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Adrenalectomy for incidentaloma: lessons learned from a single-centre series of 274 patients
Sébastien Gaujoux ,*+# Adeline Aime,* Guillaume Assie, t#§ Roberto Ciuni,* Stéphane Bonnet,*++ Florence Tenenbaum,( Jerome Bertheratt#§ and Bertrand Dousset*++
*Department of Digestive, Hepatobiliary and Endocrine Surgery, Referral Center for Rare Adrenal Diseases, Cochin Hospital, APHP, Paris, France tParis Descartes Medical School, University Paris Descartes, Sorbonne Paris Cité, Paris, France
INSERM Unit 1016, CNRS UMR 8104, Institute Cochin, Paris, France
§Department of Endocrinology, Referral Center for Rare Adrenal Diseases, Cochin Hospital, APHP, Paris, France and
1Department of Nuclear Medicine, Cochin Hospital, APHP, Paris, France
Key words
adrenalectomy, adrenocortical carcinoma, incidentaloma, non-secreting adenoma, pheochromocytoma, subclinical cortisol-secreting adenoma.
Correspondence
Professor Sébastien Gaujoux, Department of Digestive, Hepatobiliary and Endocrine Surgery, Referral Center for Rare Adrenal Diseases, Cochin Hospital, APHP, Université Paris Descartes, 27, rue du Faubourg Saint Jacques, 75014 Paris, France. Email: sebastien.gaujoux@aphp.fr
S. Gaujoux MD, PHD; A. Aimé MD; G. Assié MD, PhD; R. Ciuni MD; S. Bonnet MD; F. Tenenbaum MD; J. Bertherat MD, PhD; B. Dousset MD.
Sébastien Gaujoux and Adeline Aimé contributed equally to this work.
Accepted for publication 3 May 2017.
doi: 10.1111/ans.14095
Abstract
Background: Adrenal incidentalomas are increasingly diagnosed and include a wide spec- trum of lesions from benign adenomas to secreting or malignant lesions. The aim of the present study is to report a large single-institution experience of patients undergoing surgery for adrenal incidentaloma with particular attention to their diagnosis and post-operative course and the evolution of surgical practice over time.
Methods: From 1993 to 2013, 274 patients underwent adrenalectomy for incidentaloma. All patients underwent standardized clinical, hormonal and imaging assessments.
Results: Patients were mainly female (63.1%; n = 173), and the median age of patients was 56.5 years. After a complete hormonal evaluation, 47.9% (n = 129) of incidentalomas were classified as secreting tumours, including 24.4% (n = 67) subclinical cortisol-secreting adenomas and 18.9% (n = 52) pheochromocytomas. Adrenocortical carcinomas represented 9.5% (n = 26) of incidentalomas, and the risk of malignancy was significantly correlated with tumour size. The conversion rate after laparoscopic adrenalectomy (90.9%; n = 249) was 3.2% (n = 8). The overall morbidity rate was 13.9%, which included a 4.4% rate of severe morbidity (Clavien-Dindo ≥3). From 2008 onwards, there was a significant decrease (P < 0.001) in the use of surgical approaches for non-secreting adenomas.
Conclusion: After a complete work-up, half of the incidentalomas were classified as sub- clinical oversecreting adrenal lesions and 10% proved to be malignant adrenocortical carci- nomas. The debatable use of surgical approaches for benign nonfunctioning adenomas significantly decreased over time.
Introduction
With widespread use of cross-sectional imaging, adrenal incidentalo- mas are being increasingly diagnosed.1 These tumours include a wide spectrum of lesions, including non-secreting adenomas, sub- clinical secreting tumours, various other benign lesions and malig- nant adrenocortical carcinomas.2 Because routine resection of all lesions is not advocated, these asymptomatic lesions require accurate preoperative diagnosis. According to various recommendations,1,3-5 surgical resection is only required for large/atypical and/or secreting lesions because they are most likely to be malignant or cause symp- toms secondary to oversecretion of steroids or catecholamines. The identification of patients requiring surgical resection represents a
medico-surgical challenge and necessitates accurate assessment of the benefit/risk balance associated with surgical treatment.
The aim of this study was to report experience of patients who underwent surgery for adrenal incidentaloma with particular atten- tion to their clinical presentation, pathological diagnosis and post- operative course and the evolution of surgical practice over time.
