J Gastroenterol (2012) 47:731–759
DOI 10.1007/s00535-012-0611-2
REVIEW
Japanese clinical practice guidelines for pancreaticobiliary
maljunction
Terumi Kamisawa • Hisami Ando • Masafumi Suyama •
Mitsuo Shimada • Yuji Morine • Hiroshi Shimada •
Working Committee of Clinical Practice Guidelines for Pancreaticobiliary Maljunction
Received: 2 May 2012 / Accepted: 2 May 2012 / Published online: 22 June 2012
 Springer 2012
Abstract There have been no clinical guidelines for the
management of pancreaticobiliary maljunction (PBM). The
Japanese Study Group on Pancreaticobiliary Maljunction
(JSPBM) has proposed to establish clinical practice guide-
lines on how to deal with PBM, with the support of the
Japan Biliary Association (JBA). Because the body of evi-
dence-based literature is relatively small, we decided to
create guidelines based on the consensus of experts, using
the medical literature for reference. A total of 46 clinical
questions (CQs) were considered by the members of the
editorial committee responsible for the guidelines. The CQs
covered distinct aspects of PBM: (1) Concepts and Patho-
physiology (10 CQs); (2) Diagnosis (10 CQs); (3) Pancre-
atobiliary complications (9 CQs); and (4) Treatments and
prognosis (17 CQs). Statements and comments for each CQ
T. Kamisawa (&)
Department of Internal Medicine, Tokyo Metropolitan
Komagome Hospital, 3-18-22 Honkomagome,
Bunkyo-ku, Tokyo 113 8677, Japan
e-mail: kamisawa@cick.jp
H. Ando
Department of Pediatric Surgery,
Nagoya University Graduate School of Medicine,
65 Tsurumai, Showa-ku, Nagoya 466-8560, Japan
M. Suyama
Department of Gastroenterology, Juntendo University
Urayasu Hospital, 2-1-1 Tomioka, Urayasu 279-0021, Japan
M. Shimada
Y. Morine
Department of Surgery, The University of Tokushima,
3-18-15 Kuramoto, Tokushima 770-8503, Japan
H. Shimada
Japanese Study Group on Pancreaticobiliary Maljunction,
3-18-15 Kuramoto, Tokushima 770-8503, Japan
were prepared by the guidelines committee members and
collaborating partners. The CQs were completed after
review by members of the editorial committee, meetings of
this committee, public comments on the homepages of the
JSPBM and the JBA, public hearings, and assessment and
approval by the guidelines evaluation board. PBM includes
cases where the bile duct is dilated (PBM with biliary
dilatation) and those in which it is not (PBM without biliary
dilatation). In these guidelines, PBM with biliary dilatation
is defined as being identical to congenital biliary dilatation
of Todani type I (except for type Ib) and type IV-A, both of
which are accompanied by PBM in almost all cases. These
guidelines are created to provide assistance in the clinical
practice of PBM management; their contents focus on
clinical utility, and they include general information on
PBM to make this disease more widely recognized.
Keywords Pancreaticobiliary maljunction
Congenital
biliary dilatation
Gallbladder cancer
Pancreatitis

Anomaly
Introduction
The Japanese Study Group on Pancreaticobiliary Maljunc-
tion (JSPBM), with the support of the Japan Biliary Associ-
ation (JBA), has proposed to establish clinical practice
guidelines on how to deal with pancreaticobiliary maljunc-
tion (PBM: also known as anomalous arrangement of the
pancreaticobiliary ducts; anomalous arrangement of the
pancreaticobiliary ductal system; anomalous pancreaticob-
iliary ductal union; anomalous union of the biliopancreatic
ducts; abnormal junction of the pancreaticobiliary ductal
system; or common channel syndrome). Accordingly, the
JSPBM formed a PBM clinical practice guidelines
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committee, in September 2010, that began to prepare a draft
of these guidelines. When a PubMed search was carried out
with the keywords ‘‘pancreaticobiliary maljunction’’ and
‘‘anomalous arrangement of pancreaticobiliary ducts’’, cov-
ering the period from August 1976 to January 2011, 169 and
56 entries, respectively, appeared in the literature. Similarly,
when the keywords ‘‘sui tankan gōryū ijō (the Japanese
translation of PBM)’’ and ‘‘sentensei tandō kakuchō-syō (the
Japanese translation of congenital biliary dilatation)’’ were
employed in the Ichushi-Web search engine (offered by the
NPO Japan Medical Abstracts Society), there were 1,165 and
1,109 entries, respectively, from February 1982 to September
2011. All these literature entries have been included in this
analysis, in addition to the articles cited in these reports and
those indicated by experts. However, because the body of
evidence-based literature is relatively small, we finally
decided to create guidelines based on the consensus of
experts, using the medical literature for reference.
A total of 46 clinical questions (CQs) were considered by
the members of the editorial committee. These CQs covered
distinct aspects of PBM: (1) Concepts and pathophysiology
(10 CQs); (2) Diagnosis (10 CQs); (3) Pancreatobiliary
complications (9 CQs); and (4) Treatments and prognosis (17
CQs). Statements and comments regarding each CQ were
prepared by the guideline committee members and collabo-
rating partners. The statements made were reviewed 2–4
times by the editorial committee members, and 3 guideline
committee meetings were held during the process of prepa-
ration. The final draft was made public for 6 weeks on the
homepages of the JSPBM and the JBA from July 2011, with a
view to receiving feedback from the medical community.
Subsequently, a public hearing was held on September 16,
2011, during the 47th Annual Meeting of the JBA, requesting
opinions from the members of this body. After partial
amendment, the guidelines were finally assessed and
approved by the guidelines evaluation board, and they were
ultimately prepared for publication.
These guidelines were created to provide assistance in the
clinical practice of the management of PBM; their contents
focus on clinical utility, and they include general information
on PBM to make this disease more widely recognized.
The complete versions of the present guidelines have
been published in Japanese (Igaku Tosho, 2012). The
digest versions are to be published in the Journal of
Gastroenterology.
The use of the term ‘‘congenital biliary dilatation’’
in these guidelines
Congenital biliary dilatation used to be known as ‘‘con-
genital choledochal cyst’’ in Western countries and, in
1959, congenital choledochal cyst was classified as 3
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distinct sub-types (Alonso-Lej et al.). Subsequently, it was
found that in many patients with congenital biliary dilata-
tion, PBM was a common co-morbidity, and as a result, in
1977, the classification of congenital biliary dilatation was
further extended to encompass 5 sub-types (Todani et al.).
In this latter classification, the appearance of PBM was
added to the conventional classification. The most frequent
subtypes of congenital biliary dilatation are: type I, in
which duct dilation is limited to the common bile duct; and
type IV-A, in which dilation of the intrahepatic bile
duct(s) is added to the features of type I. In patients with
congenital biliary dilatation with these two types (exclud-
ing type Ib, which involves a segmental dilatation) the
condition almost always appears to be accompanied by
PBM, while this condition rarely arises in the remaining
types Ib, II, III, IV-B, or V. In Japan, at present, so-called
congenital biliary dilatation almost always refers to Todani
type I (except for type Ib) or type IV-A.
Pancreaticobiliary maljunction (PBM) includes cases
where the bile duct is dilated (PBM with biliary dilatation)
and those in which it is not (PBM without biliary dilatation).
In these guidelines, PBM with biliary dilatation is defined as
being identical to congenital biliary dilatation of Todani type
I (except for type Ib) and type IV-A, both of which are
accompanied by PBM in almost all cases. Indeed, the term
‘‘congenital biliary dilatation’’ is used instead of ‘‘PBM with
biliary dilatation’’ throughout these guidelines. Whether or
not congenital biliary dilatation not accompanied by PBM
exists remains somewhat controversial.
The dilated lesion of congenital biliary dilatation used to
be called a ‘‘cyst’’. However, because there are patients
who do not present with cystic dilatation, the dilated lesion
has recently been referred to as the ‘‘dilated part of bile
duct’’, requiring prompt standardization of the term.
Accordingly, in these guidelines, we have used the term
‘‘cyst’’ to refer to the dilated lesion of congenital biliary
dilatation (‘‘dilated part of bile duct’’).
Members of the committee responsible for establishing
and publishing the guidelines
I. Guidelines Committee
Committee Chairperson, editorial committee member
Terumi Kamisawa*, Department of Internal Medicine,
Tokyo Metropolitan Komagome Hospital.
Committee Vice-Chairpersons, editorial committee
members
Hisami Ando*, Department of Pediatric Surgery,
Nagoya University Graduate School of Medicine.
Mitsuo Shimada*, Department of Surgery, The Uni-
versity of Tokushima.
J Gastroenterol (2012) 47:731–759
Masafumi Suyama*, Department of Gastroenterology,
Juntendo University Urayasu Hospital.
Committee members
Takao Itoi, Department of Gastroenterology and Hepa-
tology, Tokyo Medical University.
Naoto Urushihara, Department of Pediatric Surgery,
Shizuoka Children’s Hospital.
Itaru Oi, Department of Gastroenterology, Itabashi Chuo
Medical Center.
Takehiro Ota, Department of Surgery, Institute of Gas-
troenterology, Tokyo Women’s Medical University.
Kenitiro Kaneko, Department of Pediatric Surgery,
Nagoya University Graduate School of Medicine.
Masanao Kurata, Department of Surgery, Tokyo
Metropolitan Komagome Hospital.
Tsugumichi Koshinaga, Division of Pediatric Surgery,
Department of Surgery, Nihon University School of Medicine.
Jinkan Sai, Division of Gastroenterology, Department of
Internal Medicine, Juntendo University.
Hideo Takamatsu, Support Center for Community
Medicine, Kagoshima University Medical and Dental
Hospital.
Masami Tabata, Hepatobiliary Pancreatic and Transplant
Surgery, Mie University Graduate School of Medicine.
Eiji Tamoto*, Surgery II, School of Medicine, Hokkaido
University Graduate School of Medicine.
Kazuo Chijiiwa*, Surgical Oncology and Regulation of
Organ Function, Miyazaki University School of Medicine.
Akira Toki*, Department of Pediatric Surgery, Showa
University School of Medicine.
Bunsei Nobukawa*, Department of Molecular Patho-
genesis, Juntendo University.
Takuo Noda, Department of Pediatric Surgery, Oka-
yama University.
Keiji Hanada, Center for Gastroendoscopy, JA Ono-
michi General Hospital.
Yoshinori Hamada, Department of Pediatric Surgery,
Kansai Medical University Hirakata Hospital.
Hideki Fujii*, First Department of Surgery, University
of Yamanashi.
Hiroyuki Maguchi, Center for Gastroenterology, Teine-
Keijinkai Hospital.
Masaru Miyazaki, Department of General Surgery,
Chiba University Graduate School of Medicine.
Yuji Morine, Department of Surgery, The University of
Tokushima.
Yoshiki Morotomi, Department of Pediatric Surgery,
Osaka City University.
Editorial adviser
Hiroshi Shimada, President of the Japanese Study Group
on Pancreaticobiliary Maljunction
733
*Members of the PBM Clinical Practice Guidelines
Committee of the Japanese Study Group on Pancreaticob-
iliary Maljunction
II. Guidelines Evaluation Board
Chairperson
Kazuo Inui, Department of Gastroenterology, Second
Teaching Hospital, Fujita Health University, School of
Medicine.
Members
Masao Tanaka, Department of Surgery and Oncology,
Graduate School of Medical Sciences, Kyushu University.
Takashi Hashimoto, Department of Pediatric Surgery,
Fujita Health University.
III. Collaborators
Hidetake Amemiya, First Department of Surgery, Uni-
versity of Yamanashi.
Jiro Ohuchida, Surgical Oncology and Regulation of
Organ Function, Miyazaki University School of Medicine.
Tsukasa Takayashiki, Department of General Surgery,
Chiba University.
Naohiro Hosomura, First Department of Surgery, Uni-
versity of Yamanashi.
Concepts and pathophysiology
CQ-I-1. What kind of disease is PBM?
• PBM is a congenital anomaly in which the pancreatic
duct and bile duct join anatomically outside the duo-
denal wall.
• The duodenal papillary sphincter (sphincter of Oddi)
fails to exert any influence on the pancreaticobiliary
junction due to the abnormally long common channel;
thus, pancreatic juices and bile reflux, mix, and
accumulate, producing various pathological conditions
in the biliary tract and pancreas.
• There are cases accompanied by bile duct dilatation
(congenital biliary dilatation) as well as those where
there is no dilatation in the bile duct (PBM without
biliary dilatation).
Comments
PBM is a congenital anomaly in which the pancreatic and
bile ducts meet anatomically outside the duodenal wall [1].
Normally, at the duodenal papilla the duodenal papillary
sphincter (sphincter of Oddi) surrounds the pancreaticob-
iliary junction, from the end of the bile duct, and it regu-
lates the flow of bile while preventing the reflux of
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pancreatic juices into the bile duct. However, in PBM the
common channel is longer than normal, which abrogates
the influence of the sphincter on the pancreaticobiliary
junction, allowing the reciprocal reflux of pancreatic juices
and bile. The reflux of pancreatic juices into the biliary
tract (pancreatobiliary reflux) provokes high rates of biliary
tract cancer, and the reflux of bile into the pancreatic duct
(biliopancreatic reflux) may sometimes cause pancreatitis
[1–3] (Fig. 1).
When considering PBM, we must include both
patients with bile duct dilatation (congenital biliary
dilatation) and those who do not manifest dilation of the
bile duct (PBM without biliary dilatation), conditions
that do not share all the same clinical features. As a
prophylactic operation is recommended once a patient is
confirmed to suffer from PBM, early and accurate
diagnosis is necessary.
CQ-I-2. What is the pathogenesis of PBM?
• The pathogenesis of PBM is yet to be fully elucidated.
However, there is a convincing hypothesis suggesting
that it involves a dysplasia of the ventral pancreas that
is formed from the bilobed ventral pancreatic anlagen
by the 4th week of gestation.
• A convincing hypothesis regarding the development of
bile duct dilatation is that it is associated with the
mechanisms involved in lumen formation in the
primitive gut.
Comments
Along with the liver, the biliary system develops from the
hepatic diverticulum that originates from the foregut. The
hepatic diverticulum itself transforms into the common bile
Fig. 1 Pathophysiology of
pancreaticobiliary maljunction
(PBM)
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duct, cystic duct, and gallbladder. The bilobed ventral
pancreatic anlagen (cranial and caudal), each communi-
cating with the foregut through a duct, develops from a part
of the hepatic diverticulum that is close to where the
hepatic diverticulum is attached to the foregut, and they
subsequently fuse into a monolobed ventral pancreas at
about the 4th week of gestation [4]. PBM is understood to
develop due to a dysplasia of the ventral pancreas at around
the time the ventral pancreas is formed [5], a process that is
considered to affect the formation of the hepatic
diverticulum.
The lumen of the primitive gut, especially that of the
foregut that generates the hepatic diverticulum, becomes
occluded due to epithelial proliferation, although the very
same epithelium subsequently recanalizes to finally form
the lumen of the intestine. The abnormal dilatation of the
biliary tree is thought to occur in the common bile duct,
cystic duct, and gallbladder (all of which originate from the
hepatic diverticulum), as well as in the hepatic duct (which
originates from the hepatic diverticular epithelia) when the
continuity between the hepatic diverticular epithelia and
that of the primitive gut is lost [6]. Various hypotheses [7–
9] exist regarding the developmental mechanisms under-
lying PBM, and opinion is also divided on how the pan-
creas and the biliary tract develop.
CQ-I-3. How is PBM classified?
• According to the presence or absence of the bile duct
dilatation, PBM can be classified as congenital biliary
dilatation and PBM without biliary dilatation.
• Several classifications can be utilized, such as the one
classifying the disease into 3 types based on how the
pancreatic and bile ducts join, or the new Komi’s
classification.
J Gastroenterol (2012) 47:731–759 735

