Cholangiocarcinoma

1. Definition

Cholangiocarcinoma (CCA) — let's break the name down: "cholangio" = bile duct (Greek cholē = bile + angeion = vessel), "carcinoma" = malignant epithelial tumour. So, quite literally, cancer arising from the epithelial lining of the bile ducts.

Key definitional points:

• Cholangiocarcinoma refers to bile duct cancer arising from epithelial cells of intrahepatic, perihilar, and distal extrahepatic bile ducts ^[1][2]
• > 90% are adenocarcinoma; the remainder are squamous cell carcinoma or other rare subtypes ^[2]
• Exclusive of gallbladder carcinoma and ampullary carcinoma — these are distinct entities even though they share the biliary tree. This is a common exam pitfall. ^[2]
• Perihilar cholangiocarcinoma involving the common hepatic duct (CHD) bifurcation is historically called a Klatskin tumour (named after Gerald Klatskin, 1965) ^[1][2]

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2. Epidemiology

Incidence and Trends

• Adenocarcinoma of intrahepatic bile duct accounts for 5–20% of primary liver malignancy ^[3]
• Mostly occurs in patients > 50 years ^[3]
• Overall incidence is increasing worldwide, driven particularly by rising intrahepatic cholangiocarcinoma (iCCA) — thought to relate to metabolic risk factors (obesity, NAFLD, diabetes) and improved imaging/diagnosis ^[4]
• Perihilar CCA remains the most common subtype (~50–60%), followed by distal extrahepatic (~20–30%), then intrahepatic (~10–20%) ^[1][2]
• Geographic variation is striking:
  • Southeast Asia (Thailand, especially Isan region): highest worldwide incidence due to endemic liver fluke (Opisthorchis viverrini) infection — incidence can be 85 per 100,000
  • East Asia (including Hong Kong, China, Korea): elevated risk due to Clonorchis sinensis infection and recurrent pyogenic cholangitis (RPC)
  • Western countries: PSC is the dominant risk factor; overall incidence lower (~1–2 per 100,000)

Hong Kong Context

• Association with recurrent pyogenic cholangitis (common in Orientals) ^[3]
• Hepatitis B is endemic in Hong Kong — chronic HBV contributes to both HCC and iCCA
• Hepatolithiasis and RPC ("Hong Kong disease") are important local risk factors ^[5]
• PSC-associated CCA is common in Westerners but relatively uncommon in Hong Kong ^[3]

Sex and Age

• Slight male predominance overall (M:F ≈ 1.2–1.5:1) for extrahepatic CCA
• Intrahepatic CCA has roughly equal sex distribution
• Increasing incidence with age; peak incidence in the 7th–8th decade ^[2]

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3. Anatomy and Function

Understanding cholangiocarcinoma requires a solid grasp of biliary anatomy. Think of the biliary tree as a drainage system — like tributaries flowing into a river.

The Biliary Tree: From Periphery to Duodenum

Key anatomical landmarks for classification:

Intrahepatic CCA Sub-classification

• Intrahepatic cholangiocarcinoma originates from: ^[2]
  • Small intrahepatic ducts (peripheral cholangiocarcinoma) — these form a mass lesion within the liver parenchyma, behaving more like a liver mass
  • Large intrahepatic ducts proximal to the bifurcation of left and right intrahepatic ducts — these behave more like perihilar tumours

Extrahepatic CCA Division

• Divided into perihilar and distal segments with the transition occurring at the point where the CBD lies posterior to the duodenum, distal to the insertion of the cystic duct into the CBD ^[2]

Blood Supply and Lymphatic Drainage

• The bile ducts receive their blood supply from the hepatic arterial system (peribiliary vascular plexus), NOT the portal vein. This is important because:
  • CCA tends to cause ischaemic-type strictures as it invades the arterial plexus
  • Hepatic artery involvement is a key determinant of resectability
• Lymphatic drainage follows the hepatoduodenal ligament → coeliac, periportal, and para-aortic lymph nodes
• Common mode of spread includes lymphatic spread ^[2]

Nerve Supply

• The biliary tree has extensive perineural networks within the hepatoduodenal ligament
• This explains why CCA has a notorious tendency for perineural invasion (tumour spreads along nerve sheaths) — one of its hallmark histological features ^[2]

Function of Bile Duct Epithelium (Cholangiocytes)

Cholangiocytes are not passive conduits. They:

• Modify bile composition (secrete bicarbonate, chloride; absorb water, glucose, amino acids)
• Participate in the cholehepatic shunt for bile salt recycling
• Express various receptors and growth factors that, when dysregulated, can promote carcinogenesis

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4. Etiology and Pathophysiology

The unifying theme across most risk factors is chronic inflammation → cholestasis → DNA damage → malignant transformation of cholangiocytes. Think of it like any chronic inflammatory malignancy (e.g., Barrett's → oesophageal adenocarcinoma, UC → colorectal cancer).

4.1 Risk Factors (with Pathophysiology)

A. Cholestatic / Inflammatory Biliary Disease

i. Primary Sclerosing Cholangitis (PSC)

• Strong association with cholangiocarcinoma, especially perihilar disease ^[2]
• PSC is an inflammatory disorder of the biliary tree that leads to fibrosis and stricturing of intrahepatic and extrahepatic bile ducts ^[2]
• PSC is strongly associated with ulcerative colitis ^[2]
• Association with ulcerative colitis (common in Westerners) ^[3]
• Pathophysiology: Chronic bile duct inflammation → oxidative stress → DNA damage in cholangiocytes → dysplasia → carcinoma. The strictured, stagnant bile environment promotes bacterial overgrowth and secondary bile acid formation, which are carcinogenic.
• Lifetime risk of CCA in PSC patients: 10–20%
• PSC is the strongest known risk factor in Western populations, but is less common in Asia ^[4]

ii. Recurrent Pyogenic Cholangitis (RPC)

• Association with recurrent pyogenic cholangitis (common in Orientals) ^[3]
• Also known as "Hong Kong disease" or oriental cholangiohepatitis ^[5]
• Pathophysiology: Usually starts in left intrahepatic ducts ^[5]. Parasitic infestation (e.g., Clonorchis sinensis) → epithelial damage → bacterial translocation → stricture formation → biliary stasis → brown pigment stone formation → recurrent cholangitis → chronic inflammation → malignant transformation ^[5]
• RPC causes a cycle: stones → obstruction → infection → more stones → more damage → eventually CCA

iii. Cholelithiasis / Hepatolithiasis

• Cholelithiasis refers to gallstones; hepatolithiasis refers to chronic intrahepatic stone disease which leads to biliary stasis and recurrent pyogenic cholangitis ^[2]
• Hepatolithiasis is particularly relevant in East Asia
• Pathophysiology: Chronic mechanical irritation and inflammation of bile duct epithelium by stones → metaplasia → dysplasia → carcinoma. Biliary stasis also concentrates potentially carcinogenic substances in bile.

B. Fibrocystic Liver Disease (Congenital)

i. Choledochal Cysts

• Choledochal cysts are congenital cystic dilatation of bile ducts ^[2]
• Lifetime risk of CCA: 10–30%, increasing with age (hence why prophylactic excision is recommended)
• Associated with abnormal pancreaticobiliary junction (APBJ) in 70–90% of patients ^[6]

ii. Caroli's Disease

• Caroli's disease is a variant of choledochal cyst characterized by multiple cystic dilations of intrahepatic biliary ducts ^[2]

iii. Pathophysiology of Fibrocystic Disease → CCA

• Fibrocystic liver disease leads to cholangiocarcinoma by: ^[2]
  • Biliary stasis — pooling of bile promotes bacterial overgrowth and formation of carcinogenic secondary bile acids
  • Chronic inflammation from reflux of pancreatic juice — APBJ allows pancreatic enzymes (trypsin, lipase) to enter the biliary tree, causing chemical cholangitis
  • Abnormalities in bile salt transporter proteins → unstable bile content
  • Deconjugation of carcinogens previously conjugated in the liver → reactivation of carcinogens in bile

C. Chronic Liver Disease

• Viral hepatitis (HBV/HCV) ^[2]
• Liver cirrhosis ^[2]
• Alcoholic liver disease ^[2]
• Pathophysiology: Chronic hepatic inflammation → hepatic stellate cell activation → fibrosis → altered microenvironment with growth factor dysregulation (TGF-β, PDGF, VEGF) → cholangiocyte proliferation and malignant transformation
• HCV has a particularly strong association with iCCA (adjusted OR ~4–5) ^[4]
• HBV is relevant in Hong Kong given endemic prevalence

D. Parasitic Infection (High Yield for Hong Kong)

Infection of liver flukes by consumption of undercooked freshwater fish which leads to adult worms inhabiting and laying eggs in the biliary system: ^[2]

• Clonorchis sinensis — endemic in southern China including Hong Kong, Korea, Vietnam
• Opisthorchis viverrini — endemic in Thailand, Laos, Cambodia

Induction of chronic inflammatory state in proximal biliary tree leading to malignant transformation of the lining epithelium ^[2]

Pathophysiology (detailed):

1. Ingestion of metacercariae in raw/undercooked freshwater fish (e.g., grass carp, snakehead fish)
2. Excystation in duodenum → larvae migrate up the ampulla of Vater into bile ducts
3. Adult flukes reside in bile ducts for 15–25 years, feeding on bile duct epithelium
4. Mechanical damage from fluke suckers + toxic metabolites + egg deposition → chronic periductal inflammation
5. Cholangiocyte hyperplasia → goblet cell metaplasia → dysplasia → adenocarcinoma
6. Additionally, fluke-secreted proteins (e.g., granulin-like growth factor) directly promote cell proliferation

Diagnosis of Clonorchis: stool microscopy for eggs, duodenal aspirate for eggs, USG for adult flukes, intra-op choledochoscopy for adult flukes ^[5] Treatment: praziquantel 25 mg/kg PO tds × 1 day ^[5]

E. Genetic Disorders

• Lynch syndrome (Hereditary nonpolyposis colorectal cancer) ^[2]

  • Autosomal dominant disorder caused by germline mutation in one of several DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) ^[2]
  • Lifetime risk of CCA is elevated but still relatively low (~2%)
  • The MMR deficiency leads to microsatellite instability → accumulation of mutations in cholangiocytes

• Multiple biliary papillomatosis ^[2]

  • Multiple adenomatous polyps of variable distribution and extent in intrahepatic bile ducts ^[2]
  • These are premalignant lesions with high recurrence rate

F. Other Risk Factors

• Obesity, Diabetes mellitus, Metabolic syndrome ^[2][4]
  • Pathophysiology: Insulin resistance → hyperinsulinaemia → IGF-1 activation → cell proliferation. Adipose tissue inflammation → IL-6, TNF-α → pro-carcinogenic microenvironment. NAFLD/NASH → hepatic inflammation
• Thorotrast (thorium dioxide) exposure ^[2][4]
  • Historical contrast agent used in the 1930s–50s for radiological imaging
  • Alpha-emitting radioactive material deposited in the reticuloendothelial system → chronic radiation-induced DNA damage
  • Latency period of 20–40 years before CCA development
  • Now banned, but elderly patients may still present with Thorotrast-related cancers

4.2 Summary Table: Risk Factors by Category

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5. Pathogenesis and Histopathology

5.1 Molecular Pathogenesis

The carcinogenesis of CCA follows a multi-step model, similar to the adenoma–carcinoma sequence in colorectal cancer but occurring in cholangiocytes:

Normal cholangiocyte → Hyperplasia → Dysplasia → Carcinoma in situ → Invasive carcinoma

Key molecular pathways:

1. Chronic inflammation → NF-κB activation → COX-2 upregulation → prostaglandin-mediated cell proliferation and inhibition of apoptosis
2. IL-6/STAT3 pathway — IL-6 released by inflammatory cells activates STAT3 in cholangiocytes → promotes survival and proliferation
3. Bile acid toxicity — hydrophobic bile acids cause oxidative DNA damage and activate EGFR/MAPK signalling
4. Growth factor dysregulation — overexpression of VEGF, PDGF, HGF → angiogenesis and tumour growth
5. Tumour suppressor loss — p53 mutations (especially in Thorotrast-related CCA), p16/CDKN2A silencing, SMAD4 loss
6. Oncogenic mutations — IDH1/IDH2 mutations (especially in iCCA, ~15–20%), FGFR2 fusions (iCCA, ~15%), KRAS mutations (extrahepatic CCA)

5.2 Histological Features

Majority of cholangiocarcinoma (> 90%) are adenocarcinoma ^[2]

Cholangiocarcinoma is characterized by: ^[2]

• Slow growth
• High rate of local invasion
• Mucin production
• Tendency to invade perineural sheath and spread along nerves (perineural invasion is a hallmark and explains why margins are often positive even after seemingly complete resection)

5.3 Macroscopic Subtypes of Adenocarcinoma

Adenocarcinoma is further divided into 3 types: ^[2]

Why does the sclerosing type have such dense fibrosis? Because the tumour cells secrete TGF-β and PDGF, which activate surrounding stromal fibroblasts (cancer-associated fibroblasts) to produce collagen. This desmoplastic reaction actually creates a protective microenvironment for the tumour and makes it resistant to chemotherapy penetration.

