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Abstract

Objective

To examine the effect of supplementary microcoil embolization on the long-term progression of angiomyolipomas embolized using gelatin sponge particles (GSPs).

Methods

This retrospective study included 29 unruptured angiomyolipomas in 25 patients, treated by complete embolization and radiological follow-up for ≥3 years. Embolization was performed using GSPs and supplementary microcoils. Supplementary microcoil embolization affecting >90% of the tumor vasculature was defined as microcoil embolization. Tumor volumes pre- and post-embolization were measured by computed tomography or magnetic resonance imaging.

Results

Eleven tumors received supplementary microcoil embolization and 18 tumors did not. Relative tumor reduction at >3 years post-embolization was significantly greater in tumors with supplementary microcoil embolization compared with tumors without microcoil embolization (81% ± 8% vs. 55% ± 29%). Fourteen tumors tended to show volume regrowth and the volumes of the remaining 15 tumors continued to decline. Tumors without supplementary microcoil embolization were more likely to show volume regrowth during follow-up than tumors with supplementary microcoil embolization (78% vs. 0%, respectively).

Conclusions

When using a combination of GSPs and microcoils, supplementary microcoil embolization should be carried out to ensure maximum long-term reduction in tumor volume in patients with angiomyolipomas.

Keywords

Angiomyolipoma embolization intervention kidney primary neoplasm tuberous sclerosis complex lymphangioleiomyomatosis

Introduction

Renal angiomyolipomas (AMLs) are benign tumors of the kidney consisting of varying proportions of smooth muscle, blood vessels, and fat, occurring in 1% to 3% of the general population.¹ They can occur sporadically or can be associated with other diseases, such as tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM).² Symptoms of renal AML arise from compression or replacement of normal parenchyma by the tumor,³ and serious complications of renal AMLs include retroperitoneal hemorrhage secondary to tumor rupture and impaired renal function. Renal AMLs are usually diagnosed by the detection of fat on computed tomography (CT) or magnetic resonance imaging (MRI).⁴

Prophylactic treatments to prevent rupture of renal AMLs include transcatheter arterial embolization (TAE), surgery, radiofrequency ablation, and pharmacological treatment with a mammalian target of rapamycin (mTOR) inhibitor (in cases of TSC-AML and sLAM-AML).² Among these treatment methods, TAE is also the first-line therapy for ruptured renal AMLs and the preferred management strategy for symptomatic tumors or tumors including intratumoral aneurysms with a high risk of rupture (i.e., aneurysms ≥5 mm in diameter).^2,5,6

Numerous agents can be used for the embolization of renal AMLs, including ethanol, polyvinyl alcohol particles, gelatin sponge particles (GSPs), microspheres, lipiodol and cyanoacrylate, and microcoils.^2,7,8 However, there is currently no consensus on the most appropriate agent for the embolization of AMLs, and few studies have compared the effects of different agents on post-embolization tumor reduction.^9–12 GSPs are impermanent, easily administered, and relatively large agents, and have the lowest complication rates among the various embolic agents.^13,14 In contrast, microcoils are permanent embolic agents, but when used alone, they have the drawback that collateral pathways can readily form around the level of occlusion.¹⁵ Embolization with both GSPs and microcoils is the routine strategy for renal AMLs in Juntendo University Hospital.

Here, we retrospectively evaluated the long-term reduction in the volume of renal AMLs embolized using GSPs with or without supplementary microcoil embolization.

Materials and methods

The reporting of this study conforms to the STROBE guidelines.¹⁶

Subjects

This retrospective study was approved by the institutional review board of Juntendo University Hospital (Tokyo, Japan) (approval number: No. 18-299; approval date: 16 April 2020). The need for informed consent was waived due to the retrospective nature of the study and all patient details were de-identified. Records of patients who had received TAE(s) for renal AMLs between July 2010 and July 2018 were retrieved from our radiological information system. The inclusion criteria were as follows: 1) tumors with no active or prior bleeding at the time of TAE; 2) tumors with no previous treatment before TAE; 3) no embolic agents other than GSPs and microcoils; 4) complete embolization; and 5) post-embolization radiological follow-up for at least 3 years. Complete embolization was defined as the disappearance of >90% of the tumor vasculature on confirmatory renal arteriography after embolization. Confirmation of complete embolization was performed by two radiologists who both reviewed the angiography images to reach a consensus.

