Pathological, molecular, and clinical characteristics of cholangiocarcinoma: A comprehensive review

Table 1 Definite and probable risk factors for cholangiocarcinoma

Definite risk factors
Primary sclerosing cholangitis
Liver fluke infection (Opisthorchis viverrine, Clonorchis sinensis)
Hepatolithiasis
Biliary malformation (choledochal cysts, Caroli’s disease, congenital hepatic fibrosis)
Thorotrast
Probable risk factors
Alcohol
Hepatitis B
Hepatitis C
Cirrhosis
Toxins (dioxin, polyvinyl chloride)
Biliary–enteric drainage procedures
Inflammatory bowel disease
Asbestos
Non-alcoholic fatty liver disease
Metabolic syndrome, type 2 diabetes, obesity
Smoking
Chronic pancreatitis

Table 2 Histological classification of cholangiocarcinoma

Based on histological differentiation
Well (> 95% of tumour composed of glands)
Moderately (50%-95% of tumour composed of glands)
Poor (5%-49% of tumour composed of glands)
Undifferentiated type (< 5% of tumor composed of glands)
Based on glandular features
Conventional type (bile duct type)
Small bile duct type (intrahepatic)
Large bile duct type
Cholangiocellular (intrahepatic)
Uncommon variants
Ductal plate malformation type (intrahepatic)
Lymphoepithelioma type
Clear cell type
Squamous/adenosquamous type
Mucinous carcinoma
Sarcomatoid
Signet ring carcinoma
Neuroendocrine
HCC-like

HCC: Hepatocellular carcinoma.

Table 3 Clinicopathologic, immunohistochemical, and molecular characteristics

	Large duct type	Small duct type
Location	Proximal to hepatic hilum	Peripheral
Risk factors	PSC, Liver fluke infection, Hepatolithiasis	Chronic liver disease, viral hepatitis
Gross features	Periductal infiltrating, Mixed pattern	Mass forming
Precursor lesion	BilIN, IPNB, ITPN	Unknown
Pathology	Large, widely spaced glands, Columnar with mucin production, desmoplastic stroma	Small tubules, fused or anastomosing glands, cuboidal to low columnar, central scarring, minimal to no mucin
Perinerual invasion	Common	Rare
Lymphovascular invasion/lymph node metastases	Common	Rare
Tumour border	Infiltrative	Expansile or pushing, rarelyinfiltrative
Immunohistochemical features	S100P and TFF1	CD56, N-cadherin, CRP
Molecular alterations	KRAS and GNAS mutationsCOX2 upregulations	IDH1/IDH2 and BRAF mutations, FGFR2 fusion

BilIN: Biliary intraepithelial neoplasia; CRP: C-reactive protein; IPNB: Intraductal papillary neoplasm of the bile duct; ITPN: Intraductal tubulopapillary neoplasms; PSC: Primary sclerosing cholangitis.