Intraductal Tubulopapillary Neoplasm of the Pancreas
An Update From a Pathologist’s Perspective
Sarah L. Rooney, MD; Jiaqi Shi, MD, PhD
Context.—Intraductal tubulopapillary neoplasm (ITPN)
is a rare intraductal epithelial neoplasm of the pancreas
recently recognized as a distinct entity by the World
Health Organization classification in 2010. It is defined as
an intraductal, grossly visible, tubule-forming epithelial
neoplasm with high-grade dysplasia and ductal differenti-
ation without overt production of mucin. The diagnosis can
be challenging owing to morphologic overlap with other
intraductal lesions and its rarity. While recent advances in
molecular genetic studies of ITPN have provided new tools
to facilitate clinical diagnosis, the limited number of cases
has yielded limited follow-up data to guide management.
Object iv e. — To provide a clinical, pathologic, and
molecular update on ITPN with r espect to clinical
presentation, imaging findings, histopathologic features,
differential diagnosis, biological behavior, molecular char-
acteristics, and treatment options.
Data Sources.—Ana lysis of the pertinent literatur e
(PubMed) and authors’ research and clinica l practice
experience based on institutional and consultation mate-
rials.
Conclusions.—Clinical presentation, imaging findings,
histopathology, immunohistochemistry studies, molecular
characteristics, prognosis, and treatment options of ITPN
are reviewed. Important differential diagnoses with other
intraductal neoplasms of the pancreas—especially intra-
ductal papillary mucinous neoplasm—using histopatholog-
ic, molecular, a nd i mmunohistochemical studies, are
discussed. Despite the recent progress, more studies are
necessary to assess the biology and genetics of ITPN for a
better understanding of the prognostic factors and treat-
ment options.
(Arch Pathol L ab Med. 2016;140 :1068–1073; doi:
10.5858/arpa.2016-0207-RA)
T
he intraductal neoplasms of the pancreas are defined by
the current 4th edition of the World Health Organiza-
tion (WHO) classification as macroscopic epithelial neo-
plasms with ductal differentiation that grow in the
pancreatic ductal system. The 2 entities included in this
category are intraductal papillary mucinous neoplasm
(IPMN) and intraductal tubulopapillary neoplasm (ITPN).
Note that intraductal lesions with nonductal differentiation,
such as acinar cell carcinoma, are not included in this
category. Interestingly, before the current WHO classifica-
tion, intraductal neoplasms of the pancreas were classified
into 3 groups: IPMN, pancreatic intraepithelial neoplasia
(PanIN), and intraductal tubular neoplasm.
1,2
Intraductal
tubular neoplasm was then further classified into intraductal
tubular adenoma and intraductal tubular carcinoma, with
intraductal tubular adenoma considered as the precursor of
intraductal tubular carcinoma.
3
Both IPMN and ITPN can be
either cystic or solid-mass forming. The distinction between
the intraductal neoplasms and PanIN is that PanIN is
microscopic. On the contrary, by definition, both IPMN and
ITPN are grossly and radiographically detectable lesions
with an arbitrary minimal size criterion of 1 cm. Intraductal
tubulopapillary neoplasms can have variable components of
tubular and/or papillary histologic growth patterns. These
neoplasms are considered to be premalignant owing to their
common association with and demonstrated progression to
invasive carcinoma.
Intraductal tubulopapillary neoplasm is a rare intraduc-
tal epithelial neoplasm of the pancreas recently recognized
as a distinct ent ity by WHO classification in 2010.
4–10
It
was ac tua ll y first recogn iz ed by J ap an es e inves ti ga t or s in
the mid 1990s and then was prop os ed to be named
intraductal tubular carcinoma by the Jap an Pancr e as Society
in 2002.
11,12
In 2009, Yamaguchi et al
13
proposed renaming
this entity as intraductal tubul opapill ary neoplasm.It
accounts for less than 1% of all pancreatic exocrine
neoplasms and approximately 3% of intraductal pancreatic
neoplasms. Accor ding to the most recent 4th edit ion of
WHO, the definition of ITPN is as follows: an intraductal,
grossly visible, tubule-forming epithelial neoplasm with
high-grade dysplasia a nd ductal differentiation without
overt production of mucin. The confusing change in
nomenclature, in conjunction with infrequent exposure
to these lesions that can have histolog i c overla p , poses a
diagnostic challenge for practicing pathologists. Never-
theless, careful correlation of clinical presentation, imag-
ing, gross pathology, and histopathol ogic and
immunohistochemistry findings allows for correct diagno-
Accepted for public ation May 11, 2016.
