| The vast majority of malignant tumors of
the bile duct are adenocarcinomas of high-grade scirrhous, nodular, or
papillary forms. These make up at least 90% of malignant extrahepatic bile
duct tumors. Approximately 10% of malignant tumors of the extrahepatic bile
ducts are squamous cell carcinomas. Rare types of malignant tumors of the
bile ducts include cystadenocarcinoma, sarcoma, lymphoma, and nodal
metastases. The most common clinical manifestations of patients with
cholangiocarcinoma include jaundice, pruritus, right upper quadrant
abdominal pain, and insidious weight loss. On occasion, patients with
cholangiocarcinoma present with typical signs and symptoms of cholangitis;
however, infection of the bile duct is uncommon with high-grade malignant
obstruction before instrumentation. On physical examination, patients with
cholangiocarcinoma are often deeply jaundiced and may have moderate
hepatomegaly and a palpable mass. A palpable, nontender gallbladder in a
patient with deep jaundice is commonly known as Courvoisier's sign. The
diagnosis of cholangiocarcinoma is likewise suspected by virtue of markedly
increased serum alkaline phosphatase, usually from two- to ten-fold
elevation above upper limits of normal. Variable increases in serum
bilirubin and modest increases in serum transaminase levels are often noted.
Bilirubin elevation usually trails serum alkaline phosphatase elevation;
however, it is not uncommon for patients with high-grade malignant
obstruction of the bile duct to present with serum bilirubin levels greater
than 20 mg/dL. Elevated serum levels of CA-19-9 (>100 U/mL) are noted in
from 55% to 65% of patients with cholangiocarcinoma.The initial suspicion of
high-grade malignant bile duct obstruction is usually made at the time of
ultrasonography. CT is likewise helpful at suggesting both the site and the
source of high-grade obstruction. The most promising clinical presentation
would be a CT or ultrasound demonstration of dilatation of the entire
biliary system without an identifiable mass lesion. Unfortunately, the
majority of patients with bile duct cancer are found to have extensive
intrahepatic bile duct dilatation and a large mass with an abrupt cutoff of
the extrahepatic biliary tree. The usual means of defining the cause of
high-grade bile duct obstruction is ERCP or percutaneous transhepatic
cholangiography Supplementary diagnostic tests consist of brush cytology,
which has a variable yield but generally ranges up to 75%. Negative findings
on brush cytology do not definitively exclude cholangiocarcinoma, since
these tumors tend to be scirrhous and in general paucicellular. At the time
of initial ERCP evaluation, careful consideration needs to be given to
placing a temporary No. 7 French polyethylene stent. Once a high-grade bile
duct stricture has been contaminated by retrograde injected contrast, the
biliary system may well become infected. Thus, temporary stenting should be
strongly considered to avoid subsequent presentations with suppurative
cholangitis. Temporary stenting also allows careful elective evaluation of
patients for potential surgical resection for cure.
In the best surgical hands, only 25% of cholangiocarcinomas are resectable
of the time of diagnosis. Only 5% of patients survive 5 years. The only real
hope for cure is with small distal bile duct neoplasms that present early
with jaundice or pruritus. Distal tumors of the bile duct are best treated
by Whipple's resection. For those treated by the most experienced surgeons,
the operative mortality is under 5%. More proximal tumors require some
liver resection and reconstruction of the biliary tree using a Roux-en-Y
hepaticojejunostomy.When at all possible, total resection is preferred to
"debulking" or minor resection, since, in good hands, the survival rate is
significantly better (total versus debulking, P = .05; total versus minor
resection.
In most instances, bile duct cancers are not
resectable and therapy is largely palliative. The most common means of
palliating jaundice and pruritus is by placement of stents or by surgical
bypass. Stenting of the biliary system is now more commonly available, and
strong consideration needs to be given to using expandable metal stents with
large diameters rather than placing No. 10 or 11.5 French polyethylene
stents. In one study using self-expanding metal stents, median interval of
stent patency was 8.2 months and 79% of patients were free of jaundice or
cholangitis for a median follow-up of 14.6 months. Great care and judgment
need to be exercised when placing stents in the proximal biliary system.
Although the main left bile duct can be drained with a
single stent, the right hepatic duct bifurcates extensively just proximal to
its confluence with the left hepatic duct. Thus, a single right intrahepatic
stent is not likely to result in significant palliation. In addition,
placement of a single right hepatic stent may be complicated by recurrent
bouts of cholangitis owing to contamination of the injected but undrained
adjacent bile ducts. Proximal bile duct obstruction is best decompressed by
transhepatic stent placement, while more distal malignant obstructions of
the biliary tree can be handled equally well by ERCP or percutaneous
transhepatic drainage.
Radiation therapy does provide limited palliation.
Four techniques have been applied to administer radiotherapy, including
intraoperative radiotherapy, external-beam conventional radiation therapy,
charged particle radiation therapy, and iridium 192 wires. The results with
radiotherapy are modest at best. Median survival time for primary or
definitive radiation therapy ranges from 12 to 22 months.In a recent
univariate analysis, favorable prognostic factors included male sex, limited
(versus extensive) tumor extent, and external-beam radiation therapy dose
greater than 45 Gy. In a retrospective review of 129 patients treated at the
University of California, San Francisco (UCSF), and the Lawrence Berkeley
Laboratory, increased survival was noted for surgical patients receiving
adjuvant radiation therapy. For patients with microscopic residual disease,
increased survival was noted, especially for patients receiving charged
particle radiation therapy ( P = .0005) but also for those receiving
conventional radiation therapy ( P = .0109). Even for patients with gross
residual disease, the UCSF group reported less marked but still
significantly increased survival after radiation therapy ( P = .05 for
patients receiving surgery plus conventional radiation therapy and P = .0423
for those receiving surgery plus charged particle radiation therapy).
Chemotherapeutic regimens based largely on
5-fluorouracil are futile in most instances. No significant improvement in
survival has been demonstrated. Cholangiocarcinomas express somatostatin
receptors, SSTR2, and in vitro these tumors are inhibited by somatostatin
and its analogs. Future studies are needed to investigate whether analogs of
somatostatin may be useful both diagnostically and therapeutically. The role
of hepatic transplantation is limited in patients with known
cholangiocarcinoma. On occasion, patients with diffuse intrahepatic
sclerosing cholangitis and an incidental cholangiocarcinoma have been
transplanted with favorable long-term survival. However, recurrence rates in
patients with known cholangiocarcinoma are high following liver
transplantation; thus, these patients do not routinely undergo
transplantation.
As mentioned, the overall prognosis for patients with
cholangiocarcinoma is poor with a 5-year survival rate of only 5%. The best
chances for long-term survival favor patients younger than 65 years of age
with small, nearly incidental, tumors of the distal common bile duct (i.e.,
lower "T" and "N" staging) who undergo Whipple's resection by experienced
surgeons. Nonetheless, palliation with large-diameter metal stents is good,
and the quality of life may be substantially enhanced for these patients.
Furthermore, clinicians need to be mindful of the fact that
cholangiocarcinoma may be slow-growing, so that long-term survival is
possible even with nonresectable tumors.
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