• Clinical science

Cholangiocarcinoma

Abstract

Cholangiocarcinoma, or carcinoma of the bile ducts, is rare and has a very poor diagnosis. It is classified as either intrahepatic or extrahepatic carcinoma based on the anatomical site of origin. Extrahepatic carcinoma, which is more common, is further divided into perihilar (Klatskin tumor; occurs at the bifurcation of the hepatic duct) and distal extrahepatic carcinoma. Risk factors include primary sclerosing cholangitis and chronic liver disease. Patients are often initially asymptomatic or only show nonspecific abdominal complaints (e.g., abdominal pain, fever, weight loss) until late stages, meaning that most tumors are already highly advanced at diagnosis. Extrahepatic cholangiocarcinoma also presents with signs of cholestasis (e.g., jaundice, dark urine, pruritus, etc.) and a painless, enlarged gallbladder (Courvoisier's sign). If liver transaminases and tumor markers are raised, and/or imaging is highly suggestive of cholangiocarcinoma, MRCP or MDCT are recommended for diagnosis. Although surgical resection of early stage tumors may be curative, 90% of patients require palliative care.

Epidemiology

  • Incidence: 1/100,000 per year[1]
  • Peak incidence: 60–70 years[1][2]
  • Sex: > [2]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

  • Risk factors[3]
    • Chronic inflammation of the gallbladder, bile ducts, or liver
    • Congenital abnormalities of the bile ducts (e.g., choledochal cysts, congenital hepatic fibrosis)
    • Parasitic infection of the biliary tracts (e.g., Clonorchis sinensis, or the Chinese liver fluke)
    • Diabetes, obesity, and alcohol consumption

Cholelithiasis is not recognized as a risk factor for cholangiocarcinoma; however, it is a strong risk factor for gallbladder carcinoma!

Classification

  • Cholangiocarcinomas are bile duct cancers.[2] Bile duct carcinomas formerly encompassed carcinomas of the gallbladder, extrahepatic ducts, and the ampulla of Vater, while the term cholangiocarcinoma only referred to carcinomas of the intrahepatic biliary ducts. Cholangiocarcinoma is now understood as including the intrahepatic, perihilar (Klatskin tumor), and distal extrahepatic biliary ducts, independent of carcinomas of the gallbladder and ampulla of Vater.
  • Classified according to anatomical site of origin[4]
    • Extrahepatic cholangiocarcinoma are most common (80% of cases): further divided into perihilar and distal extrahepatic cholangiocarcinomas[5]
    • Intrahepatic cholangiocarcinoma involves the intrahepatic bile ducts.

Perihilar cholangiocarcinoma

  • Develops between the second-order biliary ducts and cystic duct
  • Usually well-differentiated adenocarcinomas
  • The Bismuth-Corlette classification describes the pattern and extent of involvement within the hepatic ducts in more detail:
Type Extent
I Tumor below the confluence of the left and right hepatic ducts
II Tumor reaching the confluence
IIIa Tumor occluding the right and common hepatic ducts
IIIb Tumor occluding the left and common hepatic ducts
IV Tumor that involves the common, left and right hepatic ducts or is multicentric

Distal extrahepatic cholangiocarcinoma

  • Arises between the cystic duct and the ampulla of Vater (however, the ampulla of Vater is not included)
  • Usually moderate to well-differentiated adenocarcinomas

Clinical features

Clinical features depend on the location (intrahepatic or extrahepatic) and stage of the tumor.

Intrahepatic bile duct carcinoma

  • Nonspecific abdominal symptoms (e.g., weight loss, nausea)
  • Symptoms often first arise in later stages.
  • Dull right upper quadrant (RUQ) pain
  • Signs of cholestasis are rare.

Extrahepatic bile duct carcinoma

References:[5]

Stages

Tumor node metastasis (TNM) classification of malignant tumors

Intrahepatic bile duct carcinomas

TNM Extent
Tis Tumor in-situ (intraductal tumor)
T1 Solitary tumor, no vascular invasion
T2a Solitary tumor, with vascular invasion
T2b Multiple tumors, with or without vascular invasion
T3 Perforation of the visceral peritoneum or infiltration of extrahepatic adjacent structures
T4 Periductal invasion
N1 Regional lymph node metastases
M1 Distant metastases

Perihilar bile duct carcinomas (Klatskin tumor)

TNM Extent
Tis Tumor in-situ
T1 Tumor limited to the bile ducts
T2a Infiltration beyond the bile duct walls into adipose tissue
T2b Infiltration of the liver
T3 Infiltration (unilateral branches) of the portal vein or common hepatic artery
T4 Infiltration (main or bilateral branches) of the portal vein or common hepatic artery or intrahepatic biliary tracts
N1 Regional lymph node metastases
M1 Distant metastases

Distal extrahepatic bile duct carcinoma (distal cholangiocarcinoma)

