Japanese Journal of Clinical Oncology 31:107-111 (2001)
© 2001 Foundation for Promotion of Cancer Research
Is Preventive Resection of the Extrahepatic Bile Duct Necessary in Cases of Pancreaticobiliary Maljunction Without Dilatation of the Bile Duct?
Department of Surgery, Tokyo Medical University, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: No consensus has been reached on whether preventive resection of the extrahepatic bile duct is necessary in cases of pancreaticobiliary maljunction (PBM) without dilatation of the extrahepatic bile duct (undilated type).
Methods: Sixty-eight patients with PBM underwent corrective surgery and several clinical characteristics and pathological findings including K-ras point mutation were evaluated.
Results: Unlike dilated bile duct, none of the patients with undilated type duct had clinical symptoms in early childhood. In patients with either cystic or spindle type duct, amylase levels in the bile duct were >104 U/l, whereas those in patients with undilated type duct were <104 U/l. Postoperative scintigraphy of the biliary system of undilated type revealed no evidence of cholestasis. After surgery, eight patients with undilated type duct, in whom the bile duct had been preserved, had no further clinical symptoms and no evidence of malignancy. Bile duct tissue specimens revealed no hyperplasia, dysplasia or cancerous lesions and they had no K-ras mutation in undilated type.
Conclusion: The results showed that there was little bile stasis, injury to the mucosa was mild and less genetic changes could be seen in patients with undilated type duct. Therefore, in patients without dilatation of bile duct and advanced cancer, cholecystectomy alone is sufficient.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Pancreaticobiliary maljunction (PBM) is a congenital anomaly frequently associated with malignancy of the biliary tract caused by continuous regurgitation of pancreatic juice into the biliary tract (1,2). To prevent carcinogenesis, therefore, surgical therapy, such as resection of the gallbladder or extrahepatic bile duct or both, is performed in diagnosed cases of PBM regardless of whether malignancy exists. However, for cases of PBM without dilatation of the extrahepatic bile duct, the optimal treatment is controversial. Some investigators believe that both the extrahepatic bile duct and the gallbladder must be resected in these cases (3,4), whereas others believe that cholecystectomy is sufficient because associated bile duct carcinoma is extremely rare in cases without dilatation (5,6). In the present study, we classified cases of PBM according to the form of the extrahepatic duct and compared cases with and without dilatation on the basis of clinical characteristics, including the frequency of associated malignancy, the amylase level in bile and the presence of K-ras point mutations. We also investigated whether preventive resection of extrahepatic duct is necessary in cases of PBM without dilatation or malignancy.
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MATERIALS AND METHODS |
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The subjects were 68 patients with PBM who had undergone corrective surgery from 1986 through 1998 in the Department of Surgery, Tokyo Medical University Hospital. All the patients underwent endoscopic retrograde cholangiopancreatography (ERCP) or intraoperative cholangiography to diagnose PBM. Cases of PBM were classified into three types, cystic type (n = 37), spindle type (n = 19) and (3) undilated type (n = 12), according to type of extrahepatic duct by the diagnostic criteria of the Japanese Study Group on Pancreaticobiliary Maljunction. Extrahepatic ducts measuring
10 in maximum diameter were considered ‘dilated’ and those <10 mm were considered ‘undilated’. We investigated the clinical characteristics, amylase levels of bile in 29 patients compared with those in the control group (10 patients with gallstones but without PBM were used) and postoperative scintigraphy of bile duct in seven patients with undilated type duct.
We examined histopathologically specimens from 47 gallbladders and 37 bile ducts, of which the epithelium had no mechanical damage due to surgery or no severe inflammatory degeneration. After staining with hematoxylin and eosin, the epithelium was classified into normal, hyperplastic, dysplastic and cancerous epithelium and the incidence of each type was determined.
Point mutations of the K-ras gene at codon 12 were detected with enzyme-linked mini-sequence assay (7). For each type of bile duct dilatation and histology of the epithelium, the incidence of K-ras mutation in cancerous and in non-cancerous epithelium was examined and they were compared with the patient’s age at operation.
Tests for differences in age at operation and the incidence of K-ras mutation in different types of epithelium were performed with Student’s t-test and Fisher’s exact probability test, respectively (StatView 4.0, Abacus Concepts, USA). Differences with P < 0.05 were considered significant.
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RESULTS |
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Twenty-six of 37 patients with cystic type duct, four of 19 patients with spindle type duct and none of the patients with undilated type duct had clinical symptoms in early childhood. All patients with undilated type duct were found to have PBM after 20 years of age. Age at operation was 37.9 ± 14.8 years in cystic type, 56.5 ± 8.5 years in spindle type and 49.2 ± 11.1 years in undilated type, which showed significant differences between each group. Biliary carcinoma was associated with PBM in six patients with cystic type duct (five in the gallbladder, one in the bile duct), six patients with spindle type duct and six patients with undilated type duct (all in the gallbladder). During the period of observation from 2.8 years to 16.3 years, eight patients with undilated type, in whom the bile duct had been preserved, had no further clinical symptoms and no evidence of malignancy.
