Hepatocellular carcinoma: a review of diagnostic challenges for the pathologist

Abstract

Histopathologists retain a critical role in the diagnosis and management of hepatocellular carcinoma (HCC). HCC arises usually but not exclusively in a background of advanced-stage chronic liver disease. The histological diagnosis of HCC poses many challenges particularly when dealing with liver biopsy specimens due to the heterogeneity of HCC and the difficulty to confirm hepatocellular differentiation in some instances. Primary liver tumors should be considered as a continuum with typical hepatocellular and cholangiocarcinoma at the two ends and a whole range of tumors showing both hepatocellular and cholangiocellular differentiation with or without an associated progenitor/stem cell component in the middle. Characterization of combined (or mixed) hepatocellular-cholangiocarcinoma can be very challenging. In advanced-stage chronic liver disease, the main challenge for the histopathologist is still to differentiate between HCC and its precursors, although this is rarely critical in the clinical setting at present. HCC originating in non-cirrhotic livers needs to be differentiated from other primary and extrahepatic tumors and from hepatocellular adenoma, bearing in mind that progression to malignancy is more through a continuum that watertight histological categories.

Keywords: combined hepatocholangiocarcinoma; dysplastic nodule; hepatocellular adenoma; hepatocellular carcinoma; large regenerative nodule; mixed hepatocholangiocarcinoma.

Figure 1

Eighty-year-old woman with a large intrahepatic tumor in the right lobe suspect for hepatocellular carcinoma. Notes: Histological examination of the resected specimen shows (A; H&E) that the tumor is composed of solid sheets or trabeculae of medium to large size cohesive cells with abundant eosinophilic cytoplasm resembling hepatocytes (hepatoid). Immunohistochemistry shows that the tumor cells do not form canaliculi (B; CEA, polyclonal antibody) and do not stain for Hep-Par 1 (C; background liver on the left and tumor on the right side of the figure) but stain for vimentin (D; same field as C) melan-A, inhibin, synaptophysin and calretinin. The final diagnosis was of liver infiltration by adrenal cortical carcinoma.

Figure 2

c-HCC-CCA, classic type with the hepatocellular component on the left side and the cholangiocellular component on the right side (H&E). Abbreviation: c-HCC-CCA, combined (or mixed) hepatocellular-cholangiocarcinoma.

Figure 3

Inflammatory hepatocellular adenoma with focal signs of concomitant beta-catenin activation. Notes: (A) H&E section showed an area of increased cell density (asterisks) in comparison to a nearby one in which hepatocytes are more of normal size (arrows). (B) Beta-catenin immunostain from the same area shows nuclear staining in places (arrows). (C) Glutamine synthetase is diffusely expressed in this area. (D) Serum amyloid A is expressed by nearby hepatocytes (arrows). Courtesy Dr Andrew Drake, Christchurch, New Zealand.