5.4 Growth Patterns (WHO Classification)

Particularly for iCCA, the WHO recognizes:

• Mass-forming — a discrete intrahepatic mass (most common pattern for iCCA)
• Periductal-infiltrating — tumour grows along bile duct walls causing strictures without a discrete mass
• Intraductal-growing — papillary growth within the bile duct lumen (best prognosis)
• Mixed patterns — combinations of the above

5.5 Immunohistochemistry

Cytokeratin-7 (CK7) positivity is consistent with biliary tract origin ^[2]

Typical IHC profile of CCA:

This IHC panel is critical when distinguishing iCCA from HCC, especially when a liver mass is identified and biopsy is performed.

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6. Classification

6.1 Anatomical Classification (Most Clinically Important)

Classification by site: ^[4]

• Klatskin's tumour: cholangiocarcinoma that involves the common hepatic duct bifurcation (usually perihilar type) ^[4]

6.2 Bismuth-Corlette Classification (for Perihilar CCA)

This classification describes the extent of ductal involvement and is crucial for surgical planning:

Bismuth-Corlette classification for perihilar tumour: ^[2][4]

Bile duct tumours that involve common hepatic duct bifurcation are referred to as Klatskin tumour regardless of whether they arise from intrahepatic or extrahepatic portion of biliary tree ^[2]

6.3 Staging (AJCC TNM 8th Edition)

Note: iCCA, pCCA, and dCCA each have separate TNM staging systems because they behave as biologically distinct diseases.

Intrahepatic CCA (staged like liver tumours):

• T1a: Solitary ≤ 5 cm without vascular invasion
• T1b: Solitary > 5 cm without vascular invasion
• T2: Solitary with intrahepatic vascular invasion, OR multiple tumours
• T3: Tumour perforating visceral peritoneum
• T4: Direct invasion of local extrahepatic structures

Perihilar CCA:

• Staging considers depth of invasion into bile duct wall, hepatic artery, portal vein, and unilateral vs bilateral hepatic duct involvement

Distal CCA:

• Staged similarly to other pancreaticobiliary cancers, based on depth of invasion into bile duct wall and surrounding structures

6.4 Metastatic Patterns

Metastatic sites depend on type of cholangiocarcinoma: ^[2]

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7. Clinical Features

Conceptual Framework

The clinical presentation of CCA depends heavily on anatomical location:

• Intrahepatic CCA behaves like a liver mass — often silent until large
• Perihilar CCA causes early biliary obstruction — presents with jaundice
• Distal CCA presents like other periampullary tumours — painless obstructive jaundice

7.1 Symptoms

A. Jaundice (Obstructive / Post-hepatic)

• ONLY in extrahepatic (perihilar/distal) cholangiocarcinoma, especially Klatskin tumour in which blockage of the bifurcation of left and right hepatic duct will cause jaundice in early stage ^[2]
• Intrahepatic cholangiocarcinoma will NOT cause jaundice since bilirubin can be reabsorbed into blood and re-excreted through unaffected parts of liver ^[2]

Pathophysiological explanation:

• The liver has enormous reserve capacity. If one segmental duct is blocked, the rest of the liver continues to excrete bilirubin normally. Only when the CHD bifurcation (or both main ducts) is blocked does conjugated bilirubin back up into the blood → jaundice
• Perihilar CCA (Klatskin tumour) blocks this critical junction early → early jaundice
• iCCA must grow very large or directly invade the hilum before causing jaundice
• The jaundice is typically progressive and painless (vs. the colicky, intermittent jaundice of choledocholithiasis)

This is a classic painless jaundice presentation — one of the most important clinical scenarios in surgery exams ^[7]

B. Dark Urine and Pale Stools

Dark urine and pale stools ^[2]

Pathophysiology:

• Dark urine: Conjugated bilirubin (water-soluble) that cannot drain into the duodenum backs up into the blood → filtered by kidneys → excreted in urine → dark "cola-coloured" or "tea-coloured" urine
• Pale stools: Normally, conjugated bilirubin reaches the gut → bacterial conversion to stercobilinogen → stercobilin (gives stool its brown colour). In obstruction, no bilirubin reaches the gut → acholic (pale/clay-coloured) stools
• These features together with jaundice = obstructive (post-hepatic) jaundice triad

C. Pruritus

Pruritus ^[2]

Pathophysiology:

• Bile salts that cannot be excreted into the gut accumulate in the blood → deposit in the skin → irritate cutaneous nerve endings
• The exact mechanism remains debated; lysophosphatidic acid (LPA) and autotaxin (bile salt metabolites) acting on itch-specific nerve fibres (via TGR5 receptors) may be involved
• Can be severe and debilitating — often worse at night, affecting palms and soles first
• Pruritus may precede jaundice (as sub-clinical cholestasis can cause bile salt accumulation before bilirubin rises enough to cause visible jaundice)

D. Right Upper Quadrant (RUQ) Pain

RUQ pain ^[2][3]

Pathophysiology:

• Intrahepatic CCA: Hepatomegaly from tumour growth stretches Glisson's capsule (the fibrous capsule of the liver) → dull, aching RUQ pain. The liver parenchyma itself has no pain receptors — it's the capsular distension that hurts
• Extrahepatic CCA: Biliary obstruction → upstream ductal dilatation → stretching of the bile duct wall. If superimposed cholangitis occurs, acute inflammation of the duct wall causes more intense pain
• Pain is typically dull and constant (unlike biliary colic which is episodic)

E. Constitutional Symptoms

• Anorexia, weight loss ^[3]
  • Pathophysiology: Cancer-related cachexia mediated by pro-inflammatory cytokines (TNF-α, IL-6) → increased basal metabolic rate, decreased appetite, muscle wasting. Additionally, bile salt malabsorption → fat malabsorption → steatorrhoea → weight loss
• Fever ^[2][3]
  • Pathophysiology: Biliary obstruction → biliary stasis → bacterial colonisation of stagnant bile → ascending cholangitis. Tumour necrosis can also release pyrogens. Cholangitis occurs particularly in perihilar CCA where obstruction is proximal

F. Malabsorption Symptoms

• Steatorrhoea (fatty, foul-smelling stools) — because bile salts cannot reach the duodenum → impaired fat emulsification → fat malabsorption
• Fat-soluble vitamin deficiency (A, D, E, K) — prolonged obstruction leads to:
  • Vitamin K deficiency → coagulopathy (prolonged PT/INR) — this is important pre-operatively!
  • Vitamin D deficiency → osteomalacia
  • Vitamin A deficiency → night blindness (rare, requires prolonged obstruction)

7.2 Signs

A. General Examination

• Jaundice — yellow discolouration of skin and sclera (scleral icterus is detectable at bilirubin > 35–40 µmol/L)
• Cachexia / wasting — evidence of advanced malignancy
• Scratch marks / excoriations — secondary to pruritus
• Xanthomata / xanthelasma — cholesterol deposits in skin, seen in chronic cholestasis

B. Abdominal Examination

• Hepatomegaly ^[3]

  • iCCA: palpable liver mass from tumour itself
  • Perihilar/distal CCA: hepatomegaly from biliary obstruction → hepatic congestion and bile duct dilatation

• Palpable gallbladder (Courvoisier's sign)

  • In distal CCA: the gallbladder distends because bile cannot drain past the obstruction. The cystic duct is patent → gallbladder fills with mucus → palpable, non-tender
  • Courvoisier's Law: "In the presence of painless obstructive jaundice, a palpable gallbladder is unlikely to be due to gallstones" — because chronic gallstone disease causes fibrosis and a shrunken, non-distensible gallbladder. A palpable gallbladder + painless jaundice suggests malignant obstruction (pancreatic head cancer, distal CCA, ampullary cancer)
  • Important: In perihilar CCA (Klatskin tumour), the obstruction is ABOVE the cystic duct entry → gallbladder does NOT distend → Courvoisier's sign is NEGATIVE ^[7]

• Ascites — suggests peritoneal metastasis (advanced disease) or portal hypertension in cirrhotic patients
• Splenomegaly — rare; suggests portal hypertension from advanced liver disease or portal vein involvement

C. Signs of Chronic Liver Disease (if underlying cirrhosis)

• Spider naevi, palmar erythema, gynaecomastia, caput medusae, etc.

D. Metastatic Disease Signs

• Sister Mary Joseph nodule — periumbilical nodule suggesting peritoneal metastasis
• Virchow's node (left supraclavicular lymphadenopathy) — suggests distant lymphatic spread
• Blumer's shelf — drop metastasis in the rectovesical/rectouterine pouch (palpable on PR exam)

7.3 Clinical Presentation by Subtype (Summary)

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8. Differential Diagnosis of Cholangiocarcinoma

The differential depends on the clinical presentation:

For Obstructive Jaundice (Extrahepatic CCA)

Differential diagnosis: ^[2]

• Choledocholithiasis — intermittent jaundice, colicky pain, fluctuating LFTs
• Pancreatic cancer (head) — painless jaundice, Courvoisier's sign, weight loss
• Cancer of the ampulla of Vater — intermittent jaundice (tumour sloughs → obstruction relieved), better prognosis
• Viral hepatitis — hepatocellular pattern LFTs, viral markers positive
• Primary sclerosing cholangitis (PSC) — "beaded" appearance on MRCP, multifocal strictures
• Primary biliary cholangitis (PBC) — AMA positive, cholestatic LFTs, middle-aged women
• IgG4-related sclerosing cholangitis — important mimic! Responds to steroids; elevated IgG4 levels
• Mirizzi syndrome — extrinsic compression of CHD by impacted gallstone
• Benign biliary stricture — post-surgical, post-ERCP, chronic pancreatitis

For Liver Mass (Intrahepatic CCA)

• Hepatocellular carcinoma (HCC) — AFP elevated, arterial enhancement + washout on CT/MRI
• Liver metastases — look for primary tumour (CRC, breast, lung)
• Hepatic abscess — fever, leukocytosis, rim-enhancing lesion
• Haemangioma — peripheral nodular enhancement, centripetal fill-in
• Focal nodular hyperplasia — central scar, homogeneous enhancement

Key: Immunohistochemical stain is useful in differential diagnosis of cholangiocarcinoma with other malignancy ^[2] — CK7/CK19 positive for CCA vs. HepPar-1/Glypican-3/AFP positive for HCC

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Key points from lecture slides ^[3]:

• Tumour markers: carcinoembryonic antigen (CEA), CA 19-9 (may or may not be elevated, nonspecific)
• USG, CT scan, MRI for diagnosis
• FNAC or Trucut biopsy (ONLY for unresectable cases) — because biopsy risks tumour seeding along the needle tract in potentially resectable disease
• Hepatic resection is the treatment of choice (resectability rate about 20%)
• Other treatment: no proven effect (this was 2019; now in 2025, gemcitabine-cisplatin ± durvalumab is standard for advanced CCA — TOPAZ-1 trial)

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Active Recall - Cholangiocarcinoma (Definition to Clinical Features)

1. Why does intrahepatic cholangiocarcinoma NOT cause jaundice early, whereas perihilar cholangiocarcinoma does?

Your answer

Grade

Show mark scheme

Intrahepatic CCA only blocks segmental ducts; remaining liver continues to excrete bilirubin through unaffected ducts. Perihilar CCA blocks the CHD bifurcation, preventing drainage from both lobes, causing early jaundice.

