This article reviews the currently available information on the clinicopathological/molecular features, differential diagnosis, and biological behavior of intraductal neoplasms of the pancreas namely; intraductal papillary mucinous neoplasm (IPMN) (including intraductal oncocytic neoplasm) as well as intraductal tubulopapillary neoplasm (ITPN).
Intraductal Papillary Mucinous Neoplasms
Definition
The term intraductal papillary mucinous neoplasm (IPMN)
was first described by Klöppel et al. in 1994 as grossly visible,
mucin-producing, predominantly papillary, epithelial
neoplasm arising from the main pancreatic duct or branch
ducts, with varying degrees of duct dilatation[6]. As per
the international guidelines[7], which was also endorsed
by the 2010 WHO Classification System[8], greater than
1 cm diameter by radiologic/gross examination is required
to distinguish IPMNs from large pancreatic intraepithelial
neoplasms (PanINs).
Clinical Features
IPMNs occur slightly more frequently in men than in
women with a male to female ratio of 3 to 2. The mean
age at the time of diagnosis ranges between 62 and 67
years[8-12]. Most patients diagnosed with IPMNs
are asymptomatic[13,14] and when associated with
symptoms, it can mimic chronic pancreatitis[11,15-18].
The etiology of IPMNs is not so clear, however, a previous
history of diabetes, especially with insulin use, smoking,
and a family history of pancreatic ductal adenocarcinoma
are regarded as risk factors[10,19]. Interestingly, the rate
of extrapancreatic malignant tumors (colonic, gastric,
bile duct, breast and prostate carcinoma) is reported to be
higher in patients with IPMN than in those with pancreatic
ductal adenocarcinoma (PDAC)[11,12,20-24].
Diagnostic Imaging Techniques
Typical signs on computed tomography (CT) are a diffusely
distended pancreatic duct with filling defects and cystic
lesions with connection to the pancreatic duct system[12,25-27]. However, magnetic resonance imaging (MRI)
seems superior to CT in terms of characterizing the lesion[28]. Endoscopic retrograde cholangiopancreatography
(ERCP) also usually reveals a dilated pancreatic duct with
filling defects[12,29,30].
Classification
IPMNs are currently classified based on their radiologic
(and also macroscopic) appearance, cell type, and grade of dysplasia[31]. Most IPMNs are localized, but they can
diffusely involve the entire gland.
Radiologic (and Also Macroscopic) Classification
All IPMNs connect to larger pancreatic duct(s); however,
not all IPMNs arise in the main pancreatic duct. Therefore,
they are classified as branch duct-type and main duct-type[12].
Branch duct-type IPMN (BD-IPMN) is one of the most common incidentalomas due to the recent widespread use of imaging modalities[32]. It arises in younger patients and is more likely to involve the uncinate process[12,16,33]. BD-IPMN manifests either as a cyst or a cluster of cysts without dilation of the main pancreatic duct. The cysts are usually not larger than 1-2 cm with smooth and glistening cyst lining (Figure 1A)[10,15,26,31]. Many BD-IPMNs lack nodular formation and commonly contain inspissated mucinous material[34].
Main duct-type IPMN (MD-IPMN) is usually located in the head of the pancreas. It is characterized by a markedly dilated (average diameter, 4.1 cm), tortuous main pancreatic duct that may be filled with mucin or solid but friable mass[12,31,35,36] (Figure 1B).
Microscopic Classification
IPMNs differ in the cell type that composes the papillary
epithelium, allowing their classification into gastric,
intestinal, pancreatobiliary, and oncocytic subtypes[37] based on the histomorphologic features and the
immunohistochemical characteristics. Although the
oncocytic-type was originally described as a separate entity
(intraductal oncocytic papillary neoplasm) (See below)[38], the current (2010) WHO puts this neoplasm under
the general category of IPMNs, due to overlap between the
clinicopathologic features of IOPNs and other subtypes of
IPMNs[39].
In gastric-type, the papillae are lined by simple epithelium that resembles gastric foveolar epithelium. BD-IPMNs often show gastric foveolar differentiation[12,40-42] (Figure 2A). The tumor cells have low proliferative activity, and rarely exhibit malignant transformation. Intestinal-type IPMNs have papillae lined by pseudostratified columnar cells with cigar-shaped nuclei and apical goblet like mucin resembling colonic villous adenomas (Figure 2B). Most main duct IPMNs are of intestinal type[12,41,43,44]. Pancreatobiliary-type IPMNs usually involve the main pancreatic duct and are characterized by more complex, interconnecting papillae lined by atypical cuboidal cells that have little intracellular mucin, enlarged round nuclei, and prominent eccentric nucleolus (Figure 2C)[10,41]. This type epithelium is often seen in an intimate association with less atypical gastric type epithelium, and for this reason, some observers believe that it represents the high-grade dysplastic version of gastric type rather than a specific type of its own[42]. Of note, both intestinaland pancreatobiliary-types of IPMN may have areas lined by gastric-type epithelium; however, it is extremely uncommon to find both intestinal- and pancreatobiliarytype papillae within the same IPMN.
Microscopically, IPMNs also exhibit various degrees of dysplasia. Based on the degree of architectural and cytological atypia, the current (2010) WHO classification system subclassifies these neoplasms as IPMN with lowgrade, intermediate-grade, and high-grade dysplasia[8]. In this 3-tiered grading system, low-grade dysplasia is defined as neoplastic cells that form a single layer of well oriented, have small and uniform nuclei, lack of nucleoli and mitoses (Figure 3A). Intermediate-grade dysplasia is defined as tumor cells with nuclear stratification, high nuclear to cytoplasmic ratio, loss of polarity, enlarged nuclei and pleomorphism, but papillae still have fibrovascular cores. High-grade dysplasia has more complex architecture with nuclear pleomorphism, increased mitotic figures, atypia, and cribriforming additional to these features (Figure 3B)[43]. In a given case, the final grade of IPMN is based on the highest grade, no matter how small it is[45].
However, lately it has been shown that IPMNs with lowgrade or intermediate-grade dysplasia have low progression rate compared to ones with high-grade dysplasia[45-51]. Also, the goal of clinical management is to observe lowgrade and intermediate-grade precursor lesions and to resect high-grade precursor lesions in order to decrease the risk of invasive cancer. Therefore, at a recent international consensus meeting held in Baltimore to revise the grading system and reporting of precursor lesions in pancreas, a 2-tiered classification scheme was felt to be more in line with practical consequences: low-grade and intermediate-grade dysplasia likely has no immediate clinical consequences, whereas high-grade dysplasia usually requires clinical attention. According to this new 2-tiered grading system, intermediate-grade is now categorized as low-grade, and high-grade is used only for most advanced dysplastic lesions[52].
Invasive Carcinoma Associated with IPMNs
The most important determinant of outcome in the
management of patients with IPMNs is whether an associated
invasive carcinoma is present or not[1,11,13,16,53-57].
Approximately 40-60% of resected IPMNs have had an
associated invasive carcinoma, either of the colloid-type
or ductal-type[11,58]. Various authors have reported that
MD-IPMNs have a higher potential of having invasive
disease, compared to BD-IPMNs[13,43,59,60].
Gastric-type IPMNs rarely have an invasive carcinoma[61]; however, when a carcinoma develops, it is typically ductal-type and has aggressive behavior[62]. Intestinaltype IPMNs tend to be large, complex, and prone to have invasive carcinoma, and when they are associated with an invasive carcinoma, it is typically of colloid type (Figure 4A) characterized by nodules of stromal mucin that contain relatively scant clusters of carcinoma cells[10,41,63-65]. This form of invasive carcinoma has to be distinguished from benign spillage of mucin into the stroma called pseudoinvasion. In contrast to invasive carcinoma, benign spillage of mucin does not contain neoplastic cells and is usually associated with an inflammatory response at the periphery. In some cases, it can be very difficult to distinguish pseudoinvasion from true invasive colloid carcinoma. For such cases, the diagnosis of indeterminate for invasion may have to be rendered[45]. Invasive carcinoma associated with pancreatobiliary-type IPMNs is usually tubular type, characterized by infiltrating small to medium tubular units separated by desmoplastic stroma with all the morphologic features of PDAC (Figure 4B) (10,16,24,54,66-68).
Grossing
First of all, every attempt should be made to measure the
diameter of the main pancreatic duct. Then, for unifocal but
multilocular lesions, overall size of locules; for multifocal
lesions, the range of the foci should be documented[45].
