Transcatheter Arterial Embolization for Renal Angiomyolipoma Using a Micro-balloon Catheter and a Mixture of Ethanol and Lipiodol

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1 Cardiovasc Intervent Radiol (2017) 40: DOI /s TECHNICAL NOTE Transcatheter Arterial Embolization for Renal Angiomyolipoma Using a Micro-balloon Catheter and a Mixture of Ethanol and Lipiodol Yusuke Sawada 1 Masashi Shimohira 1 Takuya Hashizume 1 Ryoji Sobue 2 Soichiro Mori 3 Motoo Nakagawa 1 Yoshiyuki Ozawa 1 Taku Naiki 4 Takashi Nagai 4 Takahiro Yasui 4 Yuta Shibamoto 1 Received: 6 March 2017 / Accepted: 23 June 2017 / Published online: 6 July 2017 Ó Springer Science+Business Media, LLC and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2017 Abstract Purpose To evaluate the efficacy and safety of transcatheter arterial embolization (TAE) for renal angiomyolipoma (AML) using a micro-balloon catheter and a mixture of ethanol and lipiodol. Materials and Methods Twelve consecutive patients with 15 AMLs, 9 females and 3 males, with a median age of 44 years (range, 11 81), underwent this procedure between 2011 and In all procedures, a micro-balloon catheter was advanced to the feeding artery of the AML and TAE was performed with a mixture of ethanol and lipiodol under balloon inflation. We reviewed medical records and images, and evaluated the technical success rate, clinical success rate, and complications. Technical success was defined as completion of TAE using the micro-balloon catheter and the mixture of ethanol and lipiodol. Clinical success was defined as reduction of tumor size on CT, which was performed before and after TAE. Results In 14 of 15 AMLs, the micro-balloon catheter could be advanced to the feeding artery, and TAE was performed successfully. Thus, the technical success rate was 93%. Among these 14 AMLs of 11 patients, 13 AMLs of 10 patients could be followed and tumor shrinkage was & Masashi Shimohira mshimohira@gmail.com Department of Radiology, Graduate School of Medical Sciences, Nagoya City University, Nagoya , Japan Department of Radiology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan Department of Radiology, Komono Kosei Hospital, Komono, Japan Department of Nephro-urology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan confirmed in all. Thus, the clinical success rate was 100%. Four patients had mild symptoms after TAE; the minor complication rate was 33% (4/12), and the major complication rate was 0%. Conclusion TAE for renal AML using the micro-balloon catheter and mixture of ethanol and lipiodol appears to be effective and safe. Introduction Renal angiomyolipoma (AML) is an uncommon benign hamartomatous tumor that contains variable amounts of abnormal blood vessels, smooth muscle, and fat [1]. It has a propensity to bleed spontaneously; size, multifocality, and vascular abnormality are the main risk factors. A tumor size of 40 mm or larger and an aneurysm size of 5 mm or larger were reported to be predictors of rupture [2]. Usefulness of selective transcatheter arterial embolization (TAE) with ethanol for renal AML has been reported with good results; improvement of clinical symptoms was observed in 85%, and prevention of tumor progression was obtained in 97% [3]. In TAE, the advantage of ethanol compared with other embolic agents is permanent occlusion at a capillary level, thereby inducing tissue necrosis [4]. Lipiodol mixed with ethanol improves visualization of the material, leading to prevention of reflux and non-target embolization. Lipiodol also acts as an embolic agent [3]. Furthermore, a microballoon catheter that can be inserted to a 4-Fr catheter or 4-Fr guiding sheath has become available in our country. To the best of our knowledge, there has been no study on TAE for renal AML using the micro-balloon catheter and a mixture of ethanol and lipiodol. The aim of this study is to evaluate the usefulness and safety of TAE for renal AML

