23299088

Adrenal tumours are more predominant in females regardless of their histological subtype: a review

François Audenet · Arnaud Méjean · Emmanuel Chartier-Kastler · Morgan Rouprêt

Received: 12 November 2012/ Accepted: 11 December 2012 @ Springer-Verlag Berlin Heidelberg 2013

Abstract

Objectives Adrenal tumours are a heterogeneous group of rare tumours. The aim of this article was to critically review gender-specific differences in the incidence, prog- nosis and symptoms of the different subtypes of adrenal tumours.

Methods Data acquisition regarding gender differences in adrenal tumours was performed using MEDLINE searches with combinations of the following keywords: adrenal tumours, gender, sex differences, adrenocortical carci- noma, pheochromocytoma, incidentaloma, risk factors and genetic aspects.

Results Data are scarce in the literature concerning the effects of gender on adrenal lesions. Although the incidence of most types of tumours (other than breast cancer and other gender-related tumours) is higher in men than in women, evidence suggests that adrenal tumours (i.e. incidentalomas, adrenal carcinomas, oncocytomas and adrenal cysts) are more frequent in women than in men. In addition, female patients have significantly increased numbers of self-reported signs and symptoms of pheochromocytoma than male patients, irrespective of biochemical phenotype and tumour presentation. Relatively little research has been performed

F. Audenet · A. Méjean

Academic Department of Urology of Georges Pompidou European Hospital (HEGP), Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Descartes , University Paris V, Paris, France

E. Chartier-Kastler · M. Rouprêt Academic Department of Urology of la Pitié-Salpêtrière

Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Pierre et Marie Curie and Institut Universitaire de Cancérologie GRC ONCOTYPE, University Paris VI, 47-83 Boulevard de l’hôpital, 75013 Paris, France

e-mail: mroupret@gmail.com; morgan.roupret@psl.aphp.fr

examining the reasons for these disparities. However, hor- monal interactions involving complex adrenal, endocrine and neurocrine functions together with variations in hormonal receptor sensitivity have been hypothesised to be involved. Conclusion Gender differences exist in the incidence and symptoms of several subtypes of adrenal tumours. The reasons for these disparities are not well established. In addition to epidemiological data, these results need to be further investigated to better understand the role of genetic and hormonal predispositions in the development, behav- iour and aggressiveness of adrenal tumours.

Keywords Adrenal tumours · Gender . Sex differences . Adrenocortical carcinoma · Pheochromocytoma · Incidentaloma · Risk factors · Genetic aspects

Introduction

Tumours of the adrenal gland are a heterogeneous group of lesions that arise from either the adrenal cortex or the medulla. These tumours are extremely rare and exhibit an average annual age-adjusted incidence of 0.29 cases per 100,000 individuals [1]. They include several subtypes of lesions that can be either malignant or benign. Some of these tumours are functional and produce hormonal and metabolic syndromes that can lead to their discovery. Other adrenal tumours (up to 50 % of tumours, depending on the histological subtype) are silent and are only discovered when they attain a large size and produce localised abdominal symptoms or metastases. However, the discov- ery of adrenal incidentalomas is becoming increasingly frequent due to the widespread use of abdominal ultraso- nography, computed tomography and magnetic resonance imaging. One study reported a 4 % prevalence of adrenal

incidentaloma, a fact that results in a significant clinical dilemma concerning the management of these patients [2].

Most of these tumours are sporadic, and their aetiology remains unknown. However, several syndromes have been associated with an increased risk of adrenal tumours, and the underlying molecular defects of these syndromes have advanced our understanding of the molecular pathways involved in the tumourigenesis of adrenal tumours. Gender represents one of the most significant genetic risk factors for cancer, with the vast majority of cancers affecting men at higher rates than women [3, 4]. In addition, gender has also been reported to be associated with discrepancies in oncologic outcomes. The reasons for the reported gender disparities in oncologic outcomes may be complex and could include differences in modifiable risk factors, dif- ferences in health care utilisation and intrinsic biological differences between genders [5, 6].

There are relatively few reports in the published literature concerning the effects of gender on adrenal tumours [7]. The aim of this article was to critically review the published studies examining gender differences in the incidence, prog- nosis and symptoms of different subtypes of adrenal tumours.

