Biliary cancer

Cancers of the biliary tract are rare and develop in the extrahepatic or intrahepatic bile ducts (cholangiocarcinoma), the gallbladder, or the ampulla of Vater (ampullary cancer). Risk factors include causes of hepatic or biliary tract inflammation, e.g., primary sclerosing cholangitis (PSC), liver flukes, and chronic cholelithiasis. Biliary cancer is typically advanced at diagnosis because symptoms often do not appear until late stages of the disease. Clinical features may be nonspecific and include cholestasis, abdominal pain, gallbladder enlargement, nausea, and weight loss. Initial diagnostic studies include liver chemistries and abdominal ultrasound, followed by cross-sectional imaging, such as MRI/MRCP or multidetector computed tomography (MDCT), and cholangiography. CT chest and abdomen is performed for staging. Tissue sample is obtained via endoscopic or percutaneous biopsy or following surgical resection of the gallbladder. While early-stage disease is treatable with surgery followed by adjuvant chemotherapy, approximately 90% of patients have advanced, unresectable disease at presentation. For these patients, disease progression can be delayed with chemotherapy, targeted treatments, and/or radiotherapy. Patients with biliary obstruction may benefit from biliary decompression and stenting.

Premalignant biliary lesions include cystic gallbladder polyps (common) and biliary cysts (rare). Gallbladder polyps are often detected incidentally and are usually benign. Risk factors for malignant gallbladder polyp include size ≥ 10 mm, patient age ≥ 60 years, and PSC. Biliary cysts are areas of cystic dilatation, typically identified in early childhood. Given the high risk of malignant transformation, surgical excision is advised for biliary cysts.

Cholangiocarcinoma (CCA) is a malignancy of the bile duct.

Epidemiology ^[1]

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

Classification ^[1][2]

• Extrahepatic CCA: 90% of CCA cases
  • Perihilar CCA (Klatskin tumor): junction of the right and left hepatic ducts (50% of cases)
  • Distal extrahepatic CCA: common bile duct (40% of cases)
• Intrahepatic CCA: 10% of CCA cases; the second most common intrahepatic malignancy after hepatocellular carcinoma (HCC) ^[3]

Risk factors ^[1][4][5]

• PSC
• Liver fluke infection, e.g., Clonorchis sinensis, Opisthorchis viverrini
• Cholelithiasis
• Chronic liver disease
• Chronic viral hepatitis, e.g., HBV, HCV
• Environmental toxin exposure, e.g., asbestos, thorium dioxide
• Congenital biliary tract abnormalities, e.g., biliary cysts, congenital hepatic fibrosis
• Fibropolycystic liver disease

Clinical features ^[1]

• Extrahepatic CCA
  • 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 CCA
  • 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.

Diagnostics

General principles ^[6]

• Suspected CCA lesions are often found during imaging surveillance for PSC or cirrhosis.
• Initial workup includes routine liver studies and transabdominal ultrasound.
• Obtain MRCP or ERCP to assess disease extent.
• Confirm the diagnosis with tissue obtained via ERCP, EUS, or percutaneous biopsy. ^[6][7][8]

Laboratory studies

• Routine liver studies: to assess for obstructive jaundice and hepatocellular injury
  • ↑ Total bilirubin, ↑ conjugated bilirubin and ↑ ALP (↑ GGT confirms hepatobiliary cause) ^[9]
  • AST and ALT may be increased or unchanged. ^[9]
• Tumor markers
  • ↑ CA19-9 and/or ↑ CEA: often elevated in patients with PSC ^[6][8]
  • ↑ AFP: typically elevated in HCC; not recommended for screening or diagnosis of CCA
• Additional studies: to detect underlying hepatobiliary disease
  • Hepatitis serology ^[8]
  • IgG4 levels ^[6]

Imaging

• Transabdominal ultrasound: : first-line in suspected CCA; may show biliary dilatation ^[10]
• Cross-sectional imaging: if ultrasound findings suggest CCA; to evaluate for a mass, local invasion, and vasculature
  • Abdominal MRI/MRCP or MDCT ^[6][8][10]
    • Extrahepatic CCA: Bile duct dilatation > 6 mm suggests malignancy; the mass itself may not be visualized. ^[6]
    • Intrahepatic CCA: lobulated irregular mass with rim enhancement ^[6]
  • CT chest and abdomen with or without whole body PET-CT for staging ^[10][11]
• ERCP
  • Recommended in extrahepatic CCA to visualize the biliary tree ^[6]
  • Facilitates endoscopic biopsy, decompression, and/or stenting
• EUS: occasionally used for more accurate visualization (e.g., to evaluate distal extrahepatic CCA) ^[6]

Tissue sample

• Extrahepatic CCA: ERCP or EUS with either core biopsy (preferred) or bile duct brushing, including cytology and fluorescence in situ hybridization (FISH) ^[6]
• Intrahepatic CCA: Percutaneous transhepatic biopsy before intervention is widely recommended, although some centers omit preoperative biopsy in resectable disease. ^[8][10]

