Cholangiocarcinoma (CCA)

Cholangiocarcinoma is a relatively rare type of primary liver cancer that effects the biliary system, used to
transport bile from the liver to the intestines. The malignancy originates in the bile duct epithelium and represents
less than 10% of primary hepatic malignancies. Risk factor for the development of cholangiocarcinoma include
ong standing inflammation and chronic injury of the biliary epithelium3. The tumors are classified as either
intrahepatic, occuring with the liver, or extrahepatic, located outside the liver. Intrahepatic cholangiocarcinomas
are further classified as either peripheral or hilar. The hilar variety are located in the hepatic hilum region and
appear as discrete masses. Peripheral cholangiocarcinoma is the most common and develops in the interlobular
ducts of the liver, where the interlobular bile duct branches within the portal triads. They may be a single or
multiple masses.

Histology:
Many varieties of cholangiocarcinomas exist. The Japanese Society for Biliary Surgery classified the types of
cholangiocarcinoma histologically as papillary, tubular, mucinous, signet ring cell, adenosquamous, squamous,
anaplastic, undifferentiated miscellaneous, and unclassified.

The Atlas of Liver Pathology described the histology of cholangiocarcinoma:

"The histology of cholangiocarcinomas is that of small glandular structures which often appear deceptively bland.
The nuclei are often quite oval and vesicular. There is characteristically a dense sparsely cellular fibrous stroma.
There may be a papillary configuration. Mucin production is frequently demsonstrable, and, when present, clearly
excludes hepatocellular carcinoma. Another variable clue to ductal origin is the presence of nuclear atypia in
surrounding triads. There has been much recent interest centering on immunoperoxidase methods for identifying
cholangio-carcinoma. Markers such as CA 19-9 and CA-50 are said to be consistently positive in
cholangiocarcinoma and negative in hepatocellular carcinoma. A polyclonal CEA tends to strain canalculi; if
present, this pattern is specific for hepatocellular carcinoma. Keratin straining with AE-1 is highly suggestive of
bile duct rather than hepatocyte origin. Once hepatocellular carcinoma is excluded, the problem of excluding
metastatic adenocarcinoma remains. This can be done in a rigorous fashion only after autopsy has been
performed. However, the diagnosis of cholangiocarcinoma can usually be made reasonably reliably based on the
clinical information and characteristic histology; it is virtually certain when one of the predisposing conditions
listed earlier is present."

Incidence and Symptoms:

- Symptoms include: clay colored stools, progressive jaundice, itching, right upper abdominal pain that may
radiate to the back, loss of appetite, weight loss, fever, chills.
-Obstructive jaundice often signals hilar tumor localization
-Tumors usually grow and metastasize slowly.
-Occurs most commonly between 50 and 70 and affects 5 out of 100,000 people1.
-Affects males and females equally.
 
Predisposing factors:
-primary sclerosing cholangitis
-ulcerative colitis
-parasitic infection (Clonorchis sinensis or Opistorchis viverrini)
-hepatobiliary fibropolycystic disease
-Thorotrast exposure
-intrahepatic calculi
 
Diagnostic Tests:
-ERCP (endoscopic retrograde cholagiopancreatography)
-percutaneous transhepatic cholangiogram (PTCA)
-abdominal CT scan
-abdominal ultrasound
-CT scan directed biopsy of the biliary tract
-biliary cytology (examination of the cells found in a sample of bile) that shows cholangiocarcinoma
-Abnormal blood tests: elevated liver function tests or elevated biliruben1.
-Pathological levels of tumor markers carcinoembryonic antigen (CEA) and CA 19-98.
-MRIs are starting to be used for diagnosis4.
 
Treatment Options:
1) Cholangiocarcinomas are surgically removed and/or irradiated, chemotherapy has generally not been
successful.
2) Tumors are considered unresectable if they involve both liver lobes, bilateral IHDs, encase common hepatic
artery or bil portal vein or branches, extrahepatic metastases, or the caudate lobe.
3) Palliative treatments include surgical bypass or drainage, percutaneous drainage, and internal stent14.
3)Molecular chemotherapy combined with radiation has shown promising results. This involves using the gene
therapy strategy of toxin gene conversion of nontoxic prodrug to chemotherapeutic drug in combination with
radiation therapy. The chemotherapeutic agent of choice would be 5-FU12.
4) Liver transplantation has generally not been effective8.
 