Comments Ic) or to those that have the same feature but with the
additional dilatation of the intrahepatic bile duct
PBM includes one type that is associated with bile duct (Todani type IV-A). PBM develops in almost all
dilatation (congenital biliary dilatation), and another that is cases.
not (PBM without biliary dilatation). In adults, a common
bile duct diameter of 10 mm is often adopted in order to
Comments
distinguish between these two conditions.
In addition, PBM can be classified into 3 distinct types
Congenital biliary dilatation used to be called ‘‘congenital
based on imaging findings, taking into account features
choledochal cyst’’ or ‘‘congenital cystic dilatation of the
such as the angle at which the pancreatic and bile ducts
common bile duct’’. However, when it was discovered
join: (1) bile duct (junction) type, in which the bile duct
that bile duct dilatation was not limited to the common
joins the pancreatic duct at a right angle; (2) pancreatic
bile duct but rather, it was also present in the intrahepatic
duct (junction) type, in which the pancreatic duct joins the
bile duct, the etiology of the disease, as well as its
bile duct at an acute angle; and (3) complex type, in which
classification, became more complex. The classic Alonso-
the two ducts meet in such a complex manner that the
Lej classification [12] had for some time been used to
junction cannot be classified as either of the previous two
classify this disease. But in later years, the Todani
types [1] (Fig. 2).
classification [13, 14] superseded and improved the
PBM is often accompanied by pancreas divisum; above
Alonso-Lej classification, and the Todani classification is
all, by incomplete pancreas divisum (partial pancreas div-
now the one that is more often used (Fig. 3). According
isum). The new Komi’s classification [10] added the
to the Todani classification [14], the common bile duct
presence/absence of the common channel dilatation and the
alone is dilated in types Ia and Ic, whereas in type IV-A
concept of pancreas divisum to Komi’s original classifi-
both the intra- and extra-hepatic bile ducts are dilated,
cation [11].
with each of these types almost always accompanied by
PBM. These three types of the disease are those that are
CQ-I-4. What kind of disease is congenital biliary
detected most commonly. Conversely, type Ib (the seg-
dilatation?
mental type), type II (the supraduodenal diverticulum
type), type III (choledochocele type), type IV-B (multiple
• In a broad sense, congenital biliary dilatation is a
cystic dilatation type), and type V (intrahepatic bile duct
congenital anomaly of the bile duct associated with
cyst type) are less frequent and they are not normally
different degrees of dilatation at various sites in the bile
accompanied by PBM.
duct. The Todani classification divides it into 5 types.
In recent years in Japan, the term ‘‘congenital biliary
• In a narrower sense, congenital biliary dilatation
dilatation’’ has been used in a narrow sense to refer mostly
corresponds to cases where the dilation of the bile
to type I (except for type Ib) or type IV-A of the Todani
duct is limited to the extrahepatic bile duct, including
classification, where dilatation of the extrahepatic bile duct
the common bile duct (Todani classification type Ia or

Fig. 2 PBM classification

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Fig. 3 The Todani
classification of congenital
biliary dilatation
(including the common bile duct) is observed and almost
all cases are accompanied by PBM. Accordingly, in these
guidelines, types I (except for type Ib) and IV-A of the
Todani classification are considered as congenital biliary
dilatation.
CQ-I-5. Are there any differences in the incidence
of congenital biliary dilatation between the different
sexes or in distinct regions?
• The male-to-female ratio in congenital biliary dilatation
is approximately 1:3, and it is especially predominant
in young women.
• Orientals are considered to be more susceptible to this
disease than Occidentals.
Comments
According to the results of a nationwide study conducted
by the JSPBM, women are approximately 3 times more
likely to be affected by this disease than men, and women
younger than 30 years of age account for the majority of
patients [15]. While the exact incidences in various ethnic
groups are unknown, there are often reports from Japan,
China, and South Korea, and the incidence of congenital
biliary dilatation appears to be higher in Orientals than in
Occidentals [16]. Approximately 1 in every 1,000 persons
is affected by this disease in Japan [17], and the incidences
of congenital biliary dilatation and PBM are 0.3 and 4.1 %,
respectively, in South Korea [18]. In Western countries, it
is reported that congenital biliary dilatation occurs in 1 of
every 50,000–150,000 individuals, and in 1 neonate in 2
million births [19–21].
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CQ-I-6. What are the pathological features of the major
papilla in PBM?
• The major part of the papillary sphincter in PBM sur-
rounds the common channel below the pancreaticobil-
iary junction and serves as what corresponds to the
sphincter ampullae in healthy subjects. In PBM, the
pancreatic juices reflux back into the biliary tract when
the sphincter contracts.
Comments
In a normal healthy state, the junction of the main pan-
creatic duct and the common bile duct lies within the
duodenal wall. However, due to the long common channel
in PBM patients, the effect of the papillary sphincter does
not reach the pancreaticobiliary junction, allowing the
reciprocal reflux of pancreatic juices and bile [22] (Fig. 4).
Boyden classified the papillary sphincter into the categories
of sphincter choledochus, sphincter pancreaticus, and
sphincter ampullae, and further divided the sphincter cho-
ledochus into its superior and inferior regions [23]. In
control subjects, the main part of the papillary sphincter
surrounds the terminus of the common bile duct, forming
the sphincter choledochus according to the Boyden clas-
sification. This structure serves to regulate biliary flow
while simultaneously preventing the reflux of pancreatic
juices. By contrast, in PBM patients it is the common
channel distal to the junction of the pancreatic and bile
ducts that is encircled by the major part of the papillary
sphincter, which corresponds to the so-called sphincter
ampullae. As a result, reflux of the pancreatic juices occurs
on contraction of the sphincter [22].
J Gastroenterol (2012) 47:731–759 737

Fig. 4 Reconstruction of the sphincter of Oddi at the papilla. While
the pancreaticobiliary junction lies within the duodenal wall in
healthy individuals, it is located outside the duodenal wall in patients
with PBM. In control subjects, the major part of the papillary
sphincter surrounds the terminus of the common bile duct, forming
the sphincter choledochus according to the Boyden classification [23],
and it regulates biliary flow while simultaneously preventing the
reflux of pancreatic juices. By contrast, in PBM patients it is the
common channel distal to the junction of the pancreatic and bile ducts
that is encircled by the major part of the papillary sphincter, which
corresponds to the so-called sphincter ampullae

CQ-I-7. What pathological changes occur in the biliary

tract of patients with PBM?

