Biliary tract cancers occur infrequently in the United
States. Approximately 7,500 new cases are diagnosed each year, consisting of
5,000 gallbladder cancers and 2,500 cholangiocarcinomas. Worldwide, they
represent a more significant health burden, with a high frequency in Chile and
parts of Asia.
The associated mortality rate in the United States is high, with
approximately 4,000 to 6,000 deaths annually. Few patients with unresectable
cholangiocarcinomas survive longer than 1 year, and the outlook for gallbladder
cancer patients is equally poor. The median survival for the latter is less than
6 months, and fewer than 5% survive 5 years. The roles of chemotherapy and
irradiation, particularly in the adjuvant setting, have not been well defined in
Epidemiology and Pathogenesis
Cholangiocarcinomas are cancers of the biliary tree. Extrahepatic tumors are
more common than tumors within the liver. Hilar cancers, also called Klatskin
tumors, are the most common, occurring approximately two to three times more
often than distal cholangiocarcinomas. Although more than 10 different
histologic subtypes of extrahepatic cholangiocarcinomas have been reported, over
98% are adenocarcinomas. Of the other histologic subtypes, papillary tumors
are rarely invasive (and thus have a favorable prognosis), whereas the
small-cell subtype metastasizes early and is nearly invariably fatal.
Little is known about the pathogenesis of adenocarcinomas except that these
tumors are associated with inflammation of the biliary system.
Cholangiocarcinomas express a receptor for interleukin (IL)-6, and exposure to
this cytokine stimulates tumor growth in vitro. They also express Fas ligand,
which induces apoptosis of lymphocytes, but they escape Fas-mediated
apoptosis by expressing an apoptosis inhibitor (I-FLICE). Thus,
cholangiocarcinomas can proliferate while avoiding the effector cells activated
by the inflammation-triggered immune response.
Risk factors for the development of cholangiocarcinoma are moderately well
characterized. Patients with primary sclerosing cholangitis have the highest
risk, with a 7% to 10% lifetime risk of developing this cancer. These tumors
also occur with increased frequency in patients with hepatitis C-related
cirrhosis, ulcerative colitis, and parasitic infestations. Although less
common than the association of hepatitis C and hepatocellular carcinoma, as many
as 2% of patients with the hepatitis C virus develop cholangiocarcinoma.
Environmental factors have also been associated with biliary tumors. An
increased incidence of cholangiocarcinomas is seen in patients exposed to the
contrast agent thorium dioxide (Thorotrast). Other chemical carcinogens
inducing this cancer include cigarette smoke, asbestos, radon, dioxin, and
Cholangiocarcinomas rarely present symptomatically until they are quite large
and cause obstruction of the biliary tract. Painless jaundice occurs in up to
90% of patients, with serum bilirubin often exceeding 10 mg/dL. Approximately
50% of patients experience weight loss. Obstruction caused by cholangiocarcinoma
can also result in the symptoms of cholangitis, manifesting as fever and right
upper quadrant abdominal pain. Unfortunately, none of these symptoms are
specific for neoplasm.
Screening and Early Detection
Due to the poor outcome of patients with advanced cholangiocarcinomas as well
as the fact that surgery can be curative in limited-stage disease, early
detection through a dedicated screening program could conceivably decrease
mortality. However, the rarity of biliary tumors makes this approach difficult.
Tumor markers have been considered because of their simplicity. The carbohydrate
antigen CA 19-9 is often elevated in the serum of patients with
A study from the Mayo Clinic compared the CA 19-9 levels of 9 patients with
primary sclerosing cholangitis and known cholangiocarcinoma to 28 control
patients with primary sclerosing cholangitis and no malignancy. In this
setting, CA 19-9 levels exceeding 100 U/mL were 89% sensitive and 86%
specific for the detection of cancer. Patients with cholangiocarcinoma without
primary sclerosing cholangitis have also been studied. A CA 19-9 level exceeding
100 U/mL also correlated with a diagnosis of cholangiocarcinoma in this
group. However, the sensitivity decreased to 50%.
