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Cancer of the bile duct (also called cholangiocarcinoma) is extremely rare. The true incidence of bile duct cancer is unknown, however, because establishing an accurate diagnosis is difficult.
Traditionally, bile duct tumors located within the liver had been classified with hepatocellular carcinoma as primary liver tumors. In contrast, bile duct tumors located outside of the liver had been classified with gallbladder cancer as extrahepatic biliary tract tumors. The classification of bile duct tumors has changed to include intrahepatic tumors of the bile ducts and extrahepatic tumors (perihilar and distal) of the bile ducts.
Approximately 50% of cholangiocarcinomas arise in the bile ducts of the perihilar region; 40% arise in the distal region; and 10% arise in the intrahepatic region.
Many bile duct cancers are multifocal. In most patients, the tumor cannot be completely removed by surgery and is incurable. Palliative measures such as resection, radiation therapy (e.g., brachytherapy or external-beam radiation therapy), or stenting procedures may maintain adequate biliary drainage and allow for improved quality of life.
The biliary system consists of a network of ducts that carry bile from the liver to the small bowel and is classified by its anatomic location (Figure 1). Bile is produced by the liver and is important for fat digestion.
Intrahepatic bile duct
The bile ducts located within the liver are called intrahepatic bile ducts. Tumors of the intrahepatic bile ducts originate in small intrahepatic ductules or large intrahepatic ducts that are proximal to the bifurcation of the right and left hepatic ducts. These tumors are also known as intrahepatic cholangiocarcinomas.
Figure 1. Anatomy of the intrahepatic bile duct.
Extrahepatic bile duct
The bile ducts located outside of the liver are called extrahepatic bile ducts. They include part of the right and left hepatic ducts that are outside the liver, the common hepatic duct, and the common bile duct. The extrahepatic bile ducts can be further divided into the perihilar (hilum) region and distal region.
Figure 2. Anatomy of the extrahepatic bile duct.
Bile duct cancer may occur more frequently in patients with a history of primary sclerosing cholangitis, chronic ulcerative colitis, choledochal cysts, or infections with the liver fluke Clonorchis sinensis.
Distal and perihilar bile duct cancers frequently cause biliary tract obstruction, leading to the following symptoms:
Intrahepatic bile duct cancer may be relatively indolent and difficult to clinically differentiate from metastatic adenocarcinoma deposits in the liver.
Diagnostic and Staging Evaluation
Clinical evaluation is dependent on laboratory and radiographic imaging tests that include the following:
These tests demonstrate the extent of the primary tumor and help determine the presence or absence of distant metastases.
If a patient is medically fit for surgery and the tumor is amenable to surgical resection, surgical exploration is performed. Pathologic examination of the resected specimen is done to establish definitive pathologic staging.
Prognosis depends in part on the tumor's anatomic location, which affects its resectability. Because of its proximity to major blood vessels and diffuse extension within the liver, a bile duct tumor can be difficult to resect. Total resection is possible in 25% to 30% of lesions that originate in the distal bile duct; the resectability rate is lower for lesions that occur in more proximal sites.
Complete resection with negative surgical margins offers the only chance of cure for bile duct cancer. For localized, resectable extrahepatic and intrahepatic tumors, the presence of involved lymph nodes and perineural invasion are significant adverse prognostic factors.[4,5,6]
Additionally, the following have been associated with worse outcomes among patients with intrahepatic cholangiocarcinomas:[7,8,9]
Other PDQ summaries containing information related to bile duct cancer include the following:
Intrahepatic Bile Duct Cancer
The most common histopathologic types of intrahepatic bile duct tumor include the following:
Perihilar Bile Duct Cancer
Adenocarcinomas are the most common type of perihilar bile duct tumor. The histologic types of perihilar bile duct cancer include the following:
Distal Bile Duct Cancer
Adenocarcinomas are the most common type of distal bile duct tumors. The histologic types of distal bile duct cancer include the following:
Staging for Bile Duct Cancer
Bile duct cancer is classified as resectable (localized) or unresectable, with obvious prognostic importance. The TNM (tumor, node, metastasis) staging system is used for staging bile duct cancer, commonly after surgery and pathologic examination of the resected specimen. Evaluation of the extent of disease at laparotomy is an important component of staging.
AJCC Staging System for Bile Duct Cancer
AJCC staging system for intrahepatic bile duct cancer
The AJCC has designated staging by TNM classification to define intrahepatic bile duct cancer.
Tables 1, 2, 3, 4, and 5 pertain to the intrahepatic bile duct cancer stages.
