ELSEVIER
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JSR Surgical Research
Association for Academic Surgery
Risk of concomitant malignancy in hyperfunctioning adrenal incidentalomas
Bassan J. Allan, MD, MBA, * Chad M. Thorson, MD, MSPH, Robert M. Van Haren, MD, Punam P. Parikh, BS, and John I. Lew, MD, FACS
Division of Surgical Endocrinology, DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, Florida
ARTICLE INFO
Article history: Received 28 December 2012 Received in revised form 1 March 2013
Accepted 12 March 2013 Available online 31 March 2013
Keywords: Adrenal Adrenalectomy Incidentaloma Malignancy Predictors
ABSTRACT
Background: Adrenal masses are common incidental findings on radiologic imaging. The association between malignancy and hormonal hyperactivity found in incidentally discovered adrenal tumors, however, remains unclear.
Methods: A retrospective analysis of prospectively collected data from patients who underwent adrenalectomy for incidentally discovered adrenal tumors at a single institu- tion. Outcomes and operative data were compared by univariate analysis. Area under the curve was used to analyze the effect of tumor size in predicting malignancy.
Results: There were 49 patients who initially presented with adrenal incidentalomas that underwent adrenalectomy. Most patients were Caucasian women with an average age of 51 + 14 years. Of this group, 24 patients underwent resection for hyperfunctioning adrenal glands. There were no significant differences in malignancy rates between hyperfunctional and nonfunctional tumors (4.1% vs. 12.0%, P = 0.32). On final histopathology, there were four patients with adrenal malignancies: two adrenocortical carcinomas and two meta- static from renal carcinoma. Only one patient with a hyperfunctioning adrenal tumor had underlying malignancy. Overall, invasion of adjacent structures (P < 0.001), presence of lymphadenopathy (P = 0.02), metastasis (P = 0.03), irregular tumor margins (P = 0.01), heterogeneity (P = 0.05), and tumor size >6 cm (P = 0.04) on radiologic imaging were strongly associated with malignancy in adrenal incidentalomas.
Conclusions: The risk of concomitant malignancy and hormonal hyperactivity in adrenal incidentalomas is very low. Tumor size (>6 cm) and radiographic features remain the most important predictors of adrenal malignancy, regardless of tumor function.
@ 2013 Elsevier Inc. All rights reserved.
1. Introduction
Adrenal masses represent a growing number of tumors serendipitously discovered during evaluation for other
unrelated medical conditions [1,2]. The routine use of high- resolution body imaging has resulted in the incidental discovery of adrenal masses with an estimated prevalence ranging between 0.5% and 4.5% [3-6]. The management of
* Oral Presentation at the 8th Annual Meeting of the Academic Surgical Congress in New Orleans, Louisiana, February, 2013.
* Corresponding author. Division of Surgical Endocrinology, DeWitt-Daughtry Family Department of Surgery, University of Miami Leo- nard M. Miller School of Medicine, 1120 NW 14th St, Clinical Research Building, 410P, Miami, FL 33136. Tel .: +1 954 240 3174; fax: +1 305 585 6043.
E-mail address: ballan@med.miami.edu (B.J. Allan).
these newly discovered adrenal tumors or “incidentalomas” remains a diagnostic challenge to clinicians. Adrenal inci- dentalomas are often defined as underlying adrenal masses discovered when radiologic imaging is performed for reasons other than a suspected or known adrenal condition. When confronted with an adrenal incidentaloma, there are two main questions to be addressed by the clinician: (1) is the lesion cancerous; and (2) is it hyperfunctioning [7]. All patients with an adrenal incidentaloma require a thorough clinical evalua- tion. Based on worrisome radiologic features for malignancy and/or biochemical confirmation of adrenal hyperactivity, patients with adrenal incidentalomas may require surgical excision for definitive diagnosis and treatment.
Currently, tumor size and appearance on imaging studies are widely accepted as predictors of underlying malignancy within adrenal incidentalomas [8-14]. Among patients most commonly with cancers of breast, kidney, lung, and mela- noma, up to 75% of adrenal incidentalomas are metastases from these malignant primaries [7]. Conversely, the absence of a primary cancer in a patient with a true adrenal inci- dentaloma makes a metastatic lesion less likely. In such patients, primary adrenocortical cancer would most likely represent the underlying malignant pathology.