2. Name the Bismuth-Corlette classification types I through IV for perihilar cholangiocarcinoma.

Your answer

Grade

Show mark scheme

Type I: below confluence. Type II: at confluence. Type IIIa: CHD + right hepatic duct. Type IIIb: CHD + left hepatic duct. Type IV: both hepatic ducts or multicentric.

3. Explain why Courvoisier's sign is positive in distal CCA but negative in perihilar CCA (Klatskin tumour).

Your answer

Grade

Show mark scheme

In distal CCA, obstruction is below the cystic duct insertion, so bile backs up into the gallbladder causing distension. In Klatskin tumour, obstruction is above the cystic duct, so bile cannot reach the gallbladder and it does not distend.

4. What is the pathophysiology of CCA development in patients with liver fluke infection (Clonorchis sinensis)?

Your answer

Grade

Show mark scheme

Ingestion of metacercariae in raw freshwater fish. Adult flukes reside in bile ducts for decades. Mechanical damage plus toxic metabolites cause chronic periductal inflammation. Cholangiocyte hyperplasia leads to goblet cell metaplasia, then dysplasia, then adenocarcinoma. Fluke-secreted granulin-like growth factor also promotes cell proliferation.

5. A liver biopsy shows CK7+, CK19+, HepPar-1 negative, AFP negative. What is the most likely diagnosis, and how does this distinguish it from HCC?

Your answer

Grade

Show mark scheme

Cholangiocarcinoma (biliary origin). HCC is typically CK7 negative, CK19 negative, HepPar-1 positive, AFP often positive, Glypican-3 positive.

6. List 4 risk factors for cholangiocarcinoma that are particularly relevant to Hong Kong.

Your answer

Grade

Show mark scheme

Any 4 of: Recurrent pyogenic cholangitis (RPC), hepatolithiasis, Clonorchis sinensis infection from raw freshwater fish, chronic HBV infection, choledochal cysts (common in Asians), obesity and diabetes mellitus.

References

^[1] Senior notes: felixlai.md (Cholangiocarcinoma, sections I–III) ^[2] Senior notes: felixlai.md (Cholangiocarcinoma, sections III–VI) ^[3] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p5, Cholangiocarcinoma) ^[4] Senior notes: maxim.md (Cholangiocarcinoma section) ^[5] Senior notes: maxim.md (Recurrent pyogenic cholangitis section) ^[6] Senior notes: felixlai.md (Biliary cysts / Choledochal cyst section) ^[7] Lecture slides: WCS 056 - Painless jaundice and epigastric mass - by Prof R Poon.ppt (1).pdf

Differential Diagnosis of Cholangiocarcinoma

The differential diagnosis of cholangiocarcinoma depends entirely on how the patient presents. Think about it from first principles: a patient walks into your clinic — what do they look like? There are essentially two main clinical scenarios:

1. Obstructive jaundice (extrahepatic CCA — perihilar or distal)
2. Liver mass / hepatomegaly (intrahepatic CCA)

Each scenario has its own differential. Let's work through them systematically.

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Framework: Approach by Clinical Presentation

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A. Differential Diagnosis of Obstructive Jaundice (Extrahepatic CCA)

When a patient presents with painless progressive obstructive jaundice, you need to think about causes at three anatomical levels: intraluminal, mural, and extramural. This is the classic surgical approach ^[8].

Painless progressive obstructive jaundice in elderly is malignant biliary obstruction until proven otherwise ^[8]

Differentiating Stone vs Tumour

This is one of the most important clinical distinctions to make at the bedside. The history alone often tells you the answer ^[8]:

Why is stone jaundice intermittent but tumour jaundice progressive?

• A gallstone can act as a ball-valve — sometimes it obstructs the CBD, sometimes it dislodges and bile flows again. Hence the jaundice waxes and wanes.
• A tumour grows relentlessly. Once it narrows the duct, it only gets worse. The obstruction never relieves spontaneously.

Why is stone disease more commonly associated with fever?

• When a stone obstructs the CBD, stagnant bile becomes infected (bacteria from the duodenum reflux upwards). The stone creates a closed space → pressure builds → bacteria translocate into the bloodstream → cholangitis/sepsis.
• Tumours obstruct more gradually, and until the duct is completely occluded, some bile still flows → less stasis → less infection (until late stage).

1. Malignant Causes of Biliary Obstruction (MBO)

Pathology causing malignant biliary obstruction: ^[9][10]

i. Cholangiocarcinoma at hilum (Klatskin tumour)

• Cholangiocarcinoma at hilum, Klatskin tumour ^[9]
• Obstruction to just left or right hepatic duct alone will not cause obstructive jaundice ^[1] — you need bilateral obstruction or obstruction at the confluence for clinical jaundice. Why? Because the contralateral liver lobe continues to excrete bilirubin through its unobstructed duct.

ii. Carcinoma of Head of Pancreas

• Carcinoma of pancreas ^[9]
• The most common cause of malignant obstructive jaundice overall
• 70% of pancreatic cancers are in the head → they compress or invade the intrapancreatic CBD → progressive painless jaundice
• Severe epigastric pain radiating to the back is characteristic (retroperitoneal infiltration of coeliac plexus) — but this is a feature of body/tail tumours rather than head tumours ^[11]
• Double duct sign on CT/MRCP: simultaneous dilatation of both the CBD and pancreatic duct — highly suggestive of pancreatic head cancer ^[11]

iii. Periampullary Carcinoma

• Periampullary carcinoma ^[9][10]
• This is a group term for tumours arising at or near the ampulla of Vater, including:
  • Carcinoma of the ampulla of Vater — has the best prognosis among periampullary tumours because it presents earlier (even a small tumour at the ampulla blocks bile flow and causes jaundice) ^[1]
  • Carcinoma of the duodenum ^[9][10]
  • Carcinoma of lower end of (distal) CBD ^[1]
  • Carcinoma of head of pancreas ^[1]
• These are grouped because their presentation (painless jaundice) and surgical management (Whipple procedure) are similar ^[1]

iv. Carcinoma of Gallbladder

• Carcinoma of gallbladder — cystic duct LN, direct infiltration of CBD, tumour fragments ^[9]
• Can cause obstructive jaundice by three mechanisms ^[1]:
  • Spread to cystic duct lymph nodes → extrinsic compression of CBD
  • Direct infiltration of CBD
  • Tumour fragments breaking off into the CBD

v. Hepatocellular Carcinoma (HCC)

• HCC — direct infiltration, compression, tumour fragments in CBD ^[9]
• Usually occurs when mass is situated near confluence site of left and right intrahepatic ducts ^[1]
  • From anterior liver = Segment 4/5 ^[1]
  • From posterior liver = Caudate segment (uncommon) ^[1]
• HCC causing obstructive jaundice is NOT common — it is much more likely to cause jaundice from loss of hepatic reserve in the cirrhotic liver ^[12]

vi. Secondary Lymphadenopathy

• Porta lymphadenopathy ^[10]
• Lymph node metastases to the coeliac axis or porta hepatis ^[13]
• Carcinoma of stomach with metastatic lymph node in the porta hepatis ^[13]
• GI malignancy (CRC), Lymphoma ^[1]
• Extrinsic compression of the bile duct by enlarged lymph nodes at the hepatoduodenal ligament

2. Benign Causes of Biliary Obstruction

Benign causes of biliary obstruction: ^[1]

i. Choledocholithiasis

• Choledocholithiasis ^[2]
• Most common benign cause of obstructive jaundice
• Key differentiating feature: intermittent jaundice with pain and fever (Charcot's triad) vs. the painless progressive jaundice of CCA

ii. Primary Sclerosing Cholangitis (PSC)

• Primary sclerosing cholangitis (PSC) ^[2]
• Creates multifocal strictures with a "beaded" appearance on MRCP
• Important: PSC itself is a risk factor for CCA, and a dominant stricture in PSC may represent superimposed CCA → always suspect malignancy in any PSC patient with worsening jaundice or a new dominant stricture
• Common in Westerners, less common in Asia ^[3]

iii. IgG4-Related Sclerosing Cholangitis

• A critical mimic of CCA! Can produce a stricture that looks identical to CCA on imaging
• Elevated serum IgG4 level is a clue
• Responds dramatically to corticosteroids — which CCA obviously does not
• Always check serum IgG4 before assuming a biliary stricture is malignant ^[2]

iv. Primary Biliary Cholangitis (PBC)

• Primary biliary cirrhosis (PBC) ^[2] (now renamed Primary Biliary Cholangitis)
• Autoimmune destruction of small intrahepatic bile ducts
• Anti-mitochondrial antibody (AMA) positive
• Predominantly affects middle-aged women
• Causes intrahepatic cholestasis rather than extrahepatic obstruction — so it causes cholestatic LFTs and pruritus, but the bile ducts are NOT dilated on imaging

v. Other Benign Causes

• Blood clot (Haemobilia) / Mucus / Foreign body / Tumour thrombus ^[1]
• Benign strictures: TB, Autoimmune, Iatrogenic, RPC ^[1]
• Chronic pancreatitis, Pancreatic cysts ^[1]
• Mirizzi syndrome — common hepatic duct obstruction caused by extrinsic compression from an impacted stone in the cystic duct or Hartmann's pouch of the gallbladder ^[1]

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B. Differential Diagnosis of Liver Mass / Hepatomegaly (Intrahepatic CCA)

When intrahepatic CCA presents as a liver mass, the differential is that of any hepatic space-occupying lesion ^[14]:

Malignant liver tumours: ^[14]

• Primary: Hepatocellular carcinoma, Cholangiocarcinoma, Others (e.g. lymphoma) ^[14]
• Secondary: Metastasis from GI tract, Metastasis from other primary ^[14]

1. Primary Malignant Liver Tumours

How to distinguish iCCA from HCC on imaging?

• HCC: Arterial hyperenhancement → portal venous washout (the tumour "lights up then fades"). Classic LIRADS-5 pattern.
• iCCA: Peripheral arterial rim enhancement → progressive centripetal fill-in on delayed phase (because the dense desmoplastic stroma enhances slowly). Does NOT show washout.

