Aldosterone-producing Adenoma in Primary Aldosteronism: CT-guided Radiofrequency Ablation Long-term Results and Recurrence Rate 1

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1 This copy is for personal use only. To order printed copies, contact Shirley Yuk Wah Liu, MBChB, FRCSEd Charmant Cheuk Man Chu, MBChB, FRCR(UK) Teresa Kam Chi Tsui, MBChB, FRCPA Simon Kin Hung Wong, MBChB, FRCSEd Alice Pik Shan Kong, MBChB, FRCP, MD Philip Wai Yan Chiu, MBChB, FRCSEd, MD Francis Chun Chung Chow, MBChB, FRCP Enders Kwok Wai Ng, MBChB, FRCSEd, MD Aldosterone-producing Adenoma in Primary Aldosteronism: CT-guided Radiofrequency Ablation Long-term Results and Recurrence Rate 1 Purpose: Materials and Methods: To evaluate the long-term biochemical, clinical, and recurrence outcomes of radiofrequency (RF) ablation in treating primary aldosteronism due to aldosterone-producing adenoma (APA). Institutional review board approval and written informed consent were obtained. The use of computed tomographically (CT) guided percutaneous RF ablation was evaluated in 36 patients (19 men; mean age 6 standard deviation, 52.1 years ) with APA (17 right and 19 left side; mean size, 15.5 mm 6 5.0). Primary aldosteronism was confirmed by using the oral sodium-loading test. After RF ablation, CT images, aldosterone-to-renin ratio (ARR), serum potassium level, and blood pressure control were assessed at 3 months and at the latest follow-up examination. Long-term treatment success was defined as normalization of ARR at the latest assessment. Comparison of ARR, potassium, and blood pressure levels before and after RF ablation was performed by using the Wilcoxon signed-rank test. Original Research n Vascular and Interventional Radiology 1 From the Departments of Surgery (S.Y.W.L., S.K.H.W., P.W.Y.C., E.K.W.N.), Diagnostic Radiology and Organ Imaging (C.C.M.C.), Chemical Pathology (T.K.C.T.), and Medicine and Therapeutics (A.P.S.K., F.C.C.C.), Faculty of Medicine, Prince of Wales Hospital, Chinese University of Hong Kong, Ngan Shing St, Shatin, New Territories, Hong Kong, SAR. Received October 16, 2015; revision requested December 18; revision received February 8, 2016; accepted March 8; final version accepted March 18. Address correspondence to E.K.N. ( EndersNg@ surgery.cuhk.edu.hk). Results: Conclusion: Primary technical success was achieved in 33 (92%) patients who underwent a single RF ablation session. Secondary technical success was achieved in three (8%) patients who required a second RF ablation. At 3-month follow-up, primary aldosteronism was resolved in 33 (92%) patients, with a starting median ARR of 8583 pmol/l per µg/(l h) that normalized to 97 pmol/l per µg/(l h) (P,.01). Mean serum potassium levels increased from 2.6 mmol/l to 4.0 mmol/l (P =.01). At long-term follow-up (mean, 6.2 years 6 2.5), treatment success was maintained in 33 patients (92%), all of whom had ARRs in the normal range (P,.01). The long-term recurrence rate was 0%. Hypokalemia was resolved in all patients (2.6 mmol/l to 4.1 mmol/l 6 0.3, P =.01). Hypertension was resolved in 13 (36%) patients, and its control was improved in seven (19%) patients. One (3%) patient had major complications and six (17%) had minor complications. CT-guided RF ablation is an effective treatment for APA, with high sustainable long-term treatment success. It may serve as a justifiable treatment alternative to surgery and medical therapy for APA. q RSNA, 2016 q RSNA, 2016 Radiology: Volume 281: Number 2 November 2016 n radiology.rsna.org 625

2 Aldosterone-producing adenoma (APA) is a benign functional adrenal tumor that oversecretes aldosterone to result in primary aldosteronism (PA) and secondary hypertension. While laparoscopic adrenalectomy is regarded as the reference standard treatment, medical therapy with mineralocorticoid receptor antagonists is often recommended as an alternative for patients who are not candidates for or reluctant to undergo surgery (1). Despite comparable blood pressure and cardiovascular outcomes (2), medical treatment is found to be less favorable than surgery for quality-of-life improvement (2 5), cost consumption (6,7), and number of antihypertensive