You are in: eMedicine Specialties > General Surgery > Abdomen Bile Duct TumorsArticle Last Updated: Aug 2, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 12
  Author: Carol E H Scott-Conner, MD, PhD, Professor, Department of Surgery, University of Iowa College of Medicine Carol E H Scott-Conner is a member of the following medical societies: American Association for Cancer Research, American Association for the Surgery of Trauma, American Burn Association, American Cancer Society, American College of Gastroenterology, American College of Surgeons, American Medical Association, American Society for Gastrointestinal Endoscopy, Association for Academic Surgery, Association for Surgical Education, Association of VA Surgeons, Iowa Medical Society, Sigma Xi, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, Society of Critical Care Medicine, Society of Surgical Oncology, Society of University Surgeons, and Southeastern Surgical Congress Coauthor(s): Ravi Pokala Kiran, MBBS, MS, FRCS (Eng), FRCS (Glas), Staff Physician, Department of General Surgery, St Mary's Hospital; Naveen Pokala, MBBS, MS, FRCS, Staff Physician, Department of Surgery, Bronx Lebanon Hospital; Richard E Glass, MBBS, MS, FRCS, Consultant General and Gastrointestinal Surgeon, Department of Gastrointestinal and General Surgery, Princess Margaret Hospital, UK Editors: Marc D Basson, MD, PhD, MBA, Professor, Department of Surgery, Wayne State University School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Michael A Grosso, MD, Consulting Staff, Department of Cardiothoracic Surgery, St Francis Hospital; Paolo Zamboni, MD, Professor of Surgery, Chief of Day Surgery Unit, Chair of Vascular Diseases Center, University of Ferrara, Italy; John Geibel, MD, DSc, MA, Professor, Department of Surgery, Section of Gastrointestinal Medicine and Department of Cellular and Molecular Physiology, Yale University School of Medicine; Director of Surgical Research, Department of Surgery, Yale-New Haven Hospital Author and Editor Disclosure Synonyms and related keywords: bile duct cancer, cholangiocarcinoma, Klatskin tumor, cholangiocarcinoma of the hepatic duct bifurcation INTRODUCTIONSection 2 of 12
  Tumors of the biliary tract are uncommon but serious problems. The spectrum of lesions ranges from benign tumors, such as adenomas, to malignant lesions, such as adenocarcinomas. This discussion excludes tumors of the gallbladder, which are discussed separately. Most patients with such lesions present with jaundice due to obstruction of the biliary tree by the tumor. Because the tumors are generally small, standard imaging studies, such as ultrasound and computed tomographic scanning, may fail to show the lesion. These techniques may, however, provide a clue to the level of the obstruction and help exclude metastatic disease. Cholangiography via a transhepatic or endoscopic approach is required to define the biliary anatomy and extent of the lesion. Magnetic resonance cholangiography is a noninvasive alternative available in an increasing number of centers. The anticipated course of most cases of bile duct tumors includes recurrent biliary obstruction with infectious complications, local spread, and death in 6-12 months. Treatment depends on the site and extent of the lesion, and surgical resection improves survival and prognosis. History of the ProcedureTumors of the bile ducts have been recognized for over a century. Musser first reported 18 cases of primary extrahepatic biliary cancer. Sako et al found 570 cases of extrahepatic bile duct cancer when reviewing literature from 1935-1954. Malignancy of the intrahepatic bile ducts, on the other hand, was described more recently by Altmeir (1957), while Klatskin described cancer of the hepatic duct bifurcation in 1965. ProblemTumors of the bile duct are rare. They constitute about 2% of all cancers found at autopsy. Benign adenomas or papillomas are exceedingly rare compared to malignant tumors. Even benign tumors tend to recur after excision and have been reported to undergo malignant change. Patients usually present with jaundice. Occult gastrointestinal hemorrhage may occur. Cholangiocarcinoma is the most important primary tumor of the bile ducts. This may involve either the intrahepatic or the extrahepatic biliary ducts. The former variety is the second