2. Benign Primary Liver Tumours

3. Metastatic / Secondary Liver Tumours

Metastatic carcinoma to liver is commoner than primary liver cancer ^[15] Commonest site from GI tract (portal venous circulation): colorectal, stomach, pancreas ^[15]

• Always look for a primary source — CRC is the most common (CEA elevated), followed by gastric, pancreatic, breast, lung
• Elevated CEA or CA 19-9 in some cases with primary GI malignancy ^[15]
• Investigation for primary: CXR, endoscopy, CT scan abdomen ^[15]
• Multiple liver lesions with a known primary → likely metastatic rather than primary liver cancer

4. Other Causes

• Cysts (simple cyst, polycystic disease) ^[14]
• Liver abscess (pyogenic or amoebic) — fever, raised WCC, rim-enhancing lesion with internal debris
• Haematological malignancies (lymphoma, leukaemia, myeloproliferative disease) ^[14]

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C. Other Conditions Mimicking CCA

i. Recurrent Pyogenic Cholangitis (RPC)

• Can cause biliary strictures that mimic CCA on cholangiography
• Complications of RPC include cholangiocarcinoma ^[5] — so RPC and CCA can coexist
• Key clue: intrahepatic pigment stones, left lobe predilection, middle-age onset, recurrent cholangitis episodes ^[5]

ii. Choledochal Cysts

• Complications: cholangiocarcinoma ^[6]
• A choledochal cyst with a mural nodule or wall thickening should raise suspicion for malignant transformation

iii. Viral Hepatitis

• Viral hepatitis ^[2]
• Acute viral hepatitis can cause cholestatic LFTs mimicking biliary obstruction
• Key differences: hepatocellular pattern (ALT >> ALP), positive viral serology, no bile duct dilatation on imaging

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D. Pathology Producing Jaundice AND Epigastric Mass

This is a specific clinical scenario worth highlighting as it comes directly from the lecture ^[13]:

Pathology producing jaundice and epigastric mass: ^[13]

• Hepatomegaly secondary to biliary obstruction
• Hepatomegaly due to metastases or HCC
• Lymph node metastases to the coeliac axis or porta hepatis
• Carcinoma of stomach with metastatic lymph node in the porta hepatis
• Distended stomach due to duodenal obstruction by tumour which obstructs the bile duct as well

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E. Summary: DDx Listed by Felix Notes [2]

Differential diagnosis of cholangiocarcinoma:

• Choledocholithiasis
• Viral hepatitis
• Hepatocellular carcinoma
• Malignant obstruction of biliary tract:
  • Pancreatic cancer
  • Cancer of the ampulla of Vater
• Intrahepatic cholestasis:
  • Primary sclerosing cholangitis (PSC)
  • Primary biliary cirrhosis (PBC)

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F. Key Differentiating Investigations (Preview)

When working up the differential, the following investigations help narrow the diagnosis:

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Active Recall - Differential Diagnosis of Cholangiocarcinoma

1. List 6 malignant causes of biliary obstruction as taught in lectures.

Your answer

Grade

Show mark scheme

1. Cholangiocarcinoma at hilum (Klatskin tumour). 2. CA head of pancreas. 3. Periampullary carcinoma (ampulla of Vater, duodenum, distal CBD). 4. CA gallbladder. 5. HCC (direct infiltration, compression, tumour fragments in CBD). 6. Porta lymphadenopathy (CRC, lymphoma, gastric CA).

2. How do you clinically differentiate biliary obstruction caused by gallstones from that caused by a tumour?

Your answer

Grade

Show mark scheme

Stone: intermittent jaundice, painful (colic), more likely to have fever/cholangitis, no constitutional symptoms. Tumour: progressive jaundice, painless (until advanced), less likely fever (until late), constitutional symptoms (LOW, LOA, night sweats).

3. What is IgG4-related sclerosing cholangitis and why is it a critical differential for cholangiocarcinoma?

Your answer

Grade

Show mark scheme

IgG4-related sclerosing cholangitis is an autoimmune condition causing biliary strictures that can be radiologically and clinically indistinguishable from CCA. It is critical because it responds to corticosteroids and does not require surgery. Serum IgG4 levels should be checked. Failure to consider it may lead to unnecessary surgery.

4. On cross-sectional imaging, how does intrahepatic CCA differ from HCC in enhancement pattern?

Your answer

Grade

Show mark scheme

HCC: arterial hyperenhancement with portal venous washout (LIRADS-5 pattern). iCCA: peripheral arterial rim enhancement with progressive centripetal (delayed) fill-in due to desmoplastic stroma. iCCA does NOT show washout.

5. Why does obstruction of only the left or right hepatic duct alone NOT cause clinical jaundice?

Your answer

Grade

Show mark scheme

Because the contralateral liver lobe continues to excrete bilirubin through its unobstructed duct. Jaundice only occurs when both hepatic ducts are obstructed (e.g. at the confluence) or when the common hepatic duct or CBD is blocked.

References

^[1] Senior notes: felixlai.md (Biliary obstruction, causes by level) ^[2] Senior notes: felixlai.md (Cholangiocarcinoma, sections IV–V, differential diagnosis) ^[3] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p5, Cholangiocarcinoma) ^[5] Senior notes: maxim.md (Recurrent pyogenic cholangitis section) ^[6] Senior notes: maxim.md (Choledochal cyst section) ^[8] Senior notes: maxim.md (Obstructive jaundice, stone vs tumour table) ^[9] Lecture slides: WCS 056 - Painless jaundice and epigastric mass - by Prof R Poon.ppt (1).pdf (p23, Pathology causing MBO) ^[10] Lecture slides: Malignant biliary obstruction.pdf (p5, Causes of MBO) ^[11] Senior notes: maxim.md (Pancreatic carcinoma section) ^[12] Senior notes: maxim.md (Hepatocellular carcinoma section) ^[13] Lecture slides: WCS 056 - Painless jaundice and epigastric mass - by Prof R Poon.ppt (1).pdf (p32, Pathology producing jaundice and epigastric mass) ^[14] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p2, Hepatomegaly DDx and Malignant liver tumours) ^[15] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p6, Metastatic carcinoma to liver)

Diagnosis of Cholangiocarcinoma

Diagnostic Principles — The "Why" Behind the Workup

Before diving into individual tests, let's understand what we're trying to achieve when working up suspected cholangiocarcinoma. There are essentially five diagnostic goals, and every investigation serves at least one:

1. Confirm biliary obstruction — Is there truly an obstruction? At what level?
2. Characterise the lesion — Is it benign or malignant? What type of malignancy?
3. Define the anatomy — Exactly where is the tumour? How far does it extend along the ducts?
4. Stage the disease — Is there vascular invasion? Nodal metastasis? Distant metastasis?
5. Assess resectability — Can we offer curative surgery? Is the future liver remnant (FLR) adequate?

There is no single diagnostic criterion for CCA (unlike, say, the Tokyo Guidelines for cholangitis). The diagnosis is established through a combination of clinical features, biochemistry, imaging, and histology. Let me walk you through each component systematically.

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Diagnostic Algorithm

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1. Physical Examination

Physical examination is the first step and can give you crucial clues about the nature and level of obstruction.

General Examination

• Jaundice ^[2] — scleral icterus first (detectable at bilirubin > 35–40 µmol/L)
• Cachexia, pallor ^[14] — suggests advanced malignancy
• Lymphadenopathy ^[14] — check left supraclavicular (Virchow's node), periumbilical (Sister Mary Joseph nodule)
• Chronic stigmata of liver disease ^[14] — spider naevi, palmar erythema, gynaecomastia → suggests underlying cirrhosis

Abdominal Examination

• Hepatomegaly – size, tenderness, consistency, surface, edge, bruit ^[14]
  • iCCA: palpable mass with firm/hard consistency, irregular surface
  • Extrahepatic CCA: hepatomegaly from biliary obstruction (smooth, non-tender)
• Right upper quadrant tenderness ^[2]
• Palpable gallbladder ^[2]
  • Courvoisier's law: In painless jaundice if the gallbladder is palpable, it is unlikely to be due to gallstones and points towards biliary or pancreatic malignancy (lower end of CBD / head of pancreas / ampulla of Vater) ^[2]
  • Why does Courvoisier's law work? Gallstones develop chronically → chronic cholecystitis → fibrosed, contracted gallbladder → cannot distend. Malignant obstruction is "acute" to the gallbladder (the gallbladder was previously healthy) → distends with mucus under back-pressure ^[16]
  • Remember: Courvoisier's sign is positive only in distal CCA (obstruction below cystic duct insertion). In perihilar CCA (Klatskin tumour), the obstruction is ABOVE the cystic duct → gallbladder cannot fill → Courvoisier's sign is NEGATIVE
• Other organomegaly (spleen), mass, ascites ^[14]
• PR examination ^[14] — check for Blumer's shelf (peritoneal drop metastasis)

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2. Biochemical Tests (Blood Investigations)

2.1 Complete Blood Count (CBC) with Differentials

• Anaemia — anaemia of chronic disease (normocytic normochromic) in malignancy; or iron deficiency from chronic blood loss
• Leukocytosis — if superimposed cholangitis; or pancytopenia if underlying cirrhosis with hypersplenism ^[16]
• Thrombocytopenia — important to check before any invasive procedure (ERCP, PTC, biopsy) ^[16]

2.2 Clotting Profile (PT/INR)

• ↑ PT/INR ^[2]
• Why? Biliary obstruction → no bile salts in gut → no fat absorption → no absorption of fat-soluble vitamins (A, D, E, K) → Vitamin K deficiency → impaired synthesis of clotting factors II, VII, IX, X → prolonged PT/INR ^[16]
• Clinical importance: Must correct coagulopathy before any invasive procedure (give IV Vitamin K or FFP). This is also important pre-operatively.

2.3 Liver Function Tests (LFT)

This is where understanding the pattern matters more than individual values:

Key pattern recognition:

• Cholestatic pattern (ALP >> ALT): Suggests biliary obstruction → think CCA, CA pancreas, CBD stones
• Hepatocellular pattern (ALT >> ALP): Suggests hepatitis, drug injury → less likely CCA
• In CCA, expect cholestatic pattern with conjugated hyperbilirubinaemia ^[4]

2.4 Electrolyte Profile

• Hypercalcemia and hypophosphatemia ^[2]
  • Hypercalcemia of malignancy associated with low PTH and vitamin D levels ^[2]
  • Mechanism: PTHrP secretion by tumour (humoral hypercalcaemia of malignancy) — this is uncommon in CCA but can occur

2.5 Hepatitis Serology

• HBV and HCV serology ^[14]
• Why? To assess for underlying chronic liver disease/cirrhosis which affects both aetiology and surgical planning (cirrhotic livers tolerate less resection)

2.6 Serum AFP (Alpha-Fetoprotein)

• Serum AFP: Differentiate between intrahepatic cholangiocarcinoma and HCC ^[2]
• AFP is typically normal in pure CCA
• Rare combined hepatocellular-cholangiocarcinoma tumour may have high levels of AFP ^[2]
• AFP sensitivity in cholangiocarcinoma is only ~10% ^[17]
• In contrast, AFP is elevated in 70–90% of HCC

2.7 Serum IgG4

• Serum IgG4: Evaluate for the possibility of IgG4-related sclerosing cholangitis ^[2]
• Why is this critical? IgG4-related sclerosing cholangitis is the most important benign mimic of CCA. It creates strictures that look identical on imaging. If you miss it, you may subject a patient to unnecessary major hepatectomy for a disease that responds to steroids.

2.8 Tumour Markers

Tumour markers: carcinoembryonic antigen (CEA), CA 19-9 (may or may not be elevated, nonspecific) ^[3]

CA 19-9

Why is CA 19-9 not a good screening test? Because it lacks both sensitivity (misses ~30% of CCA) and specificity (elevated in many benign conditions like cholangitis and any cause of cholestasis). However, very high levels ( > 1000 U/mL) in the absence of cholangitis are more suggestive of malignancy.

Why is CA 19-9 still useful clinically? For serial monitoring — a rising CA 19-9 after resection suggests recurrence; a falling CA 19-9 during chemotherapy suggests response.

CEA

• ↑ CEA: May be elevated in cholangiocarcinoma but neither sensitive nor specific ^[2]
• Primarily a tumour marker for CRC but can be used in CC workup ^[2]
• Also elevated in GI diseases such as gastritis, peptic ulcer disease, diverticulitis and other cancers including lung, breast, gastric and colorectal cancer ^[2]
• CEA upper normal limit: 5 ng/mL ^[17]
• CEA sensitivity in CRC: 30–70% ^[17]

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3. Radiological Investigations

3.1 Ultrasound (USG) Abdomen — First Line

USG, CT scan, MRI ^[3]

USG is always the initial imaging test ^[2]. It is cheap, non-invasive, widely available, and radiation-free. Here's what it tells you:

What to look for:

Why does the level of ductal dilatation tell you the level of obstruction?

• If only intrahepatic ducts are dilated but the CBD is normal → the block is at the hilum (perihilar CCA)
• If both intrahepatic and extrahepatic ducts are dilated → the block is at the distal CBD (distal CCA or pancreatic head cancer)
• This is analogous to diagnosing the level of a river dam by seeing which tributaries are flooded

Invasion into portal vein or hepatic artery is an important finding as it may indicate surgical unresectability ^[2]

Normal bile duct measurements:

• Intrahepatic ducts: normally < 2–3 mm (often not visible on USG) ^[16]
• CBD: normal ≤ 6–8 mm in adults; CBD > 0.8 cm is pathological ^[16]
• CBD limit: 0.1 cm for every 10 years old (i.e., acceptable CBD diameter increases slightly with age and post-cholecystectomy) ^[8]

3.2 Contrast-Enhanced CT Scan (Triphasic / Multiphase)

Contrast-enhanced multidetector-row helical triphasic CT scan ^[2]:

• Indicated in patients with suspected perihilar or intrahepatic cholangiocarcinoma ^[2]

What CT tells you (the 4 key questions):

Why triphasic (three phases)?

