Endothelium-Coated Tumor Clusters Are Associated With Poor Prognosis and Micrometastasis of Hepatocellular Carcinoma After Resection

BACKGROUND: Distinct morphologic features of microvascular endothelium exist in tumor tissues. The objective of this study was to investigate the prognostic value of endothelium-coated tumor clusters (ECTCs) in hepatocellular carcinoma (HCC). METHODS: ECTCs were evaluated by immunohistochemical staining for cluster of differentiation 34 (CD34) (a cell surface glycoprotein which is expressed specifically on tumor microvascular endothelium in HCC) in 239 specimens from patients with primary HCC. Overall survival (OS) and time to recurrence (TTR) were determined using Kaplan-Meier analysis and a Cox proportional hazards regression model. Levels of terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, and Ki-67 expression, and E-cadherin expression were assessed to determine tumor apoptosis, proliferation, and invasiveness, respectively. RESULTS: The presence of ECTCs was associated with a poor prognosis in all patients and in patient subgroups stratified by tumor size, TNM classification, and Barcelona Clinic Liver Cancer stage and tumor invasiveness. In a multivariate Cox proportional hazards analysis, the presence of ECTCs emerged as an independent prognostic indicator of both poor OS (P = .001; hazard ratio, 1.949) and shorter TTR (P < .001; hazard ratio, 2.085). Furthermore, the presence of ECTCs was associated with micrometastatic endothelium-coated emboli (P < .001; chi-square test) and early relapse after resection (P < .001; chi-square test). In addition, patients who had endothelium-coated emboli, in which tumor cells displayed high proliferation and low apoptosis, had poor OS and shorter TTR. CONCLUSIONS: The current results suggested that the presence of ECTCs was an efficient, simple, and convenient predictor of a poor prognosis in patients with HCC that potentially may serve as a novel target for the prevention and treatment of HCC metastasis. Cancer 2011; 117: 4878-89. (C) 2011 American Cancer Society.