Hepatolithiasis Associated With Cholangiocarcinoma

Possible Etiologic Significance

AKlTOSHl KOGA, MD, HlTOSHl ICHIMIYA, MD, KOHJl YAMAGUCHI, MD,

KOHJI MIYAZAKI, MD, AND FUMIO NAKAYAMA, MD

Three cases of primary bile duct carcinomas (cholangiocarcinomas) were found among 61 cases of
hepatolithiasis. Cholangiocarcinoma arose from the extrahepatic bile duct in one and from the dilated
intrahepatic bile duct in two patients. Hyperplasia of the columnar cells was often present. These
hyperplastic epithelial cells often show papillomatous or adenomatous pattern, which are frequently
associated with the presence of stones and the contaminated bile, and may show malignant changes
leading to the development of cholangiocarcinoma.
Cancer 55:2826-2829, 1985.

INTRAHEPATIC CALCULI or hepatolithiasis is fairly com-

mon a m o n g t h e Japanese, the incidence being 3% to
6% of all patients undergoing operation for gallstones.'
Hepatolithiasis is said to be rarely associated with chol-
angiocarcinoma. Recently we treated three patients with
cholangiocarcinoma among 6 1 cases of hepatolithiasis
(4.9%) between January 1973 and December 1982. The
pathogenetic implication of the presence of intrahepatic
stones, cholangitis, and bile stasis on t h e development
of carcinoma is reported.
Case Reports
Case 1
A 56-year-old woman had had occasional abdominal pain
and fever since childhood and received conservative medical
treatment with the occurrence of symptoms. There was no
family history of hepatobiliary disease. In February 1977, she
was admitted to our department with severe right upper
abdominal pain and fever. Endoscopic retrograde cholangio-
pancreatography (ERCP) revealed stricture of the left lateral
segmental bile duct and the multiple stones peripheral to the
stenotic site. Cholecystectomy, choledochotomy with sphinc-
teroplasty, and left lateral hepatic segmentectomy were per-
formed. Stones in the liver were dark-brown-colored and soft.
Chemical analysis of the stones proved to be composed of
bilirubin calcium. Bile culture taken at the operation revealed
a variety of bacilli, chiefly Escherichia coli. Kleb.siellu, and
Enterobacter, There was no evidence of malignancy either
intraoperatively or in the later pathologic examinations. In
From the Department of Surgery I, Kyushu University Faculty of
Medicine, Fukuoka, Japan.
Supported in part by Research Grants from the Ministry of Health
and Welfare, Japan.
Address for reprints: Akitoshi Koga. MD. Department of Surgery I,
Kyushu University Faculty of Medicine, Fukuoka 812, Japan.
The authors thank Prof. M. Enjoji for pertinent advice on the
histology.
Accepted for publication July 5, 1984.
June 1979. she was readmitted with fever, chills, and severe
jaundice. Percutaneous transhepatic cholangiography (PTC)
revealed marked stricture in the common hepatic duct and
marked dilatation of the right intrahepatic bile duct (Fig. 1).
Laparotomy was performed under the diagnosis of cancer of
the hilar bile duct. Frozen section from the paracholedochal
lymph node showed adenocarcinoma. The bile duct resection
would have been noncurative. as there was peritoneal seeding.
She died of septicemia in August 1979. At autopsy, the liver
hilum was massively infiltrated with malignant cells and peri-
toneal seeding was conspicuous. Multiple liver abscesses were
also present.
Case 2
A 68-year-old woman had undergone cholecystectomy and
choledochotomy with T-tube drainage 14 years previously.
Nausea. vomiting, fever, and right upper quadrant pain per-
sisted. In November 1981, she was admitted to our department
with fever, chills, and jaundice. PTC revealed cystic dilatation
of left lateral segmental duct filled with stones (Fig. 2). At
laparotomy. large lymph nodes were present in the liver hilum.
Serosal implantations on the mesenterium and in the Douglas
cavity were evident. Intraoperative histologic examination of
the lymph node revealed adenocarcinoma. The primary lesion
was searched extensively, and the left hepatic lobe was consid-
ered to be the most suspicious site. The left lobe was atrophic
and fibrous, with increased consistency. Left lateral hepatic
segmentectomy was performed. The resected liver was slightly
firm due to fibrotic change. The cut surface of the liver showed
a cystic dilatation of the intrahepatic bile duct containing
brown-colored stones. The liver was almost totally replaced
with cancerous infiltration and fibrous tissue. The bile duct
wall was markedly thickened due to the presence of cholangitis.
Bacteriology of choledochal bile taken during the operation
revealed E. coli and Klebsiella. Chemical analysis of the
intrahepatic stones was composed of predominantly bilirubin.
Histologic examination showed malignant tubules accompa-
nying well-developed fibrous stroma. The histologic diagnosis
was well-differentiated adenocarcinoma originating from the

2826
No. 12 HEPATOLITHIASIS
AND CHOLANGIOCARCINOMA * KOgU 6'1 U l . 2827

intrahepatic bile duct. Perineural invasions of the malignant

cells were conspicuous. There was periductal fibrosis with a
moderate inflammatory infiltrate, predominantly of plasma
cells and focal areas of regenerative glandular formations.