• Arterial phase: Shows hepatic arterial anatomy (surgical planning) and tumour arterial enhancement
• Portal venous phase: Shows portal vein anatomy, portal vein invasion/thrombosis, and liver parenchymal enhancement
• Delayed phase (equilibrium): Critical for CCA — the desmoplastic stroma of CCA enhances LATE, so delayed-phase images show the tumour best. This distinguishes CCA from HCC (which washes out on delayed phase)

CT-guided biopsy can be obtained if a mass lesion is seen, with a risk of seeding the biopsy tract with malignant cells ^[2]

Lower sensitivity than MRI scan to detect extra-regional nodal disease such as metastasis to periaortic, pericaval or celiac artery LN and peritoneum ^[2]

3.3 MRI / MRCP (Magnetic Resonance Imaging / Cholangiopancreatography)

MRCP deserves special attention because it is the single most informative non-invasive investigation for CCA, especially perihilar disease.

MRCP = Non-contrast, T2-weighted imaging of the biliary system ^[8]

MRCP

• Indicated in patients with suspected perihilar or intrahepatic cholangiocarcinoma ^[2]
• Superior to ERCP for assessing tumour anatomy and resectability ^[2]
• Does NOT require contrast injection into ductal system unlike in ERCP and PTC ^[2]
• Higher sensitivity than CT scan to detect extra-regional nodal disease such as metastasis to periaortic, pericaval or celiac artery LN and peritoneum ^[2]

What MRCP specifically shows:

• Precise extent of ductal involvement (which Bismuth-Corlette type)
• Length of the stricture
• Presence/absence of intrahepatic metastases
• Biliary anatomy proximal to the obstruction (CT and ERCP cannot see ducts above a complete obstruction as well)

MRI Liver with Primovist (Gadoxetic acid)

• Liver-specific contrast (Primovist): superior to CT in detecting small HCC vs regenerative nodules ^[8] — also excellent for detecting small intrahepatic metastases from CCA
• Primovist is taken up by functioning hepatocytes → hepatobiliary phase at 20 minutes shows lesions that LACK hepatocyte function (tumours appear as "dark holes")
• Particularly useful for distinguishing iCCA from HCC

MRI enhancement pattern of iCCA:

1. T1-weighted: Hypointense mass
2. T2-weighted: Hyperintense (due to high water content and mucin)
3. Arterial phase: Peripheral rim enhancement
4. Delayed phase: Progressive centripetal enhancement (desmoplastic stroma retains contrast)
5. Hepatobiliary phase (Primovist): Hypointense (tumour cells are not hepatocytes → no Primovist uptake)

This pattern is essentially opposite to HCC, which is hyperintense on arterial phase and hypointense on portal venous/delayed phase (washout).

3.4 Cholangiography (ERCP, PTC, Cholangioscopy)

These are invasive investigations that directly visualize the bile duct lumen and allow tissue sampling and therapeutic intervention.

ERCP (Endoscopic Retrograde Cholangiopancreatography)

• ERCP: indicated in patients with suspected distal extrahepatic cholangiocarcinoma ^[2]
• ERCP are both diagnostic and therapeutic ^[16]
• Direct visualization of the area of abnormality ^[2]
• Superior to MRCP by enabling biopsy with FNA or brush cytology and therapeutic intervention using stent placement ^[2]
• Involves injection of contrast into bile duct and hence risk for ascending cholangitis in cases of impaired biliary drainage ^[2]

Key findings on ERCP cholangiogram:

• Abrupt stricture with "apple-core" or "rat-tail" narrowing
• Shouldering (irregular margins of the stricture)
• Upstream ductal dilatation proximal to the stricture
• Non-passage of contrast beyond the stricture

ERCP tissue sampling:

• Brush cytology: Sensitivity ~40–70% (low because CCA is desmoplastic with few cancer cells)
• Intraductal biopsy: Slightly better sensitivity (~50–80%)
• FISH (Fluorescence In Situ Hybridisation): Can be performed on brush cytology specimens to detect polysomy, increasing sensitivity

Cholangiography: ERCP for distal tumours, PTC for proximal tumours — define level of obstruction ± stenting ^[4]

PTC (Percutaneous Transhepatic Cholangiography)

• PTC: Preferred to ERCP in stricture/obstruction at or above the level of confluence of hepatic ducts ^[8]
• Examples: cholangiocarcinoma, PSC, RPC ^[8]
• Why PTC for proximal lesions? ERCP approaches from below — in perihilar CCA, the scope reaches the stricture but cannot opacify the ducts ABOVE the obstruction (you cannot push contrast past a complete block). PTC approaches from above via a transhepatic needle, directly opacifying the intrahepatic ducts proximal to the tumour.
• Permit direct visualization of the area of abnormality, enable biopsy with FNA or brush cytology and therapeutic intervention using stent placement ^[2]
• Complications: bacteraemia (thus antibiotic prophylaxis required), haemobilia ^[8]
• Largely replaced by MRCP and MDCT for diagnostic purposes ^[2] — now used mainly when therapeutic drainage is needed or ERCP has failed

Cholangioscopy (SpyGlass / Mother-Baby Cholangioscopy)

• Direct peroral visualization of the bile duct lumen using a miniaturized scope passed through the ERCP working channel
• Allows direct visual inspection of strictures and targeted biopsies under direct vision
• EUS with brush cytology can be performed but with low sensitivity and specificity for diagnosing cholangiocarcinoma; EUS cannot reach the lumen of bile duct in majority of cases which will require a mother-baby cholangioscopy ^[16]
• Significantly improves diagnostic yield compared to blind brush cytology (sensitivity ~75–90%)

3.5 Endoscopic Ultrasound (EUS) ± FNAC

• Endoscopic ultrasound ± FNAC or brush cytology ^[2]
• Indicated in patients with suspected distal extrahepatic cholangiocarcinoma ^[2]
• Enable biopsy with FNA or brush cytology ^[2]
• Assess local extent of primary tumour and status of regional LNs ^[2]
• Staging: EUS for nodal involvement ^[4]
• EUS is particularly good for:
  • Distal CBD lesions (the EUS transducer in the duodenum is very close to the distal CBD)
  • Regional lymph node sampling (EUS-guided FNA of suspicious nodes)
• Limitation: Not useful for perihilar lesions (too far from the EUS transducer) ^[16]

3.6 PET-CT (Positron Emission Tomography)

• PET scan with fluorodeoxyglucose (FDG) contrast ^[2]
• Evaluate for occult distant metastasis that MRCP and MDCT are unable to detect ^[2]
• FDG-PET detects metabolically active tissue — CCA cells have high glucose uptake (Warburg effect)
• Sensitivity: Good for mass-forming iCCA (~85–95%); lower for perihilar CCA (~50–60%) because the sclerosing/infiltrating growth pattern has less tumour cellularity and more fibrosis
• Main role: Detecting occult metastases (e.g., distant lymph nodes, peritoneal disease, bone) that would change management from curative to palliative
• Limitation: False positives in cholangitis, granulomatous disease, or any inflammation

3.7 Staging Laparoscopy

• Staging: staging laparoscopy ^[4]
• Performed before committing to major hepatectomy
• Detects peritoneal metastases and small liver surface metastases that CT/MRI cannot see
• Yield: Upstages ~25–30% of patients thought to be resectable on cross-sectional imaging → avoids unnecessary laparotomy
• Particularly useful for perihilar CCA (Bismuth III/IV) and iCCA with high CA 19-9

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4. Tissue Diagnosis

The Cardinal Rule

FNAC or Trucut biopsy (ONLY for unresectable cases) ^[3] Tissue diagnosis (not must): brush cytology/CT-guided biopsy if uncertain ^[4] Biopsy: fine needle aspiration cytology (FNAC), Trucut biopsy ^[14]

Why NOT biopsy potentially resectable CCA?

• Needle-tract seeding: CCA cells can implant along the biopsy tract → peritoneal or abdominal wall metastasis → converting a potentially curative situation into an incurable one
• If imaging and clinical features strongly suggest CCA AND the tumour is resectable → proceed directly to surgery without pre-operative tissue confirmation
• Tissue diagnosis is only required when:
  1. The patient is unresectable and needs histological confirmation before starting chemotherapy
  2. There is diagnostic uncertainty (e.g., cannot distinguish from IgG4-cholangitis, lymphoma, or metastatic disease)
  3. CT failed to demonstrate typical features, before chemotherapy, or suspected secondary metastasis ^[11]

Methods of Tissue Sampling

Histology and Immunohistochemistry

Immunohistochemical stain is useful in differential diagnosis of cholangiocarcinoma with other malignancy ^[2]

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5. Comprehensive Investigation Summary by CCA Subtype

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6. Assessment of Resectability

This is the critical output of the entire diagnostic workup. The question is: can we cure this patient with surgery?

Indicators of unresectability ^[4]:

Additional considerations for resectability:

• Future liver remnant (FLR): Must be > 25–30% (or > 40% if cirrhotic). May need pre-operative portal vein embolisation (PVE) to hypertrophy the contralateral lobe
• Liver atrophy-hypertrophy complex: Ipsilateral atrophy with contralateral hypertrophy suggests chronic portal vein involvement → actually makes contralateral resection more feasible (the hypertrophied lobe is already compensating)
• Bilateral hepatic artery involvement: Absolute contraindication
• Hepatic duct involvement beyond second-order branches bilaterally: Cannot achieve R0 resection

Hepatic resection is the treatment of choice (resectability rate about 20%) ^[3]

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Active Recall - Diagnosis of Cholangiocarcinoma

1. What is the first-line imaging investigation for suspected cholangiocarcinoma, and what are the key findings that suggest malignant obstruction?

Your answer

Grade

Show mark scheme

USG abdomen. Key findings: ductal dilatation > 6 mm without visible stones suggests malignant obstruction. IHBD dilatation with normal CBD = perihilar lesion. IHBD + CBD dilatation = distal lesion. Mass lesion in non-cirrhotic liver = intrahepatic CCA.

2. Why should FNAC or Trucut biopsy be performed ONLY for unresectable cases of CCA?

Your answer

Grade

Show mark scheme

Because of the risk of tumour seeding along the needle tract, which can convert a potentially curable (resectable) case into an incurable one by causing peritoneal or abdominal wall metastasis. If imaging strongly suggests CCA and it is resectable, proceed directly to surgery.

3. For cholangiographic assessment, when would you use ERCP vs PTC?

Your answer

Grade

Show mark scheme

ERCP for distal extrahepatic CCA (approaches from below, good for distal strictures, allows stenting). PTC for perihilar/proximal CCA (approaches from above via transhepatic needle, can opacify ducts proximal to a complete obstruction that ERCP cannot pass). MRCP has largely replaced both for diagnostic purposes.

4. A patient with painless jaundice has CA 19-9 of 500 U/mL. Can you diagnose CCA based on this? Explain the limitations of CA 19-9.

Your answer

Grade

Show mark scheme

No. CA 19-9 is neither sensitive (misses approximately 30% of CCA) nor specific (elevated in cholangitis, gallstones, pancreatic cancer, gastric cancer, HCC). Also requires Lewis blood group antigen expression (5-10% of population are Lewis-negative and will never produce CA 19-9). Useful for serial monitoring of treatment response and recurrence, not for definitive diagnosis.

5. Describe the typical MRI enhancement pattern of intrahepatic CCA and explain why it differs from HCC.

Your answer

Grade

Show mark scheme

iCCA: peripheral rim arterial enhancement with progressive centripetal delayed fill-in (due to dense desmoplastic stroma retaining contrast slowly). Hypointense on hepatobiliary phase (no hepatocyte function). HCC: arterial hyperenhancement with portal venous washout (highly vascular tumour without desmoplastic stroma, composed of hepatocytes that may take up Primovist). The key difference is the desmoplastic stroma in CCA vs vascular nature of HCC.