Unfortunately both of these studies suffered from an imbalance in measured
serum bilirubin between cases and controls. Patients with cancer had a mean
serum bilirubin of 7.0 to 8.0 mg/dL, compared to controls, with a mean of
only 2.0 to 3.6 mg/dL. In nonmalignant processes, high CA 19-9 levels
correlate directly with increased bilirubin. Therefore, the sensitivity of
CA 19-9 would likely be lower than reported if better matched controls with
higher serum bilirubin levels were used.
Overall, no tumor marker studied to date has adequate sensitivity and
specificity to be recommended for general screening.
Cholangiocarcinoma may appear as an abdominal mass, hypoattenuated relative
to the liver, on computed tomography (CT) scans. The sensitivity of CT in
detecting this cancer is approximately 70%.[12,13] Although ultrasound is a less
expensive test, it is also much less sensitive, suggesting a diagnosis of cancer
in only 25% to 50% of cases. The primary use of ultrasound is to evaluate a
patient presenting with obstructive jaundice.
Cholangiography is a potentially helpful technique, with reported sensitivity
results ranging as high as 80% to 90%. It is useful in both defining the
location of the cholangiocarcinoma and determining whether a curative resection
can be performed. However, the specificity of cholangiography is only 62%
because it cannot always distinguish benign from malignant strictures.
Magnetic resonance cholangiopancreatography (MRCP) provides accurate
information about tumor extent, including vascular involvement.[14,15] MRCP in
conjunction with transcutaneous duplex ultrasound may soon replace other
modalities in the evaluation of resectability.
In the immediate preoperative period, percutaneous transhepatic
cholangiography may provide additional biliary ductal detail, facilitating the
placement of silastic stents that can help guide intraoperative dissection;
these stents may be left in place postoperatively to provide access to the
ductal system. However, prolonged biliary drainage with stents is not
advantageous and increases the incidence of infectious complication.
Due to their avid uptake of fluorodeoxyglucose, cholangiocarcinomas are very
conspicuous on positron-emission tomography (PET). Tumors as small as 1 cm
can be detected by PET. Although too costly for use as a general screening tool,
PET may prove useful in the evaluation of candidates being considered for
surgical resection and suspected of having nonlocalized disease.
Several different staging systems have been employed for biliary tract
cancers. Table 1 shows the tumor-node-metastasis (TNM) staging classification
developed by the 1998 American Joint Committee on Cancer (one of the more widely
used systems). Stage T1 and T2 disease can be cured with surgery, with 5-year
survival rates of 57% and 39%, respectively. Unfortunately, the cure rate
for T3 disease, with which most patients present, is significantly lower.
Involvement of the regional lymph nodes also results in poor survival. No
patients with N2 tumors and only 10% of patients with N1 tumors survive for 5
Another commonly used staging method is the Bismuth-Corlette system,
which classifies tumors by the extent of biliary duct involvement. This system
is preferred by many surgeons because it is said to be more clinically relevant.
However, neither the TNM nor the Bismuth-Corlette staging system reliably
predicts 5-year survival.
A more recently devised staging system has been proposed by Memorial
Sloan-Kettering Cancer Center. The T-stage classifications in this system
appear to correlate well with resectability and predict the need for
hepatectomy. Moreover, these clinical categories seem to be prognostic of 5-year
survival. If confirmed by other centers, this schema may become the preferred
clinical staging system.
1. Groen PC, Gores GJ, LaRusso NF, et al: Biliary tract cancers. N Engl J Med
2. Sheth S, Bedford A, Chopra S: Primary gallbladder cancer: Recognition of
risk factors and the role of prophylactic cholecystectomy. Am J Gastroenterol
3. Gallbladder and extrahepatic bile ducts, in Fleming J, Cooper J, Henson D,
et al (eds): AJCC Cancer Staging Handbook, pp 97-106. Philadelphia, Lippincott-Raven,
4. Park J, Tadlock L, Gores GJ, et al: Inhibition of interleukin 6-mediated
mitogen-activated protein kinase activation attenuates growth of a
cholangiocarcinoma cell line. Hepatology 30:1128-1133, 1999.
