October 2008, Vol. 15, No.

4 280 Cancer Control

Tumor Program, Moffitt Cancer Center, 12902 Magnolia Drive,
WCB-GIPROG, Tampa, FL 33612. E-mail: jason.klapman@moffitt.org
Abbreviations used in this paper: EUS = endoscopic ultrasound,
FNA = fine-needle aspiration.
Early Detection of Pancreatic Cancer:
Why, Who, and How to Screen
Jason Klapman, MD, and Mokenge P. Malafa, MD
Background: Pancreatic cancer represents the fourth-leading cause of cancer death in the United States, with
a dismal 5-year survival rate of less than 5%. Despite advancements in screening and early detection of other
cancers such as breast and colon cancer, no reliable screening test exists for pancreatic cancer. Subsequently,
the majority of patients present with advanced-stage disease leading to a poor prognosis. Because of the
relatively low incidence, current efforts are focused on early detection and screening only in patients at high
risk for the development of the disease.
Methods: We discuss the practical considerations encountered when determining if an individual should be
screened for pancreatic cancer. The current literature was reviewed regarding risk factors, genetic syndromes,
screening modalities, and screening studies of pancreatic cancer. The current high-risk pancreatic screening
program at our institute is also summarized.
Results: Current efforts to detect pancreatic cancer at a curative phase are focused on screening individuals
at high risk for the development of this disease. They include kindreds with two or more first-degree relatives
affected with this disease and those with known hereditary pancreatic cancer syndromes. Hereditary pancreatic
cancer syndromes include Peutz-Jeghers syndrome, familial breast cancer syndrome, and familial atypical
multiple mole melanoma syndrome. Of all the screening modalities available, endoscopic ultrasound is the
most sensitive and specific screening tool to evaluate the pancreas and has been proven to detect early
precancerous and cancerous changes in clinical studies.
Conclusions: Early detection and screening for pancreatic cancer in the current state should be limited to
high-risk patients, although hereditary/familial factors account for only 10% of patients with pancreatic cancer.
Continued efforts are needed to discover effective test to identify patients with nonhereditary risk factors who
will benefit from screening and also to develop less invasive and more cost-effective screening modalities aimed
at controlling pancreatic cancer.
Risk factors, genetic syndromes,
screening modalities, and
screening studies of
pancreatic cancer are reviewed.
Sofa Cceres. El Reptil y la Fruta (The Reptile and the Fruit). Mixed media on canvas, 30 46.
From the Gastrointestinal Tumor Program at the H. Lee Moffitt
Cancer Center & Research Institute, Tampa, Florida.
Submitted January 17, 2008; accepted March 26, 2008.
Address correspondence to Jason Klapman, MD, Gastrointestinal
October 2008, Vol. 15, No. 4 Cancer Control 281
Introduction
The American Cancer Society estimates that 37,680
Americans will be diagnosed with cancer of the pan-
creas during 2008.
1
An estimated 34,290 Americans
will die of pancreatic cancer in 2008, making this type
of cancer the fourth-leading cause of cancer death over-
all.
1
Approximately 75% of patients will die within 1
year of diagnosis, and only about 4% will survive 5 years
after diagnosis.
1
Even for patients diagnosed early who
undergo a curative resection, the 5-year relative survival
rate is < 20%.
1
A critical factor in the poor outcome is
due to the silent nature of pancreatic cancer until late
in the disease process. Patients present for a medical
evaluation only when the cancer is advanced and they
experience signs and symptoms of obstructive jaun-
dice, abdominal pain, and weight loss. Clearly, early
detection is an important strategy to improve out-
comes. The most practical issues regarding early detec-
tion that need to be considered include identifying
who should be screened and selecting the most appro-
priate modality to use for screening. Screening pro-
grams for pancreatic cancer need to be conducted in
the context of carefully designed studies to determine
if screening for early pancreatic neoplasia and timely
interventions results in decreased pancreatic cancer
incidence and mortality. Furthermore, molecular analy-
sis of tissue specimens and carefully collected epidemi-
ologic data may shed light and lead to the discovery of
less invasive and more widely applicable methods to
detect this highly lethal disease early. Table 1 summa-
rizes the principles of a successful screening program
and also outlines how the pancreatic cancer screening
program at our institute satisfies these principles.
