International Cancer of the Pancreas Screening
(CAPS) Consortium summit on the management
of patients with increased risk for familial pancreatic
Marcia Irene Canto,1Femme Harinck,2Ralph H Hruban,3George Johan Offerhaus,4
Jan-Werner Poley,2Ihab Kamel,5Yung Nio,6Richard S Schulick,7Claudio Bassi,8
Irma Kluijt,9Michael J Levy,10Amitabh Chak,11Paul Fockens,12Michael Goggins,1
Marco Bruno,2on behalf of the International Cancer of the Pancreas Screening (CAPS)
▸ Additional data (Appendix)
are published online only. To
view these files please visit the
journal online (http://dx.doi.org/
For numbered affiliations see
end of article
Dr Marcia Irene Canto, Division
of Gastroenterology, Johns
Hopkins University, The Sol
Goldman Pancreatic Cancer
Research Center, 1830 E
Monument Street, Room 427,
Baltimore, MD 21205, USA;
Received 19 June 2012
Accepted 17 September 2012
Published Online First
7 November 2012
Background Screening individuals at increased risk for
pancreatic cancer (PC) detects early, potentially curable,
Objective To develop consortium statements on
screening, surveillance and management of high-risk
individuals with an inherited predisposition to PC.
Methods A 49-expert multidisciplinary international
consortium met to discuss pancreatic screening and vote
on statements. Consensus was considered reached if
≥75% agreed or disagreed.
Results There was excellent agreement that, to be
successful, a screening programme should detect and
treat T1N0M0 margin-negative PC and high-grade
dysplastic precursor lesions (pancreatic intraepithelial
neoplasia and intraductal papillary mucinous neoplasm). It
was agreed that the following were candidates for
screening: first-degree relatives (FDRs) of patients with
PC from a familial PC kindred with at least two affected
FDRs; patients with Peutz–Jeghers syndrome; and p16,
BRCA2 and hereditary non-polyposis colorectal cancer
(HNPCC) mutation carriers with ≥1 affected FDR.
Consensus was not reached for the age to initiate
screening or stop surveillance. It was agreed that initial
screening should include endoscopic ultrasonography
(EUS) and/or MRI/magnetic resonance
cholangiopancreatography not CT or endoscopic
retrograde cholangiopancreatography. There was no
consensus on the need for EUS fine-needle aspiration to
evaluate cysts. There was disagreement on optimal
screening modalities and intervals for follow-up imaging.
When surgery is recommended it should be performed at
a high-volume centre. There was great disagreement as
to which screening abnormalities were of sufficient
concern to for surgery to be recommended.
Conclusions Screening is recommended for high-risk
individuals, but more evidence is needed, particularly for
how to manage patients with detected lesions.
Screening and subsequent management should take
place at high-volume centres with multidisciplinary
teams, preferably within research protocols.
Pancreatic ductal adenocarcinoma (PC) is a deadly
disease. It remains the fourth most common cause
of death from cancer in the USA1and one of the
deadliest cancers in the world. Although treat-
ments have improved, average PC 5-year survival is
<5%. Because pancreatic neoplasia detected early
is potentially curable, there is interest in pancreatic
screening. Because of the low incidence of PC in
the general population, population-based screening
has not been recommended.
Selective screening of individuals at increased risk
for PC (high-risk individuals (HRIs)) based on their
family history or identifiable genetic predisposition is
considered worthwhile. Over the past decade, centres
in the USA and Europe initiated pancreatic screening
programmes. Single-2–10and multicentre8 11cohort
studies have evaluated the diagnostic yield of screen-
ing (detection of asymptomatic precursor lesions
and PCs at baseline and follow-up) using different
imaging modalities and study populations (table 1).
AIMS AND METHODS
Scope and purpose
The International Cancer of the Pancreas Screening
(CAPS) Consortium was formed in 2010 to help
organise global pancreatic screening. After prior
formulation of key topics for discussion, the CAPS
Consortium held a multidisciplinary consensus
conference. The statements developed at this con-
ference provide recommendations related to the
following questions: (1) Who should be screened?
(2) How should HRIs be screened and followed
up? (3) When should surgery be performed?
(4) What are the goals of screening and what
outcome should be considered a success?
Bruno) selected an international multidisciplinary
group of 50 experts from 10 countries in four con-
tinents representing the fields of epidemiology,
surgery and pathology. Participant selection was
based upon expertise, publications and participa-
tion in ongoing PC screening and surveillance pro-
scientists, nurses and genetic counsellors from
community-based practices, academic institutions
and cancer centres.
chairs (Professors Cantoand
Scan to access more
Gut 2013;62:339–347. doi:10.1136/gutjnl-2012-303108 339
The international CAPS Consortium held a 2-day conference in
February 2011, in Baltimore, Maryland, USA. A comprehensive
literature search was performed and relevant publications were
reviewed by conference chairs and representative experts. At
the meeting, experts outlined the current state of the field.
Thereafter, workgroups comprising geneticists/epidemiologists,
gastroenterologists, radiologists, surgeons and pathologists met
to discuss topics relevant to each specialty. Multidisciplinary
groups met in breakout sessions to formulate concise state-
ments for voting (see table 1, online Appendix). Gaps in knowl-
edge and areas of disagreement and agreement were also
identified and specifically discussed. The statements were pre-
sented after plenary and workgroup discussions, and anonym-
ous voting was performed using touchpad technology at the
end of the meeting.
