Radiofrequency ablation compared with laparoscopic adrenalectomy for aldosterone-producing adenoma

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1 Original article Radiofrequency ablation compared with laparoscopic adrenalectomy for aldosterone-producing adenoma S. Y. Liu 1,C.M.Chu 2,A.P.Kong 3,S.K.Wong 1,P.W.Chiu 1,F.C.Chow 3 ande.k.ng 1 Departments of 1 Surgery, 2 Diagnostic Radiology and Organ Imaging, and 3 Medicine and Therapeutics, Prince of Wales Hospital, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong, China Correspondence to: Professor E. K. Ng, Department of Surgery, Prince of Wales Hospital, Faculty of Medicine, Chinese University of Hong Kong, Ngan Shing Street, Shatin, Hong Kong, China ( endersng@surgery.cuhk.edu.hk) Background: Radiofrequency ablation (RFA) is an emerging treatment for primary aldosteronism owing to aldosterone-producing adenoma. Whether RFA could be an alternative treatment to laparoscopic adrenalectomy is unknown. Methods: This was a retrospective comparative study in patients with aldosterone-producing adenoma undergoing either laparoscopic adrenalectomy or CT-guided percutaneous RFA between 2004 and Short-term outcomes and long-term resolution rates of primary aldosteronism (normalized aldosterone to renin ratio), hypokalaemia and hypertension (BP lower than 140/90 mmhg without antihypertensive medical therapy) were evaluated. Results: Some 63 patients were included, 27 in the laparoscopic adrenalectomy group and 36 in the RFA group. RFA was associated with shorter duration of operation (median 12 versus 124 min; P < 0 001), shorter hospital stay (2 versus 4days;P < 0 001), lower analgesic requirements (13 of 36 versus 23 of 27 patients; P < 0 001) and earlier resumption of work (median 4 versus 14 days; P = 0 006). Morbidity rates were similar in the two groups. With median follow-up of 5 7(range ) years, resolution of primary aldosteronism was seen in 33 of 36 patients treated with RFA and all 27 patients who had laparoscopic adrenalectomy (P = 0 180). Hypertension was resolved less frequently after treatment with RFA compared with laparoscopic adrenalectomy (13 of 36 versus 19 of 27 patients; P = 0 007). Hypokalaemia was resolved in all patients. Conclusion: For patients with aldosterone-producing adenoma the efficacy of resolution of primary aldosteronism and hypertension was inferior after treatment with RFA compared with laparoscopic adrenalectomy. Presented to the World Congress of Surgery, Bangkok, Thailand, August 2015, and awarded International Association of Endocrine Surgeons Best Clinical Paper prize Paper accepted 25 April 2016 Published online 11 August 2016 in Wiley Online Library ( DOI: /bjs Introduction Aldosterone-producing adenoma (APA) is a surgically curable cause of primary aldosteronism characterized by secondary hypertension with or without hypokalaemia 1 3. Laparoscopic adrenalectomy is currently recommended as the standard treatment for APA 4,5. However, in a study of the German Conn Registry 6 evaluating 555 patients in five centres, adrenalectomy was undertaken in only per cent, which indicates that the majority of patients with APA were not considered for surgery. For patients who are unfit or do not wish to undergo surgery, medical treatment with mineralocorticoid receptor antagonists is often recommended, although lifelong follow-up and drug compliance are necessary 4. In a recent systematic review 7 comparing the outcomes of surgery and medical therapy, BP control and cardiovascular complications were found to be comparable. Medical therapy was considered less favourable than surgery owing to the greater number of antihypertensive medications needed to maintain BP control 7 9, smaller improvement in quality of life 10,11,and higher cost 7,12,13 compared with surgery. Radiofrequency ablation (RFA) has recently emerged as a new treatment for primary alosteronism In 2010, the investigators of the present study 18 reported on the 2016 BJS Society Ltd BJS 2016; 103:

2 Radiofrequency ablation versus adrenalectomy for aldosterone-producing adenoma 1477 feasibility of CT-guided percutaneous RFA in 24 patients with APA. At a median follow-up of 25 5 months, RFA had induced remission of primary aldosteronism and resolution of hypertension in 96 and 67 per cent of patients respectively. Several smaller series 19 21,23 have demonstrated a high short-term cure rate after treatment with RFA in patients with primary aldosteronism. A comparative study between surgery and RFA in patients with APA is lacking 18,23. The aim of the present study was to compare the short- and long-term outcomes of treatment with laparoscopic adrenalectomy versus RFA in patients with APA. Methods This was a retrospective comparative study in a consecutive series of patients with APA who were treated with either laparoscopic adrenalectomy or CT-guided percutaneous RFA between August 2004 and August The study protocol was approved by the local institutional review board (CREC ) and the study was conducted in accordance with the ethical standards of the Helsinki Declaration of Biochemistry Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured by liquid chromatography tandem mass spectrometry. The normal range of PRA was ng per ml per h and the limit of detection was 0 07 ng per ml per h. The analytical coefficients of variation (CV) for PRA were as follows: 6 9 per cent for 2 0ngpermlperh,5 6 per cent for 4 3ngper ml per h, and 5 9 per cent for 13 7 ng per ml per h. For PAC, the upper limit of the normal range and the limit of detection were 488 pmol/l and 50 pmol/l respectively. The analytical CV for PAC were as follows: 6 9 per cent for 202 pmol/l, 3 9 per cent for 322 pmol/l, and 4 5 per cent for 1515 pmol/l. Diagnosis of primary aldosteronism The diagnosis of primary aldosteronism was performed by calculation of the aldosterone to renin ratio (ARR). Blood samples for the measurement of PAC and PRA were drawn after at least 2 h of the patient being in the upright position (walking or standing) and then again after 15 min in the sitting position. An ARR value of 750 pmol/l per ng per ml per h or above was considered positive for the diagnosis of primary aldosteronism. The diagnosis of primary aldosteronism was confirmed by increased 24-h urinary aldosterone excretion (more than 28 nmol/day), or raised PAC after an oral salt load test consisting of a 3-day high-salt diet 4. Medications that might interfere with the renin angiotensin axis, including diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, spironolactone, beta-blockers and non-steroidal antiinflammatory drugs, were stopped for at least 4 weeks before the test. Diagnosis of aldosterone-producing adenoma The diagnosis of APA was established when a unilateral adrenal adenoma and a normal contralateral adrenal gland were detected unequivocally on CT or MRI in patients with confirmed primary aldosteronism who showed a paradoxical decrease in PAC from supine to upright posture during the posture test 4,25. Adrenal venous sampling was performed selectively when bilateral or multiple lesions in the adrenal glands were detected on CT or MRI, when no nodular lesion was evident on imaging, or when the posture test showed equivocal results. During venous sampling, the adrenal veins were catheterized through a percutaneous femoral vein approach. Continuous intravenous infusion of cosyntropin was started at a rate of 50 μg/h about 30 min before adrenal vein catheterization and continued throughout the procedure. Blood samples were collected from the bilateral adrenal veins and inferior vena cava to determine the cortisol and aldosterone concentrations. Successful venous sampling was confirmed when the ratio of the cortisol concentration at the adrenal vein to the cortisol concentration at the inferior vena cava was 10 or higher. To correct for dilution, the cortisol-corrected aldosterone ratio (aldosterone concentration divided by cortisol concentration) was used. Lateralization of aldosterone secretion was considered when the cortisol-corrected aldosterone ratios between the adrenal veins were 4 0 orhigher. Patient recruitment Among patients with unilateral APA, those who met the inclusion criteria and with no exclusion criteria (Table 1) were included in the study. In addition to written information, treatment details relating to the benefits and risks of laparoscopic adrenalectomy and RFA were explained fully to all patients by one designated surgeon. Counselling towards either treatment option was avoided and the mode of treatment was decided entirely by the patients. Written informed consent was obtained from all patients for participation in the study.