Although rare, patients with adrenocortical carcinoma have a poor prognosis and may present with hormonal hy- persecretion. Previous reports have focused on evaluating the long-term risk of adrenal incidentalomas becoming hyper- functioning or developing overt clinical symptoms after pre- senting only with subtle endocrine alterations. In a series of 64 patients, the cumulative risk of developing endocrine abnormalities approached 47% over 5 years, whereas the risk of malignancy, although not elevated, was still present in these patients [15]. Other reports have demonstrated that interval growth of adrenal masses may not be a reliable tool to determine malignant transformation but, rather, an index of subclinical or clinical endocrine alterations [9,16]. However, the concomitant risk of malignancy and hyperactivity in adrenal tumors with unapparent clinical symptoms that present as incidentalomas is not well described. These adrenal incidentalomas are often presumed to be benign in nature, yet may carry a risk of underlying malignancy. This study examines the concomitant risk of malignancy and adrenal hyperactivity in patients undergoing surgical resec- tion of adrenal incidentalomas.
2. Methods
Clinical and pathologic data of 49 patients with adrenal incidentalomas who underwent adrenalectomy from 2006 to 2010 were collected prospectively in an Institutional Review Board approved database at the University of Miami Health System. All patients underwent computed tomography and/ or magnetic resonance imaging for clinical indications or symptoms unrelated to adrenal disease that revealed an in- cidental adrenal tumor or “incidentaloma.” Adrenal tumors discovered during the work-up for known primary cancers of nonadrenal origin were excluded from this study. Patients were stratified into two groups based on benign and malig- nant adrenal disease by final histopathology. Patients were
also divided into two groups based on hyperfunctional or nonfunctional tumor status. Patients underwent adrenalec- tomy for incidentalomas that were hyperfunctioning; ≥4 cm by imaging studies; suspicious for malignancy by radiographic features; and/or patient preference. Demographic data, preoperative laboratory values, radiographic tumor charac- teristics, operative data, and postoperative outcomes were collected and analyzed.
After history and physical examination, all patients under- went preoperative biochemical studies to assess aldosterone, plasma renin activity, 24-h fractional catecholamine, and 1 mg overnight dexamethasone suppression tests. A hyperfunctional incidentaloma was defined as an adrenal gland with aldosterone, catecholamine, and/or cortisol hypersecretion without initially appreciated clinical signs or symptoms. A nonfunctional inci- dentaloma was defined as an adrenal gland with no hormonal excess. Patients possessing urinary metanephrine or normeta- nephrine levels three times the upper limit of normal were confirmed to have pheochromocytoma and, therefore, treated with preoperative «-adrenergic, ß-blockade and volume reple- tion. Patients with elevated cortisol levels >5 ug/dL following 1 mg dexamethasone suppression test were confirmed to have subclinical hypercortisolism. Lastly, patients with a ratio of plasma aldosterone concentration to plasma renin activity (PAC/ PRA) >20 were confirmed to have primary hyperaldosteronism (Conn’s syndrome).
Laparoscopic adrenalectomy was initially attempted unless clinical suspicion for adrenal cancer was very high, in which an open procedure was then performed. Laparoscopic procedures were performed via an anterior (lateral trans- abdominal) approach, unless patients had a history of extensive abdominal surgeries or if tumors were in a loca- tion deemed more accessible via the retroperitoneum, for which a posterior laparoscopic approach was used. For the anterior laparoscopic procedures, patients were placed in the decubitus position, the spleen and pancreatic tail were mobilized, and the adrenal gland was removed after clipping all feeding vessels. Posterior laparoscopic resections were performed with the patient in the prone position. The ret- roperitoneum was entered below the 12th rib, and the upper pole of the kidney was mobilized to identify and remove the abnormal adrenal gland. Postoperatively, patients with hyperfunctioning adrenal glands were observed in the intensive care unit for hemodynamic monitoring overnight, whereas other patients were taken to a surgical floor and generally discharged home between 2 to 4 d after the procedure.
