Laparoscopic bilateral adrenalectomy for persistent Cushing[apos ]s disease after transsphenoidal surgery

Laparoscopic bilateral adrenalectomy for persistent Cushing’s disease after transsphenoidal surgery Roberto Lanzi, MD, Francesco Montorsi, MD, Marco Losa, MD, Antonella Centemero, MD, Marco Federico Manzoni, MD, Patrizio Rigatti, MD, Gabriele Cornaggia, MD, Antonio Ettore Pontiroli, MD, and Giorgio Guazzoni, MD, Milan, Italy

Background. We performed bilateral laparoscopic adrenalectomies on four patients (three women and one man) with Cushing’s disease (pituitary-dependent Cushing’s syndrome) showing persistent hypercortisolism after transsphenoidal surgery. Methods. The technique for bilateral transperitoneal laparoscopic adrenalectomy was derived from the one previously adopted by our group for unilateral adrenalectomy and previously described. Eight trocars were used, of which two were used for both left and right adrenalectomy. Results. Bilateral laparoscopic adrenalectomy was performed in a one-stage procedure in the three women and, because of the abundant abdominal fat of the patient, in a two-stage procedure (after a 1-week interval) in the man. Operating times for the three women were 255 minutes, 230 minutes, and 220 minutes , and for the man 170 minutes for right adrenalectomy and 140 minutes for left adrenalectomy. No surgical or anesthesiologic complications were encountered. All patients were discharged from the hospital within 5 days after operation. At present, after follow-up periods of 23, 8, 6, and 18 months, all patients show remission of Cushing’s disease and undetectable cortisol levels. Conclusions. Our experience suggests that bilateral laparoscopic adrenalectomy is a safe and effective procedure and a valid therapeutic option in patients with Cushing’s disease showing persistent hypercortisolism after transsphenoidal surgery. However, the decision to remove both adrenal glands in such patients needs to be weighed against the risk of their having Nelson’s syndrome or other long-term complications. (Surgery 1998;123:144-50.) From the Divisions of Internal Medicine, Urology, Neurosurgery, and Intensive Care, Istituto Scientifico Ospedale San Raffaele, University of Milan, Milan, Italy

BILATERAL ADRENALECTOMY WAS widely used in the past to treat patients with Cushing’s disease (pituitary-dependent Cushing’s syndrome). Although the preferred initial therapy for Cushing’s disease is currently transsphenoidal surgery,1,2 this approach has a success rate of only 75% to 80%.3,4 Moreover, hypercortisolism relapse occurs in about 7% to 12% of successfully operated patients.3,4 Current therapeutic options for patients with persistent or recurrent hypercortisolism after transsphenoidal surgery include repeat transsphenoidal surgery,5,6 conventional radiation therapy,7 stereotactic radiosurgery,8 medical therapy,9 and bilateral adrenalectomy.10,11 With regard to bilateral adrenalectomy, several Accepted for publication May 28, 1997. Reprint requests: Giorgio Guazzoni, MD, Division of Urology, Istituto Scientifico Ospedale San Raffaele, Via Olgettina 60, 20132 Milano, Italy. Copyright © 1998 by Mosby, Inc. 0039-6060/98/$5.00 + 0

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previous reports, extensively reviewed by Miller and Crapo,3 McCance et al.,10 and van Heerden et al.,11 indicate that this therapeutic alternative is weighed down by significant perioperative mortality (up to 19%) and morbidity (7% to 83%) rates, by the risk of developing Nelson’s syndrome (4% to 22%), and by other long-term complications resulting in reduced life expectancy. Furthermore, as a result of the presence of accessory adrenal tissue in other organs or of adrenal remnants left behind after operation,12,13 persistence or recurrence of hypercortisolism after bilateral adrenalectomy has been reported in 1% to 24% of patients.3,12 High perioperative mortality and morbidity rates result from hemorrhage, infections, thromboembolism, and multiorgan failure related to the high degree of invasiveness of the traditional (open) surgical approach and to decreased wound healing and immunologic competence on the part of the patient. On the other hand, persistence of adrenal remnants may be related to the