Screening: Targeting Individuals at
High Risk
The ideal goal of screening for pancreatic cancer is to
detect the disease at an early phase (preinvasive or
early invasive) when it is curable. It is well established
that pancreatic adenocarcinoma arises from pancreatic
ductal cells and progresses through precursor lesions.
The three known precursor lesions are pancreatic
intraductal neoplasia, intraductal pancreatic mucinous
neoplasm, and mucinous cystic neoplasm (Fig 1). The
grading scheme reflects increasing atypia until eventu-
ally it leads to carcinoma. Since patients seldom exhib-
it disease-specific symptoms at the early phase of the
disease, screening needs to be done in asymptomatic
individuals. However, given the low incidence and
prevalence of pancreatic cancer, it would not be cost
effective or worthwhile to screen the general popula-
tion since the yield of screening would be extremely
low. For screening to be cost effective, a recent study
estimated that the probability of detecting preinvasive
or invasive disease needs to be 16% or greater.
2
There-
fore, screening should be targeted to individuals at high
risk for developing pancreatic cancer in order to enrich
the screening population.
Risk Factors
Several risk factors have been identified that increase
an individuals risk of developing pancreatic cancer.
Table 2 summarizes these factors and the relative risk
for developing pancreatic cancer if present in the
patients medical history.
Familial Pancreatic Cancer
Familial pancreatic cancer is defined as a clinical setting
in which a family has at least 2 first-degree relatives
affected with pancreatic cancer without accumulation
of other cancers or familial diseases. It is estimated that
up to 10% of pancreatic cancers may have a familial
component.
3,4
Population-based studies have shown
that almost 8% of patients with pancreatic cancer have
a family history of pancreatic cancer.
5
Based on data
from the National Familial Pancreatic Tumor Registry
(NFPTR), the risk of developing pancreatic cancer in
relatives of families with at least 2 affected first-degree
relatives was 18-fold higher than that of sporadic cases.
Kindreds with 3 affected first-degree relatives had a 57-
fold risk increase of developing pancreatic cancer.
6
Hereditary Pancreatic Cancer Syndromes
Certain germline mutations are known to give rise to
hereditary pancreatic cancer syndromes including
BRCA2,
7-10
p16,
11,12
STK11/LKB1,
13,14
and PRSS1.
15
Principles Moffitts Pancreas Screening Program
Reasonable yield is expected Estimated yield is 10%
The most sensitive/specific screening tool is used EUS is the most sensitive specific screening tool to evaluate the pancreas
Screening is voluntary Participation is voluntary
Results are appropriately interpreted Screening procedure is performed by an expert endoscopist
Supportive care is offered Psychosocial support and genetic counseling are offered to participants
Screening improves survival Early detection and treatment of pancreatic neoplasia improves survival
Benefits of screening outweigh risks Potential early detection of pancreatic neoplasia in an asymptomatic high-risk individual
outweighs the minimal risk of the procedure to the patient
Table 1. Principles of a Successful Screening Program
October 2008, Vol. 15, No. 4 282 Cancer Control
BRCA2: BRCA2 is a key regulator of gene transcrip-
tion. Mutation in this gene results in hereditary breast
and ovarian cancer syndromes. Over the last 10 years it
has been noted that some families with BRCA2 mutations
have a high incidence of pancreatic cancer. Recent stud-
ies have shown that BRCA2 is present in 17% to 19% of
families where at least 2 first-degree relatives have pan-
creatic cancer.
7,9
People of Ashkenazi Jewish descent
who carry a BRCA2 mutation are also at increased risk of
developing pancreatic cancer. In this patient group, can-
cer is attributable to the BRCA2 6174delT mutation in 1
of 10 patients who develop pancreatic cancer.
16
Familial Atypical Multiple Mole Melanoma
Syndrome: Familial atypical multiple mole melanoma
(FAMMM) is an autosomal dominant inherited syn-
drome characterized by multiple nevi, atypical nevi,
and multiple melanomas. Recent reports note that the
p16 mutation associated with FAMMM is responsible
for the increased risk of pancreatic cancer among
affected individuals with a lifetime risk of 16%.
11,12
Peutz-Jeghers Syndrome: Peutz-Jeghers syn-
drome is an autosomal dominant syndrome character-
ized by hamartomatous gastrointestinal polyps and
mucocutaneous pigmentation. The germline mutation
that accounts for this syndrome is the STK11/LKB1
gene. Patients with known Peutz-Jeghers syndrome
have a relative risk of 132 and a cumulative lifetime risk
of 36% for ages 15 to 64 for the development of pan-
creatic cancer.