6. List 4 criteria that make perihilar cholangiocarcinoma unresectable.

Your answer

Grade

Show mark scheme

1. Invasion of major vessels (main portal vein, main hepatic artery, coeliac trunk, SMA, SMV). 2. Extensive bilateral biliary involvement beyond second-order radicles. 3. Distant lymph node metastasis (retropancreatic, paracoeliac, paraaortic). 4. Distal organ metastasis (lung, peritoneum).

References

^[2] Senior notes: felixlai.md (Cholangiocarcinoma, sections IV–VI: Pathogenesis, Clinical manifestation, Diagnosis) ^[3] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p5, Cholangiocarcinoma) ^[4] Senior notes: maxim.md (Cholangiocarcinoma section: Investigations, Management, Unresectable criteria) ^[8] Senior notes: maxim.md (HBP investigations section: USG, MRCP, PTC) ^[11] Senior notes: maxim.md (Pancreatic carcinoma section: Investigations) ^[14] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p2, Clinical Approach to Hepatomegaly) ^[16] Senior notes: felixlai.md (Obstructive jaundice / MBO sections: Physical exam, Biochemical tests, Radiological tests) ^[17] Lecture slides: Malignant biliary obstruction.pdf (p8, Tumour marker table)

Management of Cholangiocarcinoma

Management Principles — Thinking From First Principles

Before we go into specific treatments, let's understand the strategic logic of managing CCA. There are only three questions you need to answer, in this exact order:

1. Is the patient septic? → If yes, treat the sepsis FIRST (biliary drainage + antibiotics)
2. Is the tumour resectable? → If yes, surgery is the ONLY curative option
3. Is the patient fit for surgery? → If no, palliate

Everything else flows from these three decisions.

Management: ^[18]

• Treat SEPSIS
• Assess tumour resectability + Patient general fitness + Liver function reserve
• Resectable → Surgery; Non-resectable → Palliation

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Overall Management Algorithm

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1. Initial Management — Treat Sepsis First

Treat sepsis ^[18][19]

Why treat sepsis before anything else? A jaundiced patient with cholangitis is in a life-threatening state. Obstructed, infected bile is a closed-space infection → bacteraemia → septic shock. You cannot take a septic, jaundiced patient to major hepatectomy — the mortality would be unacceptable. The liver is already compromised by obstruction; adding the stress of major surgery to an infected, failing liver is a recipe for post-operative liver failure and death.

Measures:

• Resuscitation: IV fluids, NPO, monitor vitals and urine output
• Antibiotics: Augmentin (OR) Cefuroxime (Zinacef) + Metronidazole (Flagyl) ^[16]
  • Must cover Gram-negative rods (E. coli, Klebsiella) and anaerobes
  • Why these bugs? They ascend from the GI tract into the obstructed biliary tree. The ampulla of Vater normally acts as a barrier, but obstruction → stasis → bacterial overgrowth → ascending infection
• Urgent biliary drainage if:
  • Reynolds pentad (fever + jaundice + pain + shock + confusion) ^[19]
  • Not responding to antibiotics within 24 hours ^[19]
  • Why drainage when antibiotics are given? Because antibiotics are secreted into bile — if the bile duct is obstructed, the antibiotic cannot reach the infected bile. Drainage decompresses the system and allows antibiotics to work.

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2. Assessment of Resectability

This is the pivotal decision point. Surgery is the only curative treatment, but taking an unresectable patient to laparotomy is harmful (morbidity + delays palliative care).

Criteria of Resectability

Criteria of resectability: ^[18]

• No distant metastases
• SMA and celiac axis not involved
• Patent superior mesenteric-portal venous confluence
• PV involvement is NOT absolute contraindication ^[18]
  • Venous resection is appropriate to improve resectability and achieve R0 resection ^[18]
  • Significant morbidity and mortality ^[18]
  • Reasonable survival: median = 13 months, 5-year = 7% ^[18]

Indicators of Unresectability

Unresectable if: ^[4]

• Invasion of major vessels (e.g. main PV, main hepatic artery, celiac trunk, SMA, SMV) ^[4]
• Extensive involvement of biliary tree (bilaterally > 2° radicles) ^[4] — meaning the tumour extends beyond the second-order bile duct branches on BOTH sides. Why does this make it unresectable? Because even if you resect the extrahepatic bile ducts, you cannot reconstruct drainage from both sides if the 2nd-order branches are involved bilaterally — there would be insufficient healthy duct to anastomose to a jejunal loop.
• LN metastasis (retropancreatic, paracoeliac, paraaortic) ^[4] — these are considered distant (M1) nodes, indicating systemic disease
• Distal organ metastasis (lung, peritoneum) ^[4]

Additional criteria ^[2]:

• Bilateral or multifocal intrahepatic disease ^[2]
• Hepatic artery and portal vein invasion (bilateral main branches) ^[2]
• Extrahepatic adjacent organ invasion ^[2]

Pre-operative Assessment — Patient Fitness

Assessment of patient status: ^[16]

• Age / Concomitant medical illness
• Hidden medical illness = CXR / ECG / Spirometry
• Nutrition = LFT
• Fluid and electrolytes = RFT
• Coagulopathy = CBC / Clotting profile

Assessment of tumour status: ^[16]

• Clinical signs of inoperability:
  • Irregular surface hepatomegaly
  • Troisier's sign (Virchow's node) — left supraclavicular LN
  • Blumer's shelf — peritoneal metastasis
  • Sister Mary Joseph nodules — peritoneal metastasis
  • Ascites — peritoneal metastasis

Future Liver Remnant (FLR) Assessment

For perihilar CCA, major hepatectomy is often required. You need to ensure the patient will have enough functioning liver left after resection:

• FLR must be > 25–30% of total liver volume in a normal liver
• FLR must be > 40% in a cirrhotic or cholestatic liver (impaired regeneration capacity)
• If FLR inadequate: portal vein embolisation (PVE) to induce atrophy of affected segment + hypertrophy of unaffected segments ^[4]
  • Why does PVE work? By embolising the portal vein branch feeding the side to be resected, you redirect portal blood flow to the contralateral lobe → that lobe hypertrophies over 4–6 weeks → now the FLR is large enough to sustain life after resection. Essentially you are "training" the liver before surgery.

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3. Pre-operative Biliary Drainage

Relief of biliary obstruction before surgery ^[20] Target level: Serum bilirubin < 50 µmol/L or < 20 µmol/L for concomitant partial hepatectomy ^[20]

Rationale

Reasons why MBO is high risk for operation and measures to reduce complications: ^[16]

• Cancer cachexia → Malnutrition → Nutritional support
• Liver derangement → Bleeding tendency → IV Vitamin K and FFP during surgery
• Superimposed biliary infection → Antibiotics cover

Why drain pre-operatively? A jaundiced liver is a sick liver. Biliary obstruction causes:

• Impaired hepatocyte function (cannot synthesise clotting factors, albumin)
• Vitamin K malabsorption → coagulopathy
• Impaired reticuloendothelial function → susceptibility to sepsis
• Impaired wound healing (poor protein synthesis) Operating on a deeply jaundiced patient → high risk of post-operative liver failure, bleeding, and sepsis.

Theory vs Practice (QMH Approach)

Theoretically: Do NOT need to drain if no sepsis + early surgery can be offered within 1–2 weeks ^[16]

• Pre-operative drainage itself carries risks (cholangitis, pancreatitis, stent complications)
• Some evidence suggests it increases overall complications even in expert centres

Practically (QMH): Drain ALL patients since QMH cannot offer early surgery ^[16]

• Whipple operation has to wait for 6–8 weeks and the chance of biliary sepsis will be very high without drainage while waiting for this period ^[16]

Methods of Pre-operative Drainage

ERCP with Endoprosthesis (Endoscopic Stenting) — 1st Line

ERCP with endoprosthesis is ALWAYS 1st line regardless of the level of obstruction ^[16]

Except when: ^[16]

• Contraindications for ERCP (e.g. structural upper GI abnormalities / partial gastrectomy with Billroth II or Roux-en-Y anastomosis)
• Multiple stenting required or difficulty in reaching intrahepatic bile ducts (i.e., proximal/perihilar obstruction where ERCP cannot access above the stricture)

PTBD (Percutaneous Transhepatic Biliary Drainage)

ERCP with endoprosthesis is preferred over PTBD because: ^[16]

• PTBD is technically more difficult
• Bleeding is common due to puncture of hepatic artery or portal vein before reaching the bile duct (Portal triad)

Types of PTBD:

• Simple external PTBD: indicated for short-term drainage to bridge to surgery. Prone to electrolyte and fluid loss due to bile output ^[16]
• External-internal type PTBD: indicated for long-term palliation ^[16] — catheter pushed through the obstruction so bile drains internally into the duodenum

PTBD complications and management: ^[16]

• If bleeding occurs: Stabilise and resuscitate → Clamp the PTBD catheter → Perform cholangiogram by injecting contrast into PTBD to delineate whether the catheter is in hepatic artery or portal vein → Remove catheter slowly to control bleeding and do NOT attempt to remove immediately since it will convert into free hemoperitoneum

Staging Laparoscopy

No promise of resection until laparotomy finding documents absence of spread ^[16] Look for peritoneal nodules after laparotomy before resection and send for frozen section to rule out malignancy if suspicious ^[16]

• Upstages ~25–30% of patients thought to be resectable on cross-sectional imaging
• Particularly important for Bismuth III/IV perihilar CCA, and any case with high CA 19-9

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4. Curative Surgical Treatment

Hepatic resection is the treatment of choice (resectability rate about 20%) ^[3]

The surgical approach depends entirely on the anatomical location of the tumour:

In general: ^[18]

• Whipple operation for carcinoma of pancreas, distal CBD cholangiocarcinoma, CA duodenum and CA ampulla
• Radical cholecystectomy for CA gallbladder
• Major hepatectomy + caudate lobectomy together with confluence of hepatic ducts for Klatskin tumour

4.1 Intrahepatic CCA

Intrahepatic: partial hepatectomy + portal LN dissection ^[4]

4.2 Perihilar CCA (by Bismuth-Corlette Type)

Perihilar: extrahepatic bile duct resection + cholecystectomy + portal LN dissection (± partial hepatectomy) + reconstruction (Roux-en-Y hepaticojejunostomy) ^[4]

This is the most surgically complex subtype. The operation must remove the tumour-bearing bile duct AND any liver lobe with involved duct branches, while preserving enough liver to sustain life.

Detailed surgical approach by Bismuth type: ^[2]

Why is the Roux-en-Y hepaticojejunostomy (HJ) necessary? Once you resect the extrahepatic bile ducts, you have cut the bile "highway" between liver and gut. You need to reconnect the remaining hepatic duct stump(s) to a loop of jejunum so bile can drain into the intestine. A Roux-en-Y configuration is used (defunctionalised jejunal limb) to prevent reflux of intestinal contents into the biliary tree, which would cause ascending cholangitis.

4.3 Distal Extrahepatic CCA

Distal CBD tumour: Whipple's procedure (pancreaticoduodenectomy) ^[4]

The Whipple procedure removes:

• Head of pancreas
• Duodenum (D1–D3)
• Distal CBD
• Gallbladder
• ± Distal stomach (classic Whipple) or pylorus-preserving (PPPD)

Why such an extensive operation for a bile duct tumour? Because the distal CBD runs through the head of the pancreas and behind the duodenum. You cannot resect just the distal CBD without removing the surrounding structures that share the same blood supply (the pancreaticoduodenal arteries supply all these structures en bloc). Removing one without the others would leave devascularised tissue.