The resulting 100 consensus statements were reviewed and
refined after the meeting and then voted on by 49 of 50 partici-
pants by anonymous electronic survey. Participants voted on mul-
tiple choice questions on a five-point scale (eg, a=definitely agree,
b=moderately agree, c=neutral, d=moderately disagree, e=defin-
itely disagree) or five-item selection list. A statement was accepted
if ≥75% of the participants voted ‘agree’ or ‘disagree’. Statements
that did not reach consensus are listed separately (Appendix 1).
The Appraisal of Guidelines Research and Evaluation process for
assessment of quality of evidence and strength of recommenda-
tions12 13was used to determine if the available literature was suffi-
cient to make and grade recommendations. Evidence was graded
based upon study design (randomised controlled trial=high, obser-
vational study=low, any other evidence=very low), study quality,
consistency and directness of evidence.12The grade of evidence
was modified if there was strong evidence of association (relative
risk (RR)>2) (eg, consistent evidence from multiple observational
studies, or evidence of a dose–response gradient).12The strength of
the group’s recommendation statement was based upon Grading
of Recommendations Assessment, Development and Evaluation
(GRADE) definitions for quality improvement and guidelines
development12 14: 1 (strong)= ‘definitely do it’, 2 (weak)=‘prob-
ably do it’, 3 (no recommendation), 4 (weak)= ‘probably don’t do
it’ and 5 (strong)= ‘definitely don’t do it’.
Each statement includes its grade of evidence, the voting
results (table 2) and a brief discussion.
Who should be screened?
Since the incidence of PC in the general population is low (life-
time risk 1.3%), screening is not recommended for the general
population, but instead for individuals considered to be at high
risk of developing the disease (ie, >5% lifetime risk, or fivefold
increased RR). The main tool used to quantify PC risk is still
the family history; risk stratification is determined from the
number of affected family members and the relationships
among at-risk individuals.15
family’s underlying genetic susceptibility, but it has a limited
role because the genetic basis of much of the inherited suscepti-
bility to PC remains unexplained. Additional PC susceptibility
genes may be discovered in the near future that should improve
our ability to identify individuals who would benefit most
from pancreatic screening.
Gene testing can identify a
Patients with a family history of PC
Individuals with three or more blood relatives with PC, with at
least one affected first-degree relative (FDR,) should be consid-
ered for screening (agree 91.9%, grade moderate, ‘probably do
it’). Those with at least two affected FDRs should be considered
for screening (agree 91.9%, grade moderate, ‘probably do it’).
Individuals with two affected blood relatives with PC, with at
least one FDR, should be considered for screening (agree 77.5%,
grade low, ‘probably do it’).
These recommendations for screening are primarily based on
evidence of increased risk, rather than a proven efficacy of
screening. Prospective studies demonstrate an increased risk
of developing PC in unaffected FDRs that depends on the
number of relatives with PC.16This risk has been estimated to
be 6.4-fold greater in individuals with two FDRs with PC (life-
time risk 8–12%17) and 32-fold greater in individuals with three
or more FDRs with PC (lifetime risk 40%17). Among kindreds
with familial PC, risk is higher in kindreds with a young-onset
PC (age<50 years, RR=9.3)compared with kindreds
Summary of diagnostic yield of familial pancreatic cancer screening and surveillance programmes
High-risk group Imaging testsDiagnostic yield*n (%)
Brentnall 1999 (1) n=14
Kimmey 2002 n=46‡
Canto 2004 (2) n=38
Canto 2006 (3) n=78
Poley 2009 (4) n=44
Langer 2009 (5) n=76
Verna 2010 (6) n=51
Ludwig 2011 n=109
Vasen 2011 (7) n=79
Al-Sukhni 2011 (8) n=262
Schneider 2011 (9)** n=72
Canto 2012 (10) n=216
FPC, BRCA, PJS, p16, p53, HP
FPC, BRCA, p16
FPC, BRCA, PJS, p16, HP
FPC, BRCA, PALB2
FPC, BRCA, PJS
EUS; ERCP§, EUS-FNA§, CT§
EUS; CT§,EUS-FNA§, ERCP§
EUS and/or MRCP
MRCP; EUS§, EUS-FNA§
MRI; CT§, EUS§, ERCP§
CT, MRI/MRCP , EUS; ERCP§
5/216 (2.3)†–92/216 (43)
*Yield is defined as the detection of any pathologically proven (pre)malignant lesion (≥PanIN-2/IPMN and pancreatic adenocarcinoma) and lesions that are morphologically suspicious for
†Includes only pathologically proven pancreatic neoplasms (histology or cytology).
‡Continuation of Brentnall 1999, included 14 high-risk individuals from Brentnall 1999.
§Test performed only as an additional test for detected abnormalities.
¶Includes baseline and follow-up.
**Continuation of Langer 2009, includes high-risk individuals from this series.
ERCP , endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography; FNA, fine-needle aspiration; FPC, familial pancreatic cancer; IPMN, intraductal papillary
mucinous neoplasm; MRCP , magnetic resonance cholangiopancreatography; PJS, Peutz–Jeghers syndrome; PanIN, pancreatic intraepithelial neoplasia.