most common primary hepatic malignancy after hepatocellular carcinoma. Patients with intrahepatic cholangiocarcinomas (cholangiocellular carcinoma) have a poor prognosis, and the tumor metastasizes early. This tumor has been associated with thorotrast (an intravenous contrast medium used many years ago), ulcerative colitis, and sclerosing cholangitis, and surgery is the only chance of treatment. Bile duct cancer differs from gall bladder cancer in that it is distributed more evenly between males and females, and the course is more prolonged. All cholangiocarcinomas are slow growing, locally infiltrative, and metastasize late. FrequencyThe annual incidence of bile duct cancer in the United States is approximately 1 case per 100,000 people. In autopsy studies, the incidence varies from 0.01-0.46%. Bile duct cancer is more common in Israel, Japan, and in American Indians than in the general US population. The prevalence of carcinoma of the gall bladder and bile ducts in England and Wales is 2.8 cases per 100,000 females and 2 cases per 100,000 males. EtiologyThe risk factors for bile duct cancer include the following:
PathophysiologyBile duct tumors cause bile duct obstruction with biliary stasis and a consequent alteration of liver function tests. Prolonged biliary obstruction causes hepatocellular dysfunction, progressive malnutrition, coagulopathy, pruritus, renal dysfunction, and cholangitis. Pathogenesis of bile duct cancer Long-standing inflammation with the development of chronic injury is the final common pathway for tumorigenesis in the bile ducts in patients with preexisting inflammatory conditions. Parasitic organisms induce DNA changes and mutations through the production of carcinogens and free radicals and the stimulation of cellular proliferation of the biliary epithelium, which is thought to cause cancer. Bacterial-induced, endogenous, carcinogen-derived bile salts, such as lithocholate, also have been implicated in the pathogenesis. These implications are supported by the findings of some epidemiologic studies and the higher incidence in typhoid carriers. Point mutations in codon 12 of the K-ras oncogene are found in cholangiocarcinoma. Aneuploidy is found in hilar cholangiocarcinoma and is associated with neural invasion and a shorter survival. P53 protein is expressed particularly in high-grade mid duct and distal duct cholangiocarcinomas. Cholangiocarcinoma cells contain somatostatin receptor RNA, and cell lines have specific receptors. Cell growth is inhibited by somatostatin analogues. Radionuclide scanning with a labeled somatostatin analogue has detected cholangiocarcinomas. ClinicalPatients are typically elderly; the average age is 60-65 years. In contrast to carcinoma of the gall bladder, only a minor sex difference in incidence exists, with a very slight male preponderance. Symptoms
Examination findings
INDICATIONSSection 3 of 12
Indications for surgery include the following:
If the tumor is limited to the bifurcation of the hepatic ducts, a single lobe of the liver, or involves the portal vein or hepatic artery on the same side, the lesion may be resectable. Preoperative imaging is aimed at establishing whether a viable unit of liver that is large enough to maintain adequate liver function will remain after surgical removal of the tumor. The remaining liver tissue must contain a normal branch of both the portal vein and hepatic artery and also contain a bile duct large enough to anastomose to the bowel (see Media file 1). RELEVANT ANATOMYSection 4 of 12
The liver is an epithelial-mesenchymal outgrowth of the caudal part of the foregut with which it retains its continuity by the biliary tree. Hepatocytes in the liver are arranged in anatomic plates called hepatic laminae, which are lined by endothelium and separated from each other by hepatic sinusoids. Bile secreted by hepatocytes is collected in a network of canaliculi, which drain into hepatic ductules. In turn, the hepatic ductules join other ductules, forming the biliary tree. The main right and left hepatic ducts from the liver unite near the right end of the porta hepatis as the common hepatic duct, which descends for about 1 inch before being joined by the cystic duct to form the CBD. The common hepatic duct lies to the right of the hepatic artery and anterior to the portal