From the D epartment of Pathology, University of Michigan, Ann
Arbor.
The aut hors have no relevant financial inte rest in the produc ts or
companies described in this article.
Presented in part at the New Frontiers in Path ology meeting;
October 22–24, 2015; Ann Arbo r, Michigan.
Reprints: Jiaqi Shi, MD, PhD, Department of Pathology, University
of Michigan, MSI1 Room 5231C, 1301 Catherine St, Ann Arbo r, MI
48109 (email: jiaqis@med.umich.edu).
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sis in most cases. This review provides a brief update on
the current knowledge of ITPN with an overview of
clinical, radiologic, histopathologic, and molecular fea-
tures. Furthermore, we will discuss prognosis and treat-
ment options in ITPN.
CLINICAL PRESENTATION
Owing to the rare occurrence and relatively recent
recognition and classification of ITPN, there are only limited
data on this entity so far. According to the limited cases
reported, ITPN occurs as commonly in males and females.
4
The mean age at diagnosis is 61 years (range, 35–78 years).
4
Risk factors have not been elucidated; however, a case of
ITPN in a field of irradiation has been reported.
14
In another
case report, an ITPN occurred in a 78-year-old man with a
family history of pancreatic cancer.
9
Approximately two-
thirds of patients present with nonspecific symptoms
including abdominal pain, vomiting, weight loss, exacerba-
tion of diabetes, jaundice, and fever. About one-third of
patients are asymptomatic with incidental discovery of their
lesions. Nearly half of ITPNs are located in the head of the
pancreas. However, a literature review shows that ITPNs
also occur in other pancreatic sites, including the body (5 of
30, 17%), tail (2 of 30, 7%), head and body (1 of 30, 3%),
body and tail (2 of 30, 7%), and with diffuse involvement (4
of 30, 14%).
4
These tumors are usually slow growing and are
therefore relatively large at the time of diagnosis. The size of
the tumor ranges from 1 to 15 cm (3 cm in average).
Laboratory tests are often nonspecific, including serum
tumor antigens. Treatment is surgery in most cases (22 of
30, 73%), with the most frequent procedures being pylorus-
preserving pancreatoduodenectomy and distal pancreatec-
tomy.
4
Total pancreatectomy was performed in 18% of the
patients.
IMAGING STUDIES
Radiographic studies, including endoscopic ultrasonog-
raphy, dynamic contrast-enhanced computed tomography
(CT), magnetic resonance (MR) imaging including MR
cholangiopancreatography (MRCP), a nd endoscopic ret-
rograde cholangiopa ncreatogra phy (ERCP), are of ten
performed before surgery and are helpful in assisting
diagnosis in most cases. Intraductal tubulopapillary
neoplasms are usually visualized as poorly enhancing
lesions throughout the scanned phase.
15
Motosugi et al
16
described a 2-tone duct sign in ITPNs on the dynamic CT
(7 of 10, 70%) and MR images (5 of 8, 63%), with a slight ly
higher density area representing the tumor in the main
pancreat ic duct and a lower density ar e a r ep res enting
dilated upstream duct. Most ITPNs arise in the main
pancreatic duct with ductal dilation; only about 5% (2 of
41)ofthecasesariseinbranchducts.
15
Branch-duct ITPNs
have neither a dilated main pancreatic duct nor 2-tone
duc t sign. Another characteristic feature of ITPN is a
‘‘cork-of-wine-bottle sign’’ that was observed on MRCP
and ERCP images, indicating intraductal growth.
16
Rare
ITPNcaseshavecoarsecalcificationthatcanbemistaken
for a neuroendocrine tumor.
