Pathophysiology

Cholangiocarcinomas arise 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.

Epidemiology

Frequency

United States

Each year, approximately 2500 cases of cholangiocarcinoma occur, compared with 5000
cases of gallbladder cancer and 15,000 cases of hepatocellular cancer. The average incidence
is one case per 100,000 population per year.

A study by Singal et al found that the frequency of intrahepatic cholangiocarcinoma has

increased over time and is most commonly noted in women older than 60 years.

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.

Occupational cholangiocarcinoma has been documented in workers at printing companies in

Japan who had been exposed to high concentrations of chemical compounds, including 1,2-
dichloropropane (1,2-DCP) and/or dichloromethane. Heavy infestation by the liver flukes
Clonorchis sinensis (endemic predominantly in Asian countries, including Korea, China,
Taiwan, Vietnam, and far eastern Russia) and Opisthorchis viverrini (the Southeast Asian
liver fluke) has been linked to the development of cholangiocarcinoma.

Mortality/Morbidity

Despite aggressive anticancer therapy and interventional supportive care (ie, wall stents or
percutaneous biliary drainage), the 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 and age

In both males and females, cholangiocarcinoma is most common in persons in their 60s and
70s. 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 2018 is estimated to be
30,610 for men and 11,610 for women, with deaths estimated at 20,540 and 9,660,
respectively. The estimated number of new cases of gallbladder and other biliary cancers
(extrahepatic cholangiocarcinoma) are 5,450 for men and 6,740 for women, with estimated
deaths of 1,530 and 2,260, respectively.

History

Signs and symptoms of cholangiocarcinoma include the following:

 Jaundice
 Clay-colored stools
 Bilirubinuria (dark urine)
 Pruritus
  Weight loss
 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. It may be present in one third of patients at the time of
diagnosis.

Abdominal pain is relatively common in advanced disease. It 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 is commonly known as Courvoisier sign.

An abdominal mass or palpable lymphadenopathy is uncommon, but hepatomegaly may be

noted in as many as 25% of patients.

Differential Diagnoses

- Bile Duct Strictures

- Bile Duct Tumors
- Biliary Disease
- Biliary Obstruction
- Cholangitis
- Cholecystitis
- Choledochal Cysts
- Gallstones (Cholelithiasis)
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
some form of cholangiography. Techniques used for cholangiography include magnetic
resonance cholangiography, endoscopic retrograde cholangiopancreatography (ERCP), and
percutaneous transhepatic cholangiography (PTC).

Tight stricture of a common hepatic duct in a patient presenting with jaundice. Cytologic
studies confirmed cholangiocarcinoma.

Ultrasound may demonstrate biliary duct dilatation and larger hilar lesions. Small lesions and
distal cholangiocarcinomas are difficult to visualize. Patients with underlying primary
sclerosing cholangitis (PSC) may have limited ductal dilatation secondary to ductal fibrosis.
Doppler ultrasound may show vascular encasement or thrombosis.

CT resembles ultrasound in that it may demonstrate ductal dilatation and large mass lesions.
CT also has the capability to evaluate for pathologic intra-abdominal lymphadenopathy.
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. MR cholangiography

enables imaging of bile ducts and, in combination with MR angiography, permits staging
(excluding vascular involvement). Hepatic involvement can also be detected. This technique
likely will replace angiography for vascular evaluation.

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 should enter hospice programs rapidly, as median survival
duration is only 2-8 months.

Complications

Complications include the following:

- Infection of the biliary tree (ie, cholangitis) may result from cholangiocarcinoma and
subsequent obstruction of the duct.
- Cirrhosis develops in 10-20% of patients with cholangiocarcinoma. 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. A study by Polistina et al found that chemoradiation given
by stereotactic body radiotherapy plus gemcitabine offers high local control rates and
is a promising treatment.
- 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.
- In a study of surgically resected hilar cholangiocarcinoma specimens, the presence of
necrosis was associated with a worse prognosis. Necrosis was evident in 19 of 47
tumor samples. Compared with patients whose tumors showed no necrosis, those
whose tumors showed necrosis had significantly lower 5-year recurrence-free survival
(37.9% vs. 25.7%) and 5-year overall survival (42.6% vs.12.4%).
- A study by Ghafoori et al found that patients with locally advanced extrahepatic
cholangiocarcinoma have poor survival with rare long-term survival. Most patients
treated with external beam radiation therapy (EBRT) had local control at the time of
death, which suggests that symptoms related to the local tumor effect may be
controlled using radiation therapy. The authors concluded that novel approaches are
indicated in the therapy for this condition.
- A study of prognostic scores in 219 patients with unresectable perihilar
cholangiocarcinoma concluded that the modified Glasgow Prognostic Score (mGPS)
and the neutrophil-to-lymphocyte ratio (NLR) . each have prognostic value, but the
platelet-to-lymphocyte ratio and Prognostic Nutritional Index do not. In addition, the
combination of mGPS and NLR stratified survival well: mean survival time was
12.8 months in patients with an mGPS of 0 and an NLR of 1 or 2, but was only
3.0 months in patients with an mGPS of 1 or 2 and an NLR of 2.