Hepatocellular Carcinoma Expressing Cholangiocyte Phenotype Is a Novel Subtype with Highly Aggressive Behavior

The pathobiological features and surgical outcomes of patients with classical hepatocellular carcinoma (HCC)-expressing cholangiocyte markers that we named dual-phenotype HCC (DPHCC) remain unclear. The purpose of this study was to assess the association between the phenotype and surgicopathologic features of DPHCC. A retrospective single-center study was performed on the surgicopathologic features of DPHCC from 1530 consecutive surgical specimens. Immunohistochemical staining was performed with antibodies to hepatocytes (Hep Par 1/pCEA) and cholangiocytes (cytokeratin 19 [CK19]/mucin core protein-1 [MUC-1]). DPHCC accounted for 10.1% (n = 155) of total HCCs. The serum alfa-fetoprotein and CA19-9 were elevated in 87.7% (n = 136) and 20.7% (n = 32) of patients, respectively; the former had close correlation with the immunostaining of CK19 (P < 0.01). The combination of immunostaining intensities of CK19 and MUC-1 was significantly associated with tumor size, microvascular invasion, and satellite nodule formation (P < 0.05-0.01). Compared to patients with pure HCC, those with DPHCC had significantly lower overall survival (30.4 +/- A 3.7 vs. 43.6 +/- A 3.9 months, P < 0.05) and recurrence-free survival (13.2 +/- A 2.0 vs. 23.4 +/- A 2.5 months, P < 0.01), respectively. Multivariate Cox regression analyses identified CK19-positive expression to be an independent prognostic factor for both overall survival and recurrence-free survival. DPHCC is a novel surgicopathologic entity that has a highly aggressive behavior and worse postoperative prognosis than pure HCC. Because the morphological features between DPHCC and conventional HCC overlap, we recommend that CK19 be routinely used in the pathological diagnosis of HCC for screening DPHCC.