Cholangiocarcinoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2] [3] [4], Suveenkrishna Pothuru, M.B,B.S. [5]

Cholangiocarcinoma refers to the malignant tumor of bile ducts. The epithelial cell lining the bile ducts are called cholangiocytes. The malignant transformsation of cholangiocytes leads to cholangiocarcinoma. Malignant transformation of cholangiocytes into cholangiocarcinoma include hyperplasia, metaplasia and dysplasia. Biliary intraepithelial neoplasia is believed to be the initial lesion of cholangiocarcinoma, particularly in patients with hepatolithiasis in bile ducts. On the basis of location, cholangiocarcinoma may be classified into extrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, and intrahepatic cholangiocarcinoma. Cholangiocarcinoma must be differentiated from other diseases that cause jaundice, abdominal pain, weight loss, and fatigue, such as gallbladder cancer, hepatocellular carcinoma, pancreatic cancer, cholecystitis, and choledochitis. Common complications of cholangiocarcinoma include infection, liver failure, and tumor metastasis. Prognosis is generally poor, and the survival rate of patients with cholangiocarcinoma mainly depends on extent of the tumor and resectability. The common symptoms of cholangiocarcinoma include jaundice, pruritis, abdominal pain, weight loss. Common physical examination findings of cholangiocarcinoma include jaundice, icteric sclera, hepatomegaly, right upper quadrant mass, and palpable gall bladder. The mainstay of treatment for cholangiocarcinoma is surgical resection. Surgical resection of tumors with negative margins is the best option for all subtypes of cholangiocarcinoma. Chemotherapy is indicated for unresectable cholangiocarcinoma as palliative chemotherapy. Chemotherapy agents used to treat cholangiocarcinoma include 5-fluorouracil, gemcitabine, irinotecan, cisplatin, or doxorubicin.

Cholangiocarcinoma may be classified according to location of the tumor into three subtypes such as extrahepatic bile duct cancer, perihilar bile duct cancer, and intrahepatic bile duct cancer. Perihilar cholangiocarcinoma may be classified according to Bismuth-Corlette classification into five subtypes based on the extent of ductal infiltration.

The epithelial cell lining the bile ducts are called cholangiocytes. The malignant transformsation of cholangiocytes leads to cholangiocarcinoma. Malignant transformation of cholangiocytes into cholangiocarcinoma include hyperplasia, metaplasia and dysplasia. Biliary intraepithelial neoplasia is believed to be the initial lesion of cholangiocarcinoma, particularly in patients with hepatolithiasis in bile ducts.

There are no established causes for cholangiocarcinoma.

Cholangiocarcinoma must be differentiated from other diseases that cause jaundice, abdominal pain, weight loss, and fatigue, such as gallbladder cancer, hepatocellular carcinoma, pancreatic cancer, cholecystitis, and choledochitis.

The incidence of cholangiocarcinoma is approximately 1-2 per 100,000 individuals in the United States. The prevalence of cholangiocarcinoma is approximately 0.01% to 0.46% per 100,000 individuals. Patients of all age groups may develop cholangiocarcinoma. Cholangiocarcinoma is more common in males than in females.

Common risk factors in the development of cholangiocarcinoma are chronic inflammatory conditions of bile duct, liver fluke infections, choledochal cysts, toxins, and viral infections.

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for cholangiocarcinoma.

Common complications of cholangiocarcinoma include infection, liver failure, and tumor metastasis. Prognosis is generally poor, and the survival rate of patients with cholangiocarcinoma mainly depends on extent of the tumor and resectability. Even with resection, prognosis is poor with 5-year survival of only 10-44%. The presence of primary sclerosing cholangitis is associated with a particularly poor prognosis among patients with cholangiocarcinoma.

The staging of cholangiocarcinoma varies depending on whether the tumor is primarily intrahepatic (ICC), hilar/perihilar (Klatskin), or extrahepatic. Current staging classifications of intrahepatic cholangiocarcinoma include UICC system, Okabayashi system, and AJCC system. Current staging classifications of perihilar cholangiocarcinoma include MSKCC system and AJCC system.

The common symptoms of cholangiocarcinoma include jaundice, pruritis, abdominal pain, weight loss.

Common physical examination findings of cholangiocarcinoma include jaundice, icteric sclera, hepatomegaly, right upper quadrant mass, and palpable gall bladder.