Materials and methods

Data acquisition regarding the role of gender in adrenal tumours was performed via MEDLINE searches in Pub- Med (http://www.ncbi.nlm.nih.gov) using combinations of the following keywords: adrenal tumours, gender, sex differences, adrenocortical carcinoma, pheochromocytoma, incidentaloma, risk factors and genetic aspects. Initially, only studies that were published in English between 1982 and 2012 that concerned adrenal tumours in adults were selected. However, due to the limited number of publica- tions, additional articles were selected according to their quality and relevance, including older studies. Overall, 33 publications were included in the present analysis. To facilitate the evaluation of the quality of the information provided, levels of evidence (LE) were inserted according to the general principles of evidence-based medicine [8].

Adrenal incidentalomas

The increased use of abdominal ultrasound and CT scanner has led to the discovery of incidentally identified unsus- pected adrenal mass or incidentaloma. Clinically silent adrenal masses discovered by imaging studies performed for unrelated reasons have become a rather common find- ing in clinical practice. The prevalence of adrenal inci- dentalomas varies with the source of data (either autopsies series or radiological series) and with the selection of

patients (general population or special patient categories). It increases with the patients’ age, being 0.2 % in young subjects compared with 6.9 % in patients older than 70 years of age [9]. Clinical studies show that adrenal incidentalomas are more frequent in females, with a mean female/male ratio of 1.4:1 (range 0.9-2.5) [10]. However, no sex differences have been reported in autopsy series. Thus, the higher prevalence of adrenal incidentalomas in females could be attributed to a higher rate of abdominal diagnostic procedures in women than in men.

The aetiology of incidentaloma covers a wide range of pathology. In the vast majority of cases, these masses are non-hypersecreting adrenocortical adenomas. However, they may represent primary or metastatic malignancies and show minor endocrine abnormalities or subclinical hyper- function. The probability of malignancy increases as a function of mass size. However, adrenal mass size should not be used as the only criterion of malignancy, as malignant tumours < 3 cm in diameter are not uncommon. Adrenocortical malignancies generally occur at younger ages than benign adrenal lesions and are significantly more frequent in males, with a female/male ratio of 0.5:1 for malignant tumours and 1.7:1 for benign tumours [11].

Tumours of the adrenal medulla

Pheochromocytoma

Pheochromocytoma is a tumour of the catecholamine- producing cells of the adrenal medulla. Approximately one to two cases per 100,000 individuals are diagnosed annu- ally with pheochromocytoma, although reports of the dis- ease incidence vary [12]. Given its rarity, it has been estimated that pheochromocytoma is responsible for only approximately 0.5 % of hypertension cases [13]. Among patients with incidental adrenal masses, approximately 5 % are found to have a pheochromocytoma [14]. Malignancy is rare both in sporadic cases of adrenal pheochromocy- toma (up to 5 %) and in most cases of hereditary disease. Malignant lesions are more likely to exhibit elevated dopamine levels and tend to be larger (>5 cm). However, until now, there are no good ways to predict which tumour will progress to metastases, and successful surgical exci- sion of an apparent benign tumour may be followed by a diagnosis of malignancy as long as 15 years later [12].

Men and women seem to be affected at similar fre- quencies, and no gender differences in disease prognosis have been reported. However, the diverse nature of cate- cholamine content and the variable relative production of norepinephrine versus epinephrine could contribute to the variability in clinical presentation [15]. In their study, Lai et al. [7] showed that gender was also an important

determinant in the presentation of the signs and symptoms associated with excess catecholamines in pheochromocy- toma patients. By evaluating 23 male and 35 female pheochromocytoma patients for the symptoms and signs of pheochromocytoma, with special regard to gender-related differences in presentation, significant gender differences in total symptom score were observed (12.0 for females vs. 7.8 for males, p < 0.0001) (LE: 3). Female patients reported significantly more headaches (80 vs. 52 %), dizziness (83 vs. 39 %), anxiety (85 vs. 50 %), tremors (64 vs. 33 %), weight changes (88 vs. 43 %), numbness (57 vs. 24 %) and changes in energy level (89 vs. 64 %), although females and males displayed comparable biochemical phenotypes (60 and 65 % noradrenergic phenotype, respectively). Gender differences were found to be independent of biochemical phenotype, the use of adrenoreceptor blockade or the presence of malignant disease. As a consequence, the authors concluded that female patients had significantly more self-reported signs and symptoms of pheochromocy- toma than male patients, irrespective of biochemical phe- notype and tumour presentation, a fact that is most likely related to differences in catecholamine receptor sensitivity. Indeed, gender differences in adrenergic receptor sensitivity have been reported previously. Studies have also shown increased sensitivity to ß2-adrenergic receptor stimulation [16] and greater @2-adrenoreceptor-mediated effects in women [17]. In addition, catecholamine-stress-induced cardiomyopathy appears to be more prevalent in females than in males, a fact that is thought to reflect gender-specific differences in adrenoreceptor signalling during periods of excessive levels of catecholamines [18].

