Cholangiocarcinoma Developing 42-year afterCholedochoduodenostomy

Xia Dong, Zuo Huai-quan, Dong Hong-liang, Quan Yi, Xu Liang

1 Introduction

Anastomosis between the biliary tract and duodenum or jejunum has been, and is, a relatively common surgical procedure. Choledochoduodenostomy was widely performed for the treatment of benign biliary obstructions resulting from choledocholithiasis and inflammatory stricture, especially in the 1960s and 1970s, and was once generally regarded as a low risk procedure, aside from the potential for secondary cholangitis[1]. Refluxes of intestinal contents, activated pancreatic juice, and bacterial flora have been considered the possible causes of this complication. However, in recent years the number of reports of cholangiocarcinoma occurring in patients who many years previously had biliary-enteric drainage has been increasing, and cholangiocarcinoma has been suggested as a potential long-term complication of these surgical procedures[2-3].

We report here a case of a 68-year-old woman who developed a cholangiocarcinoma 42-year after choledochoduodenostomy and was treated by a curative resection with a temporal good postoperative course. To our knowledge, this patient presented the longest time interval from initial biliary-enteric drainage to occurrence of cholangiocarcinoma in all cases reported in English-language publications so far.

2 Case Report

In February 2005, a 68-year-old Chinese woman was admitted with a history of persistent post-prandial epigastralgia for 3 months and progressive jaundice for 5 days. 42 years before presentation, the patient had undergone a choledochoduodenostomy with cholecystectomy in 1963 because of choledocholithiasis.

On physical examination she was feverish and jaundiced with mild tenderness in the right upper quadrant, without rebound tenderness or rigidity. Investigation upon admission included the following: white blood cell, 14.4×109/L; total bilirubin, 245.5 μmol/L; direct billirin, 203.7 μmol/L; alanine aminotransferase, 71.7 IU/L; aspartate aminotransferase, 64.4 IU/L; alkaline phosphatase, 1 125 IU/L; carbohydrate-associated antigen 19-9 (CA 19-9), 1 320 IU/mL.

Gastroscopy revealed a tumor in the posterior wall of the duodenal bulb. A biopsied specimen revealed a well-differentiated adenocarcinoma. Barium contrast radiography clearly demonstrated enterobiliary reflux. Intravenous contrast-enhanced CT revealed cirrhosis and focal strictures of the biliary confluence and common bile duct.

Preoperatively, we assumed this tumor to be a bile duct carcinoma developing in the stoma of the choledochoduodenostomy, and this was soon testified by the later laparotomy. We then performed a pylorus-preserving pancreatoduodenectomy. On the resected specimen, a gray spherical tumor about 3.0 cm×3.0 cm×4.0 cm with moderate texture was seen to originate mainly in the mucosa of the bile duct of the choledochoduodenostomy and the duodenal mucosa was also partly affected.

Pathologically, the tumor consisted mainly of well differentiated adenocarcinoma with a small area of moderately differentiated carcinoma. Surgical margins were free of disease. The tumor invasion was limited to the adventitia and muscularis layers of the bile duct with metastasis of two lymph nodes in the hepatoduodenal ligament. The bile duct was thickened by fibrosis and infiltrated by inflammatory cells. Intestinal metaplasia with reactive epithelial atypia was noticed in the vicinity of the cancer. According to the UICC staging system the tumor was T3N1M0 classified as stage Ⅲ.

The patient was discharged on the 12th postoperative day without any serious complication. 11 months later the patient developed a peritoneal carcinosis with a CA19-9 of 2 750 IU/mL and succumbed.

3 Discussion

Some decades ago, choledochoduodenostomy and sphincteroplasty were performed frequently for benign biliary diseases, and the unfavorable repercussions of such procedures may become apparent in the near future. It remains to be verified whether the recent epidemiological data which have shown a steady increase in the incidence of cholangiocarcinoma in England and Wales since the early 1980s[4]corresponds to the popularity of choledochoduodenostomy 2 decades previously. In China, a retrospective study[5]concluded that choledochoduodenostomy is not an ideal approach to reduce postoperative reflux cholangitis and is not the best surgical selection in the management of hepatolithiasis. As a result, we believe that the evidence is strong enough to prompt a reappraisal of policies regarding these procedures.

Although the incidence of cholangiocarcinoma followed by previous biliary-enteric drainage procedures has been reported to be relatively low, Hakamada et al[6]in 1997 reported that 7.4% of patients had developed cholangiocarcinoma after transduodenal sphincteroplasty with a mean interval of 18 years. Tocchi et al[3]in 2001 also reported that the incidence of cholangiocarcinomas after transduodenal sphincteroplasty, choledochoduodenostomy, and Roux-en-Y hepaticojejunostomy in a cohort 1 003 patients was 5.8%, 7.6%, and 1.9%, respectively, with intervals of 11-18 years. Therefore, cholangiocarcinoma as a potential and delayed complication of transduodenal sphincteroplasty and choledochoenteric anastomosis has become a serious issue today.

