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

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
FIG. I . Cholangiogram (Case 1) showing marked stricture in the 3.3% and 3.9%, respectively, whereas the incidence in
common hepatic duct and the marked dilatation of the right intrahepatic
duct. The stone is present in the left hepatic duct (arrow). Left lateral Shikoku and Tohoku, relatively rural districts, was 6.7%
hepatic segmentectomy was performed 2 years previously. and 6.3%, respectively. Possible causes for the difference
2828 CANCERJune I5 1985 VOl. 55

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- thiasis seen in Japanese patients seems to be different
tions. Rural residents are reported to eat a high-carbo- from Carolis disease.
hydrate, high-fiber, low-protein, and low-fat diet, whereas Main histologic findings are atrophic hepatic paren-
those in urban areas have a western-style diet containing chyma of the affected lobe replaced by fibrotic tissue
more refined sugar, protein, and saturated fat. These and dilated intrahepatic bile ducts, especially with the
dietary characteristics of rural residents may well be one presence of the stones. The wall of the dilated intrahepatic
of the causative factors of formation of calcium biliru- bile ducts are thickened and are surrounded by dense
binate stone, which is the main type of stone in hepa- fibrotic tissue and infiltrated by inflammatory cells. The
tolithiask6 Currently, ascaris or other parasitic infections epithelial lining of the intrahepatic bile ducts is desqua-
are extremely rare in Japan. Therefore, parasites could mated, but hyperplasia of the columnar epithelial cell
be excluded as a cause in Japanese patients. lining is often present. These hyperplastic epithelial cells
The most important causative factors seem to be bile often show papillomatous or adenomatous pattern. Nu-
stasis and bacterial infection in bile duct. Bacterial merous proliferating gland formations are present in
infection was found in 94% of the patients with hepa- and around the wall of the intrahepatic bile ducts
tolithiasis. Eighty percent of the organisms detected were containing stones. These glands stain positive with pe-
E. coli and Klebsiella. Stricture of the bile duct is riodic acid-Schiff (PAS), mucicarmine, and alcian blue.
related to bile stasis. Stone formation occurs in the Most of the epithelium of the glands are composed of
dilated bile duct distal to the ~ t r i c t u r e . Although
~~ it is columnar cells. Goblet cells are often present. Perichol-
not clear whether the strictures and dilatations are of angitis is a common feature in the portal
congenital or acquired origin, the pathologic features of Sanes and MacCallum14 reported two cases of cholan-
these bile ducts and the bacterial infection of the bile giocarcinoma associated with hepatolithiasis. The epi-
duct seem to be closely associated with stone formation. thelium of the dilated bile duct distant from the tumor
Carolis disease, congenital cystic segmental dilatation showed occasionally papillomatous and adenomatous
of the intrahepatic bile ducts, is often associated with proliferation with mitotic figures and atypical nuclei.
intrahepatic calculi. The clinicopathologic features of They believed that the carcinoma present was likely to
the disease are similar to those seen in primary hepato- be related to an intrahepatic calculous cholangitis with
lithiasis among Japanese patients. The simple type of marked papillomatous and glandular proliferation and
Carolis disease is said to be rare. lo Patients with Carolis pericholangitis. Falchuk el al. l 5 found varying degrees
disease are at a high risk of developing cholangiocarci- of papillary or adenomatous hyperplasia with moderate
noma. Our 6 1 patients with hepatolithiasis, however, atypia in some of the most severely inflamed areas of
had neither kidney involvement nor family history of the bile duct. They suspected that chronic infection and
the disease. Patients with Carolis disease have symptoms hepatolithiasis played a pathogenetic role in the devel-
since early childhood, whereas our patients become opment of cholangiocarcinoma. Gallagher and associ-
clinically symptomatic late in life. Therefore, hepatoli- ates16 reported two cases of congenital dilatation of
No. 12 HEPATOLITHIASIS
AND CHOLANGIOCARCINOMA * &gU el Ul. 2829

