Extrahepatic Bile Duct Cancer

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of extrahepatic bile duct cancer.

Extrahepatic Bile Duct Cancer

General Information

Cancer arising in the extrahepatic bile duct is an uncommon disease, curable by surgery in fewer than 10% of all cases.¹ Prognosis depends in part on the tumor’s anatomic location, which affects its resectability. Total resection is possible in 25% to 30% of lesions that originate in the distal bile duct, a resectability rate that is clearly better than for lesions that occur in more proximal sites.²

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 fluke, Clonorchis sinensis.³ The most common symptoms caused by bile duct cancer are jaundice, pain, fever, and pruritus.

In most patients, the tumor cannot be completely removed by surgery and is incurable. Palliative resections or other palliative measures such as radiation therapy (e.g., brachytherapy or external-beam radiation therapy) or stenting procedures may maintain adequate biliary drainage and allow for improved survival. Many bile duct cancers are multifocal. Perineural invasion has a negative impact on survival.^4,

¹ Henson DE, Albores-Saavedra J, Corle D: Carcinoma of the extrahepatic bile ducts. Histologic types, stage of disease, grade, and survival rates. Cancer 70 (6): 1498-501, 1992.

² Stain SC, Baer HU, Dennison AR, et al.: Current management of hilar cholangiocarcinoma. Surg Gynecol Obstet 175 (6): 579-88, 1992.

³ de Groen PC, Gores GJ, LaRusso NF, et al.: Biliary tract cancers. N Engl J Med 341 (18): 1368-78, 1999.

⁴ Bhuiya MR, Nimura Y, Kamiya J, et al.: Clinicopathologic studies on perineural invasion of bile duct carcinoma. Ann Surg 215 (4): 344-9, 1992.

Cellular Classification

The term, cholangiocarcinoma, is sometimes used to refer to any primary cancer of the biliary system; however, its use is often restricted to intrahepatic tumors and, therefore, it is not included in this summary. Adenocarcinomas are the most common type of extrahepatic bile duct cancers. The histologic types are listed below:^1,

• Carcinoma in situ.
• Adenocarcinoma, not otherwise specified (NOS).
• Adenocarcinoma, intestinal type.
• Mucinous adenocarcinoma.
• Clear cell adenocarcinoma.
• Signet-ring cell carcinoma.
• Adenosquamous carcinoma.
• Squamous cell carcinoma.
• Small cell (oat cell) carcinoma.
• Undifferentiated carcinoma.
  • Spindle and giant cell types.
  • Small cell types.
• Papillomatosis.
• Papillary carcinoma, noninvasive.
• Papillary carcinoma, invasive.
• Carcinoma, NOS.

Malignant mesenchymal tumors, although rare, include the following:

• Embryonal rhabdomyosarcoma.
• Leiomyosarcoma.
• Malignant fibrous histiocytoma.

¹ Extrahepatic bile ducts. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 145-150.

Stage Information

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

From a clinical and practical point of view, extrahepatic bile duct cancers can be considered to be localized (resectable) or unresectable. This has obvious prognostic importance.

Localized extrahepatic bile duct cancer

Patients with localized extrahepatic bile duct cancer have cancer that can be completely removed by the surgeon. These patients represent a very small minority of cases of bile duct cancer and usually are those with a lesion of the distal common bile duct where 5-year survival rate of 25% may be achieved. Extended resections of hepatic duct bifurcation tumors (Klatskin’s tumors) to include adjacent liver, either by lobectomy or removal of portions of segments 4 and 5 of the liver, may be performed. There has been no randomized trial of adjuvant therapy for patients with localized disease. Radiation therapy (external-beam radiation with or without brachytherapy), however, has been reported to improve local control.^1,2,[Level of evidence: 3iiiDii]

Unresectable extrahepatic bile duct cancer

Patients with unresectable extrahepatic bile duct cancer have cancer that cannot be completely removed by the surgeon. These patients represent the majority of patients with bile duct cancer. Often the cancer invades directly into the portal vein, the adjacent liver or along the common bile duct, and to adjacent lymph nodes. Spread to distant parts of the body is uncommon but intra-abdominal metastases, particularly peritoneal metastases, do occur. At this stage patient management is directed at palliation.

