Cancers of the Gallbladder and Biliary Ducts

July 1, 2002

Dr. Yee and his colleagues have offered a comprehensive overview of the epidemiology, diagnosis, and therapy of both gallbladder carcinoma and cholangiocarcinoma. They correctly note the infrequency of these two neoplasms, with approximately 7,500 cases diagnosed in the United States each year, two-thirds of which are gallbladder cancer. Unfortunately, neither the incidence rate nor prognosis of these neoplasms has changed substantially since biliary tumors were last reviewed in this journal[1]; the median 5-year survival rate has remained at 5%. Some progress has been made, however, in our understanding of the etiology of cancers of the biliary tract, and a body of literature continues to emerge exploring the question of how best to approach screening and prophylaxis in high-risk populations.

Dr. Yee and his colleagues have offered a comprehensiveoverview of the epidemiology, diagnosis, and therapy of both gallbladdercarcinoma and cholangiocarcinoma. They correctly note the infrequency of thesetwo neoplasms, with approximately 7,500 cases diagnosed in the United Stateseach year, two-thirds of which are gallbladder cancer. Unfortunately, neitherthe incidence rate nor prognosis of these neoplasms has changed substantiallysince biliary tumors were last reviewed in this journal[1]; the median 5-yearsurvival rate has remained at 5%. Some progress has been made, however, in ourunderstanding of the etiology of cancers of the biliary tract, and a body ofliterature continues to emerge exploring the question of how best to approachscreening and prophylaxis in high-risk populations.

Risk Factors for Gallbladder Cancer

As Yee et al discuss, while its pathogenesis has yet to be fully delineated,some risk factors for biliary tract carcinoma have been identified.Cholelithiasis has been widely recognized as a factor that predisposes towardits development, especially if the gallstones are symptomatic and large.[2]"Porcelain gallbladder" or calcification of the gallbladder wallpredicts a high risk of concurrent or future gallbladder cancer. An anomalouspancreaticobiliary ductal junction, a congenital defect most common amongAsians, is closely connected with gallbladder cancer; 15% to 40% of patientswith this anomaly go on to develop the malignancy.[3]

Other links have been made between gallbladder cancer and bacterialinfections of the biliary tract, most notably Salmonella typhi and,intriguingly, bile-resistant Helicobacter spp. Some investigators have attemptedto identify biochemical changes in the composition of bile that may predisposeto metaplasia. Although early data suggested that patients with gallstones andgallbladder cancer possess a higher biliary concentration of lithocholate—aknown carcinogen—than do patients with gallstones but no concomitantmalignancy, subsequent data have failed to confirm this.[4]

Whether one or more of these factors contributes to the striking geographicand ethnic differences identified by Yee et al in gallbladder cancer incidencerates is unclear, but the suggestions posited by preliminary data merit furtherinvestigation. Less clear are the potential roles of estrogens and tobacco inthe etiology of gallbladder cancer. Some case-control and observational serieshave identified them as risk factors, but the incidence of gallbladder cancer isnot higher than predicted among patients who have developed other more clearlydefined tobacco- and estrogen-associated tumors.[5]

Risk Factors for Cholangiocarcinoma

High-risk populations for cholangiocarcinoma have been identified as well.Patients with gallstones are also at increased risk for cholangiocarconoma,although less so than for gallbladder cancer. However, other patient populationsare at far greater risk. Notably, patients with primary sclerosing cholangitishave a lifetime risk of at least 10% (some have reported this risk to exceed30%). Patients with ulcerative colitis in the absence of primary sclerosingcholangitis are at increased risk of developing cholangiocarcinoma as well, asare those with rarer conditions, including Caroli’s disease, multiple biliarypapillomatosis, exposure to thorium dioxide (Thorotrast), and, in endemicregions, infestation with the trematodes Clonorchis sinensis or Opisthorchisviverrini.

Screening Techniques

Although the low incidence of these malignancies in the general populationrenders broad screening programs impractical, identification of the abovehigh-risk groups raises the question of whether focused screening may befeasible. The need for screening is made all the greater, as Yee et al discuss,because the greatest chance for cure lies with early diagnosis or prevention.

Many have looked at potential markers, either in bile or serum, forcholangiocarcinoma. The best studied serum marker is CA 19-9. This has beenfound, either alone or in combination with carcinoembryonic antigen (CEA), tooffer a sensitivity and specificity of 85% to 90% in the diagnosis ofcholangiocarcinoma among patients with primary sclerosing cholangitis.

