Predictive factors for cholangiocarcinoma associated with hepatolithiasis determined on the basis of Japanese Multicenter study

Aim: The aim of this study was to delineate predictive factors for cholangiocarcinoma in patients with hepatolithiasis, and to establish optimal management for hepatolithiasis from the viewpoint of carcinogenesis on the basis of a Japanese nationwide survey for hepatolithiasis. Methods: The Hepatolithiasis Research Group was organized in 2006 by the Ministry of Health, Labour and Welfare of Japan, and conducted a nationwide survey. The research group collected data on 336 cases of hepatolithiasis in 2006, in a cross-sectional survey involving 2592 institutions in Japan. Predictive factors for cholangiocarcinoma associated with hepatolithiasis were analyzed by univariate and multivariate analyses of clinicopathological and therapeutic factors. Results: Twenty-three patients had cholangiocarcinoma. Histories of choledocoenterostomy and liver atrophy were found to be significantly predictive factors by multivariate analysis. In 87.5% of cases of cholangiocarcinoma with liver atrophy, cholangiocarcinoma was located in the atrophic lobes. The method of reconstruction did not affect the incidence of cholangiocarcinoma (choledochojejunostomy vs. choledochoduodenostomy; side-to-end vs. side-to-side anastomosis). Conclusions: Choledocoenterostomy and liver atrophy may increase the risk of developing cholangiocarcinoma. Choledocoenterostomy is thus contraindicated in patients with hepatolithiasis. An aggressive resection strategy is recommended for an atrophic segment.     

Intrahepatische Gallengangsteine und Gallengangmissbildungen

In cases of recurrent cholangitis, hepatolithiasis should be considered in the differential diagnosis. Intrahepatic bile duct stones are associated with a significantly elevated risk for the development of cholangiocarcinoma. In cases of hepatolithiasis a differential diagnosis between cholangiocarcinoma and peribiliary inflammation may be difficult by ultrasound, CT or MRI imaging alone. The primary therapeutic goal in patients with hepatolithiasis is the elimination of cholangitis and bile stasis and avoidance of the development of secondary biliary cirrhosis or cholangiocarcinoma. Dependent on localization and extent of hepatolithiasis, interventional endoscopic as well as surgical therapeutic strategies may be chosen. Adjuvant pharmacologic prevention of recurrence of bile duct stones is under development. In cases of bile duct malformations, such as bilobar Caroli’s disease or Caroli’s syndrome, liver transplantation should be considered at an early stage. An interdisciplinary approach is of vital importance.     

Expression of epidermal growth factor receptor, ErbB2 and matrix metalloproteinase-9 in hepatolithiasis and cholangiocarcinoma]

BACKGROUND/AIMS: Hepatolithiasis is a common disease in East Asia and presents as a histological feature of proliferative glands containing mucin. 5-10% of hepatolithiasis is known to be associated with cholangiocarcinoma. Recent studies reported that epidermal growth factor receptor (EGFR) could be activated through heparin binding- EGF cleavage by metalloproteinases. Matrix metalloproteinases (MMPs) which digest the extracellular matrix are required for cancer cell invasion and the expression of MMP-9 is known to be increased in cholangiocarcinoma. However, there has been few studies on the expressions and roles of EGFR and MMP in hepatolithiasis. This study was performed to clarify and compare the expressions of EGFR, erbB2 and MMP-9 in hepatolithiasis and cholangiocarcinoma. METHODS: Surgically resected liver tissues with hepatolithiasis (n = 14), cholangiocarcinoma (n = 20) and trauma (n = 2 as controls) were included. The expressions of EGFR, erbB2 and MMP-9 in tissue samples were examined by immunohistochemistry using respective monoclonal antibodies. RESULTS: In traumatic livers, the expressions of EGFR, erbB2 and MMP-9 were all negative. The expression of EGFR was increased in hepatolithiasis group (79%, 11/14) compared with cholangiocarcinoma group (25%, 5/20) (p < 0.05). The expression of erbB2 was detected only in cholangiocarcinoma (25%, 5/20). MMP-9 was increased in both hepatolithiasis (79%, 11/14) and cholangiocarcinoma (95%, 19/20) (p > 0.05). CONCLUSIONS: EGFR expression appears to be the dominant component in periductular hyperplasia of hepatolithiasis and MMP-9 is upregulated not only in cholangiocarcinoma but also in hepatolithiasis. This study suggests that EGFR and MMP-9 are associated with cholangiocarcinoma and hepatolithiasis.     