• Persistent inflammation and regeneration of the biliary

tract mucosa may develop due to the reflux of pancre-
atic juices into the biliary tract (pancreatobiliary
reflux).
• In the dilated bile duct and gallbladder, cell cycle
turnover is enhanced due to the persistent inflammation
and regeneration, and this enhanced cell cycle turnover
may eventually induce hyperplasia, dysplasia, and the
development of malignancy.

Comments
Reflux of pancreatic juices stimulates and induces inflam-
mation of the biliary tract mucosa, leading to the erosion
and subsequent regeneration of the mucosal epithelia.
Accordingly, cell cycle turnover is enhanced due to the
persistent inflammation and regeneration, causing dyspla-
sia and eventually cancer. Among the phenomena often
observed in the wall of the dilated bile duct associated with
congenital biliary dilatation, there is an increase in collagen
fiber deposition, wall thickening, inflammatory cell infil-
tration, and pseudopyloric gland metaplasia of the bile
ducts’ mucous gland. Dysplasia and/or cancer may develop
in the epithelia (Fig. 5). In the gallbladder, where the
Fig. 5 The dilated bile duct wall in congenital biliary dilatation. An
increase in collagen fibers, wall thickening, inflammatory cell
infiltration, and pseudopyloric gland metaplasia of the bile duct
mucous gland are evident in the wall of this structure, and dysplasia
can be observed in the epithelia
refluxed pancreatic juices mix with the bile, diffuse
mucosal hyperplasia is very frequently observed. More-
over, a sequence of events called hyperplasia-dysplasia-
carcinoma is assumed to take place in the gallbladder of
patients with PBM [3, 24]. Furthermore, mutations in the
K-ras and p53 genes may be observed [25].

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CQ-I-8. How does the papilla function in PBM? Comments

• In PBM, the papillary sphincter muscles are only found In PBM, the pancreatic and bile ducts join at a site that lies
around the common channel, and these muscles are outside the area of influence of the papillary sphincter, and
morphologically identical to those of the normal pap- this phenomenon leads to the reciprocal reflux of pancre-
illary sphincter. atic juices and bile. Normally, the intraductal pressure in
• The function of the papilla varies from patient to the pancreatic duct is higher than that in the bile duct [28]
patient. However, in patients whose symptoms are and thus, the idea that pancreatic juices reflux into the
considered to be attributable to PBM, their papillary biliary tract is beyond dispute. Pancreatic juice reflux into
sphincter may not function normally. the biliary tract is also apparent from the findings that the
bile samples from the gallbladder or bile duct of patients
with PBM contain abnormally high levels of pancreatic
Comments
enzymes such as amylase and lipase [29]. Recently, it has
become possible to track this reflux in images using
In PBM, the papillary sphincter is only found around the
secretin-stimulated dynamic MRCP [30].
common channel [1]. The sphincter surrounding the
Regarding the reflux of bile into the pancreatic duct, in
common channel is mainly restricted to the mucosal side
PBM the pancreatic duct is enhanced in direct cholangi-
of the muscularis propria of the duodenum, identical to
ography, such as that performed through a T-tube. How-
how it is observed in the healthy population [22].
ever, as this procedure is a condition in which artificial
Secretin-stimulated dynamic magnetic resonance cholan-
pressure is applied, it is unclear whether the reflux is
giopancreatography (MRCP) has produced images of the
physiological. In fact, even in patients with no PBM the
pancreatic juices mixed with bile being excreted into the
pancreatic duct is enhanced with contrast medium in
duodenal lumen, as well as images of the pancreatobil-
13.3–27 % of cases when examined by T-tube cholangi-
iary reflux [26]. In these images, the papillary sphincter
ography [31–33]. It was reported that on computed
contracted and relaxed repeatedly and rhythmically,
tomography combined with drip-infusion cholangiography
therefore appearing to show no clear dysfunction.
(DIC-CT), the pancreatic duct could be seen in 6 out of 15
Meanwhile, when the function of the papilla in con-
patients with PBM, visualizing the reflux of bile into the
genital biliary dilatation was analyzed with biliary scin-
pancreatic duct by means of imaging [34]. However, it is
tigrams [27], the isotope was stagnant in the bile duct
not clear under what conditions such reflux against the
and its excretion into the duodenal lumen was delayed in
pressure gradient can occur. Similarly, it remains unclear
symptomatic patients with congenital biliary dilatation,
what kind of clinical condition the reflux of the pancreatic
suggesting abnormal papillary function. In scintigrams of
juices causes, and whether this reflux contributes to the
asymptomatic patients there was normal isotope excre-
onset of pancreatitis; both of these issues require further
tion into duodenal lumen, and the papillae of these
study.
patients were considered to function normally. The rea-
sons for the altered papillary function in patients with
CQ-I-10. What is ‘‘high confluence
PBM remain unknown.
of pancreaticobiliary ducts’’?
CQ-I-9. What are pancreatobiliary reflux
• High confluence of pancreaticobiliary ducts (HCPBD)
and biliopancreatic reflux?
is a disease state in which the common channel is at
least 6 mm long and the effect of the sphincter does
• In PBM, the reciprocal reflux of pancreatic juices and
reach the pancreaticobiliary junction.
bile occurs because the papillary sphincter fails to
• The clinical features of HCPBD are similar to those
control the pancreaticobiliary junction.
observed in PBM, including pancreatobiliary reflux and
• The reflux of pancreatic juices into the biliary tract is
biliopancreatic reflux.
evident from the abnormally high levels of pancreatic
enzymes in bile, which may subsequently be one of the
causes of biliary tract carcinogenesis. Comments
• It is clear that reflux of bile into the pancreatic duct also
occurs, although further research is necessary to According to the current diagnostic criteria [1], even if the
determine its involvement in disease states such as common channel is relatively long, a patient would not be
pancreatitis. diagnosed with PBM if the sphincter can exert an influence

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Fig. 6 Endoscopic retrograde

cholangiopancreatography
images of high confluence of
pancreaticobiliary ducts
(HCPBD). a The bile and
pancreatic ducts form a
common channel (arrows) of
8 mm long during sphincter
relaxation, b although such
communication between the two
ducts is interrupted during
contraction

Fig. 7 Abdominal ultrasonography (US) findings. a Common bile biliary dilatation. b The inner layer of the gallbladder wall is
duct dilatation (white arrows) can been seen, as well as the thickening thickened in PBM without biliary dilatation
of the inner layer of the gallbladder wall (black arrows) in congenital

on the pancreaticobiliary junction. In a study measuring the
length of the common channel in autopsied cases by
enhanced contrast of the pancreas, the mean length was
found to be 4.4 mm [35]. Based on this finding, HCPBD
was defined as a disease state in which the common
channel measures at least 6 mm in length even though the
effect of the sphincter does reach the pancreaticobiliary
junction [36] (Fig. 6a, b).
A T-tube cholangiography demonstrated the clear reflux
of contrast medium into the pancreatic duct in 86% of
HCPBD cases, and elevated amylase levels in bile were
observed in all patients diagnosed with HCPBD [3]. Fur-
thermore, 8 % of patients with HCPBD developed gall-
bladder cancer. In addition, hyperplastic changes, enhanced
cell cycle progression and proliferation, and mutations in
the K-ras gene were detected in the gallbladder mucosa of
patients with HCPBD, findings that are also seen in the
gallbladder mucosa of PBM patients, leading to the
assumption that similar events take place in patients with
HCPBD and those with PBM [2, 37, 38]. However, there
are differences between HCPBD and PBM without biliary
dilatation in other features, such as the gender most
affected, the age at diagnosis, the incidence of accompa-
nying gallbladder cancer, and the biliary amylase levels [3,
36]. HCPBD represents an intermediate clinical condition
which is difficult to clearly differentiate from PBM when
considering both morphological and functional aspects.
However, in terms of the appropriate therapeutic strategies,