340 Gut 2013;62:339–347. doi:10.1136/gutjnl-2012-303108
without.18No consensus was reached on whether to screen
individuals without an affected FDR, including individuals
with a young-onset PC relative, or patients with new-onset
Germline mutations in the BRCA2, PALB2, p16, STK11, ATM,
PRSS1 genes and the hereditary colon cancer (Lynch syndrome)
genes, are associated with significantly increased risk of PC.19
Mutations in these genes explain only ∼10% of the familial
susceptibility to PC. Individuals with PC susceptibility gene
mutations may not have many affected family members.
Patients with apparently sporadic pancreatic cancer can have
mutations in BRCA2, as can those without a family history of
breast, ovarian cancer.20Incomplete or low penetrance is a
common feature of familial PC susceptibility gene mutations.
Patients with Peutz–Jeghers syndrome, regardless of family
history, should be considered for screening (agree 96%, grade
moderate, ‘do it’).
Patients with Peutz–Jeghers syndrome (who generally carry
germline STK11 gene mutations) have a very high (132-fold21)
Table 2 Summary of consensus statements for the management of high risk individuals
Who should be screened?
Individuals with three or more affected blood relatives, with at least one affected FDR, should be considered for screening.
Individuals with at least two affected FDRs with PC, with at least one affected FDR, should be considered for screening once they reach a certain age.
Individuals with two or more affected blood relatives with PC, with at least one affected FDR, should be considered for screening.
All patients with Peutz–Jeghers syndrome should be screened, regardless of family history of PC.
p16 carriers with one affected FDR should be considered for screening.
BRCA2 mutation carriers with one affected FDR should be considered for screening.
BRCA2 mutation carriers with two affected family members (no FDR) with PC should be considered for screening.
PALB2 mutation carriers with one affected FDR should be considered for screening.
Mismatch repair gene mutation carriers (Lynch syndrome) with one affected FDR should be considered for screening.
How should high-risk individuals be screened?
Initial screening should include (multiple answers allowed):
EUS 83.7%, MRI/MRCP 73.5%, CT 26.5%, abdominal ultrasound 14.3%, ERCP 2.0%.
When previous screening did not detect an abnormality that met criteria for shortening of the interval or surgical resection, follow-up screening should include (multiple
answers allowed): EUS 79.6% MRI/MRCP 69.4%, CT 22.4%, abdominal ultrasound 4.1%, ERCP 2.0%.
Standardised nomenclature should be used to define chronic pancreatitis-like abnormalities.
Whenever a cystic lesion is detected, an additional ERCP should not be performed.
Patients with a cystic lesion without worrisome features for malignancy should have an imaging test after 6–12 months.
When a solid lesion is detected, CT should also be performed.
When a solid lesion is detected, ERCP should not be performed.
When a solid lesion is detected at baseline with an indeterminate diagnosis and the patient is not referred for immediate surgery, imaging should be repeated after
When a new solid lesion is detected at follow-up with an indeterminate diagnosis and the patient is not referred for immediate surgery, imaging should be repeated after
If an indeterminate main pancreatic duct stricture without a mass is detected, repeat imaging should be performed within 3 months.
When should surgery be performed?
Screening should only be offered to individuals who are candidates for surgery.
Pancreatic resections should be performed at specialty centres (taking into account volume, morbidity and mortality rates and expertise available).
Intraoperatively, further pancreatectomy (up to a possible total) should be performed in patients with otherwise reasonable life expectancy to achieve R0 resection of
Intraoperatively, further pancreatectomy (up to a possible total) should not be performed in a patient with otherwise reasonable life expectancy and no cancer but with
unifocal PanIN-2 in the resected specimen but not at the margin.
Postoperatively, further pancreatectomy (up to a possible total) should be not performed in patients with otherwise reasonable life expectancy in a patient without cancer
in the resected specimen but with PanIN-2 at margin.
Postoperatively, further pancreatectomy (up to possible total) should be not be performed in patients with otherwise reasonable life expectancy in a patient who did not
have cancer but had unifocal PanIN-2 in the resected specimens but not at the margin.
Postoperatively, further pancreatectomy (up to a possible total) should be not performed in patients with otherwise reasonable life expectancy in a patient without cancer
but who has multifocal PanIN-2 in the resected specimens but not at the margin.
What are the goals of screening? What outcome(s) would be considered a ‘success’?
Resectable carcinoma is a potential target for early detection and treatment.
PanINs are a potential target for early detection and treatment.
IPMNs are a potential target for early detection and treatment.
Detection and treatment of multifocal PanIN-3 should be considered a success of a screening/surveillance programme.
Detection and treatment of IPMNs with high-grade dysplasia should be considered a success of a screening/surveillance programme.
Detection and treatment of invasive cancer-T1N0M0 detected at baseline should be considered a success of a screening programme.
Treatment of invasive cancer-T1N0M0 detected at follow-up should be considered a success of a screening programme.
Detection and treatment of invasive cancer >T1N0M0 resectable with margins negative at baseline, should be considered a success of a screening programme.
ERCP , endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography; FDR, first-degree relative; IPMN, intraductal papillary mucinous neoplasm; MRCP , magnetic
resonance cholangiopancreatography; PC, pancreatic cancer; PanIN, pancreatic intraepithelial neoplasia.