Some IPMNs have very thin-walled cysts that can rupture
during gross examination. Therefore, for such IPMNs, the true size needs to be determined by close correlation
with radiologic findings. Documenting the gross size
of any solid or gelatinous component is also required as
invasive carcinomas are often solid or gelatinous and this
component often corresponds to mural nodule'' detected
by imaging preoperatively[69]. More importantly, it
should be kept in mind that an invasive carcinoma arising
in association with an IPMN can only be definitely excluded
by thorough evaluation of not only the entire lesion but
also the uninvolved pancreas as well[45,70,71].
Frozen Section
Evaluation of margins by frozen section may be indicated in
some cases of IPMNs. The presence of low-grade dysplasia
at the resection margin does not need further resection,
while involvement by high-grade dysplasia or invasive
carcinoma is important as it usually means more aggressive
surgery[72-74]. Although intestinal- and oncocytic-type
IPMNs are easy to distinguish from PanIN, gastric- or
pancreatobiliary-type IPMNs are virtually indistinguishable
from PanIN. For this reason, it is recommended that lowgrade
intraductal mucinous lesions in pancreatic margins
be reported as No high-grade dysplasia or invasive
carcinoma is identified; low-grade mucinous epithelium
is present (differential diagnoses include low-grade PanIN
or low-grade IPMN).'' Similarly, high-grade intraductal
mucinous lesions should be reported as High-grade
mucinous epithelium is present (differential diagnoses
include high-grade PanIN or high-grade IPMN).
Evaluation of denuded duct epithelium is also problematic on frozen section. For such cases, deeper sections are suggested to find whether any adherent epithelium is present. If deeper sections are also similar, the case may be reported as denuded epithelium, cannot assess for neoplastic process[45,53]
Reporting
In reporting IPMNs, if there is no associated invasive
carcinoma, it is recommended that the diagnosis should
start with the name of the precursor lesions, followed by
the grade, morphologic subtype and size (i.e. IPMN with
low-grade dysplasia, intestinal type, 2 cm). If there is any
associated invasive carcinoma, the pathology report should
separately document the characteristics of both precursor
and invasive lesions. The term IPMN with invasive
carcinoma or invasive carcinoma with an associated
IPMN may be used. The terms malignant IPMN or
minimally invasive IPMN should not be used as these
terms are non-specific and potentially misleading. If the
invasive carcinoma is unifocal, the largest diameter of the invasive focus should be measured. If it is multifocal, it is
recommended that both the diameter of the largest invasive
focus and the overall estimated size of all foci in aggregate
be provided in the comment of the report[45,52].
Immunohistochemical Features
All IPMNs express cytokeratin (AE1/AE3, CAM5.2, CK7,
8,18,19), and except for the intestinal type, all are negative
for CK20[75,76]. Different patterns of MUC expression
are seen in IPMNs and correlate with morphologic
differentiation (Table I)[24,41,44]. MUC5AC is detected
in most IPMNs, regardless of the type. The gastric-type
just labels with MUC5AC, while the pancreatobiliarytype
IPMNs also label with MUC1 and is negative for
MUC2[12,41,42,44,77-80]. Intestinal-type IPMNs
express the intestinal lineage markers such as MUC2,
and CDX2 that are not expressed in the normal
pancreas or other IPMN types[11,12,24,41,44,78].
When pancreatobiliary- and intestinal-type IPMNs
are associated with invasive carcinoma, the invasive
component also expresses the same markers as noninvasive
component does. It should be noted that
scattered goblet cells can be seen in non-intestinal types
of IPMNs rendering the tumor focal positivity for MUC2,
CDX2, and CK20[34]. Immuno labeling can also reveal
scattered chromogranin positive cells at the base of the
neoplastic epithelium[81].
Table I: Immunohistochemical profile of IPMNs (including IOPNs)
Molecular Features
Whole-exome sequencing of IPMNs revealed about 26
mutations per IPMN[82,83]. The most common mutations
seen in IPMNs are KRAS, GNAS and RNF43 genes. KRAS
mutation is identified in approximately 80% of IPMNs, while
GNAS mutation is seen in approximately 60%, and RNF43
in approximately 75%. KRAS mutation is most commonly
seen in gastric-, and secondly in pancreatobiliary-type [84-86]. GNAS mutation is commonly identified in intestinaltype
of IPMNs and if the neoplasm is associated with invasive
carcinoma this mutation is seen in both invasive and noninvasive
component[87]. Although KRAS mutation is common in both IPMN and PDAC, GNAS mutation is not
identified in PDAC and the frequency of RNF43 mutation
in PDAC is not known[84]. Less common alterations seen
in IPMNs involves PIK3CA, AKT1, CDKN2a/p16, SMAD4,
TP53, BRAF, CTNNB1/β-catenin, IDH1, STK11, PTEN,
ATM, CDH1, and FGFR3 genes[54,82,88,89].
Treatment
Nowadays, IPMNs represent the 10-30% of all resectable
pancreatic tumors and the treatment of MD-IPMNs has not
changed much over the past three decades. Most patients
with MD-IPMNs who fit for surgery, undergo tumor
resection. BD-IPMNs measuring >3 cm in diameter, even
without mural nodules is also recommended for resection
according to Sendai guidelines although Fukuoka guidelines
include more conservative criteria for resection[7]
Prognosis
Malignant progression is more closely associated with older
age (>70 years) and female gender[90]. Not surprisingly,
invasive carcinoma stage is the most significant predictor
of survival followed by the invasive carcinoma histological
subtype[55,91-93] and half of those with an associated
invasive carcinoma die of the disease[15,66] [94-98]. In
a relatively recent study comparing stage matched IPMNassociated
colloid carcinoma, IPMN-associated tubular
carcinoma, and conventional pancreatic adenocarcinoma,
the colloid carcinoma was found to have a more favorable
survival outcome than the tubular carcinoma (The 5-year
estimated survival rates for colloid carcinoma and tubular
carcinoma were 87% and, 55%, respectively (p=0.01)). Also,
patients with invasive tubular IPMN had no statistically significant difference in survival as matched patients with
conventional ductal pancreatic carcinoma (The 3-year
estimated survival rates were 61% and, 21%, respectively
(p=0.87))[99].
Series from large centers also allow the conclusion that non-invasive IPMNs recur in up to 13% after resection. The recurrence rate is higher (28-60%) for IPMNs with invasive component[100,101]. Invasive carcinoma may also develop in the remnants after partial pancreatectomy for IPMNs. This is likely related to the multicentricity of IPMNs[102] that is why careful examination of the remaining pancreas by the surgeon is as important as extensive, if not total, sampling of the resected pancreas by the pathologists.
Differential Diagnosis
The most common problem is to distinguish IPMNs from
MCNs. IPMNs are defined as mucin producing tumors
arising from the main or branch pancreatic ducts[8], while
MCNs are characterized by de-novo mucin-producing
tumors with ovarian-type type stroma (Figure 5) (i.e.
MCNs don't have any communication with pancreatic
ductal system)[103]. They have different clinical, gross
and microscopic findings (Table II). For example, MCNs
generally involve the tail of the pancreas in perimenopausal
women, while IPMNs are seen in older men and involve the
head of the pancreas. Grossly, the most important finding
that favors MCN over IPMN is the lack of communication
with pancreatic duct system[11,14,77,103-105]. Microscopically,
both neoplasms are lined by mucinous
epithelium, but MCNs have distinct ovarian-type stroma,
which is positive for estrogen, and progesterone receptors
as well as smooth muscle actin (SMA), inhibin and
calponin[12,103-113]. The cyst lining of both lesions
might be papillary or flat, and sometimes be almost entirely
denuded, which makes rendering the diagnosis difficult. In
this situation, additional sectioning is recommended to
identify the epithelial lining[104,114,115]. The epithelial
cells of MCNs label with CK7, 8, 18, 19, CAM 5.2, as well
as MUC5AC. MUC6 expression is also reported[114,116].
MUC1 expression can be identified in the invasive
component. Unlike IPMNs, MCNs do not show intestinal
differentiation, so they generally do not express CDX2 and CK20[115,117].
