Surgical Oncology 20 (2011) e109ee118

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Surgical Oncology
journal homepage: www.elsevier.com/locate/suronc

Review

Primary pancreatic cystic neoplasms revisited. Part III. Intraductal papillary

mucinous neoplasms
George H. Sakorafas a, *, Vasileios Smyrniotis a, Kaye M. Reid-Lombardo b, Michael G. Sarr b
a
4th Department of Surgery, Medical School, University of Athens, Attikon University Hospital, Arkadias 19-21, Athens 12462, Greece
b
Department of Surgery, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA

a r t i c l e i n f o a b s t r a c t

Article history: Intraductal papillary mucinous neoplasms (IPMNs) represent about 25% of all primary pancreatic cystic
Accepted 27 January 2011 neoplasms and are increasingly recognized during the last two decades. They are characterized by
intraductal proliferation of neoplastic mucinous cells forming papillary projections into the pancreatic
Keywords: ductal system, which is typically dilated and contains globules of mucus. IPMNs may be multifocal and
IPMN have malignant potential. Modern imaging is essential in establishing preoperative diagnosis and in
Surgery
differentiating different subtypes of IPMNs (i.e., main-duct vs. branch-type disease). Endoscopic retro-
Cystic neoplasms
grade or magnetic resonance cholangiopancreatography accurately delineate the morphologic changes of
Pancreas
Tumors
the pancreatic ductal system. Endoscopic ultrasonography (usually used in conjunction with image-
Pancreatectomy guided FNA and analysis of the aspirated material) is commonly used for differential diagnosis of IPMNs
from other pancreatic cystic lesions. Surgical resection (usually anatomic pancreatectomy, depending on
the location of the disease) is the treatment of choice. Total pancreatectomy may occasionally be required
in selected patients, but is associated with formidable long-term morbidity. A conservative approach has
recently been proposed for carefully selected patients with branch-duct IPMNs. Recurrences following
surgical resection can be observed, especially in patients with multifocal disease or in the presence of
underlying malignancy.
Ó 2011 Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e110
Pathology and biologic behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e110
Diagnostic evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e112
Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e112
Cross-sectional imaging (ultrasonography [US], computed tomography [CT], magnetic resonance imaging [MRI]) . . . . . . . . . . . . . . . . . . . . . . . . . e112
Endoscopic retrograde cholangiopancreatography (ERCP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e112
Magnetic resonance cholangiopancreatography (MRCP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e114
Positron emission tomography (PET) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e114
Intraductal pancreatoscopy and intraductal US . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e114
Endoscopic ultrasonography (EUS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e114
FNA cytology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e115
Analysis of cystic fluid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e115
Mucin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e115
CEA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e115

Abbreviations: CEA, carcinoembryonic antigen; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography;
FNA, fine needle aspiration; IPMN, intraductal papillary mucinous neoplasm; MCN, mucinous cystic neoplasm; MRCP, magnetic resonance cholangiopancreatography; MRI,
magnetic resonance imaging; PET, positron emission tomography; PPCN, primary pancreatic cystic neoplasm; SCN, serous cystic neoplasm; US, ultrasonography; WHO,
World Health Organization.
* Corresponding author. Tel.: þ30 210 74 87 318; fax: þ30 210 74 87 192.
E-mail addresses: georgesakorafas@yahoo.com (G.H. Sakorafas), vsmyrniotis@hotmail.com (V. Smyrniotis), reidlombardo.kaye@mayo.edu (K.M. Reid-Lombardo),
sarr.michael@mayo.edu (M.G. Sarr).

0960-7404/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.suronc.2011.01.004
e110 G.H. Sakorafas et al. / Surgical Oncology 20 (2011) e109ee118

Amylase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e115
Other tumor markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e115
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e115
Adjuvant/neoadjuvant therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e116
Prognosis and follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e116
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e117
Authorship statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e117
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e117

Introduction pancreatic duct by papillary neoplasm, but more commonly,

a duct dilated throughout the gland is due to the neoplasm
Intraductal papillary mucinous neoplasm (IPMN) was first involving the proximal duct and obstructing the entire duct
described formally as a unique entity by Ohashi et al. in Japan in mechanically by copious mucous secretion as well as intra-
1982, as a new type of cystic neoplasm of the pancreas, which they ductal tumor tissue..
termed mucinous secreting cancer of the pancreas [1]. Over the (b) Branch-duct IPMN, appearing as a cystic dilation of a side branch
ensuing decades, multiple terms have been used to describe this of the main pancreatic ductal system, communicating with the
type of primary pancreatic cystic neoplasm (PPCN). The term IPMN pancreatic ductal system, usually in the head or uncinate process
has now been accepted to better describe this specific type of PPCN of the pancreas. This pattern is often seen in asymptomatic,
[2]. IPMN was formally defined in 1996 by the World Health younger patients and causes the most diagnostic uncertainty
Organization (WHO) as an intraductal mucin-producing neoplasm [10e12]. On occasion, branch-duct IPMN may be multi-centric
with tall columnar, mucin-containing epithelium with or without and involve multiple non-contiguous side branches off the main
papillary projections, involving the main pancreatic duct and/or pancreatic duct, i.e. multi-centric branch-duct IPMN [13].