3 1478 S. Y. Liu, C. M. Chu, A. P. Kong, S. K. Wong, P. W. Chiu, F. C. Chow and E. K. Ng Table 1 Patient selection criteria Inclusion criteria Exclusion criteria Age years APA < 4cm Bilateral adrenal adenomas Multiple adrenal tumours Hormone co-secreting tumours Other concomitant adrenal diseases Potentially malignant tumours Heterogeneous contrast enhancement pattern Absolute contrast washout < 60 per cent on delayed imaging Evidence of major vascular or tissue invasion Inaccessible APA location for percutaneous treatment Refusal to undergo laparoscopic adrenalectomy and RFA APA, aldosterone-producing adenoma; RFA, radiofrequency ablation. Laparoscopic adrenalectomy Laparoscopic adrenalectomy was performed by three surgeons via a laparoscopic lateral transperitoneal approach. Prophylactic parenteral antibiotics (cefuroxime, amoxicillin clavulanate or ciprofloxacin) were given routinely. Routine urinary bladder catheterization was not performed. Alterations in haemodynamic parameters were recorded. In patients with intraoperative hypertensive crisis, defined as systolic BP more than 180 mmhg or diastolic BP over 110 mmhg, intravenous labetalol was given in bolus titration for BP control. Radiofrequency ablation All procedures were performed jointly by an interventional radiologist and a surgeon. Under local anaesthesia and sedation, patients were put in either a prone or lateral decubitus position. Prophylactic parenteral antibiotics (cefuroxime, amoxicillin, clavulanate or ciprofloxacin) and pre-emptive analgesia (intravenous pethidine 1 mg/kg) were given during the procedure. After stepwise insertion of a single-type Cool-tip TM (Medtronic, Minneapolis, Minnesota, USA) RFA needle under multidetector CT guidance, an uninterrupted 12-min ablation cycle was conducted. The extent of tumour ablation was assessed by CT. When residual adenoma tissue was detected, additional ablation cycles were applied. Haemodynamic parameters were monitored and managed in the same manner as in laparoscopic adrenalectomy. Postoperative care After treatment, mineralocorticoid receptor antagonists and potassium supplements were discontinued in both groups. Other antihypertensive medications were terminated selectively depending on BP control. Intravenous Screened for study enrolment n = 81 Excluded n = 18 Inaccessible APA n = 8 Co-secreting tumours n = 5 Multiple adenomas n = 3 Refusal to undergo surgery and RFA n = 2 Recruited to study n = 63 Received laparoscopic adrenalectomy n = 27 Received RFA n = 36 Received single RFA session n = 33 Received two RFA sessions n = 3 Resolved PA n = 27 Persistent PA n = 0 Resolved PA n = 30 Persistent PA n = 3 Resolved PA n = 3 Persistent PA n = 0 Fig. 1 Flow chart of patient selection and allocation, and long-term follow-up results. APA, aldosterone-producing adenoma; RFA, radiofrequency ablation; PA, primary aldosteronism

4 Radiofrequency ablation versus adrenalectomy for aldosterone-producing adenoma 1479 Table 2 Baseline characteristics of 63 patients treated with laparoscopic adrenalectomy or radiofrequency ablation for aldosterone-producing adenoma Laparoscopic adrenalectomy Radiofrequency ablation (n = 27) (n = 36) P Age (years)* 50 7(10 3) 52 2(10 4) Sex ratio (M : F) 9 : : ASA fitness grade I II III 0 1 Co-morbidity Cardiac disease Cerebrovascular disease Respiratory disease Renal impairment Diabetes mellitus Obesity History of previous surgery Cholecystectomy 1 1 Hysterectomy 3 2 Rectal resection 0 1 Positive family history of hypertension Clinical hypertension Duration (years)* 7 3(5 6) 8 8(5 8) Use of spironolactone Dose of spironolactone (mg)* 53(32) 65(33) No. of hypertension medications 1(1 4) 1(1 4) Highest systolic BP (mmhg) 144 ( ) 157 ( ) Highest diastolic BP (mmhg) 85 (67 106) 97 (70 120) Hypokalaemia Lowest serum potassium (mmol/l)* 2 7(0 4) 2 6(0 4) Need for potassium supplements Diagnosis of primary aldosteronism ARR (pmol/l per ng per ml per h) 7575 ( ) 6228 ( ) PRA(ngpermlperh) 0 07 ( ) 