Laboratory tests for cholangiocarcinoma include aspartate aminotransferase (AST) and alanine aminotransferase (ALT), prothrombin time, albumin and total protein, bilirubin, L-Lactate dehydrogenase and alkaline phosphatase.

On CT scan, cholangiocarcinoma is characterized by homogenously low in attenuation and demonstrate heterogenous minor peripheral enhancement with gradual enhancement centrally. Capsular retraction may be observed. Bile ducts distal to the mass are typically dilated.

On MRI, cholangiocarcinoma is characterized by either isointense or hypointense relative to the normal liver on T1 and mildly to markedly hyperintense on T2. Moderate to incomplete enhancement is observed on contrast MRI.

On abdominal ultrasound, cholangiocarcinoma is characterized by obstruction and dilation of bile ducts. Mass-forming intrahepatic cholangiocarcinoma is characterized by homogeneous mass of intermediate echogenicity with a peripheral hypoechoic halo of compressed liver. Periductal infiltrating intrahepatic cholangiocarcinoma is characterized by capsular retraction. Intraductal cholangiocarcinoma is characterized by alterations in duct caliber, usually duct ectasia with or without a visible mass.

Other imaging studies for cholangiocarcinoma include endoscopic retrograde cholangiopancreatography, endoscopic ultrasound, percutaneous transhepatic cholangiography, and MRCP.

No additional tests are recommended for the diagnosis of cholangiocarcinoma.

Chemotherapy is indicated for unresectable cholangiocarcinoma as palliative chemotherapy. Chemotherapy agents used to treat cholangiocarcinoma include 5-fluorouracil, gemcitabine, irinotecan, cisplatin, or doxorubicin.

The mainstay of treatment for cholangiocarcinoma is surgical resection. Surgical resection of tumors with negative margins is the best option for all subtypes of cholangiocarcinoma.

Effective measures for the primary prevention of cholangiocarcinoma hepatitis B vaccination, weight reduction, avoiding excess alcohol use.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

In 1973, Lubana et al reported the first case of primary intrahepatic cholangiocarcinoma with right upper quadrant pain, jaundice, and weight loss.

• In 1965, Gerald Kaltskin first described adenocarcinoma of hepatic duct at its bifurcation within porta hepatis. It is called “Kaltskin tumor”.^[1]
• In 1973, Lubana et al reported the first case of primary intrahepatic cholangiocarcinoma with right upper quadrant pain, jaundice, and weight loss.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2] [3], Suveenkrishna Pothuru, M.B,B.S. [4]

Cholangiocarcinoma may be classified according to location of the tumor into three subtypes of Intrahepatic bile duct cancer, perihilar bile duct cancer, and extrahepatic bile duct cancer.

• Cholangiocarcinoma may be classified according to location of the tumor into three subtypes:^[1][2][3]
  • Intrahepatic bile duct cancer
  • Perihilar bile duct cancer
  • Extrahepatic bile duct cancer

Intrahepatic Bile Duct Cancer

• Mass-forming tumor growth pattern
• Periductal-infiltrating tumor growth pattern
• Mixed mass-forming and periductal-infiltrating growth pattern

Perihilar Bile Duct Cancer

• Carcinoma in situ
• Adenocarcinoma

• Intestinal type
• Mucinous type
• Clear cell type

• Signet-ring cell carcinoma
• Adenosquamous carcinoma
• Squamous cell carcinoma
• Small cell (oat cell) carcinoma
• Undifferentiated carcinoma

• Spindle cell type
• Giant cell type
• Small cell type

• Papillomatosis
• Papillary carcinoma

• Noninvasive
• Invasive

• Carcinoma, NOS

Extrahepatic Bile Duct Cancer

• Carcinoma in situ
• Adenocarcinoma, not otherwise specified (NOS)
• Adenocarcinoma

• Intestinal type
• Mucinous type
• Clear cell type

• Signet-ring cell carcinoma
• Adenosquamous carcinoma
• Squamous cell carcinoma
• Small cell (oat cell) carcinoma
• Undifferentiated carcinoma

• Spindle cell type
• Giant cell type
• Small cell type

• Papillomatosis
• Papillary carcinoma

• Noninvasive

• Papillary carcinoma
  • Invasive

Bismuth-Corlette classification

• Type I: Tumors are distal to the hepatic duct confluence
• Type II: Neoplasms extend to and involve the hepatic duct confluence
• Type IIIA: Tumors involve the hepatic duct confluence and either the proximal right hepatic duct
• Type IIIB: Tumors involve the hepatic duct confluence and either the proximal left hepatic duct
• Type IV: Tumors extend into the bilateral proximal hepatic ducts up to the segmental bile ducts

