Hindawi Publishing Corporation
Gastroenterology Research and Practice
Volume 2012, Article ID 396869, 5 pages
Diagnosis of Distal Cholangiocarcinomaafter
theRemoval of Choledocholithiasis
YasuhiroIto,1Takeshi Kenmochi,1Tomohisa Egawa,1
1Department of Surgery, Saiseikai Yokohamashi Tobu Hospital, 3-6-1 Shimosueyoshi, Tsurumi-ku,
Yokohama-shi, Kanagawa 230-8765, Japan
2Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku,
Tokyo 160-8582, Japan
Correspondence should be addressed to Yasuhiro Ito, email@example.com
Received 6 August 2012; Revised 16 October 2012; Accepted 18 October 2012
Academic Editor: Michel Kahaleh
Copyright © 2012 Yasuhiro Ito et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background and Aim. Distal cholangiocarcinoma associated with choledocholithiasis has not been reported, and the causal
relationship remains to be established. We evaluated diagnosis of distal cholangiocarcinoma diagnosed after the removal of
choledocholithiasis. Patients and Methods. We assigned 9 cases of cholangiocarcinoma with choledocholithiasis to Group A. As
a control group, 37 patients with cholangiocarcinoma without choledocholithiasis were assigned to Group B. Results. Abdominal
pain at admission is the only significant difference between Group A and Group B (P = 0.001). All patients in Group A had
gall bladder stones, compared with 7 patients (19%) in Group B (P < 0.01). Of the 9 patients in Group A, endoscopic retrade
cholangiopancreatography (ERCP) detected normality in 2 patients (22%) and abnormalities in 7 patients (78%). Of the 32
patientsinGroupB,ERCPdetectednormalityin4patients(13%)andabnormalitiesin28patients(88%)(P = 0.597).Intraductal
ultrasonography (IDUS) detected a tumor in 8 patients in Group A, while in Group B, IDUS detected normality in 1 patient (3%)
and tumors in 29 patients (97%) (P = 1.000). Conclusions. IDUS after stone removal may potentially help in the detection of
unexpected tumors. Therefore, we believe that IDUS after stone removal will lead to improve outcome and prognosis.
The frequency of cholangiocarcinoma is increasing globally,
and it currently accounts for 3% of all gastrointestinal
cancers . The 5-year survival rates of patients with
23%, respectively . Early cholangiocarcinoma is difficult
to diagnose because the symptoms usually occur late in the
vessels and nerves, most patients have unresectable disease at
diagnosis and poor survival. The prognosis remains unsat-
isfactory even if the patient undergoes extensive surgery,
which is the only curative treatment for these tumors. There-
fore, early detection and diagnosis are needed to improve
long-term survival. Reports of distal cholangiocarcinoma
associated with choledocholithiasis are very rare, and the
causal relationship is not established despite the fact that
intrahepatic cholangiocarcinoma is a risk factor associated
cases of patients with distal cholangiocarcinoma diagnosed
after the removal of choledocholithiasis.
2.1. Patients. Cholangiocarcinoma is anatomically classified
as intrahepatic or extrahepatic. Extrahepatic cholangiocar-
cinoma is classified as either perihilar or distal tumors
according to the distance from the cystic ducts. This was
a retrospective study of 46 patients with distal cholangio-
carcinoma who underwent surgical treatment between April
2007 and December 2011. We assigned 9 cases of cholangio-
carcinoma with choledocholithiasis to Group A; these cases
accounted for 2.9% of all patients treated endoscopically for
choledocholithiasis at our institution. As a control group,
2Gastroenterology Research and Practice
37 patients with cholangiocarcinoma who did not undergo
choledocholithiasis resection during the same period were
diagnoses were analyzed retrospectively. Final pathological
reports were reviewed to confirm the diagnosis of distal
cholangiocarcinoma. The diameter of the distal bile duct
and the morphology of the bile duct narrowing were also
analyzed using the ERCP images.
(US), computed tomography (CT), magnetic resonance
cholangiopancreatography) underwent endoscopic removal
of bile duct stones. After stone removal, cholangiography
was performed to confirm the complete removal of choledo-
cholithiasis. Occasionally, owing to some limitations in the
detection of small stones and sludge, they were not detected
(IDUS) for all cases because of residual stones.
2.3. Surgical Procedure. Patients with distal tumors generally
underwent pancreaticoduodenectomy with or without
preservation of the pylorus. All patients underwent dissec-
tion of the regional lymph nodes, except for the para-aortic
2.4. Data Collection. Preoperative demographic and clinical
data and pathologic diagnosis data were collected prospec-
2.5. Statistical Analysis. Continuous data were expressed as
mean ± standard deviation (SD). The χ2test was used to
compare qualitative parameters, and the Student t-test was
used for quantitative parameters. P values of <0.05 were
3.1. Patient Characteristics. Three hundred and eleven
patients who were diagnosed with choledocholithiasis
between April 2007 and December 2011 underwent ERCP at
our institution. Nine of them (2.9%) were diagnosed with
distal cholangiocarcinoma by ERCP or IDUS after stone
removal despite the tumors not being detected by radio-
logical visualization. There were no statistical differences
between the patient groups regarding age or gender. The
only significant difference between Group A and Group B
(P = 0.001) was in terms of abdominal pain at admission,
and other clinical presentations were similar between both
groups. All patients in Group A had gall bladder stones,
compared with 7 patients (19%) in Group B (P < 0.01)
(Table 1). The clinicopathological findings for Group A are
summarized in Table 2.
