T- and B-Cells in the Inner Invasive Margin of Hepatocellular Carcinoma after Resection Associate with Favorable Prognosis

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, which frequently recurs after curative resection. Several options to predict recurrence of HCC have been proposed, however, their prognostic ability is limited. This study aimed to test the hypothesis that distribution and numbers of T- and B-lymphocytes in different regions of the resected tumor may have different prognostic significance. Different subregions of HCC demonstrated uneven lymphocyte infiltration. CD20+ B-lymphocytes and CD8+ T-lymphocytes, or their combination in the inner tumor invasive margin and inner/outer margin ratios, convey the best prediction for time to recurrence and disease-free survival. The results offer a novel approach to the stratification of the risk of early tumor recurrence after curative liver resection. ABSTRACT: In this retrospective study on 67 patients with hepatocellular carcinoma (HCC), after tumor resection, we evaluated the significance of CD3+ and CD8+ T-lymphocytes and CD20+ B-lymphocytes in tumor and non-tumor liver for time to recurrence (TTR), disease-free survival (DFS) and overall survival. After immunohistochemical staining, the density of nucleated lymphocyte profiles (Q(A)) was estimated stereologically in the tumor center (TC), inner margin (inn M), outer margin (out M), peritumor and non-tumor liver. In TC, intermediate and high Q(A) of CD8+ cells predicted longer TTR, whereas CD3+ and CD20+ were predictive only at high Q(A). DFS was predicted by high Q(A) of CD3+, CD8+ and CD20+ cells in TC. The inn M harbored smaller Q(A) of CD3+, CD8+ and CD20+ lymphocytes than out M. In contrast to out M, high T-cells’ Q(A) and intermediate and high B-cell Q(A) in inn M predicted longer TTR and DFS. High inn M/out M Q(A) ratios of CD3+ and CD20+ cells were associated with longer TTR and DFS, whereas high inn M/out M Q(A) ratio of CD8+ was predictive only for DFS. Patients with intermediate-high Q(A) of combined CD8+ and CD20+ cells in inn M showed longer TTR and DFS, compared to CD8+-high or CD20+-high alone. Our findings highlight overall heterogeneity of the tumor invasive margin, the importance of inn M, and the predictive role of B-cells.