Ganglioneuroma

Ganglioneuromas are extremely rare benign neuroectoder- mal neoplasms that are composed of ganglion and Schwann cells. In one large series (n = 88), 21 % of cases arose from the adrenal gland itself. Other sites of origin included the mediastinum (39 %), the retroperitoneum (31 %), and iso- lated cases in the pelvis and neck. This type of tumour appears to have a predilection for the young, with only 20 % of cases affecting individuals over the age of 40 years and approximately 50 % of cases found in patients between 10 and 29 years of age. However, no gender differences have been reported for ganglioneuroma [19].

Tumours of the adrenal cortex

Adenoma

Adenomas are the most common neoplasms arising from the adrenal gland and are most often associated with the

cortex. The incidence of adenoma increases with age. These tumours are found in approximately 6 % of patients at autopsy [20]. Clinically, adrenal adenomas are most often incidentally discovered on cross-sectional imaging obtained for other indications. More than 85 % of adrenal neoplasms incidentally discovered on imaging are ulti- mately clinically proved to be adenomas [9]. They are by definition benign although they may be difficult to distin- guish histologically from adrenal adenocarcinomas. The vast majority of adenomas are metabolically silent and only 7 % exhibit metabolic hyperactivity, causing Cushing’s syndrome or primary hyperaldosteronism. No gender- related differences in presentation or symptoms have been reported in the literature.

Adrenocortical carcinoma

Adrenocortical carcinoma is a rare malignancy that accounts for 0.02 % of all cancers reported annually [21]. It has an incidence of one to two cases per 1.7 million individuals in the population [22]. There is a bimodal age distribution of affected individuals, with one peak in the first decade of life and another peak in the fourth or fifth decade of life. However, most patients with adrenocortical carcinoma are adults, with 58 % of all cases being over 50 years old. These tumours are classified as either non-functional or functional depending on whether they produce corticosteroids, androgen, oestrogen or mineralo- corticoids. Although early studies reported that up to 50 % of these tumours were functional, more recent series have noted hormone secretion in up to 79 % of adrenocortical carcinomas, an increase that most likely results from improvements in assay sensitivity [23]. Functional tumours often present with Cushing’s syndrome (40 %) and only rarely present with pure virilisation in adult women [24].

Several epidemiologic studies have reported a slight female predominance of adrenocortical carcinomas, with a female/male ratio between 1.5:1 and 2.1:1 [21]. In a review by Wooten et al., among the 1,891 adrenocortical carcinomas reported in the English language literature, 58.6 % affected women [25]. However, whether gender plays a significant role in the prognosis in these tumours has not been reported.

To examine potential risk factors, Hsing et al. conducted a case-control study based on data from the National Mortality Followback Survey, which included a question- naire sent to the families of approximately 20,000 adults deceased of any cause, aged over 25 years in the United States [26]. Information was obtained regarding a large number of items, including the use of cigarettes, alcohol and oral contraceptives and the height, weight and food consumption of all subjects. A total of 176 patients who died of adrenal cancers (88 women and 88 men) and 352 controls (176 women and 176 men) who died of causes

unrelated to smoking, drinking or oral contraception (for female controls) were included in this study. Although specific information regarding the histological type of each tumour was not available, most cases were considered to be adrenocortical carcinomas, with a small percentage being considered malignant pheochromocytomas based on inci- dence surveys. An increased tumour risk was associated with heavy smoking (≥25 cigarettes/day) among men [odds ratio (OR) = 2.0, 95 % confidence interval (95 % CI) = 1.0-4.4], but not among women (LE: 3). No clear association between cancer risk, and alcohol use, height, weight and food consumption patterns were observed in either gender. Among women, increased cancer risk was observed for users of oral contraception [OR = 1.8, 95 % CI = (1.0-3.2)], especially for individuals who used oral contraceptives before the age of 25 years [OR = 2.5, 95 % CI = (1.2-5.5)] (LE: 3). When the analysis was restricted to subjects with spousal respondents, even more pro- nounced risks were observed for users of oral contracep- tion, especially for those who used oral contraceptives before the age of 25 years.

