Letter to the editor: HCC EV ECG score: An extracellular vesicle–based protein assay for detection of early‐stage HCC

To the editor, We read the study by Sun et al., in which the HCC extracellular vesicles (EV) electrocardiogram (ECG) score demonstrated great potential for detecting early‐stage HCC.1 However, we have some concerns about this conclusion. First, in this study, we have noticed that the HCC EV ECG score is based on the comparison of patients with early‐stage HCC and liver cirrhosis, with an impressive performance of sensitivity and specificity. However, the benefit of the HCC EV ECG score would be limited, because only patients with early‐stage HCC and liver cirrhosis were included. We suggested a more appropriate comparison of early‐stage HCC and samples from a healthy population. Moreover, the cancer types and sample of the control group are too few. A recent study showed that there is a close relationship between CD147+EVs and other cancer types such as colorectal cancer and renal cell carcinoma.2,3 However, no patients with colorectal or renal cancer were included in this study, which is susceptible to selection bias. Second, in figure S14 of this study, HCC EV ECG scores from both patients with early‐stage HCC and advanced‐stage HCC were significantly higher than patients with other cancers, which deteriorates the specificity of HCC EV ECG for detecting the early stage of HCC. Third, this study aimed to discover biomarkers for early detection of HCC. However, this study used the ECG score, including three HCC EV surface protein signatures to distinguish early‐stage HCC from cirrhosis, which increases the sensitivity compared with one EV surface protein signature. Moreover, a previous study has also identified some EV markers like mothers against decapentaplegic homolog 3 (SMAD3) for early detection of HCC,4 but no statement about the SMAD3 was shown. Finally, a recent study demonstrated the significant role of cost‐effectiveness in early detection for HCC.5 In this study, detecting three HCC EVs to distinguish early‐stage HCC from cirrhosis enhances the unnecessary cost of patients for detection. In conclusion, whether the HCC EV ECG score is necessary to augment current surveillance methods and improve patients' outcomes remains controversial.