Adsay Icpn 2012

ORIGINAL ARTICLE
Intracholecystic Papillary-Tubular Neoplasms (ICPN)

of the Gallbladder (Neoplastic Polyps, Adenomas,
and Papillary Neoplasms That Are Z1.0 cm)
Clinicopathologic and Immunohistochemical
Analysis of 123 Cases
Volkan Adsay, MD,* Kee-Taek Jang, MD,w Juan Carlos Roa, MD,z Nevra Dursun, MD,y
Nobuyuki Ohike, MD,8 Pelin Bagci, MD,z Olca Basturk, MD,# Sudeshna Bandyopadhyay, MD,**
Jeanette D. Cheng, MD,ww Juan M. Sarmiento, MD,zz Oscar Tapia Escalona, MD,z
Michael Goodman, MD,yy So Yeon Kong, MPH,yy and Paul Terry, PhD, MPH88
Abstract: The literature on the clinicopathologic characteristics

of tumoral intraepithelial neoplasms (neoplastic polyps) of the
gallbladder (GB) is fairly limited, due in part to the variability in
denition and terminology. Most reported adenomas (pyloric
gland type and others) were microscopic and thus regarded as
clinically inconsequential, whereas papillary in situ carcinomas
have been largely considered a type of invasive adenocarcinoma
under the heading of papillary adenocarcinomas. In this
study, 123 GB cases that have a well-dened exophytic preinvasive neoplasm measuring Z1 cm were analyzed. The patients were predominantly female (F/M = 2:1) with a mean age
of 61 y and a median tumor size of 2.2 cm. Half of the patients
presented with pain, and in the other half the neoplasm was
From the Departments of *Pathology; zzSurgery; wwPiedmont Hospital,
Emory University School of Medicine; yyDepartment of Epidemiology, Emory University School of Public Health, Atlanta, GA;
#Memorial Sloan-Kettering Cancer Center, New York, NY; **The
Karmanos Cancer Institute and Wayne State University, Detroit,
MI; 88Department of Public Health, College of Education, Health &
Human Sciences, The University of Tennessee of Knoxville, TN;
wDepartment of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; zDepartment of
Pathology, Frontera University School of Medicine, Temuco, Chile;
yDepartment of Pathology, Istanbul Education and Research Hospital, Istanbul, Turkey; 8First Department of Pathology, Showa
University School of Medicine, Tokyo, Japan; and zDepartment of
Pathology, Rize University, School of Medicine, Rize, Turkey.
V.A. and K-T.J. contributed equally.
Presented in part at the annual meeting of the United States and
Canadian Academy of Pathology in Washington, DC, March 2010,
and San Antonio, TX, March 2011.
Conicts of Interest and Source of Funding: Supported in part by
Fondecyt Grant #1090171, Chile, and in part by the Georgia Cancer
Coalition Distinguished Cancer Clinicians and Scientists Program,
GA. The authors have disclosed that they have no signicant relationships with, or nancial interest in, any commercial companies
pertaining to this article.
Correspondence: Volkan Adsay, MD, Department of Pathology and
Laboratory Medicine, Emory University Hospital, 1364 Clifton
Road NE, Atlanta, GA 30322 (e-mail: volkan.adsay@emory.edu).
Copyright r 2012 by Lippincott Williams & Wilkins
Am J Surg Pathol
Volume 36, Number 9, September 2012
detected incidentally. Other neoplasms, most being gastrointestinal tract malignancies, were present in 22% of cases.
Gallstones were identied in only 20% of cases. Radiologically,
almost half were diagnosed as cancer, roughly half with polypoid tumor, and in 10% the lesion was missed. Pathologic
ndings: (1) The predominant conguration was papillary in
43%, tubulopapillary in 31%, tubular in 26%. (2) Each case was
assigned a nal lineage type on the basis of the predominant
pattern (> 75% of the lesion) on morphology, and supported
with specic immunohistochemical cell lineage markers. The
predominant cell lineage could be identied as biliary in 50%
(66% of which were MUC1+), gastric foveolar in 16% (all were
MUC5AC+), gastric pyloric in 20% (92% MUC6+), intestinal
in 8% (100% CK20+; 75% CDX2+; 50%, MUC2+), and oncocytic in 6% (17% HepPar+ and 17% MUC6+); however,
90% of cases had some amount of secondary or unclassiable
pattern and hybrid immunophenotypes. (3) Of the cases that
would have qualied as pyloric gland adenoma, 21/24 (88%)
had at least focal high-grade dysplasia and 18% had associated
invasive carcinoma. Conversely, 8 of 47 papillary adenocarcinoma-type cases displayed some foci of low-grade dysplasia,
and 15/47 (32%) had no identiable invasion. (4) Overall,
55% of the cases had an associated invasive carcinoma (pancreatobiliary type, 58; others, 10). Factors associated signicantly with invasion were the extent of high-grade dysplasia,
cell type (biliary or foveolar), and papilla formation. Among
systematically analyzed invasive carcinomas, tumoral intraepithelial neoplasia was detected in 6.4% (39/606). (5) The 3year actuarial survival was 90% for cases without invasion and
60% for those associated with invasion. In contrast, those associated with invasion had a far better clinical outcome compared with pancreatobiliary-type GB carcinomas (3-yr survival,
27%), and this survival advantage persisted even with stagematched comparison. Death occurred in long-term follow-up
even in a few noninvasive cases (4/55; median 73.5 mo) emphasizing the importance of long-term follow-up. In conclusion,
tumoral preinvasive neoplasms (Z1 cm) in the GB are analogous to their pancreatic and biliary counterparts (biliary
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intraductal papillary neoplasms, pancreatic intraductal papillary

mucinous neoplasms, and intraductal tubulopapillary neoplasms). They show variable cellular lineages, a spectrum of
dysplasia, and a mixture of papillary or tubular growth patterns,
often with signicant overlap, warranting their classication
under 1 unied parallel category, intracholecystic papillarytubular neoplasm. Intracholecystic papillary-tubular neoplasms
are relatively indolent neoplasia with signicantly better prognosis compared with pancreatobiliary-type GB carcinomas. In
contrast, even seemingly innocuous examples such as those referred to as pyloric gland adenomas can progress to carcinoma and be associated with invasion and fatal outcome.
Key Words: gallbladder, adenoma, carcinoma, in situ, preinvasive neoplasm, papillary, pyloric, tubular, intestinal,
oncocytic, biliary
(Am J Surg Pathol 2012;36:12791301)
n the pancreatobiliary tract, tumors composed of preinvasive neoplastic (dysplastic) cells that form clinically
detectable (Z1.0 cm) masses are now classied under a
unied category of intraductal papillary neoplasms
(IPNs) in the bile ducts1 and as intraductal papillary
mucinous neoplasms (IPMNs) or intraductal tubulopapillary neoplasms (ITPNs) in the pancreas2 (Fig. 1). It is
now well established that these preinvasive neoplasms
(what we term tumoral intraepithelial neoplasms) represent an adenoma-carcinoma sequence,318 and that
their clinicopathologic, immunophenotypic, and molecular characteristics as well as biological behavior are
dierent from the nontumoral (at)-type preinvasive neoplasms of the respective organs.5,8,10,14,15,19 At the same
time, they are also distinct from the conventional invasive
cancers of these sites for which they are often mistaken
because of their mass-forming nature.2,10,2034
In the pancreas, in which such tumors are best
characterized, the category of IPMN was created to encompass a wide spectrum of lesions ranging from innocuous cysts lined by gastric foveolar epithelium without
atypia (previously called hyperplasia by the Japanese
Pathology Society) and those that resemble villous adenomas, associated with extensive invasive carcinoma of
the mucinous type [previously called papillary mucinous
carcinoma by World Health Organization (WHO)],35 to
those that have complex papillary architecture associated
with invasive carcinoma of the pancreatobiliary type, which
used to be called papillary adenocarcinomas.2628 The
rare pyloric gland adenoma type lesions36,37 are now also
regarded as part of the IPMN category.2 More recently,
nonmucinous examples of tumoral intraepithelial neoplasia
that occur in the pancreas have also been characterized and
have been recognized by the WHO as ITPNs.2,28,3841
Recognition of pancreatic IPMNs has led to
the reappraisal of preinvasive lesions in the biliary
tract.20,22,42 Many authors originally adopted the term
biliary IPMN,4349 a category that encompasses tubular, papillary, and villous preinvasive neoplasms including
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FIGURE 1. Terminologic and conceptual analogy between

tumoral intraepithelial neoplasms occurring in the ampullopancreatobiliary tract. IPMN and ITPN of the pancreas and IPN
of the bile ducts are recognized by the WHO. IAPN is the
category designation we recently proposed for those occurring in the ampulla. These show numerous similarities to
adenomas and intracystic papillary neoplasms of the GB,
and thus warranting these lesions to be unified under 1
heading for which we propose the term ICPN.
papillomatosis.20,22,31,4245,5053 However, because mucin

production is much less evident in these biliary examples,
these are now unied under the heading of intraductal
papillary neoplasm (IPN) in the 2010 WHO classication
for both intrahepatic and extrahepatic lesions.1 Likewise,
we recently showed that in the ampulla of Vater, there
is occurrence of analogous tumoral intraepithelial neoplasms with distinctive properties. Accordingly, we proposed the term intra-ampullary papillary-tubular neoplasms
(IAPNs).54
A similar spectrum of lesions also exists but has not
yet been fully characterized in the gallbladder (GB). A
plethora of names have been used including pyloric
gland adenoma, papillary adenoma, tubulopapillary
adenoma, intestinal adenoma, biliary adenoma,
transitional adenoma, papillary neoplasm, papillary
carcinoma, intracystic papillary neoplasm,1,15,5577
and others, for many of which only a handful of cases
have been reported in the literature.7887 It should be
noted here that some of these names are based on the
growth pattern, some on cell lineage, and others on the
degree of neoplastic change, rendering this terminology
dicult to use, especially considering the frequency of
overlap and occurrence of all 3 parameters in a given case.
The most recent WHO classication attempted to address
this issue by creating 2 generic categories, adenoma
versus intracystic papillary neoplasm, each with several
subsets. However, no criteria were provided as to how
much papilla formation would qualify a lesion as intracystic papillary neoplasm rather than adenoma, or how
much high-grade dysplasia (HGD) is allowable in the
adenoma category.
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Adenoma is, in fact, one of the most commonly