Prognosis:
-Liver-fluke associated CCA generally has a poor prognosis, few survive more than six months after diagnosis.
-Often resistant to current surgical, chemotherapy, and radiotherapy interventions.
-Survival 2-3 years with biliary decompression.
-Survival for at least 5 years in 30-40% of patients with complete tumor ressection1.
-Death usually results from biliary obstruction rather than tumor metastases.

Background

Cholangiocarcinomas (CCCs) are malignancies of the biliary duct system that may originate in the liver and
extrahepatic bile ducts, which terminate at the ampulla of Vater.1,2,3,4 CCCs are encountered in 3 geographic
regions: intrahepatic, extrahepatic (ie, perihilar), and distal extrahepatic. Perihilar tumors are the most common
CCCs, and intrahepatic tumors are the least common. Perihilar tumors, also called Klatskin tumors (after
Klatskin's description of them in 19655 ), occur at the bifurcation of right and left hepatic ducts.6 Distal extrahepatic
tumors are located from the upper border of the pancreas to the ampulla. More than 95% of these tumors are
ductal adenocarcinomas; many patients present with unresectable or metastatic disease.

Pathophysiology

Cholangiocarcinoma is a tumor that arises from the intrahepatic or extrahepatic biliary epithelium. More than 90%
are adenocarcinomas, and the remainder are squamous cell tumors. The etiology of most bile duct cancers
remains undetermined. Long-standing inflammation, as with primary sclerosing cholangitis (PSC) or chronic
parasitic infection, has been suggested to play a role by inducing hyperplasia, cellular proliferation, and,
ultimately, malignant transformation. Intrahepatic cholangiocarcinoma may be associated with chronic ulcerative
colitis and chronic cholecystitis. 

Cholangiocarcinomas tend to grow slowly and to infiltrate the walls of the ducts, dissecting along tissue planes.
Local extension occurs into the liver, porta hepatis, and regional lymph nodes of the celiac and
pancreaticoduodenal chains. Life-threatening infection (cholangitis) may occur that requires immediate antibiotic
intervention and aggressive biliary drainage.

Frequency

United States

Each year, approximately 2500 cases of CCC occur, compared to 5000 cases of gallbladder cancer and 15,000
cases of hepatocellular cancer. Average incidence is 1 case per 100,000 persons per year.

International

Incidence in most Western countries ranges from 2 to 6 cases per 100,000 people per year. The highest annual
incidences are in Japan, at 5.5 cases per 100,000 people, and in Israel, at 7.3 cases per 100,000 people.

Mortality/Morbidity

Despite aggressive anticancer therapy and interventional supportive care (ie, wall stents or percutaneous biliary
drainage), median survival rate is low, since most patients (90%) are not eligible for curative resection. The
overall survival is approximately 6 months.

Race

Native Americans have the highest annual incidence in North America, at 6.5 cases per 100,000 people. This
rate is about 6 times higher than that in non – Native American populations. The high prevalence of
cholangiocarcinoma in people of Asian descent is attributable to endemic chronic parasitic infestation.
Sex

The male-to-female ratio for cholangiocarcinoma is 1:2.5 in patients in their 60s and 70s and 1:15 in patients
younger than 40 years. According to the American Cancer Society, the number of new cases of liver and
intrahepatic bile duct cancer in 2007 is estimated to be 13,650 for men and 5,510 for women,
with estimated mortality of 11,280 and 5,500, respectively. The estimated number of new cases of gallbladder
and other biliary cancers (extrahepatic cholangiocarcinoma) are 4,380 for men and 4,870 for women, with
estimated mortality rates of 1,260 and 1,990, respectively.7

Age

Highest prevalence rate occurs in males and females in their 60s and 70s.

Clinical

History

Symptoms of cholangiocarcinoma include jaundice, clay-colored stools, bilirubinuria (dark urine), pruritus, weight
loss, and abdominal pain.