medications needed (2,8,9). Extended follow-up and lifelong drug treatment also are required for patients treated with medical therapy. Therefore, other noninvasive treatments with a reliable safety profile and desirable treatment efficacy are needed to overcome the substantial invasiveness of adrenalectomy and the drawbacks of medical treatment. Imaging-guided percutaneous radiofrequency (RF) ablation is an emerging treatment for APA, with multiple considerable benefits (10 19). First, it is an ideal treatment for patients with risk factors for poor surgical outcome, because it is a minimally invasive procedure performed with local anesthesia and intravenous moderate sedation (10,13,15,19). Furthermore, RF Advances in Knowledge nn Primary aldosteronism resolved after treatment with CT-guided percutaneous radiofrequency ablation in 33 of 36 (92%) patients during mean long-term follow-up of 6.2 years nn No recurrence of primary aldosteronism was detected at longterm follow-up, and hypertension control was improved in 20 (56%) patients. nn Radiofrequency ablation is relatively safe, with only 3% major and 17% minor complication rates. ablation is a repeatable procedure that works well in the highly heat-sensitive adrenocortical cells (13,20). The perinephric fat surrounding the adrenal gland also can serve as a good heat insulator to minimize the heat sink phenomenon and thermal injury to adjacent viscera. In addition, tumor seeding and recurrence after RF ablation are not regarded as major concerns, because almost all APAs are benign lesions. In 2010, we published what is, to our knowledge, the largest prospective series in the English literature about the use of computed tomographically (CT) guided percutaneous RF ablation in patients with unilateral APA (13). Our results in 24 patients showed that RF ablation had high short-term treatment success in 23 (96%) patients. Nevertheless, to our knowledge, the long-term outcomes of RF ablation after treatment of APA have not been evaluated in a large-scale patient sample. The possibility of long-term recurrence of adenoma tissue after RF ablation also remains undefined. Therefore, the purpose of our study was to evaluate the long-term biochemical, clinical, and recurrence outcomes of RF ablation for treatment of PA due to APA. Materials and Methods This was a retrospective observational study in which we used prospectively collected data from patients who received CT-guided percutaneous RF ablation for unilateral APA. This was an extension of our previous study (13), with a larger patient sample size and new analyses of long-term treatment outcomes and recurrence. Our protocol Implications for Patient Care nn CT-guided adrenal radiofrequency ablation is an effective treatment for aldosterone-producing adenoma, with high sustainable longterm treatment success. nn Radiofrequency ablation can be adopted as a less-invasive treatment alternative for patients with aldosterone-producing adenomas. was approved by our institutional review board and was conducted in accordance with the ethical standards of the Helsinki Declaration of Written informed consent was obtained from all patients for study recruitment. The authors had no conflicts of interest to disclose. Patient Selection Between August 2004 and February 2012, consecutive patients aged years who had hypertension and confirmed PA due to a unilateral APA smaller than 4 cm were recruited. Patients with larger APAs were not included, because surgical resection is absolutely indicated for the higher risk of malignancy in adenomas greater than or equal to 4 cm (21). We used our previously described diagnostic algorithm to confirm PA and unilateral APA (13). The diagnosis of PA was confirmed by means of the oral sodium-loading test when patients had a 24-hour urinary aldosterone elevation after a 3-day high-salt diet. The diagnosis of unilateral APA was established when a unilateral adrenal adenoma and a normal contralateral adrenal gland were detected at CT or magnetic resonance imaging in patients with confirmed PA who had a paradoxical drop Published online before print /radiol Content codes: Radiology 2016; 281: Abbreviations: APA = aldosterone-producing adenoma ARR = aldosterone-to-renin ratio PA = primary aldosteronism RF = radiofrequency Author contributions: Guarantors of integrity of entire study, S.Y.W.L., F.C.C.C., E.K.W.N.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, S.Y.W.L.; clinical studies, S.Y.W.L., C.C.M.C., S.K.H.W., A.P.S.K., P.W.Y.C., F.C.C.C., E.K.W.N.; statistical analysis, S.Y.W.L.; and manuscript editing, S.Y.W.L., T.K.C.T., S.K.H.W., A.P.S.K., F.C.C.C., E.K.W.N. Conflicts of interest are listed at the end of this article. 626 radiology.rsna.org n Radiology: Volume 281: Number 2 November 2016

