Cancers of the biliary tract account for 5,000 new cancer cases and 4,300 deaths annually in the U.S. Though rare in the U.S. and elsewhere, the incidence is elevated in native and Hispanic Americans, parts of Eastern Europe, Central and South America, and rising notably in Shanghai, China. Little is understood about the etiology and a variety of possible risk factors will be evaluated.

Key hypotheses include: possible risks associated with a history of gallstones, bacterial infection of the biliary tract, other medical history, diet, use of tobacco and alcohol, obesity, reproductive factors, and family history of cancer. Information about possible risk factors will be used to examine risk patterns a) separately by anatomic subsite, b) among cancer patients vs. controls undergoing cholecystectomy, and c) to ascertain reasons for the rising incidence.

Using the population-based cancer registry to establish the target case population, a rapid reporting system will be set up and approximately 585 cases (including about 210 males and 375 females, including as estimated 345 patients with gallbladder cancer, 166 with extrahepatic bile duct cancer, and 74 with cancer arising in the ampulla of Vater) will be identified from 30-35 collaborating hospitals during a 3-year period. Cases will be compared with 600 population controls randomly selected using residence lists, but frequency-matched to cases on age and sex. Also, cases will be compared with 600 hospital patients treated for gallstones (including approximately 300 undergoing cholecystectomy and 300 treated nonsurgically).

In-person interviews will ascertain information on demographic characteristics, diet, tobacco and alcohol use, body size, reproductive factors and related treatments, other medical and family history. Blood specimens (20 ml) will be collected for biochemical and molecular analyses. Bile fluid, fresh tissue, and gallstones will be collected from as many cancer cases and cholecystectomy controls for microbiological and future molecular studies. Abdominal ultrasound examinations performed on population controls will ascertain gallstone status.

Serum collected from all subjects will be analyzed for estrogens and other hormones, vitamins C and E, cholesterol, and bacterial antibodies (including salmonella typhi, paratyphi, and escherichia coli). The file fluid will be cultured for aerobic an anaerobic bacteria, and gallstones analyzed fro color, cholesterol, and evidence of bacterial infection.

With 585 cases and 600 controls, the study will have 90% power to detect differences as small as 10-15 percent between cases and controls in levels of serum estrogens at a significance level of 0.95 (2-sided). Also, odds ratios between 1.4 and 2/0 (lowest quartile vs. highest quartile) will be detectable for most dietary, reproductive, and key medically-related factors.