5. Que FG, Phan VA, Phan VH, et al: Cholangiocarcinomas express Fas ligand
and disable the Fas receptor. Hepatology 30:1398-1404, 1999.
6. Nichols JC, Gores GJ, LaRusso NF, et al: Diagnostic role of serum CA 19-9
for cholangiocarcinoma in patients with primary sclerosing cholangitis. Mayo
Clin Proc 68:874-879, 1993.
7. Chen MF, Jan YY, Hwang TL, et al: Impact of concomitant hepatolitiasis on
patients with peripheral cholangiocarcinoma. Dig Dis Sci 45:312-316, 2000.
8. Kobayashi M, Ikeda K, Saitoh S: Incidence of primary cholangiocellular
carcinoma of the liver in Japanese patients with hepatitis C virus-related
cirrhosis. Cancer 88:2471-2477, 2000.
9. Fong Y, Kemeny N, Lawrence TS: Cancer of the liver and biliary tree, in
DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of
Oncology, 6th ed, pp 1162-1203. Philadelphia, Lippincott Williams & Wilkins,
10. Patel AH, Harnois DM, Klee GG: The utility of CA 19-9 in the diagnoses of
patients without primary sclerosing cholangitis. Am J Gastroenterol 95:204-207,
11. Mann DV, Edwards R, Ho S: Elevated tumour marker CA 19-9: Clinical
interpretation and influence of obstructive jaundice. Eur J Surg Oncol
12. Campbell WL, Ferris JV, Holbert BL, et al: Biliary tract carcinoma
complicating primary sclerosing cholangitis: Evaluation with CT,
cholangiography, US, and MR imaging. Radiology 207:41-50, 1998.
13. de Bree E, Tsiftsis DD, Santos RM, et al: Objective assessment of the
contribution of each diagnostic test and of the ordering sequence in jaundice
caused by pancreatobiliary carcinoma. Scand J Gastroenterol 4:438-445, 2000.
14. Georgopoulos S, Schwartz L, Jarnagin W, et al: Comparison of magnetic
resonance and endoscopic retrograde cholangiopancreatography in malignant
pancreaticobiliary obstruction. Arch Surg 134:1002-1007, 1999.
15. Kim M, Mitchell D, Ito K, et al: Biliary dilation: Differentiation of
benign from malignancy causesvalue of adding conventional MR imaging to MR
cholangiopancreactography. Radiology 214:173-181, 2000.
16. Hann LE, Greatrex K, Bach A, et al: Cholangiocarcinoma at the hepatic
hilum: Sonographic findings. Am J Radiol 168:985-989, 1997.
17. Hochwald SN, Burke EC, Jarnagin W, et al: Pre-operative biliary stenting
is associated with increased postoperative infectious complications in proximal
cholangiocarcinoma. Arch Surg 134:261-266, 1999.
18. Keiding S, Hansen SB, Ramsussen HH: Detection of cholangiocarcinoma in
primary sclerosing cholangitis by positron-emission tomography. Hepatology
19. Klempnauer J, Ridder GJ, von Wasielewski R, et al: Resectional surgery of
hilar cholangiocarcinoma: A multivariate analysis of prognostic factors. J Clin
Oncol 15:947-954, 1997.
20. Bismuth H, Nakache R, Diamond T: Management strategies in resection of
hilar cholangiocarcinoma. Ann Surg 215:31-38, 1992.
21. Burke E, Jarmagin W, Hochwald S, et al: Hilar cholangiocarcinoma.
Patterns of spread, the importance of hepatic resection for curative operation,
and a presurgical clinical staging system. Ann Surg 228:385-394, 1998.
22. Klempnauer J, Ridder G, Werner M, et al: What constitutes long-term
survival after surgery for hilar carcinoma? Cancer 79:26-34, 1997.
23. Todoroki T, Kawamoto T, Takahashi H, et al: Treatment of gallbladder
cancer by radical resection. Br J Surg 86:622-627, 1999.