17
However, concurrent
obstruction and dilation of the main pancreatic duct
would suggest an intraductal lesion. Knowledge a bout
fluorodeoxyglucose–positron e mission tomography find-
ings for ITPN is limited. The degree of uptake varies
depending on the characteristics within a tumor. For
example, intratumoral hemorrhage can cause interval
decreas e in the meta b ol ic a ct i vi ty and uptake within t he
tumor.
18
Many of the abovementioned findings are also
characteristic of IPMNs, which makes diagnosis by
imaging alone nearly impossible. A more solid growth
pattern favors ITPN over IPMN.
HISTOPATHOLOGY
By definition, ITPNs are macroscopic (1 cm and mass
forming), intraductal, tubule-forming epithelial neoplasms.
Compared to IPMNs, they are less often cystic. Intraductal
tubulopapillary neoplasms typically have uniform high-
grade dysplasia and frequent mitotic figures. They consist of
closely apposed tubules forming complex cribriform struc-
tures in dilated pancreatic ducts with focal areas of papillary
architecture (Figure 1, A and B). Mucin is minimal to
nonexistent. The tubules are lined by predominantly
cuboidal to low columnar epithelial cells with a moderate
amount of eosinophilic or amphophilic cytoplasm and
round to oval nuclei with moderate to marked atypia. Rare
clear cell changes and stromal osseous and cartilaginous
metaplasia have been reported in ITPN.
19,20
Sometimes,
apical apocrine snouts are present. Occasionally, there are
intraluminal secretions or comedolike necrosis. Approxi-
mately 40% to 50% of ITPN cases are associated with
invasive carcinoma.
4,21
A higher risk of invasion is associated
with male sex, larger tumor size, and high Ki-67 prolifer-
ation.
4
The diagnostic challenge posed by IPMN’s histologic
overlap with ITPN, especially the pancreatobiliary-type and
oncocytic-type IPMN (Figure 1, C and D), needs to be
addressed. A comparison between these 2 entities is listed in
Table 1. Intraductal papillary mucinous neoplasms are
typically cystic, have more abundant mucin, and their
architecture is predominantly papillary. The cytologic atypia
ranges from low- to high-grade and comedolike necrosis in
the lumen is rare. By contrast, ITPNs are typically not cystic,
have no or minimal mucin, and architecture is predomi-
nantly tubular. They have uniformly high-grade cytologic
atypia, and comedolike necrosis in the lumen is frequently
seen. However, it is important to note that diffuse high-
grade dysplasia and cribriform complex architecture are
found in many pancreatobiliary- and oncocytic-type IPMNs.
For example, we have encountered a pancreatobiliary-type
IPMN that histologically resembles ITPN with predominant
tubular and cribriform complex architecture and comedolike
necrosis in the lumen (Figure 2, A and B). In difficult cases
such as this, immunohistochemistry studies may be helpful
to confidently differentiate them, since most IPMNs are
positive for MUC5AC and negative for MUC6 (Figure 2, C
and D).
The differential diagnosis for ITPN may also include
intraductal acinar cell carcinoma, which sometimes has an
intraductal growth pattern, mimicking intraductal neo-
plasms.
22
They typically consist of sheets of back-to-back
acinar structures, but papillary structures can be seen. The
cells classically contain round uniform nuclei with a single
prominent central nucleolus and eosinophilic zymogen
granule–containing cytoplasm, characteristic features of
acinar cell differentiation. Unfortunately, these typical
cytologic features are not always present, in which case
immunohistochemical studies for trypsin, chymotrypsin,
and BCL10—all of which show positivity in acinar cell
carcinoma—are necessary.
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IMMUNOHISTOCHEMISTRY
Immunohistochemical studies are useful in rend ering the
diagnosis of ITPN i n rare cases that lack classic morphol-
ogy or overlap histologically with IPMNs. In these cases
the differential typica lly in cludes a combination of ITPN,
various IPMN subtypes, and/or intraductal acinar cell
carcinoma. Knowledge of t he characteristic immuno histo-
chemical profiles of these lesions can be very helpful in this
situation. Typically, ITPNs are pos itive for cytokeratin (CK)
7 (21 of 21, 100%), CK19 (18 of 19, 95%), MUC1 (23 of 26,
88%), and MUC6 ( 14 of 19, 74%), and they are negative for
MUC2 ( 25 of 26, 96%), MUC5AC (23 of 27, 85%), trypsin
(19 of 19, 100%), and b-catenin (16 of 17, 94%).