For statistical analysis, categorical data such as gender, race, and clinical/radiologic features were analyzed using x2 test or Fisher’s exact test. Group data with a normal distri- bution were compared using the Student t-test or analysis of variance, and nonparametric data were compared with a Mann-Whitney U test or Kruskal-Wallis test. Values are expressed as mean ± SD for data with normal distribution, and median (interquartile range) or number (percentage) as appropriate. Using the receiver operating characteristic method, we calculated the area under the curve (AUC) to determine the diagnostic accuracy of tumor size. Statistical Package for the Social Sciences software v. 19.0 (Chicago, IL) was used. Specificity, positive predictive value (PPV) and
| Table 1 - Preoperative characteristics in nonfunctional and hyperfunctional adrenal incidentalomas. | |||
|---|---|---|---|
| Nonfunctional [n = 25] | Hyperfunctional [n = 24] | P | |
| Demographics | |||
| Age | 50 ± 15 | 52 ± 14 | 0.45 |
| Gender | 0.53 | ||
| Female | 17 (68) | 17 (71) | |
| Male | 8 (32) | 7 (29) | |
| Race | 0.32 | ||
| Caucasian | 16 (64) | 11 (46) | |
| Black | 2 (8) | 5 (21) | |
| Hispanic | 6 (24) | 8 (33) | |
| Other | 1 (4) | - | |
| Preoperative radiologic data | |||
| Size [cm] | 4.9 ± 2 | 4.8 ± 2.8 | 0.32 |
| Invading adjacent | 2 (8) | 0 | 0.22 |
| structures | |||
| Lymphovascular | 1 (4) | 0 | 0.51 |
| invasion | |||
| Lymphadenopathy | 1 (4) | 2 (8) | 0.48 |
| Necrosis | 4 (16) | 9 (38) | 0.08 |
| Irregular margins | 3 (12) | 0 | 0.12 |
| Enhancement | 9 (12) | 8 (33) | 0.07 |
| Heterogeneity | 7 (25) | 6 (25) | 0.53 |
| Malignancy | 3 (12) | 1 (4.1) | 0.32 |
| Surgical approach | 0.58 | ||
| Open | 7 (28) | 7 (29) | |
| Laparoscopic | 18 (72) | 17 (71) | |
| Data are mean ± SD, or number (%) where appropriate. | |||
associated confidence intervals were calculated using Med- Calc for Windows, v. 9.5.0.0 (MedCalc Software; Mariakerke, Belgium). A P value <0.05 was considered statistically significant.
3. Results
Of 49 patients who underwent adrenalectomy for adrenal incidentalomas, there were 24 patients who underwent resection for hyperfunctional adrenal glands upon biochem- ical evaluation. Of the remaining 25 patients, the most com- mon indication for resection was size ≥4 cm and/or suspicious radiographic features (n = 16), interval growth after initial identification of the incidental adrenal mass (n = 6), and patient preference (n = 3). The majority of patients were Caucasian women. The average age of these patients who underwent adrenalectomy was 51 ± 15 y (Table 1).
Biochemical analysis revealed three patients with hyper- cortisolism (cortisol level range 16-75 µg/dL following a 1 mg dexamethasone suppression test). One of these three patients was found to have adrenal cancer. There were 20 patients with pheochromocytoma found to have urinary catechol- amine secretion values at least three times the upper limit of normal with urinary normetanephrine levels ranging between 370 and 9392 mcg and urinary metanephrine levels ranging between 40 and 20120 mcg over a 24-h collection period. All pheochromocytoma patients with elevated catecholamine secretion were found to have benign adrenal lesions. Finally,
| Table 2 - Pathologic outcomes for adrenal incidentalomas based on gland functionality. | ||
|---|---|---|
| Benign | Malignant | |
| Non-Functional (n = 25) | Adenoma (n = 14) | ACC (n = 1) |
| Benign cyst (n = 2) | Renal cell carcinoma (n = 2) | |
| Myelolipoma (n = 2) Pheochromocytoma (n = 2) | ||
| Lymphangioma (n = 1) | ||
| Ganglioneuroma (n = 1) | ||
| Total | 22 | 3 |
| Hyperfunctional (n = 24) Elevated catecholamines (n = 20) | ||
| Pheochromocytoma (n = 18) Paraganglioma (n = 2) | - | |
| Hypercortisolism (n = 3) | ||
| Adenoma (n = 2) | ACC (n = 1) | |
| Hyperaldosteronism (n = 1) | ||
| Adenoma (n = 1) | - | |
| Total | 23 | 1 |
there was one patient with hyperaldosteronism that had a PAC/PRA of 40 (normal <20) and a benign tumor (Table 2).