3 in plasma aldosterone level when they changed from supine to upright posture (1). Biopsy was not performed because APA was almost always benign (1). Exclusion criteria were (a) bilateral, multiple, or familial adrenal tumors; (b) other concomitant adrenal diseases such as bilateral adrenal hyperplasia, glucocorticoid-remediable aldosteronism, non glucocorticoid-remediable aldosteronism, Cushing syndrome, Addison disease, and pheochromocytoma; (c) cosecreting tumors (lesions concurrently secreting excessive cortisol, sex hormones, or catecholamines); (d) potentially malignant tumors at imaging (evidence of heterogeneous contrast material enhancement or absolute contrast material washout of less than 60% at delayed contrast-enhanced CT); (e) uncorrected coagulopathy; (f) patient unwillingness to undergo RF ablation; and (g) potentially inaccessible APA (lesions closely touching the inferior vena cava or renal hilum, high retroperitoneal location with proximity to the lung base, and low pararenal location deep in relation to the upper renal pole). In our study, 59 patients with confirmed PA and unilateral APA were screened for recruitment. Twenty-three patients were excluded because of concomitant adrenal diseases (n = 5), unwillingness to undergo surgical interventions (n = 2) or RF ablation (n = 8), and inaccessible APA without safe puncture access (n = 8). In those with inaccessible APAs, six were left-sided lesions close to the inferior vena cava (n = 1), renal hilum (n = 3) and lung base (n = 2), while the remaining two patients had right-sided lesions close to the lung base. Uneventful laparoscopic adrenalectomy was performed in all eight patients. A total of 36 patients (mean age 6 standard deviation, 52.1 years ) were recruited, including 19 men (mean age, 53.0 years ) and 17 women (mean age, 51.2 years 6 9.5). The baseline characteristics of the 36 recruited patients are summarized in Table 1. The mean APA size was 15.5 mm (range, 4 25 mm). There were 17 (47%) right-sided APAs and 19 (53%) left-sided APAs. Table 1 Baseline Characteristics of 36 Patients Who Underwent CT-guided Percutaneous RF Ablation Characteristics CT-guided RF Ablation All RF ablation procedures were performed jointly by a designated consultant interventional radiologist (C.C.M., with 14 years of experience in radiology) and an endocrine surgeon (L.S.Y., with 12 years of experience in surgery). Before the administration of local anesthesia and intravenous moderate sedation, prophylactic intravenous antibiotics (cefuroxime, amoxicillin clavulanate, or ciprofloxacin) and preemptive analgesia (intravenous pethidine) were given. Patients were placed in the prone or lateral decubitus position to obtain the best access route for stepwise RF ablation needle insertion under multidetector CT fluoroscopic guidance. A 15-cm 17-gauge Results Age (y)* Sex Male 19 (53) Female 17 (47) American Society of Anesthesiologists class Class II 33 (92) Class III 3 (8) Positive family history of hypertension 13 (36) Hypertension-related complications Left ventricular hypertrophy on electrocardiogram 7 (19) Proteinuria 9 (25) Renal impairment 3 (8) Retinopathy 0 (0) Clinical hypertension Duration of hypertension (y)* Use of mineralocorticoid receptor antagonist 36 (100) Use of additional antihypertensive medications 23 (64) Hypokalemia Presence of hypokalemia before diagnosis of PA 36 (100) Lowest serum potassium level measured (mmol/l)* Regular use of potassium supplements before RF ablation 28 (78) Detection of APA Laterality of APA Right 17 (47) Left 