REVIEW • REVUE

Choledochal cysts
Part 1 of 3: Classification and pathogenesis

Janakie Singham, MD Much about the etiology, pathophysiology, natural course and optimal treatment of
Eric M. Yoshida, MD cystic disease of the biliary tree remains under debate. Gastroenterologists, surgeons
and radiologists alike still strive to optimize their roles in the management of chole-
Charles H. Scudamore, MD dochal cysts. To that end, much has been written about this disease entity, and the
purpose of this 3-part review is to organize the available literature and present the var-
From the Departments of Medicine and ious theories currently argued by the experts. In part 1, we discuss the background of
Surgery, the University of British the disease, describing the etiology, classification, pathogenesis and malignant poten-
Columbia, Vancouver, BC tial of choledochal cysts.

Accepted for publication

Feb. 22, 2008 Dans une large mesure, l’étiologie, la pathophysiologie, le cours naturel et le traite-
ment optimal de la maladie kystique de l’arbre biliaire continuent de faire l’objet de
débats. Les gastroentérologues, les chirurgiens et les radiologues cherchent toujours à
Correspondence to:
optimiser leur rôle respectif dans la prise en charge des kystes du cholédoque. C’est
Dr. C.H. Scudamore
Department of Surgery
pourquoi les chercheurs ont beaucoup écrit à propos de cette entité morbide, et le
University of British Columbia présent examen en 3 parties a pour objet d’organiser les études publiées et de présen-
Gordon and Leslie Diamond Health Care ter les diverses théories que font actuellement valoir les experts. Dans la première par-
Centre tie, nous discutons du contexte de cette maladie, en décrivant l’étiologie, la classifica-
2775 Laurel St., floor 5 tion, la pathogenèse et le potentiel cancéreux des kystes du cholédoque.
Vancouver BC V5Z 1M9
fax 604 875-5869
[email protected]
lthough cystic disease of the biliary tree has been described since

A 1723, much about its etiology, pathophysiology, natural course and

optimal treatment remains under debate.1 Almost 300 years later, gas-
troenterologists, surgeons and radiologists alike still strive to optimize their
roles in the management of choledochal cysts. To that end, much has been
written about this disease entity in multiple attempts to unravel the enigma.

EPIDEMIOLOGY

Choledochal cysts (CCs) are rare medical conditions with an incidence in the
western population of 1 in 100 000–150 000 live births, although the inci-
dence has been reported to be as high as 1 in 13 500 births in the United
States and 1 in 15 000 births in Australia.2,3 The rate is remarkably higher in
Asian populations with a reported incidence of 1 in 1000, and about two-
thirds of cases occur in Japan.4 The reason for this Asian preponderance is
still unclear. There is also an unexplained female:male preponderance, com-
monly reported as 4:1 or 3:1.1–4 Distribution of the different types of CCs are
as follows: 50%–80% are type I, 2% type II, 1.4%–4.5% type III, 15%–35%
type IV and 20% type V.

