Presence of EpCAM-positive circulating tumor cells as biomarker for systemic disease strongly correlates to survival in patients with hepatocellular carcinoma Kornelius Schulze 1 , Christin Gasch 2 , Katharina Staufer 3 , Bj€ orn Nashan 4 , Ansgar W. Lohse 1 , Klaus Pantel 2 , Sabine Riethdorf 2 * and Henning Wege 1 * 1 I. Department of Medicine, Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2 Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 3 Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria 4 Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Current imaging technologies do not sufficiently detect micrometastasis and therefore do not allow adequate stratification of patients with hepatocellular carcinoma (HCC) for curative or systemic therapy. In HCC, presence of stem cell-like, epithelial cell adhesion molecule (EpCAM)-positive cells correlates with tumor aggressiveness and formation of metastasis. Therefore, we investigated the prognostic relevance of EpCAM-positive circulating tumor cells (CTCs) in patients with HCC. Blood from 78 patients (19 patients in the control cohort and 59 patients with HCC) was tested for CTCs with the CellSearch TM system. Correlation analysis to overall survival (OS), the Barcelona Clinic Liver Cancer (BCLC) staging system, macroscopic and microscopic vascular invasion and alpha-fetoprotein (AFP) levels were performed. We detected 1 CTC in 18=59 HCC patients and in 1=19 patients with cirrhosis or benign hepatic tumor (p 5 0.026). OS was significantly shorter (460 vs. 746 days) in the CTC-positive cohort (p 5 0.017). Comparing BCLC stages, significant differences in CTC detection rates were also observed: BCLC stages A 1=9, B 6=31 and C 11=19 (p 5 0.006). Ten of 18 patients with macroscopic and 10=16 patients with microscopic vascular invasion exhibited positive findings in CTC testing (p 5 0.004 and p 5 0.006). Furthermore, CTC results correlated to AFP (cutoff > 400 ng=mL) levels (p 5 0.050). Our study demonstrates frequent presence of EpCAM-positive CTC in patients with intermediate or advanced HCC and its prognostic value for OS with possible implications for future treatment stratification. Hepatocellular carcinoma (HCC), the fifth most common can- cer worldwide, has a rising incidence in Western countries, and is ranked third in global cancer-related mortality. 1–7 Most cases result from cirrhosis of the liver or chronic viral hepati- tis. It is believed that alcoholic liver disease and nonalcoholic steatohepatitis (NASH) will play a dominant role as underlying etiology in Western countries in the near future. 4 Treatment of patients with confirmed HCC is based on the Barcelona Clinic Liver Cancer (BCLC) staging system. Patients with early-stage HCC (BCLC stage A) are selected for curative resection, local ablative therapy or orthotopic liver transplantation. Unfortunately, most patients in Western countries are diagnosed in an advanced stage (BCLC stage C), characterized by vascular invasion, metastases and an impaired performance status (PS 1-2). 8,9 The key problem in curative treatment in HCC (BCLC stage A) is recurrence after curative therapy. This might be owing to undetectable micrometastasis at initial staging. Therefore, it would be pivotal to rule out a possible meta- static dissemination at the time of diagnosis, including micro- metastasis or potential “metastasis-initiating” circulating tumor cells (CTCs) in order to evaluate the true benefit of curative treatment. Furthermore, it is important to determine to what extent BCLC stage B patients (HCC limited to the liver) without CTC might benefit from curative therapy, despite a tumor burden beyond the Milan criteria (one lesion up to 5 cm or three lesions up to 3 cm), the currently estab- lished surrogate parameter for high recurrence risk after transplantation. In summary, there is an unmet need for a diagnostic tool to detect early metastatic spread, and there- fore to facilitate adequate selection of patients for curative Key words: cancer stem cells, CellSearch TM system, circulating tumor cells, epithelial cell adhesion molecule, hepatocellular carcinoma *S.R. and H.W. contributed equally to this work Conflicts of interest: Nothing to report Grant sponsor: Deutsche Forschungsgemeinschaft (DFG); Grant number: SFB 841, Project C5; Grant sponsor: European Community’s 7th Framework Programme (FP7=2007-2013, GENINCA); Grant number: 202230 DOI: 10.1002/ijc.28230 History: Received 11 Jan 2013; Accepted 9 Apr 2013; Online 24 Apr 2013 Correspondence to: Dr. Kornelius Schulze, MD, I. Department of Medicine, Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany, Tel.: 149-40-7410-52495, Fax: 149-40-7410-59092, E-mail: kschulze@uke.de Early Detection and Diagnosis Int. J. Cancer: 133, 2165–2171 (2013) V C 2013 UICC International Journal of Cancer IJC