Table II: The comparison of IPMNs and MCNs
The other problematic issue is to distinguish IPMNs from PanIN. If the IPMN is gastric- or pancreatobiliary-type, it may be impossible to distinguish IPMNs extending to smaller ducts from independent, incidental PanIN[43,54]. If the tumor is grossly and microscopically less than 0.5 cm, PanIN is favored as IPMN is, by definition, larger than 1 cm in size[10,43,73]. Also, the papillae of IPMNs are taller and more complex than those of PanIN, and the tumors cells may express MUC2 in IPMNs, while they are negative in PanIN[43]. Some PDACs with large invasive glands, a.k.a large duct-type PDAC, may also resemble IPMNs, but the irregular contours and flat epithelial lining of the glands and presence of necrotic debris within their lumen favor PDAC[118,119].
Of note, larger than 1 cm pancreatic cysts lined by nonpapillary mucinous epithelium without ovarian-type stroma (i.e. mucinous cysts that do not have characteristic features of intraductal papillary mucinous neoplasms or mucinous cystic neoplasms) may pose diagnostic challenges[120]. The term simple mucinous cyst was recently proposed for these lesions[52]. Since KRAS mutations can be detected in these typically bland cysts, and in rare instances, focal high-grade dysplasia may be present, these cysts should be viewed as neoplastic and treated similarly to other neoplastic mucinous pancreatic cysts[120].
Intraductal Oncocytic Papillary Neoplasm
Definition
The term intraductal oncocytic papillary neoplasm
(IOPN) was first described by Adsay et al in 1996, as a
grossly cystic epithelial neoplasm composed of oxyphilic
cells that grow within the pancreatic ducts (38). However,
the current (2010) WHO classification puts this neoplasm
under the general IPMN category[39].
Clinical Features
IOPN is usually seen during the seventh decade of life[58,121,122] with equal male to female ratio[58,121,122].
Patients are either asymptomatic or have non-specific
symptoms, similar to IPMNs.
Pathologic Features
Macroscopically, IOPNs usually involve the head of the
pancreas and present as cystic lesions with soft friable
papillary structures involving the main pancreatic duct.
The mean tumor size is 6 cm[38,122-124].
Microscopically, they are characterized with papillary projections lined by stratified cuboidal or columnar cells. The cells have distinctive oncocytic cytoplasm and nuclei with single, prominent, nucleoli[58,121] (Figure 6A,B). Intracellular lumens are also seen[38,121-123,125,126]. Despite highly complex morphology and atypical cytology, most examples are devoid of invasive carcinoma, and, if present, invasion is usually limited in amount[121,124]. The invasive component can be oncocytic, mucinous (colloid-like), sarcomatoid/undifferentiated, or even neuroendocrine type[38,123,125,127,128]. Similar to IPMNs, features of both invasive and non-invasive components should be documented separately[121].
Immunohistochemical Features
The tumor cells usually express MUC1 and MUC6[61,77,121,129,130], while are negative for MUC2, and
CDX2. More importantly, neuroendocrine and acinar
differentiation markers are both negative.
Molecular Features
Recent molecular studies showed that IOPNs have distinct
molecular features compared to IPMNs as they do not
reveal KRAS, GNAS, or RNF43 mutations, which are
commonly seen in IPMNs[131].
Prognosis and Treatment
The long-term follow-up of patients with IOPN reveals
that the recurrence rate is high (up to 40%)[132]. However,
survival outcomes are still favorable despite the second
resection. Also, even though these intraductal neoplasms
may develop invasive carcinoma, usually in the form of
invasive oncocytic or mucinous (colloid-like) carcinoma,
they still have more indolent course than conventional
PDAC[16,31,38,40,71,121,124,126,133].
Intraductal Tubulopapillary Neoplasm
Definition
First reported by Tajiri et al in 2004[134], intraductal
tubulopapillary neoplasm (ITPN) was classified by WHO
as a distinct type of pancreatic intraductal neoplasm in
2010[8].
Clinical Features
ITPNs are rare neoplasms seen at an average age of 53
years, with equal female to male ratio[31,135]. The
patients usually present with non-specific symptoms such
as abdominal pain, vomiting, weight loss, and steatorrhea.
Unlike PDAC, there is no jaundice[135]. The tumor is usually characterized by solid and cystic areas on imaging;
pre-operative diagnosis of IPMN might be rendered for
some cases.
Pathologic Features
On gross examination, the tumors are multinodular, with
the mean tumor size of 4.5 cm and one might see soft,
polypoid masses within dilated pancreatic ducts[135].
About 50% of the ITPNs involve the head of the pancreas,
and 30% involves the entire gland. Cyst formation is
generally uncommon, and the adjacent pancreatic tissue is
usually sclerotic[136]. Because of their intraductal growth
pattern, it is difficult to differentiate ITPNs from IPMNs
grossly[8,137].
Microscopically, these neoplasms have a nodular growth pattern (Figure 7A). Intraductal location of at least some of the tumor nodules is identified in every case as there is continuity of the neoplastic epithelium with histologically normal-appearing ductal epithelium. However, many tumor nodules show no residual non-neoplastic ductal epithelium at the periphery[135]. The nodules are composed of either back to back tubular glands or punctuated sheets of tumor cells (Figure 7B)[54,134,138]. Despite the entity's name, the predominant growth pattern is tubular in ITPNs with papilla formation seen only focally in rare cases[135,139]. Although small foci of necrosis are common, rare cases might even reveal comedo-like necrosis as shown here within the nodules. The cuboidal tumor cells have modest amount of cytoplasm without obvious intracellular mucin content. The nuclei are small, round to oval, and moderately to markedly atypical with readily identifiable mitotic figures[135].
Approximately 70% cases have invasive carcinoma component ranging from minute (representing less than 10% of the tumor) to extensive (more than 50% of the tumor)[135]. However, because[7,134] many of the individual tumor nodules lack a peripheral rim of nonneoplastic ductal epithelium, it is often very difficult to determine whether invasive carcinoma is present[24,138]. Foci in which there are thin strands of cells extending away from the edges of the nodules are regarded to represent stromal invasion (Figure 8). In some cases, there are individual malignant glands clearly infiltrating into the stroma[135].
Immunohistochemical Features
The immuno profile for ITPNs is interesting. The tumor
cells are positive with CK7,8,18,19, and MUC1 and MUC6,
while MUC2 and MUC5AC are generally negative. Most
cases also express CA19.9, which is typically expressed in
ductal epithelial cells and ductal neoplasms[135].
Molecular Features
Although their intraductal nature and some of
clinicopathological feature similar to those of IPMNs, ITPNs
appear to have distinguishing molecular characteristics.
For example, in a recent study based on targeted nextgeneration
sequencing for a panel of 51 cancer-associated genes, no mutations were identified in three ITPNs analyzed[88]. Similarly, in another study analyzing eleven ITPNs
by targeted next-generation sequencing for a panel of 300
cancer-associated genes, our group showed that ITPNs do
not harbor the majority of the previously reported IPMNrelated
mutations. In fact, only three specific genes were
mutated in more than one ITPN: MLL2, MLL3, and BAP1
(chromatin remodeling genes)[140]. Further analysis of
genetic alterations in biologically distinct pathway(s) will
likely shed new light on the mechanisms of intraductal
tumor formation in the pancreas.
Prognosis
Although ITPN is relatively newly defined entity,
preliminary data suggest that the overall clinical course of
these neoplasms was indolent. Interestingly, there seems to
be no clinical course and invasion correlation[135,139].
However, this is most likely, due to sampling phenomenon.
Therefore, careful sampling and evaluation is warranted.
Differential Diagnosis
The differential diagnosis includes other fundamentally
intraductal tumors such as IPMNs as well as other pancreatic
neoplasms that may rarely grow within the ducts (acinar
cell carcinoma and pancreatic neuroendocrine neoplasm).
Although IPMNs may have some limited tubular growth,
especially at the periphery of the involved ducts, all show
extensive intraductal papilla formation, and complete
obliteration of the ductal profiles is distinctly unusual.
The back-to-back tubules of intraductal tubular carcinoma, each of which has a relatively small lumen, closely simulate the pattern of acinar neoplasms of the pancreas. Most acinar cell carcinomas are large solid lesions and demonstrate no involvement of the native pancreatic ducts. However, rare cases have been described in which an intraductal growth pattern is present either focally or extensively. Some in fact show papillary formations within the native ducts[137,141,142]. Acinar cell carcinomas with intraductal spread can be difficult to distinguish from ITPN by routine microscopy, but immunohistochemistry is very helpful. Acinar cell carcinomas consistently express pancreatic enzymes such as trypsin, chymotrypsin, and lipase and generally lack expression of CK19[141-144].