The occurrence of cholangiocarcinoma many years following surgical biliary-enteric bypass should not be coincidental and it has raised the possibility of an aetiological link. Some causative factors have been reported concerning the etiology of biliary carcinoma. There is marked geographic variability in the prevalence of this disease, due in large part to regional environmental risk factors. In Eastern countries, intrahepatic cholangiocarcinomas have been shown to be regularly associated with hepatolithiasis[2]. Multiple factors such as mechanical irritation by calculi, bile stasis, cholangitis, bacterial infection, and liver fluke infestations seem to be common factors in the etiology of biliary carcinoma. Some data, however, point to a potential role for chronic liver disease, hepatitis C, and probably hepatitis B infections in the development of intrahepatic cholangiocarcinoma. A further specific and well-documented risk factor for biliary cancer is biliary cyst disease, which is almost always associated with the anomalous arrangement of the pancreatobiliary duct system[7]. This anomaly allows reflux of pancreatic juice into the biliary tree. Moreover, the pancreatic juice is transformed into its activated form by the admixture with bile and can play a critical role in carcinogenesis. Nevertheless, the same has not occurred in the West, where this malignancy has been most frequently reported unrelated to biliary lithiasis[8].

This dismal outcome may be due to the multifocal nature of the tumours, supporting the hypothesis of toxic carcinogenesis affecting the biliary epithelium, causing a field change. Recent experimental studies showed these changes in patients with choledochoenteric anastomosis to be a precancerous condition. Hyperplastic bile duct mucosa with metaplastic goblet cells and pyloric-like gland formation has been observed in patients with a choledochoduodenostomy and consequent long-standing cholangitis, which was interpreted as an adaptation to the new environment. Greatly accelerated cell kinetic activity of the biliary epithelium after biliary-enteric anastomosis in patients and hyperplasia, intestinal metaplasia and squamous pseudostratification of the bilary epithelium in rats were noticed and these morphological and functional differentiations were considered to be a major factor in promoting the development of biliary carcinomas. Also, aparting from those predisposing factors above, there must be susceptibility in these patients due to genetically altered enzymes that are involved in detoxifying carcinogenic products[9].

All reported cases succumbed within 9-12 months after surgery. This unfavorable prognosis is probably due to a delay in diagnosis because several main symptoms, after biliary-enteric drainage, usually tend to be treated conservatively based on the incorrect diagnosis of ascending cholangitis alone rather than considering the development of a carcinoma. Meanwhile, some unforeseeable events and the discrepancy between the length of the time from surgery to the diagnosis of cholangiocarcinoma and the usual duration of follow-up may have been responsible for the current poor outcomes. Anyway, precise preoperative diagnosis, assessment and aggressive surgery with hepatopancreatoduodenectomy may contribute to a longer survival[10].

Although a direct connection between the intestinal tract and biliary tract and reflux of activated pancreatic juice and intestinal bacteria into the biliary tract are considered as the factors causing chronic relapsing cholangitis, the latter has been suspected as a leading predisposing factor for the late development of cholangiocarcinoma. Although larger retrospective studies and prospective randomized trials are needed to establish the definitive risk for late biliary carcinogenesis after bilio-intestinal drainage, we still support the hypothesis that reflux of intestinal contents, bacterial translocation, and pancreatic juice can trigger biliary mucosal changes and the carcinogenesis process. As there are no markers to identify patients in the early stage of development of malignant transformation, we recommend that any patient treated with these procedures and experiencing relapsing cholangitis should be monitored carefully and routinely for the late development of bile duct cancer[8, 11].

[1] Olnes MJ, Erlich R. A review and update on cholangiocarcinoma[J]. Oncology, 2004, 66(3): 167-179.

[2] Bartlett DL. Intrahepatic cholangiocarcinoma: a worthy challenge[J]. Cancer J, 2009, 15(3): 255-256.

[3] Tocchi A, Mazzoni G, Liotta G, et al. Late development of bile duct cancer in patients who had biliary-enteric drainage for benign diseases: A follow-up study of more than 1,000 patients[J]. Ann Surg, 2001, 234(2): 210-214.

[4] Taylor-Robinson SD, Toledano MB, Arora S, et al. Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968-1998[J]. Gut, 2001, 48: 816-820.

[5] Ling XF, Xu Z, Wang LX, et al. Long-term outcomes of choledochoduodenostomy for hepatolithiasis[J]. Chin Med J, 2010, 123(2): 137-141.

[6] Hakamada K, Sasaki M, Endoh M, et al. Late development of bile duct cancer after sphincteroplasty: a ten-to twenty-two-year follow-up study[J]. Surgery, 1997, 121(5): 488-492.

[7] Strog RW. Late bile duct cancer complicating biliary-enteric anastomosis for benign disease[J]. Am J Surg, 1999, 177(6): 472-474.

[8] Padilla D, Cubo T, Pardo R, et al. Late development of cholangiocarcinoma after hepaticojejunostomy due to ampullary carcinoma[J]. Gut, 2004, 53(3): 472-473.

[9] Lee BI, Kim BW, Choi H, et al. Cholangiocarcinoma arising from a choledochoduodenal anastomosis without causing jaundice[J]. Gastrointest Endosc, 2004, 60(4): 659-661.

[10] Bettshart V, Clayton RAE, Parks RW, et al. Cholangiocarcinoma arising after biliary-enteric drainage procedures for benign disease[J]. Gut, 2002, 51(1): 128-129.

[11] Atsuyuki M, Shumpei Yi, Takao K, et al. Bile duct cancer developing 21 years after choledochoduo-denostomy[J]. Dig Surg, 2003, 20(4): 331-334.