 Jaundice is the most common manifestation of bile duct cancer and, in general, is best detected in direct
sunlight. The obstruction and subsequent cholestasis tend to occur early if the tumor is located in the
common bile duct or common hepatic duct. Jaundice often occurs later in perihilar or intrahepatic
tumors and is often a marker of advanced disease. The excess of conjugated bilirubin is associated with
bilirubinuria and acholic stools.
 Pruritus usually is preceded by jaundice, but itching may be the initial symptom of cholangiocarcinoma.
Pruritus may be related to circulating bile acids.
 Weight loss is a variable finding and may be present in one third of patients at the time of diagnosis.
 Abdominal pain is relatively common in advanced disease and often is described as a dull ache in the
right upper quadrant.

Physical

 If the cholangiocarcinoma is located distal to the cystic duct takeoff, the patient may have a palpable
gallbladder, which commonly is known as Courvoisier sign.
 An abdominal mass or palpable lymphadenopathy is uncommon, but hepatomegaly may be noted in as
many as 25% of patients.

Causes

The etiology of most bile duct cancers remains undetermined. Currently, gallstones are not believed to increase
the risk of cholangiocarcinoma. Chronic viral hepatitis and cirrhosis also do not appear to be risk factors.

 Infections
o In Southeast Asia, chronic infections with liver flukes, Clonorchis sinensis, and Opisthorchis
viverrini have been causally related to cholangiocarcinoma.
o Other parasites, such as Ascaris lumbricoides, have been implicated in the pathogenesis of
cholangiocarcinoma.
o Observations have raised the possibility that bacterial infections with Helicobacter species may
play an etiologic role in biliary cancer.8
 Inflammatory bowel disease
o A strong relationship exists between cholangiocarcinoma and primary sclerosing
cholangitis. Cholangiocarcinoma generally develops in patients with long-standing ulcerative
colitis and primary sclerosing cholangitis.9
o The lifetime risk of developing this cancer in the setting of primary sclerosing cholangitis is 10-
20%. At increased risk are patients with ulcerative colitis without symptomatic primary
sclerosing cholangitis and a small subset of patients with Crohn disease.
 Chemical exposures
o Certain chemical exposures have been implicated in the development of bile duct cancers,
primarily in workers in the aircraft, rubber, and wood-finishing industries.
 o Cholangiocarcinoma occasionally has developed years after administration of the radiopaque
medium thorium dioxide (ie, thorotrast).
 Congenital diseases of the biliary tree, including choledochal cysts and Caroli disease, have been
associated with cholangiocarcinoma.
 Other conditions rarely associated with cholangiocarcinoma include bile duct adenomas, biliary
papillomatosis, and alpha 1 -antitrypsin deficiency.

Laboratory Studies

 Routine lab studies

o Extrahepatic cholestasis is reflected in elevated conjugated (ie, direct) bilirubin levels. Alkaline
phosphatase levels usually rise in conjunction with bilirubin levels. Because alkaline
phosphatase is of biliary origin, gamma-glutamyltransferase (GGT) also will be elevated.
o Aminotransferases (ie, aspartate aminotransferase [AST], alanine aminotransferase [ALT])
may be normal or minimally elevated. Biochemical tests of hepatic function (ie, albumin,
prothrombin time [PT]) are normal in early disease.
o With prolonged obstruction, the prothrombin time (PT) can become elevated because
of vitamin K malabsorption. Hypercalcemia may occur occasionally in the absence of osteolytic
metastasis.
 Tumor markers
o A variety of markers have been tested in bile and serum with limited success. This becomes a
significant issue in primary sclerosing cholangitis (PSC), in which clinical features and imaging
findings overlap.
o Tumor marker carbohydrate antigen 19-9 (CA 19-9) can be evaluated in pancreatic and bile
duct malignancies, as well as in benign cholestasis. A serum CA 19-9 level greater than 100
U/mL (normal <40 U/mL) has 75% sensitivity and 80% specificity in identifying patients with
PSC who have cholangiocarcinoma.9
o In PSC, an index of markers, carcinoembryonic antigen (CEA) and CA 19-9, has an accuracy
of 86% using the following formula: CA 19-9 + (CEA × 40).
o Cholangiocarcinoma does not produce alpha-fetoprotein.