0 1 ( ) PAC (pmol/l) 618 ( ) 767 ( ) Aldosterone-producing adenoma Size (mm)* 14(5) 16(5) Location Right Left Values are *mean(s.d.) and median (range). ARR, aldosterone-to-renin ratio; PRA, plasma renin activity; PAC, plasma aldosterone concentration. χ 2 test, except t test and Mann Whitney U test. pethidine and oral paracetamol were prescribed for pain control. Haemoglobin levels were checked routinely on postoperative day 1. An oral diet was resumed when there was no clinical evidence of gastrointestinal disturbance. Immediate treatment success Immediate treatment success was defined as biochemical resolution of primary aldosteronism with a normal ARR (plasma ARR less than 750 pmol/l per ng per ml per h) 4,18. An adrenocortical adenoma on histopathology was used as an adjunct to confirm adenoma removal in the laparoscopic group. Following RFA treatment, initial evaluation for biochemical resolution of primary aldosteronism was undertaken at 3 months to permit recovery of the contralateral adrenal gland. CT was used to confirm complete adenoma ablation, defined as the absence of contrast-enhanced tissues with or without a decrease in adenoma size 18,26,27. When persistent primary aldosteronism or residual adenoma tissue on CT was detected, a second treatment with RFA was performed. In the RFA group, immediate treatment success was defined as resolution of primary aldosteronism after a maximum of two RFA sessions. Laparoscopic adrenalectomy was offered when immediate treatment success was not achieved.

5 1480 S. Y. Liu, C. M. Chu, A. P. Kong, S. K. Wong, P. W. Chiu, F. C. Chow and E. K. Ng Table 3 Short-term outcomes after laparoscopic adrenalectomy or radiofrequency ablation of aldosterone-producing adenoma Laparoscopic adrenalectomy Radiofrequency ablation (n = 27) (n = 36) P** Technical outcomes Technical success Conversion 1 Duration of operation (min)* 124(34) 12(0 9) < Blood loss (%ΔHb) 5 1 (0 16 2) 0 (0 11 1) Safety Mortality Major morbidity Intraoperative bleeding 1 0 Infected retroperitoneal haematoma 0 1 Minor morbidity Pulmonary atelectasis 1 0 Pneumothorax 0 3 Urinary tract infection 2 0 Retroperitoneal haematoma 0 3 Hypertensive crisis Highest intraoperative systolic BP (mmhg) 150 ( ) 151 ( ) Recovery Time to resume soft diet (days) 1 (0 4) 0 (0 1) < Time to resume full diet (days) 1 (0 5) 0 (0 2) < Treatment with parenteral pethidine Treatment with oral paracetamol < Dose of paracetamol (g) 4(0 9 5) 0 (0 5 7) < Length of hospital stay (days)* 4(1) 2(1) < Time to resume normal activities (days) 7 (3 60) 3 (1 14) < Time to resume work (days) 14 (3 90) 4 (1 28) Efficacy Immediate treatment success Cost ( )* 9450(781) 6612(1692) < Hypertension at 1 year Resolution of hypertension# Medications for hypertension Stopped medications Reduced number or dose of medications 4 13 Same number or dose of medications 2 4 Increased number or dose of medications 0 0 Values are *mean(s.d.) and median (range). Successful laparoscopic removal of the adrenal gland in laparoscopic adrenalectomy and successful percutaneous ablation of the adrenal adenoma in radiofrequency ablation. Systolic BP over 180 mmhg or diastolic BP greater than 110 mmhg. Biochemical resolution of primary aldosteronism with normal aldosterone-to-renin ratio of less than 750 pmol/l per ng per ml per h. #Systolic BP below 140 mmhg and diastolic BP under 90 mmhg without antihypertensive medication for at least 1 year. %ΔHb, percentage drop in haemoglobin level on postoperative day 1. **χ 2 test, except t test and Mann Whitney U test. Long-term follow-up Patients were asked to conduct home BP measurement at least twice a week. All patients were followed annually in the outpatient clinic. At each follow-up appointment, BP was measured by a nurse using an automated biceps-cuff device after the patient had rested for at least 15 min. Long-term outcomes, plasma ARR, serum potassium level and BP were evaluated. Resolution of primary aldosteronism was defined as a