used terms in the literature for these lesions but refer
mostly, and sometimes exclusively, to pyloric gland adenomas,55,65,68,73,88,89 whereas other authors also include
papillary lesions or intestinal-type neoplasms15,33,58,67 in
the adenoma category. Furthermore, in the 3 largest
published series on adenomas, the mean tumor size
was 7.2, 8.2, and 9.8 mm and included lesions as small as
0.5, 1, and 3 mm,65,73,88 most of which may represent
polypoid metaplasia. This created the impression that
adenomas are invariably benign33,88,90,91; although with
careful dissection of the literature, it becomes clear that
the ones >1 cm are commonly associated with carcinoma.13,15,59,68,73,74,90,92100 At the other end of the spectrum, papillary preinvasive neoplasms of the GB are also
tumoral intraepithelial neoplasms, but have mostly been
excluded from the analysis of preinvasive neoplasms because they are commonly associated with invasive carcinoma. They have typically been studied along with
conventional (pancreatobiliary-type) GB cancers as their
papillary adenocarcinoma type, although it was recently shown by Albores-Saavedra et al57 that noninvasive cases, not surprisingly, may have a very good
prognosis. Further, the reported percentage of invasive
GB carcinomas, which arise from the adenomacarcinoma sequence as opposed to the (at) dysplasiacarcinoma sequence11,66,73,89,101103 ranges widely, from
5% to 23%.13,15,66,68,73 Thus, because of the highly variable denitions, along with the relative rarity of these
neoplasms, it has been dicult to determine the frequency
and clinicopathologic characteristics and, more importantly, their association with invasive carcinoma and
behavior.
The aim of this study is to analyze neoplastic polypoid adenomatous and papillary preinvasive neoplasia
(tumoral intraepithelial neoplasia) of the GB through the
perspective of recently developed concepts and criteria for
elsewhere in the pancreatobiliary tract (Fig. 1). Accordingly, we performed a detailed clinicopathologic analysis
of 123 neoplasms Z1 cm in our surgical database, which
we propose to classify under the conceptual category of
intracholecystic papillary-tubular neoplasm (ICPN).
MATERIALS AND METHODS

The studies were conducted in accordance with the
Institutional Review Board requirements.
Case Selection
From the authors institutional and consultation
surgical pathology databases, all the cases carrying the
diagnosis of GB polyp, adenoma, neoplasm, and
papillary were retrieved. In addition, 3265 consecutive
routine cholecystectomies performed in the authors institutions (removed for gallstones and cholecystitis) and
606 consecutive invasive GB carcinoma cases, including
early GB carcinomas,73,104 were analyzed systematically
to determine the frequency of these lesions. Cases that
fullled the following criteria were designated as ICPN
and included in this study.
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Inclusion Criteria
Exophytic (papillary or polypoid) intramucosal GB
masses that measure Z1.0 cm and are composed of preinvasive neoplastic (dysplastic) cells forming a compact
lesion distinct from the neighboring mucosa (Table 1)
(Figs. 2, 3) are included.
The criterion of Z1.0 cm is the same as that used
elsewhere in the pancreatobiliary tract to distinguish these
tumoral intraepithelial neoplasms (pancreatic IPMN,
pancreatic ITPN, and the IPN of the extrahepatic and
intrahepatic bile duct) from their nontumoral counterparts (PanINs and BilINs).27 Furthermore, this Z1.0 cm
measurement was also adopted as the specic denition
of these entities by the recent WHO classication.2,27
Lesions <1 cm were not analyzed and were considered
either at forms of dysplasia or, if they formed a distinct nodule, as incipient forms of tumoral intraepithelial neoplasia (38 cases), in accordance with the
current practice for the pancreatic IPMNs.2,27,105 Moreover, the Z1.0 cm criterion is widely used as the indication for cholecystectomy for polypoid GB lesions
detected by imaging studies, both by surgeons and radiologists. This is based mostly on the nding from large
clinical studies that lesions <1 cm are seldom harmful to
the patient and are not removed unless symptomatic.13,59,68,74,9097,99,106113 Nevertheless, it should be
noted that the criterion of Z1.0 cm is arbitrary and by no
means indicates that dysplastic lesions <1.0 cm are unrelated or insignicant.
Exclusion Criteria
Carefully excluded were the following:
Ninety-nine cases with exuberant papillary in situ
carcinoma showing tall papilla formation but without
any distinct exophytic mass of Z1 cm were excluded as
nontumoral (at) forms of dysplasia.
Forty-four cases of invasive carcinoma with polypoid
architecture were excluded.
Micronodular collections of pyloric glands <1 cm were
disregarded as either polypoid metaplasia, bromyoglandular polyps (if the glands were separated by the
stroma), or incipient ICPNs [38 cases with all the
characteristics of ICPN (with overt dysplasia) but
measuring <1 cm]. The lattermost were regarded as
incipient ICPNs, similar to the approach taken in
other organs.105 It is acknowledged that these smaller
lesions are probably just smaller ICPNs; however, in
order to determine the clinical relevance of larger
lesions, these were excluded.
One hundred ninety non-neoplastic polyps (benign
broepithelial polyps, cholesterol polyps, and adenomyomas) were excluded. These diered from bromyoglandular polyps114 by the lack of compact growth
of the glands and by the presence of intervening myoid
stroma.
If any of the observers had any doubt that the case
fully qualied for ICPN, the case was excluded from
analysis.
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TABLE 1. Definition of ICPN

A GB neoplasm that is:
Intramucosal
Preinvasive neoplastic (dysplastic)
Mass forming; exophytic (papillary or polypoid)
Z1.0 cm
Compact
Distinct from the neighboring mucosa
Am J Surg Pathol
of this study, each case was assigned to 1 of 3 groups: (a)

papillary if the lesion had >75% papillary or villous
growth; (b) tubular if >75% tubular growth; or (c) tubulopapillary if the secondary pattern constituted >25%
of the preinvasive lesion.
Dysplasia
Demographic and Clinical Data
Information on the patients gender, age, and the
clinical outcome was obtained from patients charts or
from their primary physicians. Detailed clinical information could be obtained on 62 of the patients. For
some cases, follow-up information was obtained from the
Surveillance Epidemiology End Results database.
Histomorphologic Analysis
Growth Patterns
The preinvasive lesions were evaluated for the
amount of papillary or tubular growth. For the purposes
Dysplasia was graded as low or high33 using the

same cytologic criteria as those for at lesions of the GB.
This was preferred to the 3-tiered system that is currently
in use elsewhere in the pancreatobiliary tract, because it is
becoming increasingly clear that the pancreatobiliary
cases cluster into 2 groups, HGD/carcinoma in situ (CIS)
versus non-HGD2,115118 from both the biological and
management standpoints. Moreover, in all likelihood, the
classication will eventually revert to a 2-tiered system as
in other organs such as the cervix and bladder.119121 The
amount of HGD was scored as follows: focal, if it was
<25% of the lesion; substantial, if it was 25% to 75% of
the lesion; and extensive, if it was >75% of the lesion.
FIGURE 2. ICPNs are characterized by a distinct polypoid mass protruding into the lumen (A). Some examples, especially those
with tubular architecture, tend to be more lobulated and attached to the mucosa with a thin stalk (B). ICPNs with more papillary
configuration tend to have a more pedunculated growth (C, D).
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FIGURE 3. A spectrum of papillary and tubular patterns can be seen in ICPNs, often in a mixture (AD).
Cell Lineage Morphology
Methodology
Cell lineage was determined on the basis of morphologic criteria established for pancreatic IPMNs10,23,25
and also recently for intra-ampullary neoplasms.54 The
lesions were classied as intestinal (Fig. 4) if there was
close resemblance to colonic adenomas or intestinal-type
IPMNs. Those that bear similarity to gastric foveolar
mucosa, such as gastric foveolar IPMNs or gastric foveolar adenomas,122,123 were classied as gastric foveolar
(Fig. 5). If the lesion looked like gastric pyloric gland
adenomas,124 it was classied as gastric pyloric (Fig. 6).
Those resembling intraductal oncocytic papillary neoplasms21,23 (oncocytic IPMNs) were regarded as oncocytic. If the lesion did not qualify for one of these
metaplastic lineages,23 or if it resembled the GB epithelium, it was then classied as biliary (Fig. 7).
The existence of any cell lineage morphology was
acknowledged regardless of the amount, even if it was
minimal or underdeveloped. However, each case was assigned a nal lineage type on the basis of the predominant
pattern (> 75% of the lesion).
Immunohistochemical analysis was performed using