Finally, pancreatic neuroendocrine neoplasms can rarely show an intraductal growth pattern. Usually, these are solid neoplasms, although gland formation can occur in pancreatic neuroendocrine neoplasms. Again, immunohistochemistry is extremely helpful, as there is diffuse positivity for chromogranin and/or synaptophysin in pancreatic neuroendocrine neoplasms. In should be kept in mind that some ITPNs have a minor population of neuroendocrine cells (as can be seen in any type of exocrine pancreatic neoplasm), but these are generally arranged individually, and diffuse labeling for neuroendocrine markers is not found[135,139].
Differential diagnoses of IPMN include PanIN, IOPN, ITPN, MCN, and large duct type PDAC. In addition to imaging and histomorphologic findings, immunohistochemistry and even genetic tests summarized in this article might be used to establish the final diagnosis.
FUNDING SOURCE
This work has been supported by the Cancer Center
Support Grant (CCSG) / Core Grant / P30 CA008748.
ACKNOWLEDGMENTS
The authors thank to Ms. Tanisha Daniel and Ms. Dana
Haviland for their assistance during manuscript preparation
and Ms. Allyne Manzo and Ms. Lorraine Corsale for their
assistance with the figures.
CONFLICT of INTEREST
The authors declare no conflict of interest.
1) Klöppel G, Kosmahl M. Cystic lesions and neoplasms of the
pancreas. The features are becoming clearer. Pancreatology.
2001;1:648-55.
2) Kosmahl M, Pauser U, Peters K, Sipos B, Lüttges J, Kremer
B, Klöppel G. Cystic neoplasms of the pancreas and tumorlike
lesions with cystic features: A review of 418 cases and a
classification proposal. Virchows Arch. 2004;445:168-78.
3) Adsay NV. Cystic neoplasia of the pancreas: Pathology and
biology. J Gastrointest Surg. 2008;12:401-4.
4) Spinelli KS, Fromwiller TE, Daniel RA, Kiely JM, Nakeeb
A, Komorowski RA, Wilson SD, Pitt HA. Cystic pancreatic
neoplasms: Observe or operate. Ann Surg. 2004;239:651-7;
discussion 657-9.
5) Fernández-del Castillo C, Targarona J, Thayer SP, Rattner
DW, Brugge WR, Warshaw AL. Incidental pancreatic cysts:
Clinicopathologic characteristics and comparison with
symptomatic patients. Arch Surg. 2003;138:427-3; discussion
433-4.
6) Sessa F, Solcia E, Capella C, Bonato M, Scarpa A, Zamboni G,
Pellegata NS, Ranzani GN, Rickaert F, Klöppel G. Intraductal
papillary-mucinous tumours represent a distinct group
of pancreatic neoplasms: An investigation of tumour cell
differentiation and K-ras, p53 and c-erbB-2 abnormalities in 26
patients. Virchows Arch. 1994;425:357-67.
7) Tanaka M, Chari S, Adsay V, Fernandez-del Castillo C, Falconi
M, Shimizu M, Yamaguchi K, Yamao K, Matsuno S; International
Association of Pancreatology. International consensus guidelines
for management of intraductal papillary mucinous neoplasms
and mucinous cystic neoplasms of the pancreas. Pancreatology.
2006;6:17-32.
8) Adsay NV, Kloppel G, Fukushima N. WHO classification for
tumors of the digestive system. In: Bosman FT, Carneiro F,
Hruban RH, editors. Intraductal neoplasms of the pancreas.
Lyon:WHO;2010. 304-313.
9) Ingkakul T, Warshaw AL, Fernández-Del Castillo C.
Epidemiology of intraductal papillary mucinous neoplasms of
the pancreas: Sex differences between 3 geographic regions.
Pancreas. 2011;40:779-80.
10) Fernández-del Castillo C, Adsay NV. Intraductal papillary
mucinous neoplasms of the pancreas. Gastroenterology.
2010;139:708-13, 713.e1-2.
11) Adsay NV. The new kid on the block: Intraductal papillary
mucinous neoplasms of the pancreas: Current concepts and
controversies. Surgery. 2003;133:459-63.
12) Katabi N, Klimstra DS. Intraductal papillary mucinous
neoplasms of the pancreas: Clinical and pathological features
and diagnostic approach. J Clin Pathol. 2008;61:1303-13.
13) Nagai K, Doi R, Kida A, Kami K, Kawaguchi Y, Ito T, Sakurai
T, Uemoto S. Intraductal papillary mucinous neoplasms of
the pancreas: Clinicopathologic characteristics and longterm
follow-up after resection. World J Surg. 2008;32:271-8;
discussion 279-80.
14) Ferrone CR, Correa-Gallego C, Warshaw AL, Brugge WR,
Forcione DG, Thayer SP, Fernández-del Castillo C. Current
trends in pancreatic cystic neoplasms. Arch Surg. 2009;144:448-54.
15) Salvia R, Fernández-del Castillo C, Bassi C, Thayer SP, Falconi M,
Mantovani W, Pederzoli P, Warshaw AL. Main-duct intraductal
papillary mucinous neoplasms of the pancreas: Clinical
predictors of malignancy and long-term survival following
resection. Ann Surg. 2004;239:678-85; discussion 685-7.
16) Sohn TA, Yeo CJ, Cameron JL, Hruban RH, Fukushima N,
Campbell KA, Lillemoe KD. Intraductal papillary mucinous
neoplasms of the pancreas: An updated experience. Ann Surg.
2004;239:788-97; discussion 797-9.
17) Jang JW, Kim MH, Jeong SU, Kim J, Park DH, Lee SS, Seo DW,
Lee SK, Kim JH. Clinical characteristics of intraductal papillary
mucinous neoplasm manifesting as acute pancreatitis or acute
recurrent pancreatitis. J Gastroenterol Hepatol. 2013;28:731-8.
18) Valsangkar NP, Morales-Oyarvide V, Thayer SP, Ferrone CR,
Wargo JA, Warshaw AL, Fernández-del Castillo C. 851 resected
cystic tumors of the pancreas: A 33-year experience at the
Massachusetts General Hospital. Surgery. 2012;152:S4-12.
19) Capurso G, Boccia S, Salvia R, Del Chiaro M, Frulloni L,
Arcidiacono PG, Zerbi A, Manta R, Fabbri C, Ventrucci M,
Tarantino I, Piciucchi M, Carnuccio A, Boggi U, Leoncini E,
Costamagna G, Delle Fave G, Pezzilli R, Bassi C, Larghi A; Italian
Association for Study of Pancreas (AISP); Intraductal Papillary
Mucinous Neoplasm (IPMN) Study Group. Risk factors for
intraductal papillary mucinous neoplasm (IPMN) of the
pancreas: A multicentre case-control study. Am J Gastroenterol.
2013;108:1003-9.
20) Lubezky N, Ben-Haim M, Lahat G, Marmor S, Solar I, Brazowski
E, Nackache R, Klausner JM. Intraductal papillary mucinous
neoplasm of the pancreas: Associated cancers, family history,
genetic predisposition? Surgery. 2012;151:70-5.
21) E guchi H, Ishikawa O, Ohigashi H, Tomimaru Y, Sasaki Y,
Yamada T, Tsukuma H, Nakaizumi A, Imaoka S. Patients with
pancreatic intraductal papillary mucinous neoplasms are at high
risk of colorectal cancer development. Surgery. 2006;139:749-54.
22) R iall TS, Stager VM, Nealon WH, Townsend CM Jr, Kuo YF,
Goodwin JS, Freeman JL. Incidence of additional primary
cancers in patients with invasive intraductal papillary mucinous
neoplasms and sporadic pancreatic adenocarcinomas. J Am Coll
Surg. 2007;204:803-13; discussion 813-4.
23) Baumgaertner I, Corcos O, Couvelard A, Sauvanet A, Rebours
V, Vullierme MP, Hentic O, Hammel P, Lévy P, Ruszniewski
P. Prevalence of extrapancreatic cancers in patients with
histologically proven intraductal papillary mucinous neoplasms
of the pancreas: A case-control study. Am J Gastroenterol.
2008;103:2878-82.