Intrahepatic cholangiocarcinoma and hepatolithiasis: an unusual association in Western countries

Hepatolithiasis is uncommon in Western countries and the relationship with cholangiocarcinoma is unusual. We report the association of hepatolithiasis and a cholangiocarcinoma in a Caucasian patient with a 17-year history of recurrent pancreatitis associated with hepatolithiasis. We discuss work-up and surgical treatment, and stress the need to keep in mind the possible association between hepatolithiasis and cholangiocarcinoma even in Western countries.     

Incidence of Cholangiocarcinoma with or without Previous Resection of Liver for Hepatolithiasis

Background/Aims

To investigate the incidence of cholangiocarcinoma in patients with hepatolithiasis with or without previous resection of liver.

Methods

From 2002 to 2009, we retrospectively reviewed 117 patients who were diagnosed and treated for hepatolithiasis in Korea University Guro Hospital. Among the 117 patients, 55 patients who were lost during follow-up were excluded, and 62 patients were eligible for analysis. The hepatic resection group (n=25) included patients who underwent left hemihepatectomy (n=2); left lateral segmentectomy (n=10); left lobectomy (n=9); right lobectomy (n=3); or wedge resection (n=1). The nonhepatic resection group (n=37) included transhepatic cholangiographic lithotomy and endoscopic retrograde cholangiopancreatography-treated patients. The mean follow-up period was 47 months.

Results

The incidence of cholangiocarcinoma while patients were followed for hepatolithiasis was 12.9% (8/62) (hepatic resection group, three cases [12%] vs nonhepatic resection group, five cases [13.5%]; p=1.000). The mean follow-up period was 53 months (47±11 months) until the diagnosis of cholangiocarcinoma.

Conclusions

There was no difference in the incidence of cholangiocarcinoma according to previous liver resections. Patients with hepatolithiasis should be carefully followed up for detection of cholangiocarcinoma even after a previous liver resection.     

What is the impact of coexistence of hepatolithiasis on cholangiocarcinoma?

BACKGROUND: Hepatolithiasis is a well-known etiology of cholangiocarcinoma. However, whether or not hepatolithiasis influences the presentation of cholangiocarcinoma is not very clear. To help clarify this, we conducted the present study to investigate the clinicopathological characteristics of cholangiocarcinoma with hepatolithiasis. As well, we made a comparison between the presence and absence of hepatolithiasis in patients with cholangiocarcinoma to determine the impact of hepatolithiasis. METHODS: Among 140 patients with histologically proven cholangiocarcinoma at the Taichung Veteran General Hospital between October 1982 and December 2000, 38 were found to have concomitant hepatolithiasis. Patients were evaluated on the basis of age, gender, presenting symptom, laboratory data, preoperative liver function (indocyanine green test), tumor markers, histological differentiation, lymph node involvement, and organ metastasis. Data were statistically analyzed using the chi-squared test and Student's t-test. Analysis of survival was performed using the Kaplan-Meier method, and univariate analysis and multivariate analyses for survival were performed by Cox proportional hazard model. RESULTS: The cholangiocarcinoma with hepatolithiasis group (CC + HL) was found to be predominantly female, with more common presentation of fever and less presentation of jaundice (P < 0.05). In addition, patients with cholangiocarcinoma without hepatolithiasis (CC - HL group) had higher serum bilirubin levels and more advanced histological differentiation (P < 0.05). As well, the percentage of resectability of the CC + HL group was higher than that of the CC - HL group, although it was not statistically significant. Univariate and multivariate analyses for overall survival showed that those patients with an age older than 65 years, hypoalbuminemia, poor histological differentiation, and a presence of hepatolithiasis were prone to a graver prognosis, albeit none of them were statistically significant. Resectability was the only independent predictor of a favorable prognosis with significant difference. CONCLUSIONS: The clinicopathological features of cholangiocarcinoma with concomitant hepatolithiasis showed few differences from that without hepatolithiasis. Resectability was the only predictor that favored a good prognosis.     

