Cholangiocarcinoma is a
cancer of the
bile ducts
which drain
bile from the
liver into the
small
intestine. Other
biliary tract
cancers include
pancreatic cancer,
gall bladder cancer, and cancer of the
ampulla of Vater.
Cholangiocarcinoma is a relatively rare
adenocarcinoma (glandular cancer), with an
annual
incidence of 1–2
cases per 100,000 in the Western world, but rates of
cholangiocarcinoma have been rising worldwide over the past several
decades.
Prominent symptoms of cholangiocarcinoma include abnormal
liver function tests,
abdominal pain,
jaundice,
weight loss,
and sometimes
generalized itching,
fever, or changes in
stool
or
urine color. The disease is diagnosed
through a combination of
blood tests,
imaging,
endoscopy, and sometimes surgical
exploration. Cholangiocarcinoma is often in an
advanced stage by the time symptoms develop,
which may limit treatment options. Known risk factors for
cholangiocarcinoma include
primary sclerosing
cholangitis (an inflammatory disease of the bile ducts),
congenital liver malformations, infection with the parasitic
liver flukes Opisthorchis viverrini or
Clonorchis sinensis,
and exposure to
Thorotrast (
thorium dioxide), a chemical formerly used
in
medical imaging. However, most
patients with cholangiocarcinoma have no specific risk
factors.
Cholangiocarcinoma is considered to be an incurable and rapidly
lethal disease unless all of its tumors can
be fully
resected (cut out surgically).
There is no potentially curative treatment except surgery, but
unfortunately most patients have advanced and inoperable disease at
the time of diagnosis. Patients with cholangiocarcinoma are
generally managed, though never cured, with
chemotherapy or
radiation therapy as well as
palliative care measures, and these are also
used as
adjuvant therapies
post-surgically in cases where resection has been successful. Some
areas of ongoing
medical research
in cholangiocarcinoma include the use of newer
targeted therapies (such as
erlotinib) or
photodynamic therapy for treatment, and
the concentration of byproducts of cancer
stromal cell formation in the blood for
diagnosis.
Staging
Although there are at least three
staging
systems for cholangiocarcinoma (e.g. Bismuth, Blumgart,
American Joint
Committee on Cancer) none have been shown to be useful in
predicting survival. The most important staging issue is whether
the tumor can be
surgically removed, or
whether it is too advanced or invasive for surgical treatment.
Often, this determination can only be made at the time of
surgery.
General guidelines for operability include:
Signs and symptoms
The most common physical indications of cholangiocarcinoma are
abnormal
liver function tests,
jaundice (yellowing of the eyes and skin),
which occurs only when bile ducts are blocked by the tumor,
abdominal pain (30%–50%),
generalized itching (66%),
weight loss (30%–50%),
fever (up to 20%), or changes in
stool or
urine color. To
some extent, the symptoms depend upon the location of the tumor:
Patients with cholangiocarcinoma in the extrahepatic bile ducts
(outside the liver) are more likely to have jaundice, while those
with tumors of the bile ducts within the liver often have pain
without jaundice.
Blood tests of liver function
in patients with cholangiocarcinoma often reveal a so-called
"obstructive picture," with elevated
bilirubin,
alkaline phosphatase, and
gamma glutamyl transferase
levels, and relatively normal
transaminase levels. Such laboratory findings
suggest obstruction of the bile ducts, rather than
inflammation or infection of the liver, as the
primary cause of the jaundice.
CA19-9 is
elevated in most cases.
Risk factors
Although most patients present without any known risk factors
evident, a number of
risk factors for
the development of cholangiocarcinoma have been described; in the
Western world, the most common of these is
primary sclerosing
cholangitis (PSC), an
inflammatory disease of the bile ducts
which is in turn closely associated with
ulcerative colitis (UC). Epidemiologic
studies have suggested that the lifetime risk of developing
cholangiocarcinoma for a person with PSC is 10%–15%, although
autopsy series have found rates as high as 30% in this population.
The mechanism by which PSC increases the risk of cholangiocarcinoma
is not well understood.
Certain
parasitic liver diseases
may be risk factors as well.
Colonization with the liver flukes Opisthorchis viverrini (found in
Thailand
, Laos
, and
Malaysia
) or
Clonorchis sinensis
(found in Japan
, Korea
, and
Vietnam
) has been associated with the development of
cholangiocarcinoma. Patients with chronic liver disease,
whether in the form of viral hepatitis (e.g.
hepatitis B or
C),
alcoholic liver disease, or
cirrhosis from other causes, are at
increased risk of cholangiocarcinoma. HIV infection was also
identified in one study as a potential risk factor for
cholangiocarcinoma, although it was unclear whether
HIV itself or correlated factors (e.g. hepatitis C
infection) were responsible for the association.