2 1934 Y. Sawada et al.: Transcatheter Arterial Embolization for Renal Angiomyolipoma Using a Micro using the micro-balloon catheter and mixture of ethanol and lipiodol. Materials and Methods Characteristics of Patients and AMLs This retrospective study was approved by the Institutional Review Board. Written informed consent for the procedure had been obtained from each patient. Twelve consecutive patients with 15 renal AMLs (1 AML in 10 patients, 2 in 1, and 3 in 1), 9 females and 3 males, with a median age of 44 years (range, years), underwent TAE using the micro-balloon catheter and mixture of ethanol and lipiodol between June 2011 and September The indicative criteria for TAE for renal AML were symptomatic AML or asymptomatic AML that was 40 mm or larger, or had 5 mm or larger aneurysm, according to previous literature [2]. Four of the 12 patients had flank, and the remaining 8 patients were asymptomatic. These 8 patients had a renal AML size of 40 mm or larger or an aneurysm size of 5 mm or larger. In 1 patient, there were 2 AMLs; the maximum axial diameter of 1 AML was larger than 40 mm and that of other AMLs was smaller than 40 mm (36 mm). As they were in the same kidney, both were treated even though 1 was smaller than 40 mm. Details of the patients and renal AMLs are summarized in Table 1. Diagnosis of tuberous sclerosis was evaluated according to previously reported criteria [5], and 10 patients were judged as possible, 1 was probable, and 1 was definitive. The 1 definitive patient underwent everolimus treatment after the TAE. Technique of TAE Using the Micro-balloon Catheter and Mixture of Ethanol and Lipiodol All procedures approached via the common femoral artery with a 4- or 5-Fr guiding sheath (Parent; Medikit, Tokyo, Japan, or Ansel; Cook, Bloomington, IN, USA). The guiding sheath was introduced into the renal artery, and angiography was performed to confirm the feeding artery and the stain of the renal AML. Then, a 4-Fr catheter (Cerulean, Medikit, Tokyo, Japan) was introduced, and a 2.7-Fr micro-balloon catheter (Attendant Nexus or Attendant Delta, Terumo, Tokyo, Japan) was advanced into the feeding artery of the renal AML along a inch guidewire. When a 3.0-Fr micro-balloon (Attendant, Terumo) was introduced, it was advanced through the 4-Fr guiding sheath. The 2.7-Fr catheter had a 4.0-mm balloon, and the 3.0-Fr one had a 4.5-mm balloon. The 2.7-Fr micro-balloon catheter was used in 10 patients, and the 3.0- Fr micro-balloon catheter was used in 2 patients. A 2.7-Fr micro-balloon catheter became available since March Between June 2011 and February 2013, a 3.0-Fr micro-balloon catheter was used, and a 2.7-Fr micro-balloon catheter was employed between March 2013 and September After inflation of the balloon, angiography was performed from the micro-balloon catheter to evaluate the volume of contrast media to fill the feeding artery of the renal AML. According to the finding, the equal volume of the mixture of 70 or 90% ethanol and 30 or 10% lipiodol was injected. A mixture of 70% ethanol and 30% lipiodol was used in the first 2 patients according to a previous study [6], but it was recognized that visibility would be maintained even when the amount of lipiodol was reduced. Thereafter, a mixture of 90% ethanol and 10% lipiodol was employed. Ten minutes later, dispersal of lipiodol was confirmed, and angiography was performed from the micro-balloon catheter after deflation of the balloon. It was reported that embolization of the portal vein using ethanol was reported with 5 min of balloon occlusion [7]. In this study, we used a mixture of ethanol and lipiodol, so the occlusion time should be longer. Thus, we decided to use the occlusion time of 10 min. When the feeding artery was still visualized, the balloon was inflated again, and the mixture of ethanol and lipiodol was added according to the volume of the contrast media of the preceding angiography. This procedure was repeated until the feeding artery, and the stain of the renal AML disappeared. For aneurysms of AMLs, the mixture of lipiodol and ethanol was first used, and when aneurysm could not be occluded, coil embolization was considered. When there were multiple feeding arteries, they were embolized in the same manner. When patients had multiple renal AMLs, they were also embolized in the same manner in 1 session. For control in 11 patients, intravenous drip infusion of 15 mg pentazocine in 100 ml saline was administered during TAE, and when the patient complained of after TAE, the same regimen was added. In 1 patient, epidural anesthesia was performed, using 1% lidocaine (4 ml in a single shot) and 