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Long-Term Results of a Prospective, Randomized Trial Comparing Retroperitoneoscopic Partial Versus Total Adrenalectomy for Aldosterone Producing Adenoma
Adult Urology Oncology: Adrenal/Renal/Upper Tract/Bladder Long-Term Results of a Prospective, Randomized Trial Comparing Retroperitoneoscopic Partial Versus Total Adrenalectomy for Aldosterone Producing Adenoma Bin Fu, Xu Zhang,* Gong-xian Wang, Bin Lang, Xin Ma, Hong-zhao Li, Bao-jun Wang, Tao-ping Shi, Xing Ai, Hui-xia Zhou and Tao Zheng From the Departments of Urology, First Affiliated Hospital of Nanchang University (BF, GW), Nanchang, China People’s Liberation Army General Hospital (XZ, XM, HL, BW, TS) and Military General Hospital of Beijing People’s Liberation Army (XA, HZ), Beijing and Xiangfan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology (TZ), Xiangfan and School of Health Sciences, Macao Polytechnic Institute (BL), Macao, People’s Republic of China
Abbreviations and Acronyms APA ⫽ aldosterone producing adrenal adenoma AVS ⫽ adrenal venous sampling CT ⫽ computerized tomography PA ⫽ partial adrenalectomy TA ⫽ total adrenalectomy Submitted for publication September 8, 2010. Study received institutional review board and local ethics committee approval. Supported by the National Natural Science Funds for Distinguished Young Scholar 30725040, People’s Republic of China. * Correspondence: Department of Urology, Chinese People’s Liberation Army General Hospital, Military Postgraduate Medical College, 28 Fuxing Rd., Haidian District, Beijing 100853, People’s Republic of China (telephone: ⫹86-1066938008; FAX: ⫹86-10-66938008l; e-mail: xzhang@ tjh.tjmu.edu.cn).
Purpose: The indication for laparoscopic total or partial adrenalectomy in patients with aldosterone producing adrenal adenoma remains controversial. We compared retroperitoneoscopic partial and total adrenalectomy for aldosterone producing adrenal adenoma in a prospective, randomized, multicenter trial. Materials and Methods: Patients with aldosterone producing adrenal adenoma were randomized to retroperitoneoscopic partial or total adrenalectomy. Patient characteristics, surgical data, complications and postoperative clinical results were analyzed statistically. Results: From July 2000 to March 2004, 212 patients were enrolled in this study, including 108 and 104 who underwent total and partial adrenalectomy, respectively. The 2 groups were comparable in patient age, gender, body mass index and tumor site. Mean followup was 96 months in each group. No conversion to open surgery was needed and no major complications developed. Partial adrenalectomy required a shorter operative time than total adrenalectomy but this did not attain statistical significance. Intraoperative blood loss in the partial adrenalectomy group was significant higher than in the total adrenalectomy group (p ⬍0.05) but no patient needed blood transfusion. All patients in each group showed improvement in hypertension, and in all plasma renin activity and aldosterone returned to normal after surgery. No patient required potassium supplements postoperatively. In the total and partial adrenalectomy groups 32 (29.6%) and 29 patients (27.9%), respectively, were prescribed a decreased dose of or fewer antihypertensive medicines at final followup. Conclusions: Retroperitoneoscopic partial adrenalectomy is technically safe. It has therapeutic results similar to those of total adrenalectomy in patients with primary aldosteronism due to aldosteronoma. Key Words: adrenal glands, adrenal cortex neoplasms, hyperaldosteronism, adrenalectomy, laparoscopy
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PRIMARY hyperaldosteronism, first described in 1955 by Conn,1 is biochemically characterized by renin independent overproduction of aldosterone and hypokalemia. It represents the most common form of secondary hy-
pertension, which may account for more than 10% of hypertension cases generally and in specialty settings.2 In recent years widespread use of the plasma aldosterone-to-plasma renin activity ratio as a screening test in
0022-5347/11/1855-1578/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 185, 1578-1582, May 2011 Printed in U.S.A. DOI:10.1016/j.juro.2010.12.051
AND
RESEARCH, INC.
PARTIAL VERSUS TOTAL ADRENALECTOMY FOR ALDOSTERONE PRODUCING ADENOMA
patients with hypertension has led to a 5 to 15-fold increase in the identification of those with primary aldosteronism.3–5 The most common subtypes of primary aldosteronism are APA and bilateral adrenal hyperplasia. The best response to surgical treatment can be expected in patients with APA.6 Since laparoscopic adrenalectomy was first reported in 1992, it has become the standard treatment for benign surgical adrenal disease. There are clear advantages in terms of perioperative morbidity, convalescence and cosmesis when compared to the open surgical approach. Most laparoscopic adrenalectomies for primary hyperaldosteronism involve total removal of the affected adrenal gland.7–9 There has been an increasing trend toward PA worldwide in the last 20 years.10 –12 Although the safety and feasibility of laparoscopic PA has been noted in retrospective studies, the indication for laparoscopic TA or PA for APA remains controversial.8,12 To our knowledge prospective studies comparing long-term outcomes of retroperitoneoscopic PA and TA are lacking. We report the results of a prospective, randomized, controlled trial comparing the 2 methods of laparoscopic adrenalectomy. Our aim was to assess whether there are differences in the curative effect and in patient morbidity between laparoscopic PA and TA.