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it appears that, at this stage, HCPBD should be managed as
a disease entity that is independent of PBM.
In a recent multi-center study, a correlation was detected
between biliary amylase levels and the length of the
common channel, whereby biliary amylase levels tended to
be 1,000 IU/L or higher when the common channel was at
least 5 mm long [39].
Diagnosis
CQ-II-1. What are the diagnostic criteria for PBM?
• An abnormally long common channel and/or an abnormal
union between the pancreatic and bile ducts must be
evident by direct cholangiography, such as endoscopic
retrograde cholangiopancreatography (ERCP), percuta-
neous transhepatic cholangiodrainage (PTCD), or intra-
operative cholangiography.
• The anatomic union between the pancreatic and bile
ducts lies outside the duodenal wall.
• Abnormally high levels of pancreatic enzymes in the bile
duct and/or the gallbladder serve as an auxiliary
diagnosis.
Comments
It is necessary to confirm that the influence of the papillary
sphincter does not extend to the junction. Demonstrating an
extraordinarily long common channel and/or that there is an
abnormal union between the pancreatic and bile ducts on
imaging examinations (e.g., ERCP) is regarded as a diag-
nostic criterion [1]. In addition, multidetector-row computed
tomography (MD-CT) providing maximum intensity pro-
jection (MIP) images, MRCP, and endoscopic ultrasonogra-
phy (EUS) are now potential diagnostic tools for this disease.
Thus, the current diagnostic criteria should be revised to take
these diagnostic imaging techniques into consideration.
Abnormally high levels of pancreatic enzymes in the
bile serve as an auxiliary diagnosis, although they cannot
be used to provide a definitive diagnosis, as such findings
can be observed in other diseases, such as occult pancre-
atobiliary reflux [40] or HCPBD [36].
CQ-II-2. What kind of clinical manifestations are
associated with PBM?
• The main symptoms of PBM include abdominal pain,
vomiting, jaundice, and fever.
• A larger proportion of patients with congenital biliary
dilatation is symptomatic when compared with those
suffering from PBM without biliary dilatation.
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J Gastroenterol (2012) 47:731–759
• Abdominal pain, jaundice, and an abdominal mass have
been referred to as the triad of manifestations in
congenital biliary dilatation; however, the not many
patients present with all three manifestations together.
Comments
According to a survey carried out by the JSPBM [29], 1 %
of patients with congenital biliary dilatation were symp-
tomatic and their symptoms included abdominal pain
(78 %), vomiting (36 %), jaundice (22 %), and fever
(22 %). Of those suffering from PBM without biliary
dilatation, 77.6 % manifested symptoms that included
abdominal pain (79 %), jaundice (18 %), fever (17 %), and
vomiting (15 %). Abdominal pain, jaundice, and an
abdominal mass have been referred to as the triad of
manifestations in congenital biliary dilatation; however,
the proportion of patients who manifest all three symptoms
is variable.
The symptoms of congenital biliary dilatation are also
related to the shape of the dilated bile duct. Many patients
with neonatal/infant onset have been classified as showing
cystic type, whose main symptoms are jaundice and
abdominal mass, while patients with onset during early
childhood mostly have a bile duct of a fusiform/cylindrical
type, manifesting mainly with abdominal pain.
CQ-II-3. Can any abnormalities for PBM be found
in blood tests?
• In most cases, abnormal results do not appear in blood
tests during asymptomatic periods and any abnormali-
ties generally arise when the patient becomes
symptomatic.
• The parameters that may become abnormal include
serum levels of amylase, bilirubin, and biliary enzymes.
Comments
The symptoms of patients with PBM appear to be triggered
by the onset and/or progression of the complications, rather
than by the PBM itself. Accordingly, abnormalities in
blood tests are transient and they are only evident during
the symptomatic phase.
According to a nationwide survey conducted by the
JSPBM [41], the specific factors in blood tests and the
percentages of patients manifesting abnormal values
(numbers of patients with abnormal values/ numbers of
patients studied) were: amylase, 20.4 % (182/894); elastase
1, 31.8 % (89/280); trypsin, 35.5 % (55/155); phospholi-
pase A2, 33.3 % (34/102); total bilirubin, 29.4 % (225/
766); direct bilirubin, 23.3 % (200/859); alkaline
J Gastroenterol (2012) 47:731–759
phosphatase, 45.4 % (435/959); and c-glutamyl transpep-
tidase (c-GPT), 42.7 % (395/925).
CQ-II-4. What is the role of ultrasonography
in diagnosing PBM?
• Ultrasonography (US) is useful to screen for PBM.
• Detecting dilatation of the common bile duct and/or
intrahepatic bile duct by US may be the first opportu-
nity to diagnose congenital biliary dilatation.
• A thickening of the hypoechoic inner layer of the
gallbladder wall may be fundamental for the diagnosis
PBM without biliary dilatation.
Comments
Ultrasonography (US) is a simple and easy technique to use
when diagnosing PBM, and it serves as an important and
useful screening tool irrespective of the age of the patient
[42]. If there is dilatation of the bile duct, the common bile
duct is cystic or fusiform. In PBM without biliary dilatation
the finding is often recognized as a thickening of the
hypoechoic inner layer of the gallbladder wall (Fig. 7a, b).
In PBM, the mixture of pancreatic juices and bile is
retained in the gallbladder, and this causes repeated
inflammation and recovery of the gallbladder epithelial
wall [43]. The resulting enhanced cell proliferation in the
gallbladder wall is thought to provoke hyperplasia and
subsequent dysplasia, which is assumed to trigger carcin-
ogenisis in the gallbladder [43, 44]. PBM also develops in
some patients with gallbladder adenomyomatosis.
CQ-II-5. What are the pathognomonic ERCP findings
in PBM?
• The pancreatic and bile ducts join to form an abnor-
mally long common channel, and/or they join in an
anatomically unusual manner.
• In PBM patients with dilatation of the extrahepatic bile
duct, such a lesion is detected on ERCP as a cystic or a
cylindrical/fusiform dilatation.
Comments
Confirmation that the papillary sphincter does not exert its
effects on the pancreatic and bile duct junction is required
to diagnose PBM. The presence of a long common channel
and/or the anatomically unusual manner in which the
pancreaticobiliary ducts join should be confirmed by
radiological diagnostic techniques using ERCP [1].
PBM with a short common channel is sometimes diffi-
cult to differentiate from the symptoms produced by a
741
relatively long common channel but that are not associated
with PBM. In the latter state, a clinical condition has been
identified in which reciprocal reflux of pancreatic juices
and bile occurs through their common channel, despite the
absence of PBM [36, 45]. The differential diagnosis
between these two states can be made by ERCP, as the
common channel in PBM is depicted during both the
contraction and relaxation phases of papillary sphincter
activity. However, in healthy individuals with a relatively
long common channel, the common channel is not depicted
in the contraction phase, because the communication
between the pancreatic and bile ducts is interrupted, and
conversely, it appears in the relaxation phase [36, 39].
CQ-II-6. Can PBM be diagnosed by MRCP?
• PBM can be efficiently diagnosed by MRCP. However,
such diagnosis may sometimes be difficult in patients
with a short common channel, and in babies and
toddlers.
Comments
The diagnostic criteria for PBM using MRCP are similar to
those of ERCP and the accuracy is reported to be
60–100 % [46–52]. The rates of detecting a PBM lesion by
MRCP are reported to be 82–100 % in adults [46, 47, 49,
50] and 40–80 % in children [47, 48, 50, 51]. The rate rises
to 82 % in cases of PBM where the common channel is
15 mm or longer [49], and for patients with congenital
biliary dilatation the detection rate with MRCP is reported
to be 38–100 % [46, 48–51]. Note that ERCP is indis-
pensable to reach a definitive diagnosis. As MRCP does not
possess such a high spatial resolution as X-rays, it is
unclear how precisely it depicts the junctions of compli-
cated forms of PBM [46–52].
CQ-II-7. What roles do MD-CT and DIC-CT play
in the diagnosis of PBM?
• Multi-planar reconstruction (MPR) MD-CT images and
three-dimensional (3D) DIC-CT images can define
biliopancreatic reflux in PBM, and they can also define
the morphology of the intra- and extra-hepatic ducts.
Comments
High-resolution MD-CT, which provides MPR images, and
3D CT have become more readily available recently, and
by combining them with DIC, clear 3D images (3D-DIC-
CT) of the intra- and extra-hepatic ducts can be obtained
from PBM patients [53]. In particular, PBM can be
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diagnosed if the junction outside the wall can be depicted
by MD-CT. In addition, with DIC-CT it is possible to
detect biliopancreatic reflux, which is a physiological
correlate for PBM [34].
CQ-II-8. What is the role of EUS in diagnosing PBM?
• As EUS can confirm the status of the pancreaticobiliary
junction outside the duodenal wall, it is useful for PBM
diagnosis.
• Having diagnosed PBM using EUS, the bile duct and
gallbladder can be further examined in the same session.
• EUS must be performed by an experienced specialist as
its diagnostic accuracy is operator-dependent.
Comments
Because of its high resolution, EUS can be used to diag-
nose PBM by depicting the pancreaticobiliary junction
outside the duodenal wall [54–56]. In addition to the
pancreatic and bile ducts, the muscularis propria of the
duodenum and pancreatic parenchyma can be examined by
EUS, confirming that the pancreaticobiliary junction lies
outside the duodenal wall, irrespective of the length of the
common channel. Furthermore, the bile duct and gall-
bladder can be studied in detail in a series of scans fol-
lowing the diagnosis of PBM [57].
CQ-II-9. Is it useful to determine the levels of biliary
amylase to diagnose PBM?
• Determining the biliary amylase levels serves as an
auxiliary diagnostic feature for PBM.
Comments
In PBM, the pancreatic juices reflux into the bile duct
because the papillary sphincter does not exert an effect on
Table 1 Amylase levels in the gallbladders/bile ducts of patients with pancreatobiliary maljunction (PBM)
Amylase levels in the gallbladder (IU/L)
a a
Congenital biliary dilatation (adults) 98,700 (n = 997)
a a
Congenital biliary dilatation (children) 35,800 (n = 950)
Congenital biliary dilatation 73,000 ± 65,000 (n = 10)
PBM without biliary dilatation (adults) 66,000a (n = 514)
a
PBM without biliary dilatation (children) 17,400 (n = 68)
PBM 17,400a (n = 68)
PBM 108,000 ± 105,000 (n = 10)
Values are means ± SD
a
Median
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the pancreaticobiliary junction, and the intraductal pressure
in the pancreatic duct is higher than that in the bile duct.
Therefore, an increase in the levels of amylase in the bile is
strong evidence of pancreatobiliary reflux [2]. A level of
biliary amylase distinctly above the normal upper limit has
been used as a diagnostic criterion in different reports [26,
58, 59], including levels of 500 IU/L [60] and 1,000 IU/L
or higher [61].
The biliary amylase levels in PBM are often at least
10,000 IU/L (Table 1) [26, 62–64]. However, patients with
bile duct stones or those with decreased exocrine pancre-
atic function may sometimes not show elevated biliary
amylase levels even if they suffer from PBM [65]. Also,
age must be considered when evaluating the biliary amy-
lase levels, because the amylase levels in pancreatic juices
are low in neonates and babies.
Of note, it has been demonstrated that biliary amylase
levels of 10,000 IU/L or higher can be detected in 6 and
10.8 % of patients with biliary tract malignancies and
benign biliary tract disease, respectively [59]. Elsewhere, it
has been proposed that even in individuals whose papillary
sphincter does act on the pancreaticobiliary junction, bili-
ary amylase levels may be elevated to mean values of
48,000 IU/L if their common channel is sufficiently long,
although such levels are still lower than the mean values
seen in patients with PBM [3]. In other words, as reflux is
not something limited to PBM, PBM cannot be diagnosed
simply because there are elevated amylase levels in the
bile.
CQ-II-10. Is it possible to diagnose congenital biliary
dilatation prenatally?
• It is possible to diagnose congenital biliary dilatation
prenatally when the bile duct is dilated in a cystic form.
• Congenital biliary dilatation is often diagnosed by US
screening at 6 months of gestation if a cystic lesion
several cm in size is detected situated near the hepatic
hilum.
Amylase levels in the bile duct (IU/L) References
78,900 (n = 997) 62
18,622 (n = 950) 62
85,000 ± 60,000 (n = 11) 63
54,000a (n = 514) 62
10,900a (n = 68) 62
28,000 (n = 14) 26
146,000 ± 117,000 (n = 9) 64
J Gastroenterol (2012) 47:731–759
• It is important to rule out other possible diagnoses, such
as duodenal atresia, renal cyst, ovarian cyst, hepatic
cyst, and biliary atresia (I cyst).
Comments
Increasing numbers of cases of congenital biliary dilatation
are being diagnosed prenatally thanks to prenatal fetal US
check-ups [66] or magnetic resonance imaging (MRI). The
disease is detected as a cystic lesion adjoining the tubular
structure heading towards the lower surface of the liver, and
in many cases the intrahepatic bile duct is not dilated [67].
There is a case report of diagnosis at 15 weeks of gestation
[68], although many more cases of congenital biliary dilata-
tion are detected in the 2nd trimester (4–6 months of gesta-
tion) [67, 69, 70]. Differential diagnosis must rule out
diseases whose lesions involve a cystic mass in the right upper
quadrant of the fetal abdomen, such as duodenal atresia,
enteric duplication cyst, ovarian cyst, hepatic cyst, and biliary
atresia (I cyst) [71]. However, the ratio of cases diagnosed
prenatally is B5 % of all cases of congenital biliary dilatation.
Pancreatobiliary complications
CQ-III-1. How common are gallstones in the biliary
tract in association with PBM and what are their
characteristics?
• Patients with PBM are more predisposed to forming
biliary tract stones than individuals without this disease.
• Biliary tract stones are found in 17.9 % of patients with
congenital biliary dilatation and in 27.3 % of patients
suffering from PBM without biliary dilatation, the latter
proportion being significantly higher. Gallstones in the
Fig. 8 Distribution of biliary
stones in PBM—a summary of
reported cases
743
bile duct are most frequently found in patients with
biliary dilatation, and gallstones in the gallbladder are
most frequent in patients with PBM without biliary
dilatation.
• Adult patients develop gallstones more often than
pediatric patients.
• Of the different types of gallstones found in patients
with congenital biliary dilatation, bilirubinate gall-
stones are those most frequently seen, and this finding
is thought to be related to cholestasis and/or infection.
Comments
It is reported that biliary tract stones (gallbladder stones or
bile duct stones) develop in 17.9 % of patients with con-
genital biliary dilatation and in 27.3 % of those suffering
from PBM without biliary dilatation, the incidence being
significantly higher in the latter group. In addition, biliary
tract stones are observed in 24.1 % of adult and 9.0 % of
pediatric patients with congenital biliary dilatation, while
26.8 % of adult and 5.9 % of pediatric patients suffering from
PBM without biliary dilatation develop this complication.
Accordingly, this is a frequent complication in adults [29, 62].
Lithogenesis most often occurs in the bile duct in con-
genital biliary dilatation, whereas in PBM without biliary
dilatation it is more common in the gallbladder. In the former
group of patients, the frequency of bile duct stones increases
as the cholangiectasis becomes more severe (Fig. 8).
In patients suffering from PBM without biliary dilata-
tion, the types of gallstones observed were reported to be
cholesterol gallstones in 75 % of cases and mixed stones in
25 % of cases. By contrast, in patients with congenital
biliary dilatation, cholesterol gallstones were found in
16.7 % of cases, while mixed stones were found in 25 % of
cases, and bilirubinate gallstones were found in 58.3 % of
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cases [72]. In another study of the types of gallstones found
in PBM patients without biliary dilatation, cholesterol
gallstones represented 35 % of the stones found, while
10 % were mixed stones, 45 % were bilirubinate gall-
stones, and 5 % were black stones; also, protein plugs were
observed in 5 % of the cases [73]. As such, the frequency
of the different compositions of gallstones observed in
PBM without biliary dilatation differs from study to study.
However, in congenital biliary dilatation, bilirubinate
gallstones appear to be the predominant type of gallstones
over and above gallstones of other compositions.
CQ-III-2. How often does acute pancreatitis develop
in conjunction with PBM and what are
the characteristics?
• PBM is very often accompanied by acute pancreatitis,
occurring in 9 % of adult patients and in a much higher
proportion of children (28–43.6 %).
• Dilatation of the common channel, pancreatic duct
dilatation, complicated anomalies in the form of the
pancreatic duct in the pancreas head, and protein plugs
are thought to represent the cause of the acute
pancreatitis associated with PBM. This acute pancre-
atitis is also characterized by a tendency towards either
a transient or a mild, but recurrent clinical course.
Comments
According to a study that analyzed the patients registered
by the JSPBM, preoperative acute pancreatitis was more
common in pediatric patients (28–32 %) than in adult
patients (9 %) [62]. This condition is reported to be
extremely frequent in children, even in reports from only a
single institution [74]. When the incidence of acute child-
hood pancreatitis is compared between the different forms
of PBM, with or without biliary dilatation, it is slightly
higher in the latter form, although the difference between
these two groups is not significant [62].
In patients with acute pancreatitis accompanying PBM,
dilatation of the common channel, dilatation of the pan-
creatic duct, complicating anomalies in the pancreatic duct
in the pancreas head, or protein plugs, are often observed.
Indeed, by inhibiting the excretion of pancreatic juices and
bile, these abnormalities are thought to cause acute pan-
creatitis [75, 76]. Acute pancreatitis accompanying PBM,
as noted above, is often characterized by a clinically
transient or a clinically mild, but recurrent clinical course,
and there are reports suggesting that abnormalities in the
pancreaticobiliary system should be considered when acute
pancreatitis-like symptoms recur. Moreover, elevated lev-
els of pancreatic enzymes in the blood in the absence of
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J Gastroenterol (2012) 47:731–759
pancreatic lesions have also been reported in PBM, caused
by the pancreatic juices that enter the biliary system further
refluxing into the bloodstream.
CQ-III-3. How common is chronic pancreatitis in PBM
patients and what are its characteristics?
• At specialist hospitals that treat chronic pancreatitis, this
disease was reported to be observed in 5–8 % of patients
with PBM, while the incidence was 3 % according to a
nationwide survey carried out by the JSPBM.
• Chronic pancreatitis is often observed in patients who
have undergone biliary surgery and, in particular, it is
very frequent in patients who have undergone bilioen-
teric anastomosis without bile duct resection.
Comments
The incidence of chronic pancreatitis among patients with
PBM is reported to be 5–8 % in high-volume centers [77, 78].
However, in a nationwide survey, analyzing a total of 1,627
patients with PBM registered by the JSPBM registration
board over 10 years (from 1990 to 1999) from all over Japan,
49 patients (3 %) developed chronic pancreatitis [29].
The relationship between surgical history and the
development of chronic pancreatitis was analyzed in
patients with PBM. Of 11 patients who developed chronic
pancreatitis, 7 patients (64 %) were reported to have
undergone surgery of the biliary tree (such as a biliary
diversion procedure and internal drainage operation) [78].
The mean age of onset of chronic pancreatitis accompa-
nying PBM is quite young (30–36 years) [29]. Diagnostic
images of this disease often demonstrate pancreatic stones in
the dilated common channel alone, and/or in the main pan-
creatic duct adjacent to the common channel. Only rarely are
stones found diffusely distributed in the branches of the
pancreatic duct. The pancreatic stones most often detected are
radiolucent stones, a feature that is due to the properties of the
proteins from which they are predominantly generated [79].
The formation of radiolucent pancreatic stones due to the
retention of pancreatic juices mixed with bile in the dilated
common channel, and/or in the main pancreatic duct, is
thought to provoke chronic pancreatitis in conjunction with
PBM, although this remains to be clarified.
CQ-III-4. Are elevated levels of biliary amylase
involved in the development of pancreatitis in patients
with PBM?
• Patients with PBM often present with high levels of
amylase in bile, although the pathogenesis of pancrea-
titis in PBM has still not been fully elucidated. Indeed,
J Gastroenterol (2012) 47:731–759
high biliary amylase levels may not necessarily be
associated with pancreatitis accompanying PBM.
Comments
PBM not only involves the persistent reflux of pancreatic juices
into the biliary tract but also the reflux of bile into the pan-
creatic duct (biliopancreatic reflux), which is receiving grow-
ing attention as a possible cause of pancreatitis [80]. The reflux
of activating enzymes with strong cytotoxic effects, such as
trypsin and phospholipase A2, is regarded as an important
factor in the induction of pancreatic damage [81, 82]. On the
other hand, there are reports suggesting that protein plugs in the
common channel may cause transient pancreatic duct
obstruction, subsequently inducing pancreatitis [3, 82]. It has
been suggested that the hyperamylasemia seen in PBM may
not always reflect the onset of acute pancreatitis, but, rather, the
hyperamylasemia may sometimes be the result of the leakage
of biliary amylase (originally from the pancreatic juices that
flow back into the bile duct) into the blood through ‘‘cholangio-
venous reflux’’, and/or the leakage of pancreatic amylase into
the blood through the ‘‘lymphatic pathway’’, both being due to
a rise in biliary tract pressure [83]. This increase in biliary tract
pressure may also cause concomitant abdominal pain similar to
that associated with pancreatitis.
CQ-III-5. What is the incidence of biliary tract cancer
in PBM?
• In adult PBM patients, biliary tract cancers are frequently
observed: 21.6 % in patients with congenital biliary dila-
tation and 42.4 % in patients suffering from PBM without
biliary dilatation. The main lesions in patients with con-
genital biliary dilatation are gallbladder cancer in 62.3 %
and bile duct cancer in 32.1 %, and in patients suffering
from PBM without biliary dilatation the main lesions are
gallbladder cancer in 88.1 % and bile duct cancer in 7.3 %.
• The incidence of biliary tract cancers in pediatric
patients (younger than 15 years of age) is unknown;
however, 7 cases of bile duct cancer and one case of
gallbladder cancer have been reported in pediatric
patients with congenital biliary dilatation, as well as
one case of gallbladder cancer in a pediatric patient
suffering from PBM without biliary dilatation.
Comments
Patients with PBM have a high rate of biliary tract cancers
[29, 84]. According to a nationwide survey in Japan
(n = 2,561), biliary tract cancer is detected in 21.6 % of
adult patients with congenital biliary dilatation and in
42.4 % of adult PBM patients without biliary dilatation
745
[62]. The main malignancies are gallbladder cancer and
bile duct cancer, representing 62.3 and 32.1 %, respec-
tively, of the cancers in patients with congenital biliary
dilatation and 88.1 and 7.3 %, respectively, of the cancers
in patients suffering from PBM without biliary dilatation.
Gallbladder cancer is clearly the cancer most frequently
found in association with these conditions [62].
Regarding pediatric patients (younger than 15 years of
age), only 9 cases of biliary tract cancer have been reported
in Japan as a complication of PBM: 7 bile duct cancers and
2 gallbladder cancers.
CQ-III-6. What are the characteristics of biliary tract
cancer that accompanies PBM?
• At the age of 50–65 years, adult patients with PBM are
those most predisposed to develop biliary tract cancer,
and this age is around 15–20 years before the predis-
position is seen in the population without PBM.
• Cases of simultaneous and/or metachronous double
cancers in the biliary system are frequent.
• The simultaneous occurrence of gallstones accompa-
nied by gallbladder cancer is low in PBM patients.
Comments
The ages at which patients with PBM become predisposed to
develop biliary tract cancer are: 60.1 ± 10.4 years for gall-
bladder cancer and 52.0 ± 15.0 years for bile duct cancer in
patients with congenital biliary dilatation; and 58.6 ±
9.6 years for gallbladder cancer and 63.3 ± 6.8 years for bile
duct cancer in patients suffering from PBM without biliary
dilatation. Hence, patients with PBM may develop biliary
tract cancer 15–20 years earlier than individuals without
PBM [29, 62, 85].
In patients with PBM, biliary tract cancers frequently
develop as simultaneous double cancers. In fact, of 37
patients with simultaneous double or multiple biliary tract
cancers, 19 patients (51.4 %) suffered from concurrent
PBM [86–90]. Metachronous biliary double cancers are
also relatively frequent in PBM.
Furthermore, only 10 % of patients with PBM who
developed gallbladder cancer had gallstone(s) when the
cancer was detected [3], a ratio which is lower than the ratio in
the biliary tract cancer population without PBM [62, 91, 92].
CQ-III-7. Do the mechanisms underlying biliary
carcinogenesis in patients with PBM differ from those
in individuals without PBM?
• The carcinogenesis of biliary tract cancer accompany-
ing PBM is considered to involve the hyperplasia-
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746
Fig. 9 Hypothetical mechanisms underlying biliary tract carcinogenesis in PBM and carcinogenesis in primary biliary tract cancer
dysplasia-carcinoma sequence provoked by the chronic
inflammation that is a result of the reflux of pancreatic
juices into the biliary tract. This mechanism is thought
to be different from the adenoma–carcinoma sequence
or the de-novo carcinogenesis associated with biliary
tract cancer in the population without PBM.
Comments
In PBM, the sequence of hyperplasia-dysplasia-carcinoma
is regarded as the prevailing mechanism underlying the
development of biliary tract cancer. In this sequence of
events, strong cytotoxic substances (such as lysolecithin)
are produced when phospholipase A2 in the pancreatic
juice mixes with bile, and as a result, the chronic inflam-
mation provokes repeated cycles of damage and healing in
the biliary mucosal epithelia. These alterations in the
mucosal epithelia (mainly hyperplasia), either alone or in
conjunction with DNA mutations, finally cause cancer to
develop in this tissue [81, 93].
By contrast, multi-step carcinogenesis that involves the
formation of an adenoma (the adenoma–carcinoma
sequence), and de-novo carcinogenesis in which an inter-
mediate adenoma does not form, are considered to be the
main mechanisms responsible for the development of bil-
iary tract cancer in individuals without PBM [94–96]
(Fig. 9).
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J Gastroenterol (2012) 47:731–759
CQ-III-8. Does the risk of biliary tract cancer vary
in relation to the biliary amylase levels
in the gallbladder or bile duct?
• It remains unclear whether or not the risk of developing
biliary tract cancer varies in relation to the amylase
levels in the gallbladder or bile duct.
Comments
High amylase levels in the bile of the gallbladder
(163,131 ± 222,911 IU/L) and those in the bile duct
(204,944 ± 660,800 IU/L) have been associated with a
37.9 % incidence of biliary tract cancer in patients suf-
fering from PBM without biliary dilatation (gallbladder
cancer 93.2 %, bile duct cancer 6.8 %) [29]. It was
reported that among patients without PBM, gallbladder
cancer developed in 38 % of those whose amylase levels in
the bile of the bile duct or gallbladder were C10,000 IU/L
[97]. Moreover, in other reports of patients without PBM it
was demonstrated that the incidence of gallbladder cancer
was 10 % in individuals whose biliary amylase levels in
the bile duct or gallbladder were above 1,000 IU/L [39, 59,
98].
According to the diagnostic criteria for PBM [1], ‘‘there
are quite a few patients whose amylase levels in bile are
close to or below those in the serum, despite suffering
J Gastroenterol (2012) 47:731–759
PBM’’. Moreover, it is reported that gallbladder cancer
may even develop in patients whose biliary amylase levels
are low (below 1,000 IU/L) [65]. According to the results
obtained from a Japanese nationwide survey, biliary amy-
lase levels were higher in PBM patients who had not
developed cancer [62]. To summarize, it is unclear whether
or not the risks of developing biliary tract cancer vary in
relation to the biliary amylase levels.
CQ-III-9. Are patients with PBM more susceptible
than patients without PBM to the development
of pancreatic cancer?
• It is unknown whether or not patients with PBM are
predisposed to concomitant pancreatic cancer.
Comments
Between 1957 and 2008, there were only 35 cases in which
pancreatic cancer was reported in patients with PBM [99–
101]. While the incidence of pancreatic cancer was reported
to be 0.0162 % in the overall population in Japan, in patients
with PBM this incidence reached 0.8 %, a 49.4-fold increase
compared with that in the overall population [102]. There is
evidence of an association between bile reflux into the pan-
creatic duct and the development of pancreatic cancer [103],
although because this study was based on animal experiments
it cannot be considered to provide sufficient evidence to
support a cause-and-effect relationship between PBM and
pancreatic carcinogenesis. Thus, it still remains unclear
whether or not patients with PBM are more susceptible to
pancreatic cancer than other individuals.
Treatments and prognosis
CQ-IV-1. When is it recommended to operate
on patients with PBM?
• There are no clear evidence-based recommendations as
to when patients with PBM should undergo surgery.
Table 2 The incidence of concurrent biliary tract cancer and its locations [62]
PBM with dilatation (n = 1,947)
Pediatric (n = 950)
Biliary cancers (morbidity rate) 1 (0.1 %)
Location
Gallbladder 0 (0 %)
Bile duct 1 (100 %)
Gallbladder ? bile duct 0 (0 %)
Unknown 0 (0 %)
747
However, as PBM enhances the chances of developing
biliary carcinoma and as juvenile patients can develop
cancer, immediate surgery is recommended once a
definitive diagnosis is established.
• Symptomatic neonates and infants should be operated
on as soon as possible, whereas elective operations at
around 3–6 months of age may be considered for
asymptomatic cases while their main organ function,
such as that of the liver, is monitored carefully.
Comments
Irrespective of the presence or absence of biliary dilatation,
PBM is very often associated with the development of
biliary tract cancer and, therefore, it can be regarded as
generating a certain predisposition to develop cancer
(Table 2) [62]. The average age of patients with congenital
biliary dilatation who developed cholangiocarcinoma was
52.0 ± 15.0 years, and in this cohort, the youngest patient
was a boy of 3 years of age [104]. As there are reports of
children and young adults with concurrent cancer, surgery
should be performed as soon as a definitive diagnosis of
PBM is reached.
Concurrent bile duct cancers were reported to have
developed in 4.9 % of adult patients suffering PBM with-
out biliary dilatation (bile duct cancer 3.1 %, gallbladder
cancer ? bile duct cancer 1.8 %), while concurrent bile
duct cancers were detected in 7.9 % of adults suffering
from congenital biliary dilatation (bile duct cancer 6.9 %,
gallbladder cancer ? bile duct cancer 1.0 %; Table 2).
Considerable attention must also be paid to the possibility
of the development of bile duct cancer in patients suffering
from PBM without biliary dilatation.
For symptomatic neonates and infants, it is recom-
mended that surgery should be performed as soon as
possible, while in asymptomatic individuals it is better to
wait until they are 3–6 months old in order to avoid the
risks of ruptured sutures or anastomotic stricture, both of
which are attributed to the small diameter of their bile
ducts [105].
PBM without dilatation (n = 582)
Adult (n = 997) Pediatric (n = 68) Adult (n = 514)
215 (21.6 %) 0 (0 %) 218 (42.4 %)
134 (62.3 %) 0 (0 %) 192 (88.1 %)
69 (32.1 %) 0 (0 %) 16 (7.3 %)
10 (4.7 %) 0 (0 %) 9 (4.1 %)
2 (0.9 %) 0 (0 %) 1 (0.5 %)
123
748 J Gastroenterol (2012) 47:731–759

