Intrahepatic Cholangiocarcinoma Associated with Intrahepatic Duct Stones

Original Article Intrahepatic Cholangiocarcinoma Associated with Intrahepatic Duct Stones Hoon Hur, Il-Young Park, Gi-Young Sung, Do-Sang Lee, Wook Kim and Jong-Man Won, Department of Surgery, Holy Family Hospital, College of Medicine, The Catholic University of Korea, Gyeonggi-do, Korea. OBJECTIVE: It has been well established that the long-term prognosis of intrahepatic duct stones (IHDS) is complicated by the late development of biliary cirrhosis with associated intrahepatic cholangiocarcinoma (IHCC). Despite recent improvements in imaging studies, accurate preoperative diagnosis of IHCC is difficult. Therefore, we attempted to elucidate the clinical features of patients with IHDS with IHCC. METHODS: We reviewed 80 patients with IHDS and divided them into two groups. The DS group included 72 patients who had only IHDS. The second group was defined as the CC group and included eight patients who had IHDS and IHCC. For diagnosis of IHDS and confirmation of coexisting IHCC, patients underwent various radiological evaluations and additional laboratory tests, such as serum carbohydrate antigen 19-9 (CA 19-9). RESULTS: There was no significant difference in the symptoms and stone characteristics between the two groups. For the CC group, liver resection was performed in four patients. Three patients underwent curative resection, but only one of these patients was alive at 36 months without recurrence. CONCLUSION: IHCC with IHDS was difficult to diagnose in the early phase. Therefore, while performing diagnostic studies and surgery for IHDS, one should always consider the possibility of coexisting cholangiocarcinoma. [Asian J Surg 2009;32(1):7 12] Key Words: cholangiocarcinoma, IHDS Introduction Intrahepatic duct stones (IHDS) have a higher prevalence in Asian countries compared to other regions of the world. Although many physicians have made an effort to effectively manage patients diagnosed with IHDS, the possibility of the development of biliary cirrhosis or intrahepatic cholangiocarcinoma (IHCC) has led to a poor prognosis for these patients. 1 The possibility of the development of IHCC has been more extensively investigated because it has been reported that the effect of treatment for IHCC is very unsatisfactory. The first two cases of IHCC occurring together with IHDS were reported in 1942. 2 Recent reports have documented that the rate of the development of IHCC while patients are being treated and followed for IHDS was 4 to 11%. 3 5 Because this potential for the development of IHCC is not trivial and the diagnosis is difficult, it is important that clinicians know about the various characters of IHCC associated with IHDS. The aim of this study was to describe the clinical features of IHCC that developed in patients who were diagnosed with IHDS and to provide an aid to assess presence of characteristic features for an early diagnosis of IHCC in patients with IHDS. Patients and methods Between 1993 and 2004, we treated 80 patients with IHDS at the Holy Family Hospital, Bucheon-City, Korea Address correspondence and reprint requests to Dr Il-Young Park, Department of Surgery, Holy Family Hospital, 2 Sosa-dong, Wonmi-gu, Bucheon, Gyeonggi-do, Korea. E-mail: parkiy@catholic.ac.kr Date of acceptance: 1 August 2008 2009 Elsevier. All rights reserved. ASIAN JOURNAL OF SURGERY VOL 32 NO 1 JANUARY 2009 7

HUR et al with a mean follow-up of 35 months. We divided the 80 patients into two groups. The DS group included 72 patients who had been treated for IHDS without IHCC. The CC group included eight patients who were diagnosed with IHCC at the same time or during a follow-up period after they had been treated for IHDS. We compared the two groups with regard to clinical features such as: gender, age, previous treatment, radiologic evaluation, and symptoms. We retrospectively examined the characteristics of the stones and treatment methods in both groups. We evaluated the results of a tumour marker (CA 19-9) and other laboratory studies, radiological and surgical findings, and the outcome for both groups. A Mann-Whitney U test for continuous variables and Fisher s exact test for categorical variables were used for comparison of the study groups. A value of p < 0.05 (two-sided) was considered to be significant. Results Patient characteristics and symptoms We compared the two groups with regard to the clinical characteristics: age, gender, and previous biliary surgery. The results are summarised in Table 1. There is no difference between the two groups in any of the characteristics, and the number of female patients was three times greater than the number of male patients in both groups. In both groups, the most common previous biliary surgery was cholecystectomy. The patients presented with abdominal pain, fever