Families with Pancreatic Cancer
Who Is At Risk? | History & Physical Examination
Family History | Surveillance | Treatment | Outcomes
As physicians and patients become more aware of the importance of hereditary cancer syndromes, more patients are surfacing who have multiple family members with pancreatic cancer. Pancreatic cancer is clearly hereditary in at least 10% of cases; the risk of pancreatic cancer is increased 3-fold if one first-degree relative is affected. Having multiple affected members increases the risk even more, so that some family members have a 50-50 chance of inheriting pancreatic cancer. How will we provide cancer surveillance for these people who have family members who developed the disease?
Surveillance strategies are now unfolding. The goal of surveillance is to identify affected patients before they develop invasive cancer but after dysplasia or pre-cancer has developed. Timing is crucial for determining when a patient warrants surgery, if performed too early the patient is put at risk for the morbidity and mortality of a total pancreatectomy, including death and brittle diabetes1. The alternative of diagnosing too late leads to a patient with pancreatic cancer.
Currently there are a few published studies examining the best modalities to evaluate patients at increased risk for pancreatic cancer: one from our experience at the University of Washington and one from John’s Hopkins. These reports include patients from multiple familial pancreatic cancer kindreds. Use of endoscopic ultrasound (EUS) can be helpful for detecting early treatable cancer and precancer in high risk patients (patients with a strong family history of pancreatic cancer). Of note, however, is the fact that a small percentage of normal patients and patients who drink moderate to large amounts of alcohol can also have EUS changes in the pancreas. Thus, while EUS can be valuable for the early detection of cancer and pre-cancer in very high risk individuals, the results from the study need to be interpreted by an expert and evaluated in light of the patient's history of alcohol use.
Who Is At Risk?
Although there are no clear studies to define who warrants surveillance, at this time it may be possible to obtain guidance from experience with other familial GI cancer syndromes. The following patients are at increased risk and should be considered candidates for surveillance: a) an individual who has 2 or more first degree relatives (parent, sibling, or child) with pancreatic cancer, b) an individual with one first degree relative diagnosed with pancreatic cancer under the age of 50, c) an individual with 2 or more relatives with pancreatic cancer, one of whom has pancreatic cancer at an early age, and d) a person with a genetic disorder that predisposes to pancreatic cancer, such as Peutz-Jeghers syndrome or Familial Atypical Mole and Melanoma syndrome.
History & Physical Examination
The first job in evaluating such patients is to obtain as many clues from the history and physical as possible. Some patients have a history of loose stools or a history of adult-onset diabetes. Other common presenting symptoms can include upper abdominal pain radiating through to the back, malabsorption, and/or weight loss. Occasionally patients will have lower abdominal pain; this symptom coupled with diarrhea may lead to evaluation of their colon rather than their pancreas. Symptoms of the patient can be compared with symptoms of other affected family members. Many patients will have a positive family history but have no symptoms at all.
The next place to delve for valuable information is from the history of affected family members. Sometimes these family members may have died, but relatives, especially spouses, can be invaluable repositories of information. The following key questions should be addressed. What were the presenting symptoms of the affected family members? What was the duration of symptoms before the affected member was diagnosed? What are the ages of affected family members at the time of diagnosis? Is there any suggestion of hereditary pancreatitis (chronic relapsing abdominal pain/diarrhea often extending in to childhood)? Is there a history of diabetes in the family? Are there any other cancers in the family (especially melanoma, GI cancers, breast and ovarian cancers)? Is the patient an Ashkenazi Jew? By assessing these questions, one can determine whether the pancreatic cancer develops in the context of specific hereditary cancer syndromes such as Hereditary Non-polyposis Colon Cancer (GI cancers, breast and ovarian cancers) or due to specific tumor suppressor genes, such as BRCA2 (breast and ovarian cancers; Ashkenazi Jews) and p16 (melanoma). In addition, the diagnosis of Hereditary Pancreatitis can be considered and genetic testing performed.
Most importantly one should try to get a feeling for the pace and character of the disease in a particular family and determine the timing and tempo of surveillance. For example, some pancreatic cancer families will present with diabetes or diarrhea that may precede cancer by years or decades, while other families develop cancer abruptly, with no warning signs. Some families will develop cancer at a late age, while others at an early age.
Imaging modalities of the pancreas include endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreatography (ERCP) and spiral CT. The first two tests appear to be quite useful, while the latter appears to be ineffective for surveillance. The endoscopic ultrasound findings can be subtle and require an experienced endoscopic ultrasonographer to interpret. The same abnormal EUS findings that are present in familial pancreatic cancer patients can also be seen in patients with chronic pancreatitis.
The next step in the work-up is to perform an ERCP (an examination of the pancreatic duct). Because of the risk of inducing pancreatitis, ERCP should be reserved for those patients who are symptomatic or have abnormal changes present at EUS. While some of the ERCP changes seen in association with histologic dysplasia are similar to those seen with chronic pancreatitis (main duct stricture), other features are often present that are unusual. These features include focal side branch duct irregularities, small sacculations, and grape-like clusters of saccules. It is essential to evaluate the endoscopic findings in the context of the patient’s symptoms and familial history.
In cases where the EUS is abnormal and the ERCP is normal, we generally repeat the EUS every 6-12 months based on the degree of abnormality at EUS and whether the patient is symptomatic or not. Patients who appear to be progressing symptomatically or on EUS (increase or extension of echogenic foci or nodules, and/or development of discrete masses) would require another ERCP.
The last step in the work-up is a spiral CT scan. Our experience with other patients with pancreatic precancer has indicated that the CT scan of pancreas is usually normal in appearance. The role of pancreatic biopsy performed at CT, endoscopy, or EUS has not been studied.
The goal for management of these patients is to diagnose them prior to the development of cancer, when they have precancer or dysplasia, and to perform a complete pancreatectomy. Timing is of vital importance for determining when a patient warrants surgery; if the patient is diagnosed too late, he or she dies of pancreatic cancer. It is vital to know the histologic diagnosis of the patient before considering major surgical options. High risk patients who have an abnormal endoscopic ultrasound and abnormal pancreatic ducts on ERCP, may warrant a tissue diagnosis to confirm that precancerous changes are present in the pancreas. This can be done by using a laparoscope to obtain a sample of the pancreas for histologic evaluation. If carcinoma-in-situ is present (also called PanIN III or high grade dysplasia) a consideration for total pancreatectomy is discussed with the patient. If performed too early, the patient is put through a major operation and he or she will be diabetic. At the operation, the entire pancreas is removed because the precancerous changes can involve the whole organ--any pancreas that is left behind can potentially develop cancer.
We have now cared for 75 patients who have a strong family history of pancreatic cancer. Fifteen patients have undergone pancreatectomy because of abnormal findings at endoscopic ultrasound and ERCP and because they have evidence of precancer in a tissue sample of the pancreas. All of these patients had precancerous changes throughout the pancreas on histology. Most patients have done fairly well after surgery; all patients have developed diabetes that requires insulin injections and monitoring of blood glucose. Patients must also take enzyme tablets when they eat, so that their food is digested. None of the patients who underwent pancreatectomy, or has been followed using the surveillance program, has developed pancreatic cancer. An essential ingredient to a good patient outcome is a team approach to these patients, using experienced gastroenterologists, surgeons, and pathologists who have expertise and interest in pancreatic disease.