Patients and methods
Data collection
From January 1993 to December 2013, 276 patients underwent adre- nalectomy for incidentaloma at Cochin Hospital, Paris, France, a
tertiary referral centre for adrenal disease. Demographic, clinical, radi- ological and pathological data were obtained from a prospectively maintained database with additional retrospective review. For each patient, the diagnosis was confirmed by an experienced pathologist and classified according to the World Health Organization classifica- tion. Tumours with a Weiss score greater than 3 were considered to be adrenocortical carcinomas,6,7 and their staging was performed using the European Network for the Study of Adrenal Tumors (ENSAT) staging system.8 Post-operative mortality included all deaths occurring before or within 30 days of hospital discharge. Morbidity included all complications following surgery until discharge and/or readmission and was graded according to the Clavien-Dindo classification.9 Adre- nal incidentaloma was defined as an adrenal mass found on imaging that was not motivated by the investigation of an adrenal disorder. This consequently excludes images found during the course of a work-up for asymptomatic patients with a genetic predisposition to adrenal tumour syndrome or patients with extra-adrenal cancer undergoing staging or surveillance.
Preoperative work-up and surgical indications
As previously reported by our group,10 the preoperative work-up included a clinical evaluation and a complete hormonal and radiologi- cal evaluation with multidetector computed tomography (CT). Briefly, all investigations were performed in the Endocrine Department accord- ing to a routine standardized procedure previously reported by our group.10 The secretion of glucocorticoids was assessed by measure- ment of plasma or salivary cortisol levels at 24 h and of 24-h urinary free cortisol. The plasma level of cortisol was assessed at 08.00 hours after the overnight dexamethasone suppression test (1 mg). Androgen secretion was evaluated by measurement of plasma testosterone, androstenedione and dehydroepiandrostenedione sulphate, oestradiol secretion by the measurement of plasma 17b-oestradiol, mineralocorti- coids secretion by the measurement of plasma renin activity or plasma renin level and plasma aldosterone. Twenty-four hour urinary excre- tions of metanephrines were also assessed. Plasma 17-hydroxyproges- terone, cortisol after ACTH stimulation and morning ACTH were assayed in case of cortisol excess or bilateral lesions. Overtime, the standardized biological screening did not significantly change, except for the assay used. Magnetic resonance imaging (MRI), 131I-6-b- iodomethylnorcholesterol scintigraphy, 131I-metaiodobenzylguanidine scintigraphy or 18F-fluorodeoxyglucose positron emission tomography (PET) were additionally performed when dictated by the clinical and hormonal status of the patient. From 2008 onwards, all surgical indica- tions were discussed by a multidisciplinary adrenal tumour board that included surgeons, radiologists, nuclear physicians, endocrinologists and pathologists. Surgical indications for incidentaloma included over- secreting tumours (subclinical cortisol-secreting adenoma, pheochro- mocytoma and Conn’s adenoma), tumours with atypical radiological patterns and tumours larger than 4 cm for which malignancy could not be ruled out.
Surgical technique
All procedures were performed by three senior surgeons or under their direct supervision. Retroperitoneoscopic surgery was never
used. The lateral transabdominal approach was used for laparo- scopic adrenalectomy. When conversion was required (suspicion of malignancy, tumour diameter exceeding 10 cm or technical con- straints), an open subcostal approach with or without an upper mid- line extension was used. Patients with a large benign adrenal mass over 10 cm in diameter or adrenocortical carcinoma over 6 cm in diameter underwent surgery using an open subcostal approach.
Statistical analysis
Values are expressed as the median and interquartile (IQ) or a per- centage, as appropriate. The chi-square or Fisher’s exact test was used to compare differences in discrete or categorical variables. According to the distribution of variables, the t-test or a Wilcoxon rank-sum test was used for continuous variables. To assess the evo- lution of surgical practice, adrenalectomies performed before 2008, that is, prior to the publication of the French guidelines6 on adrenal incidentalomas and the implementation of formal discussions by a multidisciplinary adrenal tumour board, were compared with adrenalectomy performed after 2008. All tests were two-sided, and a P-value < 0.05 was considered to be statistically significant. Data were analysed using STATA 11 statistical software (StataCorp. 2009, Stata Statistical Software: Release 11, StataCorp LP, College Station, TX, USA).
