Biliary cancer

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.

• 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]

Cholangiocarcinoma ^[2]

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

Gallbladder carcinoma ^[4]

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

Epidemiological data refers to the US, unless otherwise specified.

• Risk factors for cholangiocarcinoma ^[2][3][4]
  • Primary sclerosing cholangitis
  • Liver fluke infection (e.g., Clonorchis sinensis, Opisthorchis viverrini)
  • Choledocholithiasis (both with and without hepatic duct involvement)
  • Chronic viral hepatitis (e.g., hepatitis B, hepatitis C)
  • Liver cirrhosis
  • Environmental toxin exposure (e.g., asbestos, Thorotrast contrast agent)
  • Congenital biliary tract abnormalities (e.g., choledochal cysts, congenital hepatic fibrosis)
  • Fibropolycystic liver disease
• Risk factors for gallbladder carcinoma ^[3][4]
  • Cholelithiasis with chronic inflammation (most common risk factor)
  • Porcelain gallbladder
  • Liver fluke infection (e.g., Clonorchis sinensis)
  • Choledocholithiasis
  • Chronic cholecystitis
  • Chronic cholangitis (e.g., salmonellosis)
  • Gallbladder polyps

Chronic gallbladder inflammation increases the risk of gallbladder carcinoma.

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

Cholangiocarcinoma ^[2]

• Extrahepatic cholangiocarcinoma
  • Signs of cholestasis: jaundice, pale stools, dark urine, pruritus
  • Abdominal pain and weight loss is usually a sign of late (unresectable) disease.
  • Courvoisier sign
• Intrahepatic cholangiocarcinoma
  • Usually asymptomatic in early stages
  • Nonspecific symptoms (e.g., weight loss, nausea, fever, weakness, fatigue)
  • Dull abdominal pain (RUQ or epigastric)
  • Signs of cholestasis are rare.

Gallbladder carcinoma ^[4]

• Asymptomatic in early stages
• Most commonly diagnosed incidentally (e.g., during routine histological examination after simple cholecystectomy)
• 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

Ampullary cancer ^[5]

• Definition: a rare type of gastrointestinal cancer that forms in the ampulla of Vater, usually causing symptoms of cholestasis
• Epidemiology: rare (< 1% of all gastrointestinal malignancies) ^[6]
• Etiology: usually occurs sporadically ^[7]
• Clinical features
  • Symptoms of cholestasis such as jaundice (most common) and pruritus
  • Nonspecific symptoms (e.g., weight loss, fatigue)
  • Abdominal and/or back pain
  • Nausea, vomiting, steatorrhea
• Diagnostics: Endoscopic retrograde cholangiopancreatography is used to confirm the diagnosis.
• Pathology: Adenocarcinoma of the ampulla of Vater (AAV) is the most common type of ampullary cancer. ^[8]
  • Intestinal-type AAV: originates from the intestinal epithelium that covers the ampulla
  • Pancreatobiliary-type AAV: originates from the epithelium of the distal bile and pancreatic duct
  • Mixed-type AAV
• Treatment: curative pancreaticoduodenectomy
• Prognosis ^[5]
  • 3-year survival rate ∼ 60%
  • Pancreatobiliary-type AAV is associated with a poorer prognosis than intestinal-type AVC.

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. A biopsy is generally unnecessary. ^[2][9]

Laboratory tests

• Liver function tests: possible ↑ INR, ↑ ALT, and ↑ AST (with chronic biliary obstruction and eventual hepatic dysfunction)
• Parameters of cholestasis (e.g., ALP, GGT, total bilirubin) may initially be normal.
• Tumor markers (to determine the baseline; should not be used to confirm the diagnosis)
  • ↑ AFP ^[10][11]
  • ↑ CA 19-9 and ↑ CEA
    • Especially helpful for diagnosing cholangiocarcinoma with primary sclerosing cholangitis
    • Useful for assessing therapeutic responsiveness and detecting relapse

Imaging

• 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 ^[4]

• 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.

• Cholangiocarcinoma: : usually a well-differentiated adenocarcinoma
• Gallbladder cancer ^[3]
  • Adenocarcinoma is the most common form.
  • < 10% are squamous cell tumors.