24. Su CH, Tsay S, Wu CC, et al: Factors influencing postoperative morbidity,
mortality, and survival after resection for hilar cholangiocarcinoma. Ann Surg
25. Launois B, Terblanche J, Lakehal M, et al: Proximal bile duct cancer:
High resectability rate and 5-year survival. Ann Surg 230:266-275, 1999.
26. Blom D, Schwartz S: Surgical treatment and outcomes in carcinoma of the
extrahepatic bile ducts. Arch Surg 136:209-215, 2001.
27. Meyer C, Penn G, James L: Liver transplantation for cholangiocarcinoma:
Results in 207 patients. Transplantation 69:1633-1637, 2000.
28. Kamada T, Saitou H, Takamura A, et al: The role of radiotherapy in the
management of extrahepatic bile duct cancer: An analysis of 145 consecutive
patients treated with intraluminal and/or external-beam radiotherapy. Int J
Radiat Oncol Biol Phys 34:767-774, 1996.
29. Todoroki T, Ohara K, Kawamoto T, et al: Benefits of adjuvant radiotherapy
after radical resection of locally advanced main hepatic duct carcinoma. Int J
Radiat Oncol Biol Phys 46:581-587, 2000.
30. Pitt HA, Nakeeb A, Abrams RA, et al: Perihilar cholangiocarcinoma:
Postoperative radiotherapy does not improve survival. Ann Surg 221:788-798,
31. Morganti AG, Trodella L, Valentini V, et al: Combined modality treatment
in unresectable extrahepatic biliary carcinoma. Int J Radiat Oncol Biol Phys
32. Manfredi S, Benhamiche AM, Isambert N, et al: Trends in incidence and
management of gallbladder carcinoma: A population based study in France. Cancer
33. Nagorney DM, McPherson GAD: Carcinoma of the gallbladder and extrahepatic
bile ducts. Semin Oncol 15:106-115, 1988.
34. Zou SQ, Zhang L, Zen GZ, et al: Clinical epidemiologic characteristics of
430 cases of gallbladder cancer. Chin Med J 111:391-393, 1998.
35. Vitetta L, Sali A, Little P, et al: Gallstones and gallbladder carcinoma.
Aust N Z J Surg 70:667-673, 2000.
36. Chow WH, Johansen C, Gridley G, et al: Gallstones, cholecystectomy, and
risk for cancers of the liver, biliary tract, and pancreas. Br J Cancer
37. Dutta U, Garg PK, Kumar R: Typhoid carriers among patients with
gallstones are at increased risk for carcinoma of the gallbladder. Am J
Gastroenterol 95:784-787, 2000.
38. Frezza EE, Mezghebe H: Gallbladder carcinoma: A 28-year experience. Int
Surg 82:295-300, 1997.
39. Diehl AK: Gallstone size and the risk of gallbladder cancer. JAMA
40. Lowengels A, Walker A, Althaus D, et al: Gallstone growth size and risk
of gallbladder cancer. Int J Epidemiol 18:50-54, 1989.
41. Suzuki K, Kimura T, Ogawa H: Long-term prognosis of gallbladder cancer
diagnosed after laparoscopic cholecystectomy. Surg Endosc 14:712-716, 2000.
42. Lundberg O, Kristofferson A: Wound recurrence from gallbladder cancer
after open cholecystectomy. Surgery 127:296-300, 2000.
43. Shirai Y, Yoshida K, Tsukada K, et al: Inapparent carcinoma of the
gallbladder. An appraisal of radical second operation after simple
cholecystectomy. Ann Surg 215:326-331, 1992.
44. Yamaguchi K, Chijiiwa K, Nishihara K, et al: Retrospective analysis of 70
operations for gallbladder cancer. Br J Surg 84:200-204, 1997.
45. de Aretabala XA, Roa I, Burgos L, et al: Curative resection in
potentially resectable tumors of the gallbladder. Eur J Surg 163:419-426, 1997.
46. Muratore A, Polastri R, Boujari H: Radical surgery for gallbladder
cancer: A worthwhile operation? Eur J Surg Oncol 26:160-163, 2000.
