Combined Hepatocellular-Cholangiocarcinoma: An Update on Pathology and Diagnostic Approach

Abstract

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver carcinoma displaying both hepatocytic and cholangiocytic differentiation within the same tumor. Relative to classic hepatocellular carcinoma (HCC), cHCC-CCA has more aggressive behavior and a poorer prognosis. Though recent advances have improved our understanding of the biology underlying cHCC-CCAs, they remain diagnostically challenging for pathologists because of their morphologic and phenotypic diversity. Accurate diagnosis of cHCC-CCA is important for patient management and prognostication. Herein, we review recent updates on cHCC-CCA, focusing on tumor classification, pathology, and diagnostic approach.

Keywords: adult; cholangiocarcinoma; combined hepatocellular-cholangiocarcinoma; hepatocellular carcinoma; liver cancers.

Figure 1

Computed tomography (CT) scan images of combined hepatocellular-cholangiocarcinoma in a 48-year-old female patient with chronic hepatitis B. (A) Axial non-contrast CT image shows a hypodense mass (arrow) in the right hepatic lobe. (B) Axial contrast-enhanced CT image shows a heterogeneous enhancement (arrow) in the right hepatic lobe during the arterial phase. (C) Axial contrast-enhanced CT image shows a heterogeneous enhancement (arrow) in the right hepatic lobe during the portal venous phase.

Figure 2

Combined hepatocellular-cholangiocarcinoma. (A) In part, the tumor is yellowish-brown and soft (arrow), similar to hepatocellular carcinoma, and is also in part grayish-white and fibrotic (arrowhead), similar to cholangiocarcinoma. The background liver is cirrhotic. (B) The tumor shows both a hepatocytic differentiation area of trabecular pattern and a cholangiocytic differentiation area of tubular pattern (H&E stain, ×100). (C) The tumor cells show positivity for cytokeratin 19 (left) in cholangiocytic differentiation area and HepPar-1 (right) in hepatocellular differentiation area (immunohistochemical stain for cytokeratin 19 [left] and HepPar-1 [right], ×100).

Figure 3

Intermediate cell carcinoma. (A) The tumor is subcapsular, well-demarcated, homogeneously grayish-white, and fibrotic. (B) The tumor cells show intermediate morphology between hepatocytes and cholangiocytes. They have monomorphic, round nuclei and a small amount of eosinophilic cytoplasm and are arranged in trabecular or cord-like pattern in fibrous stroma (H&E stain, ×100). (C) The tumor cells show simultaneous expression for the cholangiocytic marker cytokeratin 19 (left) and the hepatocytic marker HepPar-1 (right) (immunohistochemical stain for cytokeratin 19 [left] and HepPar-1 [right], ×100).

Figure 4

Cholangiolocarcinoma. (A) The tumor is light yellowish-white and infiltrative. (B) The tumor shows small cuboidal cells resembling the canal of Hering or bile ductule, with anastomosing pattern (antler-like pattern) in fibrous stroma (H&E stain, ×100). (C) The tumor cells are positive for cytokeratin 19 (immunohistochemical stain for cytokeratin 19, ×100).

Figure 5

Hepatocellular carcinoma with cytokeratin 19 expression. (A) The tumor is well-demarcated, lobulated, and grayish-white, with focal hemorrhage and necrosis. (B) The tumor shows typical hepatocellular carcinoma features with polygonal cells arranged in a thickened trabecular pattern (H&E stain, ×100). (C) The tumor cells are diffusely positive for cytokeratin 19 (immunohistochemical stain for cytokeratin 19, ×100).

Figure 6

Hepatocellular carcinoma with stem/progenitor cell features/phenotypes. (A) The tumor is encapsulated, light green, and soft, with central grayish-white, fibrotic areas. (B) The tumor shows solid nests composed of hepatocellular tumor cells. Stem/progenitor cells (arrows) with dark nuclei and scanty cytoplasm are present in the periphery of hepatocellular carcinoma trabeculae. The fibrous stroma surrounds the tumor cell nests (H&E stain, ×100). (C) The stem/progenitor cells are positive for the stem/progenitor cell marker cytokeratin 19 (immunohistochemical stain for cytokeratin 19, ×200).

Figure 7

Pathological diagnostic algorithm of primary liver cancers according to tumor cell morphology, immunohistochemistry (IHC), and combined forms. HCC, hepatocellular carcinoma; CCA, cholangiocarcinoma; cHCC-CCA, combined hepatocellular-cholangiocarcinoma; ICC, intermediate cell carcinoma; CLC, cholangiolocarcinoma.