MATERIALS AND PATIENTS This trial was approved by our institutional internal review board and local ethics committee. Written informed consent was obtained from all patients before surgery. Patients were assigned to retroperitoneoscopic PA or TA through a computer generated randomization process. Patients with APA were candidates for this study. Those with previous ipsilateral adrenal surgery or doubtful adrenal hyperplasia were excluded from analysis. Data were collected in prospective fashion. A single surgeon (XZ) performed all procedures to minimize operator variability factors. The criteria used to establish the diagnosis of primary aldosteronism was a history of persistent hypertension with or without hypokalemia and with biochemical evidence of hyperaldosteronism. Biochemical evidence of hyperaldosteronism was defined as a plasma aldosterone-toplasma renin activity ratio of 20 or greater with a plasma aldosterone concentration of 15 ng/dl or greater and plasma renin activity suppressed to 1 ng/ml or less per hour.4 Diagnosis was confirmed by a lack of aldosterone suppression after an intravenous saline load of 2 l 0.9% saline infused during 4 hours. High resolution CT and/or magnetic resonance imaging was required in all patients. If the contralateral adrenal gland was enlarged or the adrenal neoplasm was smaller than 1 cm, patients were selected to undergo AVS to distinguish aldosterone producing adenoma from idiopathic adrenal hyperplasia. Adrenal vein cannulation was considered successful when the adrenal vein/inferior vena caval cortisol gradient was
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at least 2. It was considered to show lateralization when the aldosterone-to-cortisol ratio in 1 adrenal vein was at least 4 times the ratio in the other adrenal vein. Retroperitoneoscopic adrenalectomy was done as described previously.13 Briefly, the patient was secured in the lateral decubitus position and the retroperitoneal working space was created routinely. After Gerota’s fascia was incised longitudinally dissection proceeded in the bloodless planes between the perirenal fat and the renal fascia. Subsequently the adrenal was sharply dissected free of the kidney from the plane between the adrenal and parenchymal surface of the upper kidney pole. For PA the central vein was not divided unless it was closely surrounded by tumor. To preserve the blood supply of the remnant adrenal gland it was not dissected. Hem-o-lok® clips were routinely used to control bleeding from the adrenal incision. The specimen was removed in an impervious extraction bag. Postoperative followup included repeat biochemical testing, blood pressure recording and documentation of antihypertensive medication. Hypertension cure was defined as normal blood pressure without treatment and improvement was defined as the achievement of normal blood pressure using fewer drugs than before adrenalectomy. Operative time was defined as the interval from skin incision to skin closure. Numerical data from a normal distribution are shown as the group mean ⫾ SD and were analyzed using Student’s t test. Numerical data from a nonnormal distribution are expressed as the group median and range (minimum and maximum), and were evaluated using the Mann-Whitney rank sum test. Pearson’s chi-square test was used to compare categorical date with p ⬍0.05 considered statistically significant. All statistical analysis was completed with SPSS® 12.0.
RESULTS Between July 2000 and March 2004, 212 patients were enrolled in this study, including 108 with TA and 104 with PA group. Table 1 lists patient characteristics. There was no significant difference in age, gender, adrenalectomy site or tumor size between the 2 groups. No open conversion or blood transfusion was needed. Table 2 lists surgical outcomes in the laparoscopic PA and TA groups. PA had a shorter operative time than TA but this did not attain statistical significance. Intraoperative blood loss in the PA group was significantly greater than in the TA group (p ⬍0.05). No major intraoperative complications occurred, including injury to adjacent organs or major vessels. No patient died in the perioperative period. Wound infection developed in only 2 of the 212 cases. Subcutaneous emphysema developed in 7 of 212 patients (3.3%), including 4 with TA and 3 with PA. No addisonian crisis occurred and steroid replacement was unnecessary. No tumor recurrence was noted during the mean 96-month followup. Only 2 patients
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Table 1. Characteristics of patients undergoing TA and PA
No. men/women Mean ⫾ SD age Mean ⫾ SD body mass index (kg/m2) Mean ⫾ SD American Society of Anesthesiologists score No. unilat tumor site: Rt Lt Mean ⫾ SD hypertension duration (yrs) Mean ⫾ SD No. preop antihypertensive drugs
Total
TA
PA
p Value*
93/119 42 ⫾ 6.3 25.9 ⫾ 3.9 2.5 ⫾ 1.5
48/60 41 ⫾ 7.8 25.7 ⫾ 3.5 2.6 ⫾ 1.3
45/59 43 ⫾ 5.8 26.2 ⫾ 4.2 2.3 ⫾ 1.7
0.52 0.61 0.65 0.45
113 99 6.2 ⫾ 1.2 2.1 ⫾ 0.8
55 53 6.3 ⫾ 1.3 2.1 ⫾ 0.8
58 46 5.9 ⫾ 1.2 2.2 ⫾ 0.8
0.51 0.42 0.79 0.21
* No p value was significant.
with TA and 3 with PA group were lost to followup about 2 years after surgery due to a change in address and telephone number. No patient required potassium supplements postoperatively. All patients in each group showed improvement in hypertension and in all plasma renin activity and plasma aldosterone recovered to normal after surgery. However, 32 of 108 patients (29.6%) with TA remained hypertensive with normal plasma aldosterone after surgery. Blood pressure recovered normally with the use of 20 or 40 mg nifedipine retard daily. Patients with PA no longer required antihypertensive medication after surgery and a further 29 (27.9%) were prescribed a decreased dose
of or fewer antihypertensive medicines at final followup. In 21 of the 212 patients (9.9%) pathological evaluation revealed associated micronodules. The rate was significantly higher in the TA than in the PA group (15 of 108 cases or 13.9% vs 6 of 104 or 5.8%, p ⬍0.01).