major side branches and lacking ovarian stroma characteristic of (c) Mixed type IPMN, involving both the main pancreatic duct and
mucinous cystic neoplasms [3]. the side branches. Each variation has important implications
IPMNs have been reported to represent about 25% of all cystic regarding the probability of underlying malignancy (carci-
neoplasms [2,4,5], but their true prevalence remains undefined; noma-in-situ or especially invasive malignancy), need for res-
indeed, as our technology allows us to image smaller and smaller ection, and the extent of resection required. The morphologic
cystic lesions, the prevalence of IPMN may very well increase. pattern of duct dilation is dependent on tumor location, mucous
IPMNs are a bit more common in men and are encountered typi- production, and the presence of ductal obstruction. Main-duct
cally in older patients (usually in the 6the7th decade of life) [2,5,6]. IPMNs tend to be larger with prominent intraductal, papillary
Most IPMNs arise in the pancreatic head, but IPMNs can be found in projections. Branch-duct IPMNs are frequently smaller, may not
any location and can occasionally involve the entire ductal system have a readily identifiable proliferative epithelial lining, and the
[5]. Unlike with MCN and SCN, multifocal disease can occur in communication with the main pancreatic duct may on occasion
IPMN. The aim of this review is to summarize critically the be difficult to visualize. There is considerable evidence that
currently available data regarding management of patients with branch-duct IPMN has a more indolent course compared to
IPMN. main-duct IPMN [5]. In about 30% of branch-duct IPMNs, the
disease is multifocal and is characterized by the presence of
Pathology and biologic behavior cystic dilation of small branches of the pancreatic ductal system
in two or more areas within the pancreatic parenchyma [14].
IPMNs are characterized by intraductal proliferation of neo- Interestingly, after resection of the area of pancreatic paren-
plastic mucinous cells which form micro- and macropapillae and chyma involvement branch-duct IPMN, in a substantial pro-
lead to cystic dilation of the main pancreatic duct and/or the portion of patients (up to 25%), histology shows concurrent
secondary branches (branch ducts) (Fig. 1). These dilated neoplastic histologic changes also within the main pancreatic duct;
ducts often contain globules of mucus forming detectable “masses”, therefore, in these cases, the correct diagnosis is IPMN of the
most commonly in the pancreatic head and usually in older men mixed type [14].
(>60 years old) [7]. The areas of dysplastia within the IPMN are
usually contiguous, but on occasion can be multifocal, especially According to the histologic classification by the WHO, IPMNs can
when involving the branch ducts. These neoplasms often produce be subdivided into the following three subgroups: (a) benign
copious mucin when they involve the main pancreatic duct. In (adenoma without dysplasia), (b) borderline (adenoma with mild to
about one third of patients (w30%), mucus can be seen exuding moderate dysplasia), and (c) carcinoma (either non-invasive or
from a bulging papilla of Vater at endoscopy when the main invasive) (Table 1) [15]. Note that this classification combines IPMN
pancreatic duct is involved. IPMNs are characterized by the specific with carcinoma-in-situ and invasive IPMN both as carcinomas;
lack of ovarian stroma, a finding which differentiates IPMN from therefore, when reading the literature, one must be careful to
a mucinous cystic neoplasm (MCN) [2,5,7]. remember this point because prognosis is much worse when inva-
Depending on the morphology of changes of the ductal system, sive disease is present. The hyperplastic or dysplastic epithelium in
IPMNs have been classified into the following three variations [1,8,9]: IPMN may be flat, micropapillary, or grossly papillary (Fig. 1) [2].
Frequently, a wide spectrum of changes of the epithelium is recog-
(a) Main-duct IPMN, characterized by involvement and dilation of nized, including normal, hyperplasia, dysplasia, and carcinoma,
the main pancreatic duct. Duct dilation may be either diffuse often within the same pancreas similar in principle to MCNs [7,14,16].
(generalized) or segmental (usually involving the body and tail Some investigators suggest that this histologic continuum implies
of the pancreas). A rare subtype of diffuse main pancreatic duct a “clonal expansion” within IPMN, just as like the “adenoma-carci-
ectasia is caused by complete filling of the dilated main noma” sequence of colorectal neoplasms and some pancreatic ductal
 G.H. Sakorafas et al. / Surgical Oncology 20 (2011) e109ee118 e111

Figure 1. Histopathology of IPMN. A) Ductal epithelium showing nondysplastic micropapillary mucinous hyperplasia (open arrow) and micropapillary dysplasia (solid arrow),
B) Gross papillomatous change associated with the micropapillary dysplasia change associated with flat micropapillary dysplasia (arrows), C) Invasive adenocarcinoma (arrows),
D) Gross findings of main pancreatic duct dilation with copious intraductal mucin and ductal adenomas (from [81] Loftus EV, Jr., Olivares-Pakzad BA, Batts KP et al. Intraductal
papillary mucinous tumors of the pancreas: clinicopathological features, outcome, and nomenclature. Members of the Pancreas Clinic, and Pancreatic Surgeons of Mayo Clinic.
Gastroenterology 1996;110:1909e18).

adenocarcinomas [17e20]. IPMN also exhibits several different carcinomas. Gastric-type epithelium is often found at the periphery
histomorphologic patterns of papillae: gastric (most commonly, of other types of IPMNs.