0.125% levobupivacaine (4 ml/h), from immediately before TAE until 1 day after TAE. Evaluation Method Medical records and images of the procedures were reviewed, and the technical success rate, clinical success rate, and complications were evaluated. Technical success was defined as completion of TAE using the micro-balloon catheter and mixture of ethanol and lipiodol. Clinical success was defined as reduction of tumor size with evaluation of CT performed before and after the TAE. Degree of tumor shrinkage was calculated from areas of AML on pre-embolization CT and follow-up CT. Areas of AMLs were calculated with the following formula [8] from axial

3 Y. Sawada et al.: Transcatheter Arterial Embolization for Renal Angiomyolipoma Using a Micro 1935 Table 1 Summary of patients, renal angiomyolipomas, TAE procedure, and outcome Patient no. Tumor no. Symptom Location Rupture Size of AML (mm) Size of aneurysm (mm) Ratio of ethanol (%) Amount of ethanol (ml) Other embolic material Technical success Follow-up period (months) Clinical success Degree of shrinkage (%) 1 1 No L No No Yes 41 Yes Flank L No No Yes 35 Yes No R No No Yes 17 Yes 40 4 R No No Yes Yes Flank L No Coils Yes 14 Yes Flank R Yes Coils Yes 8 Yes No R No No Yes 4 Yes 47 8 R No No Yes Yes 50 9 R No No Yes Yes Flank L No Coils Yes 3 Yes No R No No Yes 3 Yes No L No No Yes 3 Yes No R No No Yes 3 Yes No L No No No 2 NE No L No No Yes Not followed L left kidney, R right kidney, AML angiomyolipoma, TAE transcatheter arterial embolization, FA feeding artery, NE not evaluated

4 1936 Y. Sawada et al.: Transcatheter Arterial Embolization for Renal Angiomyolipoma Using a Micro CT images on the slices showing the maximum AML diameter: (long-axis length x short-axis length) 9 (p/4). Long- and short-axis lengths were measured from the same axial images that were obtained at the middle of the mass. The aneurysm size was also measured from the maximum diameter on an axial image. To evaluate changes of AML, the area of a lesion on the initial CT was compared with that in a follow-up CT. The pre-embolization CT was performed median period of 1 month (1 day 3 months) before the procedure. The follow-up CT was basically performed 3, 6 months, 1 year after the procedure, and once a year thereafter. Degree of tumor shrinkage was calculated with the following formula: {(initial area follow-up area)/initial area} Complications requiring prolonged hospitalization, permanent adverse sequelae, and death were classified as the major complications, and the remaining complications were considered minor. Complications were recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. [9]. When focal renal infarction was found, the degree of renal infarction was categorized into\10, 10 20, and [30% using angiography immediately after embolization and follow-up CT according to previously reported criteria [10]. These images were interpreted by 2 radiologists, both with 13 years of experience in diagnostic and interventional radiology. Any discrepancies were resolved by consensus. Results The results of the procedures are summarized in Table 1. The median size of AML was 58 mm (range, mm). One of the 15 AMLs had ruptured. Four AMLs had an aneurysm, and the median size of the aneurysms was 8.5 mm (range, 6 15 mm). In 14 AMLs of 11 patients, all feeding arteries were selected with the micro-balloon catheter, and TAE was performed using the mixture of ethanol and lipiodol under inflation of the balloon. Two AMLs had 2 feeding arteries, and thus, 16 feeding arteries were selected with the micro-balloon catheter successfully. However, in 1 AML of 1 patient, the feeding artery branched with an acute inverse angle, and it was difficult to advance the micro-balloon catheter. Thus, a conventional 1.6-Fr micro-catheter was introduced, and it was advanced successfully. Then, TAE was performed using the mixture of ethanol and lipiodol without inflation of the balloon. Thus, the technical success rate was 93% (14/15) (Fig. 1). The median amount of the mixture of ethanol and lipiodol used was 1.5 ml (range, ml). In 3 AMLs, coils were also used to embolize aneurysm. In 1 case with a ruptured AML, TAE was planned in 2 separate sessions: First, coil embolization was performed to the feeding artery of extravasation. Second, TAE