normalized ARR, and resolution of hypertension was defined as systolic BP lower than 140 mmhg and diastolic BP below 90 mmhg without antihypertensive medication for at least 1 year after treatment. In both treatment groups, long-term treatment success was defined as resolution of primary aldosteronism at the last follow-up. Outcome measurement For short-term outcomes, intraoperative hypertensive crisis, minor morbidity (Clavien Dindo grade I or II) 28, major morbidity (Clavien Dindo grade III or higher), mortality, duration of operation, blood loss (expressed as percentage drop in haemoglobin level on day 1), time to resumption of oral diet, analgesic requirement, hospital stay, and time to resumption of normal activities and work

6 Radiofrequency ablation versus adrenalectomy for aldosterone-producing adenoma 1481 Table 4 Long-term outcomes of laparoscopic adrenalectomy and radiofrequency ablation for aldosterone-producing adenoma Laparoscopic adrenalectomy Radiofrequency ablation (n = 27) (n = 36) P Primary aldosteronism Resolution of primary aldosteronism ARR (pmol/l per ng per ml per h)* 83 (10 393) 173 ( ) 0 088# PRA(ngpermlperh)* 1 2 ( ) 1 3 ( ) 0 882# PAC (pmol/l)* 85 (50 230) 163 (50 907) 0 006# Normalized PAC level Hypokalaemia Resolution of hypokalaemia Serum potassium (mmol/l) 4 1(0 3) 4 1(0 2) 0 808** Hypertension Resolution of hypertension Medication for hypertension Stopped medications Reduced number or dose of medications 6 9 Same number or dose of medications 2 13 Increased number or dose of medications 0 1 Systolic BP* 119 (99 155) 126 (95 164) 0 078# Diastolic BP* 76 (57 98) 80 (63 96) 0 350# Recurrent hypertension after 1 year 2 of 21 6 of Values are *median (range) and mean(s.d.). Defined as normal aldosterone-to-renin ratio (ARR) (less than 750 pmol/l per ng per ml per h). Systolic BP below 140 mmhg and diastolic BP under 90 mmhg without antihypertensive medication for at least 1 year. PRA, plasma renin activity; PAC, plasma aldosterone concentration. χ 2 test, except #Mann Whitney U test and **t test. were analysed. The costs of the two procedures were calculated on the basis of the total charges for hospital bed, surgeon fee, anaesthetic fee, operating theatre expenses, radiology fee and general nursing care. For long-term outcomes, the rates of resolution of primary aldosteronism, hypokalaemia and hypertension were assessed. Statistical analysis Data are presented as mean(s.d.) for continuous variables with a normal distribution and median (range) for those without a normal distribution, with statistical analysis using t test and Mann Whitney U test respectively. The χ 2 test or Fisher s exact test was used for analysis of nominal and categorical data. Two-sided P < was considered statistically significant. Statistical analysis was performed using SPSS version 22 (IBM, Armonk, New York, USA). Results During the study interval, 81 patients were diagnosed with unilateral APA. Eighteen patients were excluded and the remaining 63 were included in the study (Fig. 1). Adrenal venous sampling was performed to confirm unilateral APA in three patients (5 per cent) (2 in the adrenalectomy group and 1 in the RFA group). Some 27 patients (43 per cent) had laparoscopic adrenalectomy and 36 (57 per cent) underwent RFA. There was no difference between the two groups in the preoperative variables recorded, including ASA fitness grade, co-morbidity and history of previous abdominal surgery (Table 2). Short-term outcomes The short-term outcomes are summarized in Table 3.All RFA procedures were successful technically, whereas one patient in laparoscopic adrenalectomy group required conversion to an open procedure owing to uncontrolled bleeding from a tear in the right adrenal vein (technical success: 36 of 36 versus 26 of 27 patients respectively; P = 0 244). Open adrenalectomy was successful in this patient. RFA was associated with a shorter mean operating time, earlier resumption of normal diet, lower analgesic requirements, shorter