Aggressive local treatment for recurrent intrahepatic cholangiocarcinoma—Stereotactic radiofrequency ablation as a valuable addition to hepatic resection

Background To evaluate the efficacy, safety and overall clinical outcome of local treatment for recurrent intrahepatic cholangiocellular carcinoma after hepatic resection. Methods Between 2007 and 2019 72 consecutive patients underwent hepatic resection for primary intrahepatic cholangiocellular carcinoma. If amenable, recurrent tumors were aggressively treated by HR or stereotactic radiofrequency ablation with local curative intent. Endpoints consisted of morbidity and mortality, locoregional and de novo recurrence, disease free survival, and overall survival. Results After a median follow-up of 28 months, recurrence of intrahepatic cholangiocellular carcinoma was observed in 43 of 72 patients undergoing hepatic resection (60.3%). 16 patients were subsequently treated by hepatic resection (n = 5) and stereotactic radiofrequency ablation (n = 11) with local curative intention. The remaining 27 patients underwent palliative treatment for first recurrence. Overall survival of patients who underwent repeated aggressive liver-directed therapy was comparable to patients without recurrence (p = 0.938) and was better as compared to patients receiving palliative treatment (p = 0.018). The 5-year overall survival rates for patients without recurrence, the repeated liver-directed treatment group and the palliative treatment group were 54.3%, 47.7% and 12.3%, respectively. By adding stereotactic radiofrequency ablation as an alternative treatment option, the rate of curative re-treatment increased from 11.9% to 37.2%. Conclusion Repeated hepatic resection is often precluded due to patient morbidity or anatomical and functional limitations. Due to the application of stereotactic radiofrequency ablation in case of recurrent intrahepatic cholangiocellular carcinoma, the number of patients treated with curative intent can be increased. This leads to favorable clinical outcome as compared to palliative treatment of intrahepatic cholangiocellular carcinoma recurrence.

Peritumoral ductular reaction can be a prognostic factor for intrahepatic cholangiocellular carcinoma

Background Peritumoral ductular reaction (DR) was reported to be related to the prognosis of combined hepatocellular-cholangiocarcinoma and hepatocellular carcinoma. Non-mucin-producing intrahepatic cholangiocellular carcinoma (ICC), may be derived from small bile duct cells or liver progenitor cells (LPCs). However, whether peritumoral DR is also related to non-mucin-producing ICCs needs to be investigated. Methods Forty-seven patients with non-mucin-producing ICC were eventually included in the study. Clinicopathological variables were collected. Immunohistochemical analysis and immunofluorescence staining for cytokeratin 19, proliferating cell nuclear antigen, and α-smooth muscle actin were performed in tumor and peritumor liver tissues. Results Peritumoral DR is significantly correlated with local inflammation and fibrosis. Patients with significant peritumoral DR had high recurrence rate (81.8% vs 56.0%, P = 0.058) and poor overall and disease-free survival time (P = 0.01 and P = 0.03, respectively). Significant peritumoral DR showed high proliferation activity of LPC/cholangiocytes and abundant background extracellular matrix. Conclusions Patients with non-mucin-producing ICC having significant peritumoral DR had a poor prognosis. Peritumoral DR could be a prognostic factor for ICC; however, the mechanism should be further investigated.

Peritumoral ductular reaction can be a prognostic factor for intrahepatic cholangiocellular carcinoma

Background: Peritumoral ductular reaction (DR) was reported to be related to the prognosis of combined hepatocellular-cholangiocarcinoma and hepatocellular carcinoma. Non-mucin-producing intrahepatic cholangiocellular carcinoma (ICC), may be derived from small bile duct cells or liver progenitor cells (LPCs). However, whether peritumoral DR is also related to non-mucin-producing ICCs needs to be investigated. Methods: Forty-seven patients with non-mucin-producing ICC were eventually included in the study. Clinicopathological variables were collected. Immunohistochemical analysis and immunofluorescence staining for cytokeratin 19, proliferating cell nuclear antigen, and α-smooth muscle actin were performed in tumor and peritumor liver tissues.Results: Peritumoral DR is significantly correlated with local inflammation and fibrosis. Patients with significant peritumoral DR had high recurrence rate(81.8% vs 56.0%, P = 0.058) and poor overall and disease-free survival time ( P = 0.01 and P = 0.03, respectively). Significant peritumoral DR showed high proliferation activity of LPC/cholangiocytes and abundant background extracellular matrix. Conclusions: Patients with non-mucin-producing ICC having significant peritumoral DR had a poor prognosis. Peritumoral DR could be a prognostic factor for ICC; however, the mechanism should be further investigated. Keywords: Intrahepatic cholangiocellular carcinoma, non-mucin producing, ductular reaction, prognostic factor

Development of A New Mouse Model for Intrahepatic Cholangiocellular Carcinoma: Accelerating Functions of Pecam-1

Due to the lack of suitable in-vivo models, the etiology of intrahepatic cholangiocellular carcinoma (ICC) is poorly understood. We previously showed the involvement of platelet endothelial cell adhesion molecule-1 (Pecam-1/CD31) in acute liver damage. Here, we developed a model of ICC using thioacetamide (TAA) in drinking water of wild-type (WT)-mice and Pecam-1-knock-out (KO)-mice. Gross inspection and microscopy revealed liver-cirrhosis and ICC in both groups after 22 weeks of TAA. The severity of cirrhosis and ICC (Ck-19-positive) was reduced in Pecam-1 KO mice (stage-4 cirrhosis in WT vs. stage-3 in KO mice). Tumor networks (accompanied by neutrophils) were predominantly located in portal areas, with signs of epithelial-to-mesenchymal transition (EMT). In serum, TAA induced an increase in hepatic damage markers, with lower levels in Pecam-1 null mice. With qPCR of liver, elevated expression of Pecam-1 mRNA was noted in WT mice, in addition to Icam-1, EpCam, cytokines, cMyc, and Mmp2. Thereby, levels of EpCAM, cytokines, cMyc, and Mmp2 were significantly lower in Pecam-1 null mice. Lipocalin-2 and Ccl5 were elevated significantly in both WT and Pecam-1 null mice after TAA administration. Also, EMT marker Wnt5a (not Twist-1) was increased in both groups after TAA. We present a highly reproducible mouse model for ICC and show protective effects of Pecam-1 deficiency.