DISCUSSION Primary aldosteronism often has a higher rate of cardiovascular complications, target organ damage and metabolic syndrome than essential hypertension.14,15 Surgical removal of adenoma is more ben-
Table 2. Clinical and biological results of PA vs TA for APA
Mean ⫾ SD operative time (mins) Mean ⫾ SD intraop blood loss (ml) Mean ⫾ SD hospital stay (days) Mean ⫾ SD systolic blood pressure (mm Hg): Preop Greater than 6 mos postop Mean ⫾ SD diastolic blood pressure (mm Hg): Preop Greater than 6 mos postop Mean ⫾ SD serum aldosterone (ng/dl): Preop Greater than 6 mos postop Mean ⫾ SD plasma renin activity (ng/ml/hr): Preop Greater than 6 mos postop Mean ⫾ SD plasma aldosterone/renin: Preop Greater than 6 mos postop Mean ⫾ SD potassium (mmol/l): Preop Greater than 6 mos postop No. complication: Subcutaneous emphysema Port site infection No. pathological finding: Solitary adenoma Nodular hyperplasia Mean ⫾ SD tumor size (cm)
Total*
TA
PA
p Value
42.2 ⫾ 8 22.4 ⫾ 7 4.1 ⫾ 1.5
43.3 ⫾ 6 15.1 ⫾ 6 4.2 ⫾ 1.3
41.6 ⫾ 9 35.3 ⫾ 10 3.9 ⫾ 1.8
Not significant 0.01 Not significant 0.02
176.3 ⫾ 25 108.3 ⫾ 13
179.5 ⫾ 24 109.4 ⫾ 11
175.9 ⫾ 23 107.2 ⫾ 14
105.4 ⫾ 14 82.2 ⫾ 7
108.3 ⫾ 14 81.3 ⫾ 7
101.8 ⫾ 13 83.4 ⫾ 6
33.4 ⫾ 16 8.2 ⫾ 3.7
32.2 ⫾ 15 8.1 ⫾ 4.2
34.5 ⫾ 16 8.6 ⫾ 2.9
0.26 ⫾ 0.5 2.53 ⫾ 1.1
0.24 ⫾ 0.6 2.51 ⫾ 1.5
0.27 ⫾ 0.4 2.61 ⫾ 1.1
111.2 ⫾ 28 3.3 ⫾ 1.1
106.2 ⫾ 22 3.9 ⫾ 0.9
116.2 ⫾ 29 3.3 ⫾ 1.5
3.0 ⫾ 0.5 4.5 ⫾ 0.4
3.1 ⫾ 0.5 4.4 ⫾ 0.5
3.0 ⫾ 0.4 4.5 ⫾ 0.3
7 2
4 1
3 1
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
0.02
—
— 191 21 1.8 ⫾ 0.3
93 15 1.8 ⫾ 0.4
* No patient received blood transfusion, experienced organ injury, hematoma or addisonian crisis, or died.
98 6 1.9 ⫾ 0.2
Not significant
PARTIAL VERSUS TOTAL ADRENALECTOMY FOR ALDOSTERONE PRODUCING ADENOMA
eficial than medical treatment and laparoscopic surgery is less invasive and preferable to open surgery to manage functioning adrenal tumors. However, the approach that we should use to cure APA, namely PA or TA, remains controversial. Aldosterone producing adenomas are ideal for PA, especially by the laparoscopic approach. Most tumors are small, solitary, benign and often located peripherally on the outer surface of the adrenal cortex. Endoscopic magnification enables better visualization of small vessels than open surgery, permitting meticulous preparation and a clear operative field during resection. In our cohort tumors in 191 of the 212 cases (90.1%) were less than 2.0 cm. No malignancy was found pathologically and recurrent disease did not develop by final followup. PA has short-term and long-term results similar to those of laparoscopic TA. At followup serum potassium had increased to greater than 3.5 mmol/l in all patients in the 2 groups and spironolactone could be withdrawn in all who required this treatment preoperatively. Well controlled blood pressure after tumor removal was considered an important diagnostic parameter of APA as well as the main expected surgical outcome. All patients with PA and TA achieved satisfactory improvement in hypertension after surgery. However, the hypertension cure rate was 70.4% in the TA group and 72.1% in the PA group (p ⬎0.05), consistent with previous reports.11,16 The reasons for inadequate therapy of hypertension after adrenalectomy for primary hyperaldosteronism are not yet well understood. The duration of preoperative hypertension, patient age and vascular remodeling are the parameters with the most important influence.16,17 In our series there were no significant differences between the 2 groups in mean operative time, complications or postoperative morbidity. Ishidoya et al reported that PA had shorter operative time.8 This may be true if the tumor is small enough and located peripherally, especially on the top of the adrenal gland. Our data indicate that PA for tumors of the lower pole or medial limb of the adrenal gland needed more operative time than tumors on top or on the lateral surface. More time were spent to control bleeding and preserve the center vein or the vascular bed adjacent to the remnant adrenal gland, which is necessary for irrigation and recovery of function.11,18 Many urologists are unwilling to perform laparoscopic adrenal sparing adrenalectomy due not only to its technical difficulty but mainly to the potential development of adrenal hyperplasia accompanying the solitary adenoma. Also, since the adrenal glands are a pair of organs, TA is preferred by some urologists due to its risk-to-benefit ratio.8 Imai et al found that 9 of 89 patients (10.1%) with APA had more
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than 2 nodules in the same adrenal gland removed via the open flank approach.19 Ishidoya et al reported an unexpectedly high rate of multiple adenomas/nodules, which were found in 17 of 63 adrenal specimens (27.0%) removed by the laparoscopic approach.8 Although the patients underwent high resolution CT and AVS before surgery, which identified unilateral single APA, the final pathological results are still not completely in accord with the clinical diagnosis. In our study approximately 10% of the patients had APA along with adrenal hyperplasia tissue. Sometimes it is difficult to histopathologically distinguish adenoma from nodules or adenomatous hyperplasia. Unilateral TA in patients with APA or primary unilateral adrenal hyperplasia results in the normalization of hypokalemia in all, improved hypertension in almost all and cured hypertension in 30% to 60%.20 Similar surgical results of PA were seen in these patients. Thus, we speculated that microadenoma/nodules may exist along with the main APA but not all of