JOURNAL OF LAPAROENDOSCOPIC & ADVANCED SURGICAL TECHNIQUES Volume 25, Number 3, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/lap.2014.0430
Full Report
Long-Term Outcomes of Laparoscopic Adrenalectomy for Adrenal Masses Thomas Kang, MD, Asahel Gridley, MD, and William S. Richardson, MD
Abstract
Background: Laparoscopic adrenalectomy is the gold standard procedure for most adrenal masses. However, long-term data regarding this procedure are limited. We report our institution’s experience with laparoscopic adrenalectomy, determine if this procedure results in durable weight loss and resolves hypertension, diabetes mellitus, or hyperlipidemia, and identify predictors of pathology in nonfunctioning tumors. Materials and Methods: We retrospectively reviewed laparoscopic adrenalectomies performed for adrenal masses between May 2000 and September 2010 by nine surgeons at a single institution. Data gathered included demographics, body mass index (BMI), preoperative and postoperative imaging and biochemical testing results, length of stay, complications, pathology, medications, and resolution of hypertension, diabetes, or hyperlipidemia. Results: We removed 96 adrenal glands in 95 patients. Their average age was 55.6 years. The average length of stay was 1.8 days. Average BMI was 32.9 kg/m2 preoperatively and 31.9 kg/m2 postoperatively (P = .46). We experienced no conversions to open procedure and no perioperative mortality. Minor complications occurred at a rate of 1.2%. Indications for adrenalectomy were nonfunctioning tumor (n = 35), pheochromocytoma (n = 18), aldosteronoma (n = 17), subclinical Cushing’s syndrome (n = 15), Cushing’s syndrome (n = 9), and sex hormone–secreting tumor (n = 1). Hypertension improved or resolved in 63% of patients with Cushing’s syndrome, 56% with aldosteronoma, and 47% with pheochromocytoma. When adrenalectomy was performed for nonfunctioning tumors, neoplasia was identified in 22.9% of patients. The most predictive factors for neoplasia were previous history of cancer and abnormal appearance on computed tomography, magnetic resonance imaging, or positron emission tomography scan. Conclusions: Laparoscopic adrenalectomy is a safe procedure with a low complication rate and short hospital stay. Hypertension improves in the majority of patients with Cushing’s syndrome and aldosteronoma and just under the majority of those with pheochromocytoma. In our study, abnormal radiologic appearance was a better predictor of neoplasia than size.
the resolution of hypertension, diabetes mellitus, or hyperlipidemia and to identify predictors of pathology in nonfunctioning tumors.
Introduction
L
aparoscopic adrenalectomy is typically performed for pheochromocytoma, aldosteronoma, Cushing’s syndrome, subclinical Cushing’s syndrome, and nonfunctioning masses that are concerning for malignancy. Short-term outcomes are excellent,1–6 but we have yet to understand the long-term sequelae of laparoscopic adrenalectomy. Moreover, although the indications for laparoscopic adrenalectomy are more or less firmly established, the actual expected benefit for each indication has not been demonstrated. We report our institution’s experience with laparoscopic adrenalectomy with a focus on long-term outcomes and the resolution of comorbidities. We hope to determine if laparoscopic adrenalectomy results in durable weight loss and
Materials and Methods
We retrospectively reviewed all laparoscopic adrenalectomies performed between May 2000 and September 2010 by nine surgeons at a single institution. Patients were identified for inclusion from a database using codes of the International Classification of Diseases, 9th Edition, and procedural codes for laparoscopic adrenalectomy. Data gathered included age at the time of surgery, gender, body mass index (BMI) preoperatively and at most recent follow-up, results from preoperative and postoperative imaging and biochemical testing,
Department of General Surgery, Ochsner Clinic Foundation, New Orleans, Louisiana.
1
2
KANG ET AL.
length of stay, complications, pathology, medications, and the resolution of hypertension, diabetes, or hyperlipidemia. Biochemical testing for all patients included urine and/or plasma catecholamines/metanephrines, 24-hour urinary cortisol, plasma electrolytes, and plasma aldosterone levels. Patients with Cushing’s or subclinical Cushing’s syndrome also underwent dexamethasone suppression tests and had adrenocorticotropic hormone levels measured pre- and postoperatively. One patient found to have a sex hormone– secreting tumor had plasma dehydroepiandrosterone levels assessed. Complications were classified according to the Clavien–Dindo classification system.7,8 We define resolution of comorbidity as the cessation of all related medications on most recent follow-up. Improvement is defined as an improved control being on an identical or lower dose of medication. Patients who were converted to different medical regimens were not considered to be improved. All procedures were done with a transperitoneal technique with the patient in the lateral decubitus position with a break in the table and a four-port technique similar to that described by Gagner et al.9 Typically, trocar placement must be between the white line of Toldt (which is just lateral to the anterior superior iliac spine) and the xiphoid. It is easiest to perform the procedure with at least 5 cm between trocars. For right adrenalectomies, a 10-mm primary trocar is placed at the anteriaxillary line immediately subcostal, and after insufflation, one 5-mm trocar lateral laterally and two 5mm trocars medially are placed. A liver retractor is placed through the most medial trocar and fixed to the table. Wide mobilization of the liver, by taking most of the triangular ligament and the peritoneum attachments of the posterior liver from the triangular ligament to the inferior vena cave and then opening the peritoneum along the inferior vena cava, usually allows access to the entire right adrenal gland. Typically, the adrenal dissection starts medially, and the adrenal gland is dissected away from the inferior vena cava bluntly until the right adrenal vein is encountered. This is carefully dissected clipped and divided. The rest of the resection can be done with almost any cautery device using appropriate energy or clips on larger vessels. Once excised, the gland is placed in an extraction pouch and removed through the larger trocar site. The wounds are closed appropriately. On the left side a 10-mm primary trocar is placed in the midclavicular line subcostally, with two 5-mm trocars placed laterally and one medially. The spleen is reflected medially,
