There are distinct differences in terms of genetic alterations, gene expression, and stromal and inflammatory factors between bile duct adenomas and small-sized small duct intrahepatic cholangiocarcinoma (iCCA), according to a new study published in the journal Histopathology.

These differences can be exploited as tools for the differential diagnosis of small duct iCCA.

Read more about CCA differential diagnosis

Continue Reading

It was observed that bile duct adenoma is significantly more common concurrently with small duct iCCA compared to other types of primary liver carcinoma. So a team of researchers from Japan hypothesized that bile duct adenoma could be a precursor of small duct iCCA.

The team explored this possibility by analyzing genetic changes and other features in bile duct adenomas. They analyzed genetic alterations as well as the expression of EZH2, p16INK4a, and IMP3, which are markers associated with malignant features, plus stromal and inflammatory factors in 33 patients with bile duct adenomas and 17 patients with small duct iCCAs, which measure less than 2 cm in diameter. 

They found no genetic alterations in bile duct adenomas, while there were genetic alterations in PBRM1, p53, TERT ARID1A, IDH1, MTAP, and KRAS promoter in almost all but 1 patient with iCCA. 

Similarly, IMP3 and EZH2 were not expressed in bile duct adenomas, while they were expressed in 94% of small duct patients with iCCA. 

Finally, immature stroma and neutrophilic infiltration were significantly more common in small duct iCCA than in bile duct adenoma.

“There was no evidence suggesting that bile duct adenoma is a precursor of small duct iCCA”, the authors concluded. “Immunohistochemical staining for IMP3, EZH2, p53, ARID1A, and MTAP may be useful for differential diagnosis between bile duct adenomas and small duct iCCAs”.

CCA is a heterogeneous group of rare malignant tumors originating from biliary tree cells. iCCA is a subtype of CCA that is found inside the hepatic parenchyma and can occur at any location in the intrahepatic biliary tree. The exact cause of any type of CCA is unknown but it is thought that a combination of genetic and environmental factors play a role. 


Motoko S, Yasunori S, Yasuni N. Bile duct adenoma and small-sized small duct type intrahepatic cholangiocarcinoma show distinct differences in genetic alterations, expression of IMP3 and EZH2 and stromal and inflammatory components. Histopathology. Published online May 4, 2023. doi:10.1111/his.14932