them synthesize and secrete aldosterone.8 The existence of microadenoma/nodules in the affected adrenal specimens that could not be found by CT also makes us question whether the contralateral side was really normal. It is difficult to explain how a hyperplastic process would involve a single adrenal gland and leave the other completely normal. In situ hybridization showed decreased mRNA expression of steroidogenic enzymes in most hyperplastic zona glomerulosa and hyperplastic nodules in the adrenal cortices adhering to aldosterone producing adenoma. However, a high incidence of minute nodules indicative of active aldosterone production has been found, suggesting that subcapsular micronodules may be the root of aldosterone producing adenoma.21 Patients with unilateral aldosteronoma may have bilateral nodules.21,22 Solitary APA may be a special intermediate type between primary unilateral adrenal hyperplasia, which is rare and surgically treatable, and bilateral adrenal hyperplasia, which is most common and unsuitable for surgery. Since the simple fact of a second adrenal gland does not justify removing the afflicted gland in each case, Jeschke et al believed that a slight but distinct risk of losing the second adrenal gland later for other reasons may exist in a lifetime, which would necessitate lifelong steroid replacement therapy with all its consequences to the patient.12 With the low recurrence rate and good surgical effects previous studies23 and our data strongly support PA as a good choice for APA. A noticeable limitation of our study is that not all patients were selected for AVS, which may have led to selection bias. AVS results did not correlate well with other serum findings, which may have mainly
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PARTIAL VERSUS TOTAL ADRENALECTOMY FOR ALDOSTERONE PRODUCING ADENOMA
been due to technical differences at different hospitals. AVS is regarded by most groups as the gold standard diagnostic test to identify the side of aldosterone secretion.24 However, the increasing spatial resolution of current CT together with the invasiveness of AVS with its risks of failure and complications has led some groups to conclude that AVS is necessary only when cross-sectional imaging findings are equivocal.25,26 Recent studies showed that CT alone can reliably lateralize an aldosterone producing adenoma at least 1.0 cm in diameter and is associated with excellent clinical outcomes.27 Rossi et al suggested that AVS should be
reserved for patients who are candidates for adrenalectomy and more importantly for those who can benefit from it.16
CONCLUSIONS Results show that retroperitoneoscopic PA is technically safe and has therapeutic results similar to those of TA in patients with primary aldosteronism due to aldosteronoma. Routine PA for unilateral APA is rational with the advantage of preserving remnant adrenal function and avoiding the potential risk of steroid replacement.
REFERENCES 1. Conn JW: Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med 1955; 45: 3. 2. Funder JW, Carey RM, Fardella C et al: Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93: 3266. 3. Lim PO, Rodgers P, Cardale K et al: Potentially high prevalence of primary aldosteronism in a primary-care population. Lancet 1999; 353: 40. 4. Mulatero P, Stowasser M, Loh KC et al: Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 2004; 89: 1045. 5. Rossi GP, Bernini G, Caliumi C et al: A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 2006; 48: 2293. 6. Young WF Jr: Primary aldosteronism: a common and curable form of hypertension. Cardiol Rev 1999; 7: 207. 7. Meria P, Kempf BF, Hermieu JF et al: Laparoscopic management of primary hyperaldosteronism: clinical experience with 212 cases. J Urol 2003; 169: 32. 8. Ishidoya S, Ito A, Sakai K et al: Laparoscopic partial versus total adrenalectomy for aldosterone producing adenoma. J Urol 2005; 174: 40. 9. Shen WT, Lim RC, Siperstein AE et al: Laparoscopic vs open adrenalectomy for the treatment of primary hyperaldosteronism. Arch Surg 1999; 134: 628. 10. Al-Sobhi S, Peschel R, Bartsch G et al: Partial laparoscopic adrenalectomy for aldosterone-pro-
ducing adenoma: short-and long-term results. J Endourol 2000; 14: 497. 11. Walz MK, Peitgen K, Diesing D et al: Partial versus total adrenalectomy by the posterior retroperitoneoscopic approach: early and long-term results of 325 consecutive procedures in primary adrenal neoplasias. World J Surg 2004; 28: 1323. 12. Jeschke K, Janetschek G, Peschel R et al: Laparoscopic partial adrenalectomy in patients with aldosterone-producing adenomas: indications, technique, and results. Urology 2003; 61: 69. 13. Zhang X, Fu B, Lang B et al: Technique of anatomical retroperitoneoscopic adrenalectomy with report of 800 cases. J Urol 2007; 177: 1254. 14. Milliez P, Girerd X, Plouin PF et al: Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 2005; 45: 1243. 15. Fallo F, Veglio F, Bertello C et al: Prevalence and characteristics of the metabolic syndrome in primary aldosteronism. J Clin Endocrinol Metab 2006; 91: 454. 16. Rossi GP, Bolognesi M, Rizzoni D et al: Vascular remodeling and duration of hypertension predict outcome of adrenalectomy in primary aldosteronism patients. Hypertension 2008; 51: 1366. 17. Lumachi F, Ermani M, Basso SM et al: Long-term results of adrenalectomy in patients with aldosterone-producing adenomas: multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg 2005; 71: 864. 18. Ikeda Y, Takami H, Niimi M et al: Laparoscopic partial or cortical-sparing adrenalectomy by dividing the adrenal central vein. Surg Endosc 2001; 15: 747.