Hormonal interactions with complex adrenal, endocrine and neurocrine functions may explain the increased inci- dence of these tumours in women, particularly in cases associated with the use of oral contraception. Indeed, experimental studies have shown a higher risk of adrenal tumours in ovariectomised mice [27] and in rats adminis- tered exogenous oestrogens [28]. Prior work has compared the luteinizing hormone (LH/hCG) responsiveness of nor- mal and pathological human adrenal glands and has reported the possibility of constitutive luteinizing hormone receptor (LHR) expression in the adrenal cortex [29]. Recent studies have also shown a correlation between LHR expression and the abundant expression of transcription factors, such as GATA-4, in both metastasising and non- metastasising human adrenocortical tumours, but not in normal adrenal glands, a finding that may be relevant for adrenocortical carcinoma physiopathology [30].

The presentation, staging and prognosis of paediatric adrenocortical carcinomas differ from that observed in adults [31]. Unlike in adults, the female/male ratio is 1:1 in children under the age of 12 years, but it sharply increases to 6:1 in individuals between the ages of 13 and 20 years. In contrast, this gender difference does not exist for neu- roblastomas, which are diagnosed at a median age of 19 months. More than 90 % of the adrenocortical carci- nomas in children are functional at the time of presentation, with virilisation, which occurs in 55-70 % of patients, being the most common clinical manifestation.

Genetic syndromes should be considered in paediatric cases of adrenal carcinoma. Indeed, several syndromes have been associated with an increased incidence of adre- nocortical carcinoma, including Li-Fraumeni syndrome,

Beckwith-Wiedemann syndrome, Carney complex, multiple endocrine neoplasia type 1 (MEN1) and McCune- Albright syndrome. Most of these syndromes are autoso- mal dominant cancer predisposition syndromes that are believed to affect men and women equally. However, several recent studies have shown an overall female pre- dominance in five MEN1 studies from France (n = 734), the United States (n = 233), the United Kingdom (n = 220), Germany (n = 301) and Finland (n = 82), with a proportion of women of 58, 54, 57, 59 and 57 %, respectively [32]. Although the prevalence of adrenal tumours was similar in both sexes among patients with MEN1, a higher frequency of adrenal tumours was observed to result from MEN1 in women.

Other adrenal tumours

Oncocytoma

Given their relatively common renal origin, oncocytomas are familiar to most urologists. However, oncocytic tumours can also arise from the salivary gland and the endocrine organs. Adrenal lesions are exceedingly rare, with approximately 50 cases having been reported in the literature [33]. The path- ogenesis of oncocytic neoplasias is poorly understood. Females have been reported to be affected 2.5 times more frequently than males, and left-sided lesions outnumber right-sided lesions 3.5-1. Tumours can grow to approxi- mately 20 cm, and at least two cases have been reported during pregnancy [33]. Most lesions that are documented in the literature are metabolically inactive, but some oncocytic adrenal neoplasms (n = 6, or approximately 10 % of all cases reported) hypersecrete sex steroids, cytokines and/or cortisol [34]. Classically, these lesions have been considered benign; however, over 30 % of reported lesions have been classified as malignant, with an additional 23 % having been designated as pathologically indeterminate [35].

Myelolipoma

Myelolipomas are rare, benign, metabolically silent lesions that, like healthy bone marrow, contain hematopoietic elements and mature adipose tissue. They arise primarily from the adrenal gland in patients in all age groups. Based on historical autopsy series, the incidence of these lesions is estimated to be <0.1 % [36]. Several reports have sug- gested that 15 % of all myelolipomas are extra-adrenal, with up to a half arising in the pre-sacral area. Thoracic, retroperitoneal, pelvic, renal, hepatic and gastric lesions have all been reported [37]. Classically, myelolipomas are metabolically non-functional lesions that affect men and women with approximately equal frequency.

