Definition and PathogenesisTop
The most common type is adenocarcinoma (95%) originating in the epithelium of the biliary mucosa.
Classification by location:
1) Intrahepatic cholangiocarcinoma (iCCA).
2) Extrahepatic cholangiocarcinoma (eCCA) subdivided into perihilar cholangiocarcinoma (pCCA; Klatskin tumor; located superior to or at the bifurcation of the common hepatic duct into the right and left hepatic ducts) and distal cholangiocarcinoma (dCCA; cancer of the common hepatic or common bile duct).
Risk factors: Biliary cysts (types I, IV, and V, including Caroli disease), gallstones (predominantly choledocholithiasis), cirrhosis, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, primary sclerosing cholangitis (PSC), hepatobiliary flukes (Clonorchis sinensis, Opisthorchis viverrini, or O felineus infection).
Clinical Features and Natural HistoryTop
Signs and symptoms: Cholestatic jaundice (especially in eCCA; may be absent in intrahepatic carcinoma), pruritus, abdominal pain and discomfort (usually in iCCA; persistent, dull, localized in the right subcostal area), weight loss, hepatomegaly, fever, tumor in the right hypochondrium palpable through the abdominal wall, enlarged, hard, nonpainful gallbladder (Courvoisier sign in extrahepatic tumors located at the junction of the cystic and the common hepatic duct).
The course is usually insidious. The appearance of jaundice and itching typically indicates advanced cancer; in most patients at this stage the tumor is already unresectable, and survival usually does not exceed 12 months from diagnosis.
1. Laboratory tests: Elevated serum bilirubin (predominantly conjugated), elevated activity of alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST); increased concentration of cancer antigens (CA) 19-9 (persisting after decompression of obstructive jaundice) and 125.
1) Ultrasonography is the first-line examination in the diagnostic workup of obstructive jaundice. It can visualize bile duct dilatation (which, in the absence of gallstones in the bile ducts, may indicate a tumor narrowing their lumen). Ultrasound-guided needle biopsy of the intrahepatic lesion can be performed.
2) Computed tomography (CT) enables detection of a focal lesion and determination of the extent of the tumor (detection of lymph node metastases, infiltration of large vessels and adjacent organs).
3) Magnetic resonance imaging (MRI) is a definitive examination to visualize the tumor.
4) Magnetic resonance cholangiopancreatography (MRCP) allows for a more precise visualization of the stenosis or dilatation of the bile ducts than the endoscopic retrograde cholangiopancreatography (ERCP), and for assessment of the extent of tumor.
5) Endoscopic ultrasonography (EUS) is used for a thorough assessment of the extrahepatic bile ducts, gallbladder, liver hilar structures, regional lymph nodes, and vessels; EUS-guided tumor or lymph node biopsy is a very sensitive diagnostic method.
6) ERCP allows for specimen collection through biopsy or brushing and for stent placement into the bile ducts at the site of stenosis to improve bile outflow.
7) Cholangioscopy enables visualization of the bile ducts and collection of tissue specimens through biopsy or brushing.
3. Microscopic examination: Sample collected during the ERCP, cholangioscopy, or ultrasound-, CT-, or EUS-guided needle biopsy.
In patients with a resectable tumor, preoperative histologic confirmation is not necessary, and initial diagnosis is based on imaging studies. In all patients with hilar tumor or extrahepatic bile duct stenosis on imaging, diagnostic workup of cholangiocarcinoma should be performed.
Cancer of the head of the pancreas, ampulla of Vater, duodenum, or gallbladder; biliary obstruction (usually postoperative); primary sclerosing cholangitis; cholelithiasis; Mirizzi syndrome; liver metastases; IgG4-associated autoimmune cholangitis.
1. Curative-intent treatment: iCCA → liver resection; pCCA → the extent of resection depends on the position of the tumor in relation to the hilar structures (ie, hepatic artery): segmental resection of the bile ducts, possibly extended to adjacent liver segments, hemihepatectomy, and dCCA → pancreatoduodenectomy. After complete resection → adjuvant treatment (capecitabine) or capecitabine/gemcitabine for 6 months. For pCCA and unresectable cancer consider liver transplant (limited to tumor diameter ≤2 cm).
2. Palliative treatment: If resection is not possible use palliative systemic treatment (assuming the patient’s condition is acceptable and taking into account the tumor genomic profiling). First-line therapy most often involves gemcitabine with cisplatin, and second-line therapy, the FOLFOX regimen (oxaliplatin, leucovorin, fluorouracil). Depending on the patient’s clinical condition, radioembolization, stereotactic body radiation therapy (SBRT) or external beam radiation, tumor ablation (eg, microwave), and molecularly targeted treatment are used. In order to reduce the symptoms of cholestasis, endoscopic biliary drainage with stent placement or, less often, percutaneous or surgical drainage are performed.
In most patients cholangiocarcinoma is unresectable at the time of diagnosis; 5-year survival is in the range of 5% to 10% (20%-30% for eCCA). In patients undergoing potentially curative resection and subsequent chemotherapy, the average survival may reach >50 months.Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and indirectness. Primrose JN, Fox RP, Palmer DH, et al; BILCAP study group. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019 May;20(5):663-673. doi: 10.1016/S1470-2045(18)30915-X. Epub 2019 Mar 25. PMID: 30922733.