Results
Patient demographics and diagnostic characteristics
From 1993 to 2013, 274 patients underwent adrenalectomy for adrenal incidentaloma. Patient demographics and diagnostic charac- teristics are summarized in Table 1. Briefly, patients were primarily female (63.1%; n = 173), and the median age of patients was 56.5 years (45.8-64.2 years). After a complete hormonal evalua- tion, 47.9% (n = 129) of incidentalomas were classified as overse- creting tumours, including 24.4% (n = 67) subclinical cortisol- secreting adenomas and 18.9% (n = 52) pheochromocytomas. After a dedicated imaging work-up, all patients except one had a CT scan performed; approximately 82.5% (n = 226) of the patients had an MRI performed, demonstrating a significant increase in MRI use over time (P < 0.001). Overall, approximately 48% (n = 132) of patients underwent a PET scan, the use of which also showed a sig- nificant increase over time (27.4% before 2008 versus 71.8% after 2008; P < 0.001). All three imaging modalities were performed on almost half of the patients (46.35%; n = 27), a practice demonstrat- ing a significant increase in use over time (23.97% before 2008 ver- sus 71.8% after 2008; P < 0.001).
Patient intra- and post-operative courses
The intra- and post-operative courses of the patients are summar- ized in Table 2. Briefly, most procedures were performed laparo- scopically (90.9%; n = 249), with a conversion rate of 3.2% (n = 8) due to technical constraints (n = 7) or intraoperative suspi- cion of adrenocortical carcinoma (n = 1). Open procedures were required for primary adrenal malignant tumours suspected due to
| Variable | Overall (n = 274) | Before 200. (n = 146) | After 200. (n = 128) | P |
|---|---|---|---|---|
| Demographics | ||||
| Gender (female) | 63.1% (173) | 60.3% (88) | 66.4% (84) | 0.317 |
| Age (years) | 56.5 (45.8-64.2) | 55.7 (44.9-65) | 57 (46.7-63.3) | 0.803 |
| ASA (I and II) | 90.8% (249) | 93.8% (137) | 87.5% (112) | 0.092 |
| BMI (kg/m2) | 25.8 (22.2-29.1) | 25.7 (22.6-28.4) | 25.9 (22-29.1) | 0.880 |
| Secretion | ||||
| Non-secreting | 52.9% (145) | 69.9% (102) | 33.6% (43) | <0.0001 |
| Secreting | 47.8% (129) | 30.14% (44) | 66.4% (85) | |
| Cortisol | 51.9% (67) | 59.1% (26) | 48.2% (41) | 0.130 |
| Catecholamine | 40.3% (52) | 31.8% (14) | 44.7% (38) | |
| Aldosterone | 1.5% (2) | 2% (2) | 0% (0) | |
| Other (androgens, precursors) | 6.2% (8) | 2% (2) | 7.1% (6) | |
| Imaging work-up | ||||
| CT | 99.64% (273) | 99.3% (145) | 100% (128) | 0.348 |
| MRI | 82.5% (226) | 73.3% (107) | 92.9% (119) | <0.001 |
| PET scan | 48.2% (132) | 27.4% (40) | 71.8% (92) | <0.001 |
| All three imaging studies | 46.3% (127) | 24% (35) | 71.8% (92) | <0.001 |
ASA, American Society of Anesthesiologists; BMI, body mass index; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography.
| Variable | Overall (n = 274) | Before 200. (n = 146) | After 200. (n = 128) | P |
|---|---|---|---|---|
| Laparoscopic procedure | 90.9% (249) | 91.1% (133) | 90.6% (116) | 1.000 |
| Conversion | 3.2% (8) | 6% (8) | 0% (0) | 0.008 |
| Operative time (min) | 100 (80-120) | 100 (75-120) | 90 (80-120) | 0.990 |
| Reoperation | 0% (0) | 0% (0) | 0% (0) | — |
| Overall morbidity | 13.9% (38) | 10.2% (15) | 17.9% (23) | 0.080 |
| Severe morbidity | 4.4% (12) | 3.4% (5) | 5.5% (7) | 0.556 |
| Mortality | 0.3% (1) | 0% (0) | 1 (0.7) | 0.467 |
| Hospital stay (days) | 5 (4-6) | 5 (4-7) | 5 (4-6) | 0.382 |
hormonal, clinical and radiological evidence and/or patients with adrenal tumours greater than 10 cm in diameter. Overall, the mor- bidity rate was 13.9%, including a 4.4% rate of severe morbidity (Clavien-Dindo 3, 4 or 5). Surgical morbidity was mainly due to wound complication, haematoma or haemoperitoneum and sympto- matic retroperitoneal collection in relation with pancreatic fistula following left adrenalectomy. Medical morbidity was mainly due to pulmonary complication and deep vein thrombosis. Reoperation rate was nil. The mortality rate was 0.3% (n = 1). After a right nephroadrenalectomy for a 11-cm adrenocortical carcinoma, a 77- year-old female on Coumadin died on post-operative day 37 from a post-operative haemorrhage and multiple organ failure. The median hospital stay was 5 days (4-6).
