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Cholangiocarcinoma

Section: Hepatobiliary Sub-section: Biliary Curriculum: Curriculum, page 88

Definition

Malignant epithelial tumours arising from the biliary tree

  • Intrahepatic - 10%
  • Extrahepatic
    • Hilar - 60%
    • Mid-duct and distal duct - 20-30%

Mid-ductal - upper border of the duodenum and the cystic duct Distal bile duct - duodenum to the ampulla of Vater.

Epidemiology

  • Incidence 0.3 – 3 per 100,000.
  • Equal M & F.
  • Age 55 – 75.

Risk factors

  • Majority are sporadic
  • Chronic biliary inflammation (5%):
    • Primary sclerosing cholangitis
    • Chronic choledocholithiasis
    • Hepatolithiasis
    • Parasitic biliary infestation
    • Caroli’s disease
    • Choledochal cyst
    • Enteric reflux due to anastomosis
  • NAFLD
  • Hep B/C
  • T2DM & metabolic syndrome

Rare association with UC, and PSC is the greatest risk factor for its development.

  • 12–15% of patients transplanted for PSC have cholangiocarcinoma

Clinical presentation

  • Symptoms at advanced stage:
    • Abdominal pain
    • Malaise
    • Night sweats
    • Asthenia
    • Nausea
    • Weight loss
    • Jaundice
  • Non-specific LFTs
  • Serum markers CEA and Ca 19-9 lack sensitivity and specificity

Pathology

  • Precursor:
    • Flat or micropapillary growth of atypical biliary epithelium (biliary dysplasia or biliary intraepithelial neoplasia)
    • Intraductal papillary neoplasm
    • Mucinous cystic neoplasm
    • Intraductal tubular papillary neoplasm
  • Majority are adenocarcinoma 95% with 5% other variants
  • Adenocarcinomas are divided into three subtypes
    • Sclerosing
    • Nodular
    • Papillary

Intrahepatic cholangiocarcinoma

Arises from peripheral intrahepatic biliary radicles (different from hilar and CBD cholangio)

3 morphological subtypes :

  • Mass forming (commonest)
  • Periductal-infiltrating which spreads along bile ducts
  • Intraductal-growth type with intraluminal spread
  • Can have mixed components

Staging

TNM

T1a: < 5 cm without vascular invasion
T1b: > 5 cm without vascular invasion
T2: solitary tumour with vascular invasion or multiple tumours
T3: perforating visceral peritoneum
T4: involving local extrahepatic structures by direct invasion
N0 or 1
M0 or 1

Investigations

Imaging

  • CT

    • Arterial phase: variable rim-like enhancement
    • Delay: gradual centripetal enhancement

  • MRI

    • Hypointense on T1,
    • hyperintense on T2.
    • Large, non-encapsulated, heterogeneous, associated with narrowing of adjacent portal veins and retraction of liver capsule. May have satellite nodules.
    • MRCP useful - biliary dilation

  • FDG-PET

    • Distant mets

  • Diagnostic laparoscopy - consider

Diagnosis

  • Main differential is colorectal metastases.
  • Biopsy shows adenocarcinoma of biliary phenotype (CK7+ CK20- ) in contrast to colorectal (CK7- CK20+)

Management

Resectable disease

  • Surgical resection only curative treatment.
    • PVE can be performed with FLR inadequate
  • Portal lymphadenectomy indicated given prognostic information gained
  • 5y survival 25-40% in R0
  • Major hepatectomy in 75-80%.
  • Postop mortality 6%.
  • R1 or R2 resection 25%.

Prognostic factors:

  • Lymph node invasion
  • R1 resection
  • Infiltrating worse than mass-forming due to spread along Glisson’s capsule and high incidence of LN involvement. Intraductal growth are better.

Adjuvant treatment

Unresectable disease

  • Gemcitabine and Cisplatin
  • TACE, TACE-DEB, SIRT with yttrium-90 microspheres, radiation therapy
  • Hepatic arterial infusion (HAI) chemotherapy with floxuridine
  • Possible to down stage
  • Liver transplant not typically done

Perihilar

Investigations

  • CEA and Ca 19-9 may be elevated (but nonspecific)

Imaging

  • USS
    • Doppler US – good for delineating level of tumour, extension within bile duct and venous invasion.
  • CT
    • Arterial phase: variable rim-like enhancement
    • Delay: gradual centripetal enhancement
  • MRI
    • Hypointense on T1,
    • hyperintense on T2.
    • Large, non-encapsulated, heterogeneous, associated with narrowing of adjacent portal veins and retraction of liver capsule. May have satellite nodules.
    • MRCP useful
  • FDG-PET
    • Useful for identifying nodal or distant mets. Can differentiate between benign disease and cholangiocarcinoma

Invasive modalities

  • Percutaneous transhepatic cholangiography (PTC)
    • Can also get brushings + stent placement
    • useful for obstructive perihilar lesions
  • ERCP
    • Brushings
  • Skyglass
    • Targeted biopsies
  • Staging laparoscopy should be performed

Stage

Bismuth-Corlette classification:

Blumgart/Memorial Sloan-Kettering Cancer Center (MSKCC) (determines resectability for hilar cholangiocarcinoma)

T1Confluence +/- unilateral extension to 2nd order biliary radicles
T2Confluence +/- unilateral extension to 2nd order biliary radicles
AND ipsilateral portal vein involvement +/- ipsilateral hepatic lobar atrophy
T3Confluence +/- unilateral extension to 2nd order biliary radicles AND
contralateral portal vein involvement
OR contralateral hepatic lobar atrophy
OR main or bilateral portal venous involvement
Only T1 and T2 can be considered for resection - but the outcomes from resecting a patient with T2 disease is poor (high chance of finding metastatic disease at exploration and poor median survival)

The median survival is 20, 13, and 8 months for T1, T2, T3 respectively.

