Table 1.

Main epidemiologic and molecular differences between iCCA and extrahepatic subtypes (pCCA-dCCA)

Gene or moleculeiCCApCCA-dCAAReferences
Proportion of CCA cases5%–20%pCCA (50%–70%), dCCA (15%–20%)(12–15)
Incidence rateIncreasingStable or slightly decreasing(7–10)
Anatomic locationIntrahepatic biliary tractExtrahepatic biliary tract(3)
pCCA (near origin of cystic duct)
dCCA (lower half of large duct)
Differenctial risk factors (n = positive cases/total, % casesa)
 Biliary lithiasisb377/1,539 (24%)289/549 (52%)(17, 18, 20–23)
 Cirrhosis161/1,622 (10%)23/712 (3%)(17–23)
 HCV61/1,522 (4%)11/712 (1.5%)(17–21, 23)
 HBV129/1,411 (9%)4/712 (0.6%)(17–22)
 Alcoholc158/1,524 (10%)37/712 (5%)(17–22)
Molecular alterations (n = positive cases/total, % casesa)
 Somatic mutations
  TP5399/606 (16%)36/137 (26%)(50–53, 56–62)
  KRAS165/885 (19%)29/152 (19%)(50–53, 56–62)
  IDH1/2143/951 (15%)3/164 (2%)(51–54, 56–62)
  ARID1A50/390 (13%)20/137 (14%)(51–54, 56–57, 59, 61–62)
  BAP145/443 (11%)3/164 (2%)(51–54, 56–57, 59, 61–62)
  BRAF28/574 (5%)0/137 (0%)(50–51, 53–54, 55–59, 61)
  EGFR14/545 (3%)3/151 (2%)(50–51, 53–54, 55–59, 61)
 Fusion proteins
  FGFR2 fusions71/307 (23%)0/36 (0%)(51, 56, 57, 72, 73, 75)
 Chromosomal abberations (ampifications)d
  17q11 (ERBB2)0/170 (0%)10/55 (18%)(31, 66)
  11q13 (FGF19, CCDN1, ORAOV1)5/128 (4%)NA(31)

NOTE: Frequencies in iCCA have been calculated only in non–liver fluke cases.

Abbreviations: dCCA, distal cholangiocarcinoma; HBV, hepatitis B virus infection; HCV, hepatitis C virus infection; iCCA, intrahepatic cholangiocarcinoma; NA, not applicable; pCCA, perihilar cholangiocarcinoma.

  • aThe percentage of cases has been calculated by considering the number of samples presenting the molecular alteration over the total number of samples analyzed in all cohorts (discovery and validation set of samples).

  • bBiliary lithiasis includes patients with hepatolithiasis, cholelithiasis, and choledocholithiasis.

  • cPatients with heavy alcohol consumption or alcoholic liver disease.

  • dGenomic amplifications evaluated by FISH assay or copy number alteration by SNP array.