Case 3
A 4 I -year-old man underwent cholecystectomy, choledo-
chotomy with T-tube drainage, and left lateral hepatic segmen-
tectomy under the diagnosis of hepatolithiasis in the department
in November 1979. The resected liver was atrophic. The cut
surface showed marked fibrosis around the dilated bile duct.
with atrophy of the liver parenchyma. Microscopic examination
of the resected liver specimen revealed no evidence of malig-
nancy. He was readmitted with right upper quadrant pain and
fever in August 1982. ERCP revealed the stricture of the left
hepatic duct and cystic dilatation of the medial segmental duct
filled with stones. The carcinoembryonic antigen (CEA) value
remained normal. A medial segmentectomy was performed.
The resected liver was firm and atrophic, and the cut surface
showed dilated intrahepatic bile ducts containing dark-colored
stones. Bacteriologic study of the choledochal bile showed the
presence of E. coli, Klebsiella, and Enterobacter. Chemically,
the stones were composed primarily of bilirubin. Microscopic
examination of the resected liver specimen revealed areas of
well-differentiated adenocarcioma originating from the intra-
hepatic bile duct (Fig. 3A). Perineural permeation of malignant
cells was demonstrated (Fig. 3B). The epithelium of the dilated
bile duct distant from the tumor showed often papillomatous
and adenomatous hyperplasia with moderate atypia. There
FIG. 2. PTC (Case 2) showing cystic dilatation of the left lateral
was also proliferation of many small glands. A chronic inflam- segmental duct filled with stones.
matory infiltrate was present in the periductal fibrous stroma.

The patient was readmitted because of the recurrence of the

tumor in March 1983.
Stool examinations in the three patients presented revealed
no ova of Clonorchis sinensis. Ascaris, and Schistosomajapon-
icum. Ova or parasites were not demonstrated in the pathologic
examination of the resected specimen.
To our knowledge, there was neither family history of
hepatobiliary disease nor underlying metabolic abnormality,
and there was also no congenital disease that led first to bile
stasis or cholangitis in the three patients presented.