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Table I. Hormonal values in the four patients with Cushing’s disease before transsphenoidal operation and before bilateral laparoscopic adrenalectomy Before transsphenoidal operation Morning plasma cortisol (normal, 5-25 µg/dl) Urinary free cortisol (normal, 36-150 µg/24 hr) Morning plasma ACTH (normal, 10-100 pg/ml) Plasma cortisol after low dose dexamethasone (µg/dl) Plasma cortisol after high dose dexamethasone (µg/dl) Plasma cortisol before/after* CRH or DDAVP† (µg/dl) Plasma ACTH befpre/after* CRH or DDAVP† (pg/ml) Before bilateral laparoscopic adrenalectomy Morning plasma cortisol (normal, 5-25 µg/dl) Urinary free cortisol (normal, 36-150 µg/24 hr Morning plasma ACTH (normal, 10-100 pg/ml)

technical limitations of the classic surgical approach, particularly as a result of the limited surgical field in patients who are often obese. However, more recent series10,11,14 report a lower incidence of fatal events or major complications, particularly when a posterior approach is used.14 During the last few years several groups15-22 have shown that the laparoscopic approach is equally effective and considerably less invasive than open surgery for unilateral adrenalectomy in patients with benign adrenal tumors. Furthermore, Gagner et al.15,16 reported a positive preliminary experience with bilateral laparoscopic adrenalectomy in patients with persistent Cushing’s disease after transsphenoidal surgery. Here we discuss our experience with four patients affected by Cushing’s disease who submitted to bilateral laparoscopic adrenalectomy after unsuccessful transsphenoidal surgery. SUBJECTS From January 1993 to December 1995, 61 patients with Cushing’s disease were admitted to the Department of Neurosurgery at the Ospedale San Raffaele to undergo transsphenoidal operation. After operation, clinical and biochemical remission of the disease was observed in 45 patients (success rate 73%), whereas 16 showed persistence or recurrence of hypercortisolism. Four of these patients were considered eligible for bilateral adrenalectomy. (1) 33-year-old woman. The patient’s clinical history had begun 8 years earlier, with acne, weight gain, hirsutism, asthenia, hyperhidrosis, and easy bruising. A diagnosis of adrenocorticotropic hormone (ACTH)-dependent hypercortisolism was made on the basis of high morning serum and urinary cortisol levels and plasma ACTH levels, lack of

Pt. 1

Pt. 2

Pt. 3

Pt. 4

33 376 92 32 3.5 42/65.4 119/168

35 514 98 28 6.1 29/39 90/134

25 678 89 27 5.2 28/40 74/120

31 714 41 23 6.7 31/52 39/100

33 1166 82

42 694 84

28 414 98

29 812 34

cortisol suppression after a low but not high dose overnight dexamethasone test, and preserved ACTH and cortisol responsiveness to corticotropinreleasing hormone (CRH) administration (Table I). Therapy with ketoconazole was started at a dose of 200 mg three times a day, resulting in partial improvement of clinical and hormonal abnormalities. The patient was then referred to the Department of Neurosurgery at the Ospedale San Raffaele for surgical exploration of the pituitary gland. Before operation, magnetic resonance imaging (MRI) of the pituitary region showed a partial empty sella with a slight enlargement of the right anterior lobe of the gland, and an area of relative hypointensity in the right lobe after administration of paramagnetic contrast. The patient underwent exploration of the pituitary gland through the transsphenoidal approach. No obvious adenoma was evident during operation. A small area of dishomogeneous tissue located in the right part of the gland was removed. Careful exploration of the left side of the gland through multiple incisions was performed, but no tumor could be detected. Histologic examination of the tissue removed at operation disclosed no evidence of adenomatous tissue. After the operation the patient did not show any sign of clinical remission and her serum and urinary cortisol and plasma ACTH levels remained unmistakably high. Substitution therapy with desmopressin (DDAVP) was temporarily necessary because of a transient diabetes insipidus. At that point the possibility of an ectopic source of ACTH production was considered, but no occult tumor could be detected at imaging. (2) 32-year-old man. The patient’s clinical history had begun 5 years earlier, with weight gain and hypertension. A diagnosis of ACTH-dependent hypercortisolism was made on the basis of high

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Table II. Results of bilateral laparoscopic adrenalectomy Parameters

Pt. 1

Operative time (min.) Blood transfusions Adrenal size (cm) Ambulation (days after operation) Hospital stay (days after operation) Steroid replacement

Pt. 2

255

170 (right), 140 (left)

No (L) 7 × 3.5, (R) 7.5 × 4.5 2 5 Methylprednisolone 6 mg/day, fludrocortisone 0.1 mg/day