but the peritoneum is taken approximately 1 cm laterally to the spleen to facilitate mobilizing the tip of the pancreas with the spleen. The mobilization is not complete until the fundus of the stomach is in view. Although harder to identify than on the right side, the adrenal gland usually shows itself during this dissection. In some cases the splenic flexure of the colon must be reflected caudally, but be careful as it is easy to start mobilizing the left kidney during this procedure. We usually start our adrenal dissection laterally and identify the left adrenal vein last. Statistical analysis used GraphPad (La Jolla, CA) software. The t test and Fisher’s exact test were used for statistical analysis. A P value of < .05 was considered statistically significant. Logistic regression analysis was used to calculate odds ratios and 95% confidence intervals. Results
We removed 96 adrenal glands from 95 patients. The average age of patients was 55.6 years, and the group included 30 males and 65 females. The average length of stay was 1.8 days. No laparoscopies were converted to an open procedure, there was no perioperative mortality, and patients had no major complications (Clavien–Dindo Grades III–V). Minor complications (Clavien–Dindo Grade I or II) occurred in 1.2% of patients. Six patients had Grade I complications: nausea (n = 3), wound infection (n = 1), hypokalemia (n = 1), and fever (n = 1). Five patients had Grade II complications: adrenal insufficiency (n = 2), cognitive impairment (n = 1), diarrhea (n = 1), and seizure (n = 1, in a patient with history of prior seizure). The average length of follow-up was 34.5 months. Average BMI was 32.9 kg/m2 preoperatively and 31.9 kg/m2 postoperatively (P = .46) on the most recent follow-up. Preoperative imaging showed adrenal masses in all patients, and biochemical testing established functionality. Indications for adrenalectomy were nonfunctioning tumor (n = 35), pheochromocytoma (n = 18), aldosteronoma (n = 17), subclinical Cushing’s syndrome (n = 15), Cushing syndrome (n = 9), and sex hormone–secreting tumor (n = 1). In patients with nonfunctioning tumors, laparoscopic adrenalectomy did not result in statistically significant longterm improvement of obesity, hypertension, diabetes, or hyperlipidemia (Table 1). Hypertension improved or resolved in patients with certain functioning tumors (63% of patients with Cushing’s syndrome, 56% with aldosteronoma, and
Table 1. Improvement in Comorbidity Related to Indications for Adrenalectomy Comorbidity
Nonfunctioning tumor (n = 35) Pheochromocytoma (n = 18) Aldosteronoma (n = 17) Subclinical CS (n = 15) CS (n = 9)
Preoperative: postoperative BMI (kg/m2)
Resolution of CS or subclinical CS
34:31 [.27]
NA
28:29 32:32 36:35 35:32
[.52] [.92] [.63] [.32]
NA NA 15/15 (100%) 9/9 (100%)
Resolution or improvement of HTN
Resolution or improvement of DM
Resolution or improvement of HLP
4/17 (23%) [.46]
1/7 (14%) [1]
1/10 (10%) [1]
8/17 9/16 5/13 5/8
0/3 0/2 1/8 1/5
(46%) (56%) (38%) (63%)
[.01] [.0024] [.1086] [.0498]
(0%) [1] (0%) [1] (13%) [1] (20%) [1]
0/4 0/4 0/6 1/4
(0%) [1] (0%) [1] (0%) [1] (25%) [1]
Sex hormone–secreting tumor was not included because n = 1. P values are given in brackets. BMI, body mass index; CS, Cushing’s syndrome; DM, diabetes mellitus; HLP, hyperlipidemia; HTN, hypertension; NA, not applicable.
LAPAROSCOPIC ADRENALECTOMY OUTCOMES
47% with pheochromocytoma), but obesity, diabetes, or hyperlipidemia did not improve or resolve in any of these subgroups. When the procedure was performed for nonfunctioning tumors, pathology was identified in 23%. The most predictive factor for pathology was abnormal appearance on computed tomography (CT)/magnetic resonance imaging (MRI) and hypermetabolism on positron emission tomography (PET) scan. Thirty-six patients had postoperative abdominal CT, MRI, or PET studies; in 5 patients, these showed recurrence. Three patients developed new ipsilateral masses. One was an aldosteronoma, which was resected again. Two had adrenalectomies for Cushing’s syndrome and were observed; follow-up studies showed no growth. No patients had chemical recurrence of disease. Two patients developed contralateral masses: 1 patient with renal cell cancer had a metastasis, and 1 patient whose adenoma was resected had a CT scan consistent with an adenoma. Nonfunctioning adrenal tumor
Thirty-five patients had adrenalectomies for nonfunctioning tumors. Eight patients had a history of prior cancer. The average preoperative size of adrenal masses was 3.9 cm. Indications included size q4 cm (n = 10), growth on serial imaging (n = 7), atypical appearance on CT or MRI (including heterogenicity, calcifications, Hounsfield units, and contrast washout outside normal parameters) (n = 11), and hypermetabolic activity on PET (n = 7). Final pathology was benign in 27 patients and pathologic in 8 (22.9%) (Table 2). Pathologic findings included metastatic lung cancer (n = 2), metastatic renal cancer (n = 2), metastatic melanoma (n = 1), pheochromocytoma (n = 2), and atypical adrenal hyperplasia (n = 1). Benign findings were adenoma (n = 24), hemorrhagic mass (n = 2), and myelolipoma (n = 1). The 2 patients with pheochromocytoma were incorrectly diagnosed preoperatively as having nonfunctioning tumors: 1 patient had normal levels of plasma metanephrines preoperatively, and the other had normal levels of urine metanephrines.
