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The objective of this study was to analyze the specificity of detecting liver tumor cell dissemination by alpha-fetoprotein (AFP) mRNA in peripheral blood.Alpha-fetoprotein mRNA has been used for the detection of circulating micrometastatic tumor foci of hepatocellular carcinoma (HCC); however, the interpretation of the results has been equivocal.Sixty-four consecutive patients with malignant HCC (n = 20), liver metastases (n = 27), or nonmalignant (n = 17) liver diseases undergoing partial or total hepatectomy and orthotopic liver transplantation were included in this prospective study from January to July 1995. Peripheral blood samples were obtained before surgery, during surgery, and after surgery (range, 6-15 months). Total mRNA was extracted from nucleated cells, and cDNA synthesis and polymerase chain reaction amplification (nested polymerase chain reaction in one tube) were performed with specific AFP primers.Preoperative AFP mRNA was detected in 20 patients (17%), of which 5 of 20 had HCC. Intraoperative assessment showed positive AFP mRNA values in a total of 34 patients (53%) with various causes, of which 8 of 20 (40%) had HCC, 17 of 27 (63%) had other malignancies, and 9 of 17 (53%) had nonmalignant diseases. Recurrent tumor in patients with HCC occurred in four cases after surgery (range, 6-15 months) and did not correlate with AFP mRNA positivity before surgery, during surgery, or after surgery.Alpha-fetoprotein mRNA in peripheral blood is not a specific marker of circulating micrometastases from HCC, especially in the context of surgical treatment of HCC.