13,14
Hereditary Pancreatitis: Hereditary pancreati-
tis is inherited as an autosomal dominant trait, with 60%
of cases attributed to the PRSS1 mutation. There is a
high incidence of pancreatic cancer 30 to 40 years after
the age of onset of recurrent attacks of pancreatitis.
17
Pancreatic cancer risk is 50 times higher in patients
with hereditary pancreatitis, with an estimated lifetime
risk of pancreatic cancer of 40% by 70 years of age.
15
The risk is double in patients with hereditary pancre-
atitis who smoke, and it is diagnosed 20 years earlier
than in patients who do not smoke. Patients with non-
hereditary chronic pancreatitis also have an increased
risk of developing pancreatic cancer regardless of the
cause of pancreatitis, and the total risk increases with a
longer history of chronic pancreatitis.
18
Cigarette Smoking
Cigarette smoking is associated with 25% of pancreatic
cancers.
19,20
Patients who are long-time smokers (ie,
Fig 1. Pathways of pancreatic adenocarcinoma progression. The three known precursor lesions are pancreatic intraductal neoplasia (PanIN), mucinous
cystic neoplasm (MCN), and intraductal pancreatic mucinous neoplasm (IPMN).
Normal duct PanIN Ia PanIN Ib PanIN II PanIN III
MCN low grade
Cancer
Normal duct
IPMN low grade
Intermediate grade High grade
Risk Factor Relative Risk
Familial pancreatic cancer:
2 first-degree relatives affected 18
3 first-degree relatives affected 57
Hereditary pancreatic cancer syndromes:
BRCA2 mutation 5.9
Familial atypical multiple mole melanoma 16
Peutz-Jeghers Syndrome 36
Hereditary pancreatitis 50
Cigarette smoking:
Positive family history of pancreatic cancer 3.7
Diabetes > 20 years 2
Table 2. Risk Factors and Relative Risk for
Developing Pancreatic Cancer
October 2008, Vol. 15, No. 4 Cancer Control 283
more than 20 years) have double the risk of developing
pancreatic cancer than patients who never smoked.
19,20
In those with a family history of pancreatic cancer,
smoking has even a greater effect; they have up to a
3.7-fold increase of developing pancreatic cancer and
may present with the disease one to two decades earli-
er.
21-23
Smoking also increases the risk for pancreatic
cancer in individuals with hereditary pancreatitis by 2-
fold,
23
as noted above.
Long-Standing Diabetes
Patients who have been diagnosed with adult-onset dia-
betes have a 2-fold increase in the risk of pancreatic
cancer.
24
Whether this is a consequence of the disease
or an independent risk factor is unclear. Given the high
prevalence of long-standing diabetes in the general
population and the low incidence of pancreatic cancer,
screening patients with diabetes is likely to produce a
low yield and will not be cost effective.
Common Imaging Modalities for
Suspicion of Pancreatic Cancer
Despite advancements in technology and better capa-
bility in screening for many cancers, no ideal single
screening test exists for pancreatic cancer. Although a
variety of tumor markers have been proposed for the
diagnosis and surveillance of pancreatic cancer, includ-
ing CEA and CA19-9, none has been proven to be high-
ly sensitive or specific to pancreatic cancer and there-
fore is not ideally suited for screening. Imaging studies
are useful to diagnose pancreatic cancer once the
tumor is large enough to cause symptoms, but at this
point the disease is more likely to be at an advanced
and unresectable stage. When pancreatic cancer is sus-
pected, the most common imaging modalities include
transcutaneous ultrasound (TCUS), computed tomogra-
phy (CT) scan, magnetic resonance imaging (MRI), and
most recently endoscopic ultrasound (EUS).
EUS vs Other Imaging Modalities
Of all the imaging studies, EUS and helical CT scans are
the most sensitive imaging modalities for detecting pan-
creatic tumors and should be considered as the first
imaging studies when there is a clinical suspicion of pan-
creatic cancer.