3
A history of cancer was the most significant predictor of pathology in adrenal masses (Table 2). Five of 8 patients with a history of cancer had pathologic findings in their final specimen. Only 11.1% (3/27) of patients with no history of cancer had pathologic findings (P = .007; odds ratio = 13.3; 95% confidence interval, 2.06–86.3). Atypical appearance on CT or MRI or PET positivity was a significant predictor of pathology. Seven of 18 patients with atypical imaging had pathologic findings in the final specimen. Only 6% (1/17) of patients with benign imaging had pathologic findings (P = .04; odds ratio = 10.2; 95% confidence interval, 1.09–94.8). The size of the adrenal mass, using either 4 cm or 5 cm as a threshold, was not a good predictor of pathologic findings. In patients with adrenal mass q4 cm, 17.6% (3/17) had pathologic findings, compared with 27.8% (5/18) with adrenal mass < 4 cm. In patients with adrenal mass q5 cm, 25% (2/8) had pathologic findings versus 22.2% (6/27) of patients with adrenal mass < 5 cm. P values and odds ratios were not statistically significant with either threshold. Pheochromocytoma
All 18 patients with pheochromocytoma had biochemical evidence of a catecholamine-secreting tumor (Table 1). Seventeen of these 18 patients had preoperative hypertension; it improved (n = 1) or resolved (n = 7) in 8 patients (P = .01). Seven of the 18 had imaging on long-term follow-up; none showed signs of recurrence. One patient developed adrenal insufficiency. On final pathology, 11 had pheochromocytoma, 3 had adrenal hyperplasia, and 4 had adenoma. Aldosteronoma
Seventeen patients had biochemical evidence of an aldosterone-secreting tumor (Table 1). Sixteen of 17 patients had preoperative hypertension; at final follow-up, hypertension rates had improved (n = 5) or resolved (n = 4) in 9 of these patients (P = .0024). On final pathology, 13 had adenoma, and 4 had hyperplasia. Subclinical Cushing’s syndrome
Table 2. Predictors of Pathologic Findings in Adrenal Masses Benign Cancer History 3 No history 24 Imaging Atypical 11 CT/MRI/ PET Benign 16 Adrenal mass size q4 cm 14 < 4 cm 13 q5 cm 6 < 5 cm 21
Odds Pathologic ratios
95% CI
(37.5) (88.9)
5 (62.5) 3 (11.1)
13.3
2.06–86.3
(61.1)
7 (38.9)
10.2
1.09–94.8
(94.1)
1 (5.88)
(82.4) (72.2) (75.0) (77.8)
3 5 2 6
(17.6) (27.8) (25.0) (22.2)
0.691 0.111–2.81 1.17
0.185–7.34
Data are number of patients (%). CI, confidence interval; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography.
Subclinical Cushing’s syndrome was defined as the nonsuppression of cortisol on a dexamethasone suppression test without physical signs of Cushing’s syndrome. Resolution of subclinical Cushing’s syndrome was defined as the normal suppression of cortisol on postoperative dexamethasone suppression test. Subclinical Cushing’s syndrome resolved in all 15 patients diagnosed with it (Table 1). In addition, all patients had significant increases in adrenocorticotropic hormone: 11.4 pg/mL preoperatively and 46.2 pg/mL postoperatively (P = .005). Thirteen of 15 patients had preoperative hypertension; it resolved in 5 (P = .1086). All patients had adenoma on final pathology. Although all patients had biochemical resolution of subclinical Cushing’s syndrome, there was no statistically significant resolution of comorbidities or weight loss. Cushing’s syndrome
Signs of Cushing’s syndrome included truncal obesity (n = 7), moon facies (n = 5), neck/shoulder fat (n = 2), and striae (n = 2). Cushing’s syndrome was considered resolved
4
when cortisol levels normalized and at least one physical examination finding resolved. Cushing’s syndrome resolved in all 9 patients (Table 1). Eight of the 9 patients had hypertension preoperatively; it improved (n = 3) or resolved (n = 2) in 5 of these patients (P = .0498). All 9 patients had adenoma on final pathology. Two patients had long-term adrenal insufficiency. Laparoscopic adrenalectomy resulted in 100% resolution of Cushing’s syndrome as well as durable resolution or improvement of hypertension. There was no statistically significant improvement in weight loss, diabetes mellitus, or hyperlipidemia. Discussion
Our results show that laparoscopic adrenalectomy for adrenal mass is safe and has a complication rate of 1.2%. Previously published data have demonstrated long-term improvement of hypertension in selected patients following laparoscopic adrenalectomies. Meyer et al.10 found that hypertension resolved in 33% of patients undergoing adrenalectomy for aldosteronoma. Khorram-Manesh et al.11 found that 62% of hypertensive patients who had been resected for pheochromocytomas were no longer hypertensive by the most recent long-term follow-up. In a 100-case series, Poulose et al.12 found that hypertension was eliminated or reduced in 27% of patients with Cushing’s syndrome, 75% with aldosteronoma, and 88% with pheochromocytoma. Our fairly modest rates of hypertension resolution and improvement can be attributed in part to our conservative definition of improvement. We considered only patients whose medication regimen was identical but had lower dosages to have improved. As a result, a patient who, for instance, reduced his or her medications from two to one but used a different medication was not considered to have improved. Previous literature has used the absolute number of antihypertensive medications as a surrogate marker of functional outcomes. Because this approach does not take into account the potency of the medication, a patient may be on a fewer number of more potent medications, thus potentially overestimating the clinical benefit. Furthermore, although laparoscopic adrenalectomy can resolve functional adrenal mass–related hypertension, it cannot improve essential hypertension. The average BMI in our cohort was approximately 32 kg/m2 before and after surgery, and these patients remained at increased risk for metabolic syndrome, including hypertension. The prevalence of essential hypertension makes the postadrenalectomy resolution of hypertension in all patients difficult to achieve. Although subclinical Cushing’s syndrome resolved in all patients, laparoscopic adrenalectomy did not result in significant improvement in weight loss, diabetes mellitus, or hyperlipidemia. Thus, the clinical benefit for subclinical Cushing’s syndrome remains to be demonstrated unless it decreases further weight gain. Despite this result, laparoscopic adrenalectomy may play a role in the treatment of subclinical Cushing’s syndrome, as discussed by Rossi et al.13 Current opinion is that the majority of patients with subclinical Cushing’s syndrome will never develop Cushing’s syndrome. Nevertheless, in this population, hypertension, insulin resistance, dyslipidemia, and obesity are extremely common and exert prolonged, if more subtle, consequences on the cardiovascular system. Therefore, lap-
KANG ET AL.
