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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 the only published studies examining the best modalities
to evaluate patients at increased risk for pancreatic cancer is from
our experience at the University of Washington. This initial report
included 25 patients from multiple familial pancreatic cancer kindreds.
Seven of these 25 patients were recommended for and underwent
pancreatectomy based on the studies outlined below; all seven had
evidence of dysplasia (precancer) without invasive carcinoma.
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 with pancreatic cancer b) an
individual with one first degree relative diagnosed with
pancreatic cancer at an early age (for example, under the age of 50)
c) an individual with > 2 degree relatives with family members, one of
whom has pancreatic cancer at an early age.
The History and 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.
Family History
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.
Surveillance
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.
Treatment
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. If performed to 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. Before taking the whole pancreas out, we like 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, some time before planning pancreatectomy.
Outcome
Histologic evaluation of the pancreas from the patients who have
now undergone total pancreatectomy revealed that all of the patients
who had a positive family history, an abnormal EUS and an abnormal
ERCP and underwent total pancreatectomy--all had precancerous changes
throughout the pancreas on histology. Most patient 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 gastroenterologists, surgeons, and
pathologists who have expertise and interest in pancreatic disease.
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