Membranous Overexpression of Fibronectin Predicts Microvascular Invasion and Poor Survival Outcomes in Patients with Hepatocellular Carcinoma

Fibronectin (FN) has recently been identified as being overexpressed in patients with hepatocellular carcinoma (HCC) and deemed a promising biomarker of vascular invasion. The aim of this study was to examine the patterns of FN expression in HCC cells and their clinicopathological significance, such as their association with vascular invasion and angiogenesis patterns.

Immunohistochemical analysis of FN was conducted using tissue microarrays from 258 surgically resected HCCs and matched nontumorous liver tissues. Three distinct FN expression patterns were observed: cytoplasmic, membranous, and sinusoidal. Moderate or strong expression was considered FN-positive.

Cytoplasmic or sinusoidal FN expression was significantly more common in HCC cells than in the adjacent liver tissue (p<0.001). FN expression was detected in the membranes of HCC cells and absent in nonneoplastic hepatocytes (p<0.001). Overall survival and disease-free survival in patients with HCC cells with membranous FN expression were significantly shorter than those in patients without membranous FN expression. Membranous FN expression in HCC was significantly associated with high serum alpha-fetoprotein (AFP) and protein induced by vitamin K absence-II (PIVKA-II) levels, infiltrative gross type, poor Edmondson-Steiner grade, major vessel invasion, microvascular invasion, macrotrabecular massive subtype, advanced T stage, and vessel-encapsulating tumor cluster pattern. Sinusoidal pattern of FN expression in HCC was significantly associated with high serum AFP and PIVKA-II levels, infiltrative gross type, large tumor size, microvascular invasion, macrotrabecular massive subtype, and vessel-encapsulating tumor cluster patterns.

Evaluating FN expression in HCC cells may be useful for identifying aggressive cases of HCC with vascular invasion via biopsy.