24) Adsay NV, Merati K, Andea A, Sarkar F, Hruban RH, Wilentz RE,
Goggins M, Iocobuzio-Donahue C, Longnecker DS, Klimstra
DS. The dichotomy in the preinvasive neoplasia to invasive
carcinoma sequence in the pancreas: Differential expression
of MUC1 and MUC2 supports the existence of two separate
pathways of carcinogenesis. Mod Pathol. 2002;15:1087-95.
25) Silas AM, Morrin MM, Raptopoulos V, Keogan MT. Intraductal
papillary mucinous tumors of the pancreas. AJR Am J
Roentgenol. 2001;176:179-85.
26) Sahani DV, Kadavigere R, Blake M, Fernandez-Del Castillo C,
Lauwers GY, Hahn PF. Intraductal papillary mucinous neoplasm
of pancreas: Multi-detector row CT with 2D curved reformations-
-correlation with MRCP. Radiology. 2006;238:560-9.
27) O gawa H, Itoh S, Ikeda M, Suzuki K, Naganawa S. Intraductal
papillary mucinous neoplasm of the pancreas: Assessment of
the likelihood of invasiveness with multisection CT. Radiology.
2008;248:876-86.
28) W aters JA, Schmidt CM, Pinchot JW, White PB, Cummings
OW , Pitt HA, Sandrasegaran K, Akisik F, Howard TJ, Nakeeb A,
Zyromski NJ, Lillemoe KD. CT vs MRCP: Optimal classification
of IPMN type and extent. J Gastrointest Surg. 2008;12:101-9.
29) Yamao K, Nakamura T, Suzuki T, Sawaki A, Hara K, Kato T,
Okubo K, Matsumoto K, Shimizu Y. Endoscopic diagnosis and
staging of mucinous cystic neoplasms and intraductal papillarymucinous
tumors. J Hepatobiliary Pancreat Surg. 2003;10:142-6.
30) Basturk O, Coban I, Adsay NV. Pancreatic cysts: Pathologic
classification, differential diagnosis, and clinical implications.
Arch Pathol Lab Med. 2009;133:423-38.
31) Klöppel G, Basturk O, Schlitter AM, Konukiewitz B, Esposito
I. Intraductal neoplasms of the pancreas. Semin Diagn Pathol.
2014;31:452-66.
32) W inter JM, Cameron JL, Lillemoe KD, Campbell KA, Chang
D, Riall TS, Coleman J, Sauter PK, Canto M, Hruban RH,
Schulick RD, Choti MA, Yeo CJ. Periampullary and pancreatic
incidentaloma: A single institution's experience with an
increasingly common diagnosis. Ann Surg. 2006;243:673-80;
discussion 680-3.
33) Pelaez-Luna M, Chari ST, Smyrk TC, Takahashi N, Clain JE,
Levy MJ, Pearson RK, Petersen BT, Topazian MD, Vege SS,
Kendrick M, Farnell MB. Do consensus indications for resection
in branch duct intraductal papillary mucinous neoplasm predict
malignancy? A study of 147 patients. Am J Gastroenterol.
2007;102:1759-64.
34) Xiao SY. Intraductal papillary mucinous neoplasm of the
pancreas: An update. Scientifica (Cairo). 2012;2012:893632.
35) Sohn TA, Yeo CJ, Cameron JL, Iacobuzio-Donahue CA, Hruban
RH, Lillemoe KD. Intraductal papillary mucinous neoplasms
of the pancreas: An increasingly recognized clinicopathologic
entity. Ann Surg. 2001;234:313-21; discussion 321-2.
36) Siech M, Tripp K, Schmidt-Rohlfing B, Mattfeldt T, Görich
J, Beger HG. Intraductal papillary mucinous tumor of the
pancreas. Am J Surg. 1999;177:117-20.
37) Tanaka M. Thirty years of experience with intraductal papillary
mucinous neoplasm of the pancreas: From discovery to
international consensus. Digestion. 2014;90:265-72
38) Adsay NV, Adair CF, Heffess CS, Klimstra DS. Intraductal
oncocytic papillary neoplasms of the pancreas. Am J Surg Pathol.
1996;20:980-94.
39) Bosman FT, Carneiro F, Hruban RH. WHO classification for
tumors of the digestive system. Bosman FT, Carneiro F, Hruban
RH, editors. Geneva:WHO; 2010.417.
40) Adsay NV, Klimstra DS, Compton CC. Cystic lesions of the
pancreas. Introduction. Semin Diagn Pathol. 2000;17:1-6.
41) Adsay NV, Merati K, Basturk O, Iacobuzio-Donahue C, Levi E,
Cheng JD, Sarkar FH, Hruban RH, Klimstra DS. Pathologically
and biologically distinct types of epithelium in intraductal
papillary mucinous neoplasms: Delineation of an intestinal
pathway of carcinogenesis in the pancreas. Am J Surg Pathol.
2004;28:839-48.
42) Ban S, Naitoh Y, Mino-Kenudson M, Sakurai T, Kuroda M,
Koyama I, Lauwers GY, Shimizu M. Intraductal papillary
mucinous neoplasm (IPMN) of the pancreas: Its histopathologic
difference between 2 major types. Am J Surg Pathol.
2006;30:1561-9.
43) Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-
Saavedra J, Biankin AV, Biankin SA, Compton C, Fukushima
N, Furukawa T, Goggins M, Kato Y, Klöppel G, Longnecker
DS, Lüttges J, Maitra A, Offerhaus GJ, Shimizu M, Yonezawa
S. An illustrated consensus on the classification of pancreatic
intraepithelial neoplasia and intraductal papillary mucinous
neoplasms. Am J Surg Pathol. 2004;28:977-87.
44) Furukawa T, Klöppel G, Volkan Adsay N, Albores-Saavedra
J, Fukushima N, Horii A, Hruban RH, Kato Y, Klimstra DS,
Longnecker DS, Lüttges J, Offerhaus GJ, Shimizu M, Sunamura
M, Suriawinata A, Takaori K, Yonezawa S. Classification of types
of intraductal papillary-mucinous neoplasm of the pancreas: A
consensus study. Virchows Arch. 2005;447:794-9.
45) Adsay V, Mino-Kenudson M, Furukawa T, Basturk O, Zamboni
G, Marchegiani G, Bassi C, Salvia R, Malleo G, Paiella S, Wolfgang
CL, Matthaei H, Offerhaus GJ, Adham M, Bruno MJ, Reid MD,
Krasinskas A, Klöppel G, Ohike N, Tajiri T, Jang KT, Roa JC,
Allen P, Fernández-del Castillo C, Jang JY, Klimstra DS, Hruban
RH; Members of Verona Consensus Meeting, 2013. Pathologic
evaluation and reporting of intraductal papillary mucinous
neoplasms of the pancreas and other tumoral intraepithelial
neoplasms of pancreatobiliary tract: Recommendations of
Verona Consensus Meeting. Ann Surg. 2016;263:162-77.
46) Shimizu Y, Yamaue H, Maguchi H, Yamao K, Hirono S, Osanai
M, Hijioka S, Hosoda W, Nakamura Y, Shinohara T, Yanagisawa
A. Predictors of malignancy in intraductal papillary mucinous
neoplasm of the pancreas: Analysis of 310 pancreatic resection
patients at multiple high-volume centers. Pancreas. 2013;42:883-8.
47) O hno E, Itoh A, Kawashima H, Ishikawa T, Matsubara H,
Itoh Y, Nakamura Y, Hiramatsu T, Nakamura M, Miyahara R,
Ohmiya N, Ishigami M, Katano Y, Goto H, Hirooka Y. Malignant
transformation of branch duct-type intraductal papillary
mucinous neoplasms of the pancreas based on contrastenhanced
endoscopic ultrasonography morphological changes:
Focus on malignant transformation of intraductal papillary
mucinous neoplasm itself. Pancreas. 2012;41:855-62.
48) Hwang DW, Jang JY, Lim CS, Lee SE, Yoon YS, Ahn YJ, Han HS,
Kim SW, Kim SG, Yun YK, Han SS, Park SJ, Lim TJ, Kang KJ, Sim
MS, Choi SH, Heo JS, Choi DW, Hur KY, Lee DS, Yun SS, Kim
HJ, Cho CK, Kim HJ, Yu HC, Cho BH, Song IS. Determination
of malignant and invasive predictors in branch duct type
intraductal papillary mucinous neoplasms of the pancreas: A
suggested scoring formula. J Korean Med Sci. 2011;26:740-6.