Embolization

Pre-embolization abdominal non-contrast and contrast-enhanced CT examinations were performed and CT angiography images were obtained. Before embolization, the number of renal arteries and potential extrarenal feeders of renal AMLs were identified on CT angiography images. At the start of embolization, renal arteriography was performed to identify renal and tumoral vessels. A 1.8-F microcatheter (Carry Win, UTM Co., Ltd., Toyohashi, Japan or Carnelian PIXIE, Tokai Medical Products Inc., Kasugai, Japan), 1.98-F microcatheter (Masters Parkway Soft, Asahi Intecc Co., Ltd., Nagoya, Japan), or 2.0-F microcatheter (Excelsior 1018, Boston Scientific Corp., Marlborough, MA, USA) was then advanced into the feeding artery and confirmatory superselective angiography was performed.

The embolic agents were administered via the microcatheter used for superselective angiography. The embolic agents used were GSPs (1 mm in diameter in 28 tumors and 1–2 mm in diameter in one tumor; Gelpart, Nippon Kayaku Co. Ltd., Tokyo, Japan) and microcoils (Tornado/Hilal, Cook Medical LLC, Bloomington, IN, USA; Target/GDC/Matrix2, Stryker Corp., Kalamazoo, MI, USA; or Trufill DCS Orbit, Codman & Shurtleff Inc., Raynham, MA, USA). For each catheterized feeder, GSPs were injected until disappearance of the distal tumoral vasculature was observed, and microcoils were then used to complete the occlusion of the target feeders. However, factors such as short length or steep angle of the target feeders, or practical difficulties arising during the procedure sometimes hampered insertion or fixation of the microcoils. In these cases, although complete embolization using both GSPs and microcoils was the aim, some feeders only received GSPs.

Radiological follow-up

Radiological follow-up comprising contrast-enhanced CT or MRI examination with non-contrast magnetic resonance angiography was scheduled at 1 month, 6 months, and 1 year, and then annually after embolization. In practice, the exact time points of the radiological examinations varied among patients, and we therefore specified four follow-up time points in this study: 0.5 to 1 year, 1.5 to 2 years, 2.5 to 3 years, and >3 years.

Image analysis

For each tumor, axial CT or MRI images obtained before and after embolization were loaded into Synapse Vincent software (Fujifilm Corp., Tokyo, Japan), tumor margins were delineated, and tumor volumes were automatically calculated by the software. The delineation of tumor margins was performed by two radiologists who worked together to reach a consensus. For each tumor, the percentage reduction in volume relative to its pre-embolization volume at each follow-up time point was assessed.

Fatty components within renal AMLs were defined as tumoral areas with a density of less than −20 Hounsfield units (HU) on unenhanced CT.¹² By delineating the tumor margins and setting the pixel value of interest to less than −20 HU, fatty areas within the target tumor could be automatically calculated using the same Synapse Vincent software. The percentage of fatty components relative to the original tumor volume before embolization was determined.

As noted above, although each tumor received complete embolization, not all feeders received supplementary microcoil embolization. The percentage of the tumor vasculature occluded by supplementary microcoil embolization was determined from the angiography images of the embolization procedure. If >90% of the tumoral vasculature was occluded by supplementary microcoil embolization, the tumor was defined as having received microcoil embolization.

Statistical analysis

Continuous normally distributed data are presented as mean ± standard deviation and non-normally distributed data are presented as median and interquartile range. Continuous variables were compared between two groups using the independent t-test or Mann–Whitney U test, and categorical variable were compared using Fisher’s exact test. P < 0.05 (two-sided) was considered significant. Statistical analyses were performed using PASW Statistics for Windows, version 18.0 (IBM Corp., Armonk, NY, USA).