Of the entire study group, 35 patients underwent laparo- scopic adrenalectomy. The preferred laparoscopic approach was anterior (n = 27) with the remaining performed by a laparoscopic posterior approach (n = 8). Three cases were converted from an anterior laparoscopic approach to open procedure due to bleeding. The remaining 14 patients in the
1.0
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0.8
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| Specificity (%) | 95% CI | PPV (%) | 95% CI | |
|---|---|---|---|---|
| 4 cm Tumor | 47.7 | 31.9-62.0 | 14.3 | 4.68-33.6 |
| 6 cm Tumor | 80.0 | 64.9-89.9 | 25.0 | 6.69-57.2 |
overall cohort underwent an open procedure as the primary surgical approach because of increased tumor size ≥4 cm and/ or radiologic features suspicious for malignancy (Table 1). The size of adrenal incidentalomas on preoperative radiologic studies was significantly larger for the open (7.2 ± 3.0 cm) compared with the laparoscopic (3.9 ± 1.3 cm) group (P = 0.01). On further analysis, the accuracy of tumor size when pre- dicting malignancy was highest for a tumor size of 6 cm (AUC=0.77) compared with 4 cm (AUC = 0.73) (Fig.). Moreover, a tumor size cutoff of 6 cm demonstrated the highest PPV and specificity in comparison to a tumor size cutoff of 4 cm (Table 3). Patients with laparoscopic adrenalectomy had a significantly shorter operative time (139 min) in comparison to patients with open adrenalectomy (235 min) (P = 0.01). Furthermore, laparoscopic adrenalectomy was associated with shorter length of hospital stay (2.6 d) in comparison to open adrenalectomy (5.3 d). Three of four malignant tumors were resected using an open procedure, and one case was converted from an initial laparoscopic to open approach.
In this surgical series, 4 (8%) incidentalomas were found to be malignant and 45 (92%) were benign. Overall, invasion of adjacent structures (P < 0.001), presence of lymphadenopathy (P = 0.02), metastasis (P = 0.03), irregular tumor margins (P =
| Benign [n = 45] | Malignant [n = 4] | P | |
|---|---|---|---|
| Demographics | |||
| Age | 52 ± 14 | 42 ± 15 | 0.72 |
| Gender | 0.35 | ||
| Female | 32 (71) | 2 (50) | |
| Male | 13 (29) | 2 (50) | |
| Race | 0.79 | ||
| Caucasian | 24 (53) | 3 (75) | |
| Black | 7 (16) | - | |
| Hispanic | 13 (29) | 1 (25) | |
| Other | 1 (2) | - | |
| Preoperative radiologic data | |||
| Size [cm] | 4.5 ± 1.7 | 9.1 ± 4.5 | 0.01 |
| Invading adjacent structures | 0 | 2 (50) | <0.001 |
| Lymphovascular invasion | 0 | 1 (25) | 0.08 |
| Lymphadenopathy | 1 (2) | 2 (50) | 0.01 |
| Necrosis | 12 (27) | 1 (25) | 0.71 |
| Irregular margins | 1 (2) | 2 (50) | 0.01 |
| Enhancement | 10 (22) | 1 (25) | 0.65 |
| Heterogeneity | 10 (22) | 3 (75) | 0.05 |
| Hyperfunctional | |||
| No | 22 (49) | 3 (75) | 0.32 |
| Yes | 23 (51) | 1 (25) |
Data are mean ± SD, or number (%) where appropriate.
0.01), heterogeneity (P = 0.05), and tumor size >6 cm (P = 0.04) on radiologic imaging were strongly associated with malig- nancy in adrenal incidentalomas. Mean tumor size was also larger for the malignant group (9.1 ± 4.5 cm) compared with the benign group (4.5 ± 1.7 cm, P = 0.01) (Table 4).
Final histopathology revealed that relatively half of all benign tumors were hyperfunctioning adrenal tumors (n = 23). The most common hyperfunctioning adrenal incidentaloma was pheochromocytoma (n = 18). Additionally, there were two patients who were initially thought to have pheochro- mocytomas. However, at time of adrenalectomy, it was det- ermined that such tumors were actually paragangliomas (extra-adrenal tumors) located within the vicinity of the adrenal gland confirmed by final histopathology. Further- more, the four malignant tumors consisted of two adreno- cortical carcinomas (ACC) and two metastatic renal cell carcinomas. Of the two adrenocortical carcinomas, one se- creted excess cortisol.