Gut 2013;62:339–347. doi:10.1136/gutjnl-2012-303108341
risk of PC. Lifetime cumulative risk to age 65–70 for PC in
patients with Peutz–Jeghers syndrome is 11–36%.22
BRCA2 mutation carriers with one or more affected FDR with
PC (agree 85.7%, grade low, ‘probably do it’) and those with two
or more affected family members (even without a FDR) (agree
89.8%, grade low, ‘probably do it’) should be considered for
Germline BRCA2 gene mutations account for the highest per-
centage of known causes of inherited PC. These have been
identified in 5–17% of familial PC kindreds.23–25The RR of PC
in BRCA2 gene mutation carriers is 3.5 (95% CI 1.87 to
history of PC should be considered for genetic counselling and
testing for the founder BRCA2 gene mutation, 6174delT ,
present in 1% of Ashkenazi Jewish individuals28and 4% of
patients with PC.29It has not been established that the risk of
PC in BRCA1 gene mutation carriers is increased. One cohort
study found a modest increased risk of pancreatic cancer
(RR=2.3).30No agreement was reached on the question of
screening BRCA2 mutation carriers with no family history of
PC (agree 51.1%), or for BRCA1 mutation carriers with one
affected FDR or two affective relatives but no FDR (agree
27Individuals with Jewish ancestry and a family
PALB2 mutation carriers with one or more affected FDR with
PC should be screened (agree 77.5%, grade very low, ‘probably do
PALB2 (partner and localiser of BRCA2) was recently identi-
fied as a PC susceptibility gene.31Germline mutations have
been detected in up to 3% of patients with familial PC.31–35
The magnitude of PC risk in PALB2 mutation carriers has not
been established. However, given the function of the PALB2
gene, the risk of PC among PALB2 gene mutation carriers is
estimated to be similar to that found for BRCA2 gene mutation
p16 mutation carriers with one or more affected FDR with PC
should be considered for screening. (agree 87.8%, grade low,
‘probably do it’).
Germline p16 gene mutations are found in families with
familial atypical multiple mole melanoma syndrome (FAMMM
syndrome), an autosomal dominant disease with variable pene-
trance. PC risk among p16 gene mutation carriers is estimated
to be increased 13- to 22-fold, compared with the general popu-
Patients with Lynch syndrome and one affected FDR with PC
should be considered for screening. (agree 87.5%, grade low,
‘probably do it’).
Patients with mismatch repair gene (MLH1, MSH2, MSH6,
PMS2) gene mutations (Lynch syndrome) have an estimated
lifetime risk of 3.7% of developing PC (8.6-fold higher
risk).39 40Patients with PC having histology characteristic of
mismatch repair-deficient cancers (‘medullary’ histology)41
should have their pedigree evaluated for possible hereditary
non-polyposis colorectal cancer.
The estimated lifetime risk of PC in individuals with heredi-
tary pancreatitis is high (about 40%).42Many of these indivi-
duals have germline PRSS1 gene mutations. This PC risk is
directly related to the duration of recurrent pancreatitis and
chronic inflammation.43Screening of PRSS1 mutation carriers
with longstanding chronic pancreatitis is being performed
but itis controversial
whether healthy siblings with a PRSS1 mutation should also
At what age should screening begin and end?
There was disagreement about the age to initiate screening in
HRIs (Appendix). For individuals with familial PC, the average
age at diagnosis is 68.18Fifty-one per cent voted to recommend
starting screening at age 50. In contrast, screening typically
begins at age 40 in PRSS1 mutation carriers with hereditary
pancreatitis owing to younger age of onset of PC.45Smokers
with a family history of PC have a greater risk of developing
PC than non-smokers,18but there was no consensus as to
whether to recommend initiating screening at an earlier age for
current smokers (Appendix). There was also no consensus rec-
ommendation about the age to end screening for HRIs without
pancreatic lesions (Appendix).
How should high-risk individuals be screened?
Published screening studies have employed different screening
tests. Direct interpretation of screening modalities is limited by
differences in study populations, and reported diagnostic yields
have ranged between 1.3% and 50%, depending on whether
resected neoplasmsor pancreatic
(table 1).2 4 6–9 34 46 47Of 1040 HRIs screened, to date only 70
(6.7%)hada pancreatic lesion
resected.2 4 6–9 34 46 47Small cysts (branch-duct intraductal pap-
illary mucinous neoplasms or BD-IPMNs) are the most
common abnormality detected (in 34% and 53% of HRIs aged
50–59 and 60–69, respectively11). Solid masses are rarely
detected (20 of 70 resected were pancreatic ductal adenocarcin-
omas.2 4 6–9 34 46 47The number of incident PCs detected in
published studies is likely to be unreported (only four were
cohort studies, all with limited follow-up), but eight of 20
(40%) of the PCs diagnosed in screened HRIs were not detected
at baseline screening.
lesions were tabulated
or suspected neoplasm
Initial screening should include (multiple answers allowed):
endoscopic ultrasonography (EUS) (agree 83.7%, grade moderate,
‘do it’), MRI/magnetic resonance cholangiopancreatography
(MRCP) (agree 73.5%, grade moderate, ‘do it’), CT (26.5%),
abdominal ultrasound (14.3%), endoscopic retrograde cholangio-
pancreatography (ERCP) (2%).