Results

Records of 89 patients who received TAE(s) for renal AMLs (n = 106) between July 2010 and July 2018 were retrieved and analyzed. Based on the inclusion criteria, 31 patients with 36 tumors were included in the study. Of these 31 patients, six patients with seven tumors received mTOR inhibitors within <3 years of radiological follow-up after TAE, for the treatment of other complications of TSC or sLAM, not for the treatment of renal AMLs. These patients were therefore excluded from the study.

Twenty-five patients (mean age, 42 years; range, 28–68 years; 24 women and one man) with 29 renal AMLs were finally included in the study. These patients had received prophylactic embolotherapy either because the renal AMLs had developed aneurysms of ≥5 mm or because of the presence of symptoms. Six (24%) patients had TSC, 12 (48%) had sLAM, and seven (28%) had sporadic renal AMLs. Pre-embolization CT revealed that each of the 29 tumors contained macroscopic fat, which confirmed the diagnosis of renal AML. Sixteen tumors (55%) were located in the left kidney and 13 (45%) were located in the right kidney. Before embolization, the mean largest diameter of the target tumor was 8.6 ± 3.6 cm (range, 4.2–16.5 cm), the median tumor volume was 110 (56–305) mL, and the mean percentage of fatty components was 44% ± 31% (range, 1%–93%).

None of the 29 tumors showed post-embolization hemorrhage, underwent surgery, or had a recurrence of aneurysms ≥5 mm. All patients experienced post-embolization syndrome comprising fever, pain, vomiting, or nausea, which was alleviated by medication. No patient experienced any other procedure-associated complications.

The follow-up endpoint for tumor volume was the time point of the latest radiological examination before any post-embolization intervention (re-embolization or initiation of mTOR inhibitor therapy). For tumors with available radiological images up to the post-embolization intervention, the mean or median reductions in volume relative to the pre-embolization volume were 61% ± 16% for 27 tumors at 0.5 to 1 year, 71% (63%–82%) for 26 tumors at 1.5 to 2 years, 72% (58%–82%) for 23 tumors at 2.5 to 3 years, and 73% (47%–82%) for 26 tumors at >3 years.

Of the 29 tumors included in the study, 11 tumors received microcoil embolization (Figure 1) and 18 tumors did not (Figure 2).

Figure 1.

Embolotherapy in a 30-year-old woman with sporadic lymphangioleiomyomatosis. (a) Pre-embolization renal arteriography showed a right renal angiomyolipoma (black arrow) located at the lower pole and supplied by one feeder, with an aneurysm (white arrow) 8 mm in diameter and (b) Confirmatory renal arteriography after embolization showed that all the tumor vasculature and the aneurysm had disappeared without non-target embolization. The single feeder had been occluded with both gelatin sponge particles and microcoils, and the tumor was concluded to have received complete supplementary microcoil embolization.

Figure 2.

Embolotherapy in a 33-year-old woman with tuberous sclerosis complex. (a) Pre-embolization renal arteriography showed a right renal angiomyolipoma (black arrows) located at the upper pole and supplied by multiple feeders. (b) Confirmatory renal arteriography obtained after embolization showed the disappearance of >90% of the tumor vasculature. Only one feeder supplying a small portion of the tumor vasculature was embolized by gelatin sponge particles and supplementary microcoils, indicating that this tumor did not receive supplementary microcoil embolization. (c) Renal arteriography 3.3 years after initial embolization prior to second embolization showed recanalization of feeders (white arrows) that had not received supplementary microcoil embolization during the initial embolization and (d) Confirmatory renal arteriography after the second embolization showed that the feeders were embolized by gelatin sponge particles and microcoils, with disappearance of >90% of the tumor vasculature. Both embolization procedures were performed without non-target embolization.