19. Imai T, Tanaka Y, Kikumori T et al: Laparoscopic partial adrenalectomy. Surg Endosc 1999; 13: 343. 20. Sawka AM, Young WF, Thompson GB et al: Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med 2001; 135: 258. 21. Shigematsu K, Kawai K, Irie J et al: Analysis of unilateral adrenal hyperplasia with primary aldosteronism from the aspect of messenger ribonucleic acid expression for steroidogenic enzymes: a comparative study with adrenal cortices adhering to aldosterone-producing adenoma. Endocrinology 2006; 147: 999. 22. Doppman JL, Gill JR Jr, Miller DL et al: Distinction between hyperaldosteronism due to bilateral hyperplasia and unilateral aldosteronoma: reliability of CT. Radiology 1992; 184: 677. 23. Kaye DR, Storey BB, Pacak K et al: Partial adrenalectomy: underused first line therapy for small adrenal tumors. J Urol 2010; 184: 18. 24. Rossi GP, Seccia TM, Pessina AC: Primary aldosteronism: part II: subtype differentiation and treatment. J Nephrol 2008; 21: 455. 25. Melby JC, Spark RF, Dale SL et al: Diagnosis and localization of aldosterone-producing adenomas by adrenal-vein catheterization. N Engl J Med 1967; 277: 1050. 26. Tan YY, Ogilvie JB, Triponez F et al: Selective use of adrenal venous sampling in the lateralization of aldosterone-producing adenomas. World J Surg 2006; 30: 879. 27. Zarnegar R, Bloom AI, Lee J et al: Is adrenal venous sampling necessary in all patients with hyperaldosteronism before adrenalectomy? J Vasc Interv Radiol 2008; 19: 66.
Abbreviations and Acronyms APA ⫽ aldosterone producing adrenal adenoma AVS ⫽ adrenal venous sampling CT ⫽ computerized tomography PA ⫽ partial adrenalectomy TA ⫽ total adrenalectomy Submitted for publication September 8, 2010. Study received institutional review board and local ethics committee approval. Supported by the National Natural Science Funds for Distinguished Young Scholar 30725040, People’s Republic of China. * Correspondence: Department of Urology, Chinese People’s Liberation Army General Hospital, Military Postgraduate Medical College, 28 Fuxing Rd., Haidian District, Beijing 100853, People’s Republic of China (telephone: ⫹86-1066938008; FAX: ⫹86-10-66938008l; e-mail: xzhang@ tjh.tjmu.edu.cn).
Purpose: The indication for laparoscopic total or partial adrenalectomy in patients with aldosterone producing adrenal adenoma remains controversial. We compared retroperitoneoscopic partial and total adrenalectomy for aldosterone producing adrenal adenoma in a prospective, randomized, multicenter trial. Materials and Methods: Patients with aldosterone producing adrenal adenoma were randomized to retroperitoneoscopic partial or total adrenalectomy. Patient characteristics, surgical data, complications and postoperative clinical results were analyzed statistically. Results: From July 2000 to March 2004, 212 patients were enrolled in this study, including 108 and 104 who underwent total and partial adrenalectomy, respectively. The 2 groups were comparable in patient age, gender, body mass index and tumor site. Mean followup was 96 months in each group. No conversion to open surgery was needed and no major complications developed. Partial adrenalectomy required a shorter operative time than total adrenalectomy but this did not attain statistical significance. Intraoperative blood loss in the partial adrenalectomy group was significant higher than in the total adrenalectomy group (p ⬍0.05) but no patient needed blood transfusion. All patients in each group showed improvement in hypertension, and in all plasma renin activity and aldosterone returned to normal after surgery. No patient required potassium supplements postoperatively. In the total and partial adrenalectomy groups 32 (29.6%) and 29 patients (27.9%), respectively, were prescribed a decreased dose of or fewer antihypertensive medicines at final followup. Conclusions: Retroperitoneoscopic partial adrenalectomy is technically safe. It has therapeutic results similar to those of total adrenalectomy in patients with primary aldosteronism due to aldosteronoma. Key Words: adrenal glands, adrenal cortex neoplasms, hyperaldosteronism, adrenalectomy, laparoscopy
1578
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PRIMARY hyperaldosteronism, first described in 1955 by Conn,1 is biochemically characterized by renin independent overproduction of aldosterone and hypokalemia. It represents the most common form of secondary hy-
pertension, which may account for more than 10% of hypertension cases generally and in specialty settings.2 In recent years widespread use of the plasma aldosterone-to-plasma renin activity ratio as a screening test in
0022-5347/11/1855-1578/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 185, 1578-1582, May 2011 Printed in U.S.A. DOI:10.1016/j.juro.2010.12.051
AND
RESEARCH, INC.