49) Tomimaru Y, Takeda Y, Tatsumi M, Kim T, Kobayashi S,
Marubashi S, Eguchi H, Tanemura M, Kitagawa T, Nagano
H, Umeshita K, Wakasa K, Doki Y, Mori M. Utility of 2-(18F)
fluoro-2-deoxy-D-glucose positron emission tomography in
differential diagnosis of benign and malignant intraductal
papillary-mucinous neoplasm of the pancreas. Oncol Rep.
2010;24:613-20.
50) Mimura T, Masuda A, Matsumoto I, Shiomi H, Yoshida S,
Sugimoto M, Sanuki T, Yoshida M, Fujita T, Kutsumi H, Ku
Y, Azuma T. Predictors of malignant intraductal papillary
mucinous neoplasm of the pancreas. J Clin Gastroenterol.
2010;44:e224-9.
51) Shimamoto T, Tani M, Kawai M, Hirono S, Ina S, Miyazawa M,
Shimizu A, Uchiyama K, Yokoyama S, Tsutsumi M, Yamaue H.
MUC1 is a useful molecular marker for malignant intraductal
papillary mucinous neoplasms in pancreatic juice obtained from
endoscopic retrograde pancreatography. Pancreas. 2010;39:879-83.
52) Basturk O, Hong SM, Wood LD, Adsay NV, Albores-Saavedra
J, Biankin AV, Brosens LA, Fukushima N, Goggins M, Hruban
RH, Kato Y, Klimstra DS, Klöppel G, Krasinskas A, Longnecker
DS, Matthaei H, Offerhaus GJ, Shimizu M, Takaori K, Terris B,
Yachida S, Esposito I, Furukawa T; Baltimore Consensus Meeting.
A Revised Classification System and Recommendations From
the Baltimore Consensus Meeting for Neoplastic Precursor
Lesions in the Pancreas. Am J Surg Pathol. 2015;39:1730-41.
53) Hruban R, Pitman MB, Klimstra DS. Tumors of the Pancreas.
AFIP atlas of tumor pathology. Washington, DC: American
Registry of Pathology;2007.
54) Adsay NV, Conlon KC, Zee SY, Brennan MF, Klimstra DS.
Intraductal papillary-mucinous neoplasms of the pancreas:
An analysis of in situ and invasive carcinomas in 28 patients.
Cancer. 2002;94:62-77.
55) Grützmann R, Post S, Saeger HD, Niedergethmann M.
Intraductal papillary mucinous neoplasia (IPMN) of the
pancreas: Its diagnosis, treatment, and prognosis. Dtsch Arztebl
Int. 2011;108:788-94.
56) R aut CP, Cleary KR, Staerkel GA, Abbruzzese JL, Wolff RA,
Lee JH, Vauthey JN, Lee JE, Pisters PW, Evans DB. Intraductal
papillary mucinous neoplasms of the pancreas: Effect of invasion
and pancreatic margin status on recurrence and survival. Ann
Surg Oncol. 2006;13:582-94.
57) Chari ST. Intraductal Papillary Mucinous Neoplasm. Curr Treat
Options Gastroenterol. 2002;5:339-344.
58) Adsay NV, Longnecker DS, Klimstra DS. Pancreatic tumors with
cystic dilatation of the ducts: Intraductal papillary mucinous
neoplasms and intraductal oncocytic papillary neoplasms.
Semin Diagn Pathol. 2000;17:16-30.
59) Klöppel G, Kosmahl M, Lüttges J. Intraductal neoplasms of the
pancreas: Cystic and common. Pathologe. 2005;26:31-6.
60) Kim YI, Shin SH, Song KB, Hwang DW, Lee JH, Park KM, Lee YJ,
Kim SC. Branch duct intraductal papillary mucinous neoplasm
of the pancreas: Single-center experience with 324 patients who
underwent surgical resection. Korean J Hepatobiliary Pancreat
Surg. 2015;19:113-20.
61) Basturk O, Khayyata S, Klimstra DS, Hruban RH, Zamboni
G, Coban I, Adsay NV. Preferential expression of MUC6 in
oncocytic and pancreatobiliary types of intraductal papillary
neoplasms highlights a pyloropancreatic pathway, distinct from
the intestinal pathway, in pancreatic carcinogenesis. Am J Surg
Pathol. 2010;34:364-70.
62) Ideno N, Ohtsuka T, Kono H, Fujiwara K, Oda Y, Aishima S, Ito
T, Ishigami K, Tokunaga S, Ohuchida K, Takahata S, Nakamura
M, Mizumoto K, Tanaka M. Intraductal papillary mucinous
neoplasms of the pancreas with distinct pancreatic ductal
adenocarcinomas are frequently of gastric subtype. Ann Surg.
2013;258:141-51.
63) Adsay NV, Merati K, Nassar H, Shia J, Sarkar F, Pierson CR,
Cheng JD, Visscher DW, Hruban RH, Klimstra DS. Pathogenesis
of colloid (pure mucinous) carcinoma of exocrine organs:
Coupling of gel-forming mucin (MUC2) production with
altered cell polarity and abnormal cell-stroma interaction may
be the key factor in the morphogenesis and indolent behavior of
colloid carcinoma in the breast and pancreas. Am J Surg Pathol.
2003;27:571-8.
64) Adsay NV, Pierson C, Sarkar F, Abrams J, Weaver D, Conlon
KC, Brennan MF, Klimstra DS. Colloid (mucinous noncystic)
carcinoma of the pancreas. Am J Surg Pathol. 2001;25:26-42.
65) Seidel G, Zahurak M, Iacobuzio-Donahue C, Sohn TA, Adsay
NV, Yeo CJ, Lillemoe KD, Cameron JL, Hruban RH, Wilentz RE.
Almost all infiltrating colloid carcinomas of the pancreas and
periampullary region arise from in situ papillary neoplasms: A
study of 39 cases. Am J Surg Pathol. 2002;26:56-63.
66) Shimada K, Sakamoto Y, Sano T, Kosuge T, Hiraoka N. Invasive
carcinoma originating in an intraductal papillary mucinous
neoplasm of the pancreas: A clinicopathologic comparison
with a common type of invasive ductal carcinoma. Pancreas.
2006;32:281-7.
67) Schnelldorfer T, Sarr MG, Nagorney DM, Zhang L, Smyrk TC,
Qin R, Chari ST, Farnell MB. Experience with 208 resections for
intraductal papillary mucinous neoplasm of the pancreas. Arch
Surg. 2008;143:639-46; discussion 646.
68) Falconi M, Salvia R, Bassi C, Zamboni G, Talamini G, Pederzoli
P. Clinicopathological features and treatment of intraductal
papillary mucinous tumour of the pancreas. Br J Surg.
2001;88:376-81.
69) Jr CM, Dixon E. Intraductal papillary mucinous neoplasm:
Coming of age. World J Gastrointest Surg. 2010;2:299-305.
70) Cuillerier E, Cellier C, Palazzo L, Devière J, Wind P, Rickaert
F, Cugnenc PH, Cremer M, Barbier JP. Outcome after surgical
resection of intraductal papillary and mucinous tumors of the
pancreas. Am J Gastroenterol. 2000;95:441-5.
71) D'Angelica M, Brennan MF, Suriawinata AA, Klimstra D, Conlon
KC. Intraductal papillary mucinous neoplasms of the pancreas:
An analysis of clinicopathologic features and outcome. Ann
Surg. 2004;239:400-8.
72) Nara S, Shimada K, Sakamoto Y, Esaki M, Kosuge T, Hiraoka N.
Clinical significance of frozen section analysis during resection
of intraductal papillary mucinous neoplasm: Should a positive
pancreatic margin for adenoma or borderline lesion be resected
additionally? J Am Coll Surg. 2009;209:614-21.
73) Matthaei H, Hong SM, Mayo SC, dal Molin M, Olino K, Venkat
R, Goggins M, Herman JM, Edil BH, Wolfgang CL, Cameron
JL, Schulick RD, Maitra A, Hruban RH. Presence of pancreatic
intraepithelial neoplasia in the pancreatic transection margin
does not influence outcome in patients with R0 resected
pancreatic cancer. Ann Surg Oncol. 2011;18:3493-9.
74) Fujii T, Kato K, Kodera Y, Kanda M, Nagai S, Yamada S, Kanzaki
A, Sugimoto H, Nomoto S, Takeda S, Morita S, Nakamura S,
Nakao A. Prognostic impact of pancreatic margin status in
the intraductal papillary mucinous neoplasms of the pancreas.