Congenital liver abnormalities,
such as
Caroli's syndrome or
choledochal cysts, have been associated with an approximately 15%
lifetime risk of developing cholangiocarcinoma. The rare inherited
disorders
Lynch syndrome II and
biliary papillomatosis are associated with cholangiocarcinoma. The
presence of gallstones (
cholelithiasis) is not clearly associated
with cholangiocarcinoma. However, intrahepatic stones (so-called
hepatolithiasis), which are rare in
the West but common in parts of Asia, have been strongly associated
with cholangiocarcinoma. Exposure to
Thorotrast, a form of
thorium dioxide which was used as a
radiologic contrast medium, has been linked to
the development of cholangiocarcinoma as late as 30–40 years after
exposure; Thorotrast was banned in the United States in the 1950s
due to its
carcinogenicity.
Pathophysiology
Cholangiocarcinoma can affect any area of the bile ducts, either
within or outside the liver. Tumors occurring in the bile ducts
within the liver are referred to as
intrahepatic, those
occurring in the ducts outside the liver are
extrahepatic;
and tumors occurring at the site where the bile ducts exit the
liver may be referred to as
perihilar. A
cholangiocarcinoma occurring at the junction where the left and
right hepatic ducts meet to form the
common bile duct may be referred to
eponymously as a
Klatskin tumor.
Although cholangiocarcinoma is known to be an
adenocarcinoma of the epithelial cells lining
the biliary tract, the actual cell of origin is unknown, although
recent evidence has suggested that it may arise from a
pluripotent hepatic
stem cell. Cholangiocarcinoma is thought to
develop through a series of stages — from early
hyperplasia and
metaplasia, through
dysplasia, to the development of frank
carcinoma — in a process similar to that seen in
the development of
colon cancer.
Chronic inflammation and obstruction of
the bile ducts, and the resulting impaired bile flow, are thought
to play a role in this progression.
Histologically, cholangiocarcinomas may
vary from
undifferentiated to
well-differentiated. They are often surrounded by a brisk
fibrotic or
desmoplastic tissue response; in the presence
of extensive fibrosis, it can be difficult to distinguish
well-differentiated cholangiocarcinoma from normal reactive
epithelium. There is no entirely specific
immunohistochemical stain that
can distinguish
malignant from
benign biliary ductal tissue, although staining for
cytokeratins,
carcinoembryonic antigen, and
mucins may aid in diagnosis. Most tumors
(>90%) are
adenocarcinomas.
Diagnosis
Cholangiocarcinoma is definitively diagnosed from tissue, i.e. it
is proven by biopsy or examination of the tissue excised at
surgery. It may be suspected in a patient with
obstructive jaundice. Considering it
as the working diagnosis may be challenging in patients with
primary sclerosing cholangitis (PSC); such patients are at high
risk of developing cholangiocarcinoma, but the symptoms may be
difficult to distinguish from those of PSC. Furthermore, in
patients with PSC, such diagnostic clues as a visible mass on
imaging or biliary ductal dilatation may not be evident.
Blood tests
There are no specific
blood tests that
can diagnose cholangiocarcinoma by themselves. Serum levels of
carcinoembryonic antigen
(CEA) and CA19-9 are often elevated, but are not
sensitive or
specific enough to be used as a general
screening tool. However, they
may be useful in conjunction with
imaging methods in supporting a suspected
diagnosis of cholangiocarcinoma.
Abdominal imaging
Ultrasound of the
liver and
biliary tree is
often used as the initial imaging modality in patients with
suspected obstructive jaundice. Ultrasound can identify obstruction
and ductal dilatation and, in some cases, may be sufficient to
diagnose cholangiocarcinoma.
Computed tomography (CT) scanning may
also play an important role in the diagnosis of
cholangiocarcinoma.
Imaging of the biliary tree
While abdominal imaging can be useful in the diagnosis of
cholangiocarcinoma, direct imaging of the
bile
ducts is often necessary.
Endoscopic
retrograde cholangiopancreatography (ERCP), an
endoscopic procedure performed by a
gastroenterologist or specially trained
surgeon, has been widely used for this purpose. Although ERCP is an
invasive procedure with attendant risks, its advantages include the
ability to obtain
biopsies and to place
stents or perform other interventions to
relieve biliary obstruction.