A case of Caroli's disease with hepatolithiasis, choledocholithiasis, and cholangiocarcinoma.

A 48-year-old woman with Caroli's disease accompanied by hepatolithiasis, choledocholithiasis, and cholangiocarcinoma is reported. Magnetic resonance imaging was useful for the diagnosis of the cholangiocarcinoma. The relationship between cholangiocarcinoma and hepatolithiasis, choledocholithiasis, and chronic cholangitis in Caroli's disease is discussed.     

A case of Caroli’s disease with hepatolithiasis,choledocholithiasis, and cholangiocarcinoma

A 48-year-old woman with Caroli’s disease accompanied by hepatolithiasis, choledocholithiasis, and cholangiocarcinoma is reported. Magnetic resonance imaging was useful for the diagnosis of the cholangiocarcinoma. The relationship between cholangiocarcinoma and hepatolithiasis, choledocholithiasis, and chronic cholangitis in Caroli’s disease is discussed.     

Factors predicting concurrent cholangiocarcinomas associated with hepatolithiasis

BACKGROUND/AIMS: Hepatolithiasis is a risk factor for cholangiocarcinoma. However, it is difficult to detect early cholangiocarcinoma that occurs as a complication of hepatolithiasis. To identify the factors, which can be used for predicting cholangiocarcinomas in patients with hepatolithiasis, we compared the clinical characteristics of patients who had cholangiocarcinoma associated with hepatolithiasis with those of patients with hepatolithiasis only. METHODOLOGY: Forty patients with cholangiocarcinoma associated with hepatolithiasis (group HC) and 73 patients with hepatolithiasis only (group H) were randomly selected for this study. Mean tumor size was 6.1 +/- 2.4 cm in diameter. RESULTS: Patients of group HC were older (56.7 +/- 8.9 yr) than those of group H (49.2 +/- 12.9 yr) (p < 0.001). Weight loss was more frequent in group HC (51.5%) than in group H (5.5%) (p < 0.001) and serum alkaline phosphatase levels were higher in group HC (181 +/- 184 IU/L) than in group H (426 +/- 385 IU/L) (p < 0.001). The proportion of the patients who had hepatolithiasis in the right or both lobes of the liver was higher in group HC (72.5%) than in group H (50.6%) (p = 0.024). The optimal cutoff value of serum CEA level for cholangiocarcinoma detection was set at 4.2 ng/mL using ROC cure to give a sensitivity of 67.6% and a specificity of 90.5%. Group HC differed from group H because of its lower rates of both abdominal pain and cholangitis, longer duration of stone history, and lower serum albumin level. Factors that did not predict cholangiocarcinoma included sex ratio, white blood cell count, serum bilirubin level, and hepatic atrophy. CONCLUSIONS: Cholangiocarcinoma should be suspected in patients with hepatolithiasis, especially when, the patient is over 40 years old, has a long history of hepatolithiasis with weight loss, a higher level of serum alkaline phosphatase, a lower level of serum albumin, a serum carcinoembryonic antigen level exceeding 4.2 ng/mL, and hepatolithiasis that is located either in the right or both lobes of the liver.     