mean hospital stay, shorter time to resumption of normal activities, and shorter time to resumption of work compared with laparoscopic adrenalectomy. RFA was also less costly (Table 3). Laparoscopic adrenalectomy and RFA were comparable with respect to rates of hypertensive crisis during the procedures (2 of 27 versus 3 of 36 patients respectively; P = 0 636), mortality (no death in either group) and major morbidity (1 of 27 versus 1of36patients;P = 0 677). The major morbidities included intraoperative bleeding leading to open conversion in the laparoscopic adrenalectomy group, and infected retroperitoneal haematoma that was treated with parenteral antibiotics after RFA.

7 1482 S. Y. Liu, C. M. Chu, A. P. Kong, S. K. Wong, P. W. Chiu, F. C. Chow and E. K. Ng Pretreatment systolic BP (mmhg) Long-term systolic BP (mmhg) Laparoscopic adrenalectomy RFA 80 Laparoscopic adrenalectomy RFA a Pretreatment systolic BP b Long-term systolic BP Pretreatment diastolic BP (mmhg) Long-term diastolic BP (mmhg) Laparoscopic adrenalectomy RFA 40 Laparoscopic adrenalectomy RFA c Pretreatment diastolic BP d Long-term diastolic BP Fig. 2 Differences in systolic BP and diastolic BP before and after laparoscopic adrenalectomy or radiofrequency ablation (RFA): a systolic BP before treatment, b systolic BP at long-term follow-up, c diastolic BP before treatment and d diastolic BP at long-term follow-up. Median values (bold line), interquartile range (box) and range (error bars) excluding outliers (symbols) are shown. a P = 0 058, b P = 0 078, c P = 0 281, d P = (Mann Whitney U test) There was no difference in minor complications between the laparoscopic adrenalectomy and RFA groups (3 of 27 versus 6of36patients;P = 0 403). Minor morbidity in the laparoscopic group included pulmonary atelectasis (1 patient) and urinary tract infections due to postoperative urinary retention (2). In the RFA group, three patients developed a minor pneumothorax owing to iatrogenic puncture of the lung during RFA needle insertion, but none required chest drainage. Retroperitoneal haematomas were found in three patients with an APA larger than 15 mm; no haematoma needed active intervention. Short-term treatment efficacy Immediate treatment success was achieved in all 27 patients in the laparoscopic adrenalectomy group. In the RFA group, 33 of 36 patients were treated by a single RFA session and three required two sessions (Fig. 1). Immediate treatment success was achieved in 33 of 36 patients who had primary aldosteronism resolved at 3 months after one or two RFA sessions. In the remaining three patients, persistent primary aldosteronism was found after a single RFA session. These three patients refused further treatment with RFA or laparoscopic adrenalectomy. One of these patients eventually became normotensive, normokalaemic and medication-free. Another patient refused RFA and preferred medical therapy because of advanced age and marked improvement in BP control. The final patient was diagnosed with colonic cancer at the time of intervention and refused further treatment. The rate of remission of hypertension at 1 year was lower after treatment with RFA

8 Radiofrequency ablation versus adrenalectomy for aldosterone-producing adenoma 1483 compared with laparoscopic adrenalectomy (19 of 36 versus 21 of 27 patients; P = 0 041). treatment than laparoscopic adrenalectomy (13 of 33 versus 19 of 27 patients; P = 0 017). Long-term outcomes The long-term outcomes are summarized in Table 4. Median follow-up for the whole cohort was 5 7( ) years. There was no difference in the length of follow-up between the laparoscopic adrenalectomy and RFA groups: median 5 3 ( ) versus 6 1 ( ) years respectively (P = 0 223). One patient was lost to follow-up in the laparoscopic group compared with none in the RFA group (P = 0 244). Long-term biochemical follow-up data were available for 24 patients in laparoscopic adrenalectomy group and 36 in RFA group. Long-term treatment success was