Endoscopic ultrasound can also be
performed at the time of ERCP and may increase the accuracy of the
biopsy and yield information on
lymph
node invasion and operability. As an alternative to ERCP,
percutaneous
transhepatic cholangiography (PTC) may be utilized.
Magnetic resonance
cholangiopancreatography (MRCP) is a
non-invasive alternative to ERCP. Some authors
have suggested that MRCP should supplant ERCP in the diagnosis of
biliary cancers, as it may more accurately define the tumor and
avoids the risks of ERCP.
Surgery
Surgical exploration may be necessary to
obtain a suitable
biopsy and to accurately
stage a patient with
cholangiocarcinoma.
Laparoscopy can be
used for staging purposes and may avoid the need for a more
invasive surgical procedure, such as
laparotomy, in some patients. Surgery is also the
only curative option for cholangiocarcinoma, although it is limited
to patients with early-stage disease.
Pathology
Histologically, cholangiocarcinomas are classically well to
moderately differentiated.
Immunohistochemistry is useful in the
diagnosis and can be used to differentiate a cholangiocarcinoma
primary tumour from metastasis of most other gastrointestinal
tumours. Cytological scrapings are often nondiagnostic.
Treatment
Cholangiocarcinoma is considered to be an incurable and rapidly
lethal disease unless all the tumors can be fully
resected (that is, cut out surgically). Since the
operability of the tumor can only be assessed during surgery in
most cases, a majority of patients undergo exploratory surgery
unless there is already a clear indication that the tumor is
inoperable.
Adjuvant therapy followed by
liver
transplantation may have a role in treatment of certain
unresectable cases.
Adjuvant chemotherapy and radiation therapy
If the tumor can be removed surgically, patients may receive
adjuvant chemotherapy or
radiation therapy after the operation to
improve the chances of cure. If the tissue margins are negative
(i.e. the tumor has been totally
excised),
adjuvant therapy is of uncertain benefit. Both positive and
negative results have been reported with adjuvant radiation therapy
in this setting, and no prospective
randomized controlled trials
have been conducted as of March 2007. Adjuvant chemotherapy appears
to be ineffective in patients with completely resected tumors. The
role of combined chemoradiotherapy in this setting is unclear.
However, if the tumor tissue margins are positive, indicating that
the tumor was not completely removed via surgery, then adjuvant
therapy with radiation and possibly chemotherapy is generally
recommended based on the available data.
Treatment of advanced disease
The majority of cases of cholangiocarcinoma present as inoperable
(unresectable) disease in which case patients are generally treated
with
palliative chemotherapy, with or without
radiotherapy. Chemotherapy has been shown in a
randomized controlled
trial to improve
quality of life
and extend survival in patients with inoperable cholangiocarcinoma.
There is no single chemotherapy regimen which is universally used,
and enrollment in
clinical trials is
often recommended when possible. Chemotherapy agents used to treat
cholangiocarcinoma include
5-fluorouracil with
leucovorin,
gemcitabine as a single agent, or gemcitabine
plus
cisplatin,
irinotecan, or
capecitabine. A small pilot study suggested
possible benefit from the
tyrosine
kinase inhibitor
erlotinib in patients
with advanced cholangiocarcinoma.
Photodynamic therapy, an
experimental approach in which patients are injected with a
light-sensitizing agent and light is then applied
endoscopically directly to the tumor, has shown
promising results compared to supportive care in two small
randomized controlled trials.
However, its ultimate role in the management of cholangiocarcinoma
is unclear at present.
Prognosis
Surgical resection offers the only potential chance of cure in
cholangiocarcinoma. For non-resectable cases, the 5-year survival
rate is 0% where the disease is inoperable because distal lymph
nodes show metastases, and less than 5% in general. Overall median
duration of survival is less than 6 months in inoperable,
untreated, otherwise healthy patients with tumors involving the
liver by way of the
intrahepatic
bile ducts and
hepatic portal
vein.
For surgical cases, the odds of cure vary depending on the tumor
location and whether the tumor can be completely, or only
partially, removed. Distal cholangiocarcinomas (those arising from
the
common bile duct) are generally
treated surgically with a
Whipple
procedure; long-term survival rates range from 15%–25%,
although one series reported a
five year survival of 54% for
patients with no involvement of the
lymph
nodes. Intrahepatic cholangiocarcinomas (those arising from the
bile ducts within the
liver) are usually
treated with
partial hepatectomy.
Various series have reported survival estimates after surgery
ranging from 22%–66%; the outcome may depend on involvement of
lymph nodes and completeness of the surgery. Perihilar
cholangiocarcinomas (those occurring near where the bile ducts exit
the liver) are least likely to be operable. When surgery is
possible, they are generally treated with an aggressive approach
often including
removal of the
gallbladder and potentially part of the liver. In patients with
operable perihilar tumors, reported 5-year survival rates range
from 20%–50%.
