Institutional review board (IRB) approval was obtained for this single institution, retrospective study. Thirty-nine TSC patients who underwent transcatheter arterial embolization procedures for renal AMLs between 2000 and 2014 were identified. Of these patients, 11 received mTOR inhibitors for management of their AMLs, and 3 patients underwent angiography and transcatheter embolization of their AMLs prior to and following a course of mTOR inhibitor therapy. These three patients comprise the study group for this case series.

All patients underwent routine cross-sectional imaging of their kidneys on at least an annual basis. All patients underwent MR imaging, and one patient additionally underwent CT imaging. MR imaging was performed on a Signa 1.5-T system (GE Healthcare, Waukesha, WI) or a Magnetom 3.0-T system (Siemens, Malvern, PA). All MR examinations were monitored by a pediatric radiologist, and imaging protocols were individually tailored. Commonly, protocols included a tri-phase localizer, coronal T2-weighted HASTE, axial T1-weighted in- and opposed-phase gradient recalled echo (GRE), pre-contrast coronal or axial T1-weighted 3D GRE, and contrast-enhanced coronal or axial T1-weighted 3D GRE obtained at 30, 70, and 180 s after contrast administration. In- and opposed-phase imaging data were used to calculate “fat only” image maps of the kidneys via the Dixon method[10]. The T1 pre-contrast mask images were subtracted from the post-contrast images to generate contrast maps; the arterial phase subtraction map (difference between post-contrast images obtained at 30 s following contrast administration and the pre-contrast mask) was used as the vascularity map for the AMLs. Intravenous gadopentetate dimeglumine was used as the contrast agent.

CT scanning was performed by a 64-detector row CT scanner (GE Discovery CT 750 HD; GE Healthcare, Waukesha, WI). Pre-contrast imaging of the abdomen was obtained, followed by contrast injection at 2-3 cc/s with a total volume of 2 cc/kg. Post-contrast imaging at 30 s (arterial phase) and at 100 s (nephrographic phase) were obtained.

Transcatheter arterial embolization was performed prophylactically in all 3 patients by attending interventional radiologists. Selective renal angiography was performed using a 4 or 5 Fr selective catheter (Cook, Bloomington, IN). Superselective catheterization of arterial pedicles supplying the targeted AML was performed using a coaxial microcatheter (Renegade; Boston Scientific, Natick, MA) over a microwire (Transcend; Boston Scientific, Natick, MA). Once satisfactory microcatheter positioning was confirmed with digital subtraction angiography (DSA), embolization was performed under continuous fluoroscopy using calibrated 300-500 micron microspheres (Embosphere; Merit Medical, South Jordan, UT). Achievement of stasis within the target artery and absence of inadvertent non-target embolization of adjacent normal renal parenchyma were monitored during the embolization portion of the procedure. Stasis within the target artery was considered the standardized embolization endpoint and was confirmed with post-embolization DSA imaging. This endpoint was achieved in all embolization procedures.

Volumetric analysis of MR and CT images was performed using a standard clinical three-dimensional image analysis software package (iNtuition; TeraRecon, Foster City, CA). Segmentation analysis tools were used to automatically create a region of interest (ROI) circumscribing the AML; minor adjustments were then made manually in three orthogonal planes. The ROI was then used to calculate tumor volumes. On MR images, the “fat only” map calculated from the in- and opposed-phase GRE sequences was used to quantify fat volume within tumors (Figure 1A). Tumor vascularity was measured by applying a thresholding tool within the ROI to semi-automatically segment areas of vascular enhancement on post-contrast subtraction images (Figure 1B). On CT images, volume histogram analysis of Hounsfield unit (HU) was performed to quantify tumor tissue composition (Figure 1C). Pixels with HU ranging from -100 to -20 HU were considered to represent macroscopic fat, and pixels with HU ranging from 100 to 200 were considered to represent blood vessels; selection of these thresholds represents an adaptation from a previously published technique[11].