branch-duct IPMN), intestinal (usually, main-duct IPMN), pan- The genomic and epigenomic changes from the development of
creatobiliary, oncocytic, and null [7,21]. The prognosis of these IPMN adenoma to IPMN invasive carcinoma have not been well
subtypes differs substantially and may be a clue to their natural described or established but are thought to be distinct from those
biology [7,22,23]. Most intestinal-type IPMNs are MUC2 positive changes that have been associated with the stages of pancreatic
(a marker of differentiation) and are believed to progress to invasive intraepithelial neoplasias and development of pancreatic ductal
colloid carcinomas which have a better prognosis, whereas most carcinoma [10,26]. Most work has shown that IPMN is associated
pancreatobiliary IPMNs are MUC1 positive and believed to progress with frequent (50e80%) point mutations in K-ras, thereby estab-
to invasive ductal/tubular adenocarcinomas and portend a poorer lishing these mutations as a potential genetic marker for IPMN as
prognosis [7,24,25]. The DPC4 mutation is unusual with IPMN with typical pancreatic ductal adenocarcinoma. Other molecular
alterations associated with malignant degeneration of IPMNs include
Table 1 loss of heterozygosity in 9p21 (p16) and in 17p13 (p53), increased
World Health Organization (WHO) classification of cystic
expression of cyclooxygenese-2, up-regulation of several genes (such
neoplasms of the pancreas.
as claudin and mesothelin), increased telomerase activity, increased
Serous microcystic adenoma expression of matrix metalloproteinase-7, proliferating-cell nuclear
Serous oligocystic adenoma
antigen and vascular endothelial growth factor [10,27e29]. Telo-
Serous cystadenocarcinoma
Mucinous cystadenoma merase is in part responsible for cell immortality and is activated in
Mucinous cystic neoplasm-borderline many human malignancies and may therefore be a useful diagnostic
Mucinous cystadenocarcinoma tool in the distinction between adenoma and intraductal carcinoma
Noninvasive
in IPMNs [27,30,31]. In normal cells, telomeres shorten over time;
Invasive
Intraductal papillary mucinous adenoma with certain malignancies, telomerase activity is up regulated,
Intraductal papillary mucinous neoplasm-borderline leading to lengthening of the telomere as well as increasing the life
Intraductal papillary mucinous carcinoma span of the cell. The real question is whether any of these acquired
Noninvasive genomic mutations are involved directly in the malignant trans-
Invasive
formation to malignant IPMN or rather are just markers of a more
e112 G.H. Sakorafas et al. / Surgical Oncology 20 (2011) e109ee118
global genomic instability. The role of epigenomic abnormalities is
virtually unexplored in the pathobiology of IPMN.
Unlike serous cystic neoplasms (SCNs) and MCNs, IPMNs are
a more aggressive neoplasm; about 40% of patients at the time of
diagnosis of IPMN already have an established invasive malignancy,
especially for main-duct IPMN (see below) [23,32]. Moreover, most if
not all benign main-duct IPMNs are believed to be at very high risk of
progressing into invasive cancer [14]. Risk factors for the presence of
underlying malignancy include the following [2,5,33e35]:
(a) Main-duct disease. Patients with main-duct IPMN or mixed type
IPMN have a risk of malignancy (carcinoma-in-situ and invasive
cancer) of approximately 50e60%, but in selected situations,
the risk may be as great as 92% [10,11,20,36,37]. Invasive
malignancy is also common in these lesions and approaches
40e50% [14,38]. The risk of malignancy increases when the
main pancreatic duct is dilated >1 cm and when mural nodules
(>1 cm) are present [14,27]; the latter finding is extremely
worrisome for invasive carcinoma. In contrast, the risk of
malignancy in patients with branch-duct IPMN is much less
(range, 6e46%, mean, 25%) [10,18,33], and the risk of invasive
carcinoma in branch-duct IPMNs is even less (<30%) but
remains poorly defined, because many of these patients are
treated non-operatively [10,11,38,39]. Factors correlating with
malignancy in branch-duct IPMNs include the presence of
clinical symptoms, mural nodules (especially when >2 mm),
cyst size >3 cm, and coexistence of main-duct dilation [14,33].
(b) Branch-duct dilation. The presence of side branches > 3 cm
confers an increased risk of malignancy. The risk of malig-
nancy in branch-duct IPMN <2 cm was 10% in the study by
Jang et al. [40].
(c) Presence of a mural nodule(s).
(d) Advanced age (>70 years old).
(e) Presence of symptoms. The majority of patients with invasive
IPMN have symptoms, the most common being pain (frequently
a result of pancreatitis), weight loss, fatigue, and jaundice;
jaundice is a very worrisome finding and implies an invasive
IPMN. In contrast, about 30% of patients with malignant IPMNs
are asymptomatic, and, thus, the absence of symptoms does not
guarantee the absence of malignancy [14].
(f) Increased telomerase activity in pancreatic cystic fluid [30,33].
Unlike typical ductal adenocarcinoma of the pancreas, histo-
logic changes (atypia, dysplasia, or frank carcinoma-in-situ)
may on occasion be found in discontinuous areas throughout
the gland, raising the question of whether IPMN represents
a generalized global disorder of the epithelium of the pancre-
atic duct or rather, a more localized field defect. True multi-
centricity of main-duct IPMNs is not common (<10%), but in
branch-duct IPMNs, multicentricity has been recognized much
more frequently [14]. IPMN should be distinguished from
pancreatic intraepithelial neoplasia (PanIN), the precursor
lesion of ductal adenocarcinoma; indeed, IPMNs are radio-
graphically detectable and visible grossly, while pancreatic
intraepithelial neoplasias are detected only microscopically
[41]. Moreover, IPMN is associated with invasive colloid
(mucinous non-cystic) carcinoma in about 50% of cases, as
opposed to the more traditional tubular adenocarcinomas with
which pancreatic intraepithelial neoplasia is typically associ-
ated [5]. There does appear, however, to be an increased inci-
dence of extrapancreatic neoplasms in patients with IPMN,
especially colonic neoplasms [42] and also with typical ductal
carcinoma of the pancreas [43e47], raising the question of
either a systemic predisposition or the sharing of a local
predisposition to development of malignancies of the pancre-
atic ductal epithelium.