and jaundice as initial symptoms. Abdominal pain was the most common symptom and was found in over 90% of patients in both groups. Jaundice occurred in only 33% of the DS group and 38% of the CC group. There was no significant difference in the symptoms between the two groups (Table 2). Diagnosis and characteristics of IHDS in the two groups The diagnosis of intrahepatic duct stones was not difficult in patients where this was highly suspected. Abdominal ultrasonography (US) and computed tomography (CT) were commonly used for the detection of the stones and to identify their location in both groups. Endoscopic retrograde cholangiopancreaticogram (ERCP) or magnetic resonance cholangiopancreaticogram (MRCP) was performed when necessary to confirm clinical suspicion or to identify causes of obstruction (Table 2). Table 1. Patient characteristics in the DS and CC groups Characteristics DS group CC group (n = 72) (n = 8) Age (yr) 56.6 (29 82) 60.0 (37 83) 0.407 Male:Female 20:52 2:6 1.000 Previous biliary 32 (44%) 2 (25%) 0.457 surgery (%) *Statistical significance was tested by the Mann-Whitney U test for continuous variables and Fisher s exact test for categorical variables; presented as median (range); the most common previous biliary operation in the DS group was cholecystectomy (25 cases; 78%); two prior biliary operations in the CC group were cholecystectomies. Table 2. Symptoms and radiologic evaluations for patients in both groups DS group CC group (n = 72) (n = 8) Symptoms Abdominal pain 66 (92%) 8 (100%) 1.000 Fever 20 (28%) 3 (38%) 0.683 Jaundice 24 (33%) 3 (38%) 1.000 No symptoms 2 (3%) 0 (0%) 1.000 Radiologic methods US 52 (72%) 7 (88%) 0.674 ERCP 15 (21%) 2 (25%) 0.676 MRCP 15 (21%) 0 (0%) 0.341 CT 29 (40%) 5 (63%) 0.275 *Statistical significance was tested by Fisher s exact test. US = abdominal ultrasonography; ERCP = endoscopic retrograde cholangiopancreaticogram; MRCP = magnetic resonance cholangiopancreaticogram; CT = computed tomography. CA 19-9 level at the diagnostic time was retrospectively evaluated in the 21 patients, and the variance was too large to analyse the difference between the two groups. In the DS group, the range of CA 19-9 levels of 17 evaluated patients was 1.33 to 10,942 U/mL. The range of four patients in the CC group was 460 U/mL to 4,438 U/mL. No difference in the results between the two groups was shown in other laboratory findings such as AST, ALT, and total bilirubin. The most common site for the stones was in the left liver (51 cases of 80 patients, 64%). There was no significant difference in the incidence of IHCC on the basis of the location of the stones (Table 3). Out of a total of 80 patients, 68 patients (85%) had pigment stones. All patients in the CC group had pigmented stones, but there p* p* 8 ASIAN JOURNAL OF SURGERY VOL 32 NO 1 JANUARY 2009

CHOLANGIOCARCINOMA ASSOCIATED WITH IHDS Table 3. Classification of patients with intrahepatic duct stones by location Location DS group CC group Total Incidence of cancer (%)* Right only 17 1 18 6 Left only 44 7 51 14 Both 11 0 11 0 Total 72 8 80 10 *Incidence of cancer: proportion of CC group in total number. No significant difference in incidence by stone location (p = 0.082) by Chi-square test. Table 4. Treatment methods used in the DS group (n = 72) Stone location Cases Left IHDS patients (n = 44) LLS 24 Left hepatectomy 4 Hepatotomy 1 Choledochoscopic removal 10 Percutaneous drainage 1 No operation 4 Right IHDS patients (n = 17) Right hepatectomy 1 Choledochoscopic removal 12 No operation 4 Both IHDS patients (n = 11) LLS and choledochoscopic removal 2 Choledochoscopic removal 6 Choledochojejunostomy 1 No operation 2 IHDS = intrahepatic duct stone; LLS = left lateral sectionectomy. was also no significant difference in stone type between the two groups. Treatment methods used for patients in the DS group Table 4 shows the treatment methods used for the DS group. Surgical intervention could not be provided in 10 patients, due to patient refusal or high surgical risk. The surgical methods used for the patients in the DS group differed according to the stone location and the status of the liver parenchyma. We performed hepatectomy for cases with severe atrophic liver parenchyma, possible malignancy, or main hepatic duct stricture. The most common operation for a left IHDS was left lateral sectionectomy (55%). However, in cases of a right IHDS or IHDS on both sides, choledochoscopic removal was used most commonly. Right hepatectomy was performed in only one patient, because of the high risk of operative mortality and morbidity. After treatment for IHDS, patients had a mean follow-up of 37 months without development of cholangiocarcinoma. Clinical characteristics of patients in the CC group We evaluated eight patients with IHCC associated with IHDS (Table 5). Two patients who were evaluated