Tumour characteristics
Tumour characteristics are summarized in Table 3. Briefly, the median size of the lesions was 44 mm. Twenty-three percent (n = 63) of patients underwent surgery for non-secreting adenoma, while 24% (n = 67) of patients underwent surgery for subclinical cortisol-secreting adenoma and 19% of patients underwent surgery for pheochromocytoma (n = 52). Overall, 90.5% (n = 248) of patients had a benign adrenal lesion. Adrenocortical carcinomas represented 9.5% (n = 26) of incidentalomas. None of the patients
selected for non-surgical management later developed proven adre- nocortical carcinoma.
As shown in Figure 1, tumour size was correlated with malig- nancy status because malignant tumours were significantly larger than benign lesions (4.2 cm versus 8.25 cm, P < 0.00001). Only 2% (n = 2) of lesions <4 cm in size were classified as adrenocorti- cal carcinomas (Weiss scores of 4 and 7), while 5% (n = 5) of lesions between 4 and 6 cm were classified as adrenocortical carci- nomas, and 23% (n = 19) of lesions >6 cm were classified as adre- nocortical carcinomas.
Evolution of surgical practice over time
The evolution of surgical practice over time is summarized in Tables 1-3. There were no significant differences over time regard- ing patient demographics and diagnostic characteristics. The only significant difference in patient intra- and post-operative courses between the two periods was a decrease in the rate of conversion from a laparoscopic to an open approach (6% versus 0%, P = 0.008) after 2008.
The proportion of benign non-functioning adrenocortical ade- noma patients who underwent surgery significantly decreased from 32.2% (n = 47) to 12.5% (n = 16) among patients with surgical indications (P < 0.0001). At the same time, the proportion of
| Variable | Overall (n = 274) | Before 200. (n = 146) | After 200. (n = 128) | P |
|---|---|---|---|---|
| Size (mm) | 45 (35-60) | 45 (35-60) | 43 (33-63) | 0.890 |
| Right side | 53.6% (147) | 81% (55.48) | 66% (51.56) | 0.545 |
| Pathology | ||||
| Benign adrenal lesion | 90.5% (248) | 91% (133) | 89.8% (115) | 0.837 |
| Non-secreting adenoma | 23% (63) | 32.2% (47) | 12.5% (16) | 0.0001 |
| Subclinical cortisol-secreting adenoma | 20.8% (57) | 14.4% (21) | 28.1% (36) | 0.007 |
| Pheochromocytoma | 19% (52) | 10.3% (15) | 28.9% (37) | 0.0001 |
| Aldosterone-secreting adenoma | 0.7% (2) | 1.4% (2) | 0% (0) | 0.500 |
| Adrenocortical carcinoma | 9.5% (26) | 8.9% (13) | 10.2% (13) | 0.837 |
| Lymphangioma | 7.3% (20) | 8.9% (13) | 5.5% (7) | 0.354 |
| Neurogenic tumour | 6.6% (18) | 9.6% (14) | 3.1% (4) | 0.048 |
| Myelolipoma | 2.9% (8) | 2.7% (4) | 3.1% (4) | 1 |
| Haematoma | 2.2% (6) | 3.4% (5) | 0.8% (1) | 0.220 |
| Cyst | 3.3% (9) | 4.1% (6) | 2.3% (3) | 0.509 |
| Hyperplasia | 1% (3) | 0.7% (1) | 1.6% (2) | 0.600 |
| Miscellaneous | 4% (10) | 3.4% (5) | 3.9% (5) | 1.000 |
15
Tumor size (cm)
10
5
0
Benign lesions
Malignant lesions
subclinical pheochromocytoma patients who underwent surgery significantly increased from 10.3% (n = 15) to 28.9% (n = 37) (P < 0.0001), and the proportion of subclinical cortisol-secreting adenoma patients who underwent surgery significantly increased from 14.4% (n = 21) to 28.1% (n = 36) among patients with surgi- cal indications (P = 0.007). The proportions of incidentally diag- nosed adrenocortical carcinoma patients who underwent surgery remained similar (8.9% versus 10.2%; 0.837) during the two peri- ods of the study.