Diagnostic evaluation
Clinical presentation
Patients with IPMN (mainly the main-duct variant) may present
with recurrent episodes of pancreatitis or a scenario of “idiopathic”
chronic pancreatitis. Episodes of acute pancreatitis or development
of chronic pancreatitis appear to be secondary to the presence of
mucus or papillary projections within the pancreatic duct causing
obstruction of the ductal system. Branch-duct IPMNs are most often
asymptomatic, especially when the ‘cyst’ size is <3 cm. The clinical
symptomatology typical of pancreatic adenocarcinoma (i.e., pain-
less jaundice, weight loss, new onset diabetes, etc) may be observed
in malignant IPMNs [10,20,48]. Routine laboratory blood tests,
including liver function tests, amylase, and lipase, should be
obtained but are usually within normal limits or show non-specific
changes. Serum levels of tumor markers, such as serum CA 19-9,
carcinoembryonic antigen (CEA), and CA 125 have limited value for
diagnostic purposes.
Cross-sectional imaging (ultrasonography [US], computed
tomography [CT], magnetic resonance imaging [MRI])
As noted in Parts I and II [49,50], the suspicion of a PPCN
(including IPMN) is almost always first evident after a non-invasive
imaging procedure (US, CT, or MRI). The suspicion of a PPCN is often
at the time of evaluation for unrelated reasons, e.g. during follow-
up for another indication or for vague abdominal complaints not
necessarily correlated with PPCNs. Imaging should include the
entire thorax, abdomen, and pelvis for appropriate staging. Special
focus, of course, should be directed at the liver and lung as the most
common sites for distant metastases for invasive PPCNs.
The characteristic feature of IPMNs on imaging is cystic dilation
of either the main pancreatic duct (main-duct IPMN) (Fig. 2) or of
a primary, segmental side branch of the main-duct (branch-duct
IPMN); the branch-duct IPMNs occur most often in the uncinate
lobe (Fig. 3). Serial sections of the entire pancreatic specimen and
three-dimensional reconstruction can be extremely useful in
determining the full extent of IPMNs. The mucinous globules and
the areas of malignant transformation may both appear as filling
defects within the ductal system (Fig. 4). CT (and alternatively MRI e
see below MRCP) can detect the location and degree of pancreatic
duct dilation and often can differentiate IPMNs from other causes of
duct dilation, such as chronic pancreatitis or obstructing neoplasms.
MRI has been suggested to be superior to CT, particularly in
demonstrating ductal communication with the cyst, but its routine
use in place of CT awaits an improved availability, local radiologic
expertise, and the ability to interpret MRI by physician specialties
other than radiology [51,52]. Improved imaging techniques allow
the detection of small cystic dilation of branch ducts, with no or only
mild dilation of the main pancreatic duct [37,53]. Main-duct IPMN
(in contrast to branch-duct IPMN), especially when associated with
a markedly dilated main pancreatic duct (>10 mm), the presence of
mural nodules, and dilation of the biliary tree are imaging findings
associated with a much greater probability of underlying malig-
nancy [7,14,41,53]. Accurate preoperative discrimination of benign
from malignant IPMNs, however, is practically impossible; this
problem has obvious clinical implications.
Endoscopic retrograde cholangiopancreatography (ERCP)
In contrast to SCN and MCN, ERCP may be important for several
reasons in patients with IPMN. First, ERCP can depict the commu-
nication between the cystic dilation (or side branch dilation) and
the main pancreatic duct, thereby supporting the diagnosis of IPMN
 G.H. Sakorafas et al. / Surgical Oncology 20 (2011) e109ee118
Figure 2. Main-duct IPMN. A) CT showing marked dilation of pancreatic duct, B) EUS
of the main pancreatic duct (MPD) of patient in Fig. 2A (from [5] Fasanella KE, McGrath
K. Cystic lesions and intraductal neoplasms of the pancreas. Best Pract Res Clin Gas-
troenterol 2009;23:35e48).
(Fig. 5); in contrast, SCN and MCN do not communicate with the
pancreatic ductal system. Second, ERCP can reveal a markedly
dilated main pancreatic duct that may contain filling defects related
to either mucinous concretions, papillary growths (intraductal
Figure 3. Branch-duct IPMN. CT shows a 2.5 cm cystic mass in the uncinate process
(from [18] Katz MH, Mortenson MM, Wang H et al. Diagnosis and management of
cystic neoplasms of the pancreas: an evidence-based approach. J Am Coll Surg
2008;207:106e20).
e113
Figure 4. Imaging of intraductal “masses.” ERCP of main-duct IPMN with multiple
filling defects secondary to mucinous globules (from [2] Sarr MG, Murr M, Smirk TC
et al. Primary cystic neoplasms of the pancreas: neoplastic disorders of emerging
importance-current state of the art and unanswered questions. J Gastrointest Surg
2003;7:417e28).
papillomas), or areas of frank malignant degeneration/invasion
(Fig. 4) [53,55]. Often, however, the intraductal mural nodules
(adenomas or carcinomas) are obscured by the mucus, and some-
times the mucous globules can be misinterpreted as ductal nodules.
In about 30% of patients with main or mixed duct IPMN, copious
egress of mucin will be noted from a bulging papilla on ERCP. This
finding is a virtually pathognomonic endoscopic finding supporting
strongly the diagnosis of an IPMN (Fig. 6) [6]. ERCP may be
particularly helpful in the differential diagnosis between branch-
duct IPMN and MCN, which on occasion can be difficult on non-
invasive imaging [37,56]. Pancreatic juice can also be obtained
during ERCP for cytology and analysis. ERCP may also have a ther-
apeutic role by allowing placement of a temporary (preoperative)
biliary endoprosthesis for decompression in jaundiced patients.