Reconstruction after Whipple (3 anastomoses):

1. Pancreaticojejunostomy — reconnect pancreatic remnant to jejunum
2. Hepaticojejunostomy — reconnect bile duct to jejunum
3. Gastrojejunostomy (or duodenojejunostomy in PPPD) — reconnect stomach/duodenum to jejunum

4.4 Summary Table: Surgical Approach by Location

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5. Adjuvant Therapy (Post-operative)

Adjuvant chemotherapy has survival advantage for patients with resected cholangiocarcinoma ^[2]

Chemotherapy Regimens

Current standard (2025):

• Capecitabine for 6 months — this became standard after the BILCAP trial (2019), which showed significantly improved overall survival in resected biliary tract cancers (including CCA) with adjuvant capecitabine vs observation
• Alternatives: ^[2]
  • Gemcitabine
  • Capecitabine
  • Leucovorin-modulated fluorouracil (5-FU)

Why capecitabine? Capecitabine ("cape" = capacity to become 5-FU) is an oral prodrug that is converted to 5-FU preferentially in tumour tissue by thymidine phosphorylase (which is overexpressed in tumour cells). This provides targeted drug delivery with less systemic toxicity than IV 5-FU.

Liver Transplantation

• Role: Very select patients with perihilar CCA (unresectable by conventional surgery but no distant metastases) may be considered for liver transplantation
• This follows the Mayo Clinic protocol: neoadjuvant chemoradiation → staging laparoscopy → liver transplant
• Strict selection criteria: tumour ≤ 3 cm, no intrahepatic/extrahepatic metastasis, arising in PSC background
• 5-year recurrence-free survival ~65–70% in selected patients
• Not widely available and requires a specialised transplant centre with dedicated protocol

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6. Systemic Therapy for Advanced/Unresectable CCA

Other treatment: no proven effect — this was stated in the 2019 lecture ^[3]. However, since then, landmark trials have dramatically changed the landscape:

First-Line Systemic Therapy

Current standard (2025): Gemcitabine + Cisplatin + Durvalumab

• TOPAZ-1 trial (Oh et al., NEJM Evidence 2022): Adding durvalumab (anti-PD-L1 immune checkpoint inhibitor) to gemcitabine-cisplatin improved overall survival in advanced biliary tract cancer (median OS 12.8 vs 11.5 months; 2-year OS 24.9% vs 10.4%)
• This is now the global standard first-line regimen

Previous standard: Gemcitabine + Cisplatin (GemCis)

• Established by the ABC-02 trial (Valle et al., NEJM 2010)
• Remains the backbone; durvalumab is added on top

Second-Line and Targeted Therapy

Molecular-targeted therapies (precision oncology):

Why is molecular profiling now essential? Because ~40–50% of iCCA and ~15–25% of extrahepatic CCA harbour actionable mutations. All patients with advanced CCA should undergo comprehensive genomic profiling (next-generation sequencing) to identify targetable alterations.

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7. Palliative Management

Palliative care: ^[18][19]

• Treat sepsis
• Relieve obstruction (enteric / biliary)
• Pain control

The three pillars of palliative care in CCA match the three main symptoms: sepsis (from biliary stasis), jaundice (from obstruction), and pain (from tumour invasion).

7.1 Relief of Biliary Obstruction — Palliative Stenting

Palliation for obstructive jaundice: ^[2]

• Endoscopic or percutaneous transhepatic biliary stenting
• Self-expanding metallic stent is usually used ^[2]

Approach Selection

Endoscopic method is preferred due to less inconvenience without external drainage, lower risk of bile leaks and bleeding ^[2] Percutaneous method has a higher success rate of palliation of jaundice and lower risk of early cholangitis but external drainage is inconvenient ^[2]

Stent Types

Self-expandable metallic stents (SEMS): for established malignancy (longer patency, but cannot be removed) ^[4] Uncovered stents preferred: lower risk of occluding branches of biliary system ^[4]

Use of unilateral or bilateral stents is controversial for hilar obstruction ^[2]

• For perihilar CCA: draining ≥ 50% of the liver volume is the goal
• Unilateral stent may suffice if it drains the larger lobe
• Bilateral stenting increases complication risk but may be needed for bilateral obstruction

Complications of stenting: ^[4]

• Stent occlusion (e.g. tumour ingrowth, bile sludge): Management by sweeping or placing new stent
• Stent migration
• Cholangitis / Cholecystitis ^[16]

7.2 Palliative Surgical Bypass

Surgical bypass ^[2] — reserved for patients found to be unresectable at laparotomy, or those with expected survival > 6 months where stent complications would be problematic.

Single bypass = Hepaticojejunostomy / Choledochojejunostomy ^[16]

• Just bypasses the biliary tree
• Hepaticojejunostomy refers to anastomosis between common hepatic duct and jejunum ^[16]

Double bypass = + Gastrojejunostomy ^[16]

• Bypasses both biliary tree AND enteric obstruction
• Especially for CA head of pancreas since apart from compression on bile duct it also compresses on duodenum to cause gastric outlet obstruction (GOO) ^[16]

Triple bypass = + Pancreaticojejunostomy ^[16]

• Bypasses biliary tree, enteric obstruction AND pancreatic duct
• Pancreatic duct is small and anastomosis is difficult to achieve which leads to high risk of anastomotic leakage ^[16]

Stenting vs Surgical Bypass — Comparison

Comparison between stenting/PTBD with surgical bypass as palliative treatment: ^[16]

Bottom line: Stenting is preferred for patients with short expected survival ( < 6 months) or poor fitness. Surgical bypass is better for patients with longer expected survival who can tolerate surgery.

7.3 Photodynamic Therapy (PDT)

Photodynamic therapy: ^[2]

• Involves injection of IV porphyrin photosensitizer followed by the endoscopic application of light of a specific wavelength to the tumour bed ^[2]
• The photosensitizer accumulates preferentially in tumour cells → when activated by specific wavelength light → generates reactive oxygen species → local tumour necrosis
• Improves biliary drainage and may improve survival in perihilar CCA when combined with stenting
• Not widely available; considered in specialised centres for non-resectable perihilar CCA

7.4 Pain Control

Pain control ^[19]

• Analgesics: WHO pain ladder (paracetamol → weak opioids → strong opioids such as morphine)
• Celiac plexus block ^[16]
  • Endoscopic USG / CT-guided celiac plexus neurolysis ^[21]
  • Why does this work? The celiac plexus (located at the aortic bifurcation at T12–L1) transmits visceral pain from the upper abdominal organs including the biliary tree and pancreas. Chemical neurolysis (injection of absolute alcohol or phenol) destroys these pain fibres → dramatic pain relief
  • Particularly effective for pancreatic/biliary cancer pain that is refractory to opioids

7.5 Other Palliative Measures

• Nutritional support: Oral nutritional supplements, pancreatic enzyme replacement (if Whipple was considered but not done — these patients often have pancreatic exocrine insufficiency from bile duct obstruction affecting the pancreatic duct)
• Pruritus management: Cholestyramine (bile acid sequestrant), rifampicin, naltrexone, sertraline
• Duodenal stenting or gastrojejunostomy if gastric outlet obstruction develops

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8. Management Summary by Location and Stage

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9. Prognosis

Prognostic factors after resection:

• R0 (margin-negative) vs R1 (margin-positive) — most important surgical factor
• Lymph node status (N0 vs N+)
• Tumour differentiation (well vs poorly differentiated)
• Vascular invasion
• Perineural invasion
• CA 19-9 level post-resection (should normalise; persistent elevation suggests residual disease)

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Active Recall - Management of Cholangiocarcinoma

1. What are the three sequential steps in managing a patient with suspected cholangiocarcinoma presenting with jaundice and fever?

Your answer

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1. Treat sepsis first: IV antibiotics (Augmentin or Cefuroxime + Metronidazole) + urgent biliary drainage if not responding. 2. Assess tumour resectability (imaging, staging laparoscopy) and patient fitness. 3. If resectable and fit: curative surgery. If not: palliative stenting/bypass + systemic chemotherapy.

2. Describe the surgical approach for a Bismuth Type IIIa perihilar cholangiocarcinoma.

Your answer

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Right hepatectomy + caudate lobectomy + extrahepatic bile duct resection + cholecystectomy + regional lymphadenectomy + Roux-en-Y hepaticojejunostomy reconstruction. Caudate must be resected because caudate bile ducts drain directly into the confluence and are almost always involved.

3. Why is pre-operative biliary drainage performed in CCA, and what is the target bilirubin level?

Your answer

Grade

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Jaundiced liver has impaired synthetic function (coagulopathy), impaired immunity (sepsis risk), and poor wound healing. Target bilirubin less than 50 micromol/L (or less than 20 for concomitant hepatectomy). ERCP stenting is first-line. QMH drains all patients because surgery wait is 6-8 weeks.

4. What is the current standard first-line systemic therapy for advanced unresectable cholangiocarcinoma as of 2025?

Your answer

Grade

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Gemcitabine + Cisplatin + Durvalumab (anti-PD-L1), based on the TOPAZ-1 trial. This replaced the previous standard of gemcitabine-cisplatin alone (ABC-02 trial). All patients should also undergo molecular profiling for targetable mutations (IDH1, FGFR2, HER2, BRAF, MSI-H).

5. Compare ERCP stenting vs surgical bypass for palliative management of malignant biliary obstruction.

Your answer

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ERCP stenting: lower initial morbidity and mortality, shorter hospital stay, but more delayed biliary complications (sepsis), more reinterventions (stent exchange), inferior long-term results. Surgical bypass: higher initial morbidity, longer stay, but better long-term palliation. Stenting preferred for short expected survival or poor fitness; bypass for longer survival and surgical fitness.

6. What is portal vein embolisation and why is it performed before surgery for perihilar CCA?

Your answer

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PVE involves embolising the portal vein branch feeding the liver lobe to be resected. This redirects portal blood flow to the contralateral lobe, causing compensatory hypertrophy over 4-6 weeks. Performed when the future liver remnant (FLR) is inadequate (less than 25-30% in normal liver or less than 40% in cholestatic/cirrhotic liver) to prevent post-operative liver failure.

References

^[2] Senior notes: felixlai.md (Cholangiocarcinoma, sections IV–VII: Pathogenesis, Treatment, Surgical approach table) ^[3] Lecture slides: WCS 064 - A large liver - by Prof R Poon ^[20191108].doc.pdf (p5, Cholangiocarcinoma — Treatment) ^[4] Senior notes: maxim.md (Cholangiocarcinoma section: Management, Unresectable criteria, Surgical approach, Palliative care) ^[16] Senior notes: felixlai.md (MBO sections: Treatment general principles, Surgical treatment palliative/curative, ERCP vs PTBD, Pre-op drainage, Palliative bypass comparison) ^[18] Lecture slides: Malignant biliary obstruction.pdf (p18, MBO management flowchart; p23, Criteria of resectability; p30, Palliative care) ^[19] Senior notes: maxim.md (Acute cholangitis: RAD management) ^[20] Lecture slides: WCS 056 - Painless jaundice and epigastric mass - by Prof R Poon.ppt (1).pdf (p67, Relief of biliary obstruction before surgery — target bilirubin) ^[21] Senior notes: felixlai.md (Pancreatic cancer section: Treatment — celiac plexus block, chemotherapy regimens)

Complications of Cholangiocarcinoma

Complications of cholangiocarcinoma can be organized into three broad categories: (A) complications of the disease itself (i.e., what the tumour does to the patient), (B) complications of the biliary obstruction it causes (the pathophysiological cascade), and (C) complications of treatment (surgical and procedural). Understanding each from first principles means linking every complication back to a mechanism.

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A. Complications of the Disease Process

1. Biliary Sepsis (Ascending Cholangitis)

Cause of mortality in MBO: Biliary sepsis ^[22][23]

Pathophysiology: CCA obstructs the bile duct → bile stasis → bacterial colonisation of stagnant bile (normally, bile is kept sterile by constant antegrade flow and the sphincter of Oddi acting as a valve against duodenal reflux). Once bile is stagnant:

Biliary obstruction + infection → Normal ductal pressure: 7–14 cm H₂O → Increased biliary pressure > 25 cm H₂O → Bacteria reflux to hepatic veins and lymphatics → Bacteraemia and septic shock ^[24]

Excretion of antibiotics is impaired in biliary obstruction ^[24] — this is why antibiotics alone are often insufficient; biliary drainage is mandatory.