19 (53) Size of APA (mm)* ARR (pmol/l per µg/[l h] ) 6228 ( ) * Data are means 6 standard deviation. Data are medians, with the range in parentheses. ARR = aldosterone-to-renin ratio. single-type cool-tip RF ablation needle with a 1 3-cm exposure tip was used with the 500 khz cool-tip radiofrequency generator capable of producing 200 W of power (Covidien, Minneapolis, Minn) for ablation in an uninterrupted 12-minute cycle. Ablation time of 12 minutes was chosen because authors of previous studies (10 19) adopted a duration range of 6 16 minutes. The extent of tumor ablation was immediately assessed by means of contrastenhanced CT. Once residual adenoma tissues, defined as the presence of residual contrast-enhanced tissues, were detected, an additional ablation cycle was performed. In our study, the details of the RF ablation procedures were measured. These included Radiology: Volume 281: Number 2 November 2016 n radiology.rsna.org 627

4 the technical success rate, patient positioning, approach of needle insertion, length of needle tip exposure, duration of procedure, duration of ablation, and completeness of adenoma ablation at CT. Patient Monitoring During RF ablation, nurses continuously monitored all patients for blood pressure, pulse, and oxygen saturation. Once intraprocedural hypertension was detected (systolic. 180 mm Hg and/or diastolic. 110 mm Hg), intravenous labetolol was given in 20-mg boluses until blood pressure was titrated (systolic to, 180 mm Hg and diastolic to, 110 mm Hg). After RF ablation, all patients were hospitalized for overnight observation. All mineralocorticoid receptor antagonists and potassium supplements were discontinued. Other antihypertensive medications were titrated to blood pressure readings and were selectively withdrawn on assessment by endocrinologists (K.A.P. and C.F.C.; both with more than 20 years of experience in endocrinology). Repeat RF Ablation and Salvage Surgery Surgeons (L.S.Y., W.S.K., C.P.W. and N.E.K.; all with more than 10 years of experience in surgery) performed a complete evaluation of plasma ARR, serum potassium level, and contrastenhanced CT 3 months after RF ablation. Plasma ARR was measured to confirm resolution of PA, which was defined as plasma ARR less than 750 pmol/l per µg/(l h) as measured in seated patients (1). Serum potassium was measured to confirm resolution of hypokalemia (reference range, mmol/l). Contrast-enhanced CT was performed to evaluate for completeness of adenoma ablation. APA was defined as completely ablated when adenomas showed no contrast enhancement on CT images, with or without a reduction in size (22,23). When persistent PA and residual adenoma tissue were detected on CT images, another session of RF ablation was performed, and the same evaluation protocol was followed. Shortterm treatment success was defined as resolution of PA with CT evidence of complete adenoma ablation after a maximum of two RF ablation sessions. Salvage laparoscopic adrenalectomy was offered to patients (performed by surgeons L.S.Y., W.S.K., C.P.W., and N.E.K.) whose APAs were not treated completely with two successive RF ablation procedures and to those who remained hypertensive. Long-term Follow-up After RF ablation, all patients received regular follow-up at 6 weeks, 3 months, 6 months, 12 months, and then annually. The mean long-term follow-up duration and long-term lost-to-followup rate were estimated. At the latest follow-up, complete biochemical and clinical evaluations were conducted to assess for long-term treatment response to RF ablation. These included (a) plasma ARR levels to evaluate for long-term resolution of PA and possible recurrence of the condition; (b) serum potassium levels to assess for longterm resolution of hypokalemia; and (c) blood pressure evaluation to determine if hypertension was resolved, improved, persistent, or worsened. Persistent PA was defined as abnormal ARR at both 3-month and long-term evaluations. Recurrent PA was defined as normalized ARR at 3-month evaluation but abnormal ARR at long-term follow-up. When persistent or recurrent PA was detected, contrast-enhanced CT was performed to look for residual or