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Figure 1 Examples of volumetric analysis on computed tomography and magnetic resonance imaging. A: Coronal “fat-only” maps created from in- and opposed-phase gradient recalled imaging were used to measure macroscopic fat volumes within AMLs; B: Segmentation of tumoral vascularity (automatically generated regions of interest demarcated by pink line) from post-contrast subtraction imaging was used to calculate tumor vascular volumes; C: Histogram analysis from CT was used to calculate tumoral fat and vascular content (pseudocoloring depicts fatty tissue as red and vascular tissue as yellow). CT: Computed tomography; AML: Angiomyolipoma.

Tumor vascularity that was based on angiographic imaging was analyzed in a semi-quantitative manner using a previously published grading scale[12]. The lesions were characterized based upon several parameters: Mean vessel density, size, the absence or presence of a parasitized arterial supply, and the number and size of any pseudoaneurysms. Based on these observations, lesions were then classified into 3 grades of vascularity. Grade 1 lesions demonstrated small caliber peripheral arteries without significant central vascularity. Lesions with microaneurysms less than 2 mm in size were also considered grade 1. Grade 2 lesions demonstrated medium-sized and/or abundant arteries with or without a parasitized arterial supply. Additionally lesions with pseudoaneurysms between 2 and 5 mm were considered grade 2. Grade 3 lesions contained large, tortuous vessels and/or pseudoaneurysms greater than 5 mm in size.

At the time of initial presentation, patient 1 was a 15-year-old female with a history of TSC-associated seizure disorder, developmental delay, autism and bilateral renal AMLs (Table 1). During several years of serial surveillance imaging she was noted to have a gradual increase in the size and number of her renal lesions. Specifically, there was a 6.8 cm right lower pole AML, a 4.0 cm right upper pole AML, and a 3.8 cm left upper pole AML, none of which had a substantial fatty component. There was no evidence of hydronephrosis, and there were no mass-related symptoms such as flank pain. Given the tumoral size, prophylactic embolization of the right upper and lower pole AMLs was performed in 2007 in order to reduce the risk of hemorrhage. Angiographically the right upper pole lesion demonstrated grade 3 vascularity, while the right lower pole lesion demonstrated grade 2 vascularity. Despite initial control of tumoral size, both lesions began enlarging approximately 2 years after embolization (right lower pole, Figure 2A; right upper pole, Figure 2B). As a result, mTOR therapy with everolimus 10 mg daily was initiated in 2011, which resulted in a dramatic decrease in tumor volume of both the soft tissue [-521% (upper pole) and -943% (lower pole)] and vascular compartments [-1791% (upper pole) and -1257% (lower pole)]. The left upper pole AML, which was not embolized, also demonstrated a significant decrease in size (-166.7%) (Figure 2C). The patient experienced mild side effects from mTOR inhibitor therapy such as oral ulcers. In 2013, mTOR inhibitor therapy was stopped, as diminishing returns were expected with regards to further decreases in tumor size. In an effort to consolidate the gains made by mTOR inhibition, repeat embolization of the right lower pole AML was performed; at this time, grade 2 vascularity was again seen in the lesion. Upon termination of mTOR inhibitor therapy, there was immediate rebound growth of the left upper pole AML (82.5%). The two right renal AMLs which had undergone embolization demonstrated a brief period of tumoral size control, but within a year both lesions demonstrated substantial rebound growth [84.5% (upper pole) and 84.7% (lower pole) from nadir].

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Figure 2 Volumetric analysis of patient 1 angiomyolipomas. Both the right lower pole (A) and right upper pole (B) AMLs demonstrated growth several years following transarterial embolization and immediate response to mTOR inhibitor therapy. The performance of a second embolization did not prevent rebound growth following discontinuation of mTOR inhibitor; C: The left renal AML which did not undergo embolization demonstrated slow sustained growth prior to mTOR inhibitor, with a rapid increase in volume following discontinuation. AML: Angiomyolipoma; mTOR: Mammalian target of rapamycin.