using a micro-balloon catheter and mixture of ethanol and lipiodol was performed after the condition stabilized in 1 month (Fig. 2). Renal infarction was found in 5 of 12 patients, and thus, the incidence was 42%. In all of the 5, the degree of renal infarction was less than 10%. Among the 11 technical successful patients with 14 AMLs, 10 patients with 13 AMLs underwent a follow-up CT, and tumor shrinkage was confirmed in all AMLs with a median follow-up period of 4 months (range, 3 41 months). The median degree of tumor shrinkage was 46% (range, %). Thus, the clinical success rate was 100% (13/13). One patient with technical failure underwent a follow-up CT after 2 months, and tumor shrinkage was confirmed. Degree of tumor shrinkage was 26%. Four patients had grade 1 adverse event; 3 patients exhibited slight and 1 patient had slight fever, but it improved with only observation. Thus, the minor complication rate was 33% (4/12) and major complication rate was 0%. It was confirmed that there was no renal dysfunction by blood examination. All patients were discharged after TAE, and thereafter, all of them did well without any clinical symptoms or rupture. Discussion In this study, we demonstrated a high technical success rate (93%) and a clinical success rate (100%) with low complication rates (minor 33%, major 0%) of our technique. The median degree of tumor shrinkage was 46% (range, %) in our study. However, our follow-up period has not been so long yet, and we think the tumors may shrink in future. We think careful observation with CT is necessary to check the size of AML after TAE. Focal renal infarction was found in 42% (5/12), but the degree of renal infarction was less than 10%, and no patients had renal dysfunction. All renal infarction was caused by embolization of a tiny artery that branches from the feeding artery of AML, not due to reflux of mixture of ethanol and lipiodol, because it was confirmed that there was no dispersal of lipiodol at the branch arising from the proximal side of the micro-balloon. In the literature, it was reported that the incidence of renal infarction was up to 22.5% [3, 11, 12], and 1 cause was the reflux of ethanol by over injection [3]. The use of an occlusion balloon with ethanol TAE has been demonstrated to be useful to prevent reflux [3, 13], and Loffroy et al. [14] also stated that deep advancement of the balloon catheter contributes to safe and rapid TAE. However, these balloons can only be used in fairly large feeders. On the other hand, the micro-balloon catheter has a high selectability because it can be inserted to a 4-Fr catheter or guiding sheath, and has been applied in several procedures [15 17]. We think the micro-balloon catheter can be

5 Y. Sawada et al.: Transcatheter Arterial Embolization for Renal Angiomyolipoma Using a Micro 1937 Fig. 1 A case of left renal AML. The diameter of AML was 46 mm, and it contained 8-mm aneurysm. A Contrast-enhanced CT shows the AML in the left kidney. B Angiography of the left renal artery shows a feeding artery (arrow) and an aneurysm of the AML (arrow head). C Angiography of the left renal artery shows stain of AML (arrows). D A 2.7-Fr micro-balloon catheter was advanced into the feeding artery (arrow), and angiography under the balloon inflation was performed from the micro-balloon catheter to evaluate the volume of contrast media to fill the feeding artery of the AML. E Then, the mixture of the equal volume of 90% ethanol and 10% lipiodol was injected under balloon inflation and continuous fluoroscopy. F Angiography after TAE shows disappearance of the tumor enhancement. G Contrast-enhanced CT after TAE at 3 months shows shrinkage of the tumor