47. Bosset JF, Mantion G, Gillet M, et al: Primary carcinoma of the
gallbladder: Adjuvant postoperative external irradiation. Cancer 64:1843-1847,
48. de Aretxabala X, Roa I, Burgos L, et al: Preoperative chemoradiotherapy
in the treatment of gallbladder cancer. Am Surg 65:241-246, 1999.
49. Falkson G, MacIntyre JM, Moertel CG: Eastern Cooperative Oncology Group
experience with chemotherapy for inoperable gallbladder and bile duct cancer.
Cancer 54:965-969, 1984.
50. Taal BG, Audisio RA, Bleiberg H, et al: Phase II trial of mitomycin-C in
advanced gallbladder and biliary tree carcinoma. An EORTC gastrointestinal tract
cancer cooperative group study. Ann Oncol 4:607-609, 1993
51. Lozano RD, Patt YZ, Hassan MM, et al: Oral capecitabine (Xeloda) for the
treatment of hepatobiliary cancers (hepatocellular carcinoma,
cholangiocarcinoma, and gallbladder cancer) (abstract 1025). Proc Am Soc Clin
Oncol 19:264a, 2000.
52. Harby JH, Smith FP, Schein PS: 5-Fluorouracil, mitomycin, and doxorubicin
(FAM) in carcinoma of the biliary tract. J Clin Oncol 2:1245-1248, 1984.
53. Sanz-Altamira PM, Ferrante K, Jenkins RL: A phase II trial of
5-fluorouracil, leucovorin, and carboplatin in patients with unresectable
biliary tree carcinoma. Cancer 82:2321-2325, 1998.
54. Patt YZ, Jones DV, Hoque A, et al: Phase II trial of intravenous
flourouracil and subcutaneous interferon alfa-2b for biliary tract cancer. J
Clin Oncol 14:2311-2315, 1996.
55. Jones DV, Lozano R, Hoque A, et al: Phase II study of paclitaxel therapy
for unresectable biliary tree carcinomas. J Clin Oncol 14:2306-2310, 1996.
56. Pazdur R, Royce ME, Rodrigues GI, et al: Phase II trial of docetaxel
for cholangiocarcinoma. Am J Clin Oncol 22:78-81, 1999.
57. Papakostas P, Kouroussis C, Adroulakis N: First-line chemotherapy with
docetaxel for unresectable or metastatic carcinoma of the biliary tract: A
multicenter phase II study (abstract 610). Proc Am Soc Clin Oncol 20:153a, 2001.
58. Fishkin P, Alberts S, Mahoney M, et al: Irinotecan (CPT-11) in patients
with advanced gallbladder carcinoma: A North Central Cancer Treatment Group
phase II study (abstract 618). Proc Am Soc Clin Oncol 20:155a, 2001.
59. Raderer M, Hejna MHL, Valencak JB, et al: Two consecutive phase II
studies of 5-fluorouracil/leucovorin/ mitomycin C and of gemcitabine in patients
with advanced biliary cancer. Oncology 56:177-180, 1999.
60. Arroyo G, Gallardo J, Rubio B, et al: Gemcitabine in advanced biliary
tract cancer. Experience from Chile and Argentina in phase II trials (abstract
626). Proc Am Soc Clin Oncol 20:157a, 2001.
61. Doval CD, Sekhon JS, Fuloria J, et al: Gemcitabine and cisplatin in
chemotherapy naïve, unresectable gallbladder cancer: A large multicenter, phase
II study (abstract 622). Proc Am Soc Clin Oncol 20:156a, 2001.
62. Carraro S, Servient PJ, Bruno MF, et al: Gemcitabine and cisplatin in
locally advanced or metastatic gallbladder and bile duct adenocarcinomas
(abstract 2333). Proc Am Soc Clin Oncol 20:146b, 2001.
63. Kuhn R, Ridwelski K, Eichelmann K, et al: Outpatient combination
chemotherapy with gemcitabine and docetaxel in patients with cancer of the
biliary system (abstract 2272). Proc Am Soc Clin Oncol 20:130b, 2001.