Imaging Studies

 A number of potential imaging modalities are available, as depicted in the image below. In general,
ultrasonography or computed tomography (CT) is performed initially, followed by a type of
cholangiography
 Ultrasound may demonstrate biliary duct dilatation and larger hilar lesions.
o Small lesions and distal cholangiocarcinomas are difficult to visualize.
o Patients with underlying primary sclerosing cholangitis (PSC) may have limited ductal dilatation
secondary to ductal fibrosis.
o Doppler ultrasound may show vascular encasement or thrombosis.
 CT resembles ultrasound in that it may demonstrate ductal dilatation and large mass lesions.
o CT also has the capability to evaluate for pathologic intra-abdominal lymphadenopathy.
o Helical CT scans are accurate in diagnosing the level of biliary obstruction. Three-dimensional
and multiphase CT images may improve CT yield.
 Magnetic resonance imaging (MRI) demonstrates hepatic parenchyma.
o MR cholangiography enables imaging of bile ducts and, in combination with MR angiography,
permits staging (excluding vascular involvement). Hepatic involvement can also be detected.
o This technique likely will replace angiography for vascular evaluation.
 New techniques
o Preliminary evaluation with positron emission tomography (PET) has shown promise in
diagnosing underlying PSC.10 Small lesions (ie, <1 cm) have been demonstrated. PET is
accurate for detecting nodular carcinomas, but the sensitivity diminishes for infiltrating lesions.
PET should be interpreted with caution in patients with PSC and stents in place. PET/CT has
been shown to be valuable in detecting unsuspected distant metastases.11
o Endoscopic ultrasonography (EUS) enables both bile duct visualization and nodal evaluation.
This technique also has the capability to aspirate for cytologic studies. EUS-guided fine-needle
aspiration results may be positive when other diagnostic tests are inconclusive.12
o Intraductal EUS allows direct ultrasonographic evaluation of the lesion.
 Cholangiography includes MR cholangiography (as noted above), endoscopic retrograde
cholangiopancreatography (ERCP), and percutaneous transhepatic cholangiography (PTC).
Other Tests

 Angiography: Evaluation of vascular involvement is important if considering surgical treatment.

Arteriography demonstrating extensive encasement of the hepatic arteries or portal vein precludes
curative resection. Combining the findings on cholangiography with those on arteriography has been
found to have a greater accuracy in predicting unresectability. However, an occasional patient has
compression of vascular structures rather than true malignant invasion.

Procedures

 ERCP demonstrates the site of obstruction by direct retrograde dye injection and excludes ampullary
pathology by endoscopic evaluation.
o Brush cytology, biopsy, needle aspiration, and shave biopsies via ERCP can provide material
for histologic studies.
o Palliative stenting to relieve biliary obstruction can be performed at the time of evaluation.
 PTC may allow access to proximal lesions with obstruction of both right and left hepatic ducts. Material
for cytologic studies may be obtained and drainage performed.
 Other methods to obtain tissue include CT- or ultrasound-guided needle aspiration, if a mass lesion is
present, and EUS fine-needle aspiration.

Histologic Findings

Classic cholangiocarcinomas are well to moderately differentiated adenocarcinomas that exhibit glandular or
acinar structures; intracytoplasmic mucin is almost always observed. Characteristically, cells are cuboidal or low
columnar and resemble biliary epithelium. In more poorly differentiated tumors, solid cords of cells without lumina
may be present. Mitotic figures are rare. A dense fibrous stroma is characteristic and may dominate the histologic
architecture. It tends to invade lymphatics, blood vessels, perineural and periductal spaces, and portal tracts.
Spread along the lumen of large bile ducts can be seen, especially with hilar tumors.

Tumor cells provoke variable desmoplastic reactions. Cytologic studies on material obtained by any method often
yield nondiagnostic results secondary to desmoplastic reaction. For this reason, sensitivity and positive predictive
value of brush cytologic studies are rather poor for dominant strictures in primary sclerosing cholangitis.

Staging

The American Joint Committee on Cancer guidelines in the AJCC Cancer Staging Manual, Fifth Edition, following
the tumor, node, and metastasis (TNM) classification system, with depth of tumor penetration and regional
spread defined pathologically, should be followed.