There were no significant differences in the distribution of concomitant disease, original tumor volume, percentage of fatty components before embolization, or relative reduction in tumor volume within 3 years after embolization between tumors that received supplementary microcoil embolization and those that did not (Table 1). However, tumors that received supplementary microcoil embolization had a significantly greater relative reduction in tumor volume at >3 years after embolization than those that did not (81% ± 8% vs. 55% ± 29%, P = 0.002) (Table 1).

Table 1.

Tumor characteristics, type of tumor reduction, and relative volume reduction in tumors with and without complete microcoil embolization.

	Tumors receiving complete microcoil embolization	Tumors not receiving complete microcoil embolization	P value
Number of tumors	11	18
Concomitant disease, n (number of tumors)			0.707
TSC	2	6
sLAM	5	7
None	4	5
Original median tumor volume, mL (IQR)	85 (49–177)	138 (75–311)	0.418
Percentage of tumoral fatty components, % (SD)	45 (±35)	43 (±29)	0.912
Type of tumor reduction, number of tumors (frequency)			<0.001
Constantly shrinking	11 (100%)	4 (22%)
Regrowth after shrinking	0 (0%)	14 (78%)
Post-embolization median (IQR) or mean (SD) relative reduction in volume, %
At 0.5–1 year	65 (±14)	58 (±17)	0.280
At 1.5–2 years	74 (±13)	68 (60–82)	0.370
At 2.5–3 years	76 (±13)	62 (±25)	0.175
At >3 years	81 (±8)	55 (±29)	0.002

IQR, interquartile range; SD, standard deviation; sLAM, sporadic lymphangioleiomyomatosis; TSC, tuberous sclerosis complex.

Figure 3 shows the volumes of the 29 tumors at each follow-up time point relative to the tumor volume at pre-embolization. The volumes of 14 tumors (14/29, 48%) increased again during follow-up, but only one tumor (1/29, 3%) regrew to larger than its pre-embolization volume (Figure 3a). In contrast, 15 tumors (15/29, 52%) continued to decrease in volume during follow-up (Figure 3b).

Figure 3.

Volumes of 29 tumors at each follow-up time point relative to the pre-embolization volume. (a) Fourteen tumors showed volume regrowth during follow-up, but only one regrew to larger than its original volume at >3 years and (b) Fifteen tumors continued to decrease in volume during follow-up. TAE, transcatheter arterial embolization Y, year(s).

Based on these data, we defined two types of tumor according to whether they regrew or continued to shrink during follow-up. The tumor type was associated with whether or not supplementary microcoil embolization was performed, such that tumors not receiving supplementary microcoil embolization were more likely to regrow during follow-up compared with tumors receiving supplementary microcoil embolization (Fisher’s probability test, 78% vs. 0%, P < 0.001) (Table 1).

Discussion

This retrospective study compared the long-term progression of AMLs following embolization by GSPs with or without supplementary microcoil embolization.

Many previous studies have examined AML volume after embolization; however, most of these studies evaluated the degree of tumor shrinkage based on a decrease in tumor diameter^9,10,17–25 rather than a decrease in tumor volume.^11,12,26 The relative reductions in tumor volume observed in the present study were comparable to those reported in previous studies that also used a decrease in tumor volume to evaluate the degree of tumor shrinkage (mean or median value, 43%–81%), using embolic agents including absolute alcohol, microspheres, microparticles, and microcoils.^11,12,26 We also found that no tumor developed recurrent aneurysms ≥5 mm or bleeding after embolization, indicating that prophylactic TAE with GSPs and microcoils was an efficient method for reducing both tumor size and the risk of bleeding. In addition, no procedure-associated complications, other than post-embolization syndrome, were observed, demonstrating that prophylactic TAE with GSPs and microcoils was also a safe method for treating renal AMLs. There has been one case report of the use of TAE with lipiodol and cyanoacrylate for hemorrhagic AMLs with successful results, and further studies on the effectiveness of this embolic agent for prophylactic TAE are expected.⁸

Several previous studies investigated the association between tumor reduction and the type or size of embolic agent used, with no reported differences in tumor reduction among the different agents.^9,11,12 In the present study, we found that tumor progression during follow-up was influenced by whether or not supplementary microcoil embolization (>90% of the tumoral vasculature was occluded by supplementary microcoil embolization) was performed, with tumors not receiving supplementary microcoil embolization having a high probability (78%) of regrowth during follow-up, whereas those receiving supplementary microcoil embolization continued to decrease in volume.

