循环生物标记物在甲胎蛋白阴性肝细胞癌早期诊断中的研究进展

Advances in circulating biomarkers for early diagnosis of alpha-fetoprotein-negative hepatocellular carcinoma

摘要:

肝细胞癌（HCC）是最常见的肝癌类型，也是全球癌症相关死亡的主要原因之一。虽然早期诊断可以显著改善预后，但甲胎蛋白阴性肝细胞癌（ANHCC）因缺乏可靠的生物标记物而面临诊断难题。本综述系统探讨了多种循环生物标记物在ANHCC早期诊断中的潜力，包括AFP-L3、维生素K缺乏或拮抗剂Ⅱ诱导蛋白（PIVKA-Ⅱ）、淋巴细胞与单核细胞比值、外泌体、循环游离核糖核苷酸（cfDNA）、循环肿瘤细胞、骨桥蛋白、对氧磷酶1、自身抗体及RNA相关标记物。研究表明，这些标记物的联合应用，特别是AFP-L3与PIVKA-Ⅱ的结合，显著提高了诊断的准确率和特异度。此外，外泌体、cfDNA及RNA标记物凭借其无创性和高稳定性，在诊断中表现出较大潜力。尽管已有诸多进展，仍需开展大规模、多中心研究以验证相关发现，解决检测方法标准化等挑战，并进一步阐明潜在机制。这些研究进展有望为ANHCC的早期发现和个性化治疗提供重要支持。

Abstract:

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and a leading cause of cancer-related deaths worldwide. While early detection significantly improves prognosis, patients with alpha-fetoprotein-negative hepatocellular carcinoma (ANHCC) often face diagnostic challenges due to the lack of reliable biomarkers. This review systematically explores the potential of various circulating biomarkers in the early diagnosis of ANHCC, including AFP-L3, PIVKA-Ⅱ, lymphocyte-to-monocyte ratio, exosomes, circulating cell-free DNA (cfDNA), circulating tumor cells, osteopontin, paraoxonase 1, autoantibodies, and RNA-related biomarkers. The combined use of these markers, particularly AFP-L3 and PIVKA-Ⅱ, demonstrates enhanced diagnostic accuracy and specificity compared to single markers. Emerging evidence also highlights the diagnostic potential of exosomes, cfDNA, and RNA markers due to their non-invasive nature and high stability. Despite promising results, further large-scale, multicenter studies are needed to validate these findings, address challenges such as standardization of detection methods, and elucidate underlying mechanisms. These advances are anticipated to significantly improve early detection and personalized management of ANHCC.