The mean postoperative follow-up time for the 49 patients who underwent adrenal resection was 26 ± 12 mo. There were two postoperative complications: one patient with a wound infection after open adrenalectomy for ACC and one port-site hernia in a patient with benign disease after laparoscopic adrenalectomy. The two patients with ACC died within this study period for an overall mortality rate of 4%.
4. Discussion
This surgical series addresses the potential risk of malignancy in hyperfunctional adrenal incidentalomas. In this report, almost all hyperfunctioning adrenal incidentalomas were benign with only one patient having malignancy. Adrenal incidentalomas are more commonly nonfunctional benign adenomas. The prevalence of benign adrenal incidentalomas in the literature ranges between 44% and 87% [10-12]. In this surgical series, the rate of benign adrenal lesions was slightly higher at 91%. The discrepancy among the rate of benignity between reports is likely due to heterogeneity among inclu- sion of patients in most surgical series. Many descriptions of adrenal incidentalomas have included patients with a history of primary cancers outside the adrenal gland undergoing clinical evaluation for metastatic lesions that can falsely increase the published rate of malignancy. Furthermore, such studies do not specifically address the risk of concomitant malignancy in hyperfunctioning adrenal incidentalomas (Table 5) [10,11,17-25]. In this study, adrenal tumors discov- ered during the work-up for known primary cancers of non- adrenal origin were excluded and may account for the increased rate of benign disease in this series.
One of the major challenges in the management of adrenal incidentalomas remains the accurate diagnosis of underlying malignancy [1]. Guidelines for the management of adrenal incidentalomas are primarily based on case series, large center experiences and expert opinion [8]. Fortunately, the majority of adrenal incidentalomas requiring surgical resec- tion yield a benign adrenal mass [26,27]. This outcome can be explained, in part, by a more aggressive surgical approach to treat primary malignant adrenal tumors earlier, given their poor prognosis. In this study, malignant adrenal
| Table 5 - Malignancy rate in published surgical series over the past decade. | |||||||
|---|---|---|---|---|---|---|---|
| Study* | Year | No. adrenal incidentalomas | Surgical patients | ACC | Other cancers | Total no. cancers | Malignancy in surgical patients (%) |
| Kanthan et al. [17] | 2012 | 94 | 94 | 7 | 4 | 11 | 12 |
| Gust et al. [18] | 2012 | 51 | 51 | 22 | 0 | 22 | 43 |
| Muth et al. [19] | 2011 | 226 | 14 | 0 | 1 | 1 | 7.1 |
| Bin et al. [11] | 2011 | 143 | 143 | 3 | 7 | 10 | 7.0 |
| O'Neill et al. [20] | 2010 | 73 | 73 | 7 | 0 | 7 | 9.6 |
| Grogan et al. [21] | 2010 | 81 | 81 | 3 | 1 | 4 | 4.9 |
| Bhargav et al. [22] | 2008 | 59 | 49 | 4 | 2 | 6 | 12 |
| Guerrieri et al. [23] | 2007 | 78 | 78 | 1 | 0 | 1 | 1.3 |
| Bülow et al. [10] | 2006 | 229 | 11 | 0 | 0 | 0 | 0 |
| Valeri et al. [24] | 2005 | 42 | 42 | 0 | 2 | 2 | 4.8 |
| Emral et al. [25] | 2003 | 70 | 10 | 1 | 0 | 1 | 10 |
All values expressed as number, unless otherwise specified.
* Search performed using Mesh terms: “adrenal incidentaloma,” “surgery,” and “malignancy,” and limited to studies in the English language published in the last 10 years.
incidentalomas were more likely to have irregular margins, lymphadenopathy, heterogeneity, increased size, and invade adjacent structures on preoperative imaging. Malignancy among hyperfunctioning adrenal incidentalomas was found in only one patient in this surgical series.
Published studies have focused on several radiographic features suggestive of adrenal malignancy [28,29]. While current radiologic features of adrenal masses can prove to be helpful, they may engender a false negative prediction of malignancy in certain adrenal tumors [30]. Most algorithms for the treatment of incidentalomas propose surgical removal of nonfunctional adrenal masses greater than 4 cm, overt or borderline hyper- functioning tumors and lesions suspicious for malignancy ba- sed on growth patterns documented by serial imaging studies, and history of malignancy or radiologic features [7,21,26,31,32]. Like many other studies, adrenal tumor size was a statistically significant predictor of malignancy in this series. On further analysis, the PPV and specificity of using a 6 cm tumor size cutoff to determine malignancy was greater compared with a 4 cm tumor size cutoff. Therefore, in this surgical series, the accuracy of tumor size in predicting malignancy improved with larger adrenal incidentalomas.