by US only were not preoperatively diagnosed with cholangiocarcinoma. Four patients who had CT or ERCP in addition to US were preoperatively diagnosed with cholangiocarcinoma. During surgery, the correct diagnosis and extension of carcinoma was confirmed by intraoperative examination of a frozen section. Although liver resection could be performed in five patients, three patients underwent curative resection involving safe margins and lymph node dissection around the hepatic hilum. In two of these patients, cholangiocarcinoma recurred within 4 months. One patient had a recurrence in the remnant of the right medial section; in the other patient, the cholangiocarcinoma recurred at multiple sites in the peritoneal cavity. After a recurrence was identified, the patients received conservative treatment. The mean survival was 11.1 months. Only one patient survived for 36 months without recurrence. Discussion Risk factors for IHCC include: IHDS, 6 cystic liver disease, 7 Clonorchis sinensis, 8 primary biliary cirrhosis, 9 ulcerative colitis, 10 Carolis disease, 11 and congenital liver fibrosis. 12 In Asia, IHDS is one of the factors that have been highly associated with IHCC. 13,14 Since Sanes and MacCallum 2 reported two cases of cholangiocarcinoma related to hepatolithiasis that were discovered incidentally at autopsy for the first time in 1942, the association of IHDS with IHCC has been reported to be from 4 11% in reported series over the world. 3,4,15 17 In our study, the ASIAN JOURNAL OF SURGERY VOL 32 NO 1 JANUARY 2009 9

HUR et al Table 5. Clinical characteristics of the CC group No Age Clinical Radiologic Preoperative Postoperative CA 19-9 Surgical Sex symptoms evaluation diagnosis diagnosis (U/mL) procedure Follow-up 1 81 RUQ pain US Lt IHDS Lt IHDS Not T-tube ChT 16 months F Lt liver multiple checked and Bx died IHCC 2 37 RUQ pain US, CT, Lt IHDS Klatskin s Not Bx 20 months F Fever ERCP with CCC tumour checked died Jaundice (type IV) 3 75 RUQ pain US GB CBD Lt IHDS 4438 T-tube ChT 18 months F Jaundice stone, Both liver and Bx died Lt IHDS IHCC 4 70 RUQ pain CT Lt IHDS with Lt IHDS 2400 Palliative LH 5 months F Fever chronic Lt liver multiple died cholangitis IHCC 5 61 RUQ pain US Lt IHD stone Lt IHDS Not Curative LLS 36 months F Lt liver IHCC checked alive 6 59 RUQ pain US, CT, Lt IHDS Lt IHDS Not Palliative LH 5 months F Fever ERCP Lt liver IHCC Lt liver IHCC checked died 7 55 RUQ pain US,CT Lt IHDS Lt IHDS 5079 Curative LLS 2 months M Jaundice Lt liver IHCC Lt liver IHCC recurrence; 6 months died 8 46 RUQ pain US,CT Rt IHDS Rt IHDS 460 Curative LH 4 months M Lt liver IHCC Lt liver IHCC recurrence; 2 months died RUQ = right upper quadrant; US = abdominal ultrasonography; IHDS = intrahepatic duct stone; IHCC = intrahepatic cholangiocarcinoma; ChT = choledochostomy; Bx = biopsy; CT = computed tomography; ERCP = endoscopic retrograde cholangiopancreaticogram; LH = left hepatectomy; LLS = left lateral sectionectomy. proportion of patients who were diagnosed with IHCC during the evaluations and treatment for IHDS was relatively high at 10%. The most important factors that contribute to stone formation are bile stasis and bacterial infection in the bile duct. 18 Some investigators have described the association between IHDS and IHCC to be due to mechanical injury from intrahepatic calculi or chemical irritation to the bile duct wall by infected bile. 19 Other studies 20,21 have reported that recurrent cholangitis caused by IHDS results in the development of atypical epithelium which may give rise to cancerous lesions. In our study, we examined some livers with IHDS and those with IHCC that had atrophic features. Several reports in which the features of IHDS have been described have shown that the most common presenting symptoms were associated with acute cholangitis because a large portion of the liver with IHDS was affected by stenosis in the bile duct. 22,23 In some studies comparing patients with only IHDS and those with IHDS accompanied by IHCC, 6,24,25 there were no significant differences in clinical characteristics between these two groups, but the features and locations of stones in addition to the levels of tumour markers have been shown to be discriminating factors. In our study, there was no difference between the clinical features and characteristics of stones evaluated in the DS and the CC groups. With regard to radiologic evaluation, our results show no difference in the frequency of usage of US, ERCP, CT. Chen et al 26 reported that a hyperechoic mass found in the liver parenchyma by US should be considered to be an IHCC. However, because the use of US is insufficient for 10 ASIAN JOURNAL OF SURGERY VOL 32 NO 1 JANUARY 2009