aroscopic adrenalectomy may be recommended to almost all patients with subclinical Cushing’s syndrome. Our results suggest that radiologically assessed adrenal size alone does not increase the risk of adrenal cancer if features are benign. However, an adrenal mass with concerning features on imaging should be resected regardless of size. The identification of malignant adrenal masses in patients with histories of cancer in our series is consistent with previously published literature. Kloos et al.14 found that 32%–72% of incidentally discovered adrenal masses in patients with prior cancer were metastases, and Lenert et al.15 reported in an 81-case series that 52% of adrenal masses resected in patients with prior extra-adrenal malignancy were metastatic. The low morbidity and mortality of laparoscopic adrenalectomy make resection a viable option, although a full metastatic work-up, including image-guided biopsy, should be considered. Additionally, we followed several recurrent nonfunctional adrenal masses for growth. We hypothesize that these were remnant cells or adrenal rests that grew immediately after the adrenalectomy because of elevated levels of adrenocorticotropic hormone stimulating growth, while the remnant adrenal gland tried to produce hormones for both glands. This phenomenon, although concerning, appears trivial. Articles in which laparoscopic adrenalectomy is directly compared with open adrenalectomy are rare.16,17 These articles show greatly improved outcomes with laparoscopic approach over posterior or transabdominal approaches with respect to blood loss, postoperative pain, length of hospital stay, and morbidity, albeit with longer operative times. Laparoscopic adrenalectomy is a safe procedure that can result in significant long-term improvement or resolution of hypertension in patients with Cushing’s syndrome, aldosteromas, and pheochromocytomas. In patients with nonfunctioning tumors, atypical appearance on CT or MRI, hypermetabolism on PET scan, and history of cancer were the best predictors of pathology. Size criteria, whether using a standard of 4 cm or 5 cm, were not reliable predictors of neoplasia. Disclosure Statement
No competing financial interests exist. References
1. Gagner M, Pomp A, Heniford BT, et al. Laparoscopic adrenalectomy: Lessons learned from 100 consecutive procedures. Ann Surg 1997;226:238–246; discussion 246–237. 2. Henry JF, Defechereux T, Raffaelli M, et al. Complications of laparoscopic adrenalectomy: Results of 169 consecutive procedures. World J Surg 2000;24:1342–1346. 3. Kazaryan AM, Marangos IP, Rosseland AR, et al. Laparoscopic adrenalectomy: Norwegian single-center experience of 242 procedures. J Laparoendosc Adv Surg Tech A 2009;19:181–189. 4. Meria P, Kempf BF, Hermieu JF, et al. Laparoscopic management of primary hyperaldosteronism: Clinical experience with 212 cases. J Urol 2003;169:32–35. 5. Zeh HJ 3rd, Udelsman R. One hundred laparoscopic adrenalectomies: A single surgeon’s experience. Ann Surg Oncol 2003;10:1012–1017. 6. Shen ZJ, Chen SW, Wang S, et al. Predictive factors for open conversion of laparoscopic adrenalectomy: A 13-year review of 456 cases. J Endourol 2007;21:1333–1337.
LAPAROSCOPIC ADRENALECTOMY OUTCOMES
7. Dindo D, Demartines N, Clavien PA. Classification of surgical complications. A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–213. 8. Clavien PA, Barkun J, de Oliveira ML, et al. The ClavienDindo classification of surgical complications: Five-year experience. Ann Surg 2009;250:187–196. 9. Gagner M, Pomp A, Heniford BT, Pharand D, Lacroix Q. Laproscopic adrenalectomy: Lessons learned from 100 consecutive procedures. Ann Surg 1997;226:238–247. 10. Meyer A, Brabant G, Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World J Surg 2005;29:155–159. 11. Khorram-Manesh A, Ahlman H, Nilsson O, et al. Longterm outcome of a series of patients surgically treated for pheochromocytoma. J Intern Med 2005;258:55–56. 12. Poulose BK, Holzman MD, Lao OB, et al. Laparoscopic adrenalectomy: 100 resections with clinical long-term follow-up. Surg Endosc 2005;19:379–385. 13. Rossi R, Tauchmanova L, Luciano A, et al. Subclinical Cushing’s syndrome in patients with adrenal incidentaloma: Clinical and biochemical features. J Clin Endocrinol Metab 2000;85:1440–1448.
5
14. Kloos RT, Gross MD, Francis IR, et al. Incidentally discovered adrenal masses. Endocr Rev 1995;16:460–484. 15. Lenert J, Barnett C, Kudelka A, et al. Evaluation and surgical resection of adrenal masses in patients with a history of extra-adrenal malignancy. Surgery 2001;130: 1060–1067. 16. Hallfeldt KK, Mussack T, Trupka A, Hohenbleicher F, Schmidbauer S. Laparoscopic lateral adrenalectomy versus open posterior adrenalectomy for the treatment of benign adrenal tumors. Surg Endosc 2003;17:264–267. 17. Hazzan D, Shiloni E, Golijanin D, Jurim O, Gross D, Reissman P. Laparoscopic vs open adrenalectomy for benign adrenal neoplasm. Surg Endosc 2001;15:1356–1358.