Functionality of an adrenal incidentaloma as a criterion for resection is well-accepted because of the potential for progres- sion to overt clinical symptoms or the risk for the development of associated comorbidities [27]. However, the risk of cancer associated with hyperfunctioning adrenal incidentalomas is not well known, and literature regarding this concomitant association is limited. In this surgical series, there was only one patient with an adrenal incidentaloma that was concomitantly malignant and hyperfunctional. The patient had biochemically confirmed hypercortisolism and an ACC on final histopatho- logy. The incidence of ACC is estimated to be one to two cases per million people [33]. These tumors most often present with clinical symptoms due to adrenal hormone hypersecretion, most notably cortisol [34]. In this series of 49 patients, four adrenal malignancies were identified, two of which were ACC. When considering the relationship between biochemical hyperactivity and prognosis, non-functional ACC may have a more favorable prognosis in comparison to symptomatic or
subclinical hyperfunctioning ACC [19]. In this study, patients with nonfunctional and hyperfunctional ACC survived for 20 mo compared with 13 mo, respectively.
There are several limitations to this study. This was a retro- spective review of a single institution’s experience. The sample size was small with a decreased the power, leading to the possibility of a type II error. This authors’ study may also over- estimate malignant and hyperfunctional adrenal tumors due to, among other reasons, a selection bias from a surgical population, inclusion of patients with suspicious radiologic features for malignancy, inclusion of only those patients referred to an academic medical center, and exclusion of patients with small adrenal tumors. Furthermore, Hounsfield units, a parameter commonly reported in adrenal incidentaloma literature, could not be analyzed in this study because of heterogeneous and inadequate data reporting among radiologic reports. Nonethe- less, the authors’ surgical series examines excess adrenal hormonal function, tumor size, and features by radiologic studies as predictors of malignancy for incidental adrenal tumors.
In conclusion, the prevalence of adrenal incidentalomas remains unchanged with nonfunctional adrenal adenomas being most common. Tumor size and distinctive radiologic features of an incidental adrenal tumor, including irregular tumor margins, invasion of adjacent structures, and lymph- adenopathy remain highly suggestive of malignancy. Since hyperfunctioning adrenal incidentalomas can harbor under- lying malignancy, it may also be appropriate to convey this risk to patients contemplating surgical management. All hyper- functioning adrenal incidentalomas with suspicious radiologic features and tumor size ≥4 cm that lack benign radiologic features should be surgically removed. Moreover, surgeons may be able to assume greater reliability in the diagnosis of malig- nancy in patients with adrenal incidentalomas measuring 6 cm by radiologic studies. Patients should undergo biochemical testing for subclinical Cushing’s syndrome, pheochromocy- toma, and primary hyperaldosteronism. Yearly biochemical testing for most patients with adrenal tumors <4 cm for up to 5 years can be performed. This study underscores the need for early referral of all adrenal incidentalomas to an experienced surgeon, and further research efforts to identify additional
predictors of malignancy in the management of adrenal incidentalomas.
REFERENCES
[1] Duh QY. Adrenal incidentalomas. Br J Surg 2002;89:1347.
[2] Thompson GB, Young WF. Adrenal incidentaloma. Curr Opin Oncol 2003;15:84.
[3] Zarco-Gonzalez JA, Herrera MF. Adrenal incidentaloma. Scand J Surg 2004;93:298.
[4] Barzon L, Sonino N, Fallo F, et al. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol 2003; 149:273.
[5] Bovio S, Cataldi A, Reimondo G, et al. Prevalence of adrenal incidentaloma in a contemporary computerized tomography series. J Endocrinol Invest 2006;29:298.
[6] Brunt LM, Moley JF. Adrenal incidentaloma. World J Surg 2001;25:905.
[7] Zeiger MA, Siegelman SS, Hamrahian AH. Medical and surgical evaluation and treatment of adrenal incidentalomas. J Clin Endocrinol Metab 2011;96:2004.
[8] Zeiger MA, Thompson GB, Duh QY, et al. American Association of Clinical Endocrinologists; American Association of Endocrine Surgeons. The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas. Endocr Pract 2009;15:1.