Biliary cyst ^[12][13]

• Definition: : a rare, premalignant condition characterized by extrahepatic and/or intrahepatic cystic dilation of the biliary tree
• Epidemiology
  • More common in individuals of Asian, in particular Japanese, descent
  • Sex: ♀ > ♂ (3:1)
  • Most commonly diagnosed during childhood (although 25–50% are diagnosed in adulthood)
• Etiology: The exact cause is still unknown but pancreaticobiliary maljunction is thought to play a role in the majority of cases.
• Pathophysiology: pancreaticobiliary maljunction → formation of a long common channel → reflux and activation of pancreatic secretions in the common bile duct → inflammation and elevation of intraductal pressure → cystic degeneration ^[14]
  • Chronic reflux and ductal inflammation → dysplasia → malignancy
  • Dilated cysts → bile stasis → sludge and stone formation → obstruction → ascending cholangitis → ductal strictures caused by chronic inflammation → further obstruction → secondary biliary cirrhosis
• Clinical features: symptoms typically develop before the age of 10
  • The classic triad of abdominal pain, palpable abdominal mass, and jaundice is present in < 30% of affected individuals.
  • Clinical presentation varies with age:
    • Children ≤ 12 months: obstructive jaundice and abdominal mass
    • Children > 12 months and adults: right upper quadrant pain (most common), fever, and nausea
  • The first manifestation can be that of one of the complications listed below.
• Diagnostics
  • Laboratory studies
    • CBC: Leukocytosis is seen in cholangitis or pancreatitis.
    • LFTs: evidence of cholestasis, i.e., ↑ ALP, ↑ GGT, ↑ total and ↑ direct bilirubin; ALT and AST may also be elevated in the context of secondary hepatic injury.
    • Amylase and lipase: elevated in pancreatitis
  • Imaging
    • Ultrasound
      • Initial imaging modality of choice
      • Findings: choledochal cysts and/or dilation of the common bile duct
    • CT of the abdomen: higher sensitivity than ultrasound; better for visualization of the intrahepatic ducts, the distal common bile duct, and the pancreatic head
    • Cholangiography: essential for diagnosis confirmation, identification of associated ductal pathology (e.g., choledocholithiasis, cholangiocarcinoma), and mapping of the biliary tree for surgical planning
      • MRCP: usually the method of choice for preoperative imaging of the biliary tree
      • ERCP: allows better visualization of the pancreaticobiliary junction and the distal biliary tree
      • Percutaneous transhepatic cholangiography: allows for better visualization of cysts localized in the proximal biliary tree
• Treatment: complete excision of the choledocus, cholecystectomy, and Roux-en-Y hepaticojejunostomy is required for the majority of cysts
• Complications
  • Cholangitis
  • Pancreatitis
  • Secondary biliary cirrhosis
  • Cyst rupture and bile peritonitis
  • Malignancy: The entire biliary tree, not just those parts that appear dilated, are at risk of malignant transformation.
    • Risk of cholangiocarcinoma is 20–30× higher than in the general population ^[15]
    • The risk of malignancy does not disappear after surgical excision; individuals with biliary cysts require postoperative long-term surveillance.

Individuals with biliary cysts have an increased risk of cholangiocarcinoma; therefore, all patients should undergo surgery, even if asymptomatic. ^[16]

Other differential diagnoses

• Cholangiocarcinoma
  • Hepatocellular carcinoma
  • Pancreatic cancer
  • Choledocholithiasis
  • Chronic hepatitis
  • Chronic pancreatitis
  • Acalculous cholecystitis
  • Calculous cholecystitis
  • Acute cholangitis
  • Autoimmune cholangitis
• Gallbladder carcinoma
  • Cholelithiasis
  • Chronic cholecystitis

The differential diagnoses listed here are not exhaustive.

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

• < 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

Unresectable disease

• Unresectable carcinoma or metastatic disease accounts for > 90% of cases.
• Treatment is palliative
  • Chemotherapy: fluoropyrimidine-based or gemcitabine-based regimen
  • Biliary stent placement: in patients with jaundice and extrahepatic cholangiocarcinoma or gallbladder carcinoma
• Transarterial chemoembolization (TACE): local application of chemotherapy and occlusive substance → induces fibrosis and shrinkage of intrahepatic cholangiocarcinoma

• Biliary obstruction
• Biliary cirrhosis
• Liver failure
• Pancreatic duct obstruction
• Malignant ascites
• Postoperative
  • Injury to the hepatic artery or hepatic portal vein
  • Gallbladder fistulae
  • Bacterial cholangitis due to biliary obstruction

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

• Cholangiocarcinoma: 5-year survival rate following curative resection
  • ∼ 16–44% for intrahepatic bile duct tumors ^[17]
  • ∼ 20–30% for extrahepatic bile duct tumors ^[18]
• Gallbladder carcinoma: 5-year survival rate < 5% ^[19]