recurrent adenoma. Salvage laparoscopic adrenalectomy was offered to patients (performed by surgeons L.S.Y., W.S.K., C.P.W., and N.E.K.) who had persistent or recurrent PA and remained hypertensive. Long-term treatment success was defined as normalization of ARR at the latest assessment. Outcome Measurement After RF ablation, we evaluated the length of hospital stay, rate of intraprocedural hypertension, highest systolic and diastolic blood pressure measurements during RF ablation, major morbidity, minor morbidity, and mortality. At 3-month follow-up, we measured the short-term treatment success, the number of RF ablation sessions required, the number of patients who required repeat RF ablation or salvage adrenalectomy, the rate of resolution of PA, the rate of persistent PA, the mean ARR level, the rate of hypokalemia resolution, and the mean potassium level. At long-term follow-up, we assessed the long-term treatment success rate, the rate of PA resolution, the rate of persistent PA, the rate of recurrent PA, the mean ARR level, the rate of hypokalemia resolution, the mean potassium level, the number of patients who required potassium supplements, the rate of hypertension resolution, the systolic and diastolic blood pressure measurements, and the blood pressure control. Statistical Analysis Statistical analysis was performed by using software (Statistical Package for Social Science for Windows version 22; IBM, Armonk, New York). In the comparison of the differences between pre and post RF ablation levels of ARR, serum potassium, and blood pressure, the Wilcoxon signed-rank test was used. A two-sided P value of less than.05 was considered to indicate a significant difference. Results Details of RF Ablation Primary technical success was achieved in 33 (92%) patients who underwent a single RF ablation procedure, while secondary technical success was achieved in three (8%) patients who required the second RF ablation session. For patient positioning, we used the prone, ipsilateral decubitus, and contralateral decubitus positions in 29 (81%), four (11%), and three (8%) patients, respectively. The RF ablation needle was inserted by means of the posterior paraspinal approach in 31 (86%) patients, intercostal approach in three (8%) patients, and transhepatic approach in two (6%) patients. Ablation was conducted with needle tip exposure of 1 cm in 11 (31%) patients, 2 cm in 24 (67%) patients, and 3 cm in one (3%) patient. One standard 12-minute ablation cycle was 628 radiology.rsna.org n Radiology: Volume 281: Number 2 November 2016

5 Figure 1 Figure 1: Clinical vignette of a 54-year-old woman who had hypokalemic hypertension for 1 year and biochemically confirmed PA. (a) Axial contrast-enhanced CT image shows a 1.1-cm right APA (arrow). (b) Axial CT-guided percutaneous RF ablation with paraspinal approach in prone position. Arrow indicates the RF ablation needle in the adenoma. (c)axial post-rf ablation contrast-enhanced CT scan of the same right APA (arrow) shows reduction in size and no contrast enhancement. applied in all but one patient who required an additional cycle of 5-minute ablation because of the presence of residual contrast-enhancing adenoma tissue. The mean procedure time was 81.4 minutes Ablation was confirmed to be complete in all 36 (100%) patients at immediate postablation CT (Figs 1 3). Complications During RF ablation, intraprocedural hypertension was detected in three patients who required intravenous labetalol administration in an average dose of mg. Their systolic blood pressure levels were 181 mm Hg, 204 mm Hg, and 252 mm Hg. The mean highest intraprocedural systolic and diastolic blood pressure readings were 139 mm Hg 6 50 and 76 mm Hg 6 26, respectively. There were six (17%) minor complications. Three (8%) patients developed self-limiting retroperitoneal hematomas (size,, 3 cm) but none of them had a decrease in hemoglobin or required blood transfusion. A small pneumothorax was detected in three (8%) patients who were all treated conservatively without the need for thoracostomy or chest drainage. A major complication occurred in one (3%) patient who developed an infected retroperitoneal hematoma