a polymer-based detection system (Envision+; Dako,
Carpinteria, CA) with mouse monoclonal antibodies according to the manufacturers instructions. Sections were
deparanized and rehydrated with deionized water.
Then, they were heated in citrate buer, pH 6.0, using an
electric pressure cooker for 3 minutes at 12 to 15 pounds
per square inch at approximately 1201C and cooled for
10 minutes before immunostaining. All slides were loaded
onto an automated system (Autostainer; Dako) in which
they are exposed to 3% hydrogen peroxide for 5 minutes,
incubated with primary antibody for 30 minutes, incubated with labeled polymer (Envision+ dual link) for
30 minutes, incubated in 3,30 -diaminobenzidine as a
chromogen for 5 minutes, and counterstained with hematoxylin for 5 minutes. These incubations were performed
at room temperature. Between incubations sections were
Immunohistochemical Analysis
Cell Lineage Markers
Immunohistochemical analysis was performed with
cell lineage markers, which are known to be dierentially
expressed in dierent components of the gastrointestinal
(GI) tract and which have also been used for subclassication of pancreatic IPMNs, ampullary IAPNs, and
biliary IPNs: MUC1, marker of pancreatobiliary dierentiation10,23,25,40,125128; MUC2, intestinal (goblet cell)
dierentiation23,125,127132; CDX2, intestinal transcription
factor23,130,133135; MUC5AC, foveolar mucin marker (also
positive in most IPMNs)39,65,130,136,137; MUC6, pyloric
marker, also positive in pancreatic ITPNs124,130,138; HepPar, detected in oncocytic IPMNs139141; CK747,142146; and
CK20.47,142144,146,147
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FIGURE 4. Intestinal phenotype in ICPN. Morphologically the

lesion is highly similar to colonic adenomas, showing pseudostratified cigar-shaped nuclei and overall basophilia. This case
was also positive for CDX2 and MUC2.
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FIGURE 5. Gastric foveolar cell lineage in ICPNs is characterized by elongated, interconnecting tubules and relatively illformed papillae lined by tall columnar cells with abundant
apical pale mucin that pushes the nuclei at the periphery
(base) of the cells (inset). Some cases have microvesicular/
foamy quality in the cytoplasm.
washed with Tris-buered saline. Coverslipping was performed using the Tissue-Tek SCA coverslipper (Sakura
Finetek USA Inc., Torrance, CA). Positive controls and
negative controls with primary antibody replaced by Trisbuered saline were run with the patient/study slides. The
detailed specications of the antibodies are provided
in Table 2.
Am J Surg Pathol
FIGURE 7. Biliary pattern of ICPN. Nondescript cuboidal cells

are characteristic of biliary lineage. The cytologic atypia
qualifies the process as HGD.
labeling below 10% was designated focal, 10% to 50%

moderate, and >50% diuse.
Invasion
The invasive carcinoma components were classied
according to the WHO and were staged according to the
AJCC, 2010. The size of invasive carcinoma (i-size) was
recorded separately, and invasive carcinomas were also
classied as focal if they were r5 mm in size, substantial
if 6 to 29 mm, and extensive if Z30 mm.
Statistical Analysis
Evaluation of Immunohistochemical Stains
The percentage of cells showing cytoplasmic
(MUC2, MUC5AC, MUC6, CK7, CK20), apical membranous or cytoplasmic (MUC1), and nuclear (CDX2)
labeling were evaluated by 4 pathologists for extent;
Patient demographic and clinical characteristics

across the 3 study groups (noninvasive ICPN, ICPN
with invasion, and pancreatobiliary-type invasive adenocarcinoma without ICPN) were compared using w2
tests. Overall 1-, 3-, 5-, and 10-year survival in the 3
groups was examined using the life tables method. After
life table analyses, we constructed Kaplan-Meier survival
curves accompanied by the corresponding overall and
pairwise log rank tests for statistical signicance. A separate set of analyses evaluated the distribution of histologic ICPN characteristics (growth pattern, cell lineage,
and extent of HGD) and compared invasive and noninvasive lesions using w2 tests. The level of signicance for
all statistical tests was set using a cuto of <0.05 for a
2-sided a-error. All statistical analyses were performed
using SPSS version 18.0 (SPSS Inc., Chicago, IL).
RESULTS
General Characteristics
FIGURE 6. Gastric pyloric (simple mucinous in this example)

cell lineage in ICPNs. Uniform, back-to-back mucinous glands
with features characteristic of pyloric glands. This tumor was
3.5 cm in size.
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ICPNs dened as Z1.0 cm were uncommon. In the

systematic review of 3265 consecutive cholecystectomies
performed in the authors institutions, 14 cases were
identied, placing the frequency of these lesions at about
0.4% of cholecystectomies.
Among the systematically reviewed 606 cases of
invasive GB carcinoma, 39 had an ICPN component; that
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Am J Surg Pathol
TABLE 2. Specification of the Antibodies

Antibody
Clone
Dilution
Antibody Source
Retrieval Method
MUC1
MUC2
MUC5AC
MUC6
CK7
CK20
CDX2
HEPPAR
Ma695
CCp58
CLH2
CLH5
OB-TLI2/30
Ks20.8
CDX2-88
OCHIE5
1:160
1:100
1:200
1:80
1:40
1:40
1:200
1:160
Leica Microsystems, Bannockburn, IL

Leica Microsystems
Leica Microsystems
Leica Microsystems
Dako
Dako
Biogenex, San Ramon, CA
Dako
Citrate
Citrate
Trilog
Trilog
Citrate
Citrate
Citrate
Citrate
is, 6.4% of GB carcinomas arose in association with

ICPN. Of the remainder, 57% had associated overt
nontumoral intraepithelial neoplasia.
The female predominance characteristic of GB
pathologies was not as striking in ICPNs: F/M = 2.1, as
opposed to 3.9 for pancreatobiliary-type GB adenocarcinomas (Table 3). The mean age of the patients
was 61 y (range, 20 to 94 y) as compared to 64 y in pancreatobiliary-type GB adenocarcinomas.
Among the 62 patients with adequate clinical information accessible to the authors, almost half presented
with right upper outer quadrant pain, and in the other
half the lesion was detected incidentally. Twenty-two
percent of the patients had other neoplasms, most being
GI tract malignancies (gastroesophageal carcinomas, 2;
colon carcinoma, 3; pancreatic carcinoma, 2; pancreatic
mucinous cystic neoplasm with moderate dysplasia, 1;
hepatocellular carcinoma, 1; endometrial carcinoma, 2;
uterine cervical carcinoma, 1; prostate carcinoma, 1).
In preoperative radiologic evaluation, almost half of
the cases were thought to have GB cancer, whereas about
a quarter were documented to have a polypoid tumor,
and in about 10%, the lesion was missed.
In the cases from Chile, the exact frequency of
gallstones could not be determined, because in many cases
the stones had been removed and given to the patients
family before the submission of the specimen to the
pathology laboratory, and this occurrence was not reliably documented in the patient charts. In the cases from
Korea and the United States, only 20% of the properly
documented cases had gallstones (12/58).
Macroscopic Findings
ICPNs were characterized by prominent exophytic
growth within the GB (Figs. 2A, B) or by granular, friable
soft-tan excrescences (Fig. 2C). Some cases, in particular
the more granular (papillary) ones, were sessile and more
broad based (Fig. 2D), whereas others, especially the
lobulated ones, were pedunculated and had such thin
stalks that the lesions often readily detached from the
surface. In fact, for this reason, in many cases, the lesion
was mistaken as sludge or debris in the lumen and not
adequately sampled during initial macroscopic examination; their nature was recognized only after the second
round of sampling. Larger lesions often had a hemorrhagic or necrotic appearance.
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The average tumor size was 2.6 cm, and median was
2.2 cm (range, 1.0 to 7.7 cm). Seventy percent of the cases
were recorded to be solitary and 30% as multifocal. Skip
areas of normal mucosa could be identied within some
seemingly solitary lesions. The most common locations
were fundus and body (88% of the cases).
Those cases associated with invasive carcinoma
had thickened brotic walls; however, as expected,
this was dicult to distinguish from ordinary chronic
cholecystitis.
Microscopic Findings
General Characteristics
ICPNs were characterized by intraluminal growth
of back-to-back epithelial units, either in a papillary or in
a tubular conguration, or both, with minimal or no intervening stroma (Fig. 3). The base of the lesions, in
noninvasive components, was often sharply demarcated
because of the intramucosal nature of the process; however, in some cases there was extension of the lesion into
the Ascho-Rokitansky sinuses, creating invaginations
and a pseudoinvasive appearance. Fifty-one percent of
the cases had at-type dysplasia in the adjacent mucosa
that merged with the exophytic process.
Transition from low-grade dysplasia to HGD (adenoma-carcinoma sequence) in the lesion was evident in
most cases (Figs. 8A, B). Invasive carcinoma (see below),
if present, was mostly at the base of the lesion (49 cases;
72%) (Fig. 9); however, in 6 cases (9%) it was localized in
the head of the polyp, whereas 8 cases (12%) had invasion
in both the base and the head of the lesion. In addition, 5
cases (4%) had invasion elsewhere, separate from the
ICPN site.
In 31 cases (25%), particularly in those with a
papillary conguration, biliary lineage (see below), and
HGD, polymorphonuclear leukocytes showed preferential distribution in and around the epithelium, sparing
the stroma. Twenty-seven cases (22%) also had lymphoplasmacytic inltrates. Fibrosis and chronic inammation
were common, but whether this was due to the lesion
itself or other instigators such as gallstones could not be
determined. Interestingly, 13 cases had prominent follicular cholecystitis in the adjacent GB. In pyloric complex nonmucinous type, the uninvolved GB was often
devoid of chronic changes.
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TABLE 3. Comparison of Demographic and Main Clinical Characteristics Among ICPN and Pancreatobiliary (PB)-type GB
Carcinoma Cases
ICPN (N = 123)
ICPN Without Invasive
Carcinoma (N = 55)
Age (y)
< 55
55-64
65-74
Z75
Unknown
Sex
Male
Female
Unknown
T stage*
T1
T2
T3
Missing
Overall size
< 3 cm
Z3 cm
Invasion size
< 2 cm
Z2 cm
Unknown
ICPN With Invasive