PARTIAL VERSUS TOTAL ADRENALECTOMY FOR ALDOSTERONE PRODUCING ADENOMA
patients with hypertension has led to a 5 to 15-fold increase in the identification of those with primary aldosteronism.3–5 The most common subtypes of primary aldosteronism are APA and bilateral adrenal hyperplasia. The best response to surgical treatment can be expected in patients with APA.6 Since laparoscopic adrenalectomy was first reported in 1992, it has become the standard treatment for benign surgical adrenal disease. There are clear advantages in terms of perioperative morbidity, convalescence and cosmesis when compared to the open surgical approach. Most laparoscopic adrenalectomies for primary hyperaldosteronism involve total removal of the affected adrenal gland.7–9 There has been an increasing trend toward PA worldwide in the last 20 years.10 –12 Although the safety and feasibility of laparoscopic PA has been noted in retrospective studies, the indication for laparoscopic TA or PA for APA remains controversial.8,12 To our knowledge prospective studies comparing long-term outcomes of retroperitoneoscopic PA and TA are lacking. We report the results of a prospective, randomized, controlled trial comparing the 2 methods of laparoscopic adrenalectomy. Our aim was to assess whether there are differences in the curative effect and in patient morbidity between laparoscopic PA and TA.
MATERIALS AND PATIENTS This trial was approved by our institutional internal review board and local ethics committee. Written informed consent was obtained from all patients before surgery. Patients were assigned to retroperitoneoscopic PA or TA through a computer generated randomization process. Patients with APA were candidates for this study. Those with previous ipsilateral adrenal surgery or doubtful adrenal hyperplasia were excluded from analysis. Data were collected in prospective fashion. A single surgeon (XZ) performed all procedures to minimize operator variability factors. The criteria used to establish the diagnosis of primary aldosteronism was a history of persistent hypertension with or without hypokalemia and with biochemical evidence of hyperaldosteronism. Biochemical evidence of hyperaldosteronism was defined as a plasma aldosterone-toplasma renin activity ratio of 20 or greater with a plasma aldosterone concentration of 15 ng/dl or greater and plasma renin activity suppressed to 1 ng/ml or less per hour.4 Diagnosis was confirmed by a lack of aldosterone suppression after an intravenous saline load of 2 l 0.9% saline infused during 4 hours. High resolution CT and/or magnetic resonance imaging was required in all patients. If the contralateral adrenal gland was enlarged or the adrenal neoplasm was smaller than 1 cm, patients were selected to undergo AVS to distinguish aldosterone producing adenoma from idiopathic adrenal hyperplasia. Adrenal vein cannulation was considered successful when the adrenal vein/inferior vena caval cortisol gradient was
1579
at least 2. It was considered to show lateralization when the aldosterone-to-cortisol ratio in 1 adrenal vein was at least 4 times the ratio in the other adrenal vein. Retroperitoneoscopic adrenalectomy was done as described previously.13 Briefly, the patient was secured in the lateral decubitus position and the retroperitoneal working space was created routinely. After Gerota’s fascia was incised longitudinally dissection proceeded in the bloodless planes between the perirenal fat and the renal fascia. Subsequently the adrenal was sharply dissected free of the kidney from the plane between the adrenal and parenchymal surface of the upper kidney pole. For PA the central vein was not divided unless it was closely surrounded by tumor. To preserve the blood supply of the remnant adrenal gland it was not dissected. Hem-o-lok® clips were routinely used to control bleeding from the adrenal incision. The specimen was removed in an impervious extraction bag. Postoperative followup included repeat biochemical testing, blood pressure recording and documentation of antihypertensive medication. Hypertension cure was defined as normal blood pressure without treatment and improvement was defined as the achievement of normal blood pressure using fewer drugs than before adrenalectomy. Operative time was defined as the interval from skin incision to skin closure. Numerical data from a normal distribution are shown as the group mean ⫾ SD and were analyzed using Student’s t test. Numerical data from a nonnormal distribution are expressed as the group median and range (minimum and maximum), and were evaluated using the Mann-Whitney rank sum test. Pearson’s chi-square test was used to compare categorical date with p ⬍0.05 considered statistically significant. All statistical analysis was completed with SPSS® 12.0.
