Clinicopathologic study on combined hepatocellular carcinoma and cholangiocarcinoma: with emphasis on the intermediate cell morphology

Abstract

Combined hepatocellular carcinoma and cholangiocarcinoma (combined HCC-CC) is a rare subtype of primary liver cancer. We investigated the histopathologic features of transitional or intermediate areas in 21 combined HCC-CCs and immunophenotypes using different hepatic progenitor cell markers (CK7, CK19, c-kit, NCAM, and EpCAM). Major histologic findings of transitional or intermediate areas of 21 combined HCC-CCs included strands/trabeculae of small, uniform, oval-shaped cells with scant cytoplasm and hyperchromatic nuclei embedded within an abundant stroma, small cells with an antler-like anastomosing pattern, and solid nests of intermediate hepatocyte-like cells surrounded by small cells in periphery, in order of frequency. The intermediate area of one tumor was composed predominantly of spindle cells arranged in short fascicles. Immunophenotype of tumor cells with intermediate morphology suggested a progenitor cell origin for this tumor. Clinical findings of combined HCC-CC showed a closer resemblance with those of HCC than those of CC. In univariate analysis, tumor size, TNM stage, and serum alpha-fetoprotein levels showed a significant association with poor patient survival. Serum alpha-fetoprotein level was an independent prognostic indicator in multivariate analysis. In conclusion, an awareness of the clinicopathologic features, specifically the various morphologic features of intermediate areas in this tumor, is essential for prevention of potential misdiagnosis as another tumor.

Keywords: Carcinoma; Cholangiocarcinoma; Hepatocellular.

Fig. 1

Histologic features of transitional or intermediate areas in combined HCC-CC. (A) Strands of small, uniform cells with scant cytoplasm and hyperchromatic nuclei within desmoplastic stroma (H&E, × 400). (B) Proliferating tumor cells with an antler-like anastomosing pattern (H&E, × 400). (C) Solid nests comprised of intermediate hepatocyte-like cells in the center with peripheral small cells (H&E, × 400). (D) Scattered foci of abrupt glandular formation composed of cuboidal tumor cells (H&E, × 400). (E) The transitional area of the tumor is composed predominantly of spindle cells arranged in short fascicles (arrows) (H&E, × 100). (F) Transition of small, oval cells to spindle cells, suggesting the same cellular origin of mesenchymal like spindle cells (arrows) (H&E, × 400). (G) Spindle cells with a streaming pattern in case 13 (H&E, × 400). (H) A massive neutrophilic infiltration around the nest of tumor cells (H&E, × 400). (I) Sarcomatous change of tumor cells (H&E, × 200).

Fig. 2

Immunohistochemical features of transitional or intermediate areas in combined HCC-CC. (A) Strong expression of CK19 in tumor cells consisting of strands or trabeculae (× 400). (B) Peripheral small cells were positive for CK19, whereas central intermediate hepatocyte-like cells were negative for CK19 (× 400). (C) Cholangiolocarcinoma-like areas with CK7 immunoreactivity (× 200). (D) Intermediate type carcinoma cells showed strong immunoreactivity for CK7 (× 200). (E) Strong membranous staining of EpCAM (× 400). (F) Spindle carcinoma cells showed accentuated membrane staining for EpCAM (arrows) (× 400). (G) C-kit positive tumor cells with an antler-like anastomosing pattern (× 400). (H) Positive immunoreactivity for NCAM in reactive ductular cells served as internal positive controls. Most tumor cells reveal negative immunoreactivity for NCAM (× 200). (I) NCAM positive tumor cells in a cholangiolocellular pattern (× 400).