No (L) 6 × 5, (R) 7 × 4.5 2 5 Dexamethasone 0.5 mg/day, fludrocortisone 0.1 mg/day

Follow-up (mo) Urinary free cortisol* (normal, 36-150 µg/24 hr) Plasma ACTH* (normal, 10-100 pg/ml)

23 Undetectable 63

18 Undetectable 100

L, Left; R, right. *At the time of the follow-up reported in the table.

morning serum and urinary cortisol levels and plasma ACTH levels, lack of cortisol suppression after a low but not high dose overnight dexamethasone test, and preserved ACTH and cortisol responsiveness to CRH administration (Table I). A sellar computed tomography (CT) scan and MRI showed a small pituitary lesion on the right side of the gland. The patient underwent exploration of the pituitary gland through the transsphenoidal approach. At operation a microadenoma was evident in the right side of the pituitary gland and was removed. After operation the patient showed clinical and biochemical remission of hypercortisolism. One year after operation, however, there was a recurrence of Cushing’s disease, with no evidence of pituitary adenoma at MRI. Therapy with ketokonazole was started, resulting in clinical and biochemical amelioration for about 2 years. By that time a new pituitary MRI showed recurrence of the microadenoma. The patient underwent transsphenoidal operation for the second time; histologic examination showed a microadenoma strongly positive for ACTH at immunohistochemistry. Nevertheless, there was no remission of Cushing’s disease and the patient’s clinical picture gradually became worse as a result of severe hypertension and hypokalemia; in spite of a 1 gm dose of ketoconazole every 24 hours, urinary excretion of free cortisol remained high. (3) 37-year-old-woman. The patient’s clinical history had begun 2 years earlier, with weight gain, hirsutism, and hypertension. ACTH-dependent hypercortisolism was diagnosed on the basis of elevated high morning serum and urinary cortisol levels and plasma ACTH levels, loss of circadian rhythm of cortisol secretion, and lack of cortisol suppression after a low but not high dose overnight dexamethasone test (Table I). An MRI of the sella

turcica did not reveal any pituitary tumor. The patient was then referred to the Department of Neurosurgery at the Ospedale San Raffaele for further diagnostic evaluation and for treatment of hypercortisolism. A repeat MRI scan was interpreted as equivocal because of the presence of an illdelineated small area of hypointensity in the right lateral part of the pituitary. Bilateral sinus petrosal sampling was attempted but was unsuccessful because of anatomic variation in the venous drainage of both cavernous sinuses. Both cortisol and ACTH increased after the administration of CRH. The patient agreed to undergo pituitary exploration. During the operation, pathologic tissue measuring approximately 3 mm in diameter was identified in the right posterolateral part of the gland and removed. Histologic examination confirmed the presence of a basophil adenoma that was strongly immunoreactive for ACTH and infiltrating the dura. The patient recovered without any particular problems, showing a transient amelioration of symptoms. However, postoperative urinaryfree cortisol remained high and plasma cortisol levels were not suppressed after a low dose overnight dexamethasone suppression test. Four months after operation the patient was reevaluated at the referring hospital, where the diagnosis of persistent hypercortisolism was confirmed. An MRI of the sella turcica showed a possible recurrent adenoma near the right cavernous sinus. The patient was then started on low-dose ketoconazole (200 mg/24 hours) because of intolerance, without showing any clinical or biochemical improvement. (4) 37-year-old woman. The patient’s clinical history had begun 1 year earlier, with the gradual development of weight gain, asthenia, amenorrhea, easy skin bruising, acne, and hair loss. Diagnosis of ACTH-dependent hypercortisolism

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Pt. 3

Pt. 4

230

220

No (L) 5.5 × 4, (R) 5 × 3.5 2 5 Dexamethasone 0.5 mg/day, fludrocortisone 0.1 mg/day

No (L) 5 × 3.5, (R) 5.5 × 3.5 2 4 Dexamethasone 0.5 mg/day, fludrocortisone 0.1 mg/day