EUS and MRI are considered the most accurate tools for pan-
creatic imaging and do not involve ionising radiation. Few
studies have compared the diagnostic yield of imaging tests for
HRIs in screening, and most comparisons have not been per-
formed in a blinded, randomised fashion. The prospective
CAPS3 study (published after the CAPS summit) performed
blinded comparisons of standardised pancreatic-protocol CT ,
secretin-enhanced MRI/MRCP and EUS for one-time screen-
ing.11It showed that EUS and MRI are better than CT for the
detection of small, predominantly cystic, pancreatic lesions,
with good to excellent concordance of lesion number, size and
location between EUS and MRI/MRCP. EUS, MRI/MRCP and
CT identified pancreatic lesions in 42.6%, 33.3% and 11% of
screened HRIs, respectively.11MRCP provided the best visual-
isation of cyst communication with the main pancreatic duct.
Incorrect diagnosis of lesions identified by EUS and/or MRI
is a significant concern, particularly in the screening process.
Some cysts are found at resection to be benign serous cystade-
nomas, while other resected pancreata have only low-grade
pancreatic intraepithelial neoplasia (PanIN) associated with
lobulocentric parenchymal atrophy.4–7 34These results high-
light the risk of overtreatment using available screening tests.
342Gut 2013;62:339–347. doi:10.1136/gutjnl-2012-303108
The risk of overtreatment for pancreatic screening is magnified
by the risks of morbidity and mortality (∼1–2%) of pancreatic
surgery. The risk of incorrect diagnosis is particularly true for
EUS, an operator-dependent test with only modest interobser-
There was excellent agreement that radiation exposure and
the suboptimal detection rate preclude CT from being a routine
pancreatic screening test.2
ERCP were also not recommended for screening, owing to their
1146Abdominal ultrasound and
ERCP should be performed as an additional test if a solid lesion
(disagree 77.5%, grade high, ‘don’t do it’) or cystic lesion (dis-
agree 77.5%, grade moderate, ‘don’t do it’) is detected. When a
solid lesion is detected, CT should be performed (agree 75.5%,
grade, low, ‘do it’).
When ERCP was performed routinely for abnormal EUS
results, it did not improve diagnostic yield and was associated
with a 7% pancreatitis rate.4
No consensus was reached on the role of EUS-guided fine-
needle aspiration (FNA) to evaluate solid or cystic lesions in
asymptomatic HRIs (Appendix). The role of EUS-FNA in the
clinical management of most pancreatic cysts is limited, given
the low accuracy of cytology in cystic lesions,49 50and the low
volume of cyst fluid aspirated from small cysts. False-positive
cytology from subcentimetre solid indeterminate lesions may
also lead to unnecessary surgery.5 9
Multidetector pancreatic-protocol CT was recommended for
evaluation of solid lesions identified by EUS or MRI. The level
of evidence that supports this agreement is low.
For routine follow-up, the best imaging test is (multiple answers
allowed): EUS (79.6%), MRI/MRCP (69.4%), CT (22.4%),
abdominal ultrasound (4.1%), ERCP (2%).
How should surveillance be performed after baseline screening?
Published studies have generally used the same imaging tests
for follow-up as for baseline imaging. There was no consensus
reached on the ideal screening interval in the absence of pancre-
atic abnormalities at baseline, but 73.5% of participants sug-
gested a 12-month interval. There is only indirect and limited
evidence to support this recommendation. The vast majority of
individuals in whom a clinically relevant lesion developed
during follow-up had pancreatic abnormalities at baseline.4 9
Furthermore, HRIs who presented with an advanced pancreatic
malignancy after prior normal or indeterminate imaging were
diagnosed ≥12 months later.2 9
Patients with a non-suspicious cyst should have an imaging test
after 6–12 months (agree 83.7%, grade moderate, ‘do it’).
Patients with a newly detected indeterminate solid lesion should
have follow-up screening at 3 months, if surgery is not immi-
nent (agree 85.7%, grade low, ‘do it’). If an indeterminate main
pancreatic duct stricture is detected, repeat imaging should be
performed within 3 months (agree 95.9%, grade low, ‘do it’).
Cystic branch-duct lesions (presumed BD-IPMNs) without
re-evaluated at intervals depending on size, similar to accepted
international consensus guidelines for sporadic BD-IPMNs.51
The majority of such BD-IPMNs remained stable during
follow-up.2 6 7 9 34
Small (<1 cm diameter) lesions identified as solid by EUS are
difficult to manage, particularly when not detected by MRI or
CT . These lesions can be aspirated but the yield for these
lesions is low. Some indeterminate solid lesions identified only
by EUS are cancers, but they can be benign lesions, such as
non-metastatic pancreatic neuroendocrine tumours2 4 11or low-
grade PanIN with focal associated lobulocentric parenchymal
atrophy.5There was no consensus reached on the need for add-
itional tests such as CT , ERCP, FNA, or timing of repeat
imaging (although 73.5% suggested 3 months) to evaluate
these lesions (Appendix).
Long-term follow-up of PC screening cohorts is lacking,
(maximum follow-up period; 10 years,9 34mean follow-up time
of 49to 4.2 years2). Importantly, the group acknowledged that
until there are additional studies we will not know if screening
HRIs saves lives.
When should surgery be performed? What type of surgery should
Screening should only be offered to individuals who are candi-
dates for surgery (agree 75.5%, grade moderate, ‘do it’).
