Bile Duct Cancer

Cholangiocarcinoma is an uncommon tumor that may occur anywhere along the intrahepatic
or extrahepatic biliary tree. These tumors are located most commonly at the hepatic duct
bifurcation (60%-80% of cases). Less commonly, tumors originate in the distal common bile
duct or in the intrahepatic bile ducts. Most cholangiocarcinomas present with jaundice, and
the diagnosis of cholangiocarcinoma should be considered in every patient with obstructive
jaundice. When possible, surgical resection does offer a chance for long-term disease-free
survival. Many patients, however, will be candidates only for palliative bypass or operative or
nonoperative intubation aimed to provide biliary drainage and prevent cholangitis and hepatic
failure.
Incidence

The reported incidence of cholangiocarcinoma in the United States is 1 or 2 cases per

100,000 population. Incidence data from the American Cancer Society are difficult to
interpret because intrahepatic bile duct cancers are included with primary liver cancers,
whereas extrahepatic biliary cancers are in a separate category that includes gallbladder
cancer. In the United States, an estimated 17,550 primary liver cancers will be diagnosed in
2005. Data from the National Cancer Institute Surveillance, Epidemiology, and End Results
(SEER) program suggest that about 15% of these (2600 cases) will be intrahepatic
cholangiocarcinomas. About 7000 cases of extrahepatic bile duct cancer are diagnosed
annually in the United States, two thirds of which are gallbladder cancers. Thus, 2000 to 3000
cases per year are extrahepatic cholangiocarcinomas.
For unclear reasons, the incidence of intrahepatic cholangiocarcinoma has been rising over
the past 2 decades in Europe and North America, Asia, Japan, and Australia, whereas rates of
extrahepatic cholangiocarcinoma are declining internationally. The rising rates of intrahepatic
cholangiocarcinoma have not been associated with an increase in the proportion of earlystage or smaller lesions. Furthermore, incidence rates do not appear to have reached a
plateau.
Risk Factors

A number of diseases have been linked to cholangiocarcinoma, including primary sclerosing

cholangitis, choledochal cysts, and hepatolithiasis. Characteristics common to these diseases
include bile duct stones, biliary stasis, and infection. Bile duct cancers in patients with
primary sclerosing cholangitis are most often extrahepatic, commonly occur near the hepatic
duct bifurcation, and are difficult to differentiate from the multiple, benign strictures
associated with this disease. As a general rule, the incidence of biliary tract cancers increases
with age; the typical patient with cholangiocarcinoma is between 50 and 70 years of age.
However, patients with PSC and those with choledochal cysts present nearly 2 decades
earlier. In contrast to gallbladder cancer, for which female gender predominates, the incidence
of cholangiocarcinoma is slightly higher in men. This probably reflects the higher incidence
of PSC in men. Hepatolithiasis is also a definite risk factor for cholangiocarcinoma, which
will develop in 5% to 10% of patients with intrahepatic stones. Hepatitis B and C are also
now recognized as risk factors in the development of intrahepatic cholangiocarcinoma. At
least two genetic disorders are associated with an increased risk for cholangiocarcinoma: the
inherited cancer family syndrome termed Lynch syndrome II, and a rare inherited disorder
called multiple biliary papillomatosis; the latter condition is characterized by multiple

adenomatous polyps in the bile ducts, and repeated episodes of abdominal pain, jaundice, and
acute cholangitis.
Prior biliary-enteric anastomosis may also increase the future risk for cholangiocarcinoma.
Five percent of patients in a large Italian series developed cholangiocarcinoma between 11
and 18 years after a biliary-enteric anastomosis. The risk for bile duct cancer was higher after
transduodenal sphincteroplasty and choledochoduodenostomy than after hepaticojejunostomy
and was most strongly associated with recurrent episodes of cholangitis. Multiple other risk
factors for cholangiocarcinoma have been identified, including liver flukes, Thorotrast,
industrial chemicals, dietary nitrosamines, and exposure to dioxin.
Staging and Classification

Cholangiocarcinoma is best classified anatomically into three broad groups:

1.

Intrahepatic

2.

Perihilar

3.

Distal

Intrahepatic tumors are treated like hepatocellular carcinoma with hepatectomy, when
possible. The perihilar tumors make up the largest group and are managed with resection of
the bile duct, preferably with hepatic resection. Distal tumors are managed in a fashion
similar to other periampullary malignancies with pancreatoduodenectomy.
Cancers of the hepatic duct bifurcation have also been classified according to their anatomic
location ( Fig. 54-35 ). In this system, type I tumors are confined to the common hepatic duct,
and type II tumors involve the bifurcation without involvement of secondary intrahepatic
ducts. Types IIIa and IIIb tumors extend into either the right or left secondary intrahepatic
ducts, respectively, and type IV tumors involve the secondary intrahepatic ducts on both
sides.

Figure 54-35 Bismuth classification of perihilar cholangiocarcinoma by anatomic extent. Type I tumors (upper, left) are
confined to the common hepatic duct, and type II tumors (upper, right) involve the bifurcation without involvement of
secondary intrahepatic ducts. Type IIIa and IIIb tumors (lower, left) extend into either the right or left secondary intrahepatic
ducts, respectively. Type IV tumors (lower, right) involve the secondary intrahepatic ducts on both sides.