Table 1 Epidemiological and clinical characteristics of the main adrenal tumours

	Type of tumour	Incidence	Ratio men/ women	Hereditary syndromes associated	Symptoms	Treatment	Prognostic
Adrenocortical carcinoma	Malignant	0.5-2/million	1/1.5-2.1	2-6 %	Incidental detection	Surgery + Medical	Poor (60-80 % of
				Li-Fraumeni syndrome	Symptoms related to local or systemic disease burden	therapy (mitotane)	recurrent disease after surgical regression)
				Beckwith- Wiedemann syndrome	Hypersecretion of adrenal hormones in 50-79 % (Cushing's syndrome + virilisation)
				Carney complex
				Multiple endocrine neoplasia type 1
				McCune-Albright syndrome
Adenoma	Benign	6 %	1/1		Mainly asymptomatic (incidental finding)	Surgery resection if metabolically active or diagnostic doubt	Excellent
					7 % are functional (Cushing's syndrome or Conn syndrome)
Pheochromocytoma	5 % malignant	1-2/100,000	1/1	1/3 Multiple endocrine neoplasia type 2A	Related to hypersecretion of catecholamines: headache, episodic sudden perspiration and tachycardia More frequent in women	Surgery resection after catecholamine blockade	Good, but late recurrence may occur
				Multiple endocrine neoplasia type 2B
				von Hippel- Lindau syndrome type 2
				Neurofibromatosis type 1
				Familial
				paraganglioma syndrome type 4
				Familial
				paraganglioma syndrome type 1
Ganglioneuroma	Benign	100 cases	1/1		Metabolically non-functional	Surgery resection	Can grow extremely
		reported in					large and have a propensity to encase
		the
		literature					vessels

Table 1 continued

	Type of tumour	Incidence	Ratio men/ women	Hereditary syndromes associated	Symptoms	Treatment	Prognostic
Oncocytoma	2/3 benign 1/3 malignant	50 cases reported in the literature <0.1 %	1/2.5 1/1		Mainly asymptomatic (incidental finding)	Surgery resection	Excellent if benign Excellent
						Conservative treatment if asymptomatic
Myelolipoma	Benign				Metabolically non-functional Possible spontaneous rupture if >10 cm
Adrenal cyst	Benign but up to 7 % are associated with malignancy	0.064-0.18 %	Men < Women	Polycystic renal disease Klippel- Trenaunay- Weber syndrome Beckwith- Wiedemann syndrome	Metabolically non-functional Mainly asymptomatic (incidental finding)	Surgery resection	Risk of associated malignancy

Adrenal cyst

Adrenal cysts have been noted in 0.064-0.18 % of patients in autopsy series and account for 1-5 % of incidentally detected adrenal lesions [38]. Cystic adrenal lesions can be diagnosed as early as the prenatal period and continue to be diagnosed throughout life. Cyst size can range widely from several millimetres to >20 cm and can be characterised by either unilocular or multilocular components. An increased incidence of adrenal cysts has been noted in women, with a peak incidence between the third and sixth decades of life [39]. Several medical conditions have been associated with adrenal cysts, including polycystic renal disease, Klippel- Trenaunay-Weber syndrome and Beckwith-Wiedemann syndrome [40].

Main data are summarised according to the different histological subtypes of adrenal tumours in Table 1.

Conclusion

Adrenal tumours are part of a heterogeneous group of rare tumours. There have been very few reports published in the literature concerning the effects of gender on adrenal lesions. However, although the global number of men diagnosed with non-gender-specific cancers is higher than the number of women, it appears that incidentalomas, adrenal carcinomas, oncocytomas and adrenal cysts are more frequent in women than in men. Furthermore, female patients have significantly more self-reported signs and symptoms of pheochromocy- toma than male patients, irrespective of biochemical phe- notype and tumour presentation.

The reasons for these disparities are not well estab- lished. However, complex hormonal interactions with adrenal, endocrine and neurocrine functions, together with variations in the sensitivity of hormonal receptors, have been hypothesised to play an important role. Additional experimental studies are required to better understand the role of genetic and hormonal predispositions in mediating the observed gender differences in adrenal tumours.

