Cholangiocarcinoma

Cholangiocarcinoma, typically seen in older adults with risk factors including liver-fluke endemic regions or primary sclerosing cholangitis, often presents with obstructive jaundice and is characterised by a delayed enhancing mass with central hypodensity with distal bilary duct dilatation and capsular retraction.

Description

Cholangiocarcinoma, a rare and highly malignant neoplasm, originates from the epithelial cells of the bile ducts within the liver or the bile ducts outside the liver. Despite its scarcity, it is recognised as the second most common primary hepatic malignancy after hepatocellular carcinoma. Notably, the diagnosis of cholangiocarcinoma is challenging, primarily due to its insidious onset, non-specific clinical presentation, and anatomical complexity of the biliary tree.

Pathogenesis

Cholangiocarcinoma typically arises from a multi-step process initiated by chronic inflammation and progressive biliary injury that triggers genetic and epigenetic alterations in cholangiocytes, the lining cells of the bile ducts. This process encompasses transformation of normal biliary epithelium into biliary intraepithelial neoplasia (BilIN), evolving eventually into invasive carcinoma.

Subtypes

The anatomical distribution of cholangiocarcinoma allows its classification into three main subtypes, each exhibiting unique radiological, clinical, and prognostic features:

• Intrahepatic cholangiocarcinoma (iCCA): Occurs within the liver’s smaller intrahepatic bile ducts. Most common (50%). Subtypes:
  • Mass forming (the most common)
  • Periductal infiltrating: Growth along the dilated or narrowed bile duct without mass formation
  • Intraductal
• Perihilar cholangiocarcinoma (pCCA, also known as Klatskin tumour): Arises at the liver hilum where left and right hepatic ducts join.
• Distal cholangiocarcinoma (dCCA): Originates from the bile ducts distal to the hilum, down to the ampulla of Vater.

Epidemiology, Risk Factors & Associations

• More prevalent in Eastern and Southeastern Asia (linked to endemic liver fluke infection)
  • Liver flukes: Hepatobiliary parasites (Clonorchis sinensis and Opisthorchis viverrini)
• Primary sclerosing cholangitis (PSC) (increased risk 400 times than general population)
• Chronic liver disease and cirrhosis (2-6 times increased risk)
• Hepatitis B and C infection (2-3 times increased risk)
• Recurrent pyogenic cholangitis and hepatolithiasis
• Epstein-Barr virus infection
• Carcinogen exposure (e.g., Thorotrast, dioxin, polyvinyl chloride)
• Older age (>65 years), male sex, obesity, and smoking
• Choledochal cysts and Caroli disease
• Anomalous pancreaticobiliary junction

Clinical Features

• Jaundice (most common, particularly in extrahepatic disease)
• Abdominal pain, often vague and intermittent
• Weight loss, anorexia, fatigue
• Pruritus, dark urine, pale stool

Complications

• Biliary obstruction leading to ascending cholangitis
• Liver failure due to extensive disease or cirrhosis
• Metastasis: Lymph nodes are the most common sites, followed by liver and peritoneum.

Pathological Features

Histopathology

• Macroscopic: Appearance can range from an intraductal polypoid mass to an extensive sclerosing lesion or a firm white nodular intrahepatic mass. Typically they are sclerotic masses without haemorrhage or macroscopic necrosis. The active tumour is usually at the periphery, with the central portions replaced by fibrosis, causing capsular retraction.
• Microscopic: Tumour consists of glandular structures with varying degree of differentiation, lined by cuboidal or columnar cells that exhibit mucin production.

Serology

• CA 19-9: often elevated but lacks specificity, used more for follow-up than diagnosis

Biochemistry

• Marked increase in alkaline phosphatase and gamma-glutamyltransferase – indicative of cholestasis.
• Moderate elevation of serum bilirubin, and mild increase in transaminases

Radiological Features

General Features

• Characteristically presents as an intrahepatic mass lesion that can be hypo- or hyper-echoic compared to the surrounding liver parenchyma, with possible enhancement after contrast administration.
• May demonstrate capsular retraction (non-specific, see Differential Diagnosis)
• Periductal infiltrating intrahepatic tumours are most common at the hilum (70% of hilar-perihilar cholangiocarcinomas), known as Klatskin tumours. Extends longitudinally along bile ducts, often causing peripheral duct dilation.