Amylase levels of bile in all control subjects were <102 U/l in the gallbladder and the bile duct. In all patients with PBM, amylase levels in the gallbladder were elevated to 104–106 U/l regardless of bile duct form. In patients with either cystic or spindle type duct, amylase levels in the bile duct were also 104–106 U/l, whereas those in patients with undilated type duct were 102–104 U/l (Fig. 1). Scintigraphy of the biliary system, which was performed 6–12 months after surgery in seven patients with undilated type duct, revealed that the transition of radioisotope from the bile duct into the duodenum was rapid and that there was no evidence of cholestasis as seen in patients with dilated ducts.
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).Pathological features on resected specimens are summarized in Table 1. A high incidence of hyperplasia was found in the gallbladder regardless of bile duct form. One of 24 cases with cystic type duct and two of 15 cases with spindle type duct showed dysplasia, which was always located near the gallbladder cancer. However, bile duct tissue specimens revealed no dysplasia or cancerous lesions in any type of PBM except one case of bile duct cancer with cystic type. The incidence of hyperplasia was lower in the bile duct than in the gallbladder. All specimens of bile duct in undilated type consisted of normal epithelium with no hyperplasia, dysplasia or cancerous lesion.
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The incidence of K-ras point mutation at various types of epithelium is shown in Table 1. Seven of 15 specimens of hyperplasia in bile duct and one specimen of bile duct cancer could not be amplified for PCR. The incidence of K-ras point mutation ranged from 15 to 30% at each epithelium and no significant differences were recognized among types of epithelium.
The K-ras point mutation in cancerous and non-cancerous lesions according to age at operation is shown in Figure 2. K-ras mutations were not found in children younger than 4 years, but were found in patients aged over 4 years. Cancerous epithelium was detected in patients older than 40 years and the total incidence of K-ras point mutation in cancerous epithelium of the gallbladder was four (33.3%) of 12 lesions. The rate of K-ras mutation on the gallbladder in patients younger than 15 years (pediatric) and those older than 15 years (adult) were as follows: (1) in cases with cystic type duct, one (11.1%) of nine pediatric patients and one (8.3%) of 12 adult patients; (2) in cases with spindle type duct, three (75%) of four pediatric patients, three (42.9%) of seven adult patients; (3) in the cases of undilated type duct, there were no mutations in four adult patients. The rate of K-ras mutation on the bile duct were as follows; (1) in cases with cystic type duct, one (10%) of 10 pediatric patients and two (14.3%) of 14 adult patients; (2) in cases with spindle type duct, one (33.3%) of three children and four (50%) of eight adults; (3) in cases with undilated type duct, there was no mutation in only three adults. The incidence of K-ras mutation in the bile duct and the gallbladder in cases with spindle type duct was slightly but not significantly higher in both pediatric and adult patients than in cases with cystic or undilated type duct. There was also no significant difference in the incidence of mutation between pediatric and adult patients.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PBM is a congenital anomaly of the pancreas and biliary system, which is more common in Japan than in Western countries (8–10). In PBM, enzymes of pancreatic juice regurgitated into the biliary duct are activated by infectious bile juice. These activated enzymes cause injury to the biliary mucosa (11,12), which induces epithelial hyperplasia or metaplasia as the mucosa regenerates repeatedly. As a result, the risk of associated biliary tract carcinoma is increased. Thus, PBM is considered a natural carcinogenic model. PBM was first reported by Arnolds in an autopsy case of a choledochal cyst with a biliary tract of abnormal shape and a long common channel (13). Subsequently, ERCP, introduced in the 1970s, showed that the bile duct was not always dilated in cases of PBM. Some reports suggest that cases with dilated ducts and those with undilated type duct should not be treated identically because of their clinicopathological differences. Therefore, no consensus has been reached on how to treat the extrahepatic bile duct in PBM, especially in cases without dilatation of bile duct (3–6).
Cases of PBM with undilated type duct rarely produce clinical symptoms in childhood and they are usually not diagnosed until adulthood. Azuma et al. speculated that there might be many asymptomatic cases of PBM with undilated type duct (5). The differences in clinical symptoms are believed to be due to differing degrees of biliary stasis. Moreover, our analysis of amylase levels in the biliary tract and of postoperative scintigraphic images revealed that bile stasis in the bile duct of cases with undilated type duct was extremely slight. These findings suggest that cases with undilated type duct differ in character from cases with dilated ducts.
