Clinical and biological significance of precursor lesions of intrahepatic cholangiocarcinoma

Table 1 Summary of the clinical and pathological features of intrahepatic cholangiocarcinoma and its precursor lesions

	ICC	BilIN	IPNB	VMC/BDH	BDA
Incidence/prevalence	10%-20% of primary liver cancers[1]	No published data	9%-38% of bile duct carcinomas[28]	5.6% of adults, 0.9% of children (autopsy series)[40]	0.00008%-0.006% of patients (autopsy series)[52,53]
Risk factors	Chronic viral hepatitis, clonorchis, opistorchis, hepatolithiasis[1]	Hepatolithiasis, primary sclerosing cholangitis, choledochal cyst, autoimmune pancreatitis, chronic viral hepatitis, alcoholic cirrhosis[15,17-21]	Hepatolithiasis, clonorchis[31,32]	Congenital hepatic fibrosis, polycystic liver disease[40]	No known risk factors
Gross appearance	Firm, white to tan[1]	Not grossly identifiable[10]	Dilated bile ducts filled with soft, papillary white to red to tan lesions without invasion[10]	Well-circumscribed unencapsulated nodules, < 5 mm[1]	Subcapsular, well-circumscribed unencapsulated gray to white, yellow or tan firm nodules, ≤ 2 cm[47,48]
Histologic appearance	Perihilar type: Involves large bile ducts, composed of large tubules or papillae lined by columnar epithelium. Peripheral type: Involves smaller ducts and segmental branches, composed of small, tubular cords or ductular pattern lined by cuboidal epithelium[2]	Epithelium with nuclear pseudostratification and atypia (increasing from BilIN-1 to BilIN-2 to BilIN-3), often with micropapillary projections into the bile duct lumen[10]	Noninvasive papillary or villous biliary neoplasm covering delicate fibrovascular stalks (subtypes pancreatobiliary, intestinal, gastric, oncocytic)[10]	Irregular dilated to branching low cuboidal epithelium-lined ductules within fibrous stroma, often adjacent to portal areas[1]	Small uniform cuboidal epithelium-lined ductules within fibrous stroma[47,48]
Molecular alterations	Activating mutations in KRAS (22%) occurs early in cholangiocarcinogenesis[63]	Activating mutation of KRAS present in approximately 33% of BilIN lesions including in 25% of cases of BilIN-1[22]	Increased expression of Cyclin D1 and p21[26,35]	Loss of heterozygosity at key loci (5q21, 9p21, 10q23, 17p13) harboring APC, p53, p16, and PTEN[44]	BRAF V600E mutation (53%)[46]
	Loss-of-function mutations in TP53 (15%), BRAF and EGFR mutation (7% and 2%)[55,61,65,67]	Increased expression of p21, p53, cyclin D1 and EZH2[3,17,22-25]	Aberrant expression of p16[30]
	Rare NRAS and PI3K mutations have been[55,61-72]	Decreased expression of Dcp4 and p16INK4A. Loss of SMAD4/DPC4 associated with higher grade[3,30,35]	Inactivation of p53 associated with increasing grade of dysplasia and invasion[30]
	IDH1 and IDH2 mutations co-occurring with increased TP53 expression and associated with DNA hypermethylation[62,66]	Decreased membranous expression of β-catenin with increasing grade of BilIN[26]	C-myc mutations in over 50% of cases[26]
	Chromosomal aberrations including gains at 7p and 8q and losses at 1p, 4q and 9p[68,69,73-76]	Decreased expression of E-cadherin in some cases of BilIN[26]	Loss of SMAD4/DPC4 associated with higher grade[30,35]
	Aberrant methylation of p16INK4a/CDKN2 (47%), RASSFIA (56%) and APC (29%)[70,71,76]	S100P: Increased immunohistochemical expression in BilIN-2 and BilIN-3[27]

BilIN: Biliary intraepithelial neoplasia; IPNB: Intraductal papillary neoplasm of the bile duct; VMC: Von Meyenburg complex; BDH: Bile duct hamartoma; BDA: Bile duct adenoma; ICC: Intrahepatic cholangiocarcinoma.