Folate receptor-positive circulating tumor cells might function as potential biomarkers for hepatocellular carcinoma.

BACKGROUND: Early metastasis and recurrence are risk factors that negatively affect the prognosis of advanced hepatocellular carcinoma (HCC). Alpha fetoprotein (AFP) is currently the most prevalent serum biomarker for detecting HCC and predicting tumor recurrence. However, its sensitivity and specificity are not sufficient, especially in patients who are AFP negative. AIM: To detect folate receptor (FR)-positive circulating tumor cells (CTCs) and explore their role in the diagnosis and staging of HCC. METHODS: This work is a retrospective study that included 128 consecutive patients with benign or malignant disease of the liver from 2020 to 2021. FR + CTCs were collected from 3 mL of peripheral blood via immunomagnetic depletion of leukocytes. After ligand-target polymerase chain reaction, the number of FR + CTCs was measured. Receiver operating characteristic curves were used to determine the threshold of sensitivity and specificity of FR + CTCs. The Youden index was used to identify the optimal cutoff point and diagnostic efficiency of FR + CTCs counts. Univariate and multivariate Cox proportional hazards regression analyses were performed to evaluate the associations of biomarkers or clinical parameters with disease-free survival (DFS). RESULTS: The FR + CTCs counts showed excellent diagnostic efficacy in patients with HCC, with high sensitivity (0.905) and specificity (0.773) compared with patients with benign disease. Compared with that of the AFP level, the area under the receiver operating characteristic curve of the FR + CTC count is significantly greater (0.900 compared with 0.730, P < 0.05). FR + CTC levels were significantly correlated with macrovascular invasion, tumor size, tumor number, and extrahepatic tumor stage in HCC patients. FR + CTC counts were correlated with DFS in HCC patients after R0 resection. Univariate analysis of DFS revealed that the FR + CTC count, tumor number, Barcelona Clinic Liver Cancer stage and extrahepatic metastasis status were correlated with DFS. Multivariate analysis of DFS revealed that the FR + CTC count and tumor number were correlated with DFS. CONCLUSION: Ligand-target polymerase chain reaction is a sensitive tool for quantifying the number of FR + CTCs in HCC patients. These findings could provide new insight for stratifying HCC patients and predicting the recurrence of HCC.