Hepatolithiasis and intrahepatic cholangiocarcinoma: A review

Although the incidence of hepatolithiasis is decreasing as the pattern of gallstone disease changes in Asia, the prevalence of hepatolithiasis is persistently high, especially in Far Eastern countries. Hepatolithiasis is an established risk factor for cholangiocarcinoma (CCA), and chronic proliferative inflammation may be involved in biliary carcinogenesis and in inducing the upregulation of cell-proliferating factors. With the use of advanced imaging modalities, there has been much improvement in the management of hepatolithiasis and the diagnosis of hepatolithiasis-associated CCA (HL-CCA). However, there are many problems in managing the strictures in hepatolithiasis and differentiating them from infiltrating types of CCA. Surgical resection is recommended in cases of single lobe hepatolithiasis with atrophy, uncontrolled stricture, symptom duration of more than 10 years, and long history of biliary-enteric anastomosis. Even after resection, patients should be followed with caution for development of HL-CCA, because HL-CCA is an independent prognostic factor for survival. It is not yet clear whether hepatic resection can reduce the occurrence of subsequent HL-CCA. Furthermore, there are no consistent findings regarding prediction of subsequent HL-CCA in patients with hepatolithiasis. In the management of hepatolithiasis, important factors are the reduction of recurrence of cholangitis and suspicion of unrecognized HL-CCA.     

Hilar cholangiocarcinoma with intratumoral calcification: A case report

This report describes a rare case of hilar cholangiocarcinoma with intratumoral calcification that mimicked hepatolithiasis. A 73-year-old man presented to a local hospital with a calcified lesion in the hepatic hilum. At first,hepatolithiasis was diagnosed,and he underwent endoscopic stone extraction via the transpapillary route. This treatment strategy failed due to biliary stricture. He was referred to our hospital,and further examination suggested the existence of cholangiocarcinoma. He underwent left hepatectomy with caudate lobectomy and extrahepatic bile duct resection. Pathological examination revealed hilar cholangiocarcinoma with intratumoral calcification,while no stones were found. To the best of our knowledge,only one case of calcified hilar cholangiocarcinoma has been previously reported in the literature. Here,we report a rare case of calcified hilar cholangiocarcinoma and reveal its clinicopathologic features.     

Carcinoembryonic antigen and blood group-related carbohydrate antigens in glycoproteins in human bile in hepatolithiasi

We investigated whether carbohydrate antigens on biliary glycoproteins and carcinoembryonic antigen (CEA) are related to hepatolithiasis. CEA, ABO, and Lewis blood group-related antigens, as well as sialyl-Tn antigen in hepatic bile, were analyzed by Western blotting in samples from 12 patients with hepatolithiasis and 37 with other biliary diseases (choledocholithiasis,13; cholecystolithiasis, 5; acute cholecystitis, 2; cholangiocarcinoma, 5; common bile duct carcinoma, 4; pancreatic carcinoma, 6; and metastatic carcinoma of liver, 2). CEA was positive on mucinous glycoprotein in six patients (50%) with hepatolithiasis and one case (17%) with pancreatic carcinoma. CEA was also positive on a glycoprotein of approximately 200 kd in eight patients (67%) with hepatolithiasis and two (33%) with pancreatic carcinoma. Lewis X was detected on the mucinous glycoprotein in almost all samples, as well as on glycoproteins of approximately 180 kd in all hepatolithiasis samples and approximately half of those from patients with other diseases. Sialyl-Tn antigen was detected on mucinous glycoprotein in four (80%) with cholangiocarcinoma, two (50%) with common bile duct carcinoma, and all pancreatic carcinoma samples. Mucinous glycoprotein and glycoproteins containing CEA and Lewis X antigens are enriched in hepatic bile of hepatolithiasis, and they may be closely related to the formation of intrahepatic calculi. Sialyl-Tn antigen in biliary mucinous glycoprotein will be a good marker of biliary and pancreatic carcinoma, and probably for cholangiocarcinoma complicated with hepatolithiasis. (Hepatology 1996 Feb;23(2):258-63)     

Natural progression of untreated hepatolithiasis that shows no clinical signs at its initial presentation