AJCC staging system for perihilar bile duct cancer
The AJCC has designated staging by TNM classification to define perihilar bile duct cancer.
Tables 6, 7, 8, 9, and 10 pertain to the perihilar bile duct cancer stages.
AJCC staging system for distal bile duct cancer
The AJCC has designated staging by TNM classification to define distal bile duct cancer. Stages defined by TNM classification apply to all primary carcinomas arising in the distal bile duct or in the cystic duct; these stages do not apply to perihilar or intrahepatic cholangiocarcinomas, sarcomas, or carcinoid tumors.
Tables 11, 12, 13, 14, 15 pertain to the distal bile duct cancer stages.
The treatment of bile duct cancer depends primarily on whether the cancer can be completely removed by surgery.
Resectable (Localized) Bile Duct Cancer
Localized intrahepatic and extrahepatic bile duct cancer may be completely removed by surgery. These tumors represent a very small number of cases that are usually in the distal common bile duct. Among patients treated with surgical resection, long-term prognosis varies depending on primary tumor extent, margin status, lymph node involvement, and additional pathologic features.[1,2]
Extended resections of hepatic duct bifurcation tumors (Klatskin tumors, also known as hilar tumors) to include adjacent liver, either by lobectomy or removal of portions of segments 4 and 5 of the liver, may be performed. If major hepatic resection is necessary to achieve a complete resection, postoperative hepatic reserve should be evaluated. For patients with underlying cirrhosis, the Child-Pugh class and the Model for End-Stage Liver Disease score are determined.
Unresectable (Including Metastatic and Recurrent) Bile Duct Cancer
Most cases of intrahepatic, distal, and perihilar bile duct cancer are unresectable and cannot be completely removed by the surgeon. Often the cancer invades directly into the portal vein, the adjacent liver, along the common bile duct, and to adjacent lymph nodes. Portal hypertension may result from invasion of the portal vein. Spread to distant parts of the body is uncommon, but intra-abdominal metastases, particularly peritoneal metastases, do occur. Transperitoneal and hematogenous hepatic metastases also occur with bile duct cancer of all sites. Moreover, most patients who undergo resection will develop recurrent disease within the hepatobiliary system or, less frequently, at distant sites.
In locally advanced disease, phase II trials have evaluated chemoradiotherapy with the goal of improved local control and potential downstaging for surgical resection.[3,4] These approaches have not been compared with standard therapy, and the curative potential is unknown.
For patients with unresectable bile duct cancer, management is directed at palliation.
Treatment options for bile duct cancer are described in Table 16.
Standard treatment options for resectable (localized) bile duct cancer include the following:
Intrahepatic bile duct cancer
For intrahepatic bile duct cancers, hepatic resection to achieve negative margins is potentially curative. If a major liver resection is necessary to achieve negative surgical margins, preoperative portal vein embolization may be considered to optimize the volume of the remnant liver.
Partial liver resection or partial hepatectomy to achieve negative margins is a procedure with curative intent for patients with intrahepatic cholangiocarcinoma. The extent of liver resection necessary is dependent on the extent of hepatic parenchymal involvement and the proximity of the tumor to major blood vessels in this region.
The role of routine portal lymphadenectomy has not been well established because of the risk of common bile duct devascularization.
Perihilar bile duct cancer
For perihilar cholangiocarcinomas (Klatskin tumors), bile duct resection alone leads to high local recurrence rates resulting from the early confluence of the hepatic ducts and the caudate lobe. The addition of partial hepatectomy that includes the caudate lobe has improved long-term outcomes, but may be associated with increased postoperative complications. With this aggressive surgical approach, 5-year survival rates of 20% to 50% have been reported. An understanding of both the normal and varied vascular and ductal anatomy of the porta hepatis has increased the number of hepatic duct bifurcation tumors that can be resected.
The primary site of relapse after surgical resection is local; however, distant recurrence is also frequently reported.
The optimal surgical procedure for carcinoma of the perihilar bile duct varies according to the location of the tumor along the biliary tree, the extent of hepatic parenchymal involvement, and the proximity of the tumor to major blood vessels in this region. The state of the regional lymph nodes is assessed at the time of surgery because of their prognostic significance. Operations for bile duct cancer are usually extensive; a historical cohort reported an operative mortality rate of approximately 10%, along with roughly 40% risk of disease recurrence.