CT

• Non-contrast: Appears as a homongenously hypodense mass lesion compared to the surrounding liver parenchyma.
• Arterial phase: May show minor peripheral rim enhancement
• Portal venous and delayed phases:
  • Mass forming: Often demonstrate progressive centripetal enhancement with a hypodense centre. Peripheraly biliary duct dilatation distal to mass. Capsular retraction. Tumour thrombus not usually seen.
  • Periductal infiltrating: Diffuse periductal thickening and increased enhancement can be seen with a dilated or irregularly narrowed intrahepatic duct
  • Intraductal: Variable appearances;
    • Diffuse and marked duct ectasia with or without a grossly visible papillary mass
    • Intraductal polypoid mass within localised ductal dilatation
    • Intraductal cast-like lesions within a mildly dilated duct
    • Focal stricture-like lesion with mild proximal ductal dilatation

MRI

• T1WI: Hypointense mass lesion
• T2WI: Hyperintense mass lesion
• T1 C+ (gadolinium):
  • Arterial phase may show peripheral rim enhancement
  • Portal venous and delayed phases often demonstrate progressive centripetal enhancement with a hypointense centre.
• DWI/ADC: A peripherally hyperintense target appearance on DWI favours cholangiocarcinoma over hepatocellular carcinoma

PET FDG

• Hypermetabolic activity often present in the lesion, but not typically used in first-line evaluation due to variable sensitivity.

Grading and Staging

Cholangiocarcinoma staging is based on the American Joint Committee on Cancer (AJCC) 8th edition, which includes tumour (T), nodes (N), and metastasis (M) classification for intrahepatic, perihilar, and distal cholangiocarcinomas.

Intrahepatic Cholangiocarcinoma

Tumour (T)

• TX: Primary tumour cannot be assessed.
• T0: No evidence of primary tumour.
• Tis: Carcinoma in situ.
• T1a: Solitary tumour ≤5 cm without vascular invasion.
• T1b: Solitary tumour >5 cm without vascular invasion.
• T2a: Solitary tumour with intrahepatic vascular invasion.
• T2b: Multiple tumours, with or without vascular invasion.
• T3: Tumour perforating the visceral peritoneum.
• T4: Tumour involving local extrahepatic structures by direct invasion.

Nodes (N)

• NX: Regional lymph nodes cannot be assessed.
• N0: No regional lymph node metastasis.
• N1: Regional lymph node metastasis.

Metastasis (M)

• M0: No distant metastasis.
• M1: Distant metastasis present.

Perihilar Cholangiocarcinoma

Tumour (T)

• TX: Primary tumour cannot be assessed.
• T0: No evidence of primary tumour.
• Tis: Carcinoma in situ.
• T1: Tumour confined to the bile duct, with extension up to the muscle layer or fibrous tissue.
• T2a: Tumour invades beyond the wall of the bile duct to surrounding adipose tissue.
• T2b: Tumour invades adjacent hepatic parenchyma.
• T3: Tumour invades unilateral branches of the portal vein or hepatic artery.
• T4: Tumour invades the main portal vein or its branches bilaterally, or the common hepatic artery, or the second-order biliary radicals bilaterally.

Nodes (N)

• NX: Regional lymph nodes cannot be assessed.
• N0: No regional lymph node metastasis.
• N1: Metastasis to 1-3 regional lymph nodes.
• N2: Metastasis to 4 or more regional lymph nodes.

Metastasis (M)

• M0: No distant metastasis.
• M1: Distant metastasis present.

Distal Cholangiocarcinoma

Tumour (T)

• TX: Primary tumour cannot be assessed.
• T0: No evidence of primary tumour.
• Tis: Carcinoma in situ.
• T1: Tumour limited to the bile duct, with extension up to the muscle layer or fibrous tissue.
• T2: Tumour invades beyond the wall of the bile duct to surrounding adipose tissue, with extension up to the muscle layer or fibrous tissue.
• T3: Tumour invades the pancreas, gallbladder, or liver, or unilateral branches of the portal vein or hepatic artery.
• T4: Tumour involves the main portal vein or its branches bilaterally, or the common hepatic artery, or the second-order biliary radicals bilaterally.

Nodes (N)

• NX: Regional lymph nodes cannot be assessed.
• N0: No regional lymph node metastasis.
• N1: Metastasis to 1-3 regional lymph nodes.
• N2: Metastasis to 4 or more regional lymph nodes.

Metastasis (M)

• M0: No distant metastasis.
• M1: Distant metastasis present.

Diagnosis

Diagnosis is typically achieved through a combination of imaging techniques, clinical features, and histopathological confirmation, often through endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC)-guided biopsy.

