At the Boston meeting in June 2007 Dr. Steven K. Libutti of the National Cancer Institute, shared with us a snapshot of the state of his 12-year study of pancreatic lesions in VHL. He has been screening the VHL patients in the NCI study to see how many in fact have pancreatic lesions, and then closely reviewing all cases with pancreatic lesions.

“If it were not for the VHL community,” Dr. Libutti said, “and the advocacy of the Family Alliance, and the proactive nature of the people with VHL, we would not have been able to accomplish this study . . . You need to salute each other for the data that I am sharing with you.”

As a result of this study, NCI is changing its recommendations for when and how to treat pancreatic lesions. This is new information that you will not find in the 2005 edition of the VHL Handbook. An article is expected to be released in the December 2007 issue of the Journal of Surgery, making the new recommendations official. Meanwhile, he shared what he described as “a work in progress,” which may change yet again prior to publication. Her paper has been submitted to the journal Nature, acknowledging the support of the VHLFA.

About 75% of people with VHL develop cysts of the pancreas and about 12% develop solid tumors. The cysts do not require action at all unless they lead to compressive symptoms. Some of the “hard tumors” turn out to be microcystic adenomas, honeycombed clusters of small cysts, that look solid on the scans but in fact are not a problem.

But some people do get serious tumors, Pancreatic NeuroEndocrine Tumors (PNETs), which can progress to cancer in rare cases. These need to be taken quite seriously, but not all of them require intervention. In fact, only 8% of the PNETs they have seen have metastasized. The goal of his study has been to understand these tumors better, and to see if he could find some additional characteristics that would help to guide the medical team in choosing if, when, and how to intervene.

Size is traditionally our best measure, and remains an important indicator.

If a PNET were actively generating hormones that were causing symptoms, that would be an important factor. However, among the 108 VHL patients with solid lesions suggestive of PNETs in the NIH study he has not found a single functional PNET. If anyone out there, anywhere in the world, has a functional pancreatic tumor that is generating hormones and causing symptoms, Dr. Libutti wants to see you. Seriously.

They looked at gender to see if there was any correlation. The solid PNETs were evenly divided among men and women.

They also examined the DNA. They found a higher correlation of dangerous PNETs among people who have an alteration in Exon 3 of the VHL gene. The VHL gene has three distinct parts, called Exons. Each family has a particular mutation, like a misspelling of one word in the book of instructions that make up the VHL protein. That family mutation is passed intact from parent to child, so each family member has the same alteration in their VHL gene. People with a mutation in Exon 3 seem to have a more aggressive type of pancreatic tumor.

They also looked for signs of aggressive behavior. To measure aggressiveness, they took a series of images and compared the size of the largest tumor in each of these scans, then calculated its rate of growth, or “doubling rate”. If the tumor doubled in size in less than 500 days, it was deemed to be high risk. If it took longer than 500 days for the tumor to double, it was at a more moderate risk level.

In the past, recommendations for when to operate have been based entirely on size. But now, with the addition of these new measures, he has divided tumors into three categories – low risk tumors can be watched every 2-3 years; medium risk tumors should be followed more closely, and high-risk tumors should be evaluated for surgery. (see Figure 1)

High risk - evaluate for surgery	Medium risk - follow until a second criterion is present	Low risk - follow every 2-3 years
Size >= 3 cm Mutation in exon 3	Size 2-3 cm. Mutation in exon 1 or 2	Size < 2 cm. Mutation in exon 1 or 2
Doubling in <500 days
Figure 1: Assessing the risk level of a pancreatic neuroendocrine tumor - preliminary findings, June 2007

Dr. Libutti is looking for more people with pancreatic tumors to help validate his findings. He encourages anyone with a hard tumor of the pancreas to apply to be part of the NCI study. The person to call is Geoff Seidel, his clinical research nurse, at Tel: 301-496-5049; Fax: 301-402-1788.

As printed in the VHL Family Forum 15:3, September 2007. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.