Pancreatic resections should be performed at high-volume spe-
cialty centres (agree 100%, grade moderate, ‘do it’). Determining
when surgery is required for pancreatic lesions is difficult and is
best individualised after multidisciplinary assessment, preferably
within research studies.
There is little consensus about which lesions detected by
screening require surgery. The few published reports are based
on limited numbers of patients.52 53Because of the risks of
pancreatectomy, prophylactic surgery is not recommended for
asymptomatic HRIs without an identifiable lesion. When indi-
cated, pancreatic surgery is best performed at a high-volume
specialty centre. Multiple studies have shown volume directly
correlates with outcomes.54 55
Unambiguous solid lesions (≥1 cm, or seen by multiple
imaging modalities) are ominous and the threshold for remov-
ing them is much lower. There was no consensus as to whether
any indeterminate solid lesions detected by EUS should be
The majority of cystic lesions detected by screening appear
to be low-risk branch-duct IPMNs (table 1). The Sendai inter-
national consensus guidelines
updated56to help stratify patients with an IPMN as low risk
versus high risk for either developing or currently harbouring a
malignancy.51In subjects with suspected BD-IPMNs, resection
is considered if the patient has symptoms attributable to the
cyst(s), if the cysts are >3 cm in size, or if the cysts contain
mural nodules. Logic would dictate that if these are the recom-
mendations for subjects without a strong family history of PC,
then these thresholds for resection should be either the same or
lower in subjects with a strong family history. There was no
consensus on the size criterion for resection of suspected
BD-IPMNs or other cysts in HRIs but the majority agreed that
surgery should be considered for suspected BD-IPMNs which
were ≥2 cm (Appendix). Pathologically confirmed PanIN-3
lesions have been found in the pancreata of individuals who
had resections of IPMNs smaller than 1 cm.5 11High-grade dys-
plasia and main-duct involvement have been identified at resec-
tion of some individuals who had surgery for one or more
small (<3 cm) BD-IPMNs.4 5 11 34However, there is insuffi-
cient evidence to lower the threshold criteria for surgery for
patients with lesions identified during pancreatic screening.
Gut 2013;62:339–347. doi:10.1136/gutjnl-2012-303108 343
Management of patients with resected lesions was discussed,
particularly how the preliminary and final pathology results,
including margin status, should influence operative treatment.
Intraoperatively, further pancreatectomy (including total pan-
createctomy) should generally be performed to achieve R0 resec-
tion of cancer (agree 75.5%, grade low, ‘do it’). Intraoperatively,
further pancreatectomy (including total pancreatectomy) should
not be performed on patients with only unifocal PanIN-2 in the
resected specimen, (agree 77.6%, grade low, ‘don’t do it’). The
presence of PanIN-3 at the margin should be dealt with in con-
sideration of the overall medical condition and life expectancy of
the patient. The presence of PanIN-2, low-grade IPMN or
intermediate-grade IPMN (on either frozen or permanent sec-
tions) at the margin or in the resection specimen should not
drive further resection.
In patients undergoing surgery for invasive PC, complete
resection of the cancer is recommended. If only PanIN is at the
margin, it is considered unlikely that resection of additional
parenchyma would be beneficial, even if the PanIN is high
grade.57Importantly, it is difficult to grade PanIN in intraopera-
tive frozen sections.
Postoperatively, further resection of the pancreas to remove
PanIN-2 at the margin should be performed in high-risk patients
withoutPC (disagree 79.5%,
Postoperatively, further resection of the pancreas should be per-
formed because unifocal PanIN-2 (disagree 81.6%, grade low,
‘don’t do it’) or multifocal PanIN-2 (disagree 77.5%, grade low,
‘don’t do it’) was found anywhere in the resected specimen.
Multiple scenarios for consideration of further pancreatec-
tomy after R0 resection of cancer did not reach consensus
agreement, including management of PanIN-3 at the margin
(Appendix). PanIN-3 at the resection margin in non-familial
patients treated for PC does not significantly affect the post-
operative course.57However, follow-up imaging was recom-
mended less than 6 months after surgery if there was any
PanIN-3 in the resected pancreas of individuals without PC.
What are the goals of screening? What outcome(s) would be
considered a ‘success’?
Screening HRIs can be considered successful if it can be shown
that the benefits outweigh the costs of screening. The goal of
screening is the reduction of pancreatic cancer-related mortality.
Evidence for success is best provided by large randomised con-
trolled trials in which the outcomes of subjects who undergo
surveillance are compared with appropriate controls, as has
been demonstrated for colonoscopy screening.58However, given
the relatively low incidence of familial PC, such trials are diffi-
cult to undertake. Surrogate end points that define the success
of pancreatic screening are therefore needed. Pathological
staging is critical and a standard protocol for handling pancre-
atic resection specimens is recommended (Appendix). The fol-
lowing questions (What are the goals of screening? What
outcome(s) would be considered a success?) were designed to
define surrogate end points of screening, such as resection of
potentially curable lesions (high-grade precursor neoplasms and
early invasive carcinomas), as these lesions, if left untreated,
can progress to incurable and lethal disease.
One target for early detection and treatment is resectable carcin-
oma (agree 83.7%, grade high, ‘do it’). Detection and treatment
of early invasive cancer (T1N0M0) (agree 89.8%, grade high, ‘do
it’) at baseline or follow-up (agree 77.5%, grade moderate, ‘do it’)
should be considered a success. Detection and treatment of any
invasive resectable PC at baseline screening should also be
considered a success of the screening programme (agree 89.8%,
grade high, ‘do it’).