Common organisms: Gram-negative rods (E. coli, Klebsiella) > Enterococcus > Pseudomonas (especially if stent in situ) ^[19]

Clinical presentation:

• Charcot's triad (fever + jaundice + RUQ pain) → 50–70% of cholangitis cases
• Reynolds pentad (+ shock + confusion) → < 10%, indicates suppurative cholangitis with septic shock

Why is cholangitis so dangerous in CCA patients? Because these patients have:

• Already impaired hepatic immune function from biliary obstruction (see below)
• Often pre-existing malnutrition from cancer cachexia
• A permanent nidus of infection (the obstructed, stagnant bile cannot be sterilised without drainage)
• If a palliative stent is in place → the biliary stent in-situ serves as a foreign body nidus for infection ^[19]

2. Liver Failure

Cause of mortality in MBO: Liver failure ^[22][23]

Pathophysiology — the cascade of hepatic decompensation:

Pathophysiological effects of malignant biliary obstruction: ^[25]

• Impaired protein synthesis → hypoalbuminaemia → oedema, ascites, poor wound healing
• Impaired clotting factor synthesis → coagulopathy → bleeding tendency
• Impaired gluconeogenesis → hypoglycaemia (especially in the fasted state)
• Impaired ketogenesis → cannot switch to fat as fuel during starvation → accelerated malnutrition
• Endotoxaemia → gut-derived endotoxins normally cleared by Kupffer cells in the liver; when biliary obstruction impairs Kupffer cell function → endotoxins enter the systemic circulation → SIRS, organ dysfunction
• ↓ Reticuloendothelial function → impaired clearance of bacteria and toxins → increased susceptibility to infection
• ↓ Cell-mediated immunity → impaired T-cell function → further susceptibility to sepsis

Why does biliary obstruction impair liver function? Bile duct obstruction → back-pressure of bile → cholestasis → bile acids accumulate in hepatocytes → bile acid toxicity damages hepatocyte mitochondria and cell membranes → hepatocyte necrosis and apoptosis → progressive loss of functional liver mass. Simultaneously, periductal inflammation and fibrosis from the tumour itself further destroys liver parenchyma.

Why is malignant biliary obstruction so risky for operation? ^[23]

• Cancer cachexia → malnutrition
• Liver function impairment
• Superimposed biliary infection

These three factors combine to create a "perfect storm" of operative risk: a malnourished patient with a failing liver, impaired immunity, and active or potential infection. This is why pre-operative optimisation (biliary drainage, nutritional support, treating sepsis) is so critical.

3. Cancer Cachexia and Malnutrition

Cause of mortality in MBO: Cancer cachexia ^[22][23]

Pathophysiology: CCA causes cachexia through two synergistic mechanisms:

1. Tumour-mediated cachexia: Pro-inflammatory cytokines (TNF-α/"cachectin", IL-6, IL-1β) secreted by the tumour and host immune cells → increased basal metabolic rate + skeletal muscle proteolysis + lipolysis + anorexia via hypothalamic appetite suppression
2. Bile salt malabsorption: No bile salts in the duodenum → impaired fat emulsification → fat malabsorption → steatorrhoea → loss of calories and fat-soluble vitamins (A, D, E, K)
   • Vitamin K deficiency → impaired synthesis of clotting factors II, VII, IX, X → bleeding tendency (prolonged PT/INR) ^[16]
   • Vitamin D deficiency → osteomalacia, hypocalcaemia
   • Vitamin A deficiency → night blindness (rare, requires prolonged obstruction)

4. Obstructive Jaundice and Its Sequelae

Progressive biliary obstruction is the hallmark of extrahepatic CCA. Beyond just turning the patient yellow, obstructive jaundice has wide-ranging systemic effects:

5. Metastatic Complications

CCA spreads via several routes, each causing specific complications:

6. Portal Hypertension

CCA can cause portal hypertension through:

• Direct portal vein invasion — the most common mechanism in perihilar CCA; tumour encases or occludes the main portal vein or its branches
• Secondary biliary cirrhosis — prolonged biliary obstruction → chronic cholestasis → periportal fibrosis → cirrhosis → portal hypertension ^[22]
• Consequences of portal hypertension: ascites, splenomegaly, oesophageal/gastric varices → upper GI bleeding

7. Gastric Outlet / Duodenal Obstruction

• Locally advanced distal CCA or pancreatic head invasion can compress the duodenum
• Presents with vomiting, early satiety, inability to tolerate oral intake
• Management: endoscopic duodenal stenting or gastrojejunostomy (double bypass) ^[16]

8. Haemobilia

Haemobilia (UGIB from biliary tree) ^[4]

Pathophysiology: Tumour erodes into a branch of the hepatic artery or portal vein within the bile duct wall → blood enters the biliary tree → passes through the ampulla into the duodenum → presents as melaena or haematemesis. Classic triad of haemobilia = jaundice + biliary colic + GI bleeding (Quincke's triad).

Can also occur iatrogenically from:

• PTC/PTBD (needle punctures hepatic artery or portal vein in the portal triad) ^[16]
• Post-surgical bleeding from hepatic resection surface draining into the biliary tree

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B. Complications of Treatment

1. Complications of Biliary Stenting (ERCP/PTBD)

Complications: ^[4][16]

• Stent occlusion (sludge / tumour ingrowth / tumour overgrowth) ^[16]
  • Why does this happen? Uncovered metallic stents have open mesh → tumour grows through the mesh interstices (ingrowth) or extends beyond the stent ends (overgrowth). Biliary sludge (a mixture of bacteria, calcium bilirubinate, and proteinaceous debris) also deposits on stent surfaces.
  • Management: sweeping or placing new stent ^[4]
  • Stent occlusion typically presents with recurrent jaundice ± cholangitis weeks to months after stent placement
• Stent migration ^[4][16]
  • More common with plastic stents; can migrate proximally (into the liver) or distally (into the duodenum)
• Cholangitis / Cholecystitis ^[16]
  • Stent insertion disrupts the normal barrier at the ampulla → bacterial contamination of the biliary tree → ascending cholangitis
  • Stents that occlude the cystic duct opening can cause acute cholecystitis
• Pancreatitis — ERCP manipulation at the ampulla can cause papillary oedema → pancreatic duct obstruction → post-ERCP pancreatitis (occurs in ~3–10% of ERCP procedures)
• Perforation — rare but life-threatening; duodenal perforation from endoscope or sphincterotomy
• Bleeding — from sphincterotomy site, or hepatic artery/portal vein injury during PTBD

Pre-op biliary drainage has increased risk of serious complications: ^[26] Pancreatitis (7%), cholangitis (26%), blocked stent (15%), bleeding (2%), perforation (2%) ^[26]

Specific PTBD complications:

• Bleeding is common due to puncture of hepatic artery or portal vein before reaching the bile duct (Portal triad) ^[16]
• Hemobilia (communication of the tract with a major vascular structure) ^[16]
• Fluid and electrolyte loss from external bile drainage (bile contains ~600–1000 mL/day of fluid rich in sodium, bicarbonate, and chloride)
• Catheter dislodgement → bile peritonitis

2. Complications of Curative Surgery

General Surgical Complications (Post-hepatectomy / Post-Whipple)

Early complications:

Complications specific to Whipple procedure (distal CCA): ^[16]

Late complications of Whipple procedure:

Late complications specific to hepaticojejunostomy:

• Most frequent long-term complication of Roux-en-Y hepatojejunostomy is stenosis of biliary-enteric anastomosis leading to jaundice, cirrhosis or cholangitis ^[22]
  • Why does anastomotic stricture occur? Chronic inflammation, ischaemia of the anastomotic site, and scar contracture → progressive narrowing → recurrent cholestasis and cholangitis
  • Management: percutaneous balloon dilatation (PTC access), or surgical revision

3. Complications of Chemotherapy

Common adverse effects of the regimens used in CCA:

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C. Disease Recurrence

Even after R0 resection, CCA has a high recurrence rate:

• Overall recurrence rate: 50–70% within 2 years
• Sites of recurrence: Local (anastomotic/perihilar), intrahepatic (distant liver metastases), peritoneal, distant (lung, bone)
• Surveillance: Serial CA 19-9, CT/MRI every 3–6 months for the first 2 years, then annually
• Predictors of recurrence: R1 margin, lymph node positivity, perineural invasion, poorly differentiated histology, high pre-operative CA 19-9, vascular invasion

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D. Summary: Causes of Mortality in MBO

Cause of mortality in MBO: ^[22]

• Biliary sepsis — the single most common cause of death
• Liver failure — progressive hepatic decompensation from obstruction and tumour invasion
• Cancer cachexia — wasting from tumour-mediated metabolic derangement and malabsorption

These three causes form a vicious cycle: sepsis worsens liver function → liver failure worsens immune function → worsened immunity promotes more sepsis → all of this accelerates cachexia.

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Active Recall - Complications of Cholangiocarcinoma

1. List the three causes of mortality in malignant biliary obstruction.

Your answer

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1. Biliary sepsis. 2. Liver failure. 3. Cancer cachexia.

2. Explain the pathophysiology of cholangitis in CCA, including why antibiotics alone may be insufficient.

Your answer

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CCA obstructs bile duct causing stasis. Biliary pressure rises above 25 cmH2O. Bacteria reflux from duodenum into stagnant bile, then into hepatic veins and lymphatics causing bacteraemia and septic shock. Antibiotics are excreted into bile, but biliary obstruction impairs antibiotic secretion into bile. Therefore antibiotics cannot reach the infected bile adequately, and biliary drainage is mandatory.

3. Name 5 pathophysiological effects of malignant biliary obstruction on liver function.

Your answer

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Any 5 of: impaired protein synthesis, impaired clotting factor synthesis, impaired gluconeogenesis, impaired ketogenesis, endotoxaemia, decreased reticuloendothelial function, decreased cell-mediated immunity.

4. What are the three most feared early complications after major hepatectomy for perihilar cholangiocarcinoma, and why is this surgery particularly high risk?

Your answer

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1. Post-operative liver failure (insufficient FLR, cholestatic liver regenerates poorly). 2. Haemorrhage (hilar dissection is adjacent to major vessels). 3. Bile leak from hepaticojejunostomy (tiny inflamed duct stumps make watertight anastomosis difficult). High risk because patients have pre-existing malnutrition, impaired liver function from obstruction, and impaired immunity.

5. A patient with a palliative metal stent for perihilar CCA develops recurrent jaundice 4 months later. What is the most likely cause and how would you manage it?

Your answer

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Most likely cause: stent occlusion from tumour ingrowth (tumour grows through the mesh of uncovered metallic stent) or bile sludge accumulation. Management: ERCP with sweeping of the occluded stent and placement of a new stent through or alongside the blocked one. If ERCP fails, PTBD for drainage.

References

^[2] Senior notes: felixlai.md (Cholangiocarcinoma, sections I and VII: Overview, metastatic sites) ^[4] Senior notes: maxim.md (Cholangiocarcinoma section: clinical features — haemobilia; palliative care — stent complications) ^[16] Senior notes: felixlai.md (MBO sections: surgical complications, ERCP/PTBD complications, palliative bypass; Whipple complications table) ^[19] Senior notes: maxim.md (Acute cholangitis section: aetiology, pathogens, stent as nidus) ^[22] Lecture slides: Malignant biliary obstruction.pdf (p29, Cause of mortality in MBO) ^[23] Lecture slides: WCS 056 - Painless jaundice and epigastric mass - by Prof R Poon.ppt (1).pdf (p63, Why is MBO so risky for operation) ^[24] Lecture slides: Malignant biliary obstruction.pdf (p16, Cholangitis — biliary pressure, antibiotics impaired) ^[25] Lecture slides: WCS 056 - Painless jaundice and epigastric mass - by Prof R Poon.ppt (1).pdf (p64, Pathophysiological effects of MBO) ^[26] Lecture slides: Malignant biliary obstruction.pdf (p26, Pre-op biliary drainage complications)