Pathology

• Histopathology: usually well-differentiated adenocarcinoma
• FISH or immunohistochemistry: may help to distinguish CCA from other liver tumors ^[6][7]
• Molecular analysis ^[6][8][10]
  • Indications: advanced disease or disease with a high risk of recurrence
  • Use: to identify treatment targets, e.g., IDH1 mutation, HER2 expression

Treatment

Consult a multidisciplinary team with expertise in hepatobiliary malignancy to determine the treatment approach based on classification, stage, and comorbidities. ^[6]

• Surgical resection: Less than 10% of patients are candidates for resection. ; ^[8][9][10]
  • Pancreaticoduodenectomy: for distal extrahepatic CCA ^[10]
  • Radical hepatic resection plus regional lymphadenectomy: for intrahepatic or perihilar CCA ^[6][8][9]
• Liver transplant: for select patients, e.g., those with unresectable perihilar CCA with a diameter ≤ 3 cm ^[6][9][11]
• Biliary decompression: e.g., stenting; often used palliatively in unresectable distal CCA with biliary obstruction ^[6][10]
• Chemotherapy
  • Adjuvant chemotherapy with a 6-month course of capecitabine after surgical resection ^[10][11]
  • Palliative chemotherapy in unresectable disease
    • First-line: regimen, e.g., gemcitabine, cisplatin, and durvalumab ^[10][11]
    • Second-line: FOLFOX or molecularly targeted therapy, e.g., IDH1 inhibitor ^[7][9][10]
• Radiotherapy
  • Adjuvant: if node-positive or if resection margins are not clear ^[11]
  • Palliative: may be offered in advanced disease ^[10]

Surgical resection with adjuvant chemotherapy is the only curative treatment for CCA.

Prognosis

• 5-year survival rates following curative resection
  • 16–44% for intrahepatic bile duct tumors ^[12]
  • 20–30% for extrahepatic bile duct tumors ^[13]

Gallbladder cancers originate within the mucosal lining of the gallbladder. ^[4]

Epidemiology ^[5]

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

Risk factors ^[4][5]

• Cholelithiasis with chronic inflammation (most common risk factor)
• Porcelain gallbladder
• Liver fluke infection (e.g., C. sinensis)
• Choledocholithiasis
• Chronic cholecystitis
• Chronic cholangitis (e.g., due to salmonellosis)
• Gallbladder polyps

Chronic gallbladder inflammation increases the risk of gallbladder cancer.

Clinical features ^[5]

• Asymptomatic in early stages
• 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)
  • Obstructive jaundice (with or without Courvoisier sign) is a rare feature of gallbladder cancer.

Diagnostics

Gallbladder cancer is most commonly diagnosed incidentally following cholecystectomy. ^[11][14][15]

Imaging studies

• Transabdominal ultrasound: : commonly performed for biliary symptoms and may show gallbladder mass or wall thickening
• Cross-sectional imaging
  • MRI/MRCP: to evaluate local disease (e.g., gallbladder wall thickening, local invasion); multiphase imaging is included to allow for assessment of vasculature. ^[8]
  • MDCT abdomen and pelvis: provides less detailed images than MRI/MRCP
  • CT chest with or without whole body PET-CT for staging ^[8][14]
• EUS ^[8]
  • Occasionally used to provide more accurate visualization
  • Potential to obtain tissue sample during procedure

Laboratory studies

• Liver chemistries: typically normal
• Tumor markers ^[8]
  • Increased or normal CA 19-9 and/or CEA
  • Used to determine baseline level for monitoring (not for diagnosis)

Pathology

• Preoperative biopsy is usually unnecessary.
• Histopathology of resected surgical specimen ^[4]
  • Adenocarcinoma (most common)
  • < 10% of gallbladder cancers are squamous cell tumors. ^[4]
• Molecular analysis ^[8][10]
  • Indications: advanced disease or disease with a high risk of recurrence
  • Use: to identify treatment targets, e.g., IDH1 mutation, HER2 expression

Gallbladder cancer is most commonly diagnosed incidentally after cholecystectomy.

Treatment

Given the rarity of gallbladder cancer, treatment protocols for CCA are often used. ^[14]

• Surgery: The approach depends on the tumor grade.
  • Simple cholecystectomy may be sufficient in well-differentiated, minimally invasive cancers (T1a). ^[8][14]
  • Extended resection including liver tissue and portal lymph nodes is indicated in cancers that invade beyond the lamina propria (≥T1b). ^[14]
  • Preoperative percutaneous transhepatic biliary drainage may be performed in severe jaundice. ^[14]
• Chemotherapy
  • Adjuvant chemotherapy with gemcitabine and cisplatin after surgical resection of T2+ disease ^[10][11]
  • Palliative chemotherapy in unresectable disease ^[14]
    • First-line: e.g., gemcitabine and cisplatin
    • Second-line: e.g., FOLFOX or targeted treatment as for CCA
• Radiotherapy: may be used for palliative treatment ^[8]