4
However,
rare cases of MUC5AC-positive ITPNs have been report-
ed.
23
Mucin glycoproteins MUC 6 and MUC5AC are the
most useful markers to di ff er e nt ia te betwee n ITPN and
IPMN, since most IPMNs are positive for MUC5AC a nd
negative for MUC6 (Figure 2, C and D). An exception is the
oncocytic-type IPMN, which is usually positive for MUC6
and MUC1, and negative for MUC5AC and MUC2 (as is
ITPN) (Table 2). Mitochondrial stains such as phospho-
tungstic acid–hematoxylin, Novelli stain, or apoptin 111.3
antibodyinoncocyticIPMNmaybehelpfulinthis
situation.
5
In addition, the cystic gross appearance with
mucin production and the oncocytic cytology is also helpful
in distinguishing on cocytic-type IPMN from ITPN. Gas-
tric-type I PMNs can also be MUC6 positive, but should
also express MUC5AC. MUC1 typically shows positivity in
the pancreatobiliary-type IPMNs and negativity in other
types o f IPMN. MUC2 typically shows positivity in the
intestinal-type IPMNs and negativity in other types of
IPMN (Table 2).
As previously mentioned, intraductal acinar cell carcino-
ma can sometimes enter the differential diagnosis of ITPN,
Table 1. Histopathology and Molecular Comparison
Between Intraductal Papillary Mucinous Neoplasm
(IPMN) and Intraductal Tubulopapillary Neoplasm
(ITPN)
IPMN ITPN
Luminal mucin Abundant Minimal to none
Atypia Low–high-grade Uniform high-grade
Predominant
growth pattern
Papillary Tubular
Comedolike
necrosis
Rare Frequent
KRAS mutation þ/
PIK3CA mutation þ/
Abbreviations: , absent; þ/, present or absent.
Figure 1. Histologic comparison between intraductal tubulopapillary neoplasm and pancreatobiliary- and oncocytic-type intraductal papillary
mucinous neoplasm (IPMN). A and B, Intraductal tubulopapillary neoplasm. C, Pancreatobiliary-type IPMN. D, Oncocytic-type IPMN (hematoxylin-
eosin, original magnification
3
200 [A through D]).
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but it should be trypsin, chymotrypsin, and BCL10 positive.
BCL10 is a newly developed marker of acinar cell
differentiation in pancreas.
24,25
The antibody recognizes
the C-terminal portion of the BCL10 protein, which is
homologous to an enzyme (carboxylic ester hydrolase)
produced by pancreatic acinar cells. It is more sensitive than
other pancreatic enzyme markers in detecting acinar cell
carcinoma. Studies also show that BCL10 is specific to acinar
cells of normal and ectopic pancreas, of pancreatic
metaplasia, and of acinar cell carcinoma, and is not
expressed in pancreatic ductal adenocarcinoma, IPMN,
mucinous cystic neoplasm, neuroendocrine tumor, solid-
pseudopapillary neoplasm, or serous cystic tumor. One
caveat is that some of the adenosquamous carcinomas of the
pancreas can be positive for BCL10.
24
Interestingly, an unusually strong and diffuse immuno-
histochemical staining pattern for vimentin was observed in
a case of branch-duct lesion with morphologic features of
ITPN.
26
The lesion was also positive for CK7 and MUC1, but
negative for MUC5AC, chymotrypsin, CK20, chromogranin,
synaptophysin, b-catenin, and PAX8. The authors stained 3
cases of IPMNs, none of which were positive for vimentin.
Figure 2. A pancreatobiliary-type intraductal papillary mucinous neoplasm (IPMN) histologically mimicking intraductal tubulopapillary neoplasm
(ITPN). A, Back-to-back tubules with cribriform complex architecture and frequent comedolike necrosis in the lumen, histologically resembling ITPN.