Address correspondence to: William S. Richardson, MD Department of General Surgery Ochsner Clinic Foundation 1514 Jefferson Highway New Orleans, LA 70121 E-mail: [email protected]
Full Report
Long-Term Outcomes of Laparoscopic Adrenalectomy for Adrenal Masses Thomas Kang, MD, Asahel Gridley, MD, and William S. Richardson, MD
Abstract
Background: Laparoscopic adrenalectomy is the gold standard procedure for most adrenal masses. However, long-term data regarding this procedure are limited. We report our institution’s experience with laparoscopic adrenalectomy, determine if this procedure results in durable weight loss and resolves hypertension, diabetes mellitus, or hyperlipidemia, and identify predictors of pathology in nonfunctioning tumors. Materials and Methods: We retrospectively reviewed laparoscopic adrenalectomies performed for adrenal masses between May 2000 and September 2010 by nine surgeons at a single institution. Data gathered included demographics, body mass index (BMI), preoperative and postoperative imaging and biochemical testing results, length of stay, complications, pathology, medications, and resolution of hypertension, diabetes, or hyperlipidemia. Results: We removed 96 adrenal glands in 95 patients. Their average age was 55.6 years. The average length of stay was 1.8 days. Average BMI was 32.9 kg/m2 preoperatively and 31.9 kg/m2 postoperatively (P = .46). We experienced no conversions to open procedure and no perioperative mortality. Minor complications occurred at a rate of 1.2%. Indications for adrenalectomy were nonfunctioning tumor (n = 35), pheochromocytoma (n = 18), aldosteronoma (n = 17), subclinical Cushing’s syndrome (n = 15), Cushing’s syndrome (n = 9), and sex hormone–secreting tumor (n = 1). Hypertension improved or resolved in 63% of patients with Cushing’s syndrome, 56% with aldosteronoma, and 47% with pheochromocytoma. When adrenalectomy was performed for nonfunctioning tumors, neoplasia was identified in 22.9% of patients. The most predictive factors for neoplasia were previous history of cancer and abnormal appearance on computed tomography, magnetic resonance imaging, or positron emission tomography scan. Conclusions: Laparoscopic adrenalectomy is a safe procedure with a low complication rate and short hospital stay. Hypertension improves in the majority of patients with Cushing’s syndrome and aldosteronoma and just under the majority of those with pheochromocytoma. In our study, abnormal radiologic appearance was a better predictor of neoplasia than size.
the resolution of hypertension, diabetes mellitus, or hyperlipidemia and to identify predictors of pathology in nonfunctioning tumors.
Introduction
L
aparoscopic adrenalectomy is typically performed for pheochromocytoma, aldosteronoma, Cushing’s syndrome, subclinical Cushing’s syndrome, and nonfunctioning masses that are concerning for malignancy. Short-term outcomes are excellent,1–6 but we have yet to understand the long-term sequelae of laparoscopic adrenalectomy. Moreover, although the indications for laparoscopic adrenalectomy are more or less firmly established, the actual expected benefit for each indication has not been demonstrated. We report our institution’s experience with laparoscopic adrenalectomy with a focus on long-term outcomes and the resolution of comorbidities. We hope to determine if laparoscopic adrenalectomy results in durable weight loss and
Materials and Methods
We retrospectively reviewed all laparoscopic adrenalectomies performed between May 2000 and September 2010 by nine surgeons at a single institution. Patients were identified for inclusion from a database using codes of the International Classification of Diseases, 9th Edition, and procedural codes for laparoscopic adrenalectomy. Data gathered included age at the time of surgery, gender, body mass index (BMI) preoperatively and at most recent follow-up, results from preoperative and postoperative imaging and biochemical testing,
Department of General Surgery, Ochsner Clinic Foundation, New Orleans, Louisiana.
1
2
KANG ET AL.
length of stay, complications, pathology, medications, and the resolution of hypertension, diabetes, or hyperlipidemia. Biochemical testing for all patients included urine and/or plasma catecholamines/metanephrines, 24-hour urinary cortisol, plasma electrolytes, and plasma aldosterone levels. Patients with Cushing’s or subclinical Cushing’s syndrome also underwent dexamethasone suppression tests and had adrenocorticotropic hormone levels measured pre- and postoperatively. One patient found to have a sex hormone– secreting tumor had plasma dehydroepiandrosterone levels assessed. Complications were classified according to the Clavien–Dindo classification system.7,8 We define resolution of comorbidity as the cessation of all related medications on most recent follow-up. Improvement is defined as an improved control being on an identical or lower dose of medication. Patients who were converted to different medical regimens were not considered to be improved. All procedures were done with a transperitoneal technique with the patient in the lateral decubitus position with a break in the table and a four-port technique similar to that described by Gagner et al.9 Typically, trocar placement must be between the white line of Toldt (which is just lateral to the anterior superior iliac spine) and the xiphoid. It is easiest to perform the procedure with at least 5 cm between trocars. For right adrenalectomies, a 10-mm primary trocar is placed at the anteriaxillary line immediately subcostal, and after insufflation, one 5-mm trocar lateral laterally and two 5mm trocars medially are placed. A liver retractor is placed through the most medial trocar and fixed to the table. Wide mobilization of the liver, by taking most of the triangular ligament and the peritoneum attachments of the posterior liver from the triangular ligament to the inferior vena cave and then opening the peritoneum along the inferior vena cava, usually allows access to the entire right adrenal gland. Typically, the adrenal dissection starts medially, and the adrenal gland is dissected away from the inferior vena cava bluntly until the right adrenal vein is encountered. This is carefully dissected clipped and divided. The rest of the resection can be done with almost any cautery device using appropriate energy or clips on larger vessels. Once excised, the gland is placed in an extraction pouch and removed through the larger trocar site. The wounds are closed appropriately. On the left side a 10-mm primary trocar is placed in the midclavicular line subcostally, with two 5-mm trocars placed laterally and one medially. The spleen is reflected medially,