3.2. Radiological Findings. The diagnostic imaging test
results are shown in Table 3. In 7 patients in Group A, US
detected no tumor in 3 patients (43%) and a dilatation of
Table 1: Patient characteristics.
n = 9
68.8 ± 9.2
n = 37
69.6 ± 9.7
∗following cholecystectomy in one case.
the bile duct in 4 patients (57%). In 34 patients in Group
B, US detected no tumor in 7 patients (21%), a dilatation
of the bile duct in 12 patients (35%), and a tumor in 15
patients (44%) (P = 0.083). Of the 9 patients in Group A,
CT detected no tumor in 6 patients (67%) and a dilatation
of the bile duct in 3 patients (33%). In 35 patients in Group
B, CT detected no tumor in 6 patients (17%), a dilatation of
the bile duct in 9 patients (26%), and a tumor in 20 patients
(57%) (P = 0.003). Of the 9 patients in Group A, ERCP
detected normality in 2 patients (22%) and abnormalities
in 7 patients (78%). Of the 32 patients in Group B, ERCP
detected normality in 4 patients (13%) and abnormalities
in 28 patients (88%) (P = 0.597). IDUS detected a tumor
in 8 patients in Group A, while in Group B, IDUS detected
normality in 1 patient (3%) and tumors in 29 patients (97%)
(P = 1.000).
3.3. Endoscopic Retrograde Cholangiopancreatography Find-
ings. A significant difference was observed in the diameter
of the common bile duct between the 2 groups (P = 0.043).
The morphology of bile duct narrowing was classified as
narrowing. The bile duct morphologies in the Group A
unilateral narrowing in 5 patients (56%), and bilateral
narrowing in 1 patient (11%). Of the Group B patients,
5 (14%) presented with normal or mild irregularity, 12
narrowing (Table 4).
3.4. Histological Findings. Tumor size was not significantly
different between the groups. The histological type of the
distal cholangiocarcinoma in all (100%) Group A patients
(9 patients in total) was well-differentiated adenocarcinoma.
In Group B patients, the histological types of the distal
cholangiocarcinoma were papillary adenocarcinomas in 3
patients (8%), well-differentiated adenocarcinoma in 20
patients (54%), moderately differentiated adenocarcinoma
Gastroenterology Research and Practice3
Table 2: Summary of the clinicopathological findings of Group A.
Jaundice, abdominal pain, fever
Jaundice, abdominal pain
Jaundice, abdominal pain
Jaundice, abdominal pain
Jaundice, abdominal pain, fever
Jaundice, abdominal pain
m: mucosa, fm: fibromuscular layer, ss: subserous layer, se: serosa.
Table 3: Radiologic findings.
n = 9
n = 37
Table 4: Endoscopic retrograde cholangiopancreatography find-
n = 9
n = 37
Diameter of the commonbile duct 9.7 ± 2.1 13.0 ± 4.7
Morphology of the bile duct
Normal or mild irregularity
in 11 patients (30%), and poorly differentiated adenocarci-
noma in 3 patients (8%). In Group A, the depth of invasion
reached the mucosa in 5 patients (56%), the fibromuscular
layer in 2 patients (22%), the subserous layer in 1 patient
(11%), and the serosa in 1 patient (11%). In Group B, the
depth of invasion reached the mucosa in 7 patients (19%),
the fibromuscular layer in 5 patients (14%), the subserous
layer in 9 patients (24%), the serosa in 7 patients (19%),
and the serosal infiltration in 9 patients (24%). In 7 patients
(78%) in Group A, the cholangiocarcinoma invaded the
Table 5: Histological findings.
n = 9
15.3 ± 9.7
n = 37
24.6 ± 14.1
Depth of invasion
Lymph node involvement
2 (22%) 25 (68%)0.022
mucosa and the fibromuscular layer at an early stage. The
cholangiocarcinoma invaded the subserous layer: invaded
the serosa in 22% of the patients (2/9) and infiltrated the
serosa in 68% of the patients (25/37) (P = 0.022). In Group
A, lymph node classification was absent in 8 patients (89%)
and present in 1 patient (11%). In Group B, the lymph node
classification was absent in 24 patients (65%) and present in
13 patients (35%) (P = 0.234) (Table 5).
3.5. Prognoses. All patients in Group A were alive. In Group
B, the median survival time was 46 months. Survival time
was not significantly different between the 2 groups (P =
0.126). Furthermore, survival time was not influenced by the
existence of choledocholithiasis.