B, Higher magnification of the same lesion as in (A) showing the tubules lined by cuboidal/columnar epithelial cells with eosinophilic cytoplasm and
atypical nuclei. Apical apocrine-like snouts and comedolike necrosis in the lumen are present. C and D, The neoplastic epithelial cells are diffusely
positive for MUC5AC (C) and negative for MUC6 (D), supporting a diagnosis of pancreatobiliary-type IPMN (hematoxylin-eosin, original
magnifications
3
100 [A] and
3
400 [B]; original magnification
3
100 [C and D]).
Table 2. Immunohistochemistry Comparison
Between Intraductal Papillary Mucinous Neoplasm
(IPMN) and Intraductal Tubulopapillary Neoplasm
(ITPN)
MUC
IPMN
ITPNGastric Intestinal PB Oncocytic
MUC1 þFocal þþ
MUC2 þ
MUC5AC þþ/þ
MUC6 þ/þ þ
Abbreviations: PB, pancreatobiliary type; þ, positive; focal þ, focal area
positive; , negative; þ/, positive or negative.
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Pancreatic neoplasms are rarely positive for vimentin, except
for solid-pseudopapillary neoplasm. It is not known
whether this is an incidental finding in a single case or
whether this is applicable to all ITPNs. Larger studies in
ITPNs are necessary to clarify this finding.
MOLECULAR CHARACTERISTICS
Evidence that ITPN and IPMN are distinct entities also lies
in their differing molecular genetic characteristics (Table 3).
Whole exome sequencing of IPMNs revealed about 26
mutations per neoplasm, with mutations in KRAS (47%–
81%), GNAS (41%–66%), and RNF43 (ubiquitin E3 ligase
ring finger 43) (75%) observed most frequently.
27
Consis-
tently, KRAS mutations are the most frequent, which
supports the hypothesis that KRAS is an important driver
gene during IPMN progression. Second most common are
mutations in GNAS, typically at codon 201. Nearly 100% of
intestinal-type IPMNs harbor a GNAS mutation. Interest-
ingly, GNAS mutations have been found in invasive
adenocarcinomatous components associated with IPMNs
but not in de novo, isolated ductal adenocarcinomas.
28
RNF43 is a potential tumor suppressor gene and a negative
regulator of the Wnt signaling pathway; it is inactivated in
75% of IPMNs.
Recently, Amato et al
29
sequenced 52 intraductal
papillary neoplasms, including 48 IPMNs and 4 ITPNs to
assess mutational profile i n 51 cance r- as so ci a ted genes by
using Ion Torrent semiconductor-based next-generation
sequencing technique (Lif e Technologies, Carlsbad, Cal-
ifornia). At least 1 somatic mutation was found in 96% (46
of 48) of IPMNs, a nd 60% (29 of 48) had multiple gene
mutations. Again, 92% (44 of 48) of IPMNs were found to
have KRAS and/or GNAS mutations. In addition, KRAS and
GNAS mutations coexist in 37.5% (18 of 48) of IPMNs.
RNF43 was the third most commonly mutated gene in
IPMNs and it was always associated with KRAS and/or
GNAS mutations. On the contrary, only 1 of 4 ITPNs
contained GNAS and NRAS m utations. Interestingly, the
gastric-type IPMNs ha d the most frequent GNAS, KRAS,
and SMAD4 mutations, compared to other types of IPMNs,
although the sample number was relatively low (n ¼ 6).
29
TP53 (5 of 52, 10%) and BRAF (3 of 52, 6%) mutations were
only found in high-grade IPMNs, with TP53 mutations
most often detected in pancreaticobiliary type. Other less
common mutations in IPMNs include PIK3CA (3%–11%),
AKT1 (3 of 36, 8%), CDKN2A/p16 (18%), SMAD4 (1 of 5 2,
2%), CTNNB1/b-catenin (2 of 52, 4%), IDH1 (2 of 52, 4%),
STK11 (2 of 52, 4%), PTEN (2 of 52, 4%), ATM (1 of 52,
2%), CDH1 (1 of 52, 2%), FGFR3 (1of52,2%),andSRC (1
of 52, 2%).
6,29,30
Most of these low-frequency mutations are
found concurrent with a GNAS an d/ o r KRAS mutation.
29
Some of these additional mutations may reflect more
advanced, higher-grade lesions, as CDKN2A/p16 and
SMAD4 mutations and/or los s of expression has been
shown to correlate with higher-grade lesions.
