Use of Cytokeratin-19 Concentration to Assess Early Recurrence and Prognosis of Hepatitis B Virus-Related Hepatocellular Carcinoma following Radical Resection in Patients with a Low Serum Alpha-Fetoprotein Concentration.

Zu-Sen Wang,Xin Yi,Wei-Dong Guo,Chao Geng,Yu-Jun Li,Li-Qun Wu,Ru-Yong Yao,Joerg F Schlaak

doi:10.1371/journal.pone.0142727

Abstract

Cytokeratin 19 (CK-19) is a prognostic indicator of recurrence and metastasis of hepatocellular carcinoma (HCC) following radical resection. To investigate the role of CK-19 in assessment of early recurrence and prognosis in patients with hepatitis B virus (HBV)-related HCC following radical resection. In total, 235 patients with HBV-related HCC (age, 15–82 years; mean age, 54 ± 10 years) undergoing radical resection were screened for inclusion from January 2005 to December 2010. Malignant tissues and adjacent non-malignant tissues were sampled during surgery, and CK-19 and Ki-67 expression was determined by tissue microarray and immunohistochemistry. CK-19 mRNA levels in 30 randomly selected frozen HCC specimens were examined by reverse transcription polymerase chain reaction from January 2011 to June 2011. Correlations of CK-19 and Ki-67 expression with tumor recurrence, metastasis, disease-free survival (DFS), and overall survival (OS) were analyzed. Elevated CK-19 expression was correlated with early recurrence (P = 0.001), shorter DFS (P = 0.001), and reduced OS (P = 0.010). CK-19 expression was correlated with the Ki-67 index (P = 0.037), histological differentiation (P = 0.016), focal number (P = 0.044), and blood vessel tumor embolism (P = 0.002). Patients with metastasis within 1 year exhibited stronger CK-19 expression than did patients without metastasis (P < 0.05). Furthermore, early recurrence was associated with elevated CK-19 mRNA levels (χ2 = 5.761, P = 0.016).When confirmed by a low alpha-fetoprotein concentration (<400 μg/L), CK-19 expression in surgical biopsy specimens taken from patients with HCC during radical resection is an additional valuable indicator of early recurrence, distant metastasis, and poor prognosis in HBV-positive patients.

Highlights

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide, accounting for 5.7% of all cancers and occurring most commonly in male patients in developing countries [1]
The current study indicated that combined Cytokeratin 19 (CK-19) and Ki-67 assessment can be used to indicate the risk for poor prognosis, including recurrence and distant metastasis in the first year doi:10.1371/journal.pone.0142727.g002
Following radical resection for HCC in hepatitis B virus (HBV)-positive patients, in patients with an AFP concentration of

Summary

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide, accounting for 5.7% of all cancers and occurring most commonly in male patients in developing countries [1]. Cytokeratin 19 (CK-19) is an intermediate filament protein that is critical to epithelial cell structural integrity and used as a highly sensitive biomarker for tumor cell dissemination in the lymph nodes, bone marrow, and peripheral blood [6]. As such, it is a reliable indicator of tumor invasiveness. An alpha-fetoprotein (AFP) serum concentration of 400 μg/L is both a conventional diagnostic factor and prognostic indicator in patients with HCC [8,9]. Assessment of the CK-19 and AFP concentrations more accurately indicate the prognosis when combined with conventional prognostic indicators for HCC, such as the Ki-67 index [10]

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Conclusion