Effect of neoadjuvant sorafenib treatment on histology of clear cell renal cell carcinoma and occurrence of circulating tumor fragments

Objective: Clear cell renal cell carcinoma (ccRCC) generally presents with a micronodular phenotype (MP) due to high expression levels of vascular endothelial growth factor (VEGF-A). Earlier we have shown that MP is associated with shedding of multicellular tumor fragments (MTF) into the circulation and pulmonary metastasis. We hypothesized that VEGF inhibition will destroy MP resulting in less MTF. Method: 8 ccRCC patients were treated for 4 weeks by daily administration of Sorafenib (400 mg bid). Three days after therapy, nephrectomy was performed and kidneys were perfused via the arteria renalis. Venous perfundate was filtered and processed to AgarCytoblocks for MTF. Treatment effects were studied using immunohistochemistry. Results: All tumors were ccRCC as demonstrated by high VEGF-A expression. None of the tumors showed MP after Sorafenib treatment. Tumors showed large areas of necrosis and fibrinoid necrosis of the blood vessels, concomitant with profound perivascular inflammation. 6/8 ccRCC patients (75 %) had MFT vs 33 % in a control group (p= 0.03 Fisher's exact test). Individual tumor cells in the MTFs showed increased mitotic activity. Conclusion: Sorafenib destroys MP in ccRCC, attacks tumor vasculature, causes extensive necrosis and inflammation. Post-treatment MTF are increased in venous perfundate. Care should therefore be taken with neo-adjuvant sorafenib treatment of ccRCC.