Morphometric analysis of liver macrophages in patients with colorectal liver metastasis

Kupffer cells, residential liver macrophages, have binding sites for carcinoembryonic antigen (CEA), but their role in metastatic liver tumor progression has not been well addressed clinically. Liver macrophages were analyzed morphometrically and their relationship with CEA and tumor microvessel density (MVD) was examined in 71 patients who underwent macroscopic curative hepatectomy for metastatic liver tumors from colorectal cancer. In paraffin-embedded sections, MVD was evaluated by CD34-positive cell counts, liver macrophages visualized using anti PG-M1 (CD68) antibody were analyzed, and membrane-bound CEA was assessed by immunoreactivity of tumor cells for CEA. The area of liver macrophages in peritumoral regions (43.0 +/- 11.6 microm2) was significantly larger than that in non-tumor regions (25.2 +/- 24.2 microm2) (P < 0.0001). The liver macrophage density in peritumoral regions was 154 +/- 49 per field, and was significantly higher than in non-tumor regions (74 +/- 24 per field) (P < 0.001). The density and the area of liver macrophages had no correlation with serum CEA levels and the degree of tumor CEA expression. A weak positive correlation was observed between MVD and liver macrophage density (P = 0.0104, Spearman rank correlation coefficient = 0.31). Cox multivariate regression analysis showed that MVD greater than 50 (P = 0.0233, hazard ratio = 2.463), and the area of liver macrophages larger than 40.9 microm2 (P = 0.0485, hazard ratio = 2.127), were significant independent prognostic factors. The present morphometric analysis suggests that the liver macrophages are accumulated and activated in peritumoral regions in patients with colorectal liver metastasis and this accumulation and activation of liver macrophages, with which soluble or membrane-bound CEA might not be associated, are related with patients' poor prognosis.