GOALS: To elucidate the natural progression of hepatolithiasis that showed no signs at the time of initial presentation. STUDY: Over a 17-year period, we observed 122 of 311 patients with hepatolithiasis who reported no symptoms and, thus, who received no treatment at initial presentation. The follow-up period was for up to 15 years (mean, 10.08 years). RESULTS: Fourteen of 112 patients (11.5%) developed some symptoms attributed to hepatolithiasis. The interval until the onset of symptoms ranged from 9 months to 7.33 years (mean, 3.42 years ). The developing symptoms included abdominal pain, hepatic abscess, cholangitis, and cholangiocarcinoma. Nine of the 14 patients (64.3%) developed stone migration to the extrahepatic bile duct at the onset of clinical symptoms. The incidence of lobar liver atrophy on computed tomography in the patients with symptomatic hepatolithiasis (13 of 14 patients; 92.9%) was significantly higher than that in the patients with asymptomatic hepatolithiasis (14 of 108 patients; 13.0%). The prognosis of the patients with symptomatic hepatolithiasis were as follows: 2 died of cholangiocarcinoma, 1 died of hepatic failure, and 11 survived. Fifteen of asymptomatic patients died, but none of these deaths were attributed to hepatolithiasis. CONCLUSIONS: Close observation is an alternative management at initial presentation for patients with asymptomatic hepatolithiasis without extrahepatic stones or lobar liver atrophy.     

Intrahepatic Stones Associated with Cholangiocarcinoma

Twenty cases of cholangiocarcinoma associated with hepatolithiasis were treated surgically. The incidence of cholangiocarcinoma associated with hepatolithiasis was 2.4%. Surgical procedures included common bile duct exploration after intraoperative choledochofiberoscopy in 20, with hepatic resection in nine. Overall survival was 8 months, with a range of 3-40 months. The hepatectomy group seemed to have a better prognosis. Accurate preoperative diagnosis of intrahepatic bile duct carcinoma associated with intrahepatic stones is difficult. All 20 patients in this series had surgery for recurrent cholangitis due to intrahepatic stones. From a retrospective review, it became apparent that early diagnosis can be obtained from the following: 1) detection of a hyperechoic mass in the liver parenchyma during abdominal ultrasonography, 2) a scintigraphic defect near the hilum, 3) filling defects or obliteration of intrahepatic ducts in ERCP or PTC, 4) gross appearance of the liver during surgery revealed a nodular tumor mass or an atrophic, fibrotic liver, and 5) intraoperative choledochoscopic findings which showed an intraluminal tumor or infiltrative lesion.     

Hepatitis B virus infection,diabetes mellitus,and their synergism for cholangiocarcinoma development: A case-control study in Korea

AIM: To identify possible risk factors and their synergism for cholangiocarcinoma development.METHODS: A hospital-based, case-control study in which we included 276 cholangiocarcinoma patients [193 extrahepatic cholangiocarcinoma (ECC) and 83 intrahepatic cholangiocarcinoma (ICC)], diagnosed at a training hospital in Korea between 2007 and 2013, and 552 healthy controls matched 2:1 for age, sex, and date of diagnosis. Risk factors for cholangiocarcinoma and possible synergism between those factors were evaluated using conditional logistic regression and synergism index, respectively.RESULTS: There was an association between cholangiocarcinoma and hepatitis B virus (HBV) infection, diabetes mellitus (DM), cholecystolithiasis, choledocholithiasis, and hepatolithiasis, with the adjusted odds ratios (AORs) of 4.1, 2.6, 1.7, 12.4, and 39.9, respectively. Synergistic interaction on the additive model was investigated between HBV infection and DM (AOR = 12.2; 95%CI: 1.9-80.1). In the subgroup analyses, cholecystolithiasis, choledocholithiasis, hepatolithiasis, and DM were significant risk factors for ECC (AOR = 2.0, 18.1, 14.9, and 2.0, respectively), whereas choledocholithiasis, hepatolithiasis, HBV infection, and DM were risk factors for ICC (AOR = 8.6, 157.4, 5.3 and 4.9, respectively). Synergistic interaction was also observed between HBV infection and DM (OR = 22.7; 95%CI: 2.4-214.1). However, there was no synergistic interaction between other significant risk factors for cholangiocarcinoma.CONCLUSION: In this Korean study, HBV infection and DM were found to exert independent and synergistic effects on the risk for cholangiocarcinoma, including ICC. Exploring the underlying mechanisms for such synergy may lead to the development of cholangiocarcinoma prevention strategies in high-risk individuals.     