25
When comparing all the modalities
available to screen patients for pancreatic cancer, EUS
should be the modality of choice due to its ability to per-
form fine-needle aspiration (FNA). When evaluating
patients with suspected pancreatic cancer, EUS has been
shown to be superior as a diagnostic modality in sensi-
tivity, specificity, and accuracy compared with other stag-
ing modalities including CT scan,TCUS, angiography, and
MRI.
26-30
This is especially true when evaluating and aspi-
rating tumors less than 2 cm in diameter.
31
Once a pancreatic mass is detected, the most com-
mon approaches to obtain a tissue diagnosis are by CT-
guided biopsy, by endoscopic retrograde cholangiopan-
creatography (ERCP) with brushings of an obstructed
bile duct/pancreatic duct if the mass is in the head of
the pancreas, or by EUS with FNA. When evaluating
pancreatic masses, EUS-guided FNA is the most accu-
rate diagnostic modality. Harewood and Wiersema
32
demonstrated this in 185 patients with pancreatic
masses and negative tissue sampling by ERCP or nega-
tive CT-guided FNA. EUS-guided FNA had a sensitivity
of 94% and accuracy of 92% for detecting malignant dis-
ease in patients with negative ERCP tissue sampling
and 90% sensitivity and 84% accuracy in patients with
negative CT-guided biopsy. The established superiority
of EUS in evaluating pancreatic masses led to exploring
its merit as a screening tool for patients at high-risk for
the development of pancreatic cancer.
EUS as a Screening Tool for Pancreatic Cancer
EUS was originally developed in the early 1980s as an
alternative diagnostic imaging modality to address the
inherent limitations of TCUS such as limited depth of
penetration and image interference from intra-abdomi-
nal gas and bony structures.
33
Initial ultrasound scopes
provided a 360 image but were unable to perform
biopsies. Over the last 20 years, technological advances
have broadened the field of endosonography. With the
development of linear array echoendoscopes and incor-
poration of FNA and color flow/Doppler data, the uti-
lization of EUS has evolved from a diagnostic tool to an
interventional procedure. EUS combines real-time
endoscopy with high-frequency ultrasound to detect
pancreatic abnormalities through the stomach and duo-
denum. The principles of EUS are based on the devel-
opment and interpretation of ultrasound waves. High-
frequency ultrasound waves are transmitted from the
transducer at the tip of the echoendoscope to the tar-
get tissue. For optimal imaging, a balloon surrounding
the transducer is inflated with water to improve ultra-
sound transmission (Fig 2). This process is known as
acoustic coupling. Images are constructed from the
reflective properties of the tissue components and uti-
lize real-time imaging techniques similar to a B-mode
Fig 2. High-frequency ultrasound waves are transmitted from the trans-
ducer at the tip of the echoendoscope to the target tissue. For optimal
imaging, a balloon surrounding the transducer is inflated with water to
improve ultrasound transmission.
October 2008, Vol. 15, No. 4 284 Cancer Control
(brightness modulation) display format. The brightness
is dependent on the amount reflected. Intensely reflect-
ed areas appear white (hyperechoic), while areas of low
reflection appear dark (hypoechoic). This allows for
high-resolution imaging of the five histologic layers of
the gastrointestinal wall and the surrounding structures,
including the pancreas. Given the minimal invasiveness
and low complication rate of the procedure, which are
similar to those of standard endoscopy for patients who
do not undergo FNA,
34
as well as an overall complica-
tion rate of 1.6% to 2%
35,36
when FNA is performed, EUS
and EUS-guided FNA have become attractive, highly
accurate, and safe procedures in the diagnosis and treat-
ment of many gastrointestinal diseases.
High-risk individual identified
Consent for pancreatic cancer screening protocol
Genetic counseling at Lifetime Cancer Screening and Prevention Center
(patients can decline)
Screening EUS
EUS-guided FNA Repeat EUS 1 year
Benign Indeterminate Positive
Pancreatic CT scan
Repeat EUS/FNA 6 months
Pancreatic CT scan
Repeat EUS/FNA 3 months
Pancreatic CT scan/CT chest
Resectable Unresectable
Referral for surgery Referral to oncology
New patients to Moffitt Cancer Center
Referrals from
patients/physicians
Normal EUS
Abnormal EUS (mass/cyst) No FNA (< 5 mm)
Total Cancer Care Consent (MCC#14690) /
Lifetime Database Consent (MCC#14453)
a. Risk factor questionnaire
b. Biospecimen collection
Moffitt Tumor Registry
Fig 3. Protocol for high-risk assessment, screening, and early detection of pancreatic cancer at Moffitt Cancer Center.