TNM Extent
Tis Tumor in-situ
T1 Tumor limited to bile duct
T2 Infiltration beyond the bile duct wall
T3 Infiltration of adjacent organs (gallbladder, liver, pancreas, duodenum, etc.)
T4 Infiltration of the celiac artery or the superior mesenteric artery
N1 Regional lymph node metastases
M1 Distant metastases

Papillary carcinoma

TNM Extent
T1 Tumor on the ampulla of Vater, especially limited to the sphincter of Oddi
T2 Infiltration of the duodenal wall
T3 Infiltration of the pancreas
T4 Infiltration beyond the pancreas
N1 Regional lymph node metastases
M1 Distant metastases

Classification of stages according to the Union for International Cancer Control (UICC)

Intrahepatic biliary tract carcinoma

UICC stage TNM
Stage I T1
Stage II T2
Stage III T3
Stage IVA T4 or N1
Stage IVB M1

Perihilar biliary tract carcinoma (Klatskin tumor)

UICC stage TNM
Stage 0 Tis (Carcinoma in situ)
Stage I T1
Stage II T2
Stage III T3 or N1
Stage IV M1

Distal extrahepatic bile duct carcinoma and papillary carcinoma

UICC stage TNM
Stage 0 Tis (Carcinoma in situ)
Stage I T1 (IA) or T2 (IB)
Stage II T3 (IIA) or N1 (IIB)
Stage III T4
Stage IV M1

Diagnostics

The diagnostic approach varies greatly and depends on the institution as well as the location of the tumor and if PSC is present. If presentation, laboratory findings (especially tumor markers), and/or imaging are highly suggestive of cholangiocarcinoma, MRCP or MDCT are generally recommended for diagnosis. In some cases, ERCP is conducted instead to diagnose the disease and assess tumor resectability. Staging and appropriate management should be initiated thereafter.

  • Laboratory findings
  • Imaging
    • Transabdominal ultrasound : gallbladder and/or ductal dilatation, helps localize the obstruction and rules out gallstones as a differential diagnosis
      • It is also useful for identifying local metastases and performing ultrasound-guided biopsy.
    • MRI/MRCP (magnetic resonance cholangiopancreatography); or MDCT (multidetector computed tomography); are generally recommended to diagnose the disease: bile duct dilatation and mass lesion
    • Endoscopic retrograde cholangiography (ERCP); or rarely percutaneous transhepatic cholangiography (PTC) for proximal lesions: may be indicated instead of MRCP or MDCT, or if these tests are inconclusive
      • Confirms tumor type via tissue sampling
      • Sometimes preferred by surgeons to assess tumor resectability and immediately place a stent if the tumor is inoperable
    • Endoscopic ultrasound may be indicated (especially for distal extrahepatic lesions and staging)
    • CT scan may be indicated (also assists in staging): findings include tumor mass, bile duct wall thickening, bile duct dilatation, and/or intraductal tissue[6]
    • PET scan: indicated if other diagnostic procedures are inconclusive and for staging
  • Surgical exploration: sometimes necessary for diagnosis or staging

References:[5]

Pathology

  • Adenocarcinoma is most common.
  • < 10% are squamous cell tumors.

References:[2]

Differential diagnoses

References:[5]

The differential diagnoses listed here are not exhaustive.

Treatment

  • Surgical treatment: curative (indicated in < 25% of cases)
    • Operability of cholangiocarcinomas is determined if none of the following are present:[7]
      • Distant metastases
      • Spread to adjacent organs
      • Hepatic artery or main portal vein involvement
      • Retropancreatic/paraceliac node involvement
    • The types of surgery depend on the exact location of the lesion and include:[5]
  • Intrahepatic bile duct carcinoma
    • Partial liver resection (in rare cases, liver transplant)
  • Perihilar bile duct carcinoma (Klatskin tumor)
  • Distal extrahepatic bile duct carcinoma
    • Depends on which third of the distal extrahepatic bile duct is affected:
    • Resection of the bifurcation of the hepatic duct, cholecystectomy,
  • Carcinoma of the ampulla of Vater
  • Palliative treatment: (indicated in 90% of cases)[1]
    • Non-resectable tumor → gallbladder drainage via stent[1]
      • Drain inwards using ERCP and stent placement (pigtail catheter)
      • Drain outward using percutaneous transhepatic gallbladder drainage (PTGD)
    • Intrahepatic cholangiocarcinoma

Complications

We list the most important complications. The selection is not exhaustive.

Prognosis

  • Poor prognosis in general (especially in intrahepatic cholangiocarcinoma)
  • After curative resection: The 5-year survival rate is ∼ 60% for intrahepatic, ∼ 30% for perihilar, and ∼ 30% for distal bile duct tumors.
  • Resection followed by chemoradiotherapy: The median survival is 17–27.5 months.
  • Inoperable tumors: The median survival is 7–17 months.
  • Longstanding retention of synthetic liver function and regeneration depends on the condition of the remaining liver tissue.
    • At least 20% of the tissue should be noncirrhotic.