In jaundiced patients, the role of percutaneous transhepatic catheter drainage or endoscopic placement of a stent for relief of biliary obstruction is controversial because of inconsistent findings of significant clinical benefit and concerns of increased risk of postoperative complications. However, percutaneous transhepatic catheter drainage or endoscopic placement of a stent for relief of biliary obstruction may be considered before surgery, particularly if jaundice is severe or an element of azotemia is present.[7,8]
Distal bile duct cancer
Complete surgical resection with negative surgical margins offers the only chance of cure for distal bile duct cancers. Bile duct tumors can be difficult to resect because of their proximity to major blood vessels and diffuse infiltration of adjacent bile ducts. Total resection is possible in 25% to 30% of lesions that originate in the distal bile duct; the resectability rate is lower for lesions that occur in more proximal sites.
The optimum surgical procedure for carcinoma of the distal bile duct will vary according to the location of the tumor along the biliary tree, the extent of hepatic parenchymal involvement, and the proximity of the tumor to major blood vessels in this region. The regional lymph nodes are assessed at the time of surgery because they have prognostic significance. Patients with cancer of the lower end of the duct and regional lymph node involvement may warrant an extensive resection (Whipple procedure). The 5-year outcomes range between 20% and 50%.[10,11] Bypass operations or endoluminal stents are alternatives if intraoperatively the tumor is found to be unresectable.[10,11]
In jaundiced patients, the role of percutaneous transhepatic catheter drainage or endoscopic placement of a stent for relief of biliary obstruction is controversial, but may be considered before surgery, particularly if jaundice is severe or an element of azotemia is present.[7,8]
Numerous retrospective series have suggested that adjuvant chemotherapy after complete surgical resection may be beneficial.[12,13][Level of evidence: 3iiiDiii] However, prospective randomized trials have failed to show a significant benefit in overall survival (OS).
On the basis of these trials, there is no consistent trend in favor of adjuvant therapy in either RFS or OS.
(Refer to the Unresectable [Including Metastatic and Recurrent] Bile Duct Cancer Treatment section of this summary for a list of regimens with potential activity.)
External beam radiation therapy (EBRT)
Numerous retrospective studies have suggested that adding EBRT after complete surgical resection may be beneficial.[19,20][Level of evidence: 1iiA] However, no prospective randomized trials have demonstrated an OS benefit.
All patients are encouraged to enroll in clinical trials for adjuvant therapies. Information about ongoing clinical trials is available from the NCI website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Standard treatment options for unresectable (including metastatic and recurrent) bile duct cancer include the following:
Relief of biliary obstruction is warranted when symptoms such as pruritus and hepatic dysfunction outweigh other symptoms of the cancer. When possible, such palliation can be achieved with the placement of bile duct stents by operative, endoscopic, or percutaneous techniques.[1,2]
Palliative radiation therapy may be beneficial, and patients may be candidates for stereotactic body radiation therapy  and intra-arterial embolization.
Systemic chemotherapy is appropriate for selected patients with adequate performance status and intact organ function. The following agents have been reported to produce transient partial remissions in a minority of patients:
Pending further clinical trials, cisplatin plus gemcitabine is considered the reference standard for patients with unresectable, metastatic, or recurrent bile duct cancer. Potential alternatives include gemcitabine plus capecitabine, GEMOX, and XELOX. Clinical trials should be considered for all patients.
All patients with unresectable, metastatic, or recurrent disease should have molecular testing for deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H). Extrapolating from a subgroup of patients with gastrointestinal and hepatopancreatobiliary tumors in the I-PREDICT (NCT02534675) and KEYNOTE-158 (NCT02628067) studies, patients with either dMMR or MSI-H tumors can be considered for treatment with pembrolizumab.[7,8][Level of evidence: 3iiiDiv]
Clinical trials of investigational therapies should be considered for patients with targetable mutations.
Evidence (targeted therapy):
Patients with IDH1-mutated disease should be encouraged to enroll in a clinical trial.
In April 2020, the FDA granted accelerated approval for pemigatinib in the treatment of adults with previously treated unresectable or metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangement. The multicenter, open-label, single-arm phase II FIGHT-202 (NCT02924376) trial enrolled 107 patients with progression of disease on or after at least one previous therapy. All patients received pemigatinib 13.5 mg orally once daily for 14 consecutive days, followed by 7 days off therapy.[Level of evidence: 3iiiDiv]
Patients with FGFR2 fusion-positive disease should be encouraged to enroll in a clinical trial.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of bile duct cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Bile Duct Cancer (Cholangiocarcinoma) Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Bile Duct Cancer (Cholangiocarcinoma) Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/liver/hp/bile-duct-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389308]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
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Last Revised: 2020-07-28
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