Caroli's disease associated with hepatolithiasis: a case report and review of the Japanese literature

A 27-year-old woman was admitted to Nagasaki University Hospital complaining of abdominal pain and fever. Percutaneous transhepatic cholangiography showed multiple cystic dilatations of the intrahepatic bile ducts without stone formation. The illness was diagnosed as a pure type of Caroli's disease. No surgical intervention was made. Subsequently, the patient suffered repeated attacks of cholangitis, and six years later, computed tomography demonstrated cystic lesions of both lobes of the liver and stones within the cystic lesions of the right lobe. We collected 62 cases of Caroli's disease reported in the Japanese literature, including our own case. Among them, cholangitis was found in 43.5%, hepatolithiasis in 30.6%, esophageal varices in 17.7% and cholangiocarcinoma in 8.1%. It is difficult to successfully treat Caroli's disease involving both lobes of the liver. Long-term repeated cholangitis could lead to fibrosis of the liver, hepatolithiasis, portal hypertension and cholangiocarcinoma. Considering the above-mentioned aspects of the disease, careful follow-up studies are required in each case.     

Different expression patterns of mucin core proteins and cytokeratins during intrahepatic cholangiocarcinogenesis from biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct--an immunohistochemical study of 110 cases of hepatolithiasis

BACKGROUND/AIMS: Two types of neoplastic lesions preceding invasive intrahepatic cholangiocarcinoma (ICC) are identified: a flat-type neoplastic lesion called 'biliary intraepithelial neoplasia (BilIN)' and an intraductal papillary neoplasm of the bile duct (IPN-B). Multi-step carcinogenesis has been suggested in both lesions, although phenotypic changes during this process remain unclarified. METHODS: We immunohistochemically examined expression patterns of MUC1, MUC2, MUC5AC, cytokeratin 7 (CK7), and CK20 in BilIN, IPN-B, and ICC in 110 cases of hepatolithiasis. RESULTS: Thirty-seven cases of ICC in hepatolithiasis were divided into 18 tubular adenocarcinomas with BilIN, 10 tubular adenocarcinomas with IPN-B and nine colloid carcinomas with IPN-B. Carcinogenesis via BilIN was characterized by MUC2-/CK7+/CK20-with increasing MUC1 expression. IPN-B was characterized by the intestinal phenotype (MUC2+/CK20+), and carcinogenesis leading to tubular adenocarcinoma was associated with increasing MUC1 expression and that to colloid carcinoma with MUC1-negativity. Pathological stages of tubular adenocarcinoma of ICC with BilIN or IPN-B were more advanced than those of colloid carcinoma with IPN-B. CONCLUSIONS: Immunophenotypes of MUCs and cytokeratins might characterize three cholangiocarcinogenetic pathways in hepatolithiasis. Increased expression of MUC1 in BilIN and also IPN-B is associated with tubular adenocarcinoma, while colloid carcinoma in IPN-B is characterized by MUC1-negativity and less advanced pathologic stages.     

Cholangiocarcinoma Presenting as Pyogenic Liver Abscess: Is Its Outcome Influenced by Concomitant Hepatolithiasis?

Objective : The etiology of pyogenic liver abscess is changing. Malignant biliary obstruction has emerged as one of the most important causes. We explored the clinical course of pyogenic liver abscess caused by cholangiocarcinoma. Methods : The medical records of 19 patients with cholangiocarcinoma presenting as pyogenic liver abscess were reviewed. Of them, 57.8% (11 of 19) had concomitant hepatolithiasis. Escherichia coli and Klebsiella pneumoniae were the most common pathogens isolated from aspirates of the abscesses. Eight patients received percutaneous drainage, whereas 11 patients initially underwent surgical drainage because of the presence of ascites or coagulopathy or lack of awareness of the underlying cholangiocarcinoma. Results : Overall, the hospital mortality rate was 36.8% (seven of 19). Patients with hepatolithiasis had a hospital mortality rate of 54.5% (six of 11), compared with 12.5% (one of eight) in those without (   p < 0.01  ). Notably, 84.2% (16 of 19) of the patients died within 6 months after the diagnosis was made. Conclusions : Cholangiocarcinoma presenting as liver abscess has a dismal prognosis. Concomitant hepatolithiasis worsened the infectious process and adversely affected the survival.     