October 2008, Vol. 15, No. 4 Cancer Control 285
Experience With Screening Using EUS
In a pilot study by Canto et al,
37
screening was per-
formed on individuals determined to be at high-risk for
developing pancreatic cancer using an EUS-based
approach. Thirty-eight asymptomatic patients with at
least 2 first-degree relatives affected with pancreatic
cancer were studied over a 3-year period. Six pancre-
atic masses were found, one was an invasive adenocar-
cinoma and one was an intraductal papillary mucinous
tumor. The study concluded that screening an asymp-
tomatic high-risk patient population could detect
prevalent pancreatic neoplasia. A follow-up study by
Canto et al
38
evaluated screening for early pancreatic
neoplasia in high-risk individuals in a prospective, con-
trolled study. The study screened 78 patients deter-
mined to be high-risk for pancreatic cancer and found
8 patients with pancreatic neoplasia (10% yield of
screening). Four of the patients were diagnosed at the
initial screening examination, and 4 were diagnosed
within the first year of follow-up. Based on this study,
the authors concluded that screening of high-risk indi-
viduals is warranted due to the number of significant
asymptomatic pancreatic neoplastic lesions found in
this cohort of individuals.
Moffitt Cancer Center Screening Program
for Pancreatic Cancer
Based on these preliminary studies, some centers are
involved in clinical trials that are screening patients
deemed to be at high-risk for the development of pan-
creatic cancer based on family history of pancreatic
cancer or rare genetic syndromes that increase the risk
of pancreatic cancer. A program for screening patients
at high-risk for the development of pancreatic cancer
was recently established at our institute. This program,
which is based on using EUS as the screening proce-
dure, is conducted under an Institutional Review Board
(IRB) protocol (Fig 3).
Patient Recruitment
Eligible subjects for the program, as described in Table 3,
may be identified and recruited either from our institute
or from the Lifetime Cancer Screening and Prevention
Center located in Tampa, Florida, by completing the self-
reported risk factor questionnaire. Patients may also be
referred from physicians at our institute or from physi-
cians in the community or by patients themselves. Also,
eligible subjects who are enrolled in the Family Cancer
Genetics Network may be contacted regarding interest
in this study. Lastly, first-degree relatives of patients with
pancreatic cancer from our institutes tumor registry
may also be contacted to determine eligibility. These
potential high-risk individuals are then referred to deter-
mine eligibility.
Total Cancer Care Protocol/Lifetime Cancer
Screening Database for Cancer Risk Assessment
and Early Detection
Patients are asked to participate and consent to the IRB-
approved Moffitt Total Cancer Care protocol. The pur-
pose of the Total Cancer Care initiative is to improve
our ability to predict diagnosis, prognosis, and response
to therapy in the management of the cancer patient.
This study requires patient permission to store (for
long-term use) their blood and tissues and also clinical
data collected during their regular medical care and
during specific therapeutic trials. The goal of the study
is to establish a unique collection of blood, tissues (nor-
mal and tumor), and associated clinical data (survey
data, medical record data, and cancer registry data)
from thousands of cancer patients. The blood, tissue,
and clinical data will be used for a number of different
Eligibility Criteria
Correlation with one of the following high-risk groups:
Patient has 2 or more relatives with pancreatic cancer and has
a first-degree relationship with at least one of the relatives with
pancreatic cancer.
If only 2 family members are affected, then both must have
had pancreatic cancer and a first-degree relationship with the
individual screened.
If there are more than 2 affected individuals on the same
side of the family, at least 1 of the individuals must have a
first-degree relationship with the member being screened.
Patient is at least 40 years of age or 10 years younger than
the youngest affected individual.