CHOLANGIOCARCINOMA ASSOCIATED WITH IHDS the diagnosis of cholangiocarcinoma, percutaneous transhepatic cholangiogram or endoscopic retrograde cholangiography should be considered for early diagnosis. Kubo et al 24 reported that portography can be used as an effective technique for the diagnosis of hepatic atrophy and cholangiocarcinoma. Obstruction of the portal vein represents the deterioration of hepatic tissue and suggests the presence of cholangiocarcinoma. Recent report presented the helical CT scans was useful for diagnosis of cholangiocarcinoma in patients with hepatolithiasis using specific CT criteria including the periductal soft tissue density, bile wall thickening, duct enhancement on portal venous phase and lymph node enlargement. 27 Therefore, periodic CT scans after treatment of hepatolithiasis should be performed in order to detect early the occurrence of cholangiocarcinoma. No specific tumour markers are available for the diagnosis of cholangiocarcinoma. However, an increase in the level of CA 19-9 is more frequently encountered than other tumour marker like carcinoembryonic antigen (CEA). 28 Su et al 29 reported that CA 19-9 levels were increased in seven of nine patients with cholangiocarcinoma and intrahepatic duct stones. We found a high level of CA 19-9 in four patients in the CC group. However, because some patients in the DS group had a level that was as high as that of the patients who had the malignancy, and other laboratory findings were not different between the two groups, it is difficult to predict whether an accompanying malignancy exists in patients having IHDS. As a result, surgeons who treat patients with IHDS using operative methods should examine carefully for cancerous lesions. In the past, most surgeons who operated on patients diagnosed with IHDS would not consider hepatic resection, since there was little knowledge between IHCC and IHDS and hepatic resection was regarded as a very risky procedure. Because of advancements in hepatic surgery, liver resection has become an option for the removal of IHDS to treat bile duct strictures and hidden malignancy. Otani et al 30 reported that the recurrence rates of IHDS and cholangitis were significantly reduced by hepatic resection, and another study showed that hepatic resection for hepatolithiasis could be performed safely with meticulous management of biliary tract abnormalities. 31,32 We performed a liver resection in 31 cases (43%) in the IHDS group; the most common operation type was the left lateral sectionectomy. Based on previously published reports, 33,34 the indications for hepatic resection included atrophy and fibrosis of a liver segment, the possibility of concomitant IHCC, or localised IHDS with biliary stricture. We performed liver resections according to the above indications. Hepatic resection, in our study, was performed in patients with left IHDS more frequently than in patients with right IHDS. Right liver resection was performed in only one patient who had severe atrophic changes in the right lobe of the liver; this was because of the high surgical risk of this procedure. 35 Recently, however, the use of right hepatectomy has been increasing for the treatment of selected patients with isolated right-sided IHDS. 36 In conclusion, our series showed there were no positive clinicopathologic or laboratory factors to predict concomitant IHCC in IHDS patients. However, in several patients, we could achieve curative resection of malignant liver lesions. Therefore, surgeons performing operations for IHDS patients should examine them thoroughly for hidden malignancies. In addition, due to the possibility of hidden malignant lesions, aggressive resection should be performed in suspicious portions of the liver. Acknowledgements The authors especially thank Dr. Sung-A Kim for helping us collect data for this paper. References 1. Chijiiwa K, Yamashita H, Yoshida J, et al. Current management and long-term prognosis of hepatolithiasis. Arch Surg 1995;130: 194 7. 2. Sanes S, MacCallum J. Primary carcinoma of the liver: cholangiocarcinoma in hepatolithiasis. Am J Pathol 1942;18: 675 83. 3. Chijiiwa K, Ichimiya H, Kuroki S, Koga A, et al. Late development of cholangiocarcinoma after the treatment of hepatolithiasis. Surg Gynecol Obstet 1993;177:279 82. 4. Sheen-Chen SM, Chou FF, Eng HL. Intrahepatic cholangiocarcinoma in hepatolithiasis: a frequently overlooked disease. J Surg Oncol 1991;47:131 5. 5. Tsunoda T, Furui J, Yamada M, et al. Caroli s disease associated with hepatolithiasis: a case report and review of the Japanese literature. Gastroenterol Jpn 1991;26:74 9. 6. Kim YT, Byun JS, Kim J, et al. Factors predicting concurrent cholangiocarcinomas associated with hepatolithiasis. Hepatogastroenterology 2003;50:8 12. 7. Vauthey JN, Maddern GJ, Blumgart LH. Adult polycystic disease of the liver. Br J Surg 1991;78:524 7. ASIAN JOURNAL OF SURGERY VOL 32 NO 1 JANUARY 2009 11

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