Abstract
Patients with chronic liver disease (CLD) and cirrhosis are at high risk for hepatocellular carcinoma (HCC). Current diagnostic tools for HCC detection include imaging techniques and serum biomarkers such as α-fetoprotein (AFP). Yet, these methods are limited in sensitivity and specificity to accurately detect early HCC. Here we focused on the potential of soluble Axl (sAxl) as a biomarker in CLD patients by analyzing serum samples of 1067 patients and healthy controls from centers in Europe and Asia. We show that serum concentrations of sAxl were significantly increased at early (82.57 ng/mL) and later stages of HCC (114.50 ng/mL) as compared to healthy controls (40.15 ng/mL). Notably, no elevated sAxl levels were detected in patients with CLD including chronic viral hepatitis, autoimmune hepatitis, cholestatic liver disease, or non-alcoholic fatty liver disease versus healthy controls. Furthermore, sAxl did not rise in liver adenomas or cholangiocarcinoma (CCA). Yet, patients with advanced fibrosis (F3) or cirrhosis (F4) showed enhanced sAxl concentrations (F3: 54.67 ng/mL; F4: 94.74 ng/mL). Hepatic myofibroblasts exhibited an increased release of sAxl, suggesting that elevated sAxl levels arise from these cells during fibrosis. Receiver operating characteristic curve analysis of sAxl displayed a strongly increased sensitivity and specificity to detect both cirrhosis (80.8%/92.0%) and HCC (83.3%/86.7%) with an area under the curve of 0.935/0.903 as compared to AFP. In conclusion, sAxl shows high diagnostic accuracy at early stage HCC as well as cirrhosis, thereby outperforming AFP. Importantly, sAxl remains normal in most common CLDs, liver adenomas and CCA.
Highlights
Hepatocellular carcinoma (HCC) is the most common liver malignancy accounting for about 5% of all cancer cases worldwide and represents the third most common cause of cancer related mortality [1, 2]
hepatocellular carcinoma (HCC) patients were grouped according to liver disease etiology, fibrosis grades, presence or absence of cirrhosis, and Barcelona Clinic Liver Cancer (BCLC) stage (Tables 1 and 2)
The present study evaluated the diagnostic performance of soluble Axl (sAxl) for the detection of early HCC and patients at high risk of HCC in a large multicentric cohort of 1067 patients
Summary
Hepatocellular carcinoma (HCC) is the most common liver malignancy accounting for about 5% of all cancer cases worldwide and represents the third most common cause of cancer related mortality [1, 2]. The majority of HCC cases is diagnosed at advanced stages, causing a median survival between less than one and up to four years, depending on the country [3]. Patients diagnosed at an early stage of tumor development show a favorable five-year survival rate of 70% subsequent to curative treatment strategies such as resection or liver transplantation [4,5,6]. An important limitation of this standard method is its poor sensitivity of 63% for detection of early stage HCC and its strong dependence on operator experience [8]. In addition to US, the still most widely used biomarker is α-fetoprotein (AFP), providing a sensitivity between 25% and 65% [8, 9]
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