Carcinoma (N = 68)
PB-type
Carcinoma (N = 411)
19
11
15
9
1
35
20
27
16
2
16
22
13
12
5
24
32
19
18
7
86
101
130
87
7
21
25
32
21
2
17
36
2
31
65
4
21
44
3
31
65
4
84
319
8
20
78
2
NA
NA
NA
NA
NA
NA
NA
NA
22
32
14
0
32
47
21
0
35
141
222
13
9
34
54
3
39
16
71
29
38
30
56
44
237
174
58
42
NA
NA
NA
NA
NA
NA
46
21
1
68
31
1
140
271
0
34
66
0
Pw
0.123
0.037
< 0.001
0.151
< 0.001
*Applies to invasive disease only.

wOn the basis of w2 test, calculations exclude subjects with unknown information.
NA indicates not applicable.
Architecture
Although 90% of the ICPNs showed a mixture of
papillary and tubular areas, 53 cases (43%) qualied as
papillary, 32 cases (26%) as tubular, and 37 cases (31%)
as tubulopapillary when cutos of 75% and 25% were
used. The mean size of the papillary group was 2.8 cm,
tubulopapillary 2.7 cm, and tubular 2.0 cm.
Papillary cases tended to be of either biliary (64%)
(Fig. 7) or mixed type showing some biliary features
(15%) and rarely of the gastric or intestinal type. In
contrast, tubular cases were more of the gastric lineage
(84%) (Fig. 5) or mixed with gastric-type features. Ninety
percent of the tubulopapillary cases had mixed cellular
lineage.
Extensive HGD appeared to be more common in
the tubulopapillary (68%) and papillary groups (55%)
than in the tubular group (32%) (P = 0.008). Compared
with neoplasms without invasion those with invasion
included higher proportions of papillary (47% vs. 38%)
and tubulopapillary (38% vs. 22%) lesions and a lower
number of tumors with tubular growth pattern (15% vs.
40%). As shown in Table 4, these dierences were statistically signicant (P = 0.005). In contrast, even cases
that may have qualied as papillary adenocarcinoma
(papillary pattern with extensive HGD) exhibited lowgrade dysplastic foci in 17%, and, furthermore, 32% of
these cases were noninvasive.
Dysplasia
The ICPNs exhibited a spectrum of neoplastic
transformation ranging from epithelium that was virtually indistinguishable from normal glands to those with
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severe cytologic atypia and all the attributes of carcinomatous transformation (HGD/CIS). This spectrum
also often occurred within a given case (Fig. 8). The
dysplastic nature of the lesion was readily identied by
cytologic atypia in many cases. In others, in particular
those with the pyloric mucinous phenotype (see below),
the neoplastic/dysplastic nature of the process was determined by the sheer size and the compact back-to-back
growth of glands with no intervening stroma, akin to
pyloric gland adenomas or serrated adenomas of the
GI tract, which are dened as preinvasive neoplasms
although they lack the conventional cytologic atypia
of dysplasia.
HGD was manifested in dierent patterns. In many
cases, pseudostratication of cells with nuclear pleomorphism and dyspolarity was the main evidence (Figs. 8,
9). In others, the epithelium formed a single layer, but
showed substantial nuclear anomalies and clear cell features with centrally located nuclei. In a smaller subset,
HGD was characterized by the cribriform arrangement of
the cells, some with clear cell features. A few examples
showed solid areas and even exhibited comedo-like necrosis (akin to those seen in ITPNs of the pancreas) focally raising the question of surface cancerization by an
underlying invasive carcinoma. However, these foci were
either far away from the invasive component of the lesion
or localized in an otherwise typical preinvasive lesion, or
the case did not have any invasive component.
HGD was more extensive in the cases with associated invasive carcinoma compared with noninvasive
ones (P < 0.001). Using the denitions set forth in the
Materials and Methods section, the proportions of focal,
substantial, and extensive HGD among noninvasive
r
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FIGURE 8. Spectrum of dysplasia (cytoarchitectural atypia) in ICPNs. Low-power examination (A) shows the architectural
complexity with disorganized and gland-in-gland appearance. B, Low-grade dysplastic cells with virtually no cytologic atypia is
seen adjacent to high-grade dysplastic cells, which reveal stratification, loss of polarity, mucin depletion, disorganization, nuclear
enlargement, and moderate nucleomegaly with chromatin clumping.
tumors were 24%, 45%, and 31%, respectively. In contrast, the corresponding percentages for cases with associated invasive carcinoma were 6%, 23%, and 71%
(Table 4).
Cell Lineage
Unlike IPMNs of pancreas or IAPNs of ampulla,
the ICPNs appeared to have more cell lineage diversity
(Fig. 10), rendering the cell lineagebased classification
more difficult to apply. Transitional forms, mixed areas,
and unclassifiable patterns were identified to some degree
in 90% of the cases: 76% had at least some foci with
biliary-like features, 72% exhibited at least some areas
recognizable as gastric differentiation, and patterns resembling but not entirely qualifying for intestinal differentiation were noted in 42%.
When the cases were classied on the basis of the
predominant (> 75%) pattern or overall pattern, the
following categories were discerned:
Biliary (n = 61; 50%): The vast majority (95%)
had a papillary growth pattern (> 25% of the lesion);
56% were in the papillary category, and 39% in the tubulopapillary group.
These commonly showed carcinomatous transformation: 67% had extensive HGD, and 69% had assor
ciated invasive carcinoma. Invasive carcinoma in this group

was focal in 14, substantial in 24, and extensive in 4 cases.
Typically, the cases in this group, by denition, had
more cuboidal cells (Figs. 7, 11A). Some had clear cell
features, and some had solid or cribriform patterns as well.
Some had more columnar cells resembling the intestinal
phenotype but with more acidophilic cytoplasm and lack of
MUC2/CDX2 expression. Commonly, a foveolar component (with MUC5AC expression) was encountered within
the lesion or in the background mucosa. Tumor-inltrating
inammatory cells appeared to be more common in this
group: the frequency of prominent neutrophilia was 36%
(vs. 14% in others) and that for lymphoplasmacytic inltrates was 28% (vs. 15% in others).
A small subset in this category was characterized by
delicate papillary lesions lined by innocuous cells similar
to normal GB epithelial cells. These cases, which presumably correspond to biliary-type (adenomas) papillomas reported by Albores-Saavedra33 had no HGD or
any invasive carcinoma. Select photos of these cases were
shared with Dr Albores-Saavedra, and it was veried that
these cases match those described by him.
In 8 cases, there were focal features characteristic of
cholesterol-type polyp associated with the lesion (in 6,
without any cholesterolosis in the uninvolved mucosa),
raising the possibility that some of these lesions may be
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focal CDX2 in 15%, CK20 in 28%, MUC5AC in 50%,

and MUC6 in 32%).
Gastric (n = 44; 36%): Gastric lineage was often
detected as a recognizable component in the biliary-type
cases but not as much in the intestinal type, akin to what
is observed in pancreatic IPMNs.2,23 However, as in the
pancreas, this may be partly denitional because once
gastric-type cells become HGD and lose their mucin, they
acquire biliary-type morphology (Fig. 8) or become oncocytic if they acquire voluminous cytoplasm with
abundant mitochondria.
Gastric-type metaplastic changes were also frequently observed in the uninvolved epithelium of ICPN
cases, which is not surprising as they are very common in
the general population as well.151
Cases classied as the gastric type on the basis of the
predominant or overall pattern were mostly tubular (61%
tubular and 25% tubulopapillary).
This was also the group with the least number of
carcinomatous transformations: 29 cases (66%) were
noninvasive, and only 27% had extensive HGD. However, as mentioned above, this may be denitional.
Three interrelated but also distinct subsets were
identied in this category:
(a) Foveolar (n = 20; 16% of ICPNs): This group is
characterized by relatively larger elongated glands, often
with tubulopapillary architecture, lined by foveolar-like
cells with abundant pale cytoplasm (Figs. 5, 11C) and
peripherally located nuclei. This is the group that appeared to be closely related to the biliary type and was
often associated with HGD changes (95%) and invasive
carcinoma (55%).
MUC5AC was positive in all cases (100%)
(Fig. 11D), and on occasion MUC6 could also be positive
(54%). MUC1 was less common and detected mostly in
the areas with HGD.
FIGURE 9. Invasive carcinoma arising in ICPNs. Although

most invasive carcinomas are ordinary (pancreatobiliary-type)
adenocarcinomas, some are unusual types, such as colloid (as
shown here) or neuroendocrine.
arising within cholesterol polyps, as observed in a few

cases in the literature.148150
The biliary group typically showed CK7 (100%)
and MUC1 expression (74%) (Fig. 11B), particularly in
the areas with HGD. Most of them also showed weak
expression of other lineage markers (focal MUC2 in 15%,
TABLE 4. Comparison of Histologic Characteristics Among ICPN Cases With and Without Invasive Carcinoma
Disease Group
Patient and Disease
Characteristics
Histologic growth pattern
Papillary
Tubular
Tubulopapillary
Cell lineage
Biliary (including oncocytic)*
Gastric foveolar
Gastric pyloric
Intestinal
Extent of HGD (%)w
Focal (< 25)
Substantial (25-75)
Extensive (> 75)
ICPN Without Invasive Carcinoma (N = 55)
ICPN With Invasive Carcinoma (N = 68)
21
22
12
38
40
22
32
10
26
47
15
38
22
9
20
4
40
16
36
7
47
11
4
6
69
16
6
9
12
23
16
24
45
31
4
15
47
6
23
71
Pz
0.005
< 0.001
< 0.001
*Oncocytic cases grouped together with biliary ones, as they showed similarity in aspect of HGD and MUC1 expression.
wExcludes 6 persons with no HGD.
zOn the basis of w2 test.
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FIGURE 10. Mixed cell lineages and hybrid or difficult-to-classify patterns are common in ICPNs. In many cases of the biliary type,
the cells focally exhibit columnar morphology and mimic intestinal differentiation (A and C). In some others (B), the cells are
cuboidal and show biliary-type pattern, but the mucin content and presence of goblet-like cells make it difficult to place this lesion
into a specific type. In some of the tubular examples, the surface component shows a different cytology with stratification of cells
(D).
(b) Pyloric, simple, mucinous (n = 13; 11% of