intrahepatic bile ducts with cholangiocarcinoma with the pathologic changes such as papillomatous or ade-
biliary mud or calculi, and concluded that any condition nomatous changes of the bile duct epithelium often
in which the bile duct epithelium was exposed to slow- associated with the presence of the intrahepatic calculi
flowing bile for a long period predisposes to cholangio- and infected bile may show malignant changes leading
carcinoma. On the other hand, Jones and Shreeve" to the development of cholangiocarcinoma.
speculated that carcinomatous change may occur in case
of congenital abnormalities of the biliary tree. It is well REFERENCES
known that cholangiocarcinoma may arise in the wall I . Nakayama F, Furusawa T, Nakama T. Hepatolithiasis in Japan:
of a choledochal cyst. According to the collective review Present status. Am J Surg 1980; I39:2 16-220.
2. Wen CC, Lee HC. Intrahepatic stones: A clinical study. Ann
of Bloustein," the frequency of neoplastic changes in Surg 1972: 175:166-177.
congenital choledochal cyst is approximately 4%, and 3. Balasegaram M. Hepatic calculi. Ann Surg 1972: 175:149-154.
the increased risk was in the order of 80 times the 4. Cook J, Hou PC, Ho HC, McFadzean ATS. Recurrent pyogenic
cholangitis. Br J Surg 1954; 43: 188-203.
control figure. Totani et d . I 9 reported 59 patients with 5. Maki T, Sat0 T, Yamaguchi T, Sat0 T. Treatment of intrahepatic
carcinoma arising in the wall of choledochal cysts, of gallstones. Arch Surg 1964; 88:260-270.
whom 39 (66.1%) were Japanese. Both authors suggested 6. Matsushiro T. Suzuki N, Sat0 T, Maki T. Effects of diet on
glucaric acid concentration in bile and the formation of calcium
that the bile or biliary constituent may well be carcino- bilirubinate gallstones. Gastroenterology 1977; 72:630-633.
genic or may in some manner potentiate a neoplastic 7. Tabata M, Nakayama F. Bacteria and gallstones: Etiological
change. significance. Dig Dis Sci 1981; 26:2 18-224.
8. Glenn F, Moody FG. Intrahepatic calculi. Ann Surg 1961: 153:
Hou2' demonstrated that chronic infestation of clo- 71 1-724.
norchis sinensis can ultimately lead to adenomatous 9. Nishimura M, Kitamura S. Diagnosis and treatment of intrahepatic
hyperplasia of the epithelium and further to cholangio- stones: Surgical treatment (in Japanese). Gekachiryo 1967: I7:406-
419.
carcinoma from the post mortem examination of 200 10. Caroli J. Diseases of intrahepatic bile ducts. Isr J Med Sci 1968:
cases of primary carcinoma of the liver in Hong Kong, 4:2 1-35.
of which 30 cases were proved to be associated with 11. Ludwig J, Wiesner RH, LaRusso NF. Focal dilatation of intra-
hepatic bile ducts (Caroli's disease), cholangiocarcinoma, and sclerosis
clonorchis infestation. Huang and co-workers2' reported of extrahepatic bile ducts: A case report. J Clin Gastroenterol 1982; 4:
the infestation rate of clonorchis in Hong Kong to be 53-57.
36.4% of 1366 postmortem cases and 13.9% of 25,707 12. Yamamoto K. Intrahepatic periductal glands and their signifi-
cance in primary intrahepatic lithiasis. Jpn J Surg 1982; 12:163-170.
cases on fecal examination of clinical specimens. The 13. Ohta G, Nakanuma Y. Pathology and etiology of hepatolithiasis:
incidence of clonorchis sinensis in Japan seems to be Liver, Bile Duct and Pancreas (in Japanese). Kan Tan Sui 1982; 4:
extremely low as exemplified by the report of Tutsumi,2' 337-340.
14. Sanes S, MacCallum JD. Primary carcinoma of the liver:
with the infestation rate of 0.02% in autopsy cases (45 Cholangioma in hepatolithiasis. Am J Pathol 1942; 18:675-683.
of 22,043 cases) collected from 1958 through 1970. He 15. Falchuk KR, Lesser PB, Galdabini JJ, Isselbacher KJ. Cholan-
found only two cases of cholangiocarcinoma with clo- giocarcinoma as related to chronic intrahepatic cholangitis and hepa-
tolithiasis. Am J Gastroenterol 1976; 6657-6 I .
norchis infestation. Therefore, clonorchis sinensis infes- 16. Gallagher PJ, Millis RR, Mitchinson MJ. Congenital dilatation
tation can be excluded from the possible etiologic factors of the intrahepatic bile ducts with cholangiocarcinoma. J Clin Pathol
for cholangiocarcinoma in Japan. The fact that human 1972; 251804-808.
17. Jones AW, Shreeve DR. Congenital dilatation of intrahepatic
and animal host may harbor liver-fluke such as clonorchis biliary ducts with carcinoma. Br Med J 1970: 2:277-278.
and opisthorchis in their bile duct for long periods and 18. Bloustein PA. Association of carcinoma with congenital cystic
yet never develop bile duct t ~ m o r s suggests
~ ~ - ~ that
~ the conditions of the liver and bile ducts. A m J Gastroenterol 1977: 67:
40-46.
parasite per .re does not provide the sole carcinogenic 19. Totani T, Watanabe Y, Kobuchi T. Carcinoma arising in the
stimulus leading to malignancy, and bile duct carcinoma wall of congenital bile duct cyst (in Japanese with English abstract).
arising in association with liver-fluke infestation is prob- Jpn J Pediatr Surg 1977; 9:1169-1175.
20. Hou PC. The relationship between primary carcinoma of the
ably the cumulative end result of several etiologic agents liver and infestation with clonorchis sinensis. J Pathol Bacteriol 1956;
that might include nutritional, genetic, environmental, 72:239-246.
and immunologic factors. 21. Huang CT, Wong MM, Ma SL, Sun T. Postmortem and
laboratory examinations for human intestinal helminths in Hong
Hepatolithiasis and congenital choledochal cyst are Kong. Trop Med 1969: I 1:136- 144.
both associated with cystic dilatation of the bile duct, 22. Tutsumi H. Parasitic disease in autopsy cases. J Kurume Med
infection, bile stasis, and recurrent cholangitis. These ASSOC1973; 361787-799.
23. Flavell DJ. Liver-fluke infection as an etiological factor in bile-
pathologic findings constitute chronic mechanical and duct carcinoma of man. Transact R Soc Trop Med Hyg 1981; 75:814-
chemical imtation to the biliary tract. Association of 824.
congenital choledochal cyst and cancer is well-established. 24. Atwood HD, Chou ST. The longevity of clonorchis sinensis.
Pathology 1978; 10:153-156.
Therefore, our current observations in three patients 25. Viranuvatti V. Liver fluke infestation and infestation in south-
with cholangiocarcinoma and hepatolithiasis suggest that east Asia. Prog Liver Dis 1972: 4537-547.