CLASSIFICATION

Alonso-Lej and colleagues5 proposed the first classification system for CCs in
1959, describing 3 types of bile duct dilation, which has gained wide accep-
tance. Todani and colleagues6 expanded this system in 1977 to include the
occurrence of intrahepatic and multiple cysts, and this modified classification
is now most commonly used by clinicians. Type-I cysts have subsequently
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434 J can chir, Vol. 52, N 5, octobre 2009 © 2009 Association médicale canadienne
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been subclassified into 3 types. Type IA shows marked dice, without bile duct dilation, but exhibiting an abnormal
cystic dilation of the entire extrahepatic biliary tree, with pancreaticobiliary duct junction. These patients have the
sparing of the intrahepatic ducts. The cystic duct and the same symptoms, histological evidence of inflammation and
gallbladder arise from the dilated common bile duct malignancy potential as those with CCs, and so some
(CBD). Type IB is defined by focal, segmental dilation of authors believe they should be included within the spec-
the extrahepatic bile duct. Although by definition the cyst trum of disease.14–16
can arise from anywhere within the extrahepatic biliary Kaneyama and colleagues17 described 4 patients, an inci-
tree, it is most commonly distal, with the cystic duct dence of 1.1% in that series, with a combination of type-I
branching off a normal CBD. The biliary tree proximal to and type-II cysts. Intraoperatively, all 4 patients were mor-
the gallbladder is usually normal. Type-IC cysts are phologically identical, with a fusiform type-IC cyst with a
smooth fusiform dilations of the entire extrahepatic bile type-II diverticulum arising from the middle portion of the
duct, usually extending from the pancreaticobiliary junc- cyst and the cystic duct draining into the right side of the
tion to the intrahepatic biliary tree.7 diverticulum. The authors suggested that this may be a
Type-II cysts are discrete diverticuli of the extrahepatic new clinical subtype. Four cases have also been reported of
duct with a narrow stalk connection to the CBD. Type-III diverticular cysts of the cystic duct, which the authors sug-
cysts are also called choledochocele owing to their similar- gested might be another subtype.18 The question arises,
ity in morphology, and postulated etiology, to ureteroceles. however, whether this is just a variant type-II cyst.
They consist of dilation of the distal CBD that is confined Visser and colleagues19 recently challenged the tradi-
to the wall of the duodenum, and often bulge into the duo- tional classification system, stating that it grouped together
denal lumen. Although the outer lining of the cyst is always separate disease entities, marked by differing etiologies,
lined by duodenal mucosa, the inner lining can either be natural courses, surgical options and complication profiles.
duodenal or biliary epithelium.8 Sarris and colleagues9 have They also contended that type-I and type-IVA cysts are
further subdivided choledochoceles into 5 types based on simply variations of the same disease, as in their experience
the cysts’ relations to the ampulla of Vater and the pancre- all type-I cysts had some element of intrahepatic dilatation,
atic duct. Although this system identifies the different con- and the degree of intrahepatic dilation defining one type
figurations in which choledochoceles occur, the presenta- versus the other was arbitrary. They advocated using des-
tion and management of all subtypes are identical. Thus criptive nomenclature instead of the traditional alpha-
further characterizing type-III cysts into their subclassifica- numeric classification, and this has been supported by sub-
tions has not gained popularity among clinicians. sequent authors.20
Type-IV cysts are multiple in nature and are further
subdivided based on intrahepatic duct development. Type- PATHOGENESIS
IVA cysts are multiple intrahepatic and extrahepatic dila-
tions. The intrahepatic duct dilation can be cystic, fusiform The etiology of CCs is still unclear, although many theor-
or irregular.7 Todani and colleagues10 have recommended ies have been put forth. Babbitt’s21 theory of cysts caused
further description of type-IVA cysts as cystic–cystic, by an abnormal pancreaticobiliary duct junction (APBDJ)
cystic–fusiform or fusiform–fusiform to better delineate such that the pancreatic duct and the common bile duct
the nature of their intrahepatic and extrahepatic morphol- meet outside the ampulla of Vater, thus forming a long
ogies. Type-IVB cysts refer to multiple dilations of the common channel, has gained much popularity. This the-
extrahepatic biliary tree only, described radiographically as ory postulates that the long common channel allows mix-
either a “string of beads” or “bunch of grapes” appearance.7 ing of the pancreatic and biliary juices, which then acti-
Type-V CCs refer to Caroli disease, also known as vates pancreatic enzymes. These active enzymes cause
communicating cavernous ectasia, which is multiple saccu- inflammation and deterioration of the biliary duct wall,
lar or cystic dilations of the intrahepatic bile ducts. Simple leading to dilation.21 Furthermore, greater pressures in the
Caroli disease is isolated biliary dilation, whereas Caroli pancreatic duct can further dilate weak-walled cysts.22
syndrome is cystic disease associated with congenital Many studies have measured the amylase level in CC bile,
hepatic fibrosis.11 Some authors have described Caroli dis- which is always higher in patients than in controls.23,24 Fur-
ease with associated extrahepatic CC, but the distinction thermore, higher levels of amylase were significantly asso-
between this and type-IVA cysts is unclear. Levy and col- ciated with younger age of symptom onset and higher
leagues7 state that saccular dilation of the intrahepatic bile grade of dysplasia. This lends credence to the theory that
ducts and diffuse fusiform extrahepatic bile duct dilation pancreaticobiliary reflux not only exists in these patients,
less than 3 cm marks Caroli disease as separate from type- but also leads to inflammation and dysplasia. 24–28 The
IVA cysts.12 Figure 1 shows the different types of CCs. authors also postulated that high levels of reflux (and thus
Lilly and colleagues13 described an entity that they called amylase) results in earlier symptoms, whereas low levels
“form fruste” CCs. Patients with these cysts present with result in chronic, insidious disease that presents with
typical symptoms of abdominal pain and obstructive jaun- complications later in life. Although amylase may be a