Surgery. 2010;148:285-90.
75) Nishigami T, Onodera M, Torii I, Sato A, Tao LH, Kushima R,
Kakuno A, Kishimoto M, Katsuyama E, Fujimori T, Hirano H,
Satake M, Kuroda N, Nishiguchi S, Fujimoto J, Tsujimura T.
Comparison between mucinous cystic neoplasm and intraductal
papillary mucinous neoplasm of the branch duct type of the
pancreas with respect to expression of CD10 and cytokeratin 20.
Pancreas. 2009;38:558-64.
76) Tobi M, Hatfield J, Adsay V, Galagan K, Kozarek R, Inagaki M,
Kasai S, Tokusashi Y, Obara T, Hruban RH, Lough J, Barkun
AN, Jabbari M, Sheikh R, Ruebner B, Lawson MJ, Ben-Josef
E, Fligiel S. Prognostic significance of the labeling of Adnab-9
in pancreatic intraductal papillary mucinous neoplasms. Int J
Pancreatol. 2001;29:141-50.
77) Lüttges J, Zamboni G, Longnecker D, Klöppel G. The
immunohistochemical mucin expression pattern distinguishes
different types of intraductal papillary mucinous neoplasms of
the pancreas and determines their relationship to mucinous
noncystic carcinoma and ductal adenocarcinoma. Am J Surg
Pathol. 2001;25:942-8.
78) Nakamura A, Horinouchi M, Goto M, Nagata K, Sakoda K,
Takao S, Imai K, Kim YS, Sato E, Yonezawa S. New classification
of pancreatic intraductal papillary-mucinous tumour by mucin
expression: Its relationship with potential for malignancy. J
Pathol. 2002;197:201-10.
79) Yonezawa S, Taira M, Osako M, Kubo M, Tanaka S, Sakoda K,
Takao S, Aiko T, Yamamoto M, Irimura T, Kim YS, Sato E. MUC-
1 mucin expression in invasive areas of intraductal papillary
mucinous tumors of the pancreas. Pathol Int. 1998;48:319-22.
80) Levi E, Klimstra DS, Andea A, Basturk O, Adsay NV. MUC1 and
MUC2 in pancreatic neoplasia. J Clin Pathol. 2004;57:456-62.
81) Terada T, Ohta T, Kitamura Y, Ashida K, Matsunaga Y, Kato M.
Endocrine cells in intraductal papillary-mucinous neoplasms of
the pancreas. A histochemical and immunohistochemical study.
Virchows Arch. 1997;431:31-6.
82) Furukawa T, Kuboki Y, Tanji E, Yoshida S, Hatori T, Yamamoto
M, Shibata N, Shimizu K, Kamatani N, Shiratori K. Wholeexome
sequencing uncovers frequent GNAS mutations in
intraductal papillary mucinous neoplasms of the pancreas. Sci
Rep. 2011;1:161.
83) O dze RD, Goldblum JR. Odze and Goldblum surgical pathology
of the GI tract, liver, biliary tract and pancreas. 3rd ed.
Philadelphia, PA: Saunders; 2014.
84) W u J, Matthaei H, Maitra A, Dal Molin M, Wood LD, Eshleman
JR, Goggins M, Canto MI, Schulick RD, Edil BH, Wolfgang
CL, Klein AP, Diaz LA Jr, Allen PJ, Schmidt CM, Kinzler KW,
Papadopoulos N, Hruban RH, Vogelstein B. Recurrent GNAS
mutations define an unexpected pathway for pancreatic cyst
development. Sci Transl Med. 2011;3:92ra66.
85) Xiao HD, Yamaguchi H, Dias-Santagata D, Kuboki Y,
Akhavanfard S, Hatori T, Yamamoto M, Shiratori K, Kobayashi
M, Shimizu M, Fernandez-Del Castillo C, Mino-Kenudson M,
Furukawa T. Molecular characteristics and biological behaviours
of the oncocytic and pancreatobiliary subtypes of intraductal
papillary mucinous neoplasms. J Pathol. 2011;224:508-16.
86) Mohri D, Asaoka Y, Ijichi H, Miyabayashi K, Kudo Y, Seto M,
Ohta M, Tada M, Tanaka Y, Ikenoue T, Tateishi K, Isayama H,
Kanai F, Fukushima N, Tada M, Kawabe T, Omata M, Koike K.
Different subtypes of intraductal papillary mucinous neoplasm
in the pancreas have distinct pathways to pancreatic cancer
progression. J Gastroenterol. 2012;47:203-13.
87) Tan MC, Basturk O, Brannon AR, Bhanot U, Scott SN, Bouvier
N, LaFemina J, Jarnagin WR, Berger MF, Klimstra D, Allen
PJ. GNAS and KRAS mutations define separate progression
pathways in intraductal papillary mucinous neoplasmassociated
carcinoma. J Am Coll Surg. 2015;220:845-54.e1.
88) Amato E, Molin MD, Mafficini A, Yu J, Malleo G, Rusev B,
Fassan M, Antonello D, Sadakari Y, Castelli P, Zamboni G,
Maitra A, Salvia R, Hruban RH, Bassi C, Capelli P, Lawlor RT,
Goggins M, Scarpa A. Targeted next-generation sequencing
of cancer genes dissects the molecular profiles of intraductal
papillary neoplasms of the pancreas. J Pathol. 2014;233:217-27.
89) Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras
MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C,
Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh
E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff
S, Leonard C, Newell F, Waddell N, Wood S, Xu Q, Wilson
PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A,
Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu J, Pinese M,
Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES,
Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M, Scarlett
CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG,
Lovell JA, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour
A, Zeps N, Moran-Jones K, Jamieson NB, Graham JS, Duthie
F, Oien K, Hair J, Grützmann R, Maitra A, Iacobuzio-Donahue
CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C,
Rusev B, Capelli P, Salvia R, Tortora G, Mukhopadhyay D,
Petersen GM; Australian Pancreatic Cancer Genome Initiative,
Munzy DM, Fisher WE, Karim SA, Eshleman JR, Hruban RH,
Pilarsky C, Morton JP, Sansom OJ, Scarpa A, Musgrove EA,
Bailey UM, Hofmann O, Sutherland RL, Wheeler DA, Gill AJ,
Gibbs RA, Pearson JV, Waddell N, Biankin AV, Grimmond SM.
Genomic analyses identify molecular subtypes of pancreatic
cancer. Nature. 2016;531:47-52.
90) Tanno S, Nakano Y, Sugiyama Y, Nakamura K, Sasajima J, Koizumi
K, Yamazaki M, Nishikawa T, Mizukami Y, Yanagawa N, Fujii T,
Obara T, Okumura T, Kohgo Y. Incidence of synchronous and
metachronous pancreatic carcinoma in 168 patients with branch
duct intraductal papillary mucinous neoplasm. Pancreatology.
2010;10:173-8.
91) Furukawa T, Hatori T, Fujita I, Yamamoto M, Kobayashi M,
Ohike N, Morohoshi T, Egawa S, Unno M, Takao S, Osako M,
Yonezawa S, Mino-Kenudson M, Lauwers GY, Yamaguchi H,
Ban S, Shimizu M. Prognostic relevance of morphological types
of intraductal papillary mucinous neoplasms of the pancreas.
Gut. 2011;60:509-16.
92) Mino-Kenudson M, Fernández-del Castillo C, Baba Y,
Valsangkar NP, Liss AS, Hsu M, Correa-Gallego C, Ingkakul T,
Perez Johnston R, Turner BG, Androutsopoulos V, Deshpande
V, McGrath D, Sahani DV, Brugge WR, Ogino S, Pitman MB,
Warshaw AL, Thayer SP. Prognosis of invasive intraductal
papillary mucinous neoplasm depends on histological and
precursor epithelial subtypes. Gut. 2011;60:1712-20.
93) W hite R, D'Angelica M, Katabi N, Tang L, Klimstra D, Fong Y,
Brennan M, Allen P. Fate of the remnant pancreas after resection
of noninvasive intraductal papillary mucinous neoplasm. J Am
Coll Surg. 2007;204:987-93; discussion 993-5.
94) Yamada S, Fujii T, Shimoyama Y, Kanda M, Nakayama G,
Sugimoto H, Koike M, Nomoto S, Fujiwara M, Nakao A,
Kodera Y. Clinical implication of morphological subtypes in
management of intraductal papillary mucinous neoplasm. Ann
Surg Oncol. 2014;21:2444-52.