Differential Diagnosis

• Hepatocellular carcinoma: Typically occurs in the setting of chronic liver disease or cirrhosis. Characterised by early arterial phase enhancement and washout in delayed phase on contrast-enhanced imaging. Serum alpha-fetoprotein (AFP) is often elevated. More likely to cause tumour thrombus.
• Metastatic disease: More commonly seen in the liver than primary malignancies. The lesion’s appearance varies depending on the primary tumour. Clinical history and additional imaging (e.g., chest CT for lung cancer metastasis, mammogram for breast cancer metastasis) can aid in diagnosis.
• Hepatobiliary cystadenoma or cystadenocarcinoma: These are rare cystic neoplasms of the liver, often multiloculated with internal septations. They may contain internal debris or haemorrhage. The presence of an ovarian-like stroma on histopathology helps to differentiate from other cystic lesions.
• Intrahepatic bile duct stones (hepatolithiasis): These can cause biliary obstruction and subsequent inflammation, mimicking cholangiocarcinoma. However, imaging demonstrates the presence of calculi within the bile ducts, and the absence of a mass lesion or enhancement pattern that matches cholangiocarcinoma.
• Primary sclerosing cholangitis (PSC): PSC is a risk factor for cholangiocarcinoma. Imaging typically demonstrates multifocal stricturing and dilatation of intrahepatic and/or extrahepatic bile ducts. Serum CA 19-9 levels may be raised in both conditions, but a rapid increase or very high levels may suggest cholangiocarcinoma. ERCP with brush cytology and/or intraductal biopsy can aid in differentiating the two conditions.

Differential diagnoses for liver masses which cause capsular retraction:

• Intrahepatic cholangiocarcinoma
• Metastatic carcinoma (commonly from breast cancer)
• Hepatic fibrosis/cirrhosis
• Hepatocellular carcinoma (less commonly causes capsular retraction)
• Post-treatment changes (e.g., after radiofrequency ablation or transarterial chemoembolization)
• Biliary cystadenocarcinoma
• Epithelioid hemangioendothelioma
• Fibrolamellar carcinoma

Management

Surgical Management

• Resectable Tumours:
  • Intrahepatic Cholangiocarcinoma: Hepatic resection: Segmentectomy, lobectomy, or extended hepatectomy depending on tumour size and location. Lymphadenectomy.
  • Perihilar Cholangiocarcinoma: Hilar resection with hepatic lobectomy (most common surgical approach). Hepaticojejunostomy (biliary reconstruction) to restore bile flow. Lymphadenectomy.
  • Distal Cholangiocarcinoma: Pancreaticoduodenectomy (Whipple procedure – removal of the head of the pancreas, part of the bile duct, gallbladder, and duodenum). Lymphadenectomy.
• Unresectable or Metastatic Tumours:
  • Liver Transplantation: Considered for select patients with early-stage perihilar cholangiocarcinoma meeting specific criteria (e.g., unresectable but localized disease).

Non-Surgical Management

• Neoadjuvant Therapy: Preoperative chemotherapy or chemoradiotherapy to shrink the tumour and improve resectability. Common regimens: Gemcitabine and cisplatin, capecitabine.
• Adjuvant Therapy: Postoperative chemotherapy or chemoradiotherapy to eliminate residual microscopic disease and reduce recurrence risk. Common regimens: Gemcitabine and cisplatin, fluoropyrimidine-based therapy (capecitabine or 5-fluorouracil).
• Radiation Therapy:
  • External Beam Radiation Therapy (EBRT): Often combined with chemotherapy for locally advanced tumours.
  • Brachytherapy: Internal radiation used in select cases.

Targeted Therapy and Immunotherapy

• Targeted Therapy:
  • IDH1 Inhibitors: For patients with IDH1 mutations (e.g., ivosidenib).
  • FGFR2 Inhibitors: For patients with FGFR2 fusions or rearrangements (e.g., pemigatinib, infigratinib).
• Immunotherapy:
  • Checkpoint Inhibitors: Pembrolizumab for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumours.

Palliative Care

• For advanced or metastatic disease to control tumour growth and prolong survival. Common regimens: Gemcitabine and cisplatin, fluoropyrimidine-based therapy.

Symptom Management

• Biliary Decompression: Endoscopic or percutaneous stenting to relieve biliary obstruction and jaundice. According to the ACR Appropriateness Criteria, percutaneous internal/external biliary catheter is the most appropriate procedure when there is a hilar neoplasm. An endoscopic approach may not provide adequate drainage of blocked intrahepatic ducts and may result in increased risk of biliary sepsis.
• Pain Management: Analgesics, including opioids, for pain control.
• Nutritional Support: Dietary modifications and supplements to maintain nutritional status.
• Palliative Chemotherapy: For advanced or metastatic disease to control tumour growth and prolong survival.

Followup and Monitoring

• Regular Surveillance: Post-treatment imaging (CT, MRI) and tumour marker (CA 19-9) monitoring to detect recurrence.
• Management of Recurrence: Depending on the location and extent of recurrence, options may include repeat resection, chemotherapy, radiation therapy, or targeted therapy.