that required a course of intravenous antibiotics. No drainage procedure or surgical intervention was required. There was no major vascular injury, visceral injury, or cutaneous burn detected. No procedure-related deaths occurred in our study. The other perioperative outcomes are presented in Table 2. Short-term Treatment Success The results at 3-month evaluation after RF ablation are depicted in Figure 2. PA was resolved in 30 patients after a single RF ablation session. Persistent PA was present in six (17%) patients, but residual adenoma tissue at CT was found in only four of them. Three of these six patients underwent a second RF ablation session, and PA had resolved in all of them at reevaluation. Resolution of PA was seen in 33 (92%) patients, with a median plasma ARR that returned to 97 pmol/l per µg/(l h) (range, pmol/l per µg/[l h]). There was no evidence of residual adenoma tissue on CT images in these 33 patients. The overall short-term treatment success rate was 92%. In the remaining three (8%) patients with persistent PA, repeat RF ablation was recommended, but all of the patients refused treatment. One patient refused because she remained normotensive and medication free. Another patient refused because his blood pressure control was markedly improved. The remaining patient preferred medical therapy, because he developed concurrent Radiology: Volume 281: Number 2 November 2016 n radiology.rsna.org 629

6 Figure 2 Figure 2: Flow chart shows results of RF ablation at 3-month evaluation. RFA = radiofrequency ablation, HT = hypertension. Figure 3 Figure 3: Flow chart shows results of RF ablation at long-term follow-up (6.2 years). RFA = radiofrequency ablation, HT = hypertension. colorectal cancer. No salvage laparoscopic adrenalectomy was performed in this study. At 3-month evaluation, the mean serum potassium level increased from 2.6 mmol/l to 4.0 mmol/l (P =.01). Hypokalemia was resolved in 35 (97%) patients. One (3%) patient had persistent hypokalemia due to persistent PA. Long-term Follow-up The mean follow-up duration was 6.2 years No patients were lost to follow-up. The complete clinical and biochemical parameters of all 36 patients before RF ablation and at longterm follow-up are listed in Table 3. As illustrated in Figure 3, there was no recurrent PA in the 33 patients with resolved PA at 3 months after RF ablation. Their median plasma ARR reduced significantly from 8583 pmol/l per µg/ (L h) (range, pmol/l per µg/[l h]) to 115 pmol/l per µg/(l h) (range, pmol/l per µg/[l h]) 630 radiology.rsna.org n Radiology: Volume 281: Number 2 November 2016

7 Table 2 Perioperative Outcomes of CT-guided Percutaneous RF Ablation in 36 Patients Outcome Data Hospital stay (d)* Intraprocedural hypertension 3 (8) Death 0 (0) Major morbidity: infected 1 (3) retroperitoneal hematoma Minor morbidity 6 (17) Small pneumothorax 3 (8) Retroperitoneal hematoma 3 (8) Visceral injury 0 (0) Cutaneous burn 0 (0) Note. Unless otherwise indicated, data are number of outcomes, with percentage in parentheses. * Data are mean 6 standard deviation. (P,.001). The long-term rate of resolution of PA was 92% (n = 33), and the recurrence rate of PA was 0%. The overall rate of persistent PA at long-term follow-up was 8% (n = 3). In three patients with persistent PA, an abnormal plasma ARR was persistently found at long-term evaluation (Table 3). However, none of these patients had residual adenoma tissue on repeat CT images. All of them refused salvage laparoscopic adrenalectomy. For serum potassium status, the long-term rate of hypokalemia resolution was 100%. None of the 36 patients had recurrent hypokalemia. Their mean serum potassium level increased significantly from 2.6 mmol/l to 4.1 mmol/l (P =.01). Although two patients with persistent PA were taking spironolactone, none of the remaining patients were taking potassium supplements. The long-term rate of hypertension resolution was 36% (n = 13). Compared with their status before RF ablation, seven (19%) patients showed improved blood pressure; blood pressure was static in 12 (33%) and worsened in four (11%) patients. RF ablation resulted in long-term improvement in control