but the peritoneum is taken approximately 1 cm laterally to the spleen to facilitate mobilizing the tip of the pancreas with the spleen. The mobilization is not complete until the fundus of the stomach is in view. Although harder to identify than on the right side, the adrenal gland usually shows itself during this dissection. In some cases the splenic flexure of the colon must be reflected caudally, but be careful as it is easy to start mobilizing the left kidney during this procedure. We usually start our adrenal dissection laterally and identify the left adrenal vein last. Statistical analysis used GraphPad (La Jolla, CA) software. The t test and Fisher’s exact test were used for statistical analysis. A P value of < .05 was considered statistically significant. Logistic regression analysis was used to calculate odds ratios and 95% confidence intervals. Results
We removed 96 adrenal glands from 95 patients. The average age of patients was 55.6 years, and the group included 30 males and 65 females. The average length of stay was 1.8 days. No laparoscopies were converted to an open procedure, there was no perioperative mortality, and patients had no major complications (Clavien–Dindo Grades III–V). Minor complications (Clavien–Dindo Grade I or II) occurred in 1.2% of patients. Six patients had Grade I complications: nausea (n = 3), wound infection (n = 1), hypokalemia (n = 1), and fever (n = 1). Five patients had Grade II complications: adrenal insufficiency (n = 2), cognitive impairment (n = 1), diarrhea (n = 1), and seizure (n = 1, in a patient with history of prior seizure). The average length of follow-up was 34.5 months. Average BMI was 32.9 kg/m2 preoperatively and 31.9 kg/m2 postoperatively (P = .46) on the most recent follow-up. Preoperative imaging showed adrenal masses in all patients, and biochemical testing established functionality. Indications for adrenalectomy were nonfunctioning tumor (n = 35), pheochromocytoma (n = 18), aldosteronoma (n = 17), subclinical Cushing’s syndrome (n = 15), Cushing syndrome (n = 9), and sex hormone–secreting tumor (n = 1). In patients with nonfunctioning tumors, laparoscopic adrenalectomy did not result in statistically significant longterm improvement of obesity, hypertension, diabetes, or hyperlipidemia (Table 1). Hypertension improved or resolved in patients with certain functioning tumors (63% of patients with Cushing’s syndrome, 56% with aldosteronoma, and
Table 1. Improvement in Comorbidity Related to Indications for Adrenalectomy Comorbidity
Nonfunctioning tumor (n = 35) Pheochromocytoma (n = 18) Aldosteronoma (n = 17) Subclinical CS (n = 15) CS (n = 9)
Preoperative: postoperative BMI (kg/m2)
Resolution of CS or subclinical CS
34:31 [.27]
NA
28:29 32:32 36:35 35:32
[.52] [.92] [.63] [.32]
NA NA 15/15 (100%) 9/9 (100%)
Resolution or improvement of HTN
Resolution or improvement of DM
Resolution or improvement of HLP
4/17 (23%) [.46]
1/7 (14%) [1]
1/10 (10%) [1]
8/17 9/16 5/13 5/8
0/3 0/2 1/8 1/5
(46%) (56%) (38%) (63%)
[.01] [.0024] [.1086] [.0498]
(0%) [1] (0%) [1] (13%) [1] (20%) [1]
0/4 0/4 0/6 1/4
(0%) [1] (0%) [1] (0%) [1] (25%) [1]
Sex hormone–secreting tumor was not included because n = 1. P values are given in brackets. BMI, body mass index; CS, Cushing’s syndrome; DM, diabetes mellitus; HLP, hyperlipidemia; HTN, hypertension; NA, not applicable.
LAPAROSCOPIC ADRENALECTOMY OUTCOMES
47% with pheochromocytoma), but obesity, diabetes, or hyperlipidemia did not improve or resolve in any of these subgroups. When the procedure was performed for nonfunctioning tumors, pathology was identified in 23%. The most predictive factor for pathology was abnormal appearance on computed tomography (CT)/magnetic resonance imaging (MRI) and hypermetabolism on positron emission tomography (PET) scan. Thirty-six patients had postoperative abdominal CT, MRI, or PET studies; in 5 patients, these showed recurrence. Three patients developed new ipsilateral masses. One was an aldosteronoma, which was resected again. Two had adrenalectomies for Cushing’s syndrome and were observed; follow-up studies showed no growth. No patients had chemical recurrence of disease. Two patients developed contralateral masses: 1 patient with renal cell cancer had a metastasis, and 1 patient whose adenoma was resected had a CT scan consistent with an adenoma. Nonfunctioning adrenal tumor
Thirty-five patients had adrenalectomies for nonfunctioning tumors. Eight patients had a history of prior cancer. The average preoperative size of adrenal masses was 3.9 cm. Indications included size q4 cm (n = 10), growth on serial imaging (n = 7), atypical appearance on CT or MRI (including heterogenicity, calcifications, Hounsfield units, and contrast washout outside normal parameters) (n = 11), and hypermetabolic activity on PET (n = 7). Final pathology was benign in 27 patients and pathologic in 8 (22.9%) (Table 2). Pathologic findings included metastatic lung cancer (n = 2), metastatic renal cancer (n = 2), metastatic melanoma (n = 1), pheochromocytoma (n = 2), and atypical adrenal hyperplasia (n = 1). Benign findings were adenoma (n = 24), hemorrhagic mass (n = 2), and myelolipoma (n = 1). The 2 patients with pheochromocytoma were incorrectly diagnosed preoperatively as having nonfunctioning tumors: 1 patient had normal levels of plasma metanephrines preoperatively, and the other had normal levels of urine metanephrines.