References

1. Schteingart DE, Doherty GM, Gauger PG, Giordano TJ, Hammer GD, Korobkin M et al (2005) Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer 12:667-680. doi:10.1677/erc.

1.01029

2. Mansmann G, Lau J, Balk E, Rothberg M, Miyachi Y, Bornstein SR (2004) The clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev 25:309-340

3. Cook MB, Dawsey SM, Freedman ND, Inskip PD, Wichner SM, Quraishi SM et al (2009) Sex disparities in cancer incidence by

period and age. Cancer Epidemiol Biomarkers Prev 18:1174- 1182. doi:10.1158/1055-9965.EPI-08-1118

4. Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial dispar- ities on premature cancer deaths. CA Cancer J Clin 61:212-236. doi: 10.3322/caac.20121

5. Ober C, Loisel DA, Gilad Y (2008) Sex-specific genetic architecture of human disease. Nat Rev Genet 9:911-922. doi: 10.1038/nrg2415

6. Higdon JV, Frei B (2005) Is there a gender difference in the effect of antioxidants on cancer risk? Br J Nutr 94:139-140

7. Lai EW, Perera SM, Havekes B, Timmers HJ, Brouwers FM, McElroy B et al (2008) Gender-related differences in the clinical presentation of malignant and benign pheochromocytoma. Endocrine 34:96-100. doi:10.1007/s12020-008-9108-4

8. Howick J, Chalmers I, Glasziou P, Greenhalgh T, Heneghan C, Liberati A et al (2011) Oxford centre for evidence-based medi- cine. The oxford 2011 levels of evidence. http://www.cebm.net/ index.aspx?o=5653

9. Young WF Jr (2000) Management approaches to adrenal inci- dentalomas. A view from Rochester, Minnesota. Endocrinol Metab Clin North Am 29:159-185

10. Barzon L, Sonino N, Fallo F, Palu G, Boscaro M (2003) Preva- lence and natural history of adrenal incidentalomas. Eur J Endocrinol 149:273-285

11. Barzon L, Scaroni C, Sonino N, Fallo F, Gregianin M, Macri C et al (1998) Incidentally discovered adrenal tumors: endocrine and scintigraphic correlates. J Clin Endocrinol Metab 83:55-62

12. Bravo EL, Tagle R (2003) Pheochromocytoma: state-of-the-art and future prospects. Endocr Rev 24:539-553

13. Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P et al (2002) Biochemical diagnosis of pheochromocy- toma: which test is best? JAMA 287:1427-1434

14. Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Ali A et al (2000) A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinol- ogy. J Clin Endocrinol Metab 85:637-644

15. Eisenhofer G, Lenders JW, Goldstein DS, Mannelli M, Csako G, Walther MM et al (2005) Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free metanephrines. Clin Chem 51:735-744. doi:10. 1373/clinchem.2004.045484

16. Kneale BJ, Chowienczyk PJ, Brett SE, Coltart DJ, Ritter JM (2000) Gender differences in sensitivity to adrenergic agonists of forearm resistance vasculature. J Am Coll Cardiol 36:1233-1238

17. Luzier AB, Nawarskas JJ, Anonuevo J, Wilson MF, Kazierad DJ (1998) The effects of gender on adrenergic receptor responsive- ness. J Clin Pharmacol 38:618-624

18. Lyon AR, Rees PS, Prasad S, Poole-Wilson PA, Harding SE (2008) Stress (Takotsubo) cardiomyopathy-a novel pathophys- iological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med 5:22-29. doi: 10.1038/ncpcardio1066

19. Maweja S, Materne R, Detrembleur N, de Leval L, Defechereux T, Meurisse M et al (2007) Adrenal ganglioneuroma. Am J Surg 194:683-684. doi:10.1016/j.amjsurg.2007.01.034

20. Kloos RT, Gross MD, Shapiro B, Francis IR, Korobkin M, Thompson NW (1997) Diagnostic dilemma of small incidentally discovered adrenal masses: role for 131I-6beta-iodomethyl- norcholesterol scintigraphy. World J Surg 21:36-40

