Second most common primary cancer of the liver.

Encompasses malignancies arising from epithelial cells that line the biliary tree.

Approximately 8-9 000 new diagnoses are made each year in the US.

Its fatality rate is high-the five-year survival rate for patients with intrahepatic bile duct cancers is 9%,  for all stages combined.

CCA’s poor prognosis is poor, driven by a lack of effective screening techniques.

CCA is frequently asymptomatic at early stages, and when symptoms appear, disease is advanced, and not amenable to therapy.

Global incidence is rising and East Asian countries are disproportionately affected.

It is classified as intrahepatic, or extrahepatic, which includes perihilar, also called Klatskin tumor, and distal cholangiocarcinoma.

A cholangiocarcinoma occurring at the confluence of the right and left hepatic bile ducts is referred to as a Klatskin tumor.

Cholangiocarcinoma is a rare, aggressive cancer of the bile ducts in and outside the liver.


IDH1 mutations are found in an estimated 20% of intrahepatic cholangiocarcinoma cases. 

Cholangiocarcinoma accounts for approximately 2% of all cancer diagnoses, with an overall incidence of 1.2/100,000 individuals.

Cholangiocarcinoma is the most common primary biliary tract malignancy in the second most common primary hepatic malignancy: affecting 2-3000 people each year in the US.

Approximately 8-9000 new cases are diagnosed annually with a relatively equal distribution between intrahepatic and extra hepatic cholangiocarcinomas.

It accounts for proximally 10-15% of primary hepatic malignancies.

More than 90% of cases are adenocarcinoma and are divided into histological types based on growth patterns, formation, periductal infiltration, and intraductal growth.

It generally arises de novo without associated inherited risk factors.

Risk factors include infections from endemic parasites, such as river flukes that can cause inflammation of the biliary tree and promote the development of malignancy.

Other risk factors include primary hepatobiliary diseases-Chiefly primary sclerosing cholangitis, inherited genetic disorders, such as Lynch syndrome, chronic tobacco, or alcohol use,and the metabolic syndrome.

Non-genetic risk factors include hepatitis B and C.

Two-thirds of cases over the age of 65, with a near ten-fold increase in patients over 80 years of age.

The incidence of intrahepatic cholangiocarcinoma is increasing worldwide.

The incidence is similar in both men and women.

Etiology is poorly understood.

Has unique molecular alterations not commonly found another solid tumors, such as IDH1 mutations and a large variety of FGFR2 rearrangements.

Risk factors include: primary sclerosing cholangitis, alcohol consumption, liver cirrhosis, and chronic viral hepatitis infections.

The contribution of hepatitis B and C to the development of cholangiocarcinoma differs in geography: hepatitis B is endemic in Asian countries, and hepatitis C is more prevalent in western countries.

Southeast Asia has very high incidence of cholangiocarcinoma due to a high prevalence of hepatobiliary flukes that infect humans.

Prevalence increases steadily with age, peaking in the seventh decade.

Increasing incidence is occurring in most countries.

Incidence has been increasing in intrahepatic versus extrahepatic disease, and younger versus older patients, men versus women, and Asian/pacific islanders versus other races.

In the US Hispanic men are at higher risk, and African-American man have the lowest risk, where as Asians/pacific Islanders and Caucasion prevalence rates ranging between these groups.

Cholangiocarcinoma has a high male predominance, except for Hispanic women who have higher rates of intrahepatic cholangiocarcinomas.

Intrahepatic cholangiocarcinomas have the highest rates in American Indians and Asians.

The prognosis is poor owing to a generally aggressive disease, late stage diagnosis, and limited treatment options for advanced cholangiocarcinoma.

3-year survival of 15% to 40% after resection.

For intrahepatic cholangiocarcinoma vascular vision is major if it affects the inferior vena cava or a portal vein and is generally considered a contraindication to surgery due to high intraoperative and perioperative complications.

In patients with intrahepatic cholangiocarcinoma, there is a five-year overall survival rate of less than 8%, and among those with advanced disease, the median overall survival is approximately one year.

Tumors of the biliary confluence of the right or left hepatic ducts are most common and account for 40-60% of all cases.

Can occur anywhere from the distal common bile duct in the ampulla of Vater to the peripheral intrahepatic bile ducts.

Categorization is based on location, morphology, and treatment options.

Divided into cholangiocarcinomas occurring below or distal to the biliary bifurcation are described is extrahepatic or distal carcinomas, those occurring at or near the biliary bifurcation as central cholangiocarcinomas and those occurring in the liver as intrahepatic or peripheral cholangiocarcinoma.

Classified as originating from the intra and extra-hepatic biliary epithelium.

There are significant genomic differences in the intrahepatic and extrahepetic bile duct cancers..

Extrahepatic lesions are further divided into upper third or perihilar tumors, middle third tumors and distal bile duct tumors.

Lesions involving the hepatic bifurcation are known as Klatskin’s tumors.

Distal cholangiocarcinomas manifest similar to other periampullary tumors with signs and or symptoms of obstructive jaundice.

Distal cholangiocarcinomas that are resectable should undergo pancreaticoduodenectomy or resection of extrahepatic bile duct with hepaticojejunostomy reconstruction.

In distal cholangiocarcinoma where portal vein involvement or common hepatic artery involvement is present, resection can often still be undertaken with vascular reconstruction.

5% of lesions are multifocal.

Occurs in approximately 1 in 256 patients with ulcerative colitis, and 10-20 % of patients with primary sclerosing cholangitis.

Median survival about 16 months for all patients.

Median survival for patients undergoing resection 35 months compared to 10 months for patients not able to be resected.

Outcome is associated with pathologic findings of depth of tumor penetration and lymph node metastases.

Mainstay of treatment for almost all forms of cholangiocarcinoma is complete surgical resection.

Curative resection is reserved for patients with early disease.

For  localized disease, treatment is aimed at definitive surgical resection, often followed by adjuvant therapy with systemic chemotherapy or chemoradiotherapy.

Neoadjuvant therapy is employed to downstage localized unresectable disease.

No curated medical therapies exist for advanced disease.

Many lesions are not amenable to resection due to involvement of major hepatic vascular or biliary structures or due to excessive hepatic parenchymal involvement.

Gemcitabine plus capecitabine results in a response rate of 31% and stable disease in 42% of patients with advanced disease and a median survival of 14 months.

Combination therapy with gemcitabine and cis-platinum have become standard treatments.

FOLFOX is a second line treatment with an objective response rate of 5% in a median overall survival of 6.2 months.

Approved pemigatinib for the treatment of adults with certain types of pretreated, advanced cholangiocarcinoma.

Pemazyre trade name.

107 pretreated patients with locally advanced or metastatic cholangiocarcinoma and an FGFR2 fusion or rearrangement.


Overall  response rate was found to be 36%, with 2.8% of patients having a complete response and 33% having a partial response. 


Among the 38 responders, 24 (63%) and 7 (18%) patients had responses lasting ≥6 months and ≥12 months, respectively.

Adverse reactions were: hyperphosphatemia and hypophosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, joint pain, abdominal pain, back pain, and dry skin.

Infigratinib approved for the treatment of patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring an FGFR2 fusion or rearrangement.

Futibatinib, a covalent FGFR inhibitor treatment of patients with FGFR2 fusion or rearrangement positive intrahepatic cholangiocarcinoma has a 42% response rate.

There are significant genomic differences in the intrahepatic and extrahepetic bile duct cancers.


Leave a Reply

Your email address will not be published. Required fields are marked *