vein. The CBD is 3 inches long and consists of 3 parts. The upper third lies in the free border of the lesser omentum anterior to the portal vein and to the right of the hepatic artery. The middle third lies behind the first part of the duodenum and slopes down to the right, eventually lying on the inferior vena cava. The lower third slopes down to the right behind the head of the pancreas, lying in a deep groove on the posterior surface of this organ. It opens, in common with the pancreatic duct, into the ampulla of Vater, which is situated in the second part of the duodenum. The hepatic ducts, upper and middle portions of the CBD, mainly are supplied with blood by rami from the cystic artery. In addition, the middle portion of the CBD is supplied by rami of the right hepatic and posterior superior pancreaticoduodenal arteries. The latter also supplies blood to the lower portion of the CBD. Veins from the upper portion of the biliary tree enter the liver, while those from the lower portion drain into the portal vein. In regard to lymphatic drainage, the upper portion of the biliary tree drains into the hepatic nodes, while the lower portion drains into the inferior hepatic and upper pancreaticosplenic nodes. Metastases from bile duct tumors can occur in lymph nodes lying along the common hepatic artery and the celiac axis and from distal lesions in the retropancreatic and superior mesenteric nodes. Anatomically, the upper third of the biliary tree extends from the confluence of the hepatic ducts to the level of the cystic duct, the middle third extends from the cystic duct to the upper part of the duodenum, and the lower third extends from that level to the papilla of Vater. The reported distribution of bile duct tumors is 55% in the upper third, 15% in the middle third, and 10% in the lower third. Of these tumors, 10% are diffuse. Tumors of the bifurcation of the hepatic ducts are classified by the Bismuth classification.
CONTRAINDICATIONSSection 5 of 12
WORKUPSection 6 of 12
Lab Studies
Imaging Studies
Diagnostic Procedures
Histologic FindingsThe tumor is typically quite small (see Media file 2); 95% are adenocarcinomas of varying differentiation. Grossly, the tumor may be nodular, papillary, or present as a stricture (scirrhous variety). The nodular tumors form extraductal nodules in addition to intraluminal projections. The papillary variety most commonly is found in the distal bile duct and may fill the duct lumen with friable vascular neoplastic tissue, which may cause hemobilia. The scirrhous variety usually is confined to the hilar area and forms grey annular thickenings with clear defined edges. Distinguishing this variant from sclerosing cholangitis occasionally is difficult, even on histological grounds. Microscopically, the tumor usually is a mucin-secreting adenocarcinoma with a cuboidal or columnar epithelium, and spread along neural sheaths may be noted. The scirrhous variety is intensely fibrotic and relatively acellular, often with a few well-differentiated ductal cancer cells grouped as acini in a dense connective tissue stroma. Rare types include squamous cell carcinoma, adenosquamous carcinoma, adenoacanthoma, mucoepidermoid carcinoma, cystadenocarcinoma, granular cell carcinoma, lymphoma, carcinoid tumors, and melanoma. Malignant smooth muscle tumors of the bile duct and nonsecreting apudomas of the hilar region also have been reported. Immunohistochemistry and molecular biological studies show that in addition to CEA, many tumors also stain positively for the carbohydrate antigens CA 50 and CA19-9. Some recent reports also have identified mutations in K-ras oncogenes in 60-70% of both intrahepatic and perihilar bile duct cancers. Further studies have identified abnormalities on chromosomes 5 and 17 and documented the presence of c-erb oncogenes, epidermal growth factors, and proliferating nuclear antigens. The diagnosis of bile duct cancers may be supported by positive findings in 2 of the 3 indicators, which are a positive reaction to CEA, nuclear size variation, and the formation of distended intracytoplasmic lumina. Neural invasion is another histologic finding that confirms a diagnosis of bile duct cancer. StagingStaging is performed by the (primary) tumor, (regional lymph) node, (remote) metastases (TNM) system of classification.