The
prognosis may be worse for patients
with primary sclerosing cholangitis who develop cholangiocarcinoma,
likely because the cancer is not detected until it is advanced.
Some evidence suggests that outcomes may be improving with more
aggressive surgical approaches and
adjuvant therapy.
Epidemiology
Cholangiocarcinoma is an
adenocarcinoma of the
biliary tract, along with
pancreatic cancer (which occurs about 20
times more frequently),
gall bladder
cancer (which occurs twice as often), and cancer of the
ampulla of Vater. Treatments and clinical
trials for pancreatic cancer, being far more prevalent, are often
taken as a starting point for managing cholangiocarcinoma, even
though the biologies are different enough that chemotherapies can
put pancreatic cancer into permanent remission whereas there are no
reports in the literature of long-term survival due to chemotherapy
or radiation applied to an inoperable cholangiocarcinoma
case.
Age-standardized mortality
rates from intrahepatic (IC) and extrahepatic (EC)
cholangiocarcinoma for men and women, by country. Source:
Khan et al., 2002.
| Country |
IC (men/women) |
EC (men/women) |
| U.S.A. |
0.60 / 0.43 |
0.70 / 0.87 |
| Japan |
0.23 / 0.10 |
5.87 / 5.20 |
| Australia |
0.70 / 0.53 |
0.90 / 1.23 |
| England/Wales |
0.83 / 0.63 |
0.43 / 0.60 |
| Scotland |
1.17 / 1.00 |
0.60 / 0.73 |
| France |
0.27 / 0.20 |
1.20 / 1.37 |
| Italy |
0.13 / 0.13 |
2.10 / 2.60 |
Cholangiocarcinoma is a relatively rare form of cancer; each year,
approximately 2,000 to 3,000 new cases are diagnosed in the United
States, translating into an annual
incidence of 1–2 cases per 100,000
people.
Autopsy series have reported a
prevalence of 0.01% to 0.46%. There is a
higher prevalence of cholangiocarcinoma in Asia, which has been
attributed to endemic chronic parasitic infestation. The incidence
of cholangiocarcinoma increases with age, and the disease is
slightly more common in men than in women (possibly due to the
higher rate of
primary
sclerosing cholangitis, a major risk factor, in men). The
prevalence of cholangiocarcinoma in patients with primary
sclerosing cholangitis may be as high as 30%, based on autopsy
studies.
Multiple studies have documented a steady increase in the incidence
of intrahepatic cholangiocarcinoma over the past several decades;
increases have been seen in
North
America,
Europe,
Asia, and
Australia. The
reasons for the increasing occurrence of cholangiocarcinoma are
unclear; improved diagnostic methods may be partially responsible,
but the prevalence of potential risk factors for
cholangiocarcinoma, such as
HIV infection, has
also been increasing during this time frame.
Notes
- Bile duct cancer: cause and treatment
- Epidemiologic studies which have addressed the incidence of
cholangiocarcinoma in people with primary sclerosing cholangitis
include the following: * * *
- Studies of the performance of serum markers for
cholangiocarcinoma (such as carcinoembryonic antigen and CA19-9) in
patients with and without primary sclerosing cholangitis include
the following: * * * *
- Darwin PE, Kennedy A. Cholangiocarcinoma. eMedicine.com. URL:
http://www.emedicine.com/med/topic343.htm. Accessed
on: May 5, 2007.
- Heimbach JK, Gores GJ, Haddock MG, et al., Predictors of
disease recurrence following neoadjuvant chemoradiotherapy and
liver transplantation for unresectable perihilar
cholangiocarcinoma, Transplantation. 2006 Dec
27;82(12):1703-7.
- . Accessed March 13, 2007.
- Studies of surgical outcomes in distal cholangiocarcinoma
include: * * * * *
- Studies of outcome in intrahepatic cholangiocarcinoma include:
* * * * *
- Estimates of survival after surgery for perihilar
cholangiocarcinoma include: * * * * * * *
-
http://training.seer.cancer.gov/ss_module13_biliary_tract/unit01_sec01_intro.html
Introduction
-
http://seer.cancer.gov/csr/1975_2005/results_single/sect_01_table.01.pdf
- Cancer Statistics Home Page - National Cancer
Institute
- Multiple independent studies have documented a steady increase
in the worldwide incidence of cholangiocarcinoma. Some relevant
journal articles include: * * * * * *
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