The TNM staging system should be used when staging the disease of a patient with extrahepatic bile duct cancer. Most cancers are staged following surgery and pathologic examination of the resected specimen. Evaluation of the extent of disease at laparotomy is most important for staging.

Staging depends on imaging, which often defines the limits of the tumor, and surgical exploration with pathologic examination of the resected specimen. In many cases, it may be difficult to completely resect the primary tumor.

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.³ Stages defined by TNM classification apply to all primary carcinomas arising in the extrahepatic bile duct or in the cystic duct and do not apply to intrahepatic cholangiocarcinomas, sarcomas, or carcinoid tumors.^3,

TNM definitions

Primary tumor (T)
• TX: Primary tumor cannot be assessed
• T0: No evidence of primary tumor
• Tis: Carcinoma in situ
• T1: Tumor confined to the bile duct histologically
• T2: Tumor invades beyond the wall of the bile duct
• T3: Tumor invades the liver, gallbladder, pancreas, and/or unilateral branches of the portal vein (right or left) or hepatic artery (right or left)
• T4: Tumor invades any of the following: main portal vein or its branches bilaterally, common hepatic artery, or other adjacent structures, such as the colon, stomach, duodenum, or abdominal wall

Regional lymph nodes (N)
• NX: Regional lymph nodes cannot be assessed
• N0: No regional lymph node metastasis
• N1: Regional lymph node metastasis

Distant metastasis (M)
• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis

AJCC stage groupings

Stage 0
• Tis, N0, M0

Stage IA
• T1, N0, M0

Stage IB
• T2, N0, M0

Stage IIA
• T3, N0, M0

Stage IIB
• T1, N1, M0
• T2, N1, M0
• T3, N1, M0

Stage III
• T4, any N, M0

Stage IV
• Any T, any N, M1

¹ Kopelson G, Galdabini J, Warshaw AL, et al.: Patterns of failure after curative surgery for extra-hepatic biliary tract carcinoma: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 7 (3): 413-7, 1981.

² Minsky BD, Wesson MF, Armstrong JG, et al.: Combined modality therapy of extrahepatic biliary system cancer. Int J Radiat Oncol Biol Phys 18 (5): 1157-63, 1990.

³ Extrahepatic bile ducts. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 145-150.

Treatment Option Overview

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

Localized Extrahepatic Bile Duct Cancer

In a minority of cases, proximal bile duct cancer can be completely resected. Cures are not often achieved in these patients, in contrast to patients with tumors arising in the distal bile duct, for whom a 5-year survival may be achieved in as many as 25% of patients.

Standard treatment options:

1. Surgery. The optimum surgical procedure for carcinoma of the extrahepatic bile duct will vary according to its location along the biliary tree, the extent of hepatic parenchymal involvement, and the proximity of the tumor to major blood vessels in this region. It is important to assess the state of the regional lymph nodes at the time of surgery because proven nodal involvement may preclude potentially curative resection. It should be fully recognized that operations for bile duct cancer are usually extensive and have a high operative mortality (5%-10%) and low curability. Cases with cancer of the lower end of the duct and regional lymph node involvement may warrant an extensive resection (Whipple procedure), but bypass operations or endoluminal stents are alternatives if lymph nodes are clinically involved by the cancer.¹

   In jaundiced patients, percutaneous transhepatic catheter drainage or endoscopic placement of a stent for relief of biliary obstruction should be considered before surgery, particularly if jaundice is severe or an element of azotemia is present. 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 (Klatskin’s tumors) that can be resected.^1,2,3,

2. External-beam radiation. External-beam radiation therapy has been used in conjunction with surgical resection.⁴

¹ Shutze WP, Sack J, Aldrete JS: Long-term follow-up of 24 patients undergoing radical resection for ampullary carcinoma, 1953 to 1988. Cancer 66 (8): 1717-20, 1990.

² Bismuth H, Nakache R, Diamond T: Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 215 (1): 31-8, 1992.

³ Pinson CW, Rossi RL: Extended right hepatic lobectomy, left hepatic lobectomy, and skeletonization resection for proximal bile duct cancer. World J Surg 12 (1): 52-9, 1988.

