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Malignancies of the biliary tract are uncommon in the United States, with approximately 8,000 cases reported annually; nearly two-thirds of these arise in the gallbladder, while the remainder (cholangiocarcinoma) originate from the bile ducts and periampullary region.Gallbladder carcinoma is diagnosed approximately 5,000 times a year in the United States, making it the most common biliary tract tumor and the fifth most common GI tract cancer. Approximately 4,500 cases of bile duct tumors occur each year in the United States.
Gender Bile duct tumors are found in an equal number of men and women.
Age Extrahepatic bile duct tumors occur primarily in older individuals; the median age at diagnosis is 70 years.
Ulcerative colitis is a clear risk factor for bile duct tumors. Patients with ulcerative colitis have an incidence of bile duct cancer that is 9-21 times higher than that of the general population. The risk does not decline after total colectomy for ulcerative colitis.
Other risk factors Primary sclerosing cholangitis, congenital anomalies of the pancreaticobiliary tree, and parasitic infections are also associated with bile duct tumors. No association of bile duct cancer with calculi, infection, or chronic obstruction has been found.
Jaundice is the most frequent symptom found in patients with high bile duct tumors; it is present in up to 98% of such patients.
Nonspecific signs and symptoms Patients who do not present with jaundice have vague complaints, including abdominal pain, weight loss, pruritus, fever, and an abdominal mass.
Cholangiocarcinoma may present earlier than gallbladder cancer by virtue of the development of biliary obstruction with jaundice, which may be painless. The goals of the diagnostic evaluation include the determination of the level and extent of obstruction, the extent of local invasion, and the identification of metastases.
Many patients with cholangiocarcinoma are thought to have metastatic adenocarcinoma of an unknown primary, although occasionally the metastatic lesion may produce biliary dilatation without the primary lesion itself being radiographically visualized.
Ultrasound It is generally accepted that ultrasonography should be the first imaging procedure in the evaluation of the jaundiced patient.
CT is a complementary test to ultrasonography, but both tests are accurate for staging in only 50% of patients and for determining resectability in < 45%.
Cholangiography is essential to determine the location and nature of the obstruction. Percutaneous transhepatic cholangiography (PTC) is used for proximal lesions and ERCP for distal lesions. Magnetic resonance cholangiopancreatography (MRCP) may replace invasive studies in the near future. Histologic confirmation of tumor can be made in 45%-85% of patients with the use of exfoliative or brush cytology during cholangiography.
Adenocarcinoma Morphologically, more than 90% of bile duct tumors are adenocarcinomas. Three macroscopic appearances have been identified: The papillary and nodular types occur more frequently in the distal bile duct, whereas the sclerosing type is found in the proximal bile duct. Papillary lesions have the best prognosis.
Other histologic types Unusual malignant diseases of the biliary tract include adenosquamous carcinoma, leiomyosarcoma, and mucoepidermoid carcinoma.
Route of spread Most bile duct tumors grow slowly, spreading frequently by local extension and rarely by the hematogenous route. Nodal metastases are found in up to one-third of patients.
Over 70% of patients with cholangiocarcinoma present with local extension, lymph node involvement, or distant spread.
Stage Survival for these patients is poor and is directly related to disease stage. Median survival is 12-20 months for patients with disease limited to the bile ducts and £ 8 months when the disease has spread.
Tumor location Survival is also related to tumor location, with distal lesions doing better than mid or proximal tumors.
Success of therapy Curative resections and negative margins result in improved survival.
SURGERY FOR THE BILE DUCT CANCER
Assessing resectability Higher resolution CT or MRI with biliary reconstruction may be supplemented with hepatic arteriography, portal venography, or duplex imaging preoperatively to assess resectability.
Preoperative treatments Three randomized trials have shown no benefit to preoperative decompression of the biliary tree in patients with obstructive jaundice. Some authors advocate the preoperative placement of biliary stents to facilitate dissection of the hilus. This should be performed immediately prior to resection to reduce the risk of cholangitis and maintain the duct at its maximally dilated size.
Proximal tumors Local excision is often possible for proximal lesions. Hepatic resection is indicated for high bile duct tumors with quadrate lobe invasion or unilateral intrahepatic ductal or vascular involvement. Resection is not indicated in situations in which a clear surgical margin cannot be obtained.