At the time of initial presentation, patient 2 was an 18-year-old female with a history of TSC-associated seizure disorder, facial angiofibromas, a right renal AML, and an atrophic left kidney (Table 2). She underwent serial cross sectional CT imaging of the right renal AML for several years, which demonstrated sizeable fat and vascular compartments within the tumor (Figure 3). In 2006 transcatheter embolization of the AML was performed because of lesion size, at which time the tumor vascularity was grade 2. Despite an initial volume response, the tumor began to grow, and as a result she was enrolled in an mTOR inhibitor phase II clinical trial with sirolimus 4 mg daily for one year. The patient did not experience any major side effects from this therapy. During the treatment course there was a significant decrease in tumoral volume (-52%) mirrored across the fat (-61.5%), soft tissue (-32%), and vascular (-496%) compartments. Upon discontinuation of mTOR inhibition there was rebound tumoral growth, once again across all three tissue compartments. The patient subsequently underwent repeat embolization of the AML, at which time the tumor vascularity was grade 1. This procedure, however, was not able to provide sustained control of tumor size, as continued growth of the AML occurred despite the repeat embolization.

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Figure 3 Volumetric analysis of patient 2 angiomyolipoma. A right renal AML underwent embolization prior a course of mTOR inhibitor therapy. Following this course, there was rebound growth involving the lipid, soft tissue, and vascular components of the tumor. Performance of a second embolization only temporarily curtailed tumoral growth. AML: Angiomyolipoma; mTOR: Mammalian target of rapamycin.

At the time of initial presentation, patient 3 was a 5-year-old male with a history of TSC-associated seizure disorder, developmental delay, and a left renal AML (Table 3). Cross sectional imaging demonstrated no significant fatty component to the renal lesion. He underwent prophylactic embolization of the tumor in 2004. The tumor demonstrated grade 1 vascularity on initial angiography. After embolization, initial tumor response was quickly followed by continued growth of the tumor (54.8%) (Figure 4), necessitating repeat embolization in 2006; angiography during this repeat embolization was notable for a significant increase in tumor vascularity since the initial embolization, with the development of multiple large pseudoaneurysms that were consistent with grade 3 vascularity (Figure 5). After the repeat embolization, a short period of tumor regression was again followed by steady tumor growth. mTOR inhibitor therapy was initiated in 2010 with sirolimus 2.5 mg twice daily, and for the subsequent 2 years, there was excellent control of tumor volume. The patient did not experience any major side effects from this therapy. In 2012, mTOR inhibitor therapy was stopped, as diminishing returns were expected with regards to further decreases in tumor size. In an effort to consolidate the gains made by mTOR inhibition, the patient underwent a third embolization. Tumor vascularity was notably decreased as compared to the second embolization procedure (Figure 5C). Following the third embolization, however, the tumor demonstrated immediate rebound growth (41%).

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Figure 4 Volumetric analysis of patient 3 angiomyolipoma. A left renal AML was treated with two embolization procedures prior to mTOR inhibitor therapy. Reduction in tumor volume with mTOR inhibitor affected both the soft tissue and vascular components of the tumor. However, discontinuation resulted in rebound growth, including tumor vascularity. AML: Angiomyolipoma; mTOR: Mammalian target of rapamycin.

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Figure 5 Angiographic analysis of patient 3 angiomyolipomas. A: At the time of the patient’s first embolization, initial angiography demonstrated low overall tumoral vasculature (grade 1); B: The second embolization, however, revealed interval significant expansion of tumor vascularity including development of multiple aneurysms (grade 3); C: Following a course of mTOR inhibitor, tumor vascularity was reduced to grade 1 at the third embolization. mTOR: Mammalian target of rapamycin.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder affecting approximately 2 million people globally. Mutations in the TSC1 and TSC2 genes, important regulators of the mammalian target of rapamycin signaling pathway, result in the development of tumors involving multiple organ systems. As many as 80% of patients with TSC develop renal angiomyolipomas, which are soft tissue hamartomatous tumors containing multiple soft tissue components including fat, smooth muscle, and blood vessels.

Segmentation analysis tools were used to automatically create a region of interest circumscribing the angiomyolipomas. On magnetic resonance images, the “fat only” map calculated from the in- and opposed-phase gradient recalled echo sequences was used to quantify fat volume within tumors. Tumor vascularity was measured by applying a thresholding tool within the region of interest on post-contrast subtraction images.

Transcatheter arterial embolization was performed prophylactically in all 3 patients by attending interventional radiologists.

Stasis within the target artery was considered the standardized embolization endpoint and was confirmed with post-embolization digital subtraction angiography imaging. This endpoint was achieved in all embolization procedures.

Transcatheter arterial embolization.

The authors have performed a good study, the manuscript is interesting.