RESULTS Between July 2000 and March 2004, 212 patients were enrolled in this study, including 108 with TA and 104 with PA group. Table 1 lists patient characteristics. There was no significant difference in age, gender, adrenalectomy site or tumor size between the 2 groups. No open conversion or blood transfusion was needed. Table 2 lists surgical outcomes in the laparoscopic PA and TA groups. PA had a shorter operative time than TA but this did not attain statistical significance. Intraoperative blood loss in the PA group was significantly greater than in the TA group (p ⬍0.05). No major intraoperative complications occurred, including injury to adjacent organs or major vessels. No patient died in the perioperative period. Wound infection developed in only 2 of the 212 cases. Subcutaneous emphysema developed in 7 of 212 patients (3.3%), including 4 with TA and 3 with PA. No addisonian crisis occurred and steroid replacement was unnecessary. No tumor recurrence was noted during the mean 96-month followup. Only 2 patients
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Table 1. Characteristics of patients undergoing TA and PA
No. men/women Mean ⫾ SD age Mean ⫾ SD body mass index (kg/m2) Mean ⫾ SD American Society of Anesthesiologists score No. unilat tumor site: Rt Lt Mean ⫾ SD hypertension duration (yrs) Mean ⫾ SD No. preop antihypertensive drugs
Total
TA
PA
p Value*
93/119 42 ⫾ 6.3 25.9 ⫾ 3.9 2.5 ⫾ 1.5
48/60 41 ⫾ 7.8 25.7 ⫾ 3.5 2.6 ⫾ 1.3
45/59 43 ⫾ 5.8 26.2 ⫾ 4.2 2.3 ⫾ 1.7
0.52 0.61 0.65 0.45
113 99 6.2 ⫾ 1.2 2.1 ⫾ 0.8
55 53 6.3 ⫾ 1.3 2.1 ⫾ 0.8
58 46 5.9 ⫾ 1.2 2.2 ⫾ 0.8
0.51 0.42 0.79 0.21
* No p value was significant.
with TA and 3 with PA group were lost to followup about 2 years after surgery due to a change in address and telephone number. No patient required potassium supplements postoperatively. All patients in each group showed improvement in hypertension and in all plasma renin activity and plasma aldosterone recovered to normal after surgery. However, 32 of 108 patients (29.6%) with TA remained hypertensive with normal plasma aldosterone after surgery. Blood pressure recovered normally with the use of 20 or 40 mg nifedipine retard daily. Patients with PA no longer required antihypertensive medication after surgery and a further 29 (27.9%) were prescribed a decreased dose
of or fewer antihypertensive medicines at final followup. In 21 of the 212 patients (9.9%) pathological evaluation revealed associated micronodules. The rate was significantly higher in the TA than in the PA group (15 of 108 cases or 13.9% vs 6 of 104 or 5.8%, p ⬍0.01).
DISCUSSION Primary aldosteronism often has a higher rate of cardiovascular complications, target organ damage and metabolic syndrome than essential hypertension.14,15 Surgical removal of adenoma is more ben-
Table 2. Clinical and biological results of PA vs TA for APA
Mean ⫾ SD operative time (mins) Mean ⫾ SD intraop blood loss (ml) Mean ⫾ SD hospital stay (days) Mean ⫾ SD systolic blood pressure (mm Hg): Preop Greater than 6 mos postop Mean ⫾ SD diastolic blood pressure (mm Hg): Preop Greater than 6 mos postop Mean ⫾ SD serum aldosterone (ng/dl): Preop Greater than 6 mos postop Mean ⫾ SD plasma renin activity (ng/ml/hr): Preop Greater than 6 mos postop Mean ⫾ SD plasma aldosterone/renin: Preop Greater than 6 mos postop Mean ⫾ SD potassium (mmol/l): Preop Greater than 6 mos postop No. complication: Subcutaneous emphysema Port site infection No. pathological finding: Solitary adenoma Nodular hyperplasia Mean ⫾ SD tumor size (cm)
Total*
TA
PA
p Value
42.2 ⫾ 8 22.4 ⫾ 7 4.1 ⫾ 1.5
43.3 ⫾ 6 15.1 ⫾ 6 4.2 ⫾ 1.3
41.6 ⫾ 9 35.3 ⫾ 10 3.9 ⫾ 1.8
Not significant 0.01 Not significant 0.02
176.3 ⫾ 25 108.3 ⫾ 13
179.5 ⫾ 24 109.4 ⫾ 11
175.9 ⫾ 23 107.2 ⫾ 14
105.4 ⫾ 14 82.2 ⫾ 7
108.3 ⫾ 14 81.3 ⫾ 7
101.8 ⫾ 13 83.4 ⫾ 6
33.4 ⫾ 16 8.2 ⫾ 3.7
32.2 ⫾ 15 8.1 ⫾ 4.2
34.5 ⫾ 16 8.6 ⫾ 2.9
0.26 ⫾ 0.5 2.53 ⫾ 1.1
0.24 ⫾ 0.6 2.51 ⫾ 1.5
0.27 ⫾ 0.4 2.61 ⫾ 1.1
111.2 ⫾ 28 3.3 ⫾ 1.1
106.2 ⫾ 22 3.9 ⫾ 0.9
116.2 ⫾ 29 3.3 ⫾ 1.5
3.0 ⫾ 0.5 4.5 ⫾ 0.4
3.1 ⫾ 0.5 4.4 ⫾ 0.5
3.0 ⫾ 0.4 4.5 ⫾ 0.3
7 2
4 1
3 1
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
0.02
—
— 191 21 1.8 ⫾ 0.3
93 15 1.8 ⫾ 0.4
* No patient received blood transfusion, experienced organ injury, hematoma or addisonian crisis, or died.
