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Kidney Cancer and VHL
from the VHL Family Forum, newsletter of the VHL Family Alliance, June 1994
Von Hippel-Lindau disease is a hereditary condition involving the deactivation of one tumor-suppressor gene, the VHL gene. This flaw in the body's normal tumor-suppression system causes a series of tumors in various parts of the body throughout a person's life. One of the kinds of tumors which may be involved are tumors of the kidney, which are cancer.
Deactivation of the VHL gene has been shown to be involved in the majority of cases of sporadic renal cell carcinoma (RCC) as well. But in VHL, an inherited form of kidney cancer, there are three important differences: (1) it is normal to see cysts and tumors on both sides in VHL; (2) the tumors follow a different behavior pattern than sporadic RCC, and (3) there may be other tumors in other parts of the body which also need attention.
If the patient in fact has VHL, not sporadic RCC, then this treatment might be less aggressive, other family members may be at risk, and this patient and other at-risk family members might be screened proactively to avoid the worst consequences of other tumors in the body.
A diagnosis of VHL is normally assumed to require evidence of two types of tumors in this same patient, or another of the typical VHL tumors in another closely related person. The treatment pattern for VHL must take into account that the tumor(s) that present now are probably not the last kidney tumors this patient will experience. The challenge is to avoid metastasis while keeping this patient on his or her own kidney power as long as possible. Further information is available from the VHL Family Alliance, info@vhl.org.
When to Watch; When to Act?From the VHL Family Forum, newsletter of the VHL Family Alliance, June 1994, p. 10 Both the panel in Kansas City [April 1994] and the Symposium in Freiburg [May 1994] addressed this key question: When to watch a kidney tumor, and when to act? With today's better diagnostic methods, we are able to see tumors when they are very small, but at what point should action be taken?
There is no simple formula on which all physicians agree. But the evidence is mounting that VHL tumors have different behavioral characteristics than sporadic renal cell carcinoma: they tend to grow more slowly, are less aggressive, are more numerous, and have a 50% chance that there will be more after some years in the future.
There are no definite rules to guide patients or physicians, and our speakers were divided on this subject. Dr. Mark J. Noble of the University of Kansas Medical Center said that most urologists familiar with VHL now agree that you need not remove kidney tumors less than 2-3 cm. in size. He then removes the tumors and saves as much functioning kidney as possible. Dr. Craig Hawkins shared that in the experience of the Mayo Clinic they did have one patient who seemed to have a metastatic cancer from a tumor smaller than 2 cm. While they also practice renal sparing surgery whenever possible, they tend to operate on smaller tumors and cysts. Dr. Hartmut Neumann and his colleagues at the University of Freiburg do not operate for cysts alone, but only for larger tumors. His experience is that the safety limit may be higher than 3 cm. He generally waits until 4 cm.
Because no one can be sure, it is important that the patient be involved in making the decision about when to remove the tumors. With today's surgical techniques it is unlikely that the kidney can be operated upon more than 3 times before it will need to be completely removed, so operating too soon may result in loss of the kidney earlier in life. On the other hand, waiting too long may result in the cancer spreading to another place in the body. Dr. Neumann works with his patients to evaluate the position of the tumors, their tissue densities and growth patterns, the family kidney history, and the risk the patient is willing to live with. He has ten patients with tumors ranging up to 4 cm. without metastasis.
New kidney treatments may make it possible to operate more often on the kidney with less damage to kidney function, but they still entail surgery. The best hope is that research such as Dr. Linehan's work on the genetics of kidney cancer will lead to non-surgical therapies which will constrain the growth of kidney tumors and prevent or reverse the spread of kidney cancer.
VHL Gene Linked to Kidney Cancerfrom the VHL Family Forum, newsletter of the VHL Family Alliance, June 1994, p. 7 reviewing "Mutations of the VHL tumour suppressor gene in renal carcinoma"1 A study published in the May issue of Nature Genetics shows that the VHL gene plays a role not only in the formation of tumors in people who inherit a flaw in the VHL gene, but also in 85% of the kidney cancers in the general population as well. The cancer, called sporadic (non-familial) clear cell carcinoma, accounts for about 23,500 newly diagnosed cases of kidney cancer each year in the U.S. alone.
