Comprehensive clinicopathologic study of alpha fetoprotein‐expression in a large cohort of patients with hepatocellular carcinoma

Alpha fetoprotein (AFP) is the most widely used diagnostic and prognostic serum biomarker for hepatocellular carcinoma (HCC). Despite its wide clinical use, a systematic clinicopathologic study comparing AFP expression in HCC in situ with serum AFP concentrations has not yet been conducted. To analyze AFP expression in a large cohort of patients by immunohistochemistry, we employed a comprehensive tissue microarray with 871 different HCCs of overall 561 patients. AFP immunoreactivity was detected in only about 20% of HCC core biopsies, whereas 48.9% of the patients displayed increased serum values (>12 ng/mL). Immunostaining of whole tumor slides revealed that lack of detectable immunoreactivity in core biopsies in a subgroup of patients with elevated AFP serum concentrations is due to heterogeneous intratumoral AFP expression. Serum AFP concentrations and AFP expression in situ were moderately correlated (Spearman's rank correlation coefficient .53, P = 1.2e − 13). High AFP expression detected in serum (>227.3 ng/mL) or in situ predicted unfavorable prognosis and was associated with vascular invasion, higher tumor grade and macrotrabecular‐massive tumor subtype. Multivariate and ROC curve analysis demonstrated that high AFP concentrations in serum is an independent prognostic parameter and represents the more robust prognostic predictor in comparison to AFP immunostaining of core biopsies. The previously published vessels encapsulating tumor clusters (VETC) pattern turned out as an additional, statistically independent prognostic parameter. AFP‐positivity was associated with increased tumor cell apoptosis, but not with increased vascular densities. Additionally, AFP‐positive tumors displayed increased proliferation rates, urea cycle dysregulation and signs of genomic instability, which may constitute the basis for their increased aggressiveness. What's new? While multiple biomarkers have shown promise in hepatocellular carcinoma (HCC) diagnosis and surveillance, alpha fetoprotein (AFP) remains the most clinically important and most widely used, despite poor sensitivity and specificity. Here, to better understand the clinicopathological relevance of AFP in HCC, comprehensive immunohistochemical analyses on AFP expression were performed, revealing moderate correlations between serum AFP concentrations and AFP expression in situ. AFP immunoreactivity was not detected in many patients with elevated serum AFP concentrations, due primarily to intratumoral heter