Although endoscopic retrograde cholangiopancreatography (ERCP) remains thediagnostic test of choice, small studies have shown that magnetic resonancecholangiopancreatography (MRCP) possesses adequate sensitivity, particularlywhen used in conjunction with pharmacologic stimulation with secretin.[6]Potentially interesting are the early data on positron-emission tomograpy (PET)scanning in cholangiocarcinoma. On PET scan, the malignancy presents as a"hot spot" when as small as 1 cm, while the local liver parenchyma isdark. One recent small study comparing the modality to ERCP and definitivepathology found PET to have a 92% sensitivity and 92% specificity forcholangiocarcinoma.[7] Clearly, further data need to be collected, potentiallycombining the use of serum markers and radiographic investigation in an attemptto make early diagnosis possible for the high-risk patient.

Similarly, hope for improved early diagnosis of gallbladder cancer may alsoexist. Screening for gallbladder cancer is much less often discussed in theliterature, perhaps due to the relative simplicity of cholecystectomy, andparticularly in light of the widespread experience with this laparoscopicprocedure. Traditional imaging modalities, such as transabdominal ultrasound andcomputed tomography (CT) scanning, are too nonspecific, struggling todifferentiate between benign and malignant polyps, and too insensitive to thediagnosis of this early spreading tumor to serve as feasible screeningmodalities.

Recent increased experience with the use of endoscopic ultrasound holdspromise in the diagnosis of gallbladder cancer because it offers dramaticallyimproved resolution of the gallbladder lumen relative to transabdominal imagesand allows for simultaneous ultrasound-guided biopsy of suspicious lesions.Although no formal recommendation for serial endoscopic ultrasonographicexamination yet exists, it is possible that such a program may offer a minimallyinvasive option for at-risk individuals.

Prophylactic Cholecystectomy

As mentioned, screening for gallbladder cancer is often obviated by theavailability of prophylactic cholecystectomy. It is well accepted that some ofthe risk factors for gallbladder cancer, such as porcelain gallbladder, arestrong indications for cholecystectomy. Others recommend surgery for gallbladderpolyps larger than 1 cm with any associated qualities characteristic ofmalignancy—ie, a polyp that is solitary, sessile, or echopenic.

Less well defined is the role of prophylactic surgery among patients withgallstones as their only risk factor. Given that among all American patientswith asymptomatic gallstones, the annual incidence rate of gallbladder cancer isbetween 0.01% and 0.02%—far below the mortality rate of 0.5% for laparoscopiccholecystectomy—no recommendation can be made for prophylaxis.

However, patients at increased risk for other reasons—either ethnicdifferences (Native Americans, Mexican-Americans, or Chileans) or patients withlarge (³ 3 cm) gallstones—may represent groups of patients that would benefitfrom prophylaxis. Indeed, since some studies cite a cumulative lifetimeincidence of gallbladder cancer among these at-risk groups approaching 4%, therisks of cholecystectomy may be outweighed by the potential benefits of cancerprevention.

Conclusions

In conclusion, although the ability to cure advanced disease in thesemalignancies remains frustratingly poor, our understanding of their epidemiologycontinues to evolve. The impetus now is to further study how best to parlay thisunderstanding into a focused and informed effort to screen for or surgicallyprevent biliary tract carcinoma. Through continued investigation into advancedimaging techniques (including MRCP, PET, and endoscopic ultrasound), throughclarification of the utility of known tumor markers and identification of new,more precise markers, and through continued elucidation of the true risks forthe development of biliary tract tumors among various populations, we can hopeto continue to make progress in the prevention and treatment of thesemalignancies.

References:

1. Abi-Rached B, Neugut AI: Diagnostic and management issues in gallbladdercarcinoma. Oncology 9:19-24, 1995.

2. Kahn ZR, Neugut AI, Ahsan H, et al: Risk factors for biliary tractcancers. Am J Gastroenterol 94:149-152, 1999.

3. Sheth S, Bedford A, Chopra S: Primary gallbladder cancer: Recognition ofrisk factors and the role of prophylactic cholecystectomy. Am J Gastroenterol95:1402-1410, 2000.

4. Strom BL, Soloway RD, Rios-Dalenz JL, et al: Biochemical epidemiology ofgallbladder cancer. Hepatology 23:1402-1411, 1996.

5. Yu S, Ahsan H, Neugut AI: The association between biliary tract cancer andcancers of other sites. Am J Gastroenterol 94:2256-2262, 1999.

6. Barish MA, Yucel EK, Ferrucci JT: Magnetic resonancecholangiopancreatography. N Engl J Med 341:258-264, 1999.

7. Kluge R, Schmidt F, Caca K, et al: Positron-emission tomography with[(18)F]fluoro-2-deoxy-D-glucose for diagnosis and staging of bile duct cancer.Hepatology 33:1029-1035, 2001.