21. Roman S (2006) Adrenocortical carcinoma. Curr Opin Oncol 18:36-42

22. Vaughan ED Jr (2004) Diseases of the adrenal gland. Med Clin North Am 88:443-466. doi:10.1016/S0025-7125(03)00149-4

23. Tauchmanova L, Colao A, Marzano LA, Sparano L, Camera L, Rossi A et al (2004) Andrenocortical carcinomas: twelve-year prospective experience. World J Surg 28:896-903

24. Ng L, Libertino JM (2003) Adrenocortical carcinoma: diagnosis, evaluation and treatment. J Urol 169:5-11. doi: 10.1097/01.ju. 0000030148.59051.35

25. Wooten MD, King DK (1993) Adrenal cortical carcinoma. Epi- demiology and treatment with mitotane and a review of the lit- erature. Cancer 72:3145-3155

26. Hsing AW, Nam JM, Co Chien HT, McLaughlin JK, Fraumeni JF Jr (1996) Risk factors for adrenal cancer: an exploratory study. Int J Cancer 65:432-436. doi: 10.1002/(SICI)1097-0215 (19960208)65:4<432:AID-IJC6>3.0.CO;2-Y

27. Strickland JE, Saviolakis GA, Weislow OS, Allen PT, Hellman A, Fowler AK (1980) Spontaneous adrenal tumors in the aged, ovariectomized NIH swiss mouse without enhanced retrovirus expression. Cancer Res 40:3570-3575

28. Noble RL, Hochachka BC, King D (1975) Spontaneous and estrogen-produced tumors in Nb rats and their behavior after transplantation. Cancer Res 35:766-780

29. Rahman NA, Kiiveri S, Siltanen S, Levallet J, Kero J, Lensu T et al (2001) Adrenocortical tumorigenesis in transgenic mice: the role of luteinizing hormone receptor and transcription factors GATA-4 and GATA-61. Reprod Biol 1:5-9

30. Vuorenoja S, Rivero-Muller A, Kiiveri S, Bielinska M, Heikinheimo M, Wilson DB et al (2007) Adrenocortical tumor- igenesis, luteinizing hormone receptor and transcription factors GATA-4 and GATA-6. Mol Cell Endocrinol 269:38-45. doi: 10.1016/j.mce.2006.11.013

31. Liou LS, Kay R (2000) Adrenocortical carcinoma in children. Review and recent innovations. Urol Clin North Am 27:403-421

32. Goudet P, Bonithon-Kopp C, Murat A, Ruszniewski P, Niccoli P, Menegaux F et al (2011) Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d’etude des Tumeurs Endocrines. Eur J Endocrinol 165:97-105. doi:10.1530/EJE-10-0950

33. Bisceglia M, Ludovico O, Di Mattia A, Ben-Dor D, Sandbank J, Pasquinelli G et al (2004) Adrenocortical oncocytic tumors: report of 10 cases and review of the literature. Int J Surg Pathol 12:231-243

34. Akatsu T, Kameyama K, Araki K, Ashizawa T, Wakabayashi G, Kitajima M (2008) Functioning adrenocortical oncocytoma: the first documented case producing interleukin-6 and review of the literature. J Endocrinol Invest 31:68-73

35. Juliano JJ, Cody RL, Suh JH (2008) Metastatic adrenocortical oncocytoma: a case report. Urol Oncol 26:198-201. doi: 10.1016/j.urolonc.2007.02.008

36. Olsson CA, Krane RJ, Klugo RC, Selikowitz SM (1973) Adrenal myelolipoma. Surgery 73:665-670

37. Patel VG, Babalola OA, Fortson JK, Weaver WL (2006) Adrenal myelolipoma: report of a case and review of the literature. Am Surg 72:649-654

38. Song JH, Chaudhry FS, Mayo-Smith WW (2008) The incidental adrenal mass on CT: prevalence of adrenal disease in 1,049 consecutive adrenal masses in patients with no known malig- nancy. AJR Am J Roentgenol 190:1163-1168. doi: 10.2214/AJR. 07.2799

39. Sanal HT, Kocaoglu M, Yildirim D, Bulakbasi N, Guvenc I, Tayfun C et al (2006) Imaging features of benign adrenal cysts. Eur J Radiol 60:465-469. doi: 10.1016/j.ejrad.2006.08.005

40. Erickson LA, Lloyd RV, Hartman R, Thompson G (2004) Cystic adrenal neoplasms. Cancer 101:1