Clinicopathological analysis of colorectal cancer liver metastasis and intrahepatic cholangiocarcinoma: Are they just apples and oranges?

BACKGROUNDS/AIMS: Intrahepatic cholangiocarcinoma and colorectal cancer liver metastasis are the most primary and secondary adenocarcinoma of the liver, respectively. A large-scale long-term comparative study of these two cohort patient is lacking. METHODS: A total of 166 colorectal cancer liver metastasis patients and 206 intrahepatic cholangiocarcinoma patients who had undergone curative liver resection were retrospectively analysed. Among 206 intrahepatic cholangiocarcinoma, there were 47 intraductal growth type-intrahepatic cholangiocarcinoma and 159 non-intraductal growth type-intrahepatic cholangiocarcinoma. The demographics, clinicopathological data, immunohistochemical study and survival were analysed. RESULTS: The intrahepatic cholangiocarcinoma patients were more female-predominated, associated with hepatolithiasis, symptomatic, jaundiced, and with larger tumour size compared with those of colorectal cancer liver metastasis. Prognostic factors of intrahepatic cholangiocarcinoma were pathologic staging, histologic pattern and section margin; whereas prognostic factors of colorectal cancer liver metastasis were rectal origin, differentiation, section margin and bilobar distribution. CK7 and CK20 differentiated majority of intrahepatic cholangiocarcinoma from colorectal cancer liver metastasis, while CDX2 and MUC5AC helped to differentiate inconclusive cases. The 1-, 3-, 5- and 10-year survival rates of colorectal cancer liver metastasis were 77%, 31%, 20% and 14%, compared to 53%, 21%, 13% and 7% of intrahepatic cholangiocarcinoma (p=.0001). Furthermore, the survival of colorectal cancer liver metastasis was comparable to staged II intrahepatic cholangiocarcinoma (p=.8866) and intraductal growth type-intrahepatic cholangiocarcinoma (p=.1915). CONCLUSIONS: Demographics, precipitating factor, clinical manifestations, and prognostic factors of colorectal cancer liver metastasis and intrahepatic cholangiocarcinoma differed remarkably. High incidence of CDX2 and MUC2 expression in colorectal cancer liver metastasis and intraductal growth type-intrahepatic cholangiocarcinoma might explain their similar cytoarchitecture and survival.     

In situ nucleic acid detection of human telomerase in intrahepatic cholangiocarcinoma and its preneoplastic lesion.

Human telomerase, an enzyme associated with cellular immortality and tumorigenesis, is expressed by most malignant tumor cells. Human telomerase consists of human telomerase RNA (hTR) and telomerase protein components. One of the latter has been cloned and was termed telomerase-associated protein 1 (TP1). Using an in situ hybridization method, expression of hTR and TP1 mRNA was surveyed in 20 cases of intrahepatic cholangiocarcinoma (ICC) (5 of them were associated with hepatolithiasis), 5 cases of hepatolithiasis alone and 6 normal livers. Biliary dysplasia, which is suspected as a preneoplastic lesion of ICC, was found in the biliary tree in all 5 ICC cases with hepatolithiasis and in 1 of 5 cases of hepatolithiasis alone. Normal colonic mucosa was used as positive control. In 17 (85%) of 20 ICC cases, hTR and TP1 mRNA were detected in carcinoma cells. There was no correlation between histological subtype of ICC and expression of hTR and TP1 mRNA. Biliary dysplasia was also positive for both RNA. These signals were mainly located in the cytoplasm of carcinoma and dysplastic cells, especially around their nuclei. The signals were homogeneously detected in the carcinoma, while their distribution was more or less heterogeneous in the dysplastic foci. These signals were not detected in nondysplastic biliary epithelia in hepatolithiasis and normal livers. It seems likely that almost all ICC acquired telomerase activities irrespective of histological subtype and more importantly that cellular immortalization has already occurred in biliary dysplasia and this lesion is already involved in the malignant progression of ICC.