⁴ Cameron JL, Pitt HA, Zinner MJ, et al.: Management of proximal cholangiocarcinomas by surgical resection and radiotherapy. Am J Surg 159 (1): 91-7; discussion 97-8, 1990.

Unresectable Extrahepatic Bile Duct Cancer

Patients with unresectable extrahepatic bile duct cancer have cancer that cannot be completely removed by the surgeon. These patients represent the majority of cases of bile duct cancer. Often a proximal bile duct cancer invades directly into the adjacent liver or into the hepatic artery or portal vein. Portal hypertension may result. Spread to distant parts of the body is uncommon, though transperitoneal and hematogenous hepatic metastases do occur with bile duct cancers of all sites. Invasion along the biliary tree and into the liver is common.

Standard treatment options:

• These patients cannot be cured, but relief of bile duct obstruction is warranted when symptoms such as pruritus and hepatic dysfunction outweigh other symptoms from the cancer. Such palliation can be achieved by anastomosis of the bile duct to the bowel or by the placement of bile duct stents by operative, endoscopic, or percutaneous techniques.^1,2 Palliative radiation therapy after biliary bypass or intubation may be beneficial for some patients. If a percutaneous catheter has been placed, it can be used as a conduit for placement of sources for brachytherapy.^3,4 Patients with unresectable tumors should be considered for inclusion in clinical trials whenever possible.

Treatment options under clinical evaluation:

1. Patients with unresectable disease can be considered candidates for inclusion in clinical trials that explore ways to improve the effects of radiation therapy with various radiation sensitizers such as hyperthermia, radiosensitizer drugs, or cytotoxic chemotherapeutic agents.
2. Patients with unresectable disease can be considered candidates for phase I and II studies of chemotherapeutic agents or biologics. Fluorouracil, doxorubicin, and mitomycin have been reported to produce transient partial remissions in a small proportion of patients. Other drugs and drug combinations await evaluation.^5,

Information about ongoing clinical trials is available from the NCI Web site.

¹ Nordback IH, Pitt HA, Coleman J, et al.: Unresectable hilar cholangiocarcinoma: percutaneous versus operative palliation. Surgery 115 (5): 597-603, 1994.

² Levy MJ, Baron TH, Gostout CJ, et al.: Palliation of malignant extrahepatic biliary obstruction with plastic versus expandable metal stents: An evidence-based approach. Clin Gastroenterol Hepatol 2 (4): 273-85, 2004.

³ Fritz P, Brambs HJ, Schraube P, et al.: Combined external beam radiotherapy and intraluminal high dose rate brachytherapy on bile duct carcinomas. Int J Radiat Oncol Biol Phys 29 (4): 855-61, 1994.

⁴ Shin HS, Seong J, Kim WC, et al.: Combination of external beam irradiation and high-dose-rate intraluminal brachytherapy for inoperable carcinoma of the extrahepatic bile ducts. Int J Radiat Oncol Biol Phys 57 (1): 105-12, 2003.

⁵ Hejna M, Pruckmayer M, Raderer M: The role of chemotherapy and radiation in the management of biliary cancer: a review of the literature. Eur J Cancer 34 (7): 977-86, 1998.

Recurrent Extrahepatic Bile Duct Cancer

The prognosis for any treated cancer patient with progressing, recurring, or relapsing extrahepatic bile duct cancer is poor. Deciding on further treatment depends on many factors, including prior treatment and site of recurrence, as well as individual patient considerations. Relief of recurrent jaundice will usually improve quality of life. Clinical trials are appropriate and should be considered when possible.^1,2 Information about ongoing clinical trials is available from the NCI Web site.

¹ Bartlett DL, Ramanathan RK, Deutsch M: Cancer of the biliary tree. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1009-31.

² Nordback IH, Pitt HA, Coleman J, et al.: Unresectable hilar cholangiocarcinoma: percutaneous versus operative palliation. Surgery 115 (5): 597-603, 1994.

Changes to This Summary (09/20/2005)

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.

Updated Cancer: Principles and Practice of Oncology from the 6th to the 7th edition in the corresponding sections.

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