CQ-IV-2. Is there an indication for surgery increases in the pancreatic intraductal pressure and in the
in asymptomatic cases? biliary tract pressure that result from the obstruction of the
common channel or the narrow segment by protein plugs
• Surgery is recommended for patients diagnosed with PBM [82, 108]. Hyperamylasemia does not really reflect true
irrespective of the presence or absence of symptoms. pancreatitis, but, rather, in most cases it is considered to be
the result of pancreatic enzymes flowing back from the bile
into the blood through cholangio-venous reflux [83].
Comments
Protein plugs are translucent on cholangiopancreatog-
raphy and MR images, and they are detected in at least
Asymptomatic cases are reported to account for 15 % of all
30 % of pediatric PBM patients [82]. Protein plugs, in
adult patients with PBM, and this percentage increases to
general, are fragile and disappear naturally. However,
33 % when considering patients of at least over 40 years of
when they remain incarcerated in the common channel or
age. In addition, complicating lesions, such as biliary tract
the narrow distal segment, biliary drainage, such as per-
cancer, were detected in 62.5 % of asymptomatic adults
cutaneous transhepatic biliary drainage, laparotomic/lapa-
over 40 years of age; thus, treatment is necessary even for
roscopic external drainage (such as T-tube drainage or
such asymptomatic patients [106].
external cholecystostomy), and drainage performed
Of note, only 0–2 % of children with PBM remain
through endoscopic procedures (indwelling transnasal tube,
asymptomatic. Patients with PBM are generally thought to
stenting, sphincterotomy), or emergency surgery may be
first experience an asymptomatic phase, followed by a
necessary [74, 82]. Most protein plugs disappear after
symptomatic phase during which the disease is detected
drainage and even when such plugs persist until biliary
and diagnosed. Symptoms become evident and treatment
diversion is performed, most of them can be removed
for PBM is received in 53.7 % of children by 3 years of
through the narrow distal segment, only a few cases
age and in 91.7 % by the age of 6, implying that the
requiring pancreatic ductotomy or the use of small-diam-
asymptomatic phase is relatively short in cases of onset
eter endoscopy [109, 110]. Furthermore, complete resec-
during childhood [107]. Nevertheless, surgical treatment is
tion of the intrapancreatic bile duct may help avoid the
required once PBM is diagnosed, irrespective of the pres-
postoperative formation of protein plugs that may cause
ence or absence of symptoms.
further symptoms [111].
CQ-IV-3. How should protein plugs be handled?
CQ-IV-4. Is intraoperative cholangiography necessary?
• In general, protein plugs are fragile, and they have
disappeared spontaneously in about 50 % of patients by • Intraoperative cholangiography is essential to confirm
the time they undergo radical surgery. the relative stenosis of the hepatic hilar bile duct, to
• When a protein plug is persistently incarcerated in the check for protein plugs, to define the site of bile duct
narrow distal segment or in the common channel, the resection for biliary tract reconstruction, to confirm the
symptoms may become exacerbated or protracted (lead- diagnosis, and to check other features of PBM.
ing to a worst-case scenario of biliary tract perforation),
requiring biliary drainage or emergency surgery. Most
Comments
protein plugs in patients who have received biliary
drainage also tend to disappear spontaneously or they
The relative stenosis of the hepatic hilar bile duct is diffi-
disappear as a result of lavage of the biliary drainage tube.
cult to detect by imaging tests such as abdominal ultraso-
• Protein plugs that persist until the time of surgery can
nography, CT, or MRI; therefore, direct cholangiography is
generally be eliminated by lavage through a biliary
the most useful technique for this purpose. However, in
drainage tube inserted in the narrow distal segment, or
patients who have a markedly dilated extrahepatic bile
they can be removed with a spoon-shaped sonde.
duct, employing contrast up to the intrahepatic bile duct
• The future formation of protein plugs can be avoided if
might not be possible on preoperative ERCP alone; thus,
concomitant complete resection of the intrapancreatic bile
intraoperative cholangiography may be required to more
duct is performed during the biliary diversion procedure.
accurately confirm the relative stenosis of the hepatic hilar
bile duct.
Comments Residual protein plugs may cause postoperative pan-
creatitis, cholangitis, or the postoperative formation of
In PBM, symptoms and signs such as abdominal pain, pancreatic stones. Again, intraoperative cholangiography is
vomiting, jaundice, and hyperamylasemia arise due to the useful in this respect to confirm that protein plugs no longer