98 6 1.9 ⫾ 0.2
Not significant
PARTIAL VERSUS TOTAL ADRENALECTOMY FOR ALDOSTERONE PRODUCING ADENOMA
eficial than medical treatment and laparoscopic surgery is less invasive and preferable to open surgery to manage functioning adrenal tumors. However, the approach that we should use to cure APA, namely PA or TA, remains controversial. Aldosterone producing adenomas are ideal for PA, especially by the laparoscopic approach. Most tumors are small, solitary, benign and often located peripherally on the outer surface of the adrenal cortex. Endoscopic magnification enables better visualization of small vessels than open surgery, permitting meticulous preparation and a clear operative field during resection. In our cohort tumors in 191 of the 212 cases (90.1%) were less than 2.0 cm. No malignancy was found pathologically and recurrent disease did not develop by final followup. PA has short-term and long-term results similar to those of laparoscopic TA. At followup serum potassium had increased to greater than 3.5 mmol/l in all patients in the 2 groups and spironolactone could be withdrawn in all who required this treatment preoperatively. Well controlled blood pressure after tumor removal was considered an important diagnostic parameter of APA as well as the main expected surgical outcome. All patients with PA and TA achieved satisfactory improvement in hypertension after surgery. However, the hypertension cure rate was 70.4% in the TA group and 72.1% in the PA group (p ⬎0.05), consistent with previous reports.11,16 The reasons for inadequate therapy of hypertension after adrenalectomy for primary hyperaldosteronism are not yet well understood. The duration of preoperative hypertension, patient age and vascular remodeling are the parameters with the most important influence.16,17 In our series there were no significant differences between the 2 groups in mean operative time, complications or postoperative morbidity. Ishidoya et al reported that PA had shorter operative time.8 This may be true if the tumor is small enough and located peripherally, especially on the top of the adrenal gland. Our data indicate that PA for tumors of the lower pole or medial limb of the adrenal gland needed more operative time than tumors on top or on the lateral surface. More time were spent to control bleeding and preserve the center vein or the vascular bed adjacent to the remnant adrenal gland, which is necessary for irrigation and recovery of function.11,18 Many urologists are unwilling to perform laparoscopic adrenal sparing adrenalectomy due not only to its technical difficulty but mainly to the potential development of adrenal hyperplasia accompanying the solitary adenoma. Also, since the adrenal glands are a pair of organs, TA is preferred by some urologists due to its risk-to-benefit ratio.8 Imai et al found that 9 of 89 patients (10.1%) with APA had more
1581
than 2 nodules in the same adrenal gland removed via the open flank approach.19 Ishidoya et al reported an unexpectedly high rate of multiple adenomas/nodules, which were found in 17 of 63 adrenal specimens (27.0%) removed by the laparoscopic approach.8 Although the patients underwent high resolution CT and AVS before surgery, which identified unilateral single APA, the final pathological results are still not completely in accord with the clinical diagnosis. In our study approximately 10% of the patients had APA along with adrenal hyperplasia tissue. Sometimes it is difficult to histopathologically distinguish adenoma from nodules or adenomatous hyperplasia. Unilateral TA in patients with APA or primary unilateral adrenal hyperplasia results in the normalization of hypokalemia in all, improved hypertension in almost all and cured hypertension in 30% to 60%.20 Similar surgical results of PA were seen in these patients. Thus, we speculated that microadenoma/nodules may exist along with the main APA but not all of them synthesize and secrete aldosterone.8 The existence of microadenoma/nodules in the affected adrenal specimens that could not be found by CT also makes us question whether the contralateral side was really normal. It is difficult to explain how a hyperplastic process would involve a single adrenal gland and leave the other completely normal. In situ hybridization showed decreased mRNA expression of steroidogenic enzymes in most hyperplastic zona glomerulosa and hyperplastic nodules in the adrenal cortices adhering to aldosterone producing adenoma. However, a high incidence of minute nodules indicative of active aldosterone production has been found, suggesting that subcapsular micronodules may be the root of aldosterone producing adenoma.21 Patients with unilateral aldosteronoma may have bilateral nodules.21,22 Solitary APA may be a special intermediate type between primary unilateral adrenal hyperplasia, which is rare and surgically treatable, and bilateral adrenal hyperplasia, which is most common and unsuitable for surgery. Since the simple fact of a second adrenal gland does not justify removing the afflicted gland in each case, Jeschke et al believed that a slight but distinct risk of losing the second adrenal gland later for other reasons may exist in a lifetime, which would necessitate lifelong steroid replacement therapy with all its consequences to the patient.12 With the low recurrence rate and good surgical effects previous studies23 and our data strongly support PA as a good choice for APA. A noticeable limitation of our study is that not all patients were selected for AVS, which may have led to selection bias. AVS results did not correlate well with other serum findings, which may have mainly
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PARTIAL VERSUS TOTAL ADRENALECTOMY FOR ALDOSTERONE PRODUCING ADENOMA
been due to technical differences at different hospitals. AVS is regarded by most groups as the gold standard diagnostic test to identify the side of aldosterone secretion.24 However, the increasing spatial resolution of current CT together with the invasiveness of AVS with its risks of failure and complications has led some groups to conclude that AVS is necessary only when cross-sectional imaging findings are equivocal.25,26 Recent studies showed that CT alone can reliably lateralize an aldosterone producing adenoma at least 1.0 cm in diameter and is associated with excellent clinical outcomes.27 Rossi et al suggested that AVS should be
reserved for patients who are candidates for adrenalectomy and more importantly for those who can benefit from it.16
CONCLUSIONS Results show that retroperitoneoscopic PA is technically safe and has therapeutic results similar to those of TA in patients with primary aldosteronism due to aldosteronoma. Routine PA for unilateral APA is rational with the advantage of preserving remnant adrenal function and avoiding the potential risk of steroid replacement.
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