To investigate the risk of carcinogenesis in patients with PBM, the Japanese Study Group on Pancreaticobiliary Maljunction conducted a national questionnaire survey in 1995 of 12 399 patients without PBM who underwent biliary surgery as controls and 569 patients with PBM (14). In this study, many patients with PBM associated with cystic choledochal dilatation began to show symptoms of PBM from childhood to middle age and had undergone surgery before the development of biliary cancer. In patients who grew up without symptoms, the risk of developing gallbladder cancer and cholangiocarcinoma increased with age. In contrast, few patients with non-cystic type duct underwent surgery during childhood, but many later underwent surgery for cholelithiasis, cholangitis or other benign conditions. Gallbladder carcinoma developed frequently in cases with PBM; however, the incidence of bile duct carcinomas in cases of PBM with non-cystic type duct was lower than in cases with cystic type duct regardless of patient age and was almost equal to that in control cases. Because the questionnaire cases with non-cystic type duct included both cases with undilated type duct and those with spindle type ducts, the survey did not directly compare cases with dilated ducts and those with undilated type duct. However, the survey did find that the difference in the incidence of bile duct carcinoma was not increased in cases with non-cystic type duct and without significant bile stasis. The above findings suggested that resection of the extrahepatic bile duct was not required in cases without bile duct dilatation. Our results were consistent with those of the above questionnaire.
Continuous bile stasis and pancreatic juice reflux induces various histopathological changes in patients with PBM, including inflammation, hyperplasia, metaplasia and dysplasia. In this study, we found that almost all gallbladder tissues in patients with PBM showed hyperplasia and that dysplasia was often present around gallbladder carcinomas. Based on these findings, we speculated that carcinogenic processes in PBM might involve a hyperplasia–dysplasia–carcinoma sequence. Although the number of cases with undilated type duct was small in our study, hyperplasia, dysplasia or cancerous lesion was not detected in these cases. Hence, histopathological changes of the mucosa in undilated cases seemed to decrease with less severe bile stasis.
Recent progress in molecular biology has enabled various oncogenes to be analyzed; therefore, the mechanism of carcinogenesis in PBM has gradually started to become clear. Several investigators have pointed out that K-ras mutations were detected in non-cancerous epithelium, including hyperplasia, metaplasia or inflammation, and such non-cancerous epithelium with mutations might represent a premalignant state from a genetic standpoint. Funabiki et al. considered that resection of the extrahepatic bile duct is necessary for cases with undilated type duct, because they detected K-ras mutations on non-cancerous bile duct epithelium in 57% of such cases (15). However, in the present study, K-ras mutation was not detected in non-cancerous gallbladder or bile duct epithelium in cases with undilated type duct and the incidence of K-ras mutation from non-cancerous epithelium in adults with dilated ducts was not significantly different from that in children. If an increase in the duration of injury to the bile duct epithelium can increase the number of genetic alterations, the incidence of K-ras mutation might increase with age in patients with PBM. However, our present findings suggest that the incidence of K-ras mutation is not correlated with the duration of epithelial injury due to regurgitation of pancreatic juice. In colon cancer, for example, K-ras mutation is considered an early event in tumorigenesis and carcinogenesis itself is believed to require multistep genetic changes (16). However, Tanno et al. concluded that K-ras mutation was not an early event of carcinogenesis on the basis of their findings that two of nine cases with high-grade hyperplasia had K-ras mutations and that none of the cases with the low-grade hyperplasia had mutations of the K-ras gene (17). Carcinogenic processes in patients with PBM are rarely based upon the adenoma–carcinoma sequence as found in colon cancer and the role of the K-ras gene is believed to vary among tumors. Because K-ras mutations have been detected even in mucous-producing pancreatic tumors and mucus hyperplasia of the pancreatic duct (18,19), K-ras mutations are obviously not immediately and directly connected with carcinogenesis. Thus, whether preventive resection of an extrahepatic bile duct is necessary cannot be determined only on the basis of data on K-ras mutations.
Surgical treatment of patients with PBM but without cancer is based on the idea of preventing carcinogenesis. Our study showed that in cases without dilatation, there was little bile stasis, even after regurgitation of pancreatic juice, injury to the mucosa was mild and the association with bile duct carcinoma was weak. Hence, in patients without dilatation of bile duct and advanced cancer, cholecystectomy alone is sufficient at the time of diagnosis, but long-term follow up for bile duct cancer is required.
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FOOTNOTES |
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+ For reprints and all correspondence: Tatsuya Aoki, Department of Surgery, Tokyo Medical University, 6–7–1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
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Received September 19, 2000; accepted December 11, 2000.
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