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

Abstract

Cholangiocarcinomas are a heterogeneous group of highly aggressive cancers that may arise anywhere within the biliary tree. There is a wide geographical variation with regards to its incidence, and risk-factor associations which may include liver fluke infection, primary sclerosing cholangitis, and hepatolithiasis amongst others. These tumours are classified into intrahepatic, perihilar and distal based on their anatomical location. Morphologically, intrahepatic cholangiocarcinomas are further sub-classified into small and large duct variants. Perihilar and distal cholangiocarcinomas are usually mucin-producing tubular adenocarcinomas. Cholangiocarcinomas develop through a multistep carcinogenesis and are preceded by dysplastic and in situ lesions. While clinical characteristics and management of these tumours have been extensively elucidated in literature, their ultra-structure and tumour biology remain relatively unknown. This review focuses on the current knowledge of pathological characteristics, molecular alterations of cholangiocarcinoma, and its precursor lesions (including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm).

Keywords: Cholangiocarcinoma; Classification; Molecular features; Pathology; Precursors lesions; Treatment.

Figure 1

Gross features and morphology of cholangiocarcinoma. A: Mass forming intrahepatic cholangiocarcinoma (IHCC); B: Extrahepatic cholangiocarcinoma with periductal infiltrating growth (arrow) and markedly greenish liver; C: Well differentiated cholangiocarcinoma [hematoxylin and eosin (H&E, × 25)]; D: Poorly differentiated cholangiocarcinoma (H&E, × 25); E: Large duct variant of IHCC (H&E, × 8).

Figure 2

Intrahepatic cholangiocarcinoma. A: Small duct variant of Intrahepatic cholangiocarcinoma (IHCC) (SD-IHCC) with closely packed small glands [hematoxylin and eosin (H&E, × 15)]; B: SD-IHCC with desmoplastic stroma (H&E, × 15); C: Large duct variant of IHCC (LD-IHCC) with mucin production (H&E, × 20); D: LD-IHCC with mucin [Periodic acid Schiff after diastase, × 15].

Figure 3

Intrahepatic cholangiocarcinoma. A: Intrahepatic cholangiocarcinoma (IHCC) with ductal plate malformation phenotype [hematoxylin and eosin (H&E, × 20)]; B: Cholangiocellular or bile ductular type of IHCC (H&E, × 20); C: IHCC lymphoepithelioma subtype (H&E, × 20); D: IHCC with sarcomatoid areas (H&E, × 20).

Figure 4

Extrahepatic cholangiocarcinoma. A: Extrahepatic cholangiocarcinoma (EHCC) with large mucin producing malignant glands and abundant desmoplastic stroma [haematoxylin and eosin (H&E, × 8)]; B: EHCC with perineural invasion (H&E, × 20); C: EHCC adenosquamous subtype (H&E, × 15); D: Well differentiated neuroendocrine tumour of the bile duct (H&E, × 20).

Figure 5

Immunohistochemistry in cholangiocarcinoma. A: Positive CK7 immunostaining; B: Positive CK19 immunostaining; C: Positive epithelial membrane antigen immunostaining; D: Hepatocyte nuclear factor-1 β nuclear immunostaining in a small duct variant of intrahepatic cholangiocarcinoma.

Figure 6

Precursor lesions of cholangiocarcinoma. A: Biliary intraepithelial neoplasia with low grade dysplasia [haematoxylin and eosin (H&E, × 15)]; B: Intraductal papillary neoplasm of the bile duct (IPNB) (arrow); C: IPNB pancreaticobiliary subtype (H&E, × 10); D: Intraductal tubulopapillary neoplasms of the bile duct with invasive carcinoma (H&E, × 10).

Figure 7

Other precursor lesions. A: Hepatobiliary mucinous cystic neoplasm with mucinous lining epithelial and ovarian stroma [haematoxylin and eosin (H&E, × 10)]; B: Von Mayenberg complex (H&E, × 20); C: Bile duct adenoma (H&E, × 20).