There appears to be no role of a pancreatic ductal endoprosthesis.
Overall, however, the diagnostic role of ERCP is declining due to the
improvement in quality of non-invasive imaging studies. Indeed,
we do not recommend the routine use of ERCP during the diag-
nostic evaluation of patients with IPMN.
Figure 5. ERCPs showing communication with cystic areas e branch-duct IPMN.
Uncinate and head of pancreas (from [2] Sarr MG, Murr M, Smirk TC et al. Primary
cystic neoplasms of the pancreas: neoplastic disorders of emerging importance-
current state of the art and unanswered questions. J Gastrointest Surg 2003;7:417e28).
e114 G.H. Sakorafas et al. / Surgical Oncology 20 (2011) e109ee118
Figure 6. Endoscopic view of bulging papilla of Vater with egress of copious mucous
(from [82] Roggin KK, Chennat J, Oto A et al. Pancreatic cystic neoplasm. Curr Probl
Surg 2010;47:459e510).
Magnetic resonance cholangiopancreatography (MRCP)
MRI is a non-invasive, diagnostic method with fewer procedure-
related risks than ERCP. MRCP may on occasion be more specific
than ERCP in imaging pancreatic duct anatomy (e.g. detecting the
presence of communication of a cystic lesion with the ductal
system), because filling of side-branch ducts at the time of ERCP
may be obscured by intraductal plugs of mucus [53,54]; moreover,
MRCP will help to differentiate fluid collections that do not
communicate with the pancreatic ductal system. Mural nodules or
excrescences, main-duct IPMNs, especially with a markedly dilated
main pancreatic duct (>10 mm), and common bile duct dilation are
findings on MRCP suggesting malignancy. As noted above, however,
the absence of these findings does not guarantee that the neoplasm
is benign [54]. MRCP is particularly helpful in delineating the
presence of concomitant branch-duct lesions of IPMN (Fig. 7).
Positron emission tomography (PET)
PET-CT has been proposed as a new, useful imaging modality for
the diagnosis of malignant lesions. Prospective case series have
reached sensitivities and specificities as great as 92% and 95%,
Figure 7. MRCP of IPMN. Branch-duct IPMN with mural nodule (arrow) (from [83]
Sugiyama M, Suzuki Y, Abe N et al. Management of intraductal papillary mucinous
neoplasm of the pancreas. J Gastroenterol 2008;43:181e185).
respectively [57]. Some groups have concluded that 18-FDG PET is
better than conventional imaging techniques in differentiating
patients with benign versus malignant IPMN, especially in older
and asymptomatic patients, for operative treatment or non-oper-
ative surveillance [57]. This controversial recommendation is based
on the proposed ability of PET to detect malignancy within IPMN by
the PET functional data [57,58]. Experience, however, with PET in
PPCNs remains limited, and its role in the differentiation between
patients with benign and malignant pancreatic cystic lesions has
not been established precisely.
Intraductal pancreatoscopy and intraductal US
Intraductal pancreatoscopy is performed using a small-diameter
videoscope and narrow-band imaging [59]. When successful,
intraductal pancreatoscopy can provide a clear image of the ductal
epithelium and may be useful for evaluating when the IPMN is
benign or malignant [59]. Japanese investigators have also pro-
posed the use of “virtual pancreatoscopy,” created by a multi-
detector row CT, for the diagnosis of IPMN of the pancreas; they
concluded that CT virtual pancreatoscopy provided finer quality
images, with a less invasive, faster, and less expensive methodology
[60]. The authors concluded that CT virtual pancreatoscopy might
replace endoscopic retrograde pancreatography in the future [60].
Intraductal ultrasonography is another diagnostic modality which
has been evaluated recently by some investigators in conjunction
with ERCP; the results have been promising in the diagnosis and
differential diagnosis of pancreatic cystic neoplasms [61]; Cheon
et al. concluded that preoperative intraductal ultrasonography may
be useful in determining the type and extent of pancreatic resection
required, especially in main-duct IPMN [61]. Experience with these
newer diagnostic techniques, however, remains limited to only
a few centers of endoscopic excellence.
Endoscopic ultrasonography (EUS)
Advantages of EUS have been discussed in Parts I and II [49,50]
in the evaluation of PPCN. Findings of IPMN on EUS include dilation
of the main pancreatic duct (or its branches) with or without mural
ductal nodules and intraluminal contents [18,62,63] (Figs. 2 and 8).
The presence of multiple cysts communicating with the ductal
system favor the diagnosis of branch-duct IPMN when the main
pancreatic duct is not dilated (i.e., <6 mm) [5]. EUS may prove very
Figure 8. EUS image of main-duct IPMN with a mural nodule measuring 11  8 mm
(from [5] Fasanella KE, McGrath K. Cystic lesions and intraductal neoplasms of the
pancreas. Best Pract Res Clin Gastroenterol 2009;23:35e48).
 G.H. Sakorafas et al. / Surgical Oncology 20 (2011) e109ee118
useful in demonstrating communication of the cystic lesion with
the pancreatic ductal system, but, of course, this finding is operator-
dependent [30]. EUS may be particularly useful when the findings
on CT or MRI are equivocal [64]. EUS findings indicating the pres-
ence of malignancy include a solid lesion, mural nodule(s), dilation
of the main pancreatic duct, ductal filling defects, and thickened
septa [65]. EUS has the added benefit of enabling fine needle
aspiration (FNA) of the cyst fluid for analysis (see below) or for
a trucut biopsy. Despite that some authors have reported peritoneal
dissemination following EUS-guided FNA, this intervenional diag-
nostic method is generally considered safe in experienced hands
and has been adopted in many tertiary centers with experience in
pancreatic diseases.
