Bile duct involvement by hepatocellular carcinoma: A rare occurrence and poor prognostic indicator in bile duct brushing samples

Abstract

Background: Hepatocellular carcinoma (HCC) rarely involves the biliary tree and may be inadvertently sampled on bile duct brushings (BDBs).

Methods: The pathology archives of 5 institutions were searched for BDBs with HCC involvement.

Results: A total of 17 BDBs from 14 patients were obtained. There was a male:female ratio of 6:1; the median age of the patients was 59.5 years (range, 22-80 years). The median hepatic tumor size was 6.2 cm (range, 2.2-13.0 cm). HCC risk factors included viral hepatitis (5 patients), cirrhosis (5 patients), hemochromatosis (1 patient), and alcoholic steatohepatitis (1 patient). Jaundice with elevated bilirubin, liver enzymes, and α-fetoprotein was common. Endoscopic retrograde cholangiopancreatography demonstrated bile duct dilatation, polypoid intraductal masses (5 samples), clots/debris (2 samples), or strictures (4 samples). All BDBs had single and clustered large cells with naked atypical nuclei, granular cytoplasm, high nuclear/cytoplasmic ratios, and nuclei with prominent macronucleoli. Less common findings included clear/microvesicular cytoplasm (35%), papillae (29%), and anisonucleosis (35%). Classic HCC features (widened trabeculae [35%], endothelial wrapping [24%], multinucleation [24%], and cytoplasmic bile pigment [35%]) were uncommon. A total of 11 BDBs were diagnosed as malignant (10 with HCC and 1 with cholangiocarcinoma), 2 were diagnosed as atypical, and 1 BDB was diagnosed as negative; approximately two-thirds were found to have polysomy on fluorescence in situ hybridization. Approximately 71% of patients died of disease at a median of 3.5 months.

Conclusions: HCC may extend into the intrahepatic and/or extrahepatic biliary tree, causing masses and/or strictures that may be sampled on BDB. Although cytologically malignant, the classic features of HCC are uncommon, which can cause misdiagnosis. Cytopathologists should be mindful of this differential when evaluating BDBs, particularly when concomitant liver masses and/or HCC risk factors are present. Because of the associated high mortality and rapid rate of death, its presence should be conveyed clearly in pathology reports.

Keywords: bile duct; brushing; carcinoma; hepatocellular.

Figure 1.

ThinPrep slides. (A) A mixed (2-cell) population of benign ductal cells in honeycomb sheets (Top Center) and single and clustered malignant cells (Center) with abundant granular cytoplasm, round nuclei, and cherry red macronucleoli (Papanicolaou stain, original magnification ×200). (B) Tumor cells demonstrating a high nuclear/cytoplasmic ratio, granular to clear cytoplasm, and round hypochromatic and hyperchromatic nuclei with cherry red macronucleoli (Papanicolaou stain, original magnification ×600). (C) Large hyperchromatic tumor cells with (Left) dense polygonal cytoplasm and (Right) naked nuclei (Papanicolaou stain, original magnification ×600). (D) Three-dimensional cluster with hypochromasia and markedly irregular nuclear membranes. This case was misdiagnosed as adenocarcinoma (Papanicolaou stain, original magnification ×400).

Figure 2.

ThinPrep slides showing (A) a well-differentiated hepatocellular carcinoma with monotonous tumor cells with a low nuclear/cytoplasmic ratio and clear cytoplasm (Papanicolaou stain, original magnification ×400). Examples of poorly differentiated hepatocellular carcinoma showing (B) marked (>5-fold) anisonucleosis, (C) multinucleated tumor giant cells, and (D) cytoplasmic bile pigment (Papanicolaou stain, original magnification ×600).

Figure 3.

Hepatocellular carcinoma with tumor cells arranged in widened trabeculae >2 cells in thickness is shown in panels A (H & E, original magnification ×40) and B (Papanicolaou stain, original magnification ×400). (C) Widened trabeculae were focally lined by flattened endothelial cells (arrow) (Papanicolaou stain, original magnification ×400). (D) A cell block demonstrating well-differentiated hepatocellular carcinoma (H & E, original magnification ×200).

Figure 4.

(A and B) Cell blocks demonstrating papillary units with central hyalinized cores lined with multilayered, large, eosinophilic to clear cells with relative monotony (H & E, original magnification ×200-×400). (C) Reticulin stain highlighting widened trabeculae (original magnification ×200). Tumor cells were (D) positive for arginase and negative for cytokeratin 7 whereas (E) the benign ductal cells (Upper Right) were positive (original magnification ×200). (F) Hepatectomy specimen showing tumor growing as a circumscribed, nodular, intraductal mass that compressed the duct wall. Note the presence of dark blue drug-eluting bead transarterial chemoembolization (DEB TACE) spherules on the lower right (H & E stain, original magnification ×40).