8 Undetectable 118

6 Undetectable 86

was made on the basis of high morning serum and urinary cortisol levels and normal plasma ACTH levels, loss of circadian rhythm of cortisol secretion, lack of cortisol suppression after a low but not high dose overnight dexamethasone test, and exaggerated ACTH and cortisol response to DDAVP administration (Table I). An MRI of the pituitary failed to reveal any lesion of the gland. The patient was then referred to the Department of Neurosurgery for surgical pituitary exploration. Before operation, bilateral sinus petrosal sampling confirmed the pituitary origin of pituitary hypersecretion and indicated the presence of a significant gradient of ACTH secretion in the right side. During the operation a small area (2 mm in diameter) of apparently abnormal tissue was removed, together with a generous rim of surrounding tissue. Exploration of the rest of the gland did not show other suspect areas. A histologic examination was negative for a pituitary adenoma. The patient recovered uneventfully but did not show any clinical sign of remission. Postoperative endocrine evaluation confirmed the persistence of high serum and urinary cortisol levels with measurable ACTH levels. The patient was then started on ketoconazole therapy, which relieved her symptoms. However, medical therapy had to be stopped because of toxic hepatitis. METHODS The study protocol was approved by the local ethics committee, and all patients signed a written informed consent. The decision to perform bilateral laparoscopic adrenalectomy was taken after a thorough discussion with the patients about different therapeutic alternatives (bilateral adrenalectomy, radiotherapy of the pituitary gland, transsphenoidal reoperation with total hypophysectomy, medical therapy, and radiosurgical therapy).

Patients were fully informed about the laparoscopic technique and the possible need to convert to an open operation. In all cases, operation was performed at the Department of Urology at the Ospedale San Raffaele. Laparoscopic technique has been described previously.21 In short, all patients undergo a full mechanical and antibiotic bowel preparation. A nasogastric tube and urethral catheter are positioned while the patient is under general anesthesia. The patient is placed in a right or left flank position (depending on the preferred side for starting operation) with the bed flexed to 30 degrees to increase the surgical field between the ribs and the iliac crest. A Veress needle is inserted near the umbilicus, and carbon dioxide is insufflated to achieve a 13 to 15 mm Hg pneumoperitoneum. Eight trocars are used and positioned as shown in Fig. 1. Two 10 mm trocars are used for both right and left adrenalectomy, one inserted through the umbilical incision and used for the laparoscope and the other in the midline, 5 cm above the umbilicus; both remain positioned while the patient’s position is changed for contralateral adrenalectomy. In the right side, two 10 mm trocars are positioned just lateral to the midline (1 cm below the costal margin) and in the mamillary line 2 to 3 cm above the transverse umbilical line; a 5 mm trocar is positioned at the crossing of the anterior axillary line with the eleventh and twelfth ribs. In the left side, two 10 mm trocars are positioned in the mamillary line 2 to 3 cm above the transverse umbilical line and in the anterior axillary line at the crossing with the tip of the eleventh rib; a 5 mm trocar is positioned at the crossing of the midaxillary line with the tip of the twelfth rib. On the left side the line of Toldt is incised and the descending colon is dissected free and medialized to expose

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abdomen through the umbilical incision. Great care is taken to remove all carbon dioxide from the peritoneal cavity. Tape strips are used to close the skin incisions. The nasogastric tube and urethral catheter are removed in the recovery room on the day of operation. The sequential stockings are left in place until the patient is ambulatory. Clear liquids are given 1 day after operation and an oral antibiotic preparation is continued for 7 days after completion of the intravenous course. Abdominal ultrasonography is always performed before the patient is discharged from the hospital to detect fluid or blood collections.

Fig. 1. Location and size (mm) of trocar insertion sites for bilateral laparoscopic adrenalectomy.

the anterior surface of the left kidney. After incising the Gerota’s fascia, the renal vein is identified and, by following its superior margin, the lower adrenal vein is found and dissected free. The adrenal vein is ligated between clips and the venous stump is then used as a guide to the adrenal gland and to mobilize the organ during further dissection. On the right side, after lifting the lower margin of the liver the posterior peritoneum is incised along the lateral border of the inferior vena cava. Dissection proceeds upward to reach the main adrenal vein at its entrance to the inferior vena cava. The vein is ligated between clips and severed. The dissection of the glands then proceeds by using both clip ligation and electrocautery. Care is taken on both sides to avoid direct manipulation of the adrenal tissue, as well as to avoid tears and subsequent bleeding. After excision the first adrenal gland is entrapped in a specifically designed sac, connected to a surgical line. This line is placed out of the abdomen through a trocar; the trocar is then removed with all others that are not useful for contralateral operation. The corresponding trocar sites are closed with a no. 1 absorbable suture. The patient’s position is then changed. At the end of the procedure on the contralateral adrenal gland the two sacs are simultaneously removed from the