 T - Primary tumor
o TX - Primary tumor cannot be assessed
o T0 - No evidence of primary tumor
o TIS - Carcinoma in situ
o T1a - Tumor invades mucosa
o T1b - Tumor invades muscularis
o T2 - Tumor invades perimuscular connective tissue
o T3 - Tumor invades liver, gallbladder, duodenum, stomach, pancreas, or colon
 N - Regional lymph nodes
o NX - Regional lymph nodes cannot be assessed
o N0 - No metastases in regional lymph nodes
o N1 - Metastases in cystic duct or pericholedochal or hilar lymph nodes of hepatoduodenal
ligament
o N2 - Metastases in peripancreatic (head only), periduodenal, posterior pancreatoduodenal,
periportal, celiac, or superior mesenteric regional lymph nodes
 M - Metastasis
o MX - Presence of metastases cannot be assessed
o M0 - No distant metastases
o M1 - Distant metastases (includes lymph node metastases beyond N2)
 TNM groupings by stage
o Stage 0 - TIS N0 M0
o Stage I - T1 N0 M0
 o Stage II - T2 N0 M0
o Stage III - T1-2 N1-2 M0
o Stage IVa - T3 N0-2 M0
o Stage IVb - T1-3 N0-2 M1

Medical Care

 Stenting may relieve pruritus and improve quality of life.

o Palliative plastic or metal stents can be placed by ERCP or PTC to relieve biliary obstruction.
They usually are used if the tumor is unresectable or if the patient is not a surgical candidate.
Debate exists about whether preoperative stenting is warranted, but most surgeons believe
that preoperative biliary decompression does not alter the outcome of surgery.
o Plastic stents usually occlude in 3 months and require replacement.
o Metal stents are more expensive but expand to a larger diameter and tend to stay patent
longer. Adequate biliary drainage can be achieved in a high percentage of cases.
 Photodynamic therapy (PDT) is a new experimental local cancer therapy already in use for other GI
malignancies.13,14
 PDT is a 2-step process: the first step is intravenous (IV) administration of a photosensitizer; the second
step is activation by light illumination at an appropriate wavelength.13,14
 PDT is effective in restoring biliary drainage and improving quality of life in patients with nonresectable
disseminated cholangiocarcinomas. Survival times may be longer than those reported previously. A
prospective, multicenter study showed a significant survival benefit in the PDT treatment group.13 An
additional multicenter study is being planned.
 In addition, other endoscopic forms of palliation, such as brachytherapy, have been used.15
 Most often, chemotherapy is given in low doses to act as a radiation sensitizer during a 4- to 5-week
course of external-beam radiotherapy. Primary chemotherapy has been evaluated, as well including
gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma.16,17
 Adjuvant and preoperative radiation therapy has been used to reduce tumors in an effort to make them
resectable. This therapy has been performed with and without concurrent chemotherapy as a radiation
sensitizer.
 The value of adjuvant radiotherapy has been to improve local control, with variable effect on overall
survival rate after complete resection. Several series have shown an increase in median survival
duration with postoperative radiation, from 8 months with surgery alone to more than 19 months.
 Special radiation techniques have been used, such as intraluminal brachytherapy and external-beam
therapy during surgery (ie, intraoperative radiotherapy [IORT]). See the image below for treatment
planning technique.
 Chemotherapy agents used without radiotherapy or surgery do not appear to provide any local control
or meaningful survival benefit.
 The most used agent is 5-fluorouracil, which has a partial response rate of about 12%. Gemcitabine has
a similar response rate. Although fluoropyrimidines and doxorubicin have been reported to have
response rates as high as 30-40%, partial responses lasting from weeks to months have been observed
in only 10-35% of trials.16,17 Marimastat in early trials has been reported to be associated with a higher
rate of response, but the number of patients treated with this agent is small. Overall, the duration of any
response seen has been no better than 3-6 months, and median survival has been 11 months or less.
 For palliative treatment, celiac-plexus block via regional injection of alcohol or other sclerosing agent
can relieve pain in the mid back that is associated with retroperitoneal tumor growth.