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A history of cancer was the most significant predictor of pathology in adrenal masses (Table 2). Five of 8 patients with a history of cancer had pathologic findings in their final specimen. Only 11.1% (3/27) of patients with no history of cancer had pathologic findings (P = .007; odds ratio = 13.3; 95% confidence interval, 2.06–86.3). Atypical appearance on CT or MRI or PET positivity was a significant predictor of pathology. Seven of 18 patients with atypical imaging had pathologic findings in the final specimen. Only 6% (1/17) of patients with benign imaging had pathologic findings (P = .04; odds ratio = 10.2; 95% confidence interval, 1.09–94.8). The size of the adrenal mass, using either 4 cm or 5 cm as a threshold, was not a good predictor of pathologic findings. In patients with adrenal mass q4 cm, 17.6% (3/17) had pathologic findings, compared with 27.8% (5/18) with adrenal mass < 4 cm. In patients with adrenal mass q5 cm, 25% (2/8) had pathologic findings versus 22.2% (6/27) of patients with adrenal mass < 5 cm. P values and odds ratios were not statistically significant with either threshold. Pheochromocytoma
All 18 patients with pheochromocytoma had biochemical evidence of a catecholamine-secreting tumor (Table 1). Seventeen of these 18 patients had preoperative hypertension; it improved (n = 1) or resolved (n = 7) in 8 patients (P = .01). Seven of the 18 had imaging on long-term follow-up; none showed signs of recurrence. One patient developed adrenal insufficiency. On final pathology, 11 had pheochromocytoma, 3 had adrenal hyperplasia, and 4 had adenoma. Aldosteronoma
Seventeen patients had biochemical evidence of an aldosterone-secreting tumor (Table 1). Sixteen of 17 patients had preoperative hypertension; at final follow-up, hypertension rates had improved (n = 5) or resolved (n = 4) in 9 of these patients (P = .0024). On final pathology, 13 had adenoma, and 4 had hyperplasia. Subclinical Cushing’s syndrome
Table 2. Predictors of Pathologic Findings in Adrenal Masses Benign Cancer History 3 No history 24 Imaging Atypical 11 CT/MRI/ PET Benign 16 Adrenal mass size q4 cm 14 < 4 cm 13 q5 cm 6 < 5 cm 21
Odds Pathologic ratios
95% CI
(37.5) (88.9)
5 (62.5) 3 (11.1)
13.3
2.06–86.3
(61.1)
7 (38.9)
10.2
1.09–94.8
(94.1)
1 (5.88)
(82.4) (72.2) (75.0) (77.8)
3 5 2 6
(17.6) (27.8) (25.0) (22.2)
0.691 0.111–2.81 1.17
0.185–7.34
Data are number of patients (%). CI, confidence interval; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography.
Subclinical Cushing’s syndrome was defined as the nonsuppression of cortisol on a dexamethasone suppression test without physical signs of Cushing’s syndrome. Resolution of subclinical Cushing’s syndrome was defined as the normal suppression of cortisol on postoperative dexamethasone suppression test. Subclinical Cushing’s syndrome resolved in all 15 patients diagnosed with it (Table 1). In addition, all patients had significant increases in adrenocorticotropic hormone: 11.4 pg/mL preoperatively and 46.2 pg/mL postoperatively (P = .005). Thirteen of 15 patients had preoperative hypertension; it resolved in 5 (P = .1086). All patients had adenoma on final pathology. Although all patients had biochemical resolution of subclinical Cushing’s syndrome, there was no statistically significant resolution of comorbidities or weight loss. Cushing’s syndrome
Signs of Cushing’s syndrome included truncal obesity (n = 7), moon facies (n = 5), neck/shoulder fat (n = 2), and striae (n = 2). Cushing’s syndrome was considered resolved
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when cortisol levels normalized and at least one physical examination finding resolved. Cushing’s syndrome resolved in all 9 patients (Table 1). Eight of the 9 patients had hypertension preoperatively; it improved (n = 3) or resolved (n = 2) in 5 of these patients (P = .0498). All 9 patients had adenoma on final pathology. Two patients had long-term adrenal insufficiency. Laparoscopic adrenalectomy resulted in 100% resolution of Cushing’s syndrome as well as durable resolution or improvement of hypertension. There was no statistically significant improvement in weight loss, diabetes mellitus, or hyperlipidemia. Discussion
Our results show that laparoscopic adrenalectomy for adrenal mass is safe and has a complication rate of 1.2%. Previously published data have demonstrated long-term improvement of hypertension in selected patients following laparoscopic adrenalectomies. Meyer et al.10 found that hypertension resolved in 33% of patients undergoing adrenalectomy for aldosteronoma. Khorram-Manesh et al.11 found that 62% of hypertensive patients who had been resected for pheochromocytomas were no longer hypertensive by the most recent long-term follow-up. In a 100-case series, Poulose et al.12 found that hypertension was eliminated or reduced in 27% of patients with Cushing’s syndrome, 75% with aldosteronoma, and 88% with pheochromocytoma. Our fairly modest rates of hypertension resolution and improvement can be attributed in part to our conservative definition of improvement. We considered only patients whose medication regimen was identical but had lower dosages to have improved. As a result, a patient who, for instance, reduced his or her medications from two to one but used a different medication was not considered to have improved. Previous literature has used the absolute number of antihypertensive medications as a surrogate marker of functional outcomes. Because this approach does not take into account the potency of the medication, a patient may be on a fewer number of more potent medications, thus potentially overestimating the clinical benefit. Furthermore, although laparoscopic adrenalectomy can resolve functional adrenal mass–related hypertension, it cannot improve essential hypertension. The average BMI in our cohort was approximately 32 kg/m2 before and after surgery, and these patients remained at increased risk for metabolic syndrome, including hypertension. The prevalence of essential hypertension makes the postadrenalectomy resolution of hypertension in all patients difficult to achieve. Although subclinical Cushing’s syndrome resolved in all patients, laparoscopic adrenalectomy did not result in significant improvement in weight loss, diabetes mellitus, or hyperlipidemia. Thus, the clinical benefit for subclinical Cushing’s syndrome remains to be demonstrated unless it decreases further weight gain. Despite this result, laparoscopic adrenalectomy may play a role in the treatment of subclinical Cushing’s syndrome, as discussed by Rossi et al.13 Current opinion is that the majority of patients with subclinical Cushing’s syndrome will never develop Cushing’s syndrome. Nevertheless, in this population, hypertension, insulin resistance, dyslipidemia, and obesity are extremely common and exert prolonged, if more subtle, consequences on the cardiovascular system. Therefore, lap-
KANG ET AL.