ICPNs): This group (Figs. 6, 11E) was characterized by
tightly packed, evenly sized, small, and bland-appearing
pyloric-type (Fig. 6; 8 cases) or Brunner-like (Fig. 11E
5 cases) glands showing abundant apical mucinous cytoplasm, peripherally located nuclei, low nucleo-cytoplasmic ratio, and minimal or no intervening stroma. One of
the cases in this category was associated with a Brunner
gland hamartoma in the duodenum, suggesting a genetic
tendency to form abnormal Brunner glandtype proliferations. This group had extensive HGD in only 1 case
and invasive carcinoma in 2. It is noteworthy that in 1
case, invasive carcinoma was distant from the polyp.
MUC6 expression (Fig. 11F) was strong in 11 (90%) and
focal in 2 cases.
(c) Pyloric, complex, nonmucinous (n = 11; 9% of
ICPNs): This was a highly distinctive group characterized
by complex growth of small, nonmucinous tubular units
(Figs. 11G, 12) that diusely and uniformly expressed
MUC6 (100%) (Fig. 11H). The tumors typically formed
r
pedunculated multinodular polyps that were prone to

detachment from the surface and often developed hemorrhagic material in the lumen mistaken as sludge.
These were typically composed of more complex tubular
units, which often showed irregular and mildly variegated
glandular architecture associated with cystic dilatation of
the glandular elements, and some cysts containing granular acidophilic secretory material (Fig. 12). Typically,
the lobules were covered by normal-appearing epithelium.
The nucleo-cytoplasmic ratio in this complex group was
fairly high, the nuclei were cuboidal, and nucleoli were
often visible (Fig. 13). Many cases (5/11; 45.5% of the
group) showed foci with overlapping optically clear nuclei
(Fig. 14). Paneth-type cells and cells with endocrine type
granules were also seen in certain cases with this pattern,
and were prominent in some areas. Amyloid-like hyalinization of the stroma was noted in some cases. Squamoid morule formation (Fig. 15), represented as solid
squamoid clusters of meningothelial-like cells in a
whorled conguration, some with optically clear nuclei
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Adsay et al
resembling inclusions, was noted in a signicant proportion (64%) of these cases. This was not seen in any of
the other categories.
It is noteworthy that cases in this group appeared to be
strikingly uniform, and although they were often large tumors, they rarely showed mucinous-type gastric lineage in
the background, nor transition to any of the other lineages.
In addition, the uninvolved GBs were mostly devoid of any
pathology, including the conspicuous lack of gastric metaplasia. These cases, particularly the ones with excess mucin
depletion, resemble, in terms of morphology and uniformity,
ITPNs of the pancreas.2,28,3841 Immunohistochemically,
diuse and strong MUC6 expression was uniform in this
group (100%) (Fig. 11H). Focal MUC1 expression was
identied in 4 (57%) cases, mostly limited to the areas of
HGD. MUC5AC was expressed in 42%, CK7 in 100%,
and others were mostly negative.
The frequency of associated invasive carcinoma was
quite low in this group (18%).
Am J Surg Pathol
FIGURE 12. Pyloric complex nonmucinous type is a distinct

subset that tends to have large pedunculated polyps. The
polyps are composed of a nodular pattern of tightly packed
small to medium sized tubules, some showing cystic dilatation
containing granular secretory material.
FIGURE 11. Spectrum of cell lineages in ICPNs. Biliary type is characterized by cuboidal nondescript cells (A) and common (74%)
MUC1 expression (B). Foveolar variant typically shows large elongated glands lined by tall columnar mucinous epithelium with
pale nonchromophilic cytoplasm (C) and consistent MUC5AC expression (D). Pyloric simple mucinous type reveals back-to-back
small tubular units that resemble both pyloric gland adenomas and Brunner gland adenomas (E) and reveals consistent MUC6 (F)
positivity. Pyloric complex nonmucinous type are defined by a distinctive lobulated growth pattern of small tubular units
illustrated in Figures 13 and 14, which, at the cytologic level, correspond to relatively uniform cuboidal cells with nonmucinous
cytology (G), some showing nuclear features of papillary thyroid carcinoma including clearing and overlapping. MUC6 is consistently expressed in this group (H) in virtually all cases. Intestinal lineage in ICPNs (I) is similar to colonic adenomas or intestinaltype IPMNs and exhibit common (75%), albeit not uniform, expression of CDX2 (J). Oncocytic examples of ICPN (K) are
identified by arborizing papillae that are lined by oncocytic cells, although immunophenotypically they are different from their
pancreatic/biliary counterparts by lack of HepPar, which was detected in only 1 case (L).
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FIGURE 13. Pyloric complex nonmucinous type. The cells are

cuboidal, often with round nuclei and visible nucleoli and
moderate to low amount of nonmucinous (or not overtly
mucinous) cytoplasm. The cytologic features often qualify the
process as HGD as seen here. See Figure 14 for another cytologic pattern seen in this type.
Intestinal (n = 10; 8% of ICPNs): These cases were

distinguished from other types by overall basophilia evident even at low magnication, created by nuclear
crowding of the pseudostratied cells with enlarged,
cigar-shaped nuclei and dense cytoplasmic chromophilia
(Figs. 4, 11I). In many cases, the lesions were easily dis-
FIGURE 14. Pyloric complex nonmucinous type is characterized by a distinctive low-power growth pattern illustrated
in Figures 12 and 13, which corresponds to back-to-back small
tubular units that are well formed with open lumina and relatively monotonous cuboidal lining, some with prominent
nucleoli. Others, such as this case, are more complex
and show nuclear features reminiscent of papillary thyroid
carcinomas with overlapping, elongation, and a chromatin
clearing.
r
FIGURE 15. Morules (squamoid corpuscles), some with optically clear nuclei, are encountered commonly in the gastric
pyloric types of ICPNs, but not seen in other types. On close
inspection, some of these morular cells show meningothelial
features and optically clear nuclei.
tinguishable from the adjacent uninvolved mucosa by

their clearly dysplastic nature. Immunohistochemically,
these were commonly positive for either CK20 (100%) or
CDX2 (75%) (Fig. 11J). MUC2 positivity was seen in
50%. The other markers were typically negative except
CK7 (Table 5).
Invasive carcinoma was seen in 6 cases. Four were
of pancreatobiliary type, and 2 were colloid type. Interestingly, death from disease was not observed in any of
the intestinal type cases, but the number of cases was too
small to derive a conclusion.
Oncocytic (n = 8; 6% of ICPNs): These cases were
distinguished by the complexity of the papillae and oncocytic cytology (Figs. 11K, 16).30,34,48,130,139141,152 They
diered, however, from their pancreatobiliary counterparts by the high degree of atypia, dirty background, and
lack of HepPar labeling (only 1/6) (Fig. 11L). Moreover,
only 1/6 showed MUC6 expression (Table 5). Conversely,
they all expressed MUC1, which is variable in oncocytic
IPMNs. Because of the immunophenotypic similarities to
biliary type, for the purposes of comparative analysis
(Table 4), we grouped these oncocytic cases along with
biliary type. Two had eosinophilic intracytoplasmic
globules very similar to the Mallory globules seen in
renal cell carcinomas (Fig. 16).153 Invasive carcinoma was
seen in 5 cases.
Clinicopathologic Comparison of Cell Lineage Types

There were statistically signicant dierences in the
frequency of invasion among the dierent cell lineage
groups, with the biliary type showing a signicantly
higher association with invasive carcinoma compared
with the gastric type (P < 0.001; Table 4).
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TABLE 5. Immunohistochemical Analysis of ICPN Types (Data are Shown as %)

MUC1
MUC2
MUC5AC
MUC6
CK7
CK20
CDX2
HepPar
All ICPNs
Biliary
Gastric Pyloric
Gastric Foveolar
Intestinal
Oncocytic
64
12
55
49
100
31
14
NA
74
15
47
32
100
28
16
NA
35
6
44
94
100
19
6
NA
69
8
100
54
100
25
8
NA
25
50
0
25
100
100
75
NA
100
0
50
17
100
50
0
17
NA indicates not applicable.
Immunohistochemistry
The group of cases with prominent hybrid and
dicult-to-classify morphology (56%) also showed a
complex immunohistochemistry (IHC) prole: CK7,
100%; MUC1, 64%; MUC5AC, 55%; MUC6, 49%;
MUC2, 12%; CDX2, 14%; and CK20, 31%. In most
cases, however, the cell lineage morphology in dierent
components of the same lesion had relatively predictable
correlation with the immunophenotype. This was also
manifested in the correlation of the nal diagnosis (on
the basis of the predominant or favored pattern) for each
case as discussed above (also see Table 5). IHC was also
helpful in distinguishing mimickers, such as the intestinallike appearance in biliary cases as illustrated in Figures
10A, C, from true intestinal dierentiation.
Invasive Carcinomas Arising in ICPN