123
J Gastroenterol (2012) 47:731–759
Fig. 10 Transection line into
the hepatic side of the bile duct
persist. In addition, as it is relatively difficult to locate the
junction of the bile and pancreatic ducts during the biliary
diversion procedure for PBM without biliary dilatation,
intraoperative cholangiography is important to define the
appropriate level at which to cut the bile duct, leaving as
little as possible of the intrapancreatic bile duct unresected.
CQ-IV-5. To what extent should the cyst be resected?
• Extrahepatic bile duct resection is performed essen-
tially to remove the tissue most likely to undergo
carcinogenesis.
• No clear data are available as to the extent to which the
cyst should be resected when the dilated lesion includes
the intrahepatic bile duct.
• The bile duct on the pancreatic side should be resected
just above its junction with the pancreatic duct, leaving
as little as possible of the bile duct unresected.
Comments
In congenital biliary dilatation, carcinogenesis inside the
dilated bile duct takes place at a very high rate. Therefore,
resection of the bile duct including the gallbladder is regarded
as the standard surgical procedure. If the resection of the bile
duct is insufficient, bile duct cancer will develop postopera-
tively [112]. If an intrahepatic bile duct stenosis remains due
to inadequate resection of the hepatic duct on the hepatic side,
intrahepatic cholestasis may develop and lead to the forma-
tion of intrahepatic stone(s), the formation of which is con-
sidered to finally cause cholangitis [113]. When the hepatic
side of the cyst is cut at the level of the common bile duct and a
common hepatic duct-enteric anastomosis is performed,
anastomotic stenosis may occur postoperatively. It is con-
sidered by some that the anastomosis should be sufficiently
749
large to avoid this, making a major incision in the lateral wall
of the right and left hepatic ducts so that the bile can flow
easily [114] (Fig. 10).
The distal part of the common bile duct needs to be cut
just above its junction with the pancreatic duct so as to
leave as little of the bile duct as possible [115]. The
position of the pancreaticobiliary junction is often uncer-
tain in cylindrical dilatation or in PBM without biliary
dilatation, and several approaches to determine the site for
transection have been reported, such as one in which a
hemostatic clip is put in place as a landmark during chol-
angiography [115].
CQ-IV-6. How should intrahepatic bile duct stenosis be
dealt with?
• As intrahepatic bile duct stenosis may cause hepatoli-
thiasis after extrahepatic bile duct resection, it should
be dealt with during the radical operation.
• Bile duct stenosis is mainly located at the hepatic hilum
where it is surgically accessible.
• There are 2 approaches that can be employed for
dealing with intrahepatic bile duct stenosis: performing
resection and reconstruction from inside the common
hepatic duct; or making an incision in the lateral wall of
the bile duct, cranial to the stricture (Todani and Lilly
method). However, there is no currently accepted
approach to deal with stenoses that are inaccessible
from the hepatic hilum when performing extrahepatic
bile duct resection.
Comments
Intrahepatic bile duct stenoses, which are mainly of two
types: membranous and septal, occur in 70–80 % of
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750 J Gastroenterol (2012) 47:731–759