achieved in all 27 patients in the laparoscopic adrenalectomy group compared with 33 of 36 in the RFA group (P = 0 180). Although the PAC was higher after RFA than laparoscopic adrenalectomy (median 163 versus 85 pmol/l; P = 0 006), the proportions of patients with normalized PAC were comparable (34 of 36 versus 27 of 27; P = 0 323). The ARR was 83 pmol/l per ng per ml per h in the adrenalectomy group compared with 173 pmol/l per ng per ml per h in the RFA group (P = 0 088). None of the patients required potassium supplements at long-term follow-up. Serum potassium levels were normalized in all patients in both treatment groups. Changes in BP in the two treatment groups are illustrated in Fig. 2. At long-term follow-up, the rates of resolution of hypertension were significantly lower after RFA than laparoscopic adrenalectomy (13 of 36 versus 19 of 27 patients; P = 0 007). In the laparoscopic adrenalectomy and RFA groups, the median systolic BP was 119 versus 126 mmhg respectively (P = 0 078) and the median diastolic BP was 76 versus 80 mmhg (P = 0 350). A higher proportion of patients were still taking the same number or dose of antihypertensive medications (13 of 36 versus 2 of 27) or increased number or dose of antihypertensive medications (1 of 36 versus 0 of 27) in the RFA group than in the laparoscopic adrenalectomy group (P = 0 021). Among patients with initial remission of hypertension at the first-year follow-up, recurrence of hypertension was detected at later follow-up in two of 21 and six of 19 patients in the laparoscopic adrenalectomy and RFA groups respectively (P = 0 089). In an analysis restricted to patients with resolved primary aldosteronism, the rates of resolution of hypertension at 1 year were 21 of 27 in the adrenalectomy group versus 18 of 33 in the RFA group (P = 0 061). The rates of resolution of hypertension at long-term follow-up were lower after RFA Discussion In this study, RFA treatment of APA was associated with a shorter duration of operation, faster recovery, lower analgesic requirement and shorter hospital stay compared with laparoscopic adrenalectomy, with similar morbidity. However, RFA was inferior to laparoscopic adrenalectomy in terms of resolution of primary aldosteronism and hypertension. Regardless of the short-term benefits, incomplete adenoma eradication is a major concern after RFA. Because viable adenoma tissue may escape ablation, two RFA sessions are recommended. In the present study, incomplete eradication of adenoma tissue after one RFA treatment was observed in six patients, but three of them failed to adhere to the predefined protocol to undergo the second RFA. Some of the present findings have important implications. Although RFA could be used for treatment of APA, the efficacy is inferior to that of surgery. Repeat RFA sessions may be needed in a significant number of patients. Furthermore, as complete adenoma eradication cannot be guaranteed by RFA, long-term biochemical surveillance is needed. Although the median postoperative ARR and rate of resolution of primary aldosteronism did not differ between the two treatment groups, this could well be due to the small numbers of patients included in the study. In the treatment of hypertension, RFA was clearly inferior to surgery. A smaller proportion of patients were normotensive after treatment with RFA than surgery at 1 year and at long-term follow-up. This difference persisted in an analysis restricted to patients with resolved primary aldosteronism. The rate of remission of hypertension after adrenalectomy is variable, ranging from 30 to 70 per cent Several studies have identified factors that predict resolution of hypertension after adrenalectomy for APA, including shorter duration of hypertension 29 34, smaller number of antihypertensive medications 31 36,women 31,34,37, non-obese patients 31,33,38, young age 30,34,37,39 41, normal serum creatinine concentration 32,33, absence of family history of hypertension 36, and treatment response to spironolactone As patient allocation to treatments was non-randomized in this study, it cannot be ruled out that the difference in remission rates of hypertension was related to selection biases, although the biochemical response to treatments argues against this. Treatment with RFA was not without risks. Retroperitoneal haematoma was the most common

