"In the last ten years, von Hippel-Lindau disease has gone from an obscure medical curiosity to a condition with far-reaching implications in oncology," said Dr. Alfred G. Knudson of Philadelphia, originator of the now widely accepted theory of tumor-suppressor genes, delivering the keynote address at the First International Symposium on von Hippel-Lindau (VHL) in Freiburg, Germany. He noted that study of VHL is helping scientists to understand the mechanisms of many kinds of cancer.

Eighty respected physicians and scientists gathered from Japan, the United States, England, Germany, France, Italy and the Netherlands. They shared the results of their research on the molecular genetics and clinical management of VHL. Dr. Knudson lauded the presentation of urologist Dr. Gyula Kovacs of Heidelberg, saying that he "has made an enormous contribution" to the field. Honored American attendees included Dr. Y. Edward Hsia of the University of Honolulu, and Dr. Nuzhet O. Atuk of the University of Virginia, whose studies of large VHL kindreds have provided key pieces of the VHL puzzle.

In the May issue of Nature Genetics, the VHL gene has been shown to play a role in 85% of kidney cancer cases which occur in the general population, affecting 23,000 people each year in the United States alone. [See page 7]

The meeting was hosted by Dr. Otmar Wiestler of Bonn, and Dr. Hartmut P.H. Neumann of Freiburg, who has spent the last twelve years concentrating on improving diagnosis and treatment of patients with von Hippel-Lindau disease. Dr. Neumann recently completed a tour of the United States, sponsored by the VHL Family Alliance, where he spoke on VHL in five cities. [See pages 8-9,10]

The principal questions for this symposium concerned diagnosis and therapy: how to improve diagnosis through clinical findings and/or through molecular genetics; how to reduce exposure to radiation in diagnostics; how to reduce the complexity of the diagnostic process. In the area of therapy, Dr. Neumann posed the question how to find the right balance between undertreatment and overtreatment. With improvements in diagnostics, tumors are now found at very early stages, but at what point should action be taken? The goal of the symposium was to make recommendations to physicians and to inform the decisions of the patients regarding their treatment.

Joyce Graff of Brookline, Massachusetts, and Peggy Graham of Warren, Michigan, attended the Symposium, representing the VHL Family Alliance. Both Joyce and Peggy have children affected with VHL. They met with families from Germany, and were interviewed on German television. They spent most of Saturday with Peter and Sylvine Z. from East Berlin, who send their best greetings to all the members of the VHL Family Alliance.

Nearly thirty talks and posters were presented.

The French National VHL Registry project under Dr. Stéphane Richard found hundreds of previously misdiagnosed cases of VHL. They found that 30% of all cases of cerebellar hemangioblastoma and 58% of cases of spinal hemangio-blastoma were in fact VHL. Among patients under the age of thirty, the percentages rose to 47% and 77% respectively. When tumors occur in young people, they are more likely caused by a hereditary condition.

On the last day, Dr. Neumann summarized the recommendations of the symposium regarding cerebellar hemangioblastomas. Screening is done with MRI with gadolinium. They can grow fairly large without symptoms. Early diagnosis is important to prevent loss of function. There was interest in the possible contribution of radiosurgery for cerebellar hemangioblastoma. Dr. Hsia noted that it is important to screen VHL women before childbearing because of the tendency of tumors to grow at a faster pace during pregnancy.

Dr. Dieter Schmidt of Freiburg summarized the recommendations for retinal angiomas. He screens the retina with contact glass and fluorescein angiography as needed, in an effort to find lesions when they are very small. He treats angiomas with laser, especially small ones in the periphery, treating them in multiple sessions to avoid blistering the retina. Conscientious follow-up is important, as additional lesions are not uncommon.

When lesions are close to the optic nerve or macula, treatment can be dangerous. He tends to observe these unless they are actively growing. He posed the question whether photon-beam therapy might hold promise for treatment of certain of these difficult lesions. Dr. Stéphane Richard of Paris noted that since retinal angiomas are indistinguishable under a microscope from cerebellar hemangioblastomas, we should refer to them as hemangioblastomas.

Dr. Peter Choyke of the National Institutes of Health, U.S., summarized the findings on renal cell carcinoma. CT scanning is recommended with 5 mm. slice depth and contrast. One should not only identify the presence of tumors, but their size and growth rate, but re-checking twice at 6-month intervals the first year. Once this information has been gathered and the risk calculated, watch the tumors up to a size of approximately 3 cm and then perform enucleation or partial nephrectomy. Total nephrectomy should only be performed when there are no other options. Several of those present recommended the use of MRI or ultra-sound during the surgery to maximize the benefit of each surgery. Continue a conscientious follow-up program because more tumors are not uncommon. The goals are to avoid frequent surgery, and reduce metastasis to a minimum.

Dr. Atuk summarized the recommendations on pheochromocytoma. Dr. Eamonn Maher of England recommends annual urine testing. Dr. Atuk uses CT, though some felt that MRI or MIBG were preferred. He feels that of the chemical indicators, urinary catecholamines are the most useful indicators. None of those present had experienced any malignancies among pheos. Therefore the recommendation is to enucleate the tumor whenever possible. Pheos can occur outside the adrenals, so even people with bilateral adrenalectomy should continue to be screened for pheo. The presence of a pheo must be ruled out before any surgery in VHL patients, to avoid surgical complications.

Professor J.-P. Grünfeld of Paris, in his concluding remarks, noted that VHL is often misdiagnosed in all countries, partially due to the risk of overly compartmentalized medicine. He noted that with the better information which is being gathered, with better training on VHL now available to physicians, better information for families, and with the participation of the families in the ongoing process of learning about VHL, progress will continue to be made.

Dr. Wiestler thanked everyone for coming, and for the enthusiasm generated at the meeting.

As published in the VHL Family Forum, June 1994, 2:2