[9] Barzon L, Scaroni C, Sonino N, et al. Risk factors and long- term follow-up of adrenal incidentalomas. J Clin Endocrinol Metab 1999;84:520.
[10] Bülow B, Jansson S, Juhlin C, et al. Adrenal incidentaloma-follow-up results from a Swedish prospective study. Eur J Endocrinol 2006;154:419.
[11] Bin X, Qing Y, Linhui W, et al. Adrenal incidentalomas: experience from a retrospective study in a Chinese population. Urol Oncol 2011;29:270.
[12] Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab 2000;85:637.
[13] Fajardo R, Montalvo J, Velazquez D, et al. Correlation between radiologic and pathologic dimensions of adrenal masses. World J Surg 2004;28:494.
[14] Young WF. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med 2007;356:601.
[15] Libè R, Dall’Asta C, Barbetta L, et al. Long-term follow-up study of patients with adrenal incidentalomas. Eur J Endocrinol 2002;147:489.
[16] Vassilatou E, Vryonidou A, Michalopoulou S, et al. Hormonal activity of adrenal incidentalomas: results from a long-term follow-up study. Clin Endocrinol (Oxf) 2009;70:674.
[17] Kanthan R, Senger JL, Kanthan S. Three uncommon adrenal incidentalomas: a 13-year surgical pathology review. World J Surg Oncol 2012;10:64.
[18] Gust L, Taieb D, Beliard A, et al. Preoperative 18F-FDG uptake is strongly correlated with malignancy, Weiss score, and molecular markers of aggressiveness in adrenal cortical tumors. World J Surg 2012;36:1406.
[19] Muth A, Hammarstedt L, Hellström M, et al. Cohort study of patients with adrenal lesions discovered incidentally. Br J Surg 2011;98:1383.
[20] O’Neill CJ, Spence A, Logan B, et al. Adrenal incidentalomas: risk of adrenocortical carcinoma and clinical outcomes. J Surg Oncol 2010;102:450.
[21] Grogan RH, Mitmaker E, Vriens MR, et al. Adrenal incidentaloma: does an adequate workup rule out surprises? Surgery 2010;148:392.
[22] Bhargav PR, Mishra A, Agarwal G, et al. Adrenal incidentalomas: experience in a developing country. World J Surg 2008;32:1802.
[23] Guerrieri M, De Sanctin A, Crosta F, et al. Adrenal incidentaloma: surgical update. J Endocrinol Invest 2007;30:200.
[24] Valeri A, Bergamini C, Manca G, et al. Adrenal incidentaloma: the influence of a decision-making algorithm on the short- term outcome of laparoscopy. J Laparoendosc Adv Surg Tech A 2005;15:451.
[25] Emral R, Uysul AR, Asik M, et al. Prevalence of subclinical Cushing’s syndrome in 70 patients with adrenal incidentaloma: clinical, biochemical, and surgical outcomes. Endocr J 2003;50:399.
[26] Anagnostis P, Karagiannis A, Tziomalos K, et al. Adrenal incidentaloma: a diagnostic challenge. Hormones (Athens) 2009;8:163.
[27] Bittner JG, Brunt LM. Evaluation and management of adrenal incidentaloma. J Surg Oncol 2012;106:557.
[28] Shen WT, Sturgeon C, Duh QY. From incidentaloma to adrenocortical carcinoma: the surgical management of adrenal tumors. J Surg Oncol 2005;89:186.
[29] Sturgeon C, Kebebew E. Laparoscopic adrenalectomy for malignancy. Surg Clin N Am 2004;84:755.
[30] Burt M, Heelan RT, Coit D, et al. Prospective evaluation of unilateral adrenal masses in patients with operable non- small-cell lung cancer. Impact of magnetic resonance imaging. J Thorac Cardiovasc Surg 1994;107:584.
[31] Nieman LK. Approach to the patient with an adrenal incidentaloma. J Clin Endocrinol Metab 2010;95:4106.
[32] Terzolo M, Bovio S, Pia A, et al. Management of adrenal incidentaloma. Best Pract Res Clin Endocrinol Metab 2009;23: 233.
[33] Mansmann G, Lau J, Balk E, et al. The clinically unapparent adrenal mass: update in diagnosis and management. Endocr Rev 2004;25:309.
[34] Allolio B, Fassnacht M. Clinical review: adrenocortical carcinoma-clinical update. J Clin Endocrinol Metab 2006; 91:2027.