31–33
In-
creased microRNA expression, such as miRNA-21, in
IPMNs has also been reported.
34
Com pared with IPMN s, molecu lar genetic studies of
ITPN are relatively limited owing to the small number of
cases available. According to a literature review, mutational
analysis revealed TP53 mutations in 27% (6 of 22), PIK3CA
mutations in 18% (2 of 11), BRAF mutation in 15% (2 of
13), and KR AS mutation in 10% (2 of 20) of the ITPN
cases.
4
However, other studies
6
have found lower frequen-
cy of KRAS mutation (0%–7%) in ITPNs. Although
mutati ons of PIK3CA were de scribed in 3% to 11% of
IPMNs, they are among the most fre q uen t mutat io n s in
ITPN(upto27%,3of11).
3,35
Therefore, KRAS mutations
aremuchmorecommoninIPMN,whereasPIK3CA
mutati ons are much more comm on i n ITPN ( Table 1).
5
Of note, PIK3CA mutations are often associated with an
increase in phosphorylated AKT, suggesting the activation
of the PI3K-AKT signaling pathway and a potential
therapeutic target in ITPN.
28
Altered expression of
CDKN2A/p16 was seen in 54% of ITPNs, and p53 was
overexp res s ed in 2 0% of ITPN s . Rar e BRAF V600 E
mutations have also been reported.
36
Recent deep cover-
age, targeted next-generation sequencing was performed
on 11 ITPN cases with a panel of 300 key cancer-associated
genes and none of the known IPMN-associated genetic
alterations were found in ITPN.
37
Two histon e H3
methyltransferase genes, MLL2 and MLL3, each were
mutated in 2 cases of ITPN. Six ITPN cases had MCL1 (a
member of t he B cl-2 family) ampli ficatio n, w hile 3 ITPN
cases contained no mutations in the tested genes. Taken
together, the data indicate that there are definitive genetic
differences between ITPN and IPMN, which makes genetic
analysis another valuable tool for diagnosis.
PROGNOSIS AND TREATMENT
There a re limited follow-up data available in the
literature for ITPNs. Invasive carcinoma was reported in
54% (13 of 24) o f th e I TPN ca ses.
4
Male sex, large tumor
size, increased mitosis, and high Ki-67 proliferative index,
but not age, are associated with a highe r risk of invasi ve
growth.
4,13
Therefore, one study
4
proposed that i mag in g -
guided core needle biopsy followed by Ki-67 immunohis-
tochemical staining, together with imaging to determine
the tumor size, should be used to s tratify the risk of
invasio n b ef ore s ur g er y. Rar e c as es o f dea t h fro m m ult ip le
ITPN liver metastases have been reported. Therefore,
surgery is currently preferred to treat patients with ITPN
to prevent malignant transformation. The tumor can recur
years after surgery, which is thought to be due to
intraductal colonization. However, other cases of ITPN
resected via distal pancreatectomy did not have recurrence
in the follow-up period, suggesting that total pancreatec-
tomy is not always neces sa r y. Nev ert he l e ss , close cli ni ca l
follow-u p is cons id ere d essential to detect early re cu rr en ce .
Fortunately, the prognosis of ITPN-associated invasive
carcinoma is much better than that of traditional pancreatic
Table 3. Molecular Genetic Comparison Between
Intraductal Papillary Mucinous Neoplasm (IPMN) and
Intraductal Tubulopapillary Neoplasm (ITPN)
IPMN, % ITPN, %
KRAS 47–81 0–10
GNAS 41–66 0–25
TP53 10 (5/52, high-grade) 0–23
BRAF 6 (3/52, high-grade) 0–15
SMAD4/DPC4 2 (1/52) 0–10
RNF43 75 N/A
PIK3CA 3–11 0–27
CDKN2A/p16 18 54
Abbreviation: N/A, not available.
Data derived from Kolby et al,
4
Kloppel et al,
6
Yamaguchi et al,
13
Reid
et al,
28
Amato et al,
29
Urata et al,
36
Esposito et al,
38
Wu et al,
39
and
Furukawa et al.
40
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