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Cancers of the Gallbladder and Biliary Ducts

Cancers of the Gallbladder and Biliary Ducts

ABSTRACT: Neoplasms of the biliary tract tree are uncommon and have a poor overall prognosis. Although numerous risk factors have been identified, little is known about the pathogenesis of these tumors, and no effective screening technique is available for early detection. Surgery remains the principal treatment modality and the only potential cure, with laparoscopy playing an increasingly important role in determining the resectability of these tumors. The role of postoperative adjuvant chemotherapy and radiation remains controversial. The efficacy of chemotherapy for advanced disease is relatively limited, with response rates of less than 10% for single-agent fluorouracil. Of the newer agents, gemcitabine (Gemzar) holds the most promise in the treatment of these difficult malignancies. [ONCOLOGY 16:939-957, 2002]

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.[1] 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.[2] 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.[2] The roles of chemotherapy and
irradiation, particularly in the adjuvant setting, have not been well defined in
these diseases.

Cholangiocarcinoma

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.[3] 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.[4] They also express Fas ligand,
which induces apoptosis of lymphocytes,[5] 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.[6] These tumors
also occur with increased frequency in patients with hepatitis C-related
cirrhosis, ulcerative colitis, and parasitic infestations.[7] 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.[8]
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).[1] Other chemical carcinogens
inducing this cancer include cigarette smoke, asbestos, radon, dioxin, and
nitrosamines.[1,9]

Symptoms

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
cholangiocarcinomas.

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.[6] 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.[10] 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.[11] 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.

Diagnostic Imaging

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%.[12] 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.[16]

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.[17]

Due to their avid uptake of fluorodeoxyglucose, cholangiocarcinomas are very
conspicuous on positron-emission tomography (PET).[18] 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.

Staging

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).[3] Stage T1 and T2 disease can be cured with surgery, with 5-year
survival rates of 57% and 39%, respectively.[19] 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
years.

Another commonly used staging method is the Bismuth-Corlette system,[20]
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.[21] 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.

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