95) Koh YX, Chok AY, Zheng HL, Tan CS, Goh BK. Systematic
review and meta-analysis comparing the surgical outcomes
of invasive intraductal papillary mucinous neoplasms and
conventional pancreatic ductal adenocarcinoma. Ann Surg
Oncol. 2014;21:2782-800.
96) De Moor V, Arvanitakis M, Nagy N, Coppens E, Delhaye M,
Closset J. Intraductal papillary mucinous neoplasms of the
pancreas: Clinicopathological features and long term outcome
related to histopathological group. Hepatogastroenterology.
2012;59:565-9.
97) W aters JA, Schnelldorfer T, Aguilar-Saavedra JR, Chen JH,
Yiannoutsos CT, Lillemoe KD, Farnell MB, Sarr MG, Schmidt
CM. Survival after resection for invasive intraductal papillary
mucinous neoplasm and for pancreatic adenocarcinoma: A
multi-institutional comparison according to American Joint
Committee on Cancer Stage. J Am Coll Surg. 2011;213:275-83.
98) Yamaguchi K, Kanemitsu S, Hatori T, Maguchi H, Shimizu Y,
Tada M, Nakagohri T, Hanada K, Osanai M, Noda Y, Nakaizumi
A, Furukawa T, Ban S, Nobukawa B, Kato Y, Tanaka M.
Pancreatic ductal adenocarcinoma derived from IPMN and
pancreatic ductal adenocarcinoma concomitant with IPMN.
Pancreas. 2011;40:571-80.
99) Yopp AC, Katabi N, Janakos M, Klimstra DS, D'Angelica MI,
DeMatteo RP, Fong Y, Brennan MF, Jarnagin WR, Allen PJ.
Invasive carcinoma arising in intraductal papillary mucinous
neoplasms of the pancreas: A matched control study with
conventional pancreatic ductal adenocarcinoma. Ann Surg.
2011;253:968-74.
100) Bassi C, Sarr MG, Lillemoe KD, Reber HA. Natural history of
intraductal papillary mucinous neoplasms (IPMN): Current
evidence and implications for management. J Gastrointest Surg.
2008;12:645-50.
101) Simons JP, Ng SC, Shah SA, McDade TP, Whalen GF, Tseng JF.
Malignant intraductal papillary mucinous neoplasm: Are we
doing the right thing? J Surg Res. 2011;167:251-7.
102) Ishida M, Egawa S, Sakata N, Mikami Y, Motoi F, Abe T,
Fukuyama S, Sunamura M, Furukawa T, Unno M. Intraductal
papillary-mucinous adenocarcinoma in the remnant pancreas
after pancreatoduodenectomy for cancer of Vater's papilla
associated with intraductal papillary-mucinous adenoma. J
Hepatobiliary Pancreat Surg. 2007;14:522-5.
103) Klimstra DS. Cystic, mucin-producing neoplasms of the
pancreas: The distinguishing features of mucinous cystic
neoplasms and intraductal papillary mucinous neoplasms.
Semin Diagn Pathol. 2005;22:318-29.
104) Tanaka M, Fernández-del Castillo C, Adsay V, Chari S, Falconi
M, Jang JY, Kimura W, Levy P, Pitman MB, Schmidt CM,
Shimizu M, Wolfgang CL, Yamaguchi K, Yamao K; International
Association of Pancreatology. International consensus guidelines
2012 for the management of IPMN and MCN of the pancreas.
Pancreatology. 2012;12:183-97.
105) Jang KT, Park SM, Basturk O, Bagci P, Bandyopadhyay S, Stelow
EB, Walters DM, Choi DW, Choi SH, Heo JS, Sarmiento JM, Reid
MD, Adsay V. Clinicopathologic characteristics of 29 invasive
carcinomas arising in 178 pancreatic mucinous cystic neoplasms
with ovarian-type stroma: Implications for management and
prognosis. Am J Surg Pathol. 2015;39:179-87.
106) Masia R, Mino-Kenudson M, Warshaw AL, Pitman MB, Misdraji
J. Pancreatic mucinous cystic neoplasm of the main pancreatic
duct. Arch Pathol Lab Med. 2011;135:264-7.
107) Izumo A, Yamaguchi K, Eguchi T, Nishiyama K, Yamamoto H,
Yonemasu H, Yao T, Tanaka M, Tsuneyoshi M. Mucinous cystic
tumor of the pancreas: Immunohistochemical assessment of
ovarian-type stroma. Oncol Rep. 2003;10:515-25.
108) Fukushima N, Zamboni G. Mucinous cystic neoplasms of the
pancreas: Update on the surgical pathology and molecular
genetics. Semin Diagn Pathol. 2014;31:467-74.
109) Fukushima N, Fukayama M. Mucinous cystic neoplasms of the
pancreas: Pathology and molecular genetics. J Hepatobiliary
Pancreat Surg. 2007;14:238-42.
110) Nguyen BN, Edgecombe A, Gomes M, Soucy G, Marginean
CE, Mai KT. Comparative immunohistochemical study of the
stroma of serous and mucinous cystic neoplasms: Possible
histopathogenetic relationship of the 2 entities. Pancreas.
2011;40:37-41.
111) Fukushima N, Sato N, Prasad N, Leach SD, Hruban RH, Goggins
M. Characterization of gene expression in mucinous cystic
neoplasms of the pancreas using oligonucleotide microarrays.
Oncogene. 2004;23:9042-51.
112) Yeh MM, Tang LH, Wang S, Robert ME, Zheng W, Jain D.
Inhibin expression in ovarian-type stroma in mucinous cystic
neoplasms of the pancreas. Appl Immunohistochem Mol
Morphol. 2004;12:148-52.
113) W ilentz RE, Albores-Saavedra J, Hruban RH. Mucinous cystic
neoplasms of the pancreas. Semin Diagn Pathol. 2000;17:31-42.
114) Thompson LD, Becker RC, Przygodzki RM, Adair CF, Heffess
CS. Mucinous cystic neoplasm (mucinous cystadenocarcinoma
of low-grade malignant potential) of the pancreas: A
clinicopathologic study of 130 cases. Am J Surg Pathol.
1999;23:1-16.
115) Zamboni G, Scarpa A, Bogina G, Iacono C, Bassi C, Talamini G,
Sessa F, Capella C, Solcia E, Rickaert F, Mariuzzi GM, Klöppel
G. Mucinous cystic tumors of the pancreas: Clinicopathological
features, prognosis, and relationship to other mucinous cystic
tumors. Am J Surg Pathol. 1999;23:410-22.
116) O hta T, Nagakawa T, Fukushima W, Mori K, Kayahara M,
Akiyama T, Kanno M, Ueno K, Miyazaki I, Terada T, et al.
Immunohistochemical study of carcinoembryonic antigen
in mucinous cystic neoplasm of the pancreas. Eur Surg Res.
1992;24:37-44.
117) Lüttges J, Feyerabend B, Buchelt T, Pacena M, Klöppel G. The
mucin profile of noninvasive and invasive mucinous cystic
neoplasms of the pancreas. Am J Surg Pathol. 2002;26:466-71.
118) Bagci P, Andea AA, Basturk O, Jang KT, Erbarut I, Adsay V.
Large duct type invasive adenocarcinoma of the pancreas with
microcystic and papillary patterns: A potential microscopic
mimic of non-invasive ductal neoplasia. Mod Pathol.
2012;25:439-48.
119) Kloppel G. Clinicopathologic view of intraductal papillarymucinous
tumor of the pancreas. Hepatogastroenterology.
1998;45:1981-5.
120) Krasinskas AM, Oakley GJ, Bagci P, Jang KT, Kuan SF, Reid MD,
Erbarut I, Adsay V. Simple Mucinous Cyst of the Pancreas: A
clinicopathologic analysis of 39 examples of a diagnostically
challenging entity distinct from intraductal papillary mucinous
neoplasms and mucinous cystic neoplasms. Am J Surg Pathol.
2017;41:121-127.
121) Basturk O, Chung SM, Hruban RH, Adsay NV, Askan G,
Iacobuzio-Donahue C, Balci S, Zee SY, Memis B, Shia J, Klimstra
DS. Distinct pathways of pathogenesis of intraductal oncocytic
papillary neoplasms and intraductal papillary mucinous
neoplasms of the pancreas. Virchows Arch. 2016;469:523-532.