Invasive carcinoma was seen in 68/123 (55%) of the
ICPN cases. Conversely, an ICPN component was iden-
tied in 39 of 606 systematically analyzed invasive GB

carcinomas (6.4%). Most of these (87%) were pancreatobiliary-type adenocarcinomas of the GB. However,
9 cases showed other types of carcinoma (mucinous, 4;
adenosquamous, 1; neuroendocrine, 2; signet ring, 1;
medullary, 1) (Fig. 9, mucinous). It is noteworthy that a
patient that had been originally classied as noninvasive
was found to have minute invasion in the recuts obtained
for this study but not in the original slides.
When noninvasive and invasive cases were compared, no age or gender dierence was found in these 2
groups (Table 3). Cases with associated invasive carcinoma were characterized by predominance of papillary or
tubulopapillary growth patterns (85%), biliary cell lineage (69%), and extensive HGD (71%) in their noninvasive component. Although the mean size of the
preinvasive lesion was slightly larger in the invasive group
(2.8 vs. 2.4), overall size of the tumors were not signicantly dierent between these 2 groups (P = 0.22).
Invasive carcinoma was focal (r5 mm) in 20/68,
substantial (6 to 29 mm) in 39/68, and extensive (Z30mm)
in 9/68 cases. Twenty-two cases were staged as T1 by
AJCC, 32 were T2, and 14 were T3. Invasive carcinomas
arising in ICPNs were signicantly lower-stage tumors at
the time of diagnosis compared with pancreatobiliarytype GB carcinomas (Table 3). This, however, did not
seem to be the reason for their favorable outcome (see
next section).
Prognosis
FIGURE 16. Oncocytic-type ICPNs are characterized by

complex/arborizing papillae lined by 2 to 5 cell layers of cuboidal cells showing abundant acidophilic granular cytoplasm
and single prominent nucleoli. Intraepithelial lumen formation
is also noted. Mallory-like hyaline bodies documented in renal
cell carcinomas can be encountered. It should be noted here
that immunohistochemically these oncocytic ICPNs do not
show the characteristic phenotype of their pancreatobiliary
counterparts (they lack HepPar and MUC6 and show diffuse
MUC1), which places them closer to biliary-type ICPNs.
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The overall survival after diagnosis of ICPN was

very good. Patients with noninvasive ICPNs had 1-, 3-,
and 5-year survival rates of 90%, 90%, and 78%, versus
69%, 60%, and 60%, respectively, of those with associated invasive disease. Even cases with associated invasive carcinoma appeared to have a signicantly better
prognosis than pancreatobiliary-type GB carcinomas
with median survivals of 35 versus 9 months. As shown
in Figure 17, the dierences in survival across the 3
groups were statistically signicant in both overall and
pairwise analyses (all P < 0.001). To further investigate
whether this survival dierence was dependent on
the stage, we performed a stage-matched analysis, and the
survival dierence between 2 groups was still found to be
statistically signicant (P < 0.0001) (Fig. 18). To conrm
the stage independence of this survival dierence, Cox
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Am J Surg Pathol
been sampled in 21, 12, 30, and 8 blocks, respectively. All

but the last one was submitted entirely. See Table 6 for
other characteristics of these cases.
DISCUSSION
Definition of ICPN
FIGURE 17. ICPNs have incomparably better survival than

nonICPN-associated pancreatobiliary-type adenocarcinomas
of the GB. Not surprisingly, ICPNs without invasive carcinoma
have a long protracted clinical course with only few deaths
occurring in long-term follow-up. Invasive carcinomas arising
in ICPNs are not as kind.
proportional regression and hazard ratio analysis were

performed comparing the 2 groups with and without
stage matching. The hazard ratio was statistically signicant in both cases [0.372 (95% condence interval,
0.238-0.581; P < 0.0001) without the matching vs. 0.538
(95% condence interval, 0.342-0.845; P = 0.007) with
the matching] thus conrming that the survival dierence
was independent of the stage.
Among 55 patients with noninvasive ICPNs, 4 died
of cancer, whereas 1 died at 14 months; the remaining 3
died >5 years after their diagnosis (63, 84 and 94 mo,
respectively; median 72 mo). Three of these cases were
diagnosed with biliary tract cancers on the basis of
imaging studies and signs of biliary obstruction. The
fourth one was recorded to have died of stomach cancer although no biopsy was performed. These cases had
FIGURE 18. Stage-matched comparison of invasive carcinomas arising from ICPNs versus ordinary pancreatobiliary-type
adenocarcinomas of the GB that are non-ICPN associated illustrates that the survival advantage of the former is largely
retained even within the same stage groups.
r
These tumoral intraepithelial neoplasms of the GB

are remarkably analogous to IPMNs and ITPNs of the
pancreas,27,38,41 as well as biliary IPNs 20,22,40,42,48,49,139,154
and IAPNs,54 in their exophytic nature, expression of cellular lineages (biliary, gastric, intestinal, oncocytic), and
the presence of a spectrum of dysplastic change (adenomacarcinoma sequence), all often occurring in varying degrees, thus warranting their evaluation in a parallel
category. For this category, we hereby propose the term
ICPNs to embrace all mass-forming, preinvasive neoplasia
Z1.0 cm, recognized in the WHO-2010 classication as
adenoma (tubular, papillary, pyloric gland, foveolar
gland, biliary, intestinal, or otherwise) and intracystic
papillary neoplasms (intestinal or pancreatobiliary).1 As
illustrated in this study, the overlap between these subsets
are too great (perhaps with the exception of pyloric type),
and, more importantly, a signicant proportion of the
cases cannot be readily placed into one of the WHO categories (Table 7), further warranting their collection under
1 unied entity.
The criterion of Z1 cm was chosen to dene this
category because this is widely used by surgeons and radiologists to determine indication for cholecystectomy, and it
was also used by the WHO-2010 to dene tumoral intraepithelial neoplasm in the pancreatobiliary tract.2,27,40,42,49
In addition, this Z1 cm criterion allows distinction of
mass-forming lesions from their at counterparts, and,
more importantly, it provides a specic guideline, albeit
arbitrary, to dierentiate these from smaller polypoid pyloric gland metaplasias. It is clear, from both this study and
analysis of the literature, that although the vast majority of
these subcentimeter lesions are clinically inconsequential,
the larger (Z1 cm) lesions often show cancerous transformation.13,57,59,81,92,93,95,97,107,155157
The term ICPN parallels with their ampulla-pancreatobiliary counterparts. Intracholecystic was chosen
by the suggestion of Dr Juan Rosai (personal communication, Washington, DC, March, 2010) in order to specify
both the localization (intramucosal; in the GB) and the
preinvasive nature of these neoplasms. Their exophytic
nature, in contrast, is highlighted by the name papillarytubular, which emphasizes the fact that these tumors
may have both papillary and tubular congurations or
either one of them, often in a mixture. The name papillary-tubular is favored over tubulopapillary (or
tubulovillous), because the latter is a term that denes
a specic subset of tumoral intramucosal neoplasms in
the pancreas (ITPNs),2 whereas only a small percentage
of ICPNs display features akin to these tumors. Finally,
the possibility of incorporating the word mucinous in
the category designation was considered but dismissed,
because this descriptor was recently dropped from the
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TABLE 6. Clinicopathologic Features of Patients With ICPNs Without Invasive Carcinoma Who Died of Disease
Sex
F
F
F
F
Age
Tumor Size
Growth Pattern
Cell Lineage
Extent of HGD (%)
# of Blocks Examined
Survival (mo)
64
75
63
82
3.1
2.1
6.2
1.6
Tubulopapillary
Papillary
Tubulopapillary
Papillary
Gastric foveolar
Gastric foveolar
Biliary
Biliary
25-75
25-75
25-75
> 75
21
12
30
8
14
63
84
94
nomenclature of biliary examples of this entity due to the

fact that, like in ICPNs, mucin production is only a minor
and less common feature in biliary IPNs in contrast with
pancreatic IPMNs, which are often characterized by copious mucin production.
Incidence
ICPNs are rare but their exact incidence is dicult
to determine. There are very limited data in the literature.
Moreover, the numbers are conicting, mostly owing to
the denitional variations, with most studies including
microscopic pyloric gland proliferations (presumably
metaplasias)55,65,68,88,158160 and others excluding those
that are invasive. As dened in this study, the incidence of
ICPN was found to be <0.5%.
From the perspective of invasive carcinomas,
among 606 systematically analyzed invasive carcinoma
cases, 39 were found to have convincing residual ICPN
component, placing the percentage of invasive carcinomas arising from a tumoral intraepithelial neoplasm in
this organ at 6.4%. This percentage is higher than that in
the pancreas in which, in our experience, IPMNs/ITPNs
are responsible for about 2% of invasive carcinomas,41
although other studies place this number as high as
10%.161 Nevertheless, it is signicantly lower than the
30% recently disclosed for ampullary cancers.54 It also
falls into the lower end of what has been reported in the
literature for the GB, which ranges between 5% and
23%.13,15,66,68,73 Regardless, it is clear that, unlike in the
tubular GI tract, the adenoma-carcinoma sequence is
responsible for only a small percentage of invasive
carcinomas in the ampulla-pancreatobiliary tract, and
the vast majority of invasive carcinomas in this system
arise from the at (nontumoral) forms of intraepithelial
neoplasia.
Pathologic Characteristics
There is a spectrum of cytoarchitectural atypia
(dysplasia) and variable amounts of papillary and tubular
patterns, which are often admixed. Close to half of the
cases are predominantly (> 75%) papillary. This nding
may not be surprising, considering that in the GI tract
smaller lesions often prove to be tubular, whereas larger
lesions exhibit more papillary (villous) growth, presumably because the latter have a tendency to become larger.
Also not surprisingly, the frequency and amount of HGD
and associated invasive carcinoma are signicantly higher
in papillary and tubulopapillary cases than in tubular
ones (see below).
The vast majority of the ICPN cases exhibit a
mixture of low-grade and high-grade dysplastic foci
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within the same lesion. The overall frequency of HGD,

