Intrahepatic cholangiocarcinoma: Tumour heterogeneity and its clinical relevance

Abstract

Treatment of intrahepatic cholangiocarcinoma (iCCA) is currently at a significant turning point due to the identification of isocitrate dehydrogenase (IDH) mutations and fibroblast growth factor receptor (FGFR) fusions that can be targeted with currently available therapies. Clinical trials of these targeted therapies have been promising, and the iCCA patients who may benefit from these targeted treatments can be identified by pathological examination prior to molecular investigations. This is because IDH mutations and FGFR fusions are mainly seen in the small duct type iCCA, a subtype of iCCA defined by the 5th World Health Organization classification, which can be recognized by the pathological diagnostic process. Therefore, pathology plays an important role in precision medicine for iCCA, not only in confirming the diagnosis, but also in identifying the iCCA patients who may benefit from targeted treatments. However, caution is advised with the pathological diagnosis, as iCCA shows tumour heterogeneity, making it difficult to distinguish small duct type iCCA from hepatocellular carcinoma (HCC), and combined HCC-CCA. This review focuses on the pathological/molecular features of both subtypes of iCCA (large and small duct types), as well as their diagnostic pitfalls, clinical relevance, and future perspectives.

Keywords: Adult liver cancers; Cholangiocarcinomas; Hepatocellular carcinoma; Histological types of neoplasms; Pathology.

Figure 1.

Epithelial membrane antigen (EMA) staining reflecting heterogeneity of the cholangiocytes. The large bile duct is lined by mucinproducing cylindrical cholangiocytes (A), which show cytoplasmic EMA expression (B). In contrast, the small duct is lined by mucin-negative cuboidal cholangiocytes (C) which demonstrate apical EMA positivity (D). The large duct intrahepatic cholangiocarcinoma (iCCA) shows EMA cytoplasmic expression (E), and the small duct type iCCA presents apical EMA positivity (F).

Figure 2.

Comparative macroscopic and pathological features of large and small duct type intrahepatic cholangiocarcinoma (iCCA). Macroscopically, the large duct type iCCA shows periductal infiltrating (PI) type (A), or mixed PI and mass-forming pattern (B). The tumour shows a clear glandular structure with solid fibrosis (C; HE staining, ×40). Perineural invasion (D) and lymphatic invasion (E) are also shown (HE staining, ×40). The small duct type iCCA presents with a mass-forming growth pattern (F; HE staining, ×40). Pathologically, the tumour shows variation of ductular configurations (G, H; HE staining, ×40).

Figure 3.

Cholangiolocellular carcinoma (CLC) diagnosis and categorization. Diagnosis: CLC is a tumour comprising more than 80% ductular configuration. Epithelial membrane antigen (EMA) shows an apical expression in the ductular area. Categorization: CLC with hepatocytic differentiation is defined as combined hepatocellular carcinoma (HCC)-cholangiocarcinoma (CCA), and the remaining CLC is categorized into the small duct type intrahepatic cholangiocarcinoma (iCCA).

Figure 4.

The pathological features of large duct intrahepatic cholangiocarcinoma (iCCA) (A; Hematoxylin and Eosin [H&E] staining, ×40) are very similar to those of pancreatic cancer (B; H&E staining, ×40). The small duct type iCCA (C; H&E staining, ×10) mimics breast cancer liver metastasis (D; H&E staining, ×10).