Cholangiocarcinoma is also staged according to the tumor, node, metastasis (TNM)

classification of the AJCC ( Table 54-3 ). Using this system, stage IA tumors are limited to
the bile duct, whereas stage IB tumors invade periductal tissues. Stage IIA tumors are locally
advanced without lymph node metastases, and stage IIB tumors have regional lymph node
metastases. Stage III tumors are locally advanced and unresectable, and stage IV tumors have
distant metastases. Portal vein involvement and lobar atrophy have been reported as
important prognostic factors for cholangiocarcinoma and may be incorporated in the
classification in the future.[45]

Table 54-3 -- Current American Joint Commission on Cancer TNM Staging System for
Cholangiocarcinoma
Stage 0

Tis

N0

M0

Stage I

T1

N0

M0

Stage II

T2

N0

M0

Stage III

T1 or T2

N1 or N2

M0

Stage IVA

T3

Any N

M0

Stage IVB

Any T

Any N

M1

Adapted from Greene F, Page D, Fleming I, et al (eds): AJCC Cancer Staging Manual, 6th
ed. New York, Springer-Verlag, 2002.
Tis, carcinoma in situ; T1, tumor invades the subepithelial connective tissue; T2, tumor
invades peri. bromuscular connective tissue; T3, tumor invades adjacent organs.
N0, no regional lymph node metastases; N1, metastasis to hepatoduodenal ligament lymph
nodes; N2, metastasis to peripancreatic, periduodenal, periportal, celiac, and/or superior
mesenteric artery lymph nodes.
M0, no distant metastasis; M1, distant metastasis.

Clinical Presentation

More than 90% of patients with perihilar or distal tumors present with jaundice. Patients with
intrahepatic cholangiocarcinoma are rarely jaundiced until late in the course of the disease.
Less common presenting clinical features include pruritus, fever, mild abdominal pain,
fatigue, anorexia, and weight loss. Cholangitis is not a frequent presenting finding but most
commonly develops after biliary manipulation. Except for jaundice, the physi-cal
examination is usually normal in patients with cholangiocarcinoma.
Diagnosis and Assessment of Resectability

At the time of presentation, most patients with perihilar and distal cholangiocarcinoma have a
total serum bilirubin level greater than 10 mg/dL. Marked elevations in alkaline phosphatase
are also routinely observed. Serum CA 19-9 may also be elevated in patients with
cholangiocarcinoma, although levels may fall once biliary obstruction is relieved.
The radiologic evaluation of patients with cholangiocarcinoma should delineate the overall
extent of the tumor, including involvement of the bile ducts, liver, hilar vessels, and distant
metastases. The initial radiographic studies consist of either abdominal ultrasound or CT
scanning ( Fig. 54-36 ). Intrahepatic cholangiocarcinomas are easily visualized on CT scans;
however, perihilar and distal tumors are often difficult to visualize on ultrasound and standard

CT scan. Cholangiocarcinoma can be enhanced by using delayed-phase CT acquisition (10

minutes after contrast injection). A hilar cholangiocarcinoma gives a picture of a dilated
intrahepatic biliary tree and a normal or collapsed gallbladder and extrahepatic biliary tree.
Distal tumors lead to dilation of the gallbladder and both the intrahepatic and extrahepatic
biliary tree.

Figure 54-36 Computed tomography scan visualizes mass at hepatic duct bifurcation (arrow) resulting in bilateral biliary
dilation and extensive perihilar malignancy.

After documentation of bile duct dilation, biliary anatomy has been traditionally defined
cholangiographically through either the percutaneous transhepatic or the endoscopic
retrograde route. The most proximal extent of the tumor is the most important feature in
determining resectability in patients with perihilar tumors, and the percutaneous route is
favored in these patients because it defines the proximal extent of tumor involvement most
reliably. PET will detect unsuspected distant or intrahepatic metastases in up to 30% of

patients with cholangiocarcinoma. MRC offers good resolution of both the intrahepatic and
extrahepatic biliary tree, but should be substituted with PTC or ERCP in patients that will
require preoperative or palliative biliary drainage. Biliary drainage is necessary if the patient's
bilirubin is more than 10 mg/dL, but it has been associated with an increased risk for
cholangitis and longer postoperative hospital stay in patients with obstructive jaundice who
then undergo resection.[46] Cholestasis, biliary cirrhosis, and liver dysfunction develop rapidly
in the face of unrelieved biliary obstruction.
Percutaneous fine-needle aspiration biopsy, brush and scrape biopsy, and cytologic
examination of bile all have been used to establish a tissue diagnosis; however, the sensitivity
in detecting a malignancy is low, and a benign result should be considered unreliable. Seven
to 15% of patients with preoperative symptoms and imaging studies and intraoperative
findings consistent with malignant biliary obstruction will ultimately have benign lesions on
histologic analysis of resection specimens.
Management

Hepatic lobar atrophy and hepatic ductal extension predict the need for hepatectomy in order
to achieve a margin-negative resection. [55] [57] All available data must be used to distinguish
resectability from unresectability ( Fig. 54-37 ). Radiographic criteria that suggest
unresectability of perihilar tumors include bilateral hepatic duct involvement up to secondary
radicals, encasement or occlusion of the portal vein proximal to its bifurcation, atrophy of one
liver lobe with encasement of the contralateral portal vein branch, involvement of bilateral
hepatic arteries, or atrophy of one liver lobe with contralateral secondary biliary radical
involvement ( Box 54-8 ). Ipsilateral portal vein involvement and involvement of secondary
biliary radicals do not preclude resection, nor does ipsilateral lobar atrophy.[48] Curative
treatment of patients with cholangiocarcinoma is possible only with complete resection (R0).