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marker for pancreatic reflux, it is more likely that the tration of secretin, which increases pancreatic secretion,
other enzymes actually cause epithelial breakdown. has been shown to dilate the CBD and gallbladder in
Therefore further studies have been conducted to assess patients with CC, whereas controls showed duodenal fill-
trypsinogen and phospholipase A2 levels in CC bile, ing only. This demonstrates pancreaticobiliary reflux in
which were also found to be elevated.24,29–35 Interestingly, these patients.37,38 As described previously, the existence of
61% of the trypsinogen in the bile duct and 65% of the form fruste CC supports the belief that APBDJ is related to
trypsinogen in the gallbladder was activated to trypsin, the pathogenesis, symptoms and complications of overt CC.8
which can only be accomplished by the presence of Skeptics of this theory call it into question because only
enterokinase.24 Although normal epithelium does not pro- 50%–80% of CCs are associated with APBDJ, and imma-
duce enterokinase outside of the duodenum, it is secreted ture neonatal acini do not make sufficient pancreatic
by dysplastic biliary epithelium, including the epithelium enzymes to explain antenatally diagnosed CC.39,40 Counter-
of patients with APBDJ.29,31 Therefore it is theorized that arguments by supporters of Babbitt’s theory state that long
enterokinase from diseased biliary epithelium activates common channels are arbitrarily defined in terms of
trypsinogen to trypsin, which in addition to its digestive length, with wide variation in measured length based on
and irritating effects activates phospholipase A2. Activated imaging modality and angles.41 In fact, different authors
phospholipase A2 hydrolyzes epithelial lecithin to lyso- have defined a long common channel as anywhere from 10
lecithin, resulting in further inflammation and bile wall to 45 mm. Therefore, APBDJ and a common channel may
breakdown.34,35 Also supporting this theory are animal in fact exist in a much larger proportion of patients with
studies in which both ligation of the common bile duct CC, but may be underestimated owing to unrealistic long
and surgical creation of APBDJ lead to cystic dilation of common channel definitions or inadequate imaging
the biliary tree in canine and murine models.36 Adminis- methods. Okada and colleagues35 recommend defining a

A B C D

E F G H

Fig. 1. Choledochal cyst classification. (A) Type-IA cystic dilation of the extrahepatic duct. (B) Type-IB
focal segmental dilation of the extrahepatic duct. (C) Type-IC fusiform dilation of the entire extrahep-
atic bile duct. (D) Type-II simple diverticula of the common bile duct. (E) Type-III cyst/choledochocele
distal intramural dilation of the common bile duct within the duodenal wall. (F) Type-IVA combined
intrahepatic and extrahepatic duct dilation. (G) Type-IVB multiple extrahepatic bile duct dilations. (H)
Type-V/Caroli disease multiple intrahepatic bile duct dilation.

