Cholangiocarcinoma

Epidemiology

• Common in south-east Asia (due to endemic liver flukes)
• Generally 50-70yo at diagnosis, but younger if there is a clear predisposing factor such as PSC

Risk factors

• Anything that causes biliary inflammation, and compensatory cellular proliferation

Modifiable

• • Alcohol abuse
  • Obesity (NASH/NAFLD)
  • Diabetes
  • Carcinogens
    • Thorotrast
    • COCP
    • Asbestos
    • Smoking

Non-modifiable

• • Sclerosing cholangitis (8-20% lifetime risk; 1.5% per year)

• • • Autoimmune multifocal strictures of the intra-hepatic and extra-hepatic biliary trees
    • Most common risk factor for cholangiocarcinoma in the West
    • Associated with multifocal cholangiocarcinoma

• • Choledochal cysts (3-28% lifetime risk)
  • Cirrhosis
  • Biliary parasites (liver flukes - Clonorchis sinensis and Opisthorchis viverrini)

• • • Cause chronic biliary inflammation, with obstructions and strictures

• • Hepatolithiasis
  • Recurrent pyogenic cholangitis

• • • Primary bile duct stone formation with infections

• • Infections of biliary tree (Salmonella, HCV, HBV)
  • Usually seen 60-70yo

Pathophysiology

• >90% are adenocarcinoma, with most of the remainder SCCs
• Graded as well, moderately or poorly-differentiated

Morphological subtypes:

• • Sclerosing/periductal infiltrating - most common (90%), tends to be proximal ducts/hilar area, tends to track along nerves/ducts. Causes peri-ductal fibrosis in a concentric pattern.
  • Nodular/mass-forming - firm, irregular nodules based in the duct wall that project into bile duct lumen, more distal cancers. Resectability and cure rates are very low.
  • Papillary/intra-ductal - polypoid intra-ductal lesion, soft, less peri-ductal fibrosis, higher resectability rate, better prognosis, more distal cancers.

Metastatic spread

• • Intra-hepatic spread is common
  • Vascular involvement can occur early

Anatomical classification

• Anatomical
  • Perihilar (70%)
    • Aka Klatskin's tumours
  • Intrahepatic (5-10%)
    • Often found incidentally
  • Distal extrahepatic (20%)

Presentation

• See specific sections below
• Painless jaundice is common, with dark urine, steatorrhoea, pruritis
• Obstruction at or distal to the hepatic bifurcation tends to present earlier
• Constant pain on presentation suggests more advanced disease
• Generally present with high bilirubin and ALP. If albumin and INR are affected, it is likely to be more advanced.
• Tumour markers are unreliable but may help post-operatively. Do CEA, CA 19-9 at diagnosis.
• Systemic features

Generic imaging features

• CT
  • Lower-attenuation lesion on non-contrast phases, if there is a mass present
  • Peripheral enhancement with progressive filling on contrast phases
• MRI
  • T1: hypointense
  • T2: hyperintense

Differential diagnosis

• Consider lymphoma or metastatic adenocarcinoma causing extrinsic CBD compression
  • Placement of plastic CBD stent is best treatment

Management prior to tissue diagnosis

• Tissue is not necessary prior to resection (bile cytology and brushings are unreliable with obstructive jaundice anyway, with poor sensitivity)
• No need to continue with invasive attempts to establish a diagnosis prior to resection, as it does not alter management
• 7-15% undergoing resection for suspected biliary malignancy will be found to have benign disease on formal histology
• Tissue diagnosis is only important when the patient is not a surgical candidate
• Pre-operative biliary drainage may be useful in select cases; but decision needs to be made with HPB involvement, because you risk seeding bacteria into an area of the liver you might not be able to drain in the future, leading to problems with recurrent cholangitis. The converse opinion is that you improve nutrition and liver function.
  • Distal cholangiocarcinoma with bilirubin > 171micromol/L
  • Prolonged interval between diagnosis and resection
  • Hilar cholangiocarcinoma with complete biliary obstruction - drain obstructed but unaffected segments to enhance post-resection hypertrophy, despite higher risk of peri-operative infectious complications

General surgical principles for all types

• R0 resection is the only chance for cure
• Assess resectability at time of operation
• Maintain an adequate FLR, including portal vein embolization in some cases
• Portal lymphadenectomy
• Consider frozen section of bile duct margin

Intrahepatic

Pathophysiology

• • Difficult to distinguish from adenocarcinoma
  • Biopsies especially would normally come back as adenocarcinoma rather than cholangiocarcinoma

Presentation

• • Similar to HCC
  • Generally found incidentally
  • Most common symptoms are RUQ pain and weight loss
  • Jaundice only if advanced or if biliary tree is occluded near hilum of the liver - but uncommon because these tumours tend to occur in peripheral liver
  • Can have uni-lobar obstruction of a bile duct, leading to atrophy and contralateral hypertrophy

Imaging

• • Dedicated liver MRI is best
  • Low attenuating, minor peripheral enhancement, upstream biliary dilatation, capsular retraction
  • Generally has persistent enhancement on delayed phases due to the fibrotic nature of cholangiocarcinoma, in contrast with the vascular nature of HCC