Long-term survival can be achieved by resecting small non-
metastatic PCs,59 60particularly if margins are negative for
invasive PC (R0 resection).57 61However, most patients who
undergo an R0 resection of their pancreatic cancer will die from
their disease. Survival is most likely for patients with the smal-
lest cancers (T1N0M0). A critical statistic which screening and
surveillance programmes should track is the number of high-
risk patients that need to be screened and treated,62which con-
siders the likelihood that treatment will prevent the target
event of PC at the expense of adverse events. In one prospective
screening study of high-risk Leiden p16 mutation carriers using
MRI/MRCP, nine invasive pancreatic PCs were detected and
treated in 79 patients followed up for a median of 4 years. The
number of patients needed to be screened to detect and treat
one PC was 11.9
Well-differentiated neuroendocrine tumours (PanNETs) have
been detected within familial PC screening programmes.2 4 11
PanNETs <0.5 cm (microadenomas) are essentially benign
lesions. Resection of PanNETs between 0.5 and 1.0 cm is gener-
ally curative.63There was no consensus as to whether detecting
and treating PanNETs should be considered a success of screen-
One potential target for early detection is PanIN (agree 81.7%,
grade high, ‘do it’). Detecting and treating multifocal PanIN-3
should be considered a success (agree 83.7%, grade moderate, ‘do
it’). Whether to detect and treat unifocal PanIN-3 did not reach
consensus (agree 73.5%)
The strength of the evidence linking sporadic PanIN-3 lesions
to invasive carcinoma is based on clinical associations and
genetic analyses.64–66Similarly, strong evidence supports the
hypothesis that some of the invasive PCs that arise in patients
with a family history of pancreatic cancer arise from PanIN
lesions.67 68Although PanINs are a well-accepted precursor of
sporadic and familial PC, the frequency and rate at which
PanINs progress to invasive carcinoma is not known. In a non-
familial population, it is estimated that the average adult pan-
creas has five PanINs and that 0.86% of these progress to inva-
sive cancer.69It may take a decade or more for an early
precursor cell (a low-grade PanIN) to progress to PC, and initial
estimates suggest that the first invasive cancer cell may take
several years to extend beyond the pancreas or metastasize.
Importantly, the ‘window’ for clinical detection of an invasive
PC is shorter since these lesions are only detected once they
reach a certain size.70These estimates may not apply to
patients with a strong family history of PC, especially those
with specific genetic mutations that may increase the rate at
which precursor lesions progress.
Another target for early detection and treatment is IPMN (agree
87.7%, evidence high, ‘do it’). Detection and treatment of IPMN
with high-grade dysplasia should be considered a success of a
screening/surveillance programme (agree 95.9%, evidence high,
IPMNs, particularly IPMNs with high-grade dysplasia, are
associated with a significantly increased risk of invasive
PC.67 68 71 72The IPMN phenotype has been described in famil-
ial PC relatives and gene mutation carriers.73The frequency
and rate at which IPMNs in HRIs progress to invasive PC are
not well known. In patients with apparently sporadic non-
invasive IPMNs it may take 3–5 years for a clinically detectable
non-invasive lesion toprogressto aninvasivePC.74
344 Gut 2013;62:339–347. doi:10.1136/gutjnl-2012-303108
Furthermore, in patients with small BD-IPMN(s) followed up
over 5 years, only 2.4–6.9% of these lesions progressed to inva-
sive PC.75 76
Important areas where there was lack of consensus: areas for
Topics that did not reach consensus voting are listed in the
Appendix. Additional evidence is required to more accurately
answer important questions, such as who to screen, when to
begin screening and the frequency of screening. Some of the
important gaps in knowledge pertain to the optimal age at
which to begin screening, the role of as yet unidentified PC sus-
ceptibility genes as a guide to optimising screening and how to
incorporate environmental risk factors such as smoking, dia-
betes, obesity and other exposures into risk stratification.
The CAPS summit recommended prioritising research into
areas where there was lack of consensus: diagnostic evaluation
and management of cystic and solid lesions detected by screen-
ing and postoperative management. Importantly, the group
recommends collaborative multicentre institutional review
board-approved studies to collect data on demographics, family
history, risk factors, and to bank tissue, juice, aspirated fluid
and blood to improve biomarker prediction of the risk of pro-
gression to PC in HRIs. Ultimately, research into how to
improve screening methods, the outcomes of screening and sur-
veillance for PC and the cost-effectiveness of alternative
approaches, is of the highest priority.
Screening studies have identified pancreatic neoplasms in
asymptomatic patients with strong family histories of PC.
