The Reducing Effect of Sirolimus on Angiomyolipoma is Determined by Decrease of Its Fat-Poor Compartments and Is Associated with Striking Reduction of Vascular Structures

Abstract Background: Renal angiomyolipomas hemorrhage is strongly associated with their size and vascular constitution. Since previous studies showed that mTOR inhibitors can differentially act in distinct cell lines, we analyzed the effects of sirolimus on the volume of different components of angiomyolipomas in patients with tuberous sclerosis complex, including vascular structures. We retrospectively analyzed 23 angiomyolipomas from 10 patients treated with sirolimus. An approach based on a Hounsfield-unit threshold was used to classify angiomyolipomas in fat-rich, fat-poor and intermediate-fat tumors, and to categorize tumor compartments in fat rich, fat poor, intermediate fat and highly vascularized. Diameter variations were measured to assess the effects on aneurysmatic/ectatic vascular formations. Results: Volume reduction following treatment with sirolimus was higher in fat-poor than fat-rich angiomyolipomas. Tumor reduction was mainly determined by decrease of the fat-poor and highly-vascularized compartments, with a lesser contribution of the intermediate-fat component, while the volume of the fat-rich compartment increased. Broad liposubstitution was observed in some tumors. Massive reduction of aneurysmatic/ectatic vascular structures was observed, with disappearance of such lesions in most cases. Conclusions: Our study showed that sirolimus reduces the size of angiomyolipomas by decreasing primarily their highly-vascularized and fat-poor compartments. This effect is associated with a remarkable reduction of tumoral aneurysms/ectatic vessels and other vascular structures. Our findings revealed, therefore, the likely mechanism responsible for the reported risk-decreasing effect of mTOR inhibitors on angiomyolipoma bleeding. Our findings also expand the understanding the biology of this tumor, supporting a role for mTOR in maintenance, and maybe assembling, of blood vessels in angiomyolipomas.