aroscopic adrenalectomy may be recommended to almost all patients with subclinical Cushing’s syndrome. Our results suggest that radiologically assessed adrenal size alone does not increase the risk of adrenal cancer if features are benign. However, an adrenal mass with concerning features on imaging should be resected regardless of size. The identification of malignant adrenal masses in patients with histories of cancer in our series is consistent with previously published literature. Kloos et al.14 found that 32%–72% of incidentally discovered adrenal masses in patients with prior cancer were metastases, and Lenert et al.15 reported in an 81-case series that 52% of adrenal masses resected in patients with prior extra-adrenal malignancy were metastatic. The low morbidity and mortality of laparoscopic adrenalectomy make resection a viable option, although a full metastatic work-up, including image-guided biopsy, should be considered. Additionally, we followed several recurrent nonfunctional adrenal masses for growth. We hypothesize that these were remnant cells or adrenal rests that grew immediately after the adrenalectomy because of elevated levels of adrenocorticotropic hormone stimulating growth, while the remnant adrenal gland tried to produce hormones for both glands. This phenomenon, although concerning, appears trivial. Articles in which laparoscopic adrenalectomy is directly compared with open adrenalectomy are rare.16,17 These articles show greatly improved outcomes with laparoscopic approach over posterior or transabdominal approaches with respect to blood loss, postoperative pain, length of hospital stay, and morbidity, albeit with longer operative times. Laparoscopic adrenalectomy is a safe procedure that can result in significant long-term improvement or resolution of hypertension in patients with Cushing’s syndrome, aldosteromas, and pheochromocytomas. In patients with nonfunctioning tumors, atypical appearance on CT or MRI, hypermetabolism on PET scan, and history of cancer were the best predictors of pathology. Size criteria, whether using a standard of 4 cm or 5 cm, were not reliable predictors of neoplasia. Disclosure Statement
No competing financial interests exist. References
1. Gagner M, Pomp A, Heniford BT, et al. Laparoscopic adrenalectomy: Lessons learned from 100 consecutive procedures. Ann Surg 1997;226:238–246; discussion 246–237. 2. Henry JF, Defechereux T, Raffaelli M, et al. Complications of laparoscopic adrenalectomy: Results of 169 consecutive procedures. World J Surg 2000;24:1342–1346. 3. Kazaryan AM, Marangos IP, Rosseland AR, et al. Laparoscopic adrenalectomy: Norwegian single-center experience of 242 procedures. J Laparoendosc Adv Surg Tech A 2009;19:181–189. 4. Meria P, Kempf BF, Hermieu JF, et al. Laparoscopic management of primary hyperaldosteronism: Clinical experience with 212 cases. J Urol 2003;169:32–35. 5. Zeh HJ 3rd, Udelsman R. One hundred laparoscopic adrenalectomies: A single surgeon’s experience. Ann Surg Oncol 2003;10:1012–1017. 6. Shen ZJ, Chen SW, Wang S, et al. Predictive factors for open conversion of laparoscopic adrenalectomy: A 13-year review of 456 cases. J Endourol 2007;21:1333–1337.
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7. Dindo D, Demartines N, Clavien PA. Classification of surgical complications. A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–213. 8. Clavien PA, Barkun J, de Oliveira ML, et al. The ClavienDindo classification of surgical complications: Five-year experience. Ann Surg 2009;250:187–196. 9. Gagner M, Pomp A, Heniford BT, Pharand D, Lacroix Q. Laproscopic adrenalectomy: Lessons learned from 100 consecutive procedures. Ann Surg 1997;226:238–247. 10. Meyer A, Brabant G, Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World J Surg 2005;29:155–159. 11. Khorram-Manesh A, Ahlman H, Nilsson O, et al. Longterm outcome of a series of patients surgically treated for pheochromocytoma. J Intern Med 2005;258:55–56. 12. Poulose BK, Holzman MD, Lao OB, et al. Laparoscopic adrenalectomy: 100 resections with clinical long-term follow-up. Surg Endosc 2005;19:379–385. 13. Rossi R, Tauchmanova L, Luciano A, et al. Subclinical Cushing’s syndrome in patients with adrenal incidentaloma: Clinical and biochemical features. J Clin Endocrinol Metab 2000;85:1440–1448.
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14. Kloos RT, Gross MD, Francis IR, et al. Incidentally discovered adrenal masses. Endocr Rev 1995;16:460–484. 15. Lenert J, Barnett C, Kudelka A, et al. Evaluation and surgical resection of adrenal masses in patients with a history of extra-adrenal malignancy. Surgery 2001;130: 1060–1067. 16. Hallfeldt KK, Mussack T, Trupka A, Hohenbleicher F, Schmidbauer S. Laparoscopic lateral adrenalectomy versus open posterior adrenalectomy for the treatment of benign adrenal tumors. Surg Endosc 2003;17:264–267. 17. Hazzan D, Shiloni E, Golijanin D, Jurim O, Gross D, Reissman P. Laparoscopic vs open adrenalectomy for benign adrenal neoplasm. Surg Endosc 2001;15:1356–1358.
Address correspondence to: William S. Richardson, MD Department of General Surgery Ochsner Clinic Foundation 1514 Jefferson Highway New Orleans, LA 70121 E-mail: [email protected]
