Hepatocellular carcinoma: tumor heterogeneity and recurrence after preoperative locoregional therapy

How locoregional therapy (LRT) may change tumor compositional and functional heterogeneity, consequently contributing to treatment resistance and tumor recurrence remains largely unknown. A series of hepatocellular carcinomas (HCCs) treated with preoperative locoregional therapy (LRT) that relapsed after surgery was studied. Thirty HCCs comprising 15 patients treated with LRT prior to liver transplantation (n = 14)/surgical resection (n = 1) were studied. Five patients undergoing pre-transplant LRT, comprising 11 HCCs, presented tumor recurrence (median recurrence time = 10 months). Clinicopathological data and immunoexpression of proliferation markers (Ki67, p53), cholangiocytic/hepatic progenitor cell (HPC) markers (EpCAM)/BerEp4, CK19, CK7) and mesenchymal markers (ASMA, vimentin) were evaluated in tumoral epithelial/stromal cells and in peritumoral parenchyma. Higher grading of tumor differentiation, microvascular invasion and tumoral cell p53 expression significantly associated with recurrence (p < 0.05). Piecemeal necrosis features were more frequent in tumors that recurred (p < 0,05). Tumoral and peritumoral Ki67 expression and EpCAM, CK19 and CK7 expression in tumoral cells tended to be higher in treated tumors that recurred. Peritumoral expression of cholangiocytic/HPC markers and tumoral epithelial and stromal cellular expression of mesenchymal markers tended to be higher for tumors without recurrence. Recurrence after transplant with preoperative LRT might be associated with poor HCC differentiation, higher cellular proliferation rate, peritumoral piecemeal necrosis features and cholangiocytic/HPC phenotypes. Understanding HCC progression factors after LRT might be important for optimizing patient selection for treatment, improving surveillance after LRT and to explore synergies between LRT and systemic targeted therapies to prevent recurrence.