Fig. 11 Septal stenosis. a An all-around membranous stenosis was revealed at the origin of the left hepatic duct. b On removing the
existed in the common hepatic duct and when the common hepatic stenoses, the aperture of the left hepatic duct was considerably
duct was resected cranial to the membranous stenosis, septal stenosis widened

patients with congenital biliary dilatation [116] (Fig. 11a,

b). The risk of forming postoperative intrahepatic stones
increases when dilatation and stenosis of the intrahepatic
bile duct coexist [117, 118]. Thus, stenoses must be cor-
rectly handled during surgery and not overlooked. These
stenoses mostly exist close to the hepatic hilum, and they
can be resected or reconstructed from inside the lumen of
the common hepatic duct [119]. When membranous ste-
nosis cannot be operated on from the lumen, a bilio-jejunal
anastomosis can be performed by making an incision into
the lateral wall of the hepatic duct, cranial to the stenosis
[120, 121] (Fig. 12).
In pediatric patients with dilatation limited to the
intrahepatic duct, combined hepatectomy in the primary Fig. 12 The Todani method to reconstruct membranous stenosis
intervention is considered excessively invasive [117].
However, if hepatolithiasis, attributed to a stenosis inac-
the hepatic hilum (close to the junction of the right and
cessible from the hepatic hilum, develops after the excision
left hepatic ducts).
of the extrahepatic bile duct, hepatectomy is also recom-
mended [118].
Comments
CQ-IV–7. What approaches are used for biliary tract
reconstruction? According to an analysis performed by the JSPBM over the
past 5 years, hepaticojejunostomy with Roux-en-Y anas-
• There is no agreement on what is the most suitable tomosis was the procedure most often performed in both
method of biliary tract reconstruction when combined pediatric and adult patients, followed by portojejunostomy
with a biliary diversion procedure for PBM. with Roux-en-Y anastomosis (Table 3). Hepaticoduode-
• The reconstruction methods most often adopted are nostomy used to be performed widely, as a single anasto-
hepaticojejunostomy with Roux-en-Y anastomosis and mosis of the physiological biliary outflow tract offered
hepaticoduodenostomy. certain advantages, and there was only a low incidence of
• The bile duct used for anastomosis is roughly classified postoperative ileus with this procedure. However, this
into the common hepatic duct (caudal to the junction of procedure is being performed less because of the devel-
the right and left hepatic ducts) and the hepatic duct of opment of cholangitis and/or bile duct cancer resulting

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J Gastroenterol (2012) 47:731–759
Table 3 The numbers of patients who underwent distinct reconstruction procedures, according to an analysis of the Japanese Study Group on
Pancreatobiliary Maljunction (JSPBM) patient register (data from the Japanese Study Group on Pancreaticobiliary Maljunction Proceedings,
vols. 29–33)
2004 2005
Intrahepatic hepaticojejunostomy 0 0
1 1
Hilar hepaticojejunostomy 11 7 16
11 12
Hepaticojejunostomy 42 36
27 23
Hepaticoduodenostomy 0 0
1 2
Portojejunostomy
Choledocho-jejunostomy
Upper columns, children; lower columns, adults
from the reflux of the duodenal contents into the bile duct,
and the development of gastritis and/or gastric cancer, both
of which are caused by bile reflux into the stomach [122–
124].
As Roux-en-Y reconstruction is liable to induce chole-
stasis due to insufficient motility of the elevated jejunum,
maintaining a rather short limb has been recommended
[122]. In children, the Roux-en-Y limb is reported to
extend excessively with growth, causing complications;
thus, even a limb of around 20 cm in length does not seem
to cause problems [125].
CQ-IV-8. How is bile duct perforation treated
in patients with PBM?
• It is considered safe to initially perform an external
biliary drainage and then to perform a radical operation
once the patient’s condition has stabilized.
Comments
PBM significantly influences the etiology of biliary tract
perforation [126]. To treat such perforation, it is generally
considered safest to first perform urgent external biliary
drainage, such as an abdominal cavity drainage or a biliary
drainage through the perforation site. Once the patient’s
state has become stable, a radical operation can be per-
formed after carrying out cholangiography to confirm the
morphological diagnosis [127, 128]. Alternatively, it has
been suggested that a radical operation should be per-
formed directly during the initial intervention when the
patient’s general status so permits [129].
751
2006 2007 2008 Total
1 0 1 2
3 0 0 5
14 8 56
10 18 11 62
24 26 33 161
11 6 24 91
0 0 0 0
1 0 0 4
1 1
1 1
2 2
2 2
CQ-IV-9. What is the operative procedure for PBM
without biliary dilatation?
• Prophylactic cholecystectomy should be performed for
PBM without biliary dilatation as the disease may often
lead to gallbladder cancer. There is no fixed view on the
prophylactic resection of the extrahepatic bile duct.
Comments
Of the 514 adult patients with PBM without biliary dila-
tation reported in Japan, 192 developed gallbladder cancer
[62]; thus, prophylactic cholecystectomy is recommended
for PBM without biliary dilatation [130]. However, it is not
clear whether or not preventive resection of the extrahe-
patic bile duct should be performed.
The grounds against performing extrahepatic bile duct
resection are that extrahepatic bile duct cancer developed
in only 7.3 % of patients suffering PBM without biliary
dilatation who developed biliary tract cancer (16 of 218
patients) [62]. Moreover, it has been reported that chol-
angiocarcinoma did not develop even during a long-term
postoperative follow-up period [77, 131].
However, an analysis of 1,361 patients with PBM
defined the incidence of bile duct cancer as a complication
in 4.0 % of patients suffering PBM without biliary dilata-
tion, similar to the 5.2 % in those suffering from PBM with
biliary dilatation, an incidence which is also extremely
high in comparison to the incidence of biliary tract cancer
in individuals without underlying PBM (0.003–0.01 %)
[102]. Indeed, there is evidence that pathological condi-
tions observed in PBM with biliary dilatation, such as
123
752
cholestasis and gene mutation (e.g., that of K-ras), are also
seen in patients suffering from PBM without biliary dila-
tation [132]. Moreover, the development of bile duct can-
cer in patients in whom the bile duct had been preserved
has been reported on occasion [133]. Together, these
phenomena favor performing extrahepatic bile duct resec-
tion; also, in addition to considering these carcinogenic
risks, a biliary diversion procedure is recommended in the
field of pediatric surgery to avoid the symptoms persisting.
CQ-IV-10. What kind of complications follow cyst
resection?
• Complications that occur in cyst resection include
bleeding at the site of resection, damage to the portal
vein and/or hepatic artery, pancreatic duct damage, and,
rarely, damage to the bile duct in patients with an
aberrant bile duct.
Comments
In patients with a history of cholangitis or pancreatitis, the
blood vessels of the cystic wall may become overdevel-
oped due to inflammation, or strong pericystic adhesion
may occur, sometimes resulting in increased bleeding from
the site at which the cyst is resected. Damage to the hepatic
artery or portal vein injury may cause massive bleeding,
although such an injury is avoided by exfoliating the cyst
through an internal layer of the cyst’s adventitia, along the
outline of the cyst [121]. As the right hepatic artery may
often run along the anterior surface of the cyst in this
disease, care must be taken not to cut this artery [134].
On the pancreatic side of the bile duct, it is necessary to
follow and transect the intrapancreatic bile duct close to the
junction so as not to leave any residual bile duct. However, in
cases such as those with fusiform dilatation the narrow
segment may be unclear, creating a risk of pancreatic duct
injury that may lead to a postoperative pancreatic fistula,
pancreatitis, or pancreatic duct stenosis [111]. In order to
prevent these complications, the site of transection should be
confirmed by intraoperative cholangiography, by using a
metal clip [111] or by biliary endoscopy [135]. Additionally,
although this occurs rarely, an aberrant bile duct may also
increase the risk of intraoperative bile duct damage [134].
CQ-IV-11. What measures are taken
when intraoperative damage to the pancreatic duct
has occurred?
• When damage to the pancreatic duct is detected during
the operation, it can be left untreated if the damaged
pancreatic duct is a peripheral branch. However, if a
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J Gastroenterol (2012) 47:731–759
main pancreatic duct is damaged, a pancreatic tube
must be inserted as a stent through the injured pan-
creatic duct towards the duodenal lumen.
• If pancreatic duct injury is detected postoperatively, a
stent tube must be inserted endoscopically via the
duodenal papilla.
Comments
It is most important to recognize when pancreatic duct
damage occurs, and if there is even the slightest suspicion
of damage, it must be confirmed by intraoperative pan-
creatography, checking whether the main pancreatic duct is
clearly enhanced with contrast medium and whether there
is any leakage of the contrast medium from the pancreatic
duct.
If damage to the pancreatic duct is evident, the pan-
creatic duct should be restored directly using a 6-0
absorbable suture [109]; otherwise, a thin pancreatic ductal
tube should be inserted as a stent from the damaged pan-
creatic duct towards the duodenal lumen, with its tip
passing through the duodenal papilla, which is a safe and
simple measure.
If no damage to the pancreatic duct is detected during
the operation but, rather, such damage is suspected post-
operatively because there is evidence of an outflow of
pancreatic juices from a drainage tube, the damage must be
confirmed by ERCP. If the damage is confirmed by ERCP,
an endoscopic nasopancreatic drainage (ENPD) catheter
should be immediately inserted via the duodenal papilla,
and by this means, prevention of or rapid alleviation of the
effects of a pancreatic fistula would be expected [136].
CQ-IV-12. What actions should be taken against
postoperative hepatolithiasis?
• The stone(s) must be removed surgically, and at the
same time, the cause(s) of the hepatolithiasis, such as
intrahepatic bile duct stenosis or anastomotic stricture,
must be dealt with.
• Measures involving the removal of stone(s) alone (e.g.,
endoscopy) involve the risk of leaving the intrahepatic bile
duct stenosis, which may cause further hepatolithiasis.
Comments
Hepatolithiasis tends to occur more frequently following
extrahepatic bile duct resection (here, biliary diversion)
rather than prior to the initial operation for PBM. Its
incidence varies between studies, averaging 10 % (see also
CQ-IV-15). In order to prevent the development of post-
operative hepatolithiasis, it is necessary to perform an
J Gastroenterol (2012) 47:731–759
operation where the anastomosis is widened by making a
major incision in the hepatic hilar bile duct [113], or where
membranous and/or septal stenosis is resected, so that
smooth biliary flow is achieved [119].
In patients who develop hepatolithiasis postoperatively, it
is important not only to remove the stone(s) but also to relieve
the stenoses [118]. When the stenotic site is dilated with an
instrument inserted percutaneously, such as a balloon or
metallic stent, the success rate is reported to be 70–90 %
[137]. However, there is a risk of stenosis recurring [138]
despite obtaining a favorable short-term outcome, and the
approaches noted above are not generally effective for septal
stenosis. It is important to ensure that smooth biliary flow is
resumed by resecting the lithogenic membranous and/or
septal stenosis. Hepatectomy is also a useful method to resect
the stenotic site, although in pediatric patients it should be
limited to cases in which the stenosis cannot be dealt with
from the hepatic hilum, or when the stenosis is limited to
either the right or the left lobe of the liver.
CQ-IV-13. How should stones that develop
inside the intrapancreatic residual cyst be treated?
• In principle, the stone(s) should be removed together
with the residual cyst.
• If the residual cyst is extremely small or if the patient
does not consent to such an operation, the
stone(s) inside the residual cyst should be removed
regularly by endoscopy.
Comments
Pancreatic juices may be retained in the residual cyst if the
intrapancreatic bile duct is left unresected during the initial
operation, causing periductal glands to develop, from
which a mucin-like substance may be secreted that even-
tually forms protein plugs. Such a process may lead to the
development of pancreatitis-like symptoms, principally
involving mainly abdominal pain [139–141]. The treatment
for such stone(s) is complete extraction of the residual cyst,
because lithogenesis occurs inside the cyst. When the
residual cyst can be localized from outside the pancreas,
the cyst should be extracted by a procedure similar to that
performed in the initial operation [140]. If the residual cyst
is buried deep inside the pancreas such that it is difficult to
identify from outside the pancreas, a balloon catheter
should be inserted intraoperatively via the papilla of Vater,
using endoscopy, and the balloon inflated inside the
residual cyst. Subsequently, the pancreas should be cut
open while palpating the inflated balloon as a landmark and
until the residual cyst can be reached. Once the cyst is
reached it should be removed [140].
753
If the residual cyst is extremely small or if consent to
remove it by surgery is not obtained, the pancreatic
stone(s) should be removed by endoscopy [139]. However,
as protein plugs continue to form inside the residual cyst,
repeated removal of the stone(s) will be necessary.
Pancreas head resection should be considered as a treatment
for residual cysts and stones only in cases where the removal of
the residual cysts and stones is impossible even by the afore-
mentioned methods and the symptoms are severe [142].
CQ-IV-14. Does the long-term prognosis differ
between congenital biliary dilatation and PBM
without biliary dilatation?
• As the age at diagnosis and the incidence of concurrent
biliary tract cancers (gallbladder cancer in particular)
are higher in PBM without biliary dilatation, this con-
dition is considered to have a poorer prognosis than
congenital biliary dilatation. However, there are no
clear grounds for such an assertion.
• There are increasing numbers of patients who develop
cancer following a biliary diversion procedure. How-
ever, as the reason for this increase remains to be
elucidated, further studies are necessary to clarify the
long-term prognosis of PBM without concurrent biliary
tract malignancies.
Comments
Patients with congenital biliary dilatation are likely to be
symptomatic from the early stages of the disease, and this
phenomenon often facilitates its diagnosis in childhood.
Conversely, the age at diagnosis is significantly higher in
patients suffering from PBM without biliary dilatation than
in those with congenital biliary dilatation [29, 77], and the
incidence of concurrent biliary tract cancers in those with
PBM without biliary dilatation is high. Accordingly, the
prognosis of these patients is assumed to be poorer, even
though there are no clear grounds for this assumption.
A biliary diversion procedure is a standard treatment for
PBM, particularly for congenital biliary dilatation,
although some patients have developed cancer even after
this therapeutic intervention.
CQ-IV-15. What are the frequencies of early and late
postoperative complications?
• Early postoperative complications include ruptured
suture, bleeding from the resection surface, acute pan-
creatitis, pancreatic fistula, gastrointestinal bleeding,
and ileus, most of which result from inadequate surgical
procedures and are infrequent.
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754 J Gastroenterol (2012) 47:731–759