9 1484 S. Y. Liu, C. M. Chu, A. P. Kong, S. K. Wong, P. W. Chiu, F. C. Chow and E. K. Ng complication, probably because the adrenal gland is highly vascularized 18,21 23,27. Retroperitoneal haematomas were often non-expanding and asymptomatic. Superimposed infection occurred in one patient. Routine prophylactic antibiotics for all RFA procedures are therefore recommended. Pneumothorax after RFA might also occur, although most lesions were small and of the laminar type without the need for intervention 18,19,21. Hypertensive crisis during RFA, although no more common than during laparoscopic adrenalectomy, was also diagnosed, probably because the thermal energy could stimulate the release of catecholamines into the circulation 43. Haemodynamic status should therefore be closely monitored and managed. RFA treatment of lesions in close proximity to major vasculatures should be avoided because of the risks of vascular injury and the heat-sink effect. Adenomas at high retroperitoneal or low pararenal locations are also contraindicated for treatment because of the risk of injury to the lungs or kidneys. RFA is not advisable for large lesions and those that are suspected to be malignant on imaging. Although RFA is potentially applicable to malignant adrenal conditions 14,15,19,20,44 47, its use in patients with potentially curative primary adrenocortical carcinoma should be strongly discouraged. In terms of costs, laparoscopic adrenalectomy was more expensive than RFA. However, given the lower efficacy in treatment of hypertension, the long-term cost of RFA treatment might be higher than that of laparoscopic adrenalectomy. The major limitation of this study was use of the posture test and CT for subtype classification of primary aldosteronism. Evolving evidence has suggested that the posture test has a low sensitivity (44 56 per cent) and limited specificity (71 75 per cent) for subclassification of APA, unilateral hyperplasia or bilateral hyperplasia 48. Several studies have also shown that the accuracy of adrenal imaging in lateralizing the source of hyperaldosteronism is poor because many APAs or bilateral lesions are not detectable by CT and MRI, and adrenal incidentalomas are common in elderly patients. It is therefore quite possible that idiopathic unilateral or bilateral hyperplasia could have been misdiagnosed, and a skewed distribution of adrenal hyperplasia between the treatment groups could have influenced the results. The possibility of missed unilateral hyperplasia could also have resulted in worse long-term biochemical and hypertension outcomes in the RFA group 50,51. Adrenal venous sampling should therefore be recommended for subtype classification of primary aldosteronism before contemplating surgery or RFA 4,52,53. RFA of APA had several short-term benefits compared with laparoscopic adrenalectomy, but lower efficacy for the treatment of hypertension. Nevertheless, RFA can be regarded as a good alternative to operation for patients who are unfit or reluctant to undergo surgery, provided that the risk of repeat treatments and longer-term follow-up for recurrence of primary aldosteronism are accepted. Disclosure The authors declare no conflict of interest. References 1 Conn JW. Presidential address, part II: primary aldosteronism, a new clinical syndrome. J Lab Clin Med 1955; 45: Young WF Jr. Primary aldosteronism: a common and curable form of hypertension. Cardiol Rev 1999; 7: Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol 2007; 66: Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H et al. 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