The effect of sirolimus on angiomyolipoma is determined by decrease of fat-poor compartments and includes striking reduction of vascular structures

Abstract

Renal angiomyolipomas hemorrhage is associated with their size and vascular constitution. The effects of sirolimus on different components of angiomyolipomas was analyzed in patients with tuberous sclerosis complex, sporadic lymphangioleiomyomatosis and multiple sporadic angiomyolipomas. Thirty angiomyolipomas from 14 patients treated with sirolimus were retrospectively evaluated. 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. 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 while the volume of the fat-rich compartment increased. Broad liposubstitution was observed in some tumors. A median reduction of 100% (75 to 100) in the diameter of aneurysmatic/ectatic vascular structures was observed. 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, revealing the likely mechanism responsible for the risk-decreasing effect of mTOR inhibitors on angiomyolipoma bleeding. These findings support the role of mTOR in the development of angiomyolipoma blood vessels.

Figure 1

Total tumor volume pre- and post-treatment with sirolimus for all AMLs (a), fat-rich tumors (b), intermediate-fat tumors (c) and percent response to sirolimus for each tumor type (d). Repeated measures were analyzed using the Wilcoxon test, whereas comparisons among tumor fat profiles were performed with the Kruskal–Wallis test. AML angiomyolipoma, FPT fat-poor tumor, FRT fat-rich tumor, IFT intermediate-fat tumor. *P < 0.05, ***P < 0.001.

Figure 2

Response of renal AMLs to treatment with sirolimus. (a,b) Axial corticomedullary-phase CT images obtained before treatment show lobulated fat-poor AMLs in both kidneys (arrows) and a fat-rich AML arising from the lower pole of the left kidney (arrowhead). (c,d) Axial corticomedullary-phase CT images acquired after 7 months of treatment show significant volumetric reduction of the fat-poor AMLs (arrows) and nonsignificant change in the fat-rich AML (arrowhead).

Figure 3

Percent variation of total tumor volume and volumes of tumor compartments following treatment with sirolimus (a). Variation of tumor compartment volumes—HVC (b), FPC (c), FRC (d) and IFC (e)—following treatment with sirolimus; and diameter variation of intra-tumoral ectatic vessels/aneurysms (f) in response to sirolimus. HVC, FPC and IFC presented significant volume reduction while FRC displayed volume increase. Comparisons between different groups were performed with Kruskal–Wallis test and repeated measures were analyzed with the Wilcoxon test. FPC fat-poor compartment, FRC fat-rich compartment, HVC highly-vascularized compartment, IFC intermediate-fat compartment. *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 4

Change in AML volume and fat-containing pattern in response to sirolimus. (a) Pre-treatment axial corticomedullary-phase CT scan shows a right renal fat-poor AML (white arrow). (b) Post-treatment axial corticomedullary-phase CT image reveals tumor volume reduction (white arrow) while the fat component becomes visible (black arrow). Note that the AML total volume reduction (from 76.4 cm³ to 26.9 cm³) occurred due to diminishment of the fat-poor (from 60.1 cm³ to 13.0 cm³) and highly-vascularized (from 15.4 cm³ to 11.3 cm³) compartments.

Figure 5

Response of intralesional vascular structures to sirolimus. Coronal nephrographic-phase CT images obtained (a) before the treatment and (b) after the treatment show disappearance of a left kidney large intralesional vascular structure and remarkable reduction of an intralesional aneurysm in response to treatment with sirolimus (arrows). An increase in the fat component is also seen (arrowhead).

Figure 6

Liposubstitution in angiomyolipoma in response to treatment with sirolimus. Coronal corticomedullary-phase CT images obtained (a) before treatment and (b) after treatment show the effect of sirolimus treatment on a fat-poor AML in the upper pole of the right kidney (white arrow), revealing the appearance of a fat-rich tumor (black arrow) in substitution to the previous fat-poor pattern.