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436 J can chir, Vol. 52, N 5, octobre 2009
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long common channel as any pancreaticobiliary junction lead to cystic dilation.49 Reasons for the other associations
that lies outside of the duodenal wall and thus could result remain unclear.
in pancreobiliary reflux and mixing. The above theories may explain the formation of type-I
There is a theory that CCs are instead purely congenital and type-IV cysts, but some authors contend that the eti-
in nature.42,43 This theory states that embryologic overpro- ologies of the other types are quite distinct. As described
liferation of epithelial cells results in dilation during the previously, type-II cysts are true diverticuli of the common
cannulation period of development. Davenport and Basu44 bile duct, with histological evidence of little inflammation
noted that all neonatal CCs they reviewed were cystic in and carcinogenic potential. There also have been reports of
nature, and pathologically had fewer neurons and gan- “diverticular” cysts with no apparent communication with
glions. Their theory was that round cysts are congenital in the biliary tree. 65 Therefore the question arises as to
nature, with distal obstruction due to aganglionosis and whether this is truly a cystic dilation caused by the above
proximal dilation (similar to Hirschprung disease). In this mechanisms or if it simply reflects a biliary duplication
case, chronic inflammation and symptoms occur owing to cyst. The etiology of choledochoceles is also not clear.
biliary stasis within the dilation rather than pancreatic Wheeler66 suggested that obstruction of the ampulla of
reflux. They believe that fusiform dilations are acquired Vater may result in localized dilation of the distal intra-
lesions due to APBDJ.44 Ohkawa and colleagues45 discov- mural bile duct. Others believe that increased pressure
ered that elastin fibres in the biliary tree do not develop owing to sphincter of Oddi dysfunction leads to such dila-
until 1 year of age. They assert that increased neonatal ten- tion. As mentioned previously, the inner lining of a chole-
dency for round dilation is due to APBDJ and increased dochocele can be biliary or duodenal epithelium, leading
pressure within the bile duct, which yields round dilation some authors to believe that these reflect either duodenal
before 1 year of age with the absence of elastin and or biliary duplication cysts.67,68
fusiform dilation after the age of 1 year.44–46 Contradicting Type-V CCs, or Caroli disease, is a disease entity quite
this is Xeijong’s observation that neonatal CCs are round, separate from other CCs, with very different theories of
whereas cysts associated with biliary atresia are fusiform, etiology. Embryology of the intrahepatic biliary tree is as
suggesting that round lesions are congenital and fusiform follows: a single layer of cells called a ductal plate forms
dilations are due to distal obstruction and thus acquired.10 around the portal branches, which then duplicates to form
Other authors speculate that all adult cysts are acquired a double layer. Remodelling and selective resorption of the
due to distal obstruction, with longer, narrower stenosis ductal plate commences in the 12th week and progresses to
leading to round lesions and shorter wider stenosis leading form the large bile ducts at the hilum to the small ductules
to fusiform lesions.10,44 The distal obstruction may be due in the periphery. Arrest of this remodelling results in
to sphincter of Oddi dysfunction or scarring and stone for- Caroli disease. When such duct plate malformation occurs
mation from an APBDJ.47,48 The same theorists contend at the level of the large ducts, Caroli disease results. Mal-
that type-IVA cysts result from combined distal as well as formation that continues to later stages of development
hilar and intrahepatic stenosis.10 such that the peripheral ductules are affected results in
Choledochal cysts are associated with many different Caroli syndrome, with intrahepatic cysts reflecting large
developmental anomalies, which have given to rise some duct arrest and congenital hepatic fibrosis reflecting duc-
additional etiological theories. Such associations include tule arrest.7,69 Caroli disease is associated with biliary atre-
colonic atresia, duodenal atresia, imperforate anus, pancre- sia, which is also thought to be due to duct plate malforma-
atic arteriovenous malformation, multiseptate gallbladder, tion. Caroli disease also is associated with both autosomal
OMENS plus syndrome, ventricular septal defect, aortic recessive and, less commonly, autosomal dominant poly-
hypoplasia, pancreatic divisum, pancreatic aplasia, focal cystic kidney disease.70–72 It is postulated that the genetic
nodular hyperplasia, congenital absence of the portal vein, mutations responsible for the renal malformations also
heterotopic pancreatic tissue and familial adenomatous result in hepatic duct plate malformation.71–73
polyposis.47–63 Embryologically, the pancreas forms when
the ventral and dorsal pancreatic buds rotate, fuse and form CARCINOGENESIS
connections with the biliary tree. Abnormal rotation and
fusion may result in APBDJ and CC, pancreatic divisum It is well accepted that a CC is a premalignant state, with
and pancreatic aplasia.40,50,51,56,59,64 Although the relation with cancer not only occurring more often in these patients but
enteric atresia is not clear, hypotheses include common also 10–15 years earlier.74 The overall risk of cancer has
developmental malformations or embryological cyst com- been reported to be 10%–15%, and increases with age.35,75
pression of either the gastrointestinal tract itself or its The risk rises from 2.3% in patients aged 20–30 years to
blood supply.52,53,58,60 Familial adenomatous polyposis is 75% in patients aged 70–80 years, and histopathology
associated with mutations in the adenomatosis polyposis shows increasing dysplasia with increasing age. 76,77
coli tumour suppression gene, which leads to interference Distribution of the types of cancer found in patients with
with normal biliary cell–cell adherence, and therefore may CC are as follows: adenocarcinoma 73%–84%, anaplastic