Peutz-Jeghers syndrome patients age > 30 years
Hereditary pancreatitis patients
Patients with familial atypical multiple mole melanoma (FAMMM)
syndrome
Patients with BRCA2 mutation and at least 1 first- or second-degree
relative with documented pancreatic cancer
Willingness to undergo EUS with possible FNA
Willingness to undergo surgical evaluation for abnormal
EUS/FNA finding
Willingness to undergo radiographic evaluation if screening
findings are abnormal
Exclusion Criteria
Medical contraindications to undergoing endoscopy or obstruction of
the gastrointestinal tract that precludes passage of the endoscope
Personal history of pancreatic adenocarcinoma
Previous partial or complete resection of the pancreas for
adenocarcinoma
Prior partial or total gastrectomy with Billroth II or Roux-en-Y
anastomosis
Coexisting cancer in other organs or AIDS/HIV
Life expectancy < 5 years
Pregnancy
Previous CT scan or ultrasound of the abdomen within the last
3 years
Table 3. Eligibility and Exclusion Criteria for Screening
Patients at High Risk for Pancreatic Cancer
October 2008, Vol. 15, No. 4 286 Cancer Control
types of cancer research studies defined by future IRB-
approved studies.
Patients seen at the Lifetime Cancer Screening and
Prevention Center are asked to consent to the Lifetime
Database for Cancer Risk Assessment and Early Detec-
tion protocol. The purpose of this protocol is to estab-
lish a cohort of individuals with self-reported risk factor
information and biospecimens (serum, urine, and DNA)
using the patient population at the Lifetime Cancer
Screening and Prevention Center. The goal of the pro-
tocol is to obtain permission to use the data, biospeci-
mens, medical records, and questionnaires obtained
from this patient population for investigator-initiated
studies on etiology and/or early detection of cancer. In
addition, patients may be followed actively or passively
for subsequent cancer events, and they may be con-
tacted for participation in future clinical trials to reduce
their risk of cancer.
Genetic Counseling
Patients consented for the pancreatic cancer screening
study are offered genetic counseling through the Life-
time Cancer Screening and Prevention Center. A team
of professionals at the Center, including board-certified
clinical geneticists, genetic counselors, physicians and
nurse-practitioners, help formulate and develop a
screening and surveillance plan for those patients at
increased risk for cancer. Genetic counseling includes
a detailed review of the patients family history to deter-
mine if a cancer does indeed run in the family. Coun-
seling of the patient is conducted and a cancer-screen-
ing plan formulated. Genetic testing will be offered to
individuals when appropriate.
EUS Results
Once patients are consented for the screening protocol,
EUS is performed in the usual fashion. Patients are eval-
uated for changes in the pancreatic duct and pancreatic
parenchyma, and these abnormalities are documented in
the endoscopy report. If a mass or cyst is found during
the EUS examination, FNA is performed in the usual fash-
ion with the aid of a cytopathology technician in the
endoscopy suite to ensure adequacy of the specimen.
Patients with a normal EUS examination of the pan-
creas are placed in the surveillance arm of the protocol
and undergo yearly EUS examinations. A normal exam-
ination consists of complete evaluation of the pancreas
that reveals either a completely normal-appearing pan-
creas (Fig 4) or parenchymal changes defined by strict
EUS criteria but without the development of a mass or
cyst. If at any future EUS assessment a mass/cyst is
detected, FNA is performed and the patient follows that
arm of the protocol.
An abnormal EUS examination is defined as the
finding of a mass or cyst during evaluation that requires
FNA (Fig 5). If the lesion is too small to aspirate (< 5 mm),
patients are entered into surveillance with a repeat EUS
in 3 months. If during EUS examination a mass or cyst
is found that is large enough to undergo an FNA, an FNA
is performed. If the FNA results are consistent with
cancer, patients undergo standard-of-care workup and
staging of the cancer with radiology studies to deter-
mine resectability. If the tumor appears resectable, sur-
gical evaluation is performed with an expert pancreatic
surgeon who determines and weighs the patients risks,
benefits, and alternatives to pancreatic surgery that, at
our institute, has an operative mortality of less than 1%.
Fig 4. EUS examination of a normal pancreas.
Fig 5A-B. An abnormal EUS examination defined as the finding of a
mass (A) or cyst (B) during evaluation that requires FNA.
A
B
October 2008, Vol. 15, No. 4 Cancer Control 287
If the cancer is unresectable, patients are referred for
oncologic evaluation. If the FNA results are benign or
indeterminate, patients undergo a CT scan of the pan-
creas. If the CT scan is unrevealing in both cases,
patients who had a benign FNA will undergo a repeat
EUS with FNA in 6 months, while patients who had an
indeterminate FNA will undergo a repeat EUS with FNA
in 3 months. Depending on the results of the repeat
FNA, patients enter either the treatment arm or the sur-
veillance arm of the protocol. Patients with severe dys-
plasia or cancer who decline surgery or are unable to
undergo surgery are offered surveillance follow-up
with either CT scan or EUS in 3 to 6 months to assess
stability of the abnormality.