Stages are as follows:
TREATMENTSection 7 of 12
Medical therapyMedical therapy is indicated in patients who are unfit for surgery and in patients with unresectable tumors. Jaundice and itching can be reduced with the placement of an endoprosthesis across strictures either endoscopically or percutaneously. Endoscopic techniques for relief of obstruction include sphincterotomy, balloon dilatation of the stricture, and the placement of stents. Expandable larger metal stents have better patency rates than plastic stents and include Metal-Palmaz, Strecker, Gianturco Z stent, and Wall stents. Percutaneous transhepatic endoprosthetic insertion also is successful, but an increased risk of complications, such as blood and bile leakage, exists. Of stents, 90% can be placed by a combination of endoscopic and percutaneous techniques after a failed endoscopic attempt. Chemotherapy has been tried in these patients but has not been proven to be of definite benefit. Radiotherapy may be administered by external beam therapy; intraoperative radiotherapy using biliary stents with iridium (Ir 192), radium, or cobalt (Co 60); radioimmunotherapy using sodium iodide (I 131) anti-CEA as a component of therapy; or charged particle irradiation. Internal radiotherapy may be combined with biliary drainage, but the value is unproven. Pain may be relieved with the injection of 50% alcohol for chemical splanchnicectomy. Surgical therapyResection is the best treatment and provides the best palliation. Benefits of resection include the possibility of cure or long-term survival, especially for patients with distal tumors. Resection is the best palliation in terms of duration and freedom from infectious complications. The type of surgical procedure performed depends on the site and extent of the disease. Proximal tumors (Klatskin tumors) may be managed by a variety of techniques, including the following:
Following resection of the bile duct, which may be combined with hepatic resection, reconstruction can be performed by unilateral or bilateral hepaticojejunostomy using transhepatic stents. Surgical exploration is indicated in patients who are fit for surgery when preoperative evidence of metastases is absent or when locally unresectable disease exists. If metastases are detected at the time of surgical exploration, bilateral stents that may have been placed preoperatively are left in situ, and cholecystectomy is performed to prevent the subsequent development of acute cholecystitis. Locally advanced and unresectable perihilar tumors also can be managed by Roux-en-Y cholecystodochojejunostomy with intraoperative placement of silastic biliary catheters or a segment III or V cholangiojejunostomy. Mid duct tumors can be managed by bile duct resection and Roux-en-Y reconstruction. Distal tumors may be amenable to Whipple resection (radical pancreaticoduodenectomy) (see Media file 3) or pylorus-preserving pancreaticoduodenectomy. Unresectable tumors may be managed by cholecystectomy, a Roux-en-Y hepaticojejunostomy, or choledochojejunostomy proximal to the tumor, and additional gastrojejunostomy and chemical sympathectomy are considered. Reconstruction involves anastomosis of bile ducts to a loop of jejunum (see Media file 4). Palliation Surgical bypass is indicated in patients in whom placing a stent by either endoscopic or percutaneous techniques is impossible and in patients who are found to have unresectable disease or metastases at exploration. Bypass may be performed by either a Roux-en-Y hepaticojejunostomy with intraoperative placement of a silastic transhepatic stent or a segment III bypass to the left intrahepatic ducts. In patients with distal bile duct tumors, the operation of choice is biliary enteric bypass using the upper end of the extrahepatic bile duct or gall bladder. Consider prophylactic gastrojejunostomy in these patients because a proportion of these patients may develop gastroduodenal obstruction prior to death. Bypass is less commonly required as stents have improved, and even duodenal obstruction can now be effectively palliated. Preoperative detailsStaging of the disease is determined by evaluating findings of CT scan and MRI. Delineation of the tumor and extent may be assessed by cholangiography (endoscopic and transhepatic) and magnetic resonance cholangiography. Vascular involvement can be identified and assessed by CT scan, MRI, and angiography as previously described (see Imaging Studies). Patient risk for surgery and anesthesia is determined, and cardiac and pulmonary assessment is performed. If the clinical condition of the patient does not rule out surgical intervention, the resectability and extent of tumor involvement are assessed, and metastases are sought. Low and mid bile duct