"With identification of this kidney cancer gene, it will be possible to develop new methods to improve the diagnosis and treatment of the disease and potentially to find ways to prevent it," said W. Marston Linehan, M.D., of the Surgery Branch, National Cancer Institute (NCI). "The finding also will make it possible to develop a blood or urine test that can detect kidney cancer early when it is most treatable." When detected in its earliest stages, the survival rate is 86%.
The damaged or mutated gene responsible for sporadic clear cell carcinoma of the kidney is a tumor suppressor gene located on the short arm of chromosome 3. The protein produced by the gene appears to normally restrain growth. The researchers found that this gene is mutated (inactivated) in a high percentage of tumors (57%) from patients with sporadic, non-familial cancer.
This is the same gene that was identified last year as the cause of the inherited cancer syndrome von Hippel-Lindau (VHL) disease.
"The disease appears to fit the two-hit model for development of cancer, where both copies of the critical gene are damaged or mutated," said co-investigator Berton Zbar, M.D., chief of NCI's Laboratory of Immunobiology.
Everyone has two copies of the VHL gene, as they do of every gene - one from the mother and one from the father. When we say that a person has VHL, that means that they inherited the faulty copy of the VHL gene from the parent who has VHL. One normal copy of a gene is sufficient to prevent development of a tumor. If both copies are damaged or mutated - the two-hit model - cancer may develop.
In people in the general population, the two copies of the VHL gene they inherit are both healthy. In order for a tumor to form, both copies of this gene must become deactivated. There are numerous theories of how genes get changed - environmental factors, water pollution, cigarette smoke, radiation, free radicals, etc. - we don't understand just what happens, but step by step the process is becoming clearer.
From the work on the VHL gene previously reported by Latif, Lerman, Zbar, et al.2 we know that the VHL gene is on chromosome 3p. This article reports that the gene has been cloned by the same team3 and that an article reporting the cloning has been submitted for publication. Now that the gene has been cloned, scientists can make greater headway in understanding how the gene operates. The gene appears to be important in encoding a functional protein. The next step is to understand what this protein does in the body, and what occurs when it is not present.
It is as if it takes two occurrences for a tumor to grow and become cancerous. First, the brakes have to be off; second the accelerator has to be on. The disabling of the VHL gene takes off the brakes. But what puts the accelerator on?
The researchers also found that the kidney cancer gene is affected early in the development of the disease. This finding is important, Dr. Linehan explained, because its early presence makes it possible to consider development of treatments to halt or reverse the progression of the disease in its early stages.
All this implies that exposure of the kidney to environmental carcinogens may lead to mutation of the VHL gene and subsequent tumor formation. This demonstration that mutations in the VHL gene foster tumor growth in renal cell carcinoma "should lead to a better understanding of how renal epithelial cell growth is regulated and should aid in methods of diagnosis and treatment of patients with this malignancy."4
For people with VHL, what do we learn from this?
We learn that VHL kidney tumors are indeed closely related to renal cell carcinoma. But we also learn that there is more to be learned. Dr. Linehan tells us, for example, that while he can get 80% of sporadic renal cell carcinoma tissue to grow in the lab, he has been unable to get VHL kidney tumor tissue to grow there. He still does not understand why. We know that VHL takes the brakes off, but what presses the accelerator? The same environmental factors which cause the VHL gene to change affect both people with VHL and people with sporadic kidney cancers.
World Focuses Attention on VHLReport from the International Symposium on Von Hippel-Lindau, Freiburg, Germany, May 27-28, 1994. -- from the VHL Family Forum, newsletter of the VHL Family Alliance, June 1994, pages 2-3. "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.
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.
Further information is available from the VHL Family Alliance, info@vhl.org. |
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