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carcinoma 10%, undifferentiated cancer 5%–7%, squa- same disease modality, based solely on anatomy, seems
mous cell carcinoma 5% and other carcinoma 1.5%.78–80 simplistic. Furthermore, the alphanumeric naming is eso-
The site of cancer is the extrahepatic bile duct in 50%– teric, and universal comprehension of the pathology
62% of patients, gallbladder in 38%–46%, intrahepatic involved will be facilitated by descriptive nomenclature
bile ducts in 2.5%, and the liver and pancreas in 0.7% instead. The evidence supporting APBDJ as the common
each.77 A review by Todani and colleagues79 found that etiology for CCs is impressive, ranging from pathological
68% of cancers were associated with type-I, 5% type-II, to biochemical to animal models. The distinction should
1.6% type-III, 21% type-IV and 6% type-V CCs. Abnor- be made between the term “long common channel” and
mal pancreaticobiliary duct junction has a 16%–55% risk APBDJ, as pancreaticobiliary fluid mixing and enzyme
of malignancy with or without bile duct dilation, and can- activation seems to be the factor leading to cystic dilata-
cer has been reported in 12%–39% of form fruste tion, and this may occur in the absence of a common
patients.77,81,82 Cancer usually occurs within the cyst in CC channel that exceeds an arbitrarily defined “normal” com-
and in the gallbladder in form fruste CC, leading some mon channel length. The patients with CC who fail to
authors to postulate that malignancy occurs at the site of demonstrate a long common channel may be such patients
bile stasis, irritation and inflammation (within the dilated who have a normal common channel length yet also have
cyst in CC and within the gallbladder when no cyst APBDJ and premature pancreaticobiliary mixing. In sub-
exists).77,82–84 Caroli disease is associated with a cancer risk sequent articles, we will examine the diagnosis and treat-
of 7%–15%.64,69,85 The incidence of malignancy with cho- ment of biliary cystic disease.
ledochocele is usually reported as 2.5%, but 1 study
reported a 27% incidence.86 Although not typically associ- Competing interests: None declared.
ated with APBDJ, some authors claim that the choledo- Contributors: All authors contributed to study design and writing the
chocele itself may be a site of pancreatic and biliary juice article and approved its publication. Dr. Singham acquired and analyzed
mixing, as the pancreatic duct and the CBD may both the data. Drs. Yoshida and Scudamore reviewed the article.
open into the cyst, thus creating the same inflammatory
and precancerous milieu as with an APBDJ.86,87 Cancer References
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