RESULTS No intraoperative deaths occurred. In all patients both adrenal glands were successfully removed in toto, without fragmentation. Bilateral adrenalectomy was performed in a one-stage procedure in patients 1, 3, and 4, and in a two-stage procedure (at a 1-week interval) in patient 2 as a result of length of time required to reach the adrenal glands because of the abundance of abdominal fat. Operating times are shown in Table II. Anesthesiologic complications were not encountered, and blood transfusions were not required. Steroid replacement therapy was initiated on the day of operation. Hydrocortisone was given at an initial dose of 300 mg/24 hr intravenously; this was gradually decreased and then replaced within 2 to 3 days by oral glucocorticoid and mineralcorticoid therapy (Table II). All patients complained of widespread abdominal pain during the initial 2 to 3 postoperative days, and symptoms were easily controlled by small doses of oral ketoprofen; the patients were able to ambulate by postoperative day 2 and were discharged from the hospital by postoperative day 5. Histologic examination in all patients showed bilateral adrenal hyperplasia. The sizes of the adrenal glands are shown in Table II. During the postsurgical follow-up all patients showed persistently undetectable urinary free cortisol levels and none showed evidence of pituitary adenoma regrowth in the MRI scan. DISCUSSION Our experience confirms previous observations15,16,23 indicating the feasibility, safety, and efficacy of bilateral laparoscopic adrenalectomy in patients with Cushing’s disease showing persistence or recurrence of hypercortisolism after transsphenoidal surgery. In the four patients described in this study, bilateral adrenalectomy was successfully completed, although in one patient this consisted

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of two different operations performed at a 1-week interval, as a result of the length of time required to reach the adrenal glands because of an abundance of abdominal fat. Anesthesiologic complications were not encountered and blood transfusions were not required. All patients were able to ambulate by postoperative day 2 and were discharged from the hospital by postoperative day 5 under steroid replacement therapy. No recurrence of hypercortisolism was observed during the postoperative follow-up (23, 18, 8, and 6 months, respectively). In terms of the advantages of laparoscopy versus the traditional (open) surgical approach to bilateral adrenalectomy, these results indicate the following advantages: (1) reduced invasiveness, particularly important in patients with impaired wound healing or low immunologic defenses as a result of hypercortisolism, thus reducing the perioperative risk of morbidity and mortality; (2) better visibility of the surgical field, which should translate into a lower risk of adrenal remnants being left behind after operation; and (3) reduction of the hospital stay, which, for open surgery, varies between 6 and 15 days.11,14 On the other hand, laparoscopy requires longer operating times than those reported for open surgery22; in fact, for this reason, in one patient we were forced to stop surgery after unilateral adrenalectomy; removal of contralateral adrenal was accomplished 1 week later, however, with no complications. Further experiences on a larger series of patients will clarify whether laparoscopy may be considered a first-choice approach for patients with persistent Cushing’s disease after neurosurgery once the decision to perform bilateral adrenalectomy has been taken. In this sense the last series of open bilateral adrenalectomies10,11,14 showing significantly lower mortality rates as compared with previous reports3,10,11,24 may serve as a standard for comparison. The confirmation of the safety and efficacy of the laparoscopic approach could also lead to reconsideration of the role played by adrenal surgery in cases of persistent or recurrent Cushing’s disease after neurosurgery. In fact, at present there is no consensus about the ideal treatment after unsuccessful pituitary surgery, and different limitations are evident for all alternative therapeutic strategies to bilateral adrenalectomy. Mampalam et al.25 reported a cure rate of only 31% in patients undergoing repeat pituitary operation because of persistent or recurrent Cushing’s disease, and Ram et al.6 described a 71% success rate in a group of 17 patients undergoing further oper-