Mid-ductal and distal tumors Mid-ductal lesions can often be removed by skeletonization of the bile duct. Distal or mid-ductal lesions that cannot be locally excised should be removed by pancreaticoduodenectomy.
Reconstruction techniques Biliary-enteric continuity is usually reconstructed with a Roux-en-Y anastomosis to the hilum for high lesions and in a standard drainage pattern following pancreaticoduodenectomy.
Liver transplantation has been attempted for unresectable tumors, but early recurrence and poor survival have prevented the widespread application of this approach.
Surgical bypass For patients found to have unresectable disease at surgical exploration, operative biliary bypass may be performed using a variety of techniques. Bypass results in excellent palliation and obviates the need for further intervention.
ADJUVANT RADIATION THERAPY FOR BILIARY TRACT CANCER
Local recurrence after cholecystectomy for gallbladder cancer has been reported to occur in 86% of patients, who die within 5 years after surgery. Resected bile duct tumors have a 25% to 40% rate of local recurrence.
Despite these observations, there are no good prospective data to define the role of adjuvant treatment with radiation or chemoradiation. Given the role of adjuvant chemoradiation in pancreatic cancer, it would seem reasonable to recommend similar therapy for patients with resected biliary tract cancer if transmural invasion is present or the regional lymph nodes are involved.
TREATMENT OF UNRESECTABLE DISEASE
Like pancreatic adenocarcinoma, unresectable biliary tract carcinoma has a poor prognosis.
Most patients whose disease is deemed unresectable on preoperative evaluation will benefit from nonsurgical percutaneous or endoscopic stenting.
There are little data on radiation therapy for unresectable gallbladder cancer, other than reports of intraoperative radiation therapy. External-beam radiation therapy would be anticipated to provide a palliative benefit.
There is considerable experience using brachytherapy alone or combined with external-beam radiation for unresectable bile duct tumors. Median survival times range from 10 to 24 months and 5-year survival rates are approximately 10% with these approaches.
Due to the relative infrequency of biliary tract malignancies, only a limited number of clinical trials that describe chemotherapy regimens for advanced disease have been published. However, drug activity in these cancers appears to be similar to that in adenocarcinoma of the pancreas. Clearly, additional trials with larger numbers of patients are required to establish a role for chemotherapy in this disease.
5-FU historically has been the most active single agent, although response rates are on the order of 10%-15%, and there are no published reports of either prolonged infusional administration or modulation of 5-FU as a single agent.
Gemcitabine (Gemzar) shows promise as a new agent in the treatment of biliary tract cancers. In a recent phase II trial, 7 out of 19 patients had an objective response to gemcitabine therapy. Additional controlled trials of this agent are needed. Most responders had gallbladder cancer.
Other agents that have reported activity in biliary tract cancer are mitomycin, doxorubicin, and the nitrosoureas, although the numbers of patients are too small to reliably assess the rate of response.
Combination regimens Reports of combination chemotherapy regimens are likewise hampered by small numbers. The FAM (5-FU, Adriamycin, and mitomycin) regimen, as designed for gastric cancer, produced responses in 4 of 13 patients, while the combination of the 5-FU prodrug tegafur (Ftorafur), doxorubicin, and carmustine (BCNU [BiCNU]) produced responses in 3 of 7 patients.
More recent trials have involved larger numbers of participants. The combination of 5-FU, leucovorin, and mitomycin resulted in objective responses in 5 of 20 patients and produced stable disease in another 6 patients. The regimen was generally well tolerated but needs further study.
Another study combining a continuous infusion of 5-FU with cisplatin produced 6 partial remissions out of 24 patients, 1 of whom was still alive 6 years after the initiation of therapy.
Hepatic arterial chemotherapy There is limited experience with hepatic arterial chemotherapy for locally advanced or metastatic biliary tract disease, but there are case reports of responses in the literature.
Treatment recommendations In the absence of a clinical trial, patients should be offered gemcitabine or 5-FU, with or without leucovorin. Other agents, such as doxorubicin or cisplatin, may be added, but, as noted, there is no evidence that combination chemotherapy produces any substantial benefits in terms of improving a patients quality of life or survival.