however, is very high; only a small minority (5%) of cases
is entirely devoid of HGD. Furthermore, HGD is extensive (> 75% of the lesion) in half of the cases at diagnosis. The frequency of associated invasive carcinoma
is signicantly higher in cases with extensive HGD.
Like their counterparts in the pancreatic and biliary
tract, ICPNs exhibit a spectrum of cell lineages that recapitulate those of the GI tract. Interestingly, unlike their
pancreatic counterparts, in which these lineages are often
pure and discernible, a mixture of these cell lineages is
seen in coexistence in a signicant proportion of ICPN
cases. This is also reected in the heterogenous staining
pattern by IHC.
On the basis of the predominant pattern, the most
common cell type is classiable as biliary and commonly
expresses MUC1. In addition to resembling GB epithelium or pancreatobiliary-type IPMNs, this type also
exhibits variants including clear cell and more columnar
intestinal-appearing cells. The gastric phenotype has 2
distinct types: the foveolar type, with uniform MUC5AC
expression, is closely related to the biliary phenotype
(often admixed with it) and is also commonly accompanied by invasive carcinoma (in 60% of the cases). The
pyloric type, however, is characterized by diuse/uniform
MUC6 expression, whether mucinous or nonmucinous,
and is often large, homogenous with morule formation,
and has a signicantly lower frequency of associated invasive carcinoma (18%, similar to that of the gastric type
of pancreatic IPMNs). The mucinous ones resemble
pyloric gland adenomas of the GI tract,37,123,124,162 and
they are also similar to the polypoid pyloric gland metaplasias in the GB, which appears to be the source of the
controversies regarding the nature of these lesions in the
literature, because most major studies on adenomas
were composed predominantly of subcentimeter lesions of
this morphology.65,68,73,88,90 The pyloric complex nonmucinous type (Figs. 11G, 13, 14) is quite distinctive in
that it is often associated with a relatively clean background without signicant inammation and forms
complex, pedunculated multinodular intraluminal tumors
that detach readily, such that they may be dismissed as
necrotic debris in the macroscopy room. Some examples
of this type are similar to pancreatic ITPNs, not only
because of tubular growth and MUC6 expression, but
because of their nonmucinous cytomorphology. In addition, some have nuclear overlapping and chromatin
clearing resembling papillary thyroid carcinomas. Morule
formation is most commonly encountered (64%) and
seen almost exclusively in this type. Studies have shown
that tumors with morule formation such as endometrial
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Am J Surg Pathol
TABLE 7. Comparison of the Prior Terminology and Concepts in the Literature and the Findings in This Study
Question
Previous Literature
This Study
What is the behavior of adenomas?
Impression: all are benign (on the basis

of a small number of cases). Average size
in literature B0.7 cm
Those that are >1 cm often have HGD,

and even the pyloric gland type examples
have 18% invasive carcinoma
What is the behavior of papillary carcinoma/

adenocarcinoma?
Impression: a variant of adenocarcinoma;

all malignant; dismal prognosis similar to
ordinary GB adenocarcinoma
Many are noninvasive; noninvasive ones,

5-yr survival 90%; invasive ones, 60%.
How do we designate a mass-forming preinvasive

neoplasm in the GB?
7 supposedly distinct categories collected

under 2 generic groups of adenoma
and intracystic papillary neoplasm.
Some dened by growth pattern
(tubulopapillary adenoma), some by
combination of dysplasia+growth
(papillary carcinoma), some on the
basis of cell lineage (intestinal adenoma)
A case can be reported as: ICPN, with

(amount of) HGD, (cell lineage) type,
(type of) growth pattern
What do I do with this extensive in situ carcinoma

that has prominent papillary conguration of tall
papillae, but not forming a distinct mass?
Papillary adenocarcinoma
CIS, at type, with prominent papillary

pattern (not ICPN)
What do I do if I see a GB case that looks like

intestinal-type IPMN of the pancreas?
Not clear: adenoma or intracystic

papillary neoplasm or IPMN of GB
ICPN, intestinal type
What do I do if I see a tubulopapillary neoplasm that

has intestinal phenotype?
Not clear: tubulopapillary adenoma or

intestinal adenoma
ICPN, intestinal type, with tubulopapillary

pattern
What is the clinical outcome of a tubulopapillary

neoplasm that has intestinal appearance?
No literature
If noninvasive 5-yr survival 90%; minimal

risk of recurrence at long term
What is the diagnosis and prognosis

of a tubulopapillary neoplasm with
extensive HGD?
Not clear: if regarded as tubulopapillary

adenoma, then benign; if regarded as
papillary carcinoma, then very aggressive
ICPN with HGD Good prognosis

(5-yr survival 90%); however, long-term
F/U is warranted
What do I call this papillary neoplasm that has

intestinal features but according to me does not
appear to be intestinal and in which CDX2 and
MUC2 are negative?
Not clear
ICPN, biliary type
What do I call this large polyp composed of complex

but small glandular units of nonmucinous cells?
Not clear: pyloric gland adenoma?
ICPN, pyloric complex nonmucinous
What do I call this oncocytic papillary lesion? How

common are these?
No literature; not reported
ICPN, oncocytic type; 6% of the cases
What do I call a collection of pyloric-like glands that

forms a 4-mm nodule?
Pyloric gland adenoma
Polypoid metaplasia, not ICPN
What do I call a polypoid lesion that has pyloric-type

glands with intervening bromuscular stroma?
Pyloric gland adenoma
Non-neoplastic; not ICPN;

bromyoglandular polyp152
What percentage of invasive carcinomas of the GB

arises from mass-forming preinvasive neoplasm?
Wide range; 5%-23%; all small studies
6.4% (on the basis of systematic review of 616

carcinoma cases and 3265
cholecystectomies)
I have an invasive carcinoma arising from a massforming preinvasive neoplasm. Is this going to
behave like an ordinary carcinoma?
Not clear
Limited data suggest that they may behave

better than ordinary invasive carcinoma
that arise from at IN
F/U indicates follow-up; IN, intraepitelial neoplasia.
carcinomas, cribriform-morular variant of papillary thyroid carcinomas, and fetal-type pulmonary adenocarcinomas share the common characteristics of occurring more
frequently in women and molecular association with estrogen-activated b-catenin pathway alterations.163 The
r
same concept may very well be in play in the pyloric-type

ICPNs as well. This issue warrants further investigation.
Although few examples of the pyloric complex nonmucinous type appear to be a high-grade transformation
of the mucinous type, many are uniformly complex
www.ajsp.com |
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Adsay et al
without any mucinous component in the lesion or in the

uninvolved GB. More importantly, despite their complex
architecture, large size, and the common presence of
HGD, this type of ICPNs is associated with invasive
carcinoma in only 18%.
Convincing intestinal lineage is relatively uncommon in ICPNs (8%). Furthermore, in this study, even
though stringent morphologic criteria were used, only
75% of the cases that were classied as intestinal
expressed CDX2 and 50% MUC2, suggesting that intestinal dierentiation, even when it occurs, is less complete than it is in the pancreatic IPMNs23 or IAPNs.54
The fact that the intestinal pathway is signicantly more
common in the pancreatic main-duct IPMNs than in
ICPNs despite the fact that intestinal metaplasia is more
common in the non-neoplastic GB (10%)151 may suggest
that intestinal lineage in tumorigenesis may be related to
the reux of intestinal contents rather than to an embryologic remnant phenomenon. Along these lines, the
frequency of intestinal lineage (and other cell types) occurring in the ICPNs is fairly similar to those identied
in the extrahepatic bile ducts in a recent study from
Memorial Sloan-Kettering Cancer Center,139 indicating
that the biliary tract epithelium (bile ducts and GB alike)
is less prone to follow an intestinal pathway than the main
pancreatic duct.
As in other areas of the ampullo-pancreatobiliary
tract, the oncocytic phenotype is fairly uncommon in
ICPNs. More importantly, it does not show the classic
immunophenotypic features of oncocytic IPMNs or
IPNs,30,34,48,130,139141,152 often lacking HepPar and
MUC6 expression and consistently showing MUC1 expression instead.
In addition to its aid in verifying the cell lineages
discussed above, immunophenotyping also discloses some
general characteristics of ICPNs. True to their biliary
origin, ICPNs are typically positive for CK7, even in the
cases that show intestinal dierentiation. It is also noteworthy that MUC1, in addition to being a fairly good
indicator of biliary dierentiation, is also expressed in the
high-grade areas of any type and thus may serve as a
marker of HGD. It may be important to reiterate here
that a signicant proportion of the ICPNs have hybrid
patterns and heterogenous areas that coexpress dierent
immunohistochemical markers. In fact, this pronounced
proclivity to form hybrid phenotypes further necessitates
the classication of these lesions under 1 umbrella
category.
Invasive Carcinomas Arising in ICPNs