Discussion
Adrenal incidentaloma is the most common adrenal disorder2 and has an increasing incidence that parallels the increasing diffusion of cross-sectional imaging. Data suggest that after clinical, hormonal and radiological evaluations, only a subset of patients with adrenal incidentalomas will eventually undergo surgery based on abnormal imaging patterns, that is, suspected malignancy or hormonal
oversecretion. In the present experience including 274 patients with adrenal incidentalomas selected for surgery, we observed that over time: (i) surgical indications became more accurate, with a signifi- cant decrease in the proportion of benign non-functioning adeno- mas undergoing surgery; (ii) half of the incidentalomas that underwent surgery were silent oversecreting lesions including pheo- chromocytomas and subclinical cortisol-secreting adenomas; and (iii) nearly 10% of patients selected for surgery had incidentally discovered adrenocortical carcinomas, with malignancy status sig- nificantly correlated with incidentaloma size.
The main challenge in the management of adrenal incidentalo- mas is the appropriate selection of cases for surgery to achieve a balance between the risk of excessively broad surgical indications and the observation of asymptomatic secreting or malignant lesions. Various guidelines and algorithms1,3-5,11 have been proposed; how- ever, most resected adrenal incidentalomas remain benign tumours. The large experience reported here demonstrated a significant improvement in the selection of patients over time. This improve- ment may be due to several factors including clearer guidelines from endocrinology societies, thorough imaging evaluations and the discussion of all cases within a multidisciplinary adrenal tumour board from 2008 onwards. These changes have allowed surgical treatment for most atypical benign tumours to be ruled out, that is, poor lipid nonfunctioning adenomas with atypical features on CT scan. These non-secreting undetermined adrenal masses with spon- taneous densities higher than 10 Hounsfield unit (HU), as indicated by CT scan, have been extensively studied.12-18 There are several benign imaging findings that rule out the presence of malignancy with excellent negative predictive value. These include the follow- ing: (i) spontaneous density less than 10 HU18-22 on unenhanced CT scan followed with relative or absolute washout measurement greater than 40% or 60% on contrast-enhanced CT scan; (ii) chemical shift MRI23 with a decrease of signal intensity greater than 20% between in- and opposed-phase images; and (iii) an adrenal-to-liver standard uptake value less than 1.45 on 18F-fluorodeoxyglucose PET.24 Surgery is still required in patients with indeterminate adrenal masses, especially when patients have a
long projected life expectancy,25 because of the risks of tumour growth and hormonal oversecretion development.
The high rate of incidentalomas with hormonal oversecretion should be emphasized. These patients represented approximately two-thirds of those with surgical indications during the second part of the study period. Of these incidentalomas, half were pheochro- mocytomas and half were subclinical cortisol-secreting adenomas. In a recent series, incidental pheochromocytomas represented up to 30% of newly diagnosed pheochromocytomas,26 and this finding might possibly be related to better medical screening. It has been suggested that these patients may be less likely to develop perio- perative haemodynamic instability.27 Subclinical cortisol-secreting adenomas are common and may lead to non-specific long-term con- sequences of cortisol excess, including hypertension, overweight, diabetes and cortisol-induced osteopenia. There is no clear consen- sus1,5 regarding the optimal management of subclinical cortisol- secreting adenomas. The only prospective randomized controlled trial found significant improvements in several metabolic syndrome parameters after surgery.28 While further evidence from prospective randomized controlled studies remains to be obtained, we believe that resection of subclinical cortisol-secreting adenomas remains a valid option in view of the very low post-operative morbidity observed following laparoscopic adrenalectomy.
In addition to subclinical oversecreting incidentalomas, the indi- cations for surgery are driven by the risk of adrenocortical carci- noma. As previously reported, this risk increases with tumour size and becomes significant for lesions over 4 cm in diameter. This is the reason for which adrenalectomy should be proposed for all adrenal lesions greater than 4 cm with atypical biochemical or ima- ging features. This aggressive surgical approach is further war- ranted by the poor prognosis of adrenocortical carcinoma patients29,30 and the very low morbidity associated with adrenal surgery.31 The question remains whether laparoscopy or open sur- gery is the best surgical approach for adrenal incidentalomas with preoperative suspicion of malignancy.32 In our opinion, the laparo- scopic approach for ACC should be restricted to small lesions, that is, <6 cm in diameter, and should only be performed in high- volume centres with extensive expertise in laparoscopic surgery.
In conclusion, surgical indications for incidentalomas should be restricted to patients with subclinical oversecreting lesions and lesions greater than 4 cm with atypical imaging patterns. In this large experience, the implementation of thorough preoperative work-ups and discussions of surgical indications within a multidis- ciplinary adrenal tumour board have allowed for a significantly reduction in the surgical treatment of benign nonfunctioning adenomas.
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