• Clinical science

Biliary cancer

Summary

Biliary tract cancers include cholangiocarcinoma and gallbladder carcinoma, which are both rare diseases with very poor prognoses. Cholangiocarcinoma is classified as either intrahepatic or extrahepatic according to the anatomical site of the tumor. Extrahepatic carcinoma, which is the more common form, can be further classified as perihilar (Klatskin tumor; occurs at the bifurcation of the hepatic duct) and distal extrahepatic carcinoma. Risk factors for cholangiocarcinoma include primary sclerosing cholangitis and chronic biliary tract inflammation. The greatest risk factor for gallbladder carcinoma is cholelithiasis. Patients are often initially asymptomatic or only present with nonspecific symptoms (e.g., abdominal pain, fever, weight loss) until late stages of disease, meaning that most tumors are already advanced at the time of diagnosis. Extrahepatic cholangiocarcinoma may manifest with signs of cholestasis (e.g., jaundice, dark urine, pruritus) and a painless, enlarged gallbladder (Courvoisier sign). If liver transaminases and tumor markers are raised and/or ultrasound imaging suggests bile duct or gallbladder carcinoma, MRCP or MDCT are recommended for diagnosis. Although surgical resection of early-stage tumors is curative, approximately 90% of patients have more advanced, unresectable tumors at the time of diagnosis.

Definition

  • Cholangiocarcinomas: originate in the bile ducts and are classified based on their anatomical site of origin [1][2]
    • Extrahepatic cholangiocarcinoma is the most common form (90% of cases).
      • Perihilar (Klatskin tumor): junction of the right and left hepatic ducts (50% of cases)
      • Distal extrahepatic: common bile duct (40% of cases)
    • Intrahepatic cholangiocarcinoma: intrahepatic bile ducts (10% of cases)
  • Gallbladder carcinomas: originate within the mucosal lining of the gallbladder [3]

Epidemiology

Cholangiocarcinoma [2][4]

  • Incidence: ∼ 1/100,000 per year in the US
  • Prevalence: < 1% of all cancers
  • Peak incidence: 60–70 years of age
  • Sex: >

Gallbladder carcinoma [5]

  • Incidence: ∼ 2/100,000 per year in the US but significantly higher in India, Chile, and Eastern Europe
  • Sex: >

References:[4][6]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Chronic gallbladder inflammation increases the risk of gallbladder carcinoma.

Classification

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

References:[6][1][7]

Clinical features

Clinical features depend on the location and stage of the tumor.

Cholangiocarcinoma [2]

Gallbladder carcinoma [4][5]

  • Asymptomatic in early stages
  • Most commonly diagnosed incidentally
  • Symptoms of biliary colic or chronic cholecystitis
  • Advanced disease
    • Nonspecific symptoms (e.g., weight loss, nausea, weakness, fatigue)
    • Abdominal mass
    • Abdominal pain (RUQ or epigastric)
    • Courvoisier sign

Stages

Tumor node metastasis (TNM) classification of malignant tumors

Intrahepatic bile duct carcinomas

TNM Extent
Tis Tumor in situ (intraductal tumor)
T1 Solitary tumor with 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, 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 the 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 depending on the location of the tumor and whether PSC is present. If the patient's presentation, laboratory findings (especially tumor markers), and/or transabdominal ultrasound suggest biliary cancer, then MRCP or MDCT is generally recommended for diagnosis. Biopsy is generally unnecessary.

  • Laboratory tests [2][4]
  • Imaging [2][4]
    • Transabdominal ultrasound should be the initial imaging modality for suspected biliary tract carcinoma
      • Localization of obstruction and evaluation for gallstones
      • Findings: gallbladder and/or bile duct dilatation
      • Useful for identifying local metastases and performing ultrasound-guided biopsy
    • MRCP
      • Recommended for definitive diagnosis
      • Findings: bile duct dilatation and/or mass lesion
    • Abdominal MDCT is commonly used as an alternative to MRCP
    • Endoscopic ultrasound (especially for distal extrahepatic lesions and staging)
    • Chest CT for staging
    • PET scan: indicated if other diagnostic procedures are inconclusive and for staging
  • Biopsy [2][5]
    • Cholangiocarcinoma: ERCP with ductal brushings or biopsy is recommended but not always necessary for diagnosis.
      • May be indicated if MRCP or MDCT are inconclusive
      • Allows for confirmation of tumor type via tissue sampling
      • Sometimes preferred by surgeons to assess tumor resectability; allows for immediate placement of a stent if the tumor is inoperable
      • Rarely, percutaneous transhepatic cholangiography (PTC) is used for proximal lesions.
    • Gallbladder cancer: biopsy is usually unnecessary; typically proceeds directly to surgical exploration/resection if clinical suspicion is high
  • Surgical exploration: Exploratory laparoscopy is often performed for definitive diagnosis and/or staging prior to resection.

Gallbladder carcinoma is usually diagnosed incidentally after elective cholecystectomy.

References:[4][7][8]

Pathology

Differential diagnoses

References:[7]

The differential diagnoses listed here are not exhaustive.

Treatment

The prognosis for cholangiocarcinoma and gallbladder cancer is generally poor, especially for gallbladder cancer and intrahepatic cholangiocarcinoma. Treatment is determined by tumor resectability.

Resectable disease [4]

  • < 10% of cases are resectable.
  • Resection is the only curative therapy.
  • Procedure: radical resection plus lymphadenectomy
    • Preoperative biliary drainage is performed in some cases.
    • Adjuvant chemotherapy: usually a fluoropyrimidine-based regimen
  • Operability of cholangiocarcinomas is determined if none of the following are present:
    • Distant metastases
    • Spread to adjacent organs
    • Hepatic artery or main portal vein involvement
    • Retropancreatic/celiac node involvement
  • Intrahepatic bile duct carcinoma: partial liver resection (in rare cases, liver transplant)
  • Perihilar bile duct carcinoma (Klatskin tumor)
  • Distal extrahepatic bile duct carcinoma
  • Carcinoma of the ampulla of Vater
Surgical approach Contraindications
Intrahepatic cholangiocarcinoma
  • Hepatic resection: usually partial resection (in rare cases, liver transplant)
Extrahepatic cholangiocarcinoma
  • Complete resection and regional lymphadenectomy
    • Hilar tumors: major hepatic resection
    • Distal tumors: Whipple procedure
    • Mid-ductal tumors: bile duct resection
Gallbladder carcinoma
  • Cholecystectomy and
    • Resection of hepatic segments IVb and V
    • Lymphadenectomy
    • With or without bile duct excision

Unresectable disease [4]

Complications

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

Prognosis

  • Cholangiocarcinoma: 5-year survival rate following curative resection
    • ∼ 60% for intrahepatic bile duct tumors
      • Median overall survival after surgery: 18–33 months
    • ∼ 30% for perihilar bile duct tumors
    • ∼ 30% for distal bile duct tumors
    • Resection followed by chemoradiotherapy: median survival is 17–27.5 months
    • Inoperable tumors: median survival is 7–17 months
  • Gallbladder carcinoma: 5-year survival rate ∼ 16%
  • Prognostic factors