FIG. I . Cholangiogram (Case 1) showing marked stricture in the
common hepatic duct and the marked dilatation of the right intrahepatic
duct. The stone is present in the left hepatic duct (arrow). Left lateral
hepatic segmentectomy was performed 2 years previously.
Discussion
Hepatolithiasis is a relatively rare condition in which
stones are formed in the intrahepatic bile duct. In East
Asia, the incidence is reported to be 10% to 30%.*v3 As
etiologic factors, parasites such as liver fluke or ascaris
or socioeconomic condition were c o n ~ i d e r e d . A
~ -recent
~
survey by the Japan Biliary Tract Society revealed the
incidence of 4.1% of all patients with gallstones under-
going operations.' There was a difference in prevalence
of hepatolithiasis between residents of urban and rural
areas. The incidence in the most urbanized Kanto and
Kinki districts, where Tokyo and Osaka are located, was
3.3% and 3.9%, respectively, whereas the incidence in
Shikoku and Tohoku, relatively rural districts, was 6.7%
and 6.3%, respectively. Possible causes for the difference
2828 CANCERJune I5 1985
FIGS.3A AND 3B. (A, left) Light micrograph (Case 3) showing well-differentiated adenocarcinoma with fibrous stroma (H & E, X65). (B, right)
Light micrograph (Case 3) showing invasion of the perineural spaces by malignant cells in the fibrous stroma (H & E, X80).
include diet, parasitic infection, and economic condi-
tions. Rural residents are reported to eat a high-carbo-
hydrate, high-fiber, low-protein, and low-fat diet, whereas
those in urban areas have a western-style diet containing
more refined sugar, protein, and saturated fat. These
dietary characteristics of rural residents may well be one
of the causative factors of formation of calcium biliru-
binate stone, which is the main type of stone in hepa-
tolithiask6 Currently, ascaris or other parasitic infections
are extremely rare in Japan. Therefore, parasites could
be excluded as a cause in Japanese patients.
The most important causative factors seem to be bile
stasis and bacterial infection in bile duct. Bacterial
infection was found in 94% of the patients with hepa-
tolithiasis. Eighty percent of the organisms detected were
E. coli and Klebsiella. Stricture of the bile duct is
related to bile stasis. Stone formation occurs in the
dilated bile duct distal to the ~ t r i c t u r e . Although
~~ it is
not clear whether the strictures and dilatations are of
congenital or acquired origin, the pathologic features of
these bile ducts and the bacterial infection of the bile
duct seem to be closely associated with stone formation.
Carolis disease, congenital cystic segmental dilatation
of the intrahepatic bile ducts, is often associated with
intrahepatic calculi. The clinicopathologic features of
the disease are similar to those seen in primary hepato-
lithiasis among Japanese patients. The simple type of
Carolis disease is said to be rare. lo Patients with Carolis
disease are at a high risk of developing cholangiocarci-
noma. Our 6 1 patients with hepatolithiasis, however,
had neither kidney involvement nor family history of
the disease. Patients with Carolis disease have symptoms
since early childhood, whereas our patients become
clinically symptomatic late in life. Therefore, hepatoli-
VOl. 55
thiasis seen in Japanese patients seems to be different
from Carolis disease.
Main histologic findings are atrophic hepatic paren-
chyma of the affected lobe replaced by fibrotic tissue
and dilated intrahepatic bile ducts, especially with the
presence of the stones. The wall of the dilated intrahepatic
bile ducts are thickened and are surrounded by dense
fibrotic tissue and infiltrated by inflammatory cells. The
epithelial lining of the intrahepatic bile ducts is desqua-
mated, but hyperplasia of the columnar epithelial cell
lining is often present. These hyperplastic epithelial cells
often show papillomatous or adenomatous pattern. Nu-
merous proliferating gland formations are present in
and around the wall of the intrahepatic bile ducts
containing stones. These glands stain positive with pe-
riodic acid-Schiff (PAS), mucicarmine, and alcian blue.
Most of the epithelium of the glands are composed of
columnar cells. Goblet cells are often present. Perichol-
angitis is a common feature in the portal
Sanes and MacCallum14 reported two cases of cholan-
giocarcinoma associated with hepatolithiasis. The epi-
thelium of the dilated bile duct distant from the tumor
showed occasionally papillomatous and adenomatous
proliferation with mitotic figures and atypical nuclei.
They believed that the carcinoma present was likely to
be related to an intrahepatic calculous cholangitis with
marked papillomatous and glandular proliferation and
pericholangitis. Falchuk el al. l 5 found varying degrees
of papillary or adenomatous hyperplasia with moderate
atypia in some of the most severely inflamed areas of
the bile duct. They suspected that chronic infection and
hepatolithiasis played a pathogenetic role in the devel-
opment of cholangiocarcinoma. Gallagher and associ-
ates16 reported two cases of congenital dilatation of
No. 12 HEPATOLITHIASIS
AND CHOLANGIOCARCINOMA
intrahepatic bile ducts with cholangiocarcinoma with
biliary mud or calculi, and concluded that any condition
in which the bile duct epithelium was exposed to slow-
flowing bile for a long period predisposes to cholangio-
carcinoma. On the other hand, Jones and Shreeve"
speculated that carcinomatous change may occur in case
of congenital abnormalities of the biliary tree. It is well
known that cholangiocarcinoma may arise in the wall
of a choledochal cyst. According to the collective review
of Bloustein," the frequency of neoplastic changes in
congenital choledochal cyst is approximately 4%, and
the increased risk was in the order of 80 times the
control figure. Totani et d . I 9 reported 59 patients with
carcinoma arising in the wall of choledochal cysts, of
whom 39 (66.1%) were Japanese. Both authors suggested
that the bile or biliary constituent may well be carcino-
genic or may in some manner potentiate a neoplastic
change.
Hou2' demonstrated that chronic infestation of clo-
norchis sinensis can ultimately lead to adenomatous
hyperplasia of the epithelium and further to cholangio-
carcinoma from the post mortem examination of 200
cases of primary carcinoma of the liver in Hong Kong,
of which 30 cases were proved to be associated with
clonorchis infestation. Huang and co-workers2' reported
the infestation rate of clonorchis in Hong Kong to be
36.4% of 1366 postmortem cases and 13.9% of 25,707
cases on fecal examination of clinical specimens. The
incidence of clonorchis sinensis in Japan seems to be
extremely low as exemplified by the report of Tutsumi,2'
with the infestation rate of 0.02% in autopsy cases (45
of 22,043 cases) collected from 1958 through 1970. He
found only two cases of cholangiocarcinoma with clo-
norchis infestation. Therefore, clonorchis sinensis infes-
tation can be excluded from the possible etiologic factors
for cholangiocarcinoma in Japan. The fact that human
and animal host may harbor liver-fluke such as clonorchis
and opisthorchis in their bile duct for long periods and
yet never develop bile duct t ~ m o r s suggests
~ ~ - ~ that
~ the
parasite per .re does not provide the sole carcinogenic
stimulus leading to malignancy, and bile duct carcinoma
arising in association with liver-fluke infestation is prob-
ably the cumulative end result of several etiologic agents
that might include nutritional, genetic, environmental,
and immunologic factors.
Hepatolithiasis and congenital choledochal cyst are
both associated with cystic dilatation of the bile duct,
infection, bile stasis, and recurrent cholangitis. These
pathologic findings constitute chronic mechanical and
chemical imtation to the biliary tract. Association of
congenital choledochal cyst and cancer is well-established.
Therefore, our current observations in three patients
with cholangiocarcinoma and hepatolithiasis suggest that
* &gU el Ul. 2829
the pathologic changes such as papillomatous or ade-
nomatous changes of the bile duct epithelium often
associated with the presence of the intrahepatic calculi
and infected bile may show malignant changes leading
to the development of cholangiocarcinoma.
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