FNA cytology
IPMNs are characterized on FNA cytology by the presence of
papillary clusters lined by mucin-containing columnar cells, usually
with some degree of atypia [66]. The degree of cytologic atypia has
been shown to be somewhat predictive of malignancy [5]. Although
low-grade MCNs may demonstrate a few papillary clusters, they are
not usually as tall, abundant, and striking as the clusters observed
in IPMNs. Pais et al. reported recently that EUS-guided FNA cytology
proved helpful with a sensitivity, specificity, and accuracy of EUS-
FNA for the diagnosis of malignancy of 75%, 91%, and 86% respec-
tively [65]. The ability to obtain image-guided ‘mini-biopsies’
(trucut or core biopsies), where possible, from the solid component
of a cystic neoplasm or from the wall of the cyst increases the
accuracy of preoperative differential diagnosis [67]. Endoscopic,
EUS-guided trucut biopsies are not always possible for technical
reasons, and this technique is not yet universally available.
Sampling error is a potential limitation of this diagnostic
method. Contamination of the aspirates by the presence of the
normal, mucus-producing epithelium of the gastrointestinal tract
(during the passage of the needle) may be another problem in
interpreting the results of FNA cytology.
Analysis of cystic fluid
Biochemical analysis of the cystic fluid obtained by FNA may
also be of diagnostic value. A typical analysis would include
biochemical testing for mucin, CEA, and amylase.
Mucin. A positive mucin stain or a high viscosity (mucin) is highly
specific for the mucinous (premalignant or overly malignant)
neoplasms (i.e., MCN and IPMN) and can be used for their differ-
ential diagnosis from SCN and usually from pseudocysts as well
[56]. Unfortunately, easily used and reliable assays for mucin are
not readily available; some groups no longer utilize mucin stains.
Thick, viscous mucus may be appreciated grossly in the endoscopy
suite, when smears are made.
CEA. Similarly, high intracystic levels of CEA differentiate a muci-
nous PPCN (i.e. MCN or IPMN) from an SCN with reasonable reli-
ability. Currently, no standardized cutoff level for CEA exists, but
many centers, particularly in the USA, use a CEA level of 192 ng/ml as
diagnostically sensitive (75%) and specific (84%) for differentiating
mucinous from non-mucinous neoplasms (overall diagnostic accu-
racy, 79% for mucinous lesions) [34]. CEA levels of <5 ng/ml are quite
sensitive for excluding a mucinous neoplasm [2,28,53]. Cyst CEA
levels, however, have not been shown to be a reliable marker to
differentiate benign from malignant IPMNs [65]. Interestingly, in the
study by Brugge et al., no combination of tests, including EUS
appearance, was more accurate than CEA alone [34].
Amylase. Amylase activity is of limited diagnostic value except that
a high amylase activity (>5 serum activity) suggests that the cyst
e115
has a connection to the pancreatic ductal system, thereby excluding
SCNs and MCNs (see Table 4 [49]).
Other tumor markers. CA 19-9, CA 72-4, CA 125, and CA 15.3 have
limited diagnostic value. More recently, analysis of the intracystic
fluid for telomerase activity, DNA quality, and a panel of mutations
has proved promising in differentiation of benign versus malignant
lesions [68]. Only a few drops of fluid are required, thus this
molecular analysis can be applied to most all cyst aspirates. K-ras
mutations were found to be more prevalent in malignant lesions;
however, these mutations are also found in normal and inflam-
matory pancreatic ducts [69]. The value of this expensive test to
predict the risk of progression requires confirmation in prospective
trials.
Treatment
Because of the overt or latent malignant potential of IPMN,
operative resection is the therapy of choice in many subsets of
patients with IPMN. The aim of operative resection is to remove all
the adenomatous or malignant ductal epithelium and to minimize
the probability of recurrence in the pancreatic remnant. The basic
and as yet not fully answered question is whether or not IPMN
represents a local clonal expansion of a site of neoplastic trans-
formation, a localized field defect limited to a segment of the
pancreas, or a global abnormality in the ductal epithelium with the
potential to affect all of the pancreatic ductal epithelium, possibly
because of an anatomically local or global environmental stimulus,
either exogenous or endogenous. If we knew IPMN was a localized
process, as with typical ductal cancer of the pancreas, then
a focused resection of the involved anatomic region of the gland
would be indicated. In contrast, if IPMN is a global disorder of all the
pancreatic ductal epithelium, probably then all the pancreatic duct
epithelium is at risk of malignant transformation, and therefore, in
selected individuals, a total pancreatectomy might be indicated [2].
Total pancreatectomy with its obligate apancreatic state has its own
potential problems (brittle diabetes, exocrine insufficiency) and
may not be appropriate for many patients, especially the young
(who would not be at increased risk of cardiac disease), the elderly,
or the medically unsophisticated patient. In addition, episodic
hypoglycemia can be a substantive problem.