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2], Anmol Pitliya, M.B.B.S. M.D.[3]

The epithelial cell lining the bile ducts are called cholangiocytes. The malignant transformsation of cholangiocytes leads to cholangiocarcinoma. Malignant transformation of cholangiocytes into cholangiocarcinoma include hyperplasia, metaplasia and dysplasia. Biliary intraepithelial neoplasia is believed to be the initial lesion of cholangiocarcinoma, particularly in patients with hepatolithiasis in bile ducts. Gross pathologic features characteristic to intrahepatic cholangiocarcinoma are divided in three subtypes and include mass forming type, periductal infiltrating type, and intraductal growth type. On microscopic pathology, characteristic findings of cholangiocarcinoma include cuboidal or columnar mucin producing cells and dense fibrous (desmoplastic) stroma.

• The epithelial cell lining the bile ducts are called cholangiocytes. The malignant transformsation of cholangiocytes leads to cholangiocarcinoma.^[1]
• Malignant transformation of cholangiocytes into cholangiocarcinoma include following stages:^[2]
  1. Hyperplasia
  2. Metaplasia
  3. Dysplasia
  4. Frank carcinoma
• Progression of malignancy is believed to be due to:^[2][3][4]
  • Inflammation
  • Obstruction of bile ducts
  • Biliary intraepithelia neoplasia
• Biliary intraepithelial neoplasia is believed to be the initial lesion of cholangiocarcinoma, particularly in patients with hepatolithiasis in bile ducts.

Gross pathologic features characteristic to intrahepatic cholangiocarcinoma are divided in three subtypes and include:^[8][9][10]

• Mass-forming type
  • Nodular lesion or mass in the hepatic parenchyma
  • Gray to gray-white, firm and solid carcinoma
• Periductal infiltrating type
  • Spreading of the carcinoma along the portal tracts with stricture of the affected bile ducts
  • Dilatation of the peripheral bile ducts
• Intraductal growth type
  • Polypoid or papillary tumor within the variably dilated bile duct lumen
  • Malignant progression of an intraductal papillary neoplasm of the bile duct

On microscopic pathology, characteristic findings of cholangiocarcinoma include:

• Cuboidal or columnar mucin producing cells
• Dense fibrous (desmoplastic) stroma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

Common causes of cholangiocarcinoma include cirrhosis, viral hepatitis, gallstones and primary sclerosing cholangitis.

Cholangiocarcinoma may be caused by:^[1][2][3]

• Gallstones
• Viral hepatitis
  • Hepatitis B
  • Hepatitis C
• Cirrhosis
• Primary sclerosing cholangitis

List the causes of the disease in alphabetical order.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2] Farima Kahe M.D. [3] [4]

Cholangiocarcinoma must be differentiated from other diseases that cause jaundice, abdominal pain, weight loss, and fatigue, such as gallbladder cancer, hepatocellular carcinoma, pancreatic cancer, cholecystitis, and choledochitis.

Cholangiocarcinoma must be differentiated from other diseases that cause jaundice, abdominal pain, weight loss, and fever such as Gallbladder cancer, hepatocellular carcinoma, pancreatic cancer, cholecystitis, choledochitis and liver fluke infections.

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2] [3], Suveenkrishna Pothuru, M.B,B.S. [4]

The incidence of cholangiocarcinoma is approximately 1-2 per 100,000 individuals in the United States. The prevalence of cholangiocarcinoma is approximately 0.01% to 0.46% per 100,000 individuals. Patients of all age groups may develop cholangiocarcinoma. Cholangiocarcinoma is more common in males than in females.

• The incidence of cholangiocarcinoma is approximately 1-2 per 100,000 individuals in the United States.
• The highest annual incidences of cholangiocarcinoma is 5.5 cases per 100,000 people in Japan, and 7.3 cases per 100,000 people in Israel.^[1]

• The prevalence of cholangiocarcinoma is approximately 0.01% to 0.46% per 100,000 individuals.
• The prevalence of cholangiocarcinoma in patients with primary sclerosing cholangitis may be as high as 30%, based on autopsy studies.^[1][2]

• The mortality rate for intrahepatic cholangiocarcinoma among men increased from 0.17 to 0.78 per 100,000 in period of 1975-1979 to 1993-1997.^[3]
• The mortality rate for intrahepatic cholangiocarcinoma among women, increased from 0.12 to 0.57 per 100,000 in period of 1975-1979 to 1993-1997.

