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.

and Functional Significance in the NewClassification of Primary Liver Cancers

“…Some other cases had tubules and cords in an "antlerlike" pattern. Immunohistochemically, most transition areas express CK7 and CK19 in addition to progenitor cell markers EpCAM and c-kit [19]. Theise et al also demonstrated that HPCs histologically and immunohistochemically merge with the HCC and CC components in cases of CHCC-CC [20].…”

cHCC‐CCA

“…At the current time, there are no published consensus guidelines for minimum amounts of HCC or iCCA to qualify for the diagnosis, either in biopsy material or in resected/explant samples. Examples have been illustrated . In regions in which the tumors seem to merge, the cellular morphology may be difficult to identify as either hepatocellular or cholangiocytic by pure H&E evaluation alone.…”

“…Examples have been illustrated. (7)(8)(9)(18)(19)(20)(21)(22) In regions in which the tumors seem to merge, the cellular morphology may be difficult to identify as either hepatocellular or cholangiocytic by pure H&E evaluation alone. Tumor cells of either hepatocytic or cholangiocytic morphologic type may contain intracytoplasmic inclusions common to hepatocytes such as Mallory-Denk bodies, steatosis, a1AT globules (even in an a1AT genotypically normal individual), fibrinogen, etc.…”

The CD79α (HM47/A9) antibody is effective in distinguishing between primary hepatocellular carcinoma and primary intrahepatic cholangiocarcinoma

“…However, other studies have reported similarities between cHCC-CC and HCC in terms of male/female ratio, status of hepatitis viral infection and serum AFP level (9,14). These two inconsistent findings may be attributed to different etiological roles according to the geographic situation or the existence of other carcinogenesis mechanisms (15,16). The case in this study displayed normal serum AFP level and no background chronic liver disease, with significant tumor thrombus.…”