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Radiofrequency Ablation: Inflammatory Changes in the Periablative Zone Can Induce Global Organ Effects, including
Nir Rozenblum1, Evelyne Zeira1, Baruch Bulvik1
1From the Goldyne Saved Institute for Gene Therapy (N.R., E.Z., B.B., S.G., H.Y., E.G., S.N.G.) and Department of Radiology (S.N.G.), Hadassah Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel; and Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (S.N.G.).
Purpose:
To determine the kinetics of innate immune and hepatic response to the coagulation necrosis area that remains in situ after radiofrequency (RF) ablation, the cytokine profile of this response, and its local and global effect on the whole organ in a small-animal model.
Materials And Methods:
A standardized RF ablation dose (70°C for 5 minutes) was used to ablate more than 7% of the liver in 91 C57BL6 mice (wild type) according to a protocol approved by the animal care committee. The dynamic cellular response in the border zone surrounding ablation-induced coagulation and in the ablated lobe and an untreated lobe were characterized with immunohistochemistry 24 hours, 72 hours, 7 days, and 14 days after ablation (the time points at which cells migrate to necrotic tissues). After characterization of the cellular populations that reacted to the RF treatment, cytokines secreted by these cells were blocked, either by using interleukin-6 knockout mice (n = 24) or c-met inhibitor PHA 665752 (n = 15), to elucidate the key factors facilitating the wound healing response to RF ablation. Statistical significance was assessed with nonparametric analysis of variance.
Results:
RF ablation induces a strong time-dependent immunologic response at the perimeter of the necrotic zone. This includes massive accumulation of neutrophils, activated myofibroblasts, and macrophages peaking at 24 hours, 7 days, and 14 days after ablation, respectively. In correlation with myofibroblast accumulation, RF ablation induced hepatocyte proliferation in both the ablated lobe and an untreated lobe (mean, 165.15 and 230.4 cyclin-dependent kinase 47-positive cells per ×20 field, respectively, at day 7; P < .02). Blockade of either IL-6 or c-met significantly reduced global hepatocyte proliferation (P < .05 for both), with the former reducing the accumulation of both macrophages and myofibroblasts surrounding the coagulation necrosis area (42.9 and 113.6 vs 7.3 and 46.6 macrophages and activated myofibroblasts per ×20 field, respectively; P < .036 for both).
Conclusion:
Hepatic RF ablation induces not only a local periablational inflammatory zone but also more global proliferative effects on the liver. These IL-6- and/or c-met-mediated changes could potentially account for some of the local and distant tumor recurrence observed after treatment.
