Expression of Bile Duct Transcription Factor HNF1β Predicts Early Tumor Recurrence and Is a Stage-Independent Prognostic Factor in Hepatocellular Carcinoma

Abstract

Background: Hepatocellular carcinoma (HCC) frequently exhibits biliary differentiation, which is typically overlooked. Hepatocyte nuclear factor 1β (HNF1β), a bile duct-specific transcription factor expressed in bile ducts but not in the normal hepatocytes, is also expressed in HCC. Materials and Methods: The expression of HNF1β and the biliary differentiation marker cytokeratin 19 (CK19) were retrospectively evaluated using immunohistochemistry in 159 surgically resected primary HCCs. Results: A significant correlation was observed between HNF1β protein expression and younger age (p = 0.0293), high serum α-fetoprotein levels (p = 6 × 10−4), and high tumor grade (p = 0.0255). However, HNF1β expression exhibited no correlation with tumor stage. Patients with HCCs and HNF1β expression were more likely to exhibit early tumor recurrence (ETR; p = 0.0048) and a lower 5-year survival rate (p = 0.0001). A multivariate analysis indicated HNF1β expression as an independent prognostic factor in HCC (p = 0.0048). A combinatorial analysis revealed additive adverse effects of HNF1β when concomitant with CK19 expression and p53 mutation. Furthermore, HNF1β expression can predict poor prognosis in patients with ETR. Conclusion: Our results indicated that HNF1β expression is a crucial predictor of poor prognosis in HCC and is independent of tumor stage. Moreover, concomitant HNF1β and CK19 expressions exhibited additive adverse effects in HCC, confirming that HCC with biliary differentiation has a poor prognosis.