Combination of Osteopontin with Peritumoral Infiltrating Macrophages is Associated with Poor Prognosis of Early-Stage Hepatocellular Carcinoma after Curative Resection

Background. Crosstalk between a tumor and the microenvironment plays a key role in tumor progression and metastasis. This study was performed to elucidate the prognostic significance of combining tumor-secreted osteopontin (OPN) with microenvironment-associated peritumoral macrophages (PTMs) in hepatocellular carcinoma (HCC), especially for those with early-stage disease. Methods. Tissue microarray-based immunohistochemistry was used to investigate OPN and PTMs expression in two independent cohorts consisting of 374 patients with HCC who underwent radical resection. The prognostic value for the two factors alone or in combination was investigated in these patients. Results. OPN combined with PTMs was an independent prognostic factor for both overall survival (OS; p < 0.0001) and time to recurrence (TTR; p = 0.003) from the learning cohort (n = 96). Their combined value for prognosis was validated in early-stage HCCs using another independent cohort (n = 278; OS, p < 0.001; TTR, p = 0.001). This combination remained significant in HCCs with low alpha-feto-protein levels in both cohorts, and was predictive for early recurrence/death risk (<2 years) compared with a single marker. Only OPN+HCCs had a significant correlation of PTMs levels with OS (p = 0.01) or TTR (p = 0.011). Conclusions. Tumor OPN combined with PTMs is a promising predictor of tumor recurrence and survival in patients with HCC, especially for those with early-stage disease. The interplay of OPN and PTMs represents a new insight into tumor progression and therapeutic targets for HCC.