of hypertension (resolution and improvement) in 20 patients (56%). Systolic and diastolic blood pressure improved from 158 mm Hg 6 18 to 128 mm Hg 6 10 (P,.01) and 94 mm Hg 6 12 to 76 mm Hg 6 9 (P,.01), respectively. The overall long-term treatment success rate was 92%. Discussion In this study, the long-term biochemical and clinical outcomes of RF ablation in treating APA were evaluated. While RF ablation was suggested to be an effective treatment for APA (13), we have now shown that its effectiveness was also sustainable without disease recurrence. RF ablation had an established short-term effect in treating APA (10 19). Nevertheless, evidence about its long-term success in reversing PA in APA is lacking. Most of the available studies were limited by small sample size (10 12,15,17), lack of complete biochemical and clinical outcome evaluation (15 17), and lack of sufficient follow-up duration (13,14,16,19). Mendiratta-Lala et al (14) reported on the use of RF ablation in 10 patients, but their study was limited by its retrospective nature, short follow-up duration (median 17 months only), and the fact that more than 50% of their data for their biochemical follow-up results were missing. In a study by Szejnfeld et al (19), the use of RF ablation in nine patients was retrospectively evaluated, but only short-term biochemical follow-up parameters were measured. In a recent study by Yang et al (18), although biochemical parameters were measured with a mean follow-up duration of 4.1 years, their results were generated from a small retrospective sample (n = 12). In our study of 36 patients with long follow-up duration (mean, 6.2 years) and complete biochemical and clinical evaluation, RF ablation was found to be an effective option with sustainable treatment response in relieving PA. Long-term recurrence was not a therapeutic concern. In our study, long-term treatment failure was found in three (8%) patients at follow-up. All of these patients received only a single RF ablation session and chose not to undergo a second RF ablation session. The postulated reasons for persistent PA after a single RF ablation session are related to the adenoma anatomy and the ablation process. During RF ablation, we adopted the single-type RF ablation needle that can ablate spherically shaped adenomas in a uniform spherical dimension. In lesions with oval or elongated shapes, however, some adenoma tissue may be missed in spite of overlapping zonal ablation, especially the peripheral tissue. For this reason, we recommended a second RF ablation session to achieve complete ablation of any residual adenoma tissue. In the three patients who chose not to undergo the second RF ablation, it was difficult to conclude whether RF ablation had failed or not. It was possible that complete adenoma ablation and resolution of PA could have been achieved if they had undergone the second RF ablation session. So the true effectiveness of RF ablation might be even higher. RF ablation could achieve long-term improvement in hypertension in 56% of patients. The rates of postoperative persistent hypertension have been reported to be 33% 70% after adrenalectomy (24 29). In our study, long-term hypertension resolution was achieved in 36% of patients. Our results were in concordance with the adrenalectomy data. This reflects that RF ablation is as effective as surgery in inducing resolution of hypertension for APA. The underlying causes that accounted for persistent hypertension were controversial. In addition to the possibility of essential hypertension (30), a number of potential causative factors had been postulated (26,31 41). These included preoperative duration of hypertension greater than or equal to 5 years (31 34), preoperative need of greater than two antihypertensive medications (32 35), male sex (32,36), high body mass index (32,37), advanced age (31,36,38 39), family history of hypertension (35), preoperative response to spironolactone (38,40), elevated serum creatinine (33), and variation in CY- P11B2 gene polymorphism (34,41). RF ablation can be performed safely with the patient under local anesthesia and conscious sedation without remarkable major morbidity Radiology: Volume 281: Number 2 November 2016 n radiology.rsna.org 631

