With the September 2004 issue of the VHL Family Forum we included a survey, asking people to share some information about their VHL histories that might help researchers. We had a wonderful response! Altogether 172 people reported information on 290 cases.

36 (20%) of the surveys were received from outside the United States — from Canada, England, Scotland, Ireland, Europe, Australia, New Zealand, and South Africa — a total of 15 countries were represented in this survey.

73 people (25%) were diagnosed through DNA testing. This is a sharp increase from surveys we did five years ago, which is to be expected, since the technology has improved so much since then. Fifty-six people (19% of the total) had a diagnosis of VHL before they had their first symptom. This is a wonderful advancement, allowing those people to begin screening early, and catch issues at very early stages.

We asked people at what age they were diagnosed. Ages ranged from zero to 84, with a median age at diagnosis of 25 years. Age at first symptom ranged from one to 71, with a median age of 20 years. So the ranges were very broad, with the highest probability in the young 20’s. Fifty-five (19%) of these people had their first symptom before the age of 15.

Of the 243 people who provided both an age at diagnosis and an age at first symptom, 56 (23%) were diagnosed before the first symptom, through DNA testing. Of these, 24 (40%) were under the age of 12. Eleven still have no symptoms, and a total of 124 were diagnosed within the first 1-2 years. The physicians working with these patients achieved a diagnosis within a reasonable timeframe. In other words, the system worked well for 72% of the group. See Figure 1.

Pie chart showing numbers of respondents diagnosed within 1 year, 2-5 years, 6-12 years, and 14-43 years
Figure 1: Time to diagnosis. Of the 233 respondents providing sufficient data for analysis, 23% were diagnosed before the first symptom, and another 49% were diagnosed within one year of the first symptom. The remaining 28% waited up to 43 years for a diagnosis.

Others were not so fortunate.

Thirty (12%) of these people waited 2-5 years for a diagnosis.
Twenty (8%) of these people waited 6-12 years for a diagnosis.
Seventeen (7%) of these people waited more than 14-43 years for a diagnosis.

During that time, minor issues became larger issues. In some cases a small problem treated as an isolated incident could have served as an early warning signal if it had been properly interpreted. One man, diagnosed with metastatic kidney cancer at age 66, realized in retrospect that he had been coping with the effects of an undiagnosed pheochromocytoma for 43 years. That means he spent 4 decades with an undiagnosed set of symptoms that were significantly impacting his cardiovascular system and his emotions. At any point in those four decades, if the diagnosis had been made, he might have been spared the very heavy toll of metastatic kidney cancer.

Ten years ago we did an on-site survey at the Boston meeting, where we asked some of the same questions. There were only 37 people responding to that survey, so it is not altogether fair to compare the two. But if it were, this comparison shows that there is at least a 5% improvement in the rate of diagnosis. Our sense of the situation is that it is even better than that. Both studies include history, and of course history has not changed. But the outlook for our young people is significantly brighter.

DNA diagnosis is available as a tool to determine which members of VHL families are in fact at risk. In addition, DNA diagnosis is now available for use in differential diagnosis. When a doctor is trying to decide whether you have disease A or B, the process of differentiation is often unclear. It is very helpful to have a test, like the DNA test for VHL, that can help make that decision clear.

The key is to ensure that doctors will consider VHL as a possible diagnosis. That is something we can all help with — raising the visibility of VHL, helping doctors and the general public think of it more readily.

We asked people what that first symptom was. Among the people who had a delayed diagnosis, their first symptom — the one NOT diagnosed as VHL — was reported as shown in Figure 2.

Figure 2: First Symptoms: Timeliness of Diagnosis by Tumor Type. While the majority of tumors in each category were properly identified as being VHL, there is still room for improvement, especially among ophthalmologists, neurosurgeons, and in identification and localization of pheochromocytomas and paragangliomas.

We have felt for quite a long time that the physicians most likely to make a timely diagnosis of VHL are ophthalmologists and neurosurgeons. Brain and eye tumors are most prevalent, with about 60% of people with VHL likely to have one or both of these tumors. We see that clearly shown in this survey, but we also see that there is still room for improvement. Only about 60% of eye, brain, or adrenal tumors were diagnosed within the first year.

While eye and brain tumors were likely treated as single tumors, pheos were often totally misdiagnosed as stress, mental illness, or heart problems. Cardiac issues are easier to diagnose these days, but the distinction between emotional and adrenal issues remains very difficult without testing. In your own family, if you suspect that a pheo diagnosis is being missed, do not hesitate to press for additional testing and get another opinion.

We have learned a great deal about the natural history of these tumors over the past dozen years. At this point, the VHL Family Alliance and its advisors are working to turn this information around and look at it more broadly — in the general population, what is the likelihood that a particular tumor might be VHL? How worthwhile is it for the physician to do the additional testing it takes to determine whether this person has VHL?

Here are a few of the lessons we have learned:

Bilateral epididymal cysts are considered enough to diagnose VHL.

Endolymphatic sac tumors rarely occur outside VHL.(see note 1)

People with hemangioblastomas in the retina or central nervous system are highly likely to have VHL, especially if the tumor occurs for the first time in someone under the age of 50, or if there are multiple tumors.(see note 2)

Where there are multiple tumors, on both kidneys or adrenals, there is almost certainly a genetic cause, especially in younger people (under 50).(see note 3)

24% of adrenal tumors in one large study had a genetic origin; 30% of those were found to be VHL.(see note 4)

VHL is the leading hereditary cause of clear cell kidney cancer.(see note 3)

20% of people with VHL are the first in their family to have VHL.(see note 3)

Please help us raise the visibility of VHL, to make it ever more probable that the physician will consider a diagnosis of VHL, and do the tests needed to rule it in or out. An early diagnosis will help to avoid the worst consequences of some of the later-onset issues like metastatic kidney cancer.

Note: Many thanks to all who participated in this survey, and to Robin Cochrane for the data entry and assistance with analysis. Thanks too to all the many physicians whose research on VHL has moved our knowledge forward in the last decade.

1. Russell R. Lonser et al, “Tumors of the endolymphatic sac in von Hippel-Lindau disease.” N Engl J Med 2004, 350:2481-2486
2. Stéphane Richard et al, “Central nervous system hemangioblastomas, endolymphatic sac tumors, and von Hippel-Lindau disease.” Neurosurg Rev 2000, 23:1-22; discussion 23.
3. Russell R. Lonser, Gladys M. Glenn, et al., “von Hippel-Lindau disease.” Lancet 2003, 361: 2059-2067.
4. Hartmut P.H. Neumann et al, “Germ-line mutations in nonsyndromic pheochromocytoma” N Engl J Med 2002, 346: 1459-1466.

As printed in the VHL Family Forum 12:4, December 2004. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.