TNM stage (AJCC 8th adition)

  • T1: tumour confined to the bile duct, with extension up to the muscle layer or fibrous tissue
  • T2:
    • T2a: tumour invades beyond the wall of the bile duct to surrounding adipose tissue
    • T2b: tumour invades adjacent hepatic parenchyma
  • T3: tumour invades unilateral branches of the portal vein or hepatic artery
  • T4:
    • Tumour invades the main portal vein or its branches bilaterally, or
    • unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement
  • N1 - 1-3
  • N2 - 4 or more
  • M1 - mets

Irresectability

  • Patient factors
  • Anatomical
    • Local tumor factors
      • Bilateral spread to secondary biliary radical
      • Encasement or occlusion of the main portal vein proximal to its bifurcation
      • Atrophy of one lobe with - contralateral portal vein branch encasement or occlusion - contralateral tumour extension to secondary biliary radicles
      • Unilateral tumour extension to secondary biliary radicles with contralateral portal vein branch encasement or occlusion
  • Biology
    • Metastatic disease

Management

Preoperative considerations:

  • Preop tissue dx
    • Not mandatory if no prior biliary tract operation, PSC, hepatolithiasis
  • Preop biliary stenting:
    • Controversial.
      • Pros
        • Possibly improved periop outcomes in patients with predicted FLR < 30%
        • May improve hepatic function and patient nutrition
      • Cons
        • Contamination by enteric bacteria
        • Tumour seeding
        • Cholangitis
        • Bile leak
  • Neoadjuvant therapy
    • Limited data on efficacy
    • May be a role for chemoradiotherapy, particular for locally advanced, to help achieve R0 and improve survival.
  • PVE
    • For patients with anticipated FLR < 30%

Operative considerations:

  • Negative margin
    • R0 most predictive for survival
    • Usually Bismuth IIIb need left hepatectomy and I, II, IIIa require extended right
    • Frozen section proximal and distal margins
  • Portal lymphadenectomy
    • Survival benefit not proven. Diagnostic information gained may guide decisions about adjuvant therapy
    • LN status is independent predictor for long-term survival
    • Median number of nodes is 3, despite target of 7
  • Caudate lobectomy
    • Standard for hilar cholangiocarcinoma (particularly on the left)
  • Vascular resection
    • Portal vein resection and even IVC resection are not contraindications
  • Transplantation
    • Only select cases, but not done in most centres

Postoperative oncological outcomes

  • 5-year survival
    • 20-40% for intrahepatic;
    • 30-40% for perihilar cholangio;
    • 50% for distal/extrahepatic.

Palliative therapy

  • Intrahepatic biliary-enteric bypass:
    • Most often to segment III duct – usually sufficient to relieve jaundice.
  • Systemic therapy:
    • Gemcitabine + cisplatin standard of care.
    • Median overall survival of 18 months.
  • Targeted therapy: no difference in survival
  • Regional chemotherapy/hepatic artery infusion: may prolong survival
  • Yttrium Y-90 radioembolisation: show survival benefit

Distal-duct

Staging

T1: tumour invades the bile duct wall with depth <5 mm T2: tumour invades the bile duct wall with depth 5–12 mm T3: tumour invades the bile duct wall with depth >12 mm T4: tumour involves the coeliac axis, superior mesenteric artery, and/or common hepatic artery N1 - 1-3 N2 - 4 or more M1 - Mets

Managment

Operative

  • Pancreatoduodenectomy
    • Compared with pancreatic cancer
      • Often amenable to resection
      • Less often have microscopic disease at the resection margin,
      • Less frequently have spread of tumor to adjacent lymph nodes

Adjuvant treatment

  • Adjuvant capecitabine survival benefit compared to observation.
  • Radiotherapy after R1 resection survival benefit (compared to no radiotherapy)

BILCAP Trial — Comprehensive Summary

  • Full name: Capecitabine Compared with Observation in Resected Biliary Tract Cancer
  • Published:** Lancet Oncology, 2019 (Primrose et al.) | Long-term update: JCO, 2022
  • Only ~20% of biliary tract cancer (BTC) patients are eligible for curative-intent resection; 5-year OS for all BTC patients is <10%
  • Prior to BILCAP, no RCT had demonstrated a survival benefit for adjuvant therapy in resected BTC
  • BILCAP was the first phase III RCT with positive results for adjuvant chemotherapy in BTC
  • The trial established adjuvant capecitabine 1250 mg/m² bd, days 1–14, 21-day cycle × 8 cycles as the standard of care
  • Despite a technically negative ITT primary endpoint, the totality of evidence strongly supports benefit — a clinically meaningful 14.7-month OS improvement in the ITT analysis
  • ASCO, ESMO, NCCN, and eviQ (Australia/NZ) all recommend adjuvant capecitabine for 6 months post-resection

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