Conclusions
Screening high-risk individuals for pancreatic cancer is
the only practical approach to detect precancerous or
cancerous changes in the pancreas at the phase in
which surgical intervention will have a high chance of
cure. The limitations of the current screening strategy
include the fact that we can screen only about 10% of
individuals who will develop pancreatic cancer and
that an invasive procedure (EUS) is the best screening
modality. Screening protocols that are poised to exploit
molecular advances in oncology will likely yield in-
sights that will help identify a larger subset of patients
who will be at risk to develop pancreatic cancer and
will lead to the development of less invasive and effec-
tive screening modalities.
Disclosures
No significant relationship exists between the authors and the com-
panies/organizations whose products or services may be refer-
enced in this article.
References
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer
J Clin. 2008;58(2):71-96.
2. Rulyak SJ, Kimmey MB, Veenstra DL, et al. Cost effectiveness of
pancreatic cancer screening in familial pancreatic cancer kindreds. Gas-
trointest Endosc. 2003;57(1):23-29.
3. Brand RE, Lynch HT. Hereditary pancreatic adenocarcinoma. A clinical
perspective. Med Clin North Am. 2000;84(3):665-675.
4. Lynch HT, Smyrk T, Kern SE, et al. Familial pancreatic cancer: a review.
Semin Oncol. 1996;23(2):251-275.
5. Ghadirian P, Boyle P, Simard A, et al. Reported family aggregation of
pancreatic cancer within a population-based case-control study in the Fran-
cophone community in Montreal, Canada. Int J Pancreatol. 1991;10(3-4):
183-196.
6. Tersmette AC, Petersen GM, Offerhaus GJ, et al. Increased risk of
incident pancreatic cancer among first-degree relatives of patients with
familial pancreatic cancer. Clin Cancer Res. 2001;7(3):738-744.
7. Murphy KM, Brune KA, Griffin C, et al. Evaluation of candidate genes
MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: dele-
terious BRCA2 mutations in 17%. Cancer Res. 2002;62(13):3789-3793.
8. Lal G, Liu G, Schmocker B, et al. Inherited predisposition to pancre-
atic adenocarcinoma: role of family history and germ-line p16, BRCA1, and
BRCA2 mutations. Cancer Res. 2000;60(2):409-416.
9. Hahn SA, Greenhalf B, Ellis I, et al. BRCA2 germline mutations in
familial pancreatic carcinoma. J Natl Cancer Inst. 2003;95(3):214-221.
10. Goggins M, Schutte M, Lu J, et al. Germline BRCA2 gene mutations
in patients with apparently sporadic pancreatic carcinomas. Cancer Res.
1996;56(23):5360-5364.
11. Bartsch DK, Sina-Frey M, Lang S, et al. CDKN2A germline muta-
tions in familial pancreatic cancer. Ann Surg. 2002;236(6):730-737.
12. Vasen HF, Gruis NA, Frants RR, et al. Risk of developing pancreatic
cancer in families with familial atypical multiple mole melanoma associated
with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer. 2000;87(6):
809-811.
13. Gruber SB, Entius MM, Petersen GM, et al. Pathogenesis of adeno-
carcinoma in Peutz-Jeghers syndrome. Cancer Res. 1998;58(23):5267-5270.
14. Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of
cancer in familial Peutz-Jeghers syndrome. Gastroenterology. 2000;119(6):
1447-1453.
15. Lowenfels AB, Maisonneuve P, DiMagno EP, et al. Hereditary pan-
creatitis and the risk of pancreatic cancer. International Hereditary Pancre-
atitis Study Group. J Natl Cancer Inst. 1997;89(6):442-446.
16. Ozelik H, Schmocker B, Di Nicola N, et al. Germline BRCA2 617delT
mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet. 1997;
16(1):17-18.
17. Ulrich CD; Consensus Committees of the European Registry of
Hereditary Pancreatic Diseases, Midwest Multi-Center Pancreatic Study
Group, International Association of Pancreatology. Pancreatic cancer in
hereditary pancreatitis: consensus guidelines for prevention, screening and
treatment. Pancreatology. 2001;1(5):416-422.
18. Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis and the
risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J
Med. 1993;328(20):1433-1437.
19. Fuchs CS, Colditz GA, Stampfer MJ, et al. A prospective study of
cigarette smoking and the risk of pancreatic cancer. Arch Intern Med. 1996;
156(19):2255-2260.
20. Silverman DT, Dunn JA, Hoover RN, et al. Cigarette smoking and
pancreas cancer: a case-control study based on direct interviews. J Natl
Cancer Inst. 1994;86(20):1510-1516.
21. Rulyak SJ, Lowenfels AB, Maisonneuve P, et al. Risk factors for the
development of pancreatic cancer in familial pancreatic cancer kindreds.
Gastroenterology. 2003;124(5):1292-1299.
22. Klein AP, Brune KA, Petersen GM, et al. Prospective risk of pancre-
atic cancer in familial pancreatic cancer kindreds. Cancer Res. 2004;64(7):
2634-2638.
23. Lowenfels AB, Maisonneuve P, Whitcomb DC, et al. Cigarette smok-
ing as a risk factor for pancreatic cancer in patients with hereditary pancre-
atitis. JAMA. 2001;286(2):169-170.
24. Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreat-
ic cancer. A meta-analysis. JAMA. 1995;273(20):1605-1609.
25. Legmann P, Vignaux O, Dousset B, et al. Pancreatic tumors: com-
parison of dual-phase helical CT and endoscopic sonography. AJR Am J
Roentgenol. 1998;170(5):1315-1322.
26. Ahmad NA, Kochman ML, Lewis JD, et al. Endosonography is supe-
rior to angiography in the preoperative assessment of vascular involvement
among patients with pancreatic carcinoma. J Clin Gastroenterol. 2001;
32(1):54-58.
27. DeWitt J, Devereaux B, Chriswell M, et al. Comparison of endoscopic
ultrasonography and multidetector computed tomography for detecting and
staging pancreatic cancer. Ann Intern Med. 2004;141(10):753-763.
28. Kulig J, Popiela T, Zajac A, et al. The value of imaging techniques in
the staging of pancreatic cancer. Surg Endosc. 2005;19(3):361-365. Epub
2004 Dec 2.
29. Mertz HR, Sechopoulos P, Delbeke D, et al. EUS, PET, and CT scan-
ning for evaluation of pancreatic adenocarcinoma. Gastrointest Endosc.
2000;52(3):367-371.
30. Mller MF, Meyenberger C, Bertschinger P, et al. Pancreatic tumors:
evaluation with endoscopic US, CT, and MR imaging. Radiology. 1994;190(3):
745-751.
31. Rsch T, Lorenz R, Braig C, et al. Endoscopic ultrasound in small
pancreatic tumors [in German]. Z Gastroenterol. 1991;29(3):110-115.
32. Harewood GC, Wiersema MJ. Endosonography-guided fine needle
aspiration biopsy in the evaluation of pancreatic masses. Am J Gastroen-
terol. 2002;97(6):1386-1391.
33. DiMagno EP, Buxton JL, Regan PT, et al. Ultrasonic endoscope.
Lancet. 1980;1(8169):629-631.
34. Levy MJ, Norton ID, Wiersema MJ, et al. Prospective risk assessment
of bacteremia and other infectious complications in patients undergoing
EUS-guided FNA. Gastrointest Endosc. 2003;57(6):672-678.
35. Gress F, Michael H, Gelrud D, et al. EUS-guided fine-needle aspiration
of the pancreas: evaluation of pancreatitis as a complication. Gastrointest
Endosc. 2002;56(6):864-867.
36. Wiersema MJ, Vilmann P, Giovannini M, et al. Endosonography-
guided fine-needle aspiration biopsy: diagnostic accuracy and complication
assessment. Gastroenterology. 1997;112(4):1087-1095.
37. Canto MI, Goggins M, Yeo CJ, et al. Screening for pancreatic neo-
plasia in high-risk individuals: an EUS-based approach. Clin Gastroenterol
Hepatol. 2004;2(7):606-621.
38 Canto MI, Goggins M, Hruban RH, et al. Screening for early pancre-
atic neoplasia in high-risk individuals: a prospective controlled study. Clin
Gastroenterol Hepatol. 2006;4(6):766-781; quiz 665. Epub 2006 May 6.