Surgical Care
Complete surgical resection is the only therapy to afford a chance of cure. Unfortunately, only 10% of patients
present with early stage disease and are considered for curative resection. Intrahepatic and Klatskin tumors6
require liver resection, which may not be an option for older patients with comorbid conditions. In one report, 15%
of patients with proximal lesions were candidates for complete resections, with higher rates in patients with mid-
ductal tumors (33%) or distal tumors (56%). The survival rate for patients with proximal tumors can be 40% if
negative margins are obtained. The National Comprehensive Cancer Network suggests reresection, ablation, or
chemotherapy for intrahepatic cholangiocarcinomas that are resected with microscopic margins or residual local
disease.18 Those with no residual local disease after resection can be followed with imaging periodically.

 Orthotopic liver transplantation is considered for some patients with proximal tumors who are not
candidates for resection because of the extent of tumor spread in the liver. The largest series reports a
53% 5-year survival rate and a 38% complete pathologic response rate with preoperative radiation
therapy and chemotherapy. Liver transplantation may have a survival benefit over palliative treatments,
especially for patients with tumors in the initial stages. One study has demonstrated a 5-year survival
rate greater than 80% in select patients.19
  Distal tumors are resected via Whipple procedure; periampullary region tumors have a uniformly better
prognosis, with a long-term survival rate of 30-40%.
 Patterns of treatment failure after curative surgery show disappointingly high rates of tumor bed and
regional nodal recurrence. This finding may be due in part to the narrow pathologic margins; however,
the regional node failure rate is approximately 50%, and the distal metastases rate is 30-40%. Failures
are correlated with TNM stage.
 Palliative procedures are required if internal stenting cannot be accomplished and/or external stenting is
not desirable or cannot be obtained; surgical bypass, particularly for tumors in the common bile duct,
should be performed.

Consultations

Gastroenterologists, interventional radiologists, and transplant/biliary surgeons play a key role in diagnosis and
management. Radiation oncology and medical oncology specialists are part of the multidisciplinary team taking
part in the treatment of both patients with curatively resected tumors and those with unresectable tumors.
Radiation oncologists have taken a more significant role in therapy for cholangiocarcinomas since the early
1980s.

Follow-up

Further Outpatient Care

 Most patients with cholangiocarcinoma require follow-up care for acute and late adverse effects of
therapy. Aggressive follow-up care also is necessary to treat symptoms from tumor recurrence and
persistence. Patients with the best prognosis may be seen every 2-3 months with periodic laboratory
and imaging studies (eg, CT scan).
 Patients treated palliatively may enter hospice programs rapidly, as median survival duration is only 2-8
months.

Complications

 Infection of the biliary tree (ie, cholangitis) may result from cholangiocarcinoma and subsequent
obstruction of the duct.
 Between 10 and 20% of patients with cholangiocarcinoma develop cirrhosis. This may be secondary
biliary cirrhosis resulting from neoplastic obstruction of the bile ducts or related to underlying fibrosis
from primary sclerosing cholangitis.
 Other complications are usually the result of diagnostic and therapeutic procedures.

Prognosis

 Patients with perihilar tumors that are completely resected may achieve long-term survival. Prognosis is
poorest for patients with intrahepatic tumors.
 Patients with distal extrahepatic tumors may have the best hope for survival if tumors are excised
completely; tumors at this site are the most likely to be resectable. These patients may experience a 5-
year survival rate as high as 40%. The median survival duration in patients who undergo resection and
postoperative chemoradiation may be as high as 17-27.5 months.
 An intermediate prognosis (ie, median survival duration of 7-17 mo) is achieved for patients who are
unable to undergo resection but can tolerate adjuvant chemoradiation or possibly photodynamic
therapy.
 The poorest prognosis is for the patient with unresectable disease, with or without overt metastatic
disease, who can tolerate only palliative stent placement.

Miscellaneous

Medicolegal Pitfalls

 The diagnosis of cholangiocarcinoma should be considered in patients with obstructive jaundice.

 Absence of biliary ductal dilatation may be misleading in patients with long-standing sclerosing
cholangitis. Fibrotic ducts may not dilate readily. In addition, the fibrotic nature of the stenosis may yield
false-negative brush cytology results.