8 Table 3 Complete Clinical and Biochemical Parameters before RF Ablation and at Long-Term Follow-up Before RF Ablation After RF Ablation (At Long-term Follow-up) Patient No. Age (y) Sex APA Size (mm) APA Side Plasma Aldosterone (pmol/l) ARR* Lowest K, (mmol/l) No. of Plasma HT Meds Aldosterone (pmol/l) ARR* K (mmol/l) No. of HT Medications HT Control 1 37 F 20 Left Resolved 2 51 F 20 Left Resolved 3 50 M 10 Left Static 4 57 M 18 Left Static 5 56 M 10 Left Static 6 45 M 17 Left Resolved 7 57 F 10 Left Static 8 44 M 15 Right Resolved 9 51 F 11 Right Resolved M 18 Right Resolved M 20 Left Worsened M 10 Right Worsened F 15 Right Static M 13 Left Resolved M 19 Right Resolved F 20 Left Resolved F 16 Left Improved F 4 Right Static F 12.5 Right Improved M 14 Right Static F 14 Left Resolved F 16 Left Resolved F 17 Right Resolved F 25 Right Improved M 10 Right Static M 12 Left Worsened M 20 Left Improved M 22 Right Static F 7 Left Static F 15 Right Static M 21 Left Improved M 10 Right Worsened M 12 Left Improved F 19 Left Static F 24 Right Improved M 23 Right Resolved Note. HT = hypertension, K = potassium. * ARR (pmol/l per µg/[l h]) Number of antihypertensive medications the patient takes, including mineralocorticoid receptor antagonists. 632 radiology.rsna.org n Radiology: Volume 281: Number 2 November 2016

9 or mortality (10,13,15). Self-limiting retroperitoneal hematoma, small pneumothoraces, and intraprocedural hypertensive crisis are the most common minor complications that do not necessitate aggressive interventions (13,14,16,18). In comparison with surgery, which must be performed with the patient under general anesthesia and has the potential to cause scarring, RF ablation is a justifiable alternative with low invasiveness for patients who are reluctant to undergo or not candidates for surgery (11,17). Despite its attractive benefits, RF ablation is not universally applicable to all patients. From the anatomic point of view, RF ablation is not feasible for lesions with proximity to major vasculature because of concern for vascular injury and the heat-sink phenomenon. Because of the lack of histologic proof to exclude malignancy, RF ablation is also not advisable in large, cosecreting lesions or those suspected of malignancy on the basis of imaging. Vigilant patient selection is, therefore, recommended for the sake of patient safety. Despite including extended follow-up, our study was limited by its relatively small sample size and its noncomparative nature. Prospective randomized controlled studies are needed to elucidate the true comparability and benefits of RF ablation over conventional surgery or medical therapy. Furthermore, in our study, we evaluated only one specific type of RF ablation needle and system. Whether our results could be generalizable to other types of RF ablation device or ablative modality is unknown. Furthermore, our study was restricted to APAs smaller than 4 cm. Although most APAs were small lesions (42), whether the favorable results of our study could be applicable to adenomas of larger size is unclear. In conclusion, CT-guided percutaneous RF ablation appears to be an effective treatment for APA with high sustainable long-term treatment success for resolution of PA and a low rate of disease recurrence. The use of RF ablation is a justifiable alternative to surgery and medical therapy, with a favorable 20. Hellman P, Ladjevardi S, Skogseid B, Akerström G, Elvin A. Radiofrequency tissue ablation using cooled tip for liver metassafety profile and promising effectiveness to treat patients with APA. Disclosures of Conflicts of Interest: S.Y.W.L. disclosed no relevant relationships. C.C.M.C. disclosed no relevant relationships. T.K.C.T. disclosed no relevant relationships. S.K.H.W. disclosed no relevant relationships. A.P.S.K. disclosed no relevant relationships. P.W.Y.C. disclosed no relevant relationships. F.C.C.C. disclosed no relevant relationships. E.K.W.N. disclosed no relevant relationships. References 1. Funder JW, Carey RM, Fardella C, et al. 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