Because most patients with cholangiocarcinoma tend to
invade the surrounding vessels and nerves, they are unre-
sectable at the time of diagnosis, and consequently patient
survival is poor. Early detection and diagnosis are essential
4Gastroenterology Research and Practice
for improving long-term survival because the 5-year survival
rates of patients with distal cholangiocarcinoma have been
reported to be 23% . Ekbom et al.  reported that gall
bladder stones are a probable risk factor for extrahepatic
bile duct cancer. However, choledocholithiasis has not been
reported as a cause of extrahepatic cholangiocarcinoma to
date. Reports of distal cholangiocarcinoma associated with
choledocholithiasis are very rare, and the causal relationship
remains to be established. Because we observed early distal
cholangiocarcinoma after stone removal, we investigated the
probable role of choledocholithiasis as a risk factor. Kimura
et al.  described the relationship between extrahepatic bile
duct carcinoma and stones in autopsy cases. Extrahepatic
bile duct carcinomas were present in 7 of 143 patients
(4.9%) with stones, which was significantly higher than
the rate in the patients without stones (26 of 4339; 0.6%)
(P < 0.01).Nishimuraetal.alsoreportedtherelationship
between distal cholangiocarcinoma and cholidocholithiasis.
with hepatolithiasis as a risk factor has been reported to
be 2.4–5.4% [6–8]. Chronic inflammation, biliary infection,
and cholestasis due to hepatolithiasis lead to cholangiocar-
cinoma as a result of chronic inflammation in the biliary
epithelium. Furthermore, Terada and Nakanuma reported
that carcinogenesis in biliary epithelia in livers with stones
was a multistep process involving hyperplasia, dysplasia,
and adenocarcinoma . We considered the possibility
that stones may also be associated with distal cholangio-
carcinoma as well as being a risk factor for intrahepatic
cholangiocarcinoma. In the present study, in 1 case of stone
impaction, we found that the tumor was located proximal
to the stone. Because all the other tumors were distal to the
stones, persistent chronic stimulation by stones rather than
cholestasis and infection may lead to carcinogenesis in the
The recurrence rate of choledocholithiasis after stone
removal has been reported to be 24% [10–12]. Therefore,
it is possible that a cholangiogram obtained immediately
after stone removal underestimates residual stones owing
to numerous air bubbles entering the bile duct from the
sphincterotomy. IDUS after stone removal showed residual
stones in 33–40% of cases [13, 14], although cholangiogra-
is useful because the sensitivity of IDUS for detecting
choledocholithiasis is also very high . In addition, a
prospective study for the utility of IDUS has been reported
. Additional IDUS to confirm complete stone clearance
decreases the early recurrence rate of choledocholithiasis.
For example, the recurrence rate was 13.2% in the non-
IDUS group and 3.4% in the IDUS group (P < 0.05),
and multivariate analysis identified additional IDUS as an
Three hundred and eleven consecutive patients who
underwent ERCP for choledocholithiasis between April 2005
and December 2011 were included in the study. All patients
underwent IDUS after stone removal. Fortunately, IDUS
detected biliary strictures in 2.9% of cases (9/311) that were
pathologically diagnosed as cholangiocarcinoma. In each
case, IDUS initially detected a cholangiocarcinoma in the
absence of a mass on CT or magnetic resonance imaging.
Because the early distal cholangiocarcinomas in 39% of
cases (7/18) in our institution were associated with chole-
docholithiasis, we suggest that choledocholithiasis shows an
etiologic association with cholangiocarcinoma. IDUS is very
useful for evaluating not only residual stones but also biliary
strictures [17, 18]. Because IDUS can be performed easily
and safely over a guidewire, we performed routine additional
IDUS with ERCP in all cases. In this study, ERCP and IDUS
in Group A detected biliary strictures without tumor lesions
on US or CT in 7 of 9 cases and all cases, respectively.
Because additional IDUS may underestimate the coexistence
of cholangiocarcinoma after stone removal, it should be
In another study, histological grading indicated that the
patients exhibited a significantly higher percentage of
well-differentiated tumors . Because all cases of
cholangiocarcinoma associated with choledocholithiasis
were pathologically diagnosed as well differentiated, the
result of this study is similar to that of our study. Chronic
stimulation of biliary epithelium by stones may be associated
with well-differentiated cholangiocarcinoma. It has been
hypothesized that carcinogenesis in the biliary epithelium in
livers with hepatolithiasis is a multistep process that follows
a hyperplasia-dysplasia-carcinoma sequence [9, 20, 21]. In a
study on the carcinogenic process in patients with cholan-
giocarcinoma arising from pancreaticobiliary malfunction,
it was hypothesized that carcinogenesis is involved in
chronic inflammation in the biliary epithelium and genetic
abnormalities in K-ras, p53, MUC1, and COX2 occurred
after chronic inflammation [22, 23].
In conclusion, IDUS after stone removal may potentially
help in the detection of unexpected tumors. Therefore, we
believe that IDUS after stone removal will lead to improve
outcome and prognosis. We also hope that this study will
assist in the understanding of both distal cholangiocarci-
noma associated with choledocholithiasis and the molecular
mechanisms underlying choledocholithiasis-related distal
cholangiocarcinoma, for which only limited data are avail-
able. However, further studies with a higher number of cases
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