6 1938 Y. Sawada et al.: Transcatheter Arterial Embolization for Renal Angiomyolipoma Using a Micro Fig. 2 A case of a ruptured right renal AML. The diameter of the AML was 42 mm, and it contained a 6-mm aneurysm. A Contrastenhanced CT shows a retroperitoneal hematoma and an extravasation of a contrast media (arrow) inside of the AML in the right kidney. B Angiography of the right renal artery shows an extravasation of a contrast media (arrow). C A micro-catheter was advanced into the effective to prevent reflux of ethanol at deep branches of the renal artery. Furthermore, it can strengthen the effects of ethanol by preventing dilution from the blood flow and contribute to decreasing the amount of ethanol. Postembolization syndrome has been reported to occur in 35.9% [18]. Our results were similar; the minor complication rate was 33%. However, the symptoms of our patients were mild, and prolonged hospitalization was unnecessary. The complication rate was superior to that in other studies [3]. Lee et al. [19] reported that selective embolization of the most distal branch possibly made management of postembolization syndrome with antipyretics easy. Thus, we think use of the micro-balloon catheter is effective to decrease such complications. Recently, TAE for renal AML using ethylene vinyl alcohol copolymer was reported with a mean size reduction of 45.7% and low complication rates [20]. So, we think prospective comparative studies will be required in future. Tuberous sclerosis-associated AML tends to present at a younger age, has a higher incidence of bilateral renal feeding artery (arrow). D After coil embolization, the aneurysm of the AML disappeared. E Angiography was performed 1 month later using a 2.7-Fr micro-balloon catheter, and stain of AML was confirmed (arrows). Then, TAE was performed with a mixture of 90% ethanol and 10% lipiodol. F Angiography after TAE shows disappearance of the tumor enhancement involvement, be more symptomatic, and has larger tumors [21]. Therefore, TAE is required for multiple AML, and selective TAE is necessary to decrease renal infarction areas. Thus, we believe that use of the micro-balloon catheter may be useful, especially in such cases. However, in 1 case, we could not advance the micro-balloon catheter into the feeding artery. Although the micro-balloon catheter has a high selectability, it is still less selectable than the conventional micro-catheter. Therefore, when it is difficult to advance the micro-balloon catheter into a tiny feeding artery, it should be changed to a conventional micro-catheter. In such a situation, however, there is a risk of reflux of the mixture of ethanol and lipiodol, and hence, we have to be careful. On the other hand, it was reported that aneurysmal ruptures during TAE with an occlusion balloon could be attributable to increased intravascular pressure generated by forceful injection of ethanol into a closed system or to erosion of the thin aneurysm wall by the caustic alcohol [22, 23]. In our study, however, there was no rupture during

7 Y. Sawada et al.: Transcatheter Arterial Embolization for Renal Angiomyolipoma Using a Micro 1939 TAE, and we think an appropriate amount of ethanol should be safe. Furthermore, we believe use of a microballoon catheter is safe because it can occlude the feeding artery and prevent bleeding even in case of rupture. In this study, we experienced a ruptured AML. Onethird of patients with ruptured AML were reported to be in shock [24]. So, TAE should be performed in emergent situation for ruptured AML, and it is necessary to stop bleeding in this session. However, to prevent rupture again, we think curative TAE is required, and use of a microballoon catheter and mixture of ethanol and lipiodol should be effective in this session. Our study has several limitations. The small sample size and retrospective design were key limitations. There was no single operator of TAE, and procedure was not completely standardized due to variability of technique according to individual operator preference. In 1 patient with tuberous sclerosis who underwent everolimus treatment, AML reduction might be influenced with both TAE and everolimus treatment. The follow-up period was relatively short. However, tumor shrinkage of AML was confirmed in all cases even in this short period. Therefore, we think the results of our study demonstrate that this method is valuable. In conclusion, TAE for renal AML using the microballoon catheter and mixture of ethanol and lipiodol appears to be effective and safe. Compliance with Ethical Standards Conflict of interest The authors declare that they have no conflict of interest. References 1. Wagner BJ, Wong-You-Cheong JJ, Davis CJ Jr. Adult renal hamartomas. Radiographics. 1997;17: Yamakado K, Tanaka N, Nakagawa T, Kobayashi S, Yanagawa M, Takeda K. 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