Workup

• • Consider workup for primary, if one of the differentials of the lesion is a metastasis
    • Generally need to do scopes and CT C/A/P
  • Bloods
    • Hepatitis serology
    • AFP - normal - helps with excluding HCC
    • CEA - can be high
    • CA 19-9 - can be high
    • Chromogranin A
  • Liver evaluation
    • Consider biopsy/liver remnant volumes - should be >50% if patient has cirrhosis

Staging

Intrahepatic bile duct cancer TNM staging AJCC UICC 8th edition - to follow

Resectability

• • Main determinant is adequate FLR
  • Unresectable disease
    • Advanced tumour involving either inflow or outflow bilaterally
    • Multiple bilateral intrahepatic tumours
    • Distant metastatic disease
    • Relative contraindications: small localised satellite lesions, perihepatic lymphadenopathy, portal hypertension

Treatment

• • Surgical
    • Only curative option is R0 resection (long-term survival in unresected patients is rare)
      • Transplant is not accepted.
    • Hilar nodes should be formally resected in intrahepatic cholangiocarcinoma - 30% positive
    • Mostly open procedures, however do laparoscopy first to assess for carcinomatosis (simple or left resections might be performed lap)
  • Locoregional therapy
    • TACE/TARE, ablation, external beam radiotherapy, photodynamic therapy
    • Couldn't really recommend one over another

Hilar

Presentation

• • Obstructive painless jaundice
  • Constitutional symptoms
  • Isolated intrahepatic biliary dilatation

Imaging

• • MRI/CT will show it
  • Look for portal lymphadenopathy, metastatic disease, liver atrophy, and vascular involvement (right arterial invasion more common)

Workup

• • ERCP/PTC to drain biliary system and attempt to get tissue

Staging

• • Bismuth-Corlette - may be considered old, doesn't guide resectability, but best starting point to describe the tumour anatomically. Higher stage tumours are less likely to be resectable.
  • TNM - pathologic, doesn't guide operative planning, but useful for prognostication
  • Other staging systems which have been proposed, but not universally used:
    • Blumgart - predicts resectability, and correlates with overall survival
    • International cholangiocarcinoma group staging system - combines multiple other staging systems, but still under evaluation

Resectability

• • Unresectable factors (based on Blumgart staging system):
    • Patient factors
      • Medically unfit for major operation
      • Cirrhosis
    • Local tumour-related factors (Blumgart T2 or T3)
      • Hepatic duct involvement up to secondary biliary radicals bilaterally (that is, proximal to both right and left CHD)
      • Encasement or occlusion of the main portal vein proximal to its bifurcation
      • Atrophy of one hepatic lobe with contralateral encasement of portal vein branch
      • Atrophy of one hepatic lobe with contralateral involvement of secondary biliary radicals
      • Unilateral tumour extension to secondary biliary radicles with contralateral vein branch encasement or occlusion
    • Metastatic disease
      • Histologically proven metastases to distant lymph node basins
      • Lung, liver or peritoneal mets

Treatment

• • Surgical resection
    • Initial laparoscopy to determine resectability
    • Commonly right subcostal incision
    • Bismuth-Corlette may assist with best operation choice
      • I and II: CBD resection, cholecystectomy, and 5-10mm margin of resection. Type II lesions may also require partial hepatic resection, which commonly includes caudate lobe. Reconstruction using a Roux limb of jejunum.
      • III and IV: may involve complex resection and reconstruction of the PV, hepatic artery, or both.
    • Controversial role of routine lymph node dissection. No demonstrable benefit, but may help prognosticate and direct adjuvant therapy.
  • Transplant
    • Very select patients
    • Can be granted MELD exception points to make them eligible
    • Specifically for cholangiocarcinoma in setting of severe liver disease and PSC
    • Often means neoadjuvant CTX followed LTx

Prognosis:

• • 5-year survival rates as high as 59% have been reported

Distal CBD cancer

Presentation

• • Similar to other periampullary tumours - painless jaundice and constitutional symptoms

Workup

• • Pancreas protocol CT
    • Arterial anatomy, regional lymphatic spread, relationship of tumour to nearby vascular structures
    • Secondary pancreatic signs of periampullary malignancy such as atrophy or ductal dilatation
  • ERCP - can be used as a diagnostic modality, but not recommended routinely because it colonises the biliary tree with enteric organisms and increases rate of infectious complications after whipples procedure
  • Don't need to fix jaundice pre-operatively because not doing a major hepatectomy

Staging

Distal bile duct cancer TNM staging AJCC UICC 8th edition - to follow

Management

• • Resection
    • Pancreaticoduodenectomy
      • Increasingly done lap/robotic
    • Frozen section of the proximal bile duct margin helps ensure R0 resection

Adjuvant chemotherapy and radiotherapy

• Has not been shown to improve survival
• Consider for patients with nodal disease, those with R1 resections, and those undergoing a clinical trial
• First-line is cisplatin and gemcitabine
• Second-line FOLFOX or trials

Palliation

• Relief of jaundice
  • ERCP or PTC
  • SEMS
• Alleviation of pain
  • Some benefit to coeliac plexus neurolysis
• Relief of duodenal obstruction
  • This is pre-terminal

Prognosis

• Uniformly poor, ranging from 10% to 48% at 5 years if R0 resection is obtained
• Recurrences can occur at bile ducts, nodes, liver
• Unresectable disease has a median survival of 5-8 months
• R0 resection is the most important prognostic factor - 5 year survival rates up to 50% in node-negative patients with R0 resection

Surveillance

• CT scan every six months for the first two years, then annually