However, available evidence supporting screening and surveil-
lance is limited to observational studies. The diagnostic yield
from pancreatic screening depends on many factors, including
the extent of an individual’s family history, the age at which
screening begins and the screening modality used. Screening
may also lead to the discovery of incidental or indeterminate
lesions, resulting in diagnostic confusion and uncertain man-
agement. There is a clear need to improve approaches to screen-
ing of HRIs. The management of asymptomatic pancreatic
lesions detected by imaging tests remains the most challenging
aspect of screening and surveillance programmes. Individualised
decision-making within multidisciplinary programmes and pro-
spective research studies is essential. The findings of this work-
group should standardise current efforts and serve as a
platform for the development of future multidisciplinary
1Department of Medicine (Gastroenterology), Johns Hopkins Medical Institutions,
Baltimore, Maryland, USA
2Department of Gastroenterology, Erasmus MC, University Medical Center,
Rotterdam, The Netherlands
3Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland,
4Department of Pathology, University Medical Center, Utrecht, The Netherlands
5Department of Radiology, Johns Hopkins Medical Institutions, Baltimore, Maryland,
6Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands
7Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland,
8Department of Surgery, University of Verona, Verona, Italy
9Department of Oncology, Academic Medical Center, Amsterdam, The Netherlands
10Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA
11Division of Gastroenterology, University Hospitals of Cleveland, Cleveland Ohio, USA
12Department of Gastroenterology, Academic Medical Center, Amsterdam,
Acknowledgements We thank Sandy Markowitz for her assistance in the
organisation and coordination of the CAPS Summit.
Collaborators CAPS International Consortium Summit participants: Paolo Giorgio
Arcidiacono (Milan, Italy), Detlef Bartsch (Marburg, Germany), Katharina Biermann
(Rotterdam, The Netherlands), Terri Brentnall (Washington, USA), Amitabh Chak
(Ohio, USA), Petr Dite (Brno, Czech Republic), Timothy Donahue (California, USA),
Dayna Early (Missouri, USA), James Farrell (California, USA), Carlos Fernandez-Del
Castillo (Massachusetts, USA), Harold Frucht (New York, USA), Noriyoshi Fukushima
(Tochigi, Japan), Jenny Geurts (Wisconsin, USA), Pascal Hamell (Clichy, France), Julio
Iglesias-Garcia (Santiago de Compostela, Spain), Alison Klein (Maryland, USA),
Guenter Kloeppel (Munich, Germany), Jesse Lachter (Haifa, Israel), Peter Langer
(Marburg, Germany), Jeffrey Lee (Texas, USA), Michael Levy (Minnesota, USA),
Hiroyuki Maguchi (Sapporo, Japan), Daniel Margolis (Los Angeles, USA), Takao
Ohtsuka (Fukuoka, Japan), Sara Olson (New York, NY), Gloria Petersen (Minnesota,
USA), Thomas Savides (California, USA), Sapna Syngal (Massachusetts, USA), Eric
Tamm (Texas, USA), Masao Tanaka (Fukuoka, Japan), Hans Vasen (Leiden, The
Netherlands), Anja Wagner (Erasmus, The Netherlands), Huamin Wang (Texas, USA),
David Williams (Sydney, Australia), Kenjii Yamao (Nagoya, Japan).
Contributors MIC—was the project principal investigator, helped obtain funding and
supervised the overall conduct of the conference; developed the conference concept
and programme, served as gastroenterology workgroup leader, assisted with the
acquisition, analysis and interpretation of data, drafting and critical revision of the
manuscript. FH—constructed the online survey, assisted with the acquisition of data,
analysis and interpretation of data and drafting and critical revision of the manuscript.
RHH—assisted with obtaining grant support, assisted with the conference concept
and programme, served as pathology workgroup leader and helped with the drafting
and critical revision of the manuscript. GJO—served as pathology workgroup leader
and participated in the drafting of the manuscript. J-WP—assisted with the
development of the conference concept and programme, served as gastroenterology
workgroup leader and helped with the drafting and critical revision of the manuscript.
PF— served as gastroenterology workgroup leader and helped with the drafting of
the manuscript. IK—assisted with the conference concept and design, assisted with
presentation of scientific evidence, served as radiology workgroup leader and helped
with the drafting of the manuscript. YN— served as radiology workgroup leader and
helped with the drafting of the manuscript. RSS—assisted with the conference
concept and design, assisted with presentation of scientific evidence, served as
surgery workgroup leader and helped with the drafting and critical revision of the
manuscript. CB—served as surgery workgroup leader and helped with the drafting
and revision of the manuscript. IKl—assisted with the study concept and design,
assisted with acquisition of data, served as genetics/epidemiology workgroup leader
and helped with the drafting and revision of the manuscript. MJL—helped with the
drafting and critical revision of the manuscript. AC—helped with drafting and critical
revision of the manuscript. MG—assisted with obtaining grant and material support,
assisted with the study concept and design, served as genetics/epidemiology
workgroup leader, assisted with acquisition of data and helped with the drafting and
critical revision of the manuscript. MB—served as co-director of the conference,
helped obtain funding and supervised the overall conduct of the conference; helped
develop the conference concept and programme, assisted with the interpretation of
data and helped with the drafting and critical revision of the manuscript.
Funding European Association for Gastroenterology, Endoscopy and Nutrition
(EAGEN), Olympus Corporation, Myriad Corporation, John and Peter Hooven
Endowment and The Sol Goldman Pancreatic Cancer Research Center. Role of funding
sources: All sponsors had no role in planning the content or conduct of the
conference, analysis of the results and preparation of the manuscript.
Competing interests RHH and MG receive royalty payments from Myriad Genetics.
MB is council member and treasurer of EAGEN. All other coauthors have no relevant
competing interests or financial disclosures.
Provenance and peer review Not commissioned; externally peer reviewed.
Open Access This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits
others to distribute, remix, adapt, build upon this work non-commercially, and license
their derivative works on different terms, provided the original work is properly cited
and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/
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