The operative approach to IPMN is determined based on the
type of ductal distribution (main or mixed duct IPMN vs. branch-
duct IPMN). In localized branch-duct IPMNs, a localized but formal
anatomic, oncologic pancreatectomy is the favored procedure (i.e.,
pancreatoduodenectomy [preferentially of the pylorus-preserving
type] for neoplasms located in the pancreatic head/uncinate
process, central pancreatectomy when appropriate for neck and
proximal body lesions, or distal pancreatectomy for body/tail
lesions) [33]. Recently, a consensus policy toward a more conser-
vative management of selected patients with branch-duct IPMNs
has been proposed based on the much lesser incidence of invasive
cancer in IPMN [14,70e72]. This strategy (“watchful waiting”) could
be considered for asymptomatic patients with branch-duct IPMNs
with a cyst size of <3 cm, and without mural nodules or main-duct
dilation [5,11,14,31,39,70,73e75]. Close follow-up with cross-
sectional imaging can be used under these conditions, especially in
patients who are considered relatively poor operative candidates,
to detect any increase in tumor size, change in radiographic char-
acteristics, or development of symptoms which would suggest the
need to reevaluate the role of operative resection. Obviously, the
“watchful waiting” approach is applicable only if the patient can be
kept under close supervision. This approach is based on the low
incidence of invasive malignancy (w2%) in these patients, which
approximates the mortality risk from a major operative resection
e116 G.H. Sakorafas et al. / Surgical Oncology 20 (2011) e109ee118
[73]. The high risk of pancreatic ductal adenocarcinoma in patients
with branch-duct IPMN should also be taken in consideration when
planning follow-up in conservatively treated patients (76). In
multifocal branch-duct IPMNs based on high-resolution, multislice
CT or MRI [33,39], total pancreatectomy would be the ideal
procedure theoretically, but the formidable and obligate long-term
morbidity of total pancreatectomy must be considered seriously. A
more conservative approach in this case would be an anatomic
pancreatic resection removing the cystic lesions with worrisome
characteristics (size >3 cm, mural nodules) and surveillance
observation of the remnant gland/lesions until these cystic lesions
develop findings suggestive of malignancy [14].
Management of main-duct IPMN is less controversial. Due to the
high incidence of malignancy (carcinoma-in-situ alone w30%,
invasive carcinoma w40%), resection is warranted in most all these
patients provided they are operative candidates from a medical
standpoint [2,14,28,33,53]. When main-duct IPMN is localized in
the pancreatic body/tail (10e25% of patients) [75], distal pancrea-
tectomy including splenectomy with frozen-section analysis of the
proximal pancreatic margin is the procedure of choice [2,33]. If the
frozen section is negative for true adenomatous changes in the
ductal epithelium (not reactive ductal hyperplasia), total pancrea-
tectomy is not indicated in the absence of objective evidence that
the proximal duct is involved. In contrast, when the margin is
positive for invasive or non-invasive malignant IPMN, most sur-
geons would advocate a further pancreatic resection; if a tumor-
free margin is not attainable after two further “creeping” resec-
tions, most surgeons would proceed with total pancreatectomy,
provided the patient is an appropriate candidate to manage the
“disease” of the apancreatic state [14,28,33,53]; obviously this
discussion would have occurred preoperatively between patient
and surgeon. When the entire pancreatic duct is diffusely dilated,
the assumption is that the disease is in the pancreatic head causing
obstruction by growth of the neoplasm and/or by mucous
production. Based on this assumption and provided no intraluminal
or extraluminal solid mass is evident elsewhere in the duct outside
the boundaries of a pancreatic head resection, a pan-
creatoduodenectomy is undertaken with intraoperative frozen-
section analysis of the distal margin. A positive margin for adeno-
matous changes (again, not ductal hyperplasia) necessitates
a further ‘creeping’ resection, keeping in mind that IPMNs may
involve the pancreatic duct diffusely. If frozen-section remains
positive after two attempts for further resection, total pancreatec-
tomy should be entertained (in up to 10e20% of patients)
[14,33,39]. The concept of ‘prophylactic’ total pancreatectomy is
considered by most pancreatic surgeons as both unacceptable and
unnecessary in most patients [39]. In evaluating the results of
frozen-section, it should be emphasized that the surgeon should
keep in his/her mind that even a negative margin does not assure
the absence of neoplastic cells in the remaining pancreas. Unlike
typical ductal carcinoma of the pancreas which is a contiguous
clonal expansion and not a multi-centric malignancy [76], IPMN
can be a multifocal disease in up to 8e10% of patients with main-
duct disease with ‘skip’ lesions, possibly indicating a generalized
instability of the epithelium [14]. Intraoperative pancreatic ducto-
scopy to evaluate the pancreatic remnant has been tried with some
success. While nodal metastases occur with invasive IPMN, at
present, there is no evidence to justify an extended lymphade-
nectomy in the management of malignant IPMN.
Adjuvant/neoadjuvant therapy
If tissue invasion is present, some form of adjuvant therapy should
be considered despite a ‘curative’ resection, even if there are no nodal
metastases [2,53]. Due to the absence of randomized clinical trials,
the type of treatment that has been adopted is similar to that of
ductal adenocarcinoma; i.e. gemcitabine-based chemotherapy with
radiation. In a recent study from the Johns Hopkins Hospital, 70
patients with malignant (invasive) IPMN received postoperative
(adjuvant) chemoradiotherapy, which appeared to confer a 57%
decrease in the relative risk of mortality; patients with lymph node
metastases or positive margins appeared to benefit particularly from
this adjuvant chemoradiation therapy after a curative resection [77].
Other studies, however, have not shown such an enthusiastic benefit
[78,79]. It should be stressed that there is no level 1 or level 2
evidence addressing the topic of adjuvant chemo- or radiotherapy in
IPMN.
Concerning neoadjuvant therapy, although there is anecdotal
evidence that an apparently unresectable neoplasm with no
metastases can become resectable after combined chemoradiation
therapy, the experience is limited, thereby precluding definite
recommendations. Just as for adjuvant therapy, no good studies
address neoadjuvant therapy.