Invasive carcinoma is seen in more than half of the
ICPNs at the time of diagnosis. Most of these are pancreatobiliary-type GB adenocarcinomas; however, other
types such as mucinous, neuroendocrine, etc. are also seen
and perhaps even with higher frequency than those arising from nontumoral (at) intraepithelial neoplasia.164
Conversely, when the issue is examined from the invasive
carcinoma perspective, an ICPN component is identied
in 6.4% of all invasive carcinomas of the GB. In the lit-
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Am J Surg Pathol
erature, a wide range of gures have been quoted for this

association, ranging from 5% to 23%,13,15,66,68,73 which
is most likely because of the denitional dierences
discussed earlier.
As discussed above, factors in the ICPN component, which appear to have an association with the risk of
invasion include amount of papillary conguration, extent of HGD, and predominance of nonpyloric cell lineages. Size may also be a factor but did not reach statistical
signicance in this study. All cases that have an associated
invasive carcinoma have at least focal HGD. As is the
case in lower GI tract and pancreatobiliary tract, invasive
carcinomas are more likely to develop in the papillary
than in the tubular cases, and this has also been noted in
the literature on studies of papillary adenocarcinoma of
the GB.57 As in the pancreatic IPMNs and ITPNs,152 the
gastric and pyloric lineages in ICPNs appear to have a
lesser tendency for invasion. However, even the pylorictype ICPNs with exclusively tubular patterns, which have
long been considered entirely benign innocuous lesions,
were found in this study to display HGD frequently, and,
more importantly, 18% of these were associated with
invasive carcinoma. This gure, incidentally, is virtually
identical to that reported for gastric-type/branch-duct
IPMNs.2,152,165169 In fact, when the literature on the GB
pyloric gland adenoma cases is analyzed carefully, it
becomes clear that the larger lesions often do show carcinomatous transformation; unfortunately, this fact has
been largely diluted in studies that are composed mostly
of subcentimeter lesions,65,73,88 which may be more appropriate to classify as polypoid pyloric gland metaplasias and common ndings in cholecystitis.151
Incidentally, similar pyloric gland lesions in the GI tract
are also found to be associated with invasive carcinoma
even though they are very innocuous appearing.123,124
Biological Behavior and Clinical Outcome

Parameters
The prognosis for ICPNs is incomparably better
than that for other invasive carcinomas of the GB. Not
surprisingly, noninvasive cases have a far better prognosis: the 3- and 5-year survival rates are 90% and 78%,
versus 60% and 60% in invasive ones (Fig. 17). In contrast, it would be important to note that some patients
with noninvasive cases also die of cancer. In this study,
among 55 noninvasive cases, 4 patients died of cancer, 3
of which were reported as biliary tract cancer by
imaging and biliary obstruction signs, and these deaths
mostly occurred long after the diagnosis of ICPN (median
73.5 mo), suggesting that these patients may have suered
from a new primary in the remaining biliary tract. All had
HGD, and 1 had extensive HGD. All had a papillary
growth pattern. The cell lineage of these cases was gastric
foveolar in 2 and biliary in 2 (Table 6). The fact that some
patients with noninvasive ICPNs die of tumor may not be
surprising, as it is now well established that a similar
percentage of noninvasive pancreatic IPMNs also succumb.10,170,171 Furthermore, in nontumoral (at) CIS
cases of GB, recurrences and metastasis were seen in a
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Am J Surg Pathol
similar percentage in spite of being diagnosed by the most

experienced who ruled out invasive carcinoma by thorough sampling.104 In these patients, the tumors were
sampled in 8 to 30 blocks, and 3 of 4 were submitted
entirely (Table 6). Thus, this adverse outcome of the
noninvasive cases may not necessarily be due to missed
invasive carcinomas but rather may be attributable to a
eld-defect phenomenon, although further studies would
be necessary to investigate this possibility. The fact that
many deaths occurred several years after the original diagnosis also points toward this explanation. This brings up
the question of surveillance of these patients; however, the
biliary tract still remains dicult to image and highly
challenging to biopsy. Moreover, carcinomas of this region
are often subtle and dicult to distinguish from reactive/
regenerative changes. Most importantly, even ICPNs with
associated invasive carcinoma have a better prognosis than
pancreatobiliary-type GB carcinomas (without ICPN), and
this survival advantage was independent of size and
persisted even with stage-matched comparison (Fig. 18).
This suggests that ICPN-associated invasive carcinomas
may have distinct biological properties.
Surgical Pathologic Evaluation and Reporting

In evaluation of these lesions, regardless of the
terminology, of foremost importance is to rule out invasive carcinoma by thorough sampling and careful
evaluation, considering that the prognosis of noninvasive
cases is vastly dierent from those with associated invasive carcinoma. It should be kept in mind that the
polypoid lesions often detach from the mucosa and appear as sludge in the lumen of the GB or the container.
It should also be remembered that invasive carcinoma
may be grossly inapparent and may also occur away from
the main ICPN lesion. If identied, invasive carcinoma
ought to be typed and staged as customary. For the
noninvasive cases, it is important to assess the presence
and amount of HGD, the size of the lesion, the cell lineage type, and, when possible, the amount of papillary
conguration and the margin status. For cases with hybrid patterns, immunohistochemical markers MUC1,
MUC2, MUC5AC, MUC6, and CDX2 may help to
further characterize the lineage; whether this is necessary
is debatable, as there are no established management algorithms for these lesions yet.
In reporting these lesions, the approach used in
other organs such as the breast is recommended. Accordingly, an example for a report of a noninvasive
case could read as: Intracholecystic papillary-tubular
neoplasm, 4.0 cm, with extensive HGD (> 75% of the
tumor), pyloric complex nonmucinous type, with predominantly tubular pattern. No invasive carcinoma is
identied. For a case with an associated invasive carcinoma, the diagnosis can be rendered as invasive adenocarcinoma (0.5 cm), moderately dierentiated, colloid
type, invading into but not through the muscularis
(pT1b), arising in an intracholecystic papillary-tubular
neoplasm (2.5 cm) of the biliary type with predominantly
tubulopapillary pattern. Characteristics of the invasive
r
carcinoma such as perineurial invasion are to be documented in further detail.

In conclusion, mass-forming (Z1 cm) preinvasive
neoplasms of the GB share common features and also
exhibit many similarities to biliary IPNs and pancreatic
IPMNs and ITPNs, in that they demonstrate a spectrum
of dysplastic change, variable conguration, and dierent
cell lineages, often in a mixture. We believe these neoplasms can be regarded under a generic category for
which we propose the term ICPN. ICPNs are indolent,
and even the invasive cases appear to have a signicantly
better overall prognosis than pancreatobiliary-type adenocarcinomas unaccompanied by ICPNs.
ACKNOWLEDGMENTS
The authors would like to thank Dr Juan Rosai for his
recommandation of the term intracholecystic for these
neoplasms. The authors also thank Allyne Manzo for her
assistance for the photographs and Leslie Ducato and
Rhonda Everett for their assistance in the preparation of
this manuscript.
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ORIGINAL ARTICLE

Intracholecystic Papillary-Tubular Neoplasms (ICPN)

Abstract: The literature on the clinicopathologic characteristics

Volume 36, Number 9, September 2012

Volume 36, Number 9, September 2012

intraductal papillary neoplasms, pancreatic intraductal papillary

FIGURE 1. Terminologic and conceptual analogy between

papillomatosis.20,22,31,4245,5053 However, because mucin

2012 Lippincott Williams & Wilkins

Volume 36, Number 9, September 2012

Adenoma is, in fact, one of the most commonly

MATERIALS AND METHODS

2012 Lippincott Williams & Wilkins

Intracholecystic Papillary-Tubular Neoplasms (ICPN)

TABLE 1. Definition of ICPN

Volume 36, Number 9, September 2012

of this study, each case was assigned to 1 of 3 groups: (a)

Dysplasia was graded as low or high33 using the

2012 Lippincott Williams & Wilkins

Volume 36, Number 9, September 2012

Intracholecystic Papillary-Tubular Neoplasms (ICPN)

Cell Lineage Morphology

Immunohistochemical analysis was performed using

2012 Lippincott Williams & Wilkins

FIGURE 4. Intestinal phenotype in ICPN. Morphologically the

Volume 36, Number 9, September 2012

FIGURE 7. Biliary pattern of ICPN. Nondescript cuboidal cells

labeling below 10% was designated focal, 10% to 50%

Patient demographic and clinical characteristics

FIGURE 6. Gastric pyloric (simple mucinous in this example)

ICPNs dened as Z1.0 cm were uncommon. In the

2012 Lippincott Williams & Wilkins

Volume 36, Number 9, September 2012

Intracholecystic Papillary-Tubular Neoplasms (ICPN)

TABLE 2. Specification of the Antibodies

Leica Microsystems, Bannockburn, IL

is, 6.4% of GB carcinomas arose in association with

2012 Lippincott Williams & Wilkins

Volume 36, Number 9, September 2012

ICPN With Invasive

*Applies to invasive disease only.

2012 Lippincott Williams & Wilkins

Volume 36, Number 9, September 2012

Intracholecystic Papillary-Tubular Neoplasms (ICPN)

2012 Lippincott Williams & Wilkins

ciated invasive carcinoma. Invasive carcinoma in this group

Volume 36, Number 9, September 2012

focal CDX2 in 15%, CK20 in 28%, MUC5AC in 50%,

FIGURE 9. Invasive carcinoma arising in ICPNs. Although

arising within cholesterol polyps, as observed in a few

ICPN Without Invasive Carcinoma (N = 55)

ICPN With Invasive Carcinoma (N = 68)

2012 Lippincott Williams & Wilkins

Volume 36, Number 9, September 2012

Intracholecystic Papillary-Tubular Neoplasms (ICPN)

(b) Pyloric, simple, mucinous (n = 13; 11% of

2012 Lippincott Williams & Wilkins

pedunculated multinodular polyps that were prone to

Volume 36, Number 9, September 2012

FIGURE 12. Pyloric complex nonmucinous type is a distinct

2012 Lippincott Williams & Wilkins

Volume 36, Number 9, September 2012

FIGURE 13. Pyloric complex nonmucinous type. The cells are