• Patients of all age groups may develop cholangiocarcinoma.
• The median age at the time of cholangiocarcinoma diagnosis is 70-80 years, except in patients with bile duct cystic disorders.^[4]
• Bile duct cystic disorders usually develop cholangiocarcinoma much earlier, between 30 and 40 years.

• Cholangiocarcinoma usually affects individuals of the American Indian, Alaska Natives and Asian and Pacific Islanders race.^[5]

• Cholangiocarcinoma is more common in males than in females.^[6]

• The majority of cholangiocarcinoma cases are reported in North America, Asia, and Australia.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2], Suveenkrishna Pothuru, M.B,B.S. [3]

Common risk factors in the development of cholangiocarcinoma include primary sclerosing cholangitis, fibropolycystic liver disease such as choledochal cysts, hepatolithiasis and recurrent pyogenic cholangitis.

• Common risk factors in the development of cholangiocarcinoma include primary sclerosing cholangitis, fibropolycystic liver disease such as choledochal cysts, hepatolithiasis and recurrent pyogenic cholangitis.

• Common risk factors in the development of cholangiocarcinoma include:^{[1][2][3][4][5]}
  • Primary sclerosing cholangitis
  • Cirrhosis
  • Viral infections
    • HIV
    • EBV
    • Hepatitis viruses
      • Hepatitis B
      • Hepatitis C
  • Liver fluke infections
  • Hepatolithiasis
  • Choledochal cysts
  • Infusion of certain chemical agents such as naphthenic acids
  • Recurrent pyogenic cholangitis
  • Opisthorchis viverrini
  • Clonorchis sinensis
  • Caroli’s disease
  • Inherited disorders
    • Lynch syndrome
    • Biliary papillomatosis

• Less common risk factors in the development of cholangiocarcinoma include:^[6]
  • Thorotrast
  • Diabetes
  • Obesity
  • Alcohol consumption
  • Smoking

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Farima Kahe M.D. [2] Suveenkrishna Pothuru, M.B,B.S. [3]

There is insufficient evidence to recommend routine screening for cholangiocarcinoma.

There is insufficient evidence to recommend routine screening for cholangiocarcinoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2], Suveenkrishna Pothuru, M.B,B.S. [3]

The symptoms of cholangiocarcinoma usually develop in the fourth decade of life, and start with symptoms such as abdominal pain, jaundice and fever. Common complications of cholangiocarcinoma infection, liver failure, tumor metastasis.

The symptoms of cholangiocarcinoma usually develop in the fourth decade of life, and start with symptoms such as abdominal pain, jaundice and fever.

Common complications of cholangiocarcinoma include:^[1]

• Infection
• Liver failure
• Tumor metastasis

• Depending on the extent of the cholangiocarcinoma at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as poor with 5-year survival of only 10-44%.^[2]
• The prognosis may be worse for patients with primary sclerosing cholangitis who develop cholangiocarcinoma.
• The most important factor in prognosis of cholangiocarcinoma is whether or not the tumor is able to be resected.

• Patients with multiple tumors, larger tumors and tumors that have spread to nearby blood vessels or lymph nodes have a poor outcome.

Tumors that can be completely removed by surgery (resectable) have a better prognosis than tumors that cannot be removed by surgery (unresectable).

• Distal cholangiocarcinoma: Long-term survival rates range from 15%-25%.^[3]
• Intrahepatic cholangiocarcinoma: Survival estimates after surgery ranging from 22%-66%.^[4]
• Perihilar cholangiocarcinoma: 5 years survival rates range from 20-50%.^[5]

• The best prognostic factors are resection of tumor-free surgical margin without lymph node invasion.^[6]
• Tumor diameter, histology, and differentiation are poor predictors of good outcome with 5-year survival rates varying from 20 to 60%.^[7]
• For extrahepatic cholangiocarcinoma, 5 year survival rate is approximately 30% after resection of tumor-free surgical margins. Majority of patients have recurrence due to following reasons:
  • Disseminated tumors
  • Formation of new tumors in previously oncogenic liver tissue

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