tumors usually are resectable if angiography and venography exclude vascular invasion. Cancer of the hilar region tends to be less amenable to resection. At surgery, further assessment is performed with intraoperative ultrasound and a search for lymph node involvement. Intraoperative detailsLaparoscopy can be useful in the identification of metastases and peritoneal disease and, hence, may assist in assessing resectability. Intraoperative ultrasonography also is useful and may be combined with laparoscopy. Exploratory laparotomy is performed in patients who are fit for surgery and who are without any definite evidence of metastases or unresectability on preoperative investigation. One half of these patients are found to have evidence of intraperitoneal dissemination of the tumor or extensive involvement of the porta hepatis; hence, they are candidates for minimal intervention, including bypass. Postoperative detailsThese patients are at risk for the development of general complications, including pneumonia, deep venous thrombosis, and infection. Routine perioperative antibiotic prophylaxis and coagulopathy are administered. Active physiotherapy, breathing exercises, and early ambulation are encouraged. Complications specific to the procedure performed include anastomotic leak and bile leakage. Stents may be placed across anastomoses and removed after cholangiography confirms the absence or healing of leak. Follow-upPatients who have evidence of positive tumor margins after resection and patients who develop recurrence may be candidates for adjuvant radiotherapy. This usually takes the form of extracorporeal therapy for positive surgical margins and intraluminal radiotherapy for positive duct margins. Chemotherapy has not been shown to be of benefit. COMPLICATIONSSection 8 of 12
Postoperative complications may be general or local. General complications include the following:
Technical complications related to the procedure performed include the following:
Complications arising from the placement of stents include the following:
OUTCOME AND PROGNOSISSection 9 of 12
The choice of treatment and the prognosis are influenced greatly by the location of the tumor. Prognosis is better for distal bile duct tumors, histologically differentiated, and polypoidal tumors. Factors that suggest poor prognosis include involvement of lymph nodes, vascular invasion, advanced T stage, positive tumor margins of the resected specimen, and the presence of mutations of P53 gene. With hilar cholangiocarcinoma, the overall resection rate in most series varies form 40-60%. The mean survival for patients undergoing curative resection is 67-80% at 1 year and 11-21% at 5 years. Local resection has a lower operative mortality rates (8%) than major hepatic resection (15%), with a mean survival of 21 months compared to 24 months for major hepatic resections. No clear indication exists that survival is improved significantly by major hepatic resection when compared to local bile duct resection, though some studies suggest that hepatic resection is associated with a greater incidence of tumor-free margins and, consequently, survival. In distal bile duct cancers, the resection rate is more than 60%, and the prognosis is better than for hilar tumors, the mean survival being 39 months. Percentage survival varies from 50-70% at 1 year to 17-39% at 3 years. Diffuse intrahepatic tumors have a dismal prognosis, and most patients with these tumors die within a year of diagnosis. If left untreated, 50% of patients with bile duct cancer may survive for 1 year, 20% may survive for 2 years, and 10% may survive for 3 years. FUTURE AND CONTROVERSIESSection 10 of 12
The role of adjuvant radiotherapy and chemotherapy is controversial. The use of hormones in treatment, including somatostatin analogues, cholecystokinin, and cholecystokinin antagonists, currently is being investigated. Preoperative ERCP with biliary drainage in patients with tumors of the bile duct has been suggested to increase the risk of implantation metastases after resection of the tumor. Therefore, preoperative radiotherapy is advocated in such patients, but the benefit has not been proven definitely. Transarterial chemoembolization (TACE), infusion of 5-fluorouracil into the hepatic artery or bile ducts, and percutaneous injection of ethanol (PEI) into the lesions are other modalities that are investigational. Photodynamic therapy may be useful in relieving obstruction, especially when obstruction occurs as a result of tumor outgrowth into an endoprosthesis. Liver transplantation, when performed for cholangiocarcinoma, is associated with poor survival. MULTIMEDIASection 11 of 12
REFERENCESSection 12 of 12
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