• Late postoperative complications include cholangitis, least two-thirds of the patients who underwent an
hepatolithiasis, residual biliary tract cancer, pancreatic internal drainage operation developed biliary tract
stones, pancreatitis, and ileus. Hepatolithiasis and cancer within 10 years. At present, it is concluded that
residual cholangiocarcinoma are the most serious of the incidence of cholangiocarcinomas following bilio-
these complications, often appearing several years or pancreatic undiversion is higher than that after a biliary
more than a decade after the operation. diversion procedure.
• There are no reports on the incidence of biliary tract
cancer following a biliary diversion procedure or
Comments
biliopancreatic undiversion in patients suffering from
PBM without biliary dilatation. Data from such cases
1. Early and late complications following a biliary
should be collected in the future.
diversion procedure
Early postoperative complications are infrequent, and
Comments
include bleeding, pancreatic fistula, acute pancreatitis,
gastrointestinal bleeding, and ileus. Acute pancreatitis or
There is increasing evidence of patients who develop
pancreatic fistula may occur postoperatively due to the
cancer in the intrahepatic bile duct, cancer in the hepatic
exfoliation of the intrapancreatic bile ducts, although they
duct at the site of anastomosis, or cancer in the residual
are rare complications and in general they resolve with
intrapancreatic bile duct following biliary diversion [149].
conservative treatment.
However, no large-scale study exists on the development of
Cholangitis, hepatolithiasis, pancreatic stones, and pan-
biliary tract cancers after such biliary diversion procedures
creatitis represent late postoperative complications, which
or following biliopancreatic undiversion, either for con-
may also include biliary tract cancer. Cholangitis and
genital biliary dilatation or for PBM without biliary
hepatolithiasis often result from cholestasis due to anasto-
dilatation.
motic stricture, intrahepatic bile duct stenoses, or the
The incidence of biliary tract cancers following a bil-
remnants of intrahepatic bile duct dilatation [113]. Hepa-
iary diversion procedure for congenital biliary dilatation is
tolithiasis is detected in approximately 10 % of patients
considered to be 0.7–5.4 % [112], and the relative risk of
with late postoperative complications [113, 143–145].
developing cholangiocarcinoma is not thought to be
Residual biliary tract cancer: in other words, cancer that
decreased despite the performance of a biliary diversion
develops in the residual hepatic duct on the hepatic side, in
[146]. Conversely, at least two-thirds of the patients who
the intrahepatic bile duct, or in the residual intrapancreatic
underwent a so-called ‘‘internal drainage operation’’, a
bile duct following cyst resection, is an increasing problem.
procedure rarely performed nowadays, developed biliary
There are reports demonstrating that cholangiocarcinomas
tract cancers within 10 years of the operation. Moreover,
develop in approximately 0.7 % of patients who undergo
the age at onset of the cancer in patients who underwent
cyst excision, an incidence which is 120–200 times higher
an internal drainage operation was reported to be up to
than the incidence in the population at large [112, 146].
15 years younger than the age of those who developed
2. Late postoperative complications after biliopancreatic cancer without being operated on [150]. In the internal
undiversion drainage operation in patients with congenital biliary
dilatation, intestinal juices flow into the dilated bile duct
Generally, only cholecystectomy is performed for PBM
that has not been resected and, thus, the postoperative
without biliary dilatation and postoperative carcinogenesis
pathological state of the bile duct is different from that
is the principal concern as the PBM duct lesions persist in
experienced in patients who have not undergone an
such patients. However, there have only been a few reports
operation on the dilated bile duct, not enabling a fair
on the development of such carcinomas to date [147].
comparison to be drawn between the two interventions.
There have been occasional reports of pancreatitis attrib-
However, it may be fair to conclude at present that the
uted to protein plugs [148].
incidence of biliary tract cancers following biliopancreatic
undiversion is higher than that after a biliary diversion
CQ-IV-16. What is the frequency
procedure.
of cholangiocarcinomas following a biliary diversion
By contrast, there are no reports on the development
procedure and biliopancreatic undiversion?
of biliary tract cancers following a biliary diversion
procedure for PBM without biliary dilatation, which
• The incidence of biliary tract cancer following a biliary
makes it difficult to describe the significance of this
diversion procedure for congenital biliary dilatation is
operation at present.
reported to be 0.7–5.4 %. However, in one report at

123
J Gastroenterol (2012) 47:731–759
CQ-IV-17. How long is the postoperative follow-up
period after a biliary diversion procedure
or biliopancreatic undiversion?
• Patients who have undergone a biliary diversion or
biliopancreatic undiversion must be followed for the
rest of their lives.
Comments
Diverse complications and secondary diseases, especially
late postoperative biliary carcinogenesis, have been
reported following biliary diversion procedures for PBM
without biliary dilatation or for congenital biliary dilata-
tion. Thus, at present, the postoperative follow up of such
patients must be maintained.
In Japan, there have been 32 cases where biliary tract
cancer developed after a biliary diversion, of which 8 are
cases involving intrahepatic cholangiocarcinomas (post-
operative period until the detection of the malignancy,
1–26 years), 11 are carcinomas that developed at the
hepatic duct-enteric anastomotic site (postoperative period
until the detection of the malignancy, 2–21 years), 3 are
cases in which the cancer developed in the residual bile
duct on the hepatic side (postoperative period until the
detection of the malignancy, 8–31 years), and 10 are cases
where the cancer developed in the residual intrapancreatic
bile duct (postoperative period until the detection of the
malignancy, 4–23 years) [151]. In addition, in 5 cases
cholangiocarcinomas have been reported to have devel-
oped following cholecystectomy for PBM without biliary
dilatation (postoperative period until the detection of the
malignancy, 1.5–42 years) [152]. Although the chance of
developing biliary tract cancer still remains after bilio-
pancreatic undiversion (cholecystectomy), at present pre-
dicting the postoperative development of cancer is difficult.
Conflict of interest The authors declare that they have no conflict
of interest.
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