Surgical resection with or without adjuvant chemotherapy may be curative for early gallbladder cancer. ^[15]

Prognosis

The 5-year survival rate is < 5%. ^[16]

Ampullary cancer is a rare type of gastrointestinal cancer ; (< 1% of all gastrointestinal malignancies) that forms in the ampulla of Vater, usually causing symptoms of cholestasis. ^[17][18][19]

Etiology

• Usually sporadic
• May be associated with genetic cancer syndromes, e.g., familial adenomatous polyposis, Lynch syndrome ^[20][21]

Clinical features

• Symptoms of cholestasis such as jaundice (most common) and pruritus ^[19]
• Nonspecific symptoms (e.g., weight loss, fatigue)
• Abdominal and/or back pain
• Nausea, vomiting, steatorrhea

Diagnostics

• ERCP for diagnostic confirmation
• EUS with biopsy may be used for diagnosis and staging. ^[22]

Pathology

• Adenocarcinoma of the ampulla of Vater (AAV): most common type of ampullary cancer
• Originates from intestinal or pancreaticobiliary epithelium ^[19]

Treatment ^[19]

• Curative pancreaticoduodenectomy
• Adjuvant chemotherapy and/or radiation therapy

Prognosis ^[17]

• 3-year survival rate ∼ 60% ^[17]
• Pancreatobiliary-type AAV is associated with a poorer prognosis than intestinal-type AAV.

Gallbladder polyp

• Definition: a lesion of the gallbladder wall with malignant potential
• Epidemiology
  • Less than 5% of all gallbladder polyps are premalignant adenomas. ^[23]
  • Up to two-thirds are benign, cholesterol-containing pseudopolyps. ^[24]
  • Up to 50% of polyps > 10 mm are malignant. ^[23]
• Risk factors for malignant gallbladder polyp ^[25]
  • Polyp size ≥ 10 mm
  • Patient age > 60 years
  • PSC
  • Asian ethnicity
  • Sessile polypoid lesion
  • Polyp growth ≥ 2 mm during 2 years of monitoring
• Clinical features ^[24]
  • Usually asymptomatic
  • Abdominal pain, nausea, and vomiting may occur.
• Diagnostics ^[25]
  • Ultrasound: transabdominal (first-line); EUS may be useful if there is diagnostic uncertainty. ^[25]
    • Echogenic protrusion of the gallbladder wall into gallbladder lumen ^[24]
    • No signs of other biliary pathology, e.g., rolling stone sign, posterior acoustic shadowing ^[25]
  • Laboratory studies: typically normal (e.g., LFTs, tumor markers)
  • Tissue sample: only obtained if cholecystectomy is performed
• Management: guided by polyp size and risk factors for malignant gallbladder polyp ^[25]
  • Refer for cholecystectomy if any of the following are present:
    • Polyp size ≥ 10 mm ^[25]
    • Polyp size 6–9 mm with ≥ 1 risk factor ^[25]
    • Polyp growth ≥ 2 mm within 2 years ^[25]
    • Symptoms attributable to the gallbladder that cannot otherwise be explained, e.g., RUQ pain
  • Monitor with abdominal ultrasound for growth over 2 years if either : ^[25]
    • 6–9 mm with no risk factors ^[25]
    • ≤ 5 mm with ≥ 1 risk factor ^[25]

Sonographic monitoring is not recommended for asymptomatic patients with polyps measuring ≤ 5 mm and no risk factors for malignant gallbladder polyp. ^[25]

Biliary cyst ^[26][27]

• Definition: : a rare, premalignant condition characterized by extrahepatic and/or intrahepatic cystic dilatation 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 ^[28]
  • 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 dilatation 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, CCA), 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 common bile duct, 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 CCA is 20–30× higher than in the general population ^[29]
    • 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 CCA; therefore, all patients should undergo surgery, even if asymptomatic. ^[30]

For further differential diagnoses, see “Biliary and pancreatic causes of acute abdomen” and “Common cholestatic causes of conjugated hyperbilirubinemia.”

• Biliary
  • Cholelithiasis
  • Choledocholithiasis
  • Cholangitis
  • Cholecystitis
  • Primary biliary cholangitis
  • PSC
  • Biliary cyst
• Pancreatic
  • Pancreatitis
  • Pancreatic cancer
  • Pancreatic pseudocyst
• Hepatic
  • Hepatocellular cancer
  • Benign liver mass
  • Causes of intrahepatic jaundice that result in hepatocellular injury, e.g., viral hepatitis, chronic liver disease, hepatotoxic drugs

The differential diagnoses listed here are not exhaustive.

For surgical complications, see also “Intraoperative and postoperative complications of cholecystectomy.”

• Biliary tract obstruction including biliary stent obstruction ^[8][11]
• Cholangitis
• Secondary sclerosing cholangitis
• Pancreatitis
• Pancreatic duct obstruction ^[8]
• Malabsorption following pancreaticoduodenectomy ^[8]
• Acute liver failure
• Chronic liver disease
• Gastric outlet obstruction ^[8]
• Malignant ascites

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