Although there was no significant difference in relative tumor reduction within 3 years of embolization between tumors that did and did not receive supplementary microcoil embolization, the relative tumor reduction at >3 years after embolization was significantly smaller in tumors not receiving supplementary microcoil embolization. The lack of significant differences in the distribution of concomitant diseases, percentage of fatty components, and original tumor volume between the two groups suggests that differences in tumor reduction were associated only with the degree of supplementary microcoil embolization. Furthermore, the fact that differences in relative tumor reduction only became apparent at >3 years after embolization suggests that using GSPs without microcoil embolization reduced the long-term effects of embolization.

Unlike microcoils, which are permanent agents, GSPs are impermanent and recanalization can therefore occur.^11,14 This suggests that tumor feeders not occluded by supplementary microcoils may be recanalized more easily and quickly than occluded vessels, which may in turn lead to tumor regrowth. Regarding the present study, this would explain why tumors not receiving complete supplementary microcoil embolization regrew during follow-up, and why tumor reduction was significantly smaller at >3 years in these tumors compared with tumors that received complete supplementary microcoil embolization. Indeed, renal arteriography in a representative case showed revascularization of tumoral feeders that had not been occluded by microcoils during the original embolization (Figure 2).

Our present findings highlight the importance of complete supplementary microcoil embolization for the long-term regression of AMLs. Thus, when using a combination of GSPs and microcoils, supplementary microcoil embolization should be achieved to ensure maximum long-term reduction in tumor volume.

Our study had several limitations. First, although we speculated that the revascularization of feeders that had not been occluded by microcoils was associated with tumor regrowth, we were unable to prove this by angiography imaging because only three cases of re-embolization underwent angiography during follow-up. Second, this was a retrospective study and the imaging modality and timing of follow-up could therefore not be controlled. The use of different imaging modalities (CT and MRI) for consecutive scans and the 6-month follow-up interval may thus have influenced the precise evaluation of tumor reduction. Similarly, the choice of microcatheter and embolic agent could not be controlled. Third, this study was performed in a single center and the sample size was small, which may have influenced the accuracy of the results. Finally, the renal function and patient symptoms were not presented because they were associated with the characteristics of the overall renal AMLs in a single patient, while this study focused exclusively on the characteristics of target tumors selected based on the inclusion criteria.

In conclusion, prophylactic TAE with GSPs and microcoils appears to provide an efficient and safe method for the long-term treatment of renal AMLs. Supplementary microcoil embolization reduced the tendency of tumors to regrow. These results suggest that, when performing prophylactic TAE for renal AMLs, the use of GSPs alone is not sufficient and the use of both GSPs and microcoils is strongly recommended.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231170098 - Supplemental material for Long-term volume reduction in renal angiomyolipomas embolized by gelatin sponge particles with or without supplementary microcoil embolization

Supplemental material, sj-pdf-1-imr-10.1177_03000605231170098 for Long-term volume reduction in renal angiomyolipomas embolized by gelatin sponge particles with or without supplementary microcoil embolization by Xixi Zhang, Ryohei Kuwatsuru, Hiroshi Toei, Daisuke Yashiro, Hideaki Sokooshi and Yoshiki Kuwatsuru in Journal of International Medical Research

Footnotes

Acknowledgements

We thank Mao Hayashi for editing a draft of the manuscript.

Declarations of conflicting interests

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

ORCID iDs

Ryohei Kuwatsuru

Yoshiki Kuwatsuru

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