Neoadjuvant Locoregional Therapy and Recurrent Hepatocellular Carcinoma after Liver Transplantation

Abstract

Neoadjuvant locoregional therapies (LRTs) have been widely used to reduce tumor burden or to downstage hepatocellular carcinoma (HCC) before orthotopic liver transplantation (OLT). We examined the impact of LRT response on HCC recurrence after OLT. We performed a retrospective study of 384 patients with HCC treated by OLT. Tumor necrosis was determined by pathologic evaluation. The vascular and lymphatic vessels were localized by immunofluorescence staining in formalin-fixed, paraffin-embedded tissue; expressions of vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 were analyzed by Western blot. Plasma vascular endothelial growth factor (VEGF)-A and VEGF-C levels of a consecutive cohort of 171 HCC patients were detected by ELISA. Of the 384 patients with HCC, 268 had undergone pretransplantation neoadjuvant LRTs. Patients with no tumor necrosis (n= 58; 5.2% recurrence) or complete tumor necrosis (n= 70; 6.1% recurrence) had significantly lower 5-year recurrence rates than those with partial tumor necrosis (n= 140; 22.6% recurrence; p < 0.001). Lymphatic metastases were significantly more numerous in patients with partial tumor necrosis than in those without tumor necrosis after OLT (p < 0.001). With immunofluorescence staining of peritumor zone, lymphatics were visualized around partially necrotic tumors, but not around tumors without necrosis. Plasma levels of VEGF-A and VEGF-C were elevated significantly in patients with evidence of tumor necrosis (n= 102) compared with those without necrosis (n= 69; p<0.001). By Western blot, VEGFR-2 and VEGFR-3 expression in the peritumoral tissue associated with partially necrotic tumors was significantly higher than in peritumoral tissue of non-necrosis tumors (n= 3/group, p < 0.020 and p < 0.006, respectively). Locoregional therapy-induced or spontaneous partially necrotic HCC was associated with increased risk of lymphatic metastases compared with tumors with no or complete tumor necrosis. Anti-lymphangiogenic agents with neoadjuvant LRTs can decrease the pattern of lymphatic metastasis after OLT.