Prognosis and follow-up
In IPMN, the dysplastic component may remain in situ for many
years. For single branch-duct IPMN, several studies suggest strongly
that a local anatomic resection is essentially curative. In contrast, for
non-invasive, main-duct IPMNs, occurrence in the remnant gland
has been found with variable rates (0e10%), provided that the
frozen-section margin is negative for adenomatous changes and the
resected specimen lacks invasive IPMN [2,14]. One study maintains
that after a curative resection with negative margins, recurrence is
extremely rare [20]; in contrast, another large study showed
a recurrence in the remnant of 8% [14]. Under these conditions,
recurrence in the remnant may be due to the presence of multifocal
disease [39] or to overlooked residual disease at the ductal margin.
In distinct contrast, when the resection specimen contains invasive
disease, even if the margins are negative, recurrent IPMN, either in
the pancreatic remnant but more commonly in peripancreatic and
extrapancreatic sites, occurs in 50e90% of patients, dramatically
altering prognosis and reinforcing the concept that invasive IPMN is
a serious, aggressive malignancy [5,32,75,78]. Interestingly, in the
Mayo Clinic series [75] of invasive IPMN, recurrence after partial
pancreatectomy (18/27; 67%) was similar to that observed after total
pancreatectomy (8/13; 62%), suggesting no oncologic advantage to
total pancreatectomy, similar in principle to ductal adenocarcinoma
of the pancreas [76].
The 5-year survival after curative resection of IPMN without
invasive cancer is >70% in most series [40,75]. Some reports have
even suggested a 5-year survival in excess of 90% after resection.
After resection of invasive IPMN, even with negative margins,
5-year survival ranges from 30 to 50% [32,75,78]. Features pre-
dicting decreased survival when invasive cancer is present include
lymph node metastases, vascular invasion, and positive resection
margins [78]. Invasive IPMNs should be managed as an aggressive
malignancy that behaves, in many respects, similar to ductal cancer
of the pancreas. Overall survival, however, appears better with
invasive IPMN compared to pancreatic ductal adenocarcinoma, but
whether this is due to a stage-shift with earlier diagnosis of IPMN,
as shown in some studies [78], or due to a true less aggressive
behavior of invasive IPMN remains controversial.
Routine follow-up surveillance with non-invasive imaging
appears to be relevant clinically, potentially therapeutic, and
indicated in all patients with IPMNs, because if recurrence occurs,
selected patients may benefit from further treatment [14]. There
are no established guidelines regarding the frequency or type of
surveillance imaging to detect potential recurrence. A reasonable
strategy for non-invasive IPMNs would be to obtain yearly follow-
 G.H. Sakorafas et al. / Surgical Oncology 20 (2011) e109ee118
up with CT or if available (i.e. hardware and radiologic expertise)
MRI, and then increase the interval between imaging if no cha-
nges have occurred over several years [14]. Because patients with
invasive IPMN have a significantly greater risk of recurrence, this
population probably should be evaluated every 6 months with
abdominal CT or MRI [14]. As noted previously, observation may
well be indicated for patients with branch-duct IPMN who are
asymptomatic without mural nodules in whom the main-duct is
<6 mm and the cyst size is <3 cm. The frequency of follow-up
can be based on the size of the side branch cyst: 0e1 cm, yearly,
1e2 cm every 6e12 months; 2e3 cm every 3e6 months, but we
stress that these are suggested guidelines based on best inter-
pretation of our current understanding. Abdominal CT, MRCP, and
EUS are utilized for assessing cyst size, presence of mural
nodules, and any changes in the diameter of the main-duct. The
interval of follow-up may be increased in duration if no change is
observed during the first two years postoperatively [33]. The
increased risk for pancreatic ductal adenocarcinoma develop-
ment distinct from the IPMN should also be taken into consid-
eration during the follow-up (see above) (76).
Biochemical follow-up surveillance is of little value. Tumor
markers, such as serum levels of CEA and CA 19-9, have no value
in the follow-up of these patients. The discovery of a pancreatic
cyst/mass lesion after operative resection may be related to the
presence of a postoperative contained leak, a recurrence of IPMN
linked to incomplete resection, a new site of IPMN, or rarely
a recurrence of cystadenocarcinoma after inadequate histopatho-
logic examination [2].
As mentioned above, patients with IPMN have a greater inci-
dence (w25e30%) of synchronous or metachronous extrapancre-
atic neoplasms in other organs (including colon, rectum, stomach,
lung, breast, liver etc.), but also of pancreatic cancer of ordinary
type [42,80]. Whether this association is due to increased utiliza-
tion of imaging studies in this population or represents a true
genetic or epigenomic link is unknown. Nevertheless, this impor-
tant information should be taken into consideration when sched-
uling both the initial evaluation and the follow-up plan of patients
with IPMNs; more frequent screening colonoscopy may be war-
ranted in these patients because of the increased frequency of
colonic neoplasms [42].
Conflict of interest statement
None declared.
Authorship statement
Guarantor of the integrity of the study: Michael G. Sarr.
Study concepts: George. H. Sakorafas.
Study design: George. H. Sakorafas.
Definition of intellectual content: George H. Sakorafas.
Literature research: Vasileios Smyrniotis.
Clinical studies: Vasileios Smyrniotis.
Experimental studies: Vasileios Smyrniotis.
Data acquisition: Kaye M. Reid-Lombardo.
Data analysis: Kaye M. Reid-Lombardo.
Statistical analysis:
Manuscript preparation: George H. Sakorafas.
Manuscript editing: Michael G. Sarr.
Manuscript review: Michael G. Sarr.
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