ation 7 to 46 days after the first operation. Medical therapy with steroidogenesis inhibitors3,9 is hampered by the occurrence of side effects and the need for life-long administration. Radiation therapy leads to remission of Cushing’s disease in only about 40% of patients.3 Moreover, it may take up to 2 years to achieve a full therapeutic effect, with the possible long-term development of neurologic, neoplastic, and hormonal damages. Stereotactic radiosurgery, although effective as a first option therapy,8 has not yet proved effective in cases of persistent or recurrent Cushing’s disease. In conclusion, our preliminary experience shows further evidence regarding the safety and effectiveness of bilateral laparoscopic adrenalectomy, thus suggesting that this is a valid therapeutic option in patients with Cushing’s disease showing persistent hypercortisolism after transsphenoidal surgery. However, the decision to remove both adrenal glands needs to be weighed against the risk of patients having Nelson’s syndrome or other long-term complications. With regard to the above, the recent retrospective study conducted by Sonino et al.26 showing that Nelson’s syndrome does not occur when bilateral adrenalectomy is applied to patients with no histologic evidence of pituitary adenoma at previous pituitary operation seems to point to this subgroup of patients with Cushing’s disease as ideal candidates for laparoscopic adrenalectomy. REFERENCES 1. Melby J. Therapy of Cushing’s disease: a consensus for pituitary microsurgery—Cushing’s disease. Ann Intern Med 1988;109:445-6. 2. Lamberts SWJ, van der Lely AJ, de Herder WW. Transsphenoidal selective adenomectomy is the treatment of choice in patients with Cushing’s disease: considerations concerning preoperative medical treatment and the longterm follow-up. J Clin Endocrinol Metab 1995;80:3111-3. 3. Miller JW, Crapo L. The medical treatment of Cushing’s syndrome. Endocr Rev 1993;14:443-58. 4. Bochicchio D, Losa M, Buchfelder M, European Cushing’s disease survey group. Factors influencing the immediate and late outcome of Cushing’s disease treated by transsphenoidal surgery: a retrospective study by the European Cushing’s disease survey group. J Clin Endocrinol Metab 1995;80:3114-20. 5. Trainer PJ, Lawrie HS, Verheist J, Howlett TA, Lowe DG, Grossman AB, et al. Transsphenoidal resection in Cushing’s disease: undetectable serum cortisol as the definition of successful treatment. Clin Endocrinol (Oxf) 1993;38:73-8. 6. Ram Z, Nieman LK, Cutler GB, Chrousos P, Doppman JL, Oldfield EH. Early repeat surgery for persistent Cushing’s disease. J Neurosurg 1994;80:37-45. 7. Littley MD, Shalet SM, Beardwell CG, Ahmed SR, Sutton ML. Long-term follow-up of low-dose external pituitary

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Surgery February 1998 17. Sardi A, McKinnon W. Laparoscopic adrenalectomy for primary aldosteronism [letter]. JAMA 1993;269:989-90. 18. Fernandez-Cruz L, Benarroch G, Torres E, Astudillo E, Saenz A, Taura P. Laparoscopic approach to adrenal tumors. J Laparoendosc Surg 1993;3:541-6. 19. Fernandez-Cruz L, Saenz A, Benarroch G, Torres E, Astudillo E. Technical aspects of adrenalectomy via operative laparoscopic. Surg Endosc 1994;8:1348-51. 20. Higashihara E, Tanaka Y, Horie S, Aruga S, Nutahara K, Minowada S, et al. Laparoscopic adrenalectomy: the initial 3 cases. J Urol 1993;149:973-6. 21. Guazzoni G, Montorsi F, Bergamaschi F, Rigatti P, Cornaggia G, Lanzi R, et al. Effectiveness and safety of laparoscopic adrenalectomy. J Urol 1994;152:1375-8. 22. Guazzoni G, Montorsi F, Bocciardi A, Da Pozzo L, Rigatti P, Lanzi R, et al. Transperitoneal laparoscopic versus open adrenalectomy for benign hyperfunctioning adrenal tumors: a comparative study. J Urol 1995;153:1597-600. 23. Ferrer FA, MacGillivray DC, Malchoff CD, Albala DM, Shichman SJ. Bilateral laparoscopic adrenalectomy for adrenocorticotropic Cushing’s syndrome. J Urol 1997;137:16-8. 24. Brunicardi FC, Rosman PM, Lesser KM, Andersen DK. Current status of adrenalectomy for Cushing’s disease. Surgery 1985;98:1127-33. 25. Mampalam TJ, Tyrrell GB, Wilson CB. Transsphenoidal microsurgery for Cushing’s disease. Ann Intern Med 1988;109:487-93. 26. Sonino N, Zielezny M, Fava GA, Fallo F, Boscaro M. Risk factors and long-term outcome in pituitary-dependent Cushing’s disease. J Clin Endocrinol Metab 1996;81:264752.

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