled professionals. The European Commission provided some funding to help doctors from Eastern Europe to attend. The setting was beautiful, and after the end of the conference a number of the attendees enjoyed a bit of touring together. Dr. Neumann played his violin at the Kurhaus (say cure-house), an elegant Victorian casino and spa near Amsterdam, where fashionable people used to go to "take the cure". Dr. Lips is arranging for some of the scientific papers from this meeting to be published in the Journal of Internal Medicine over the course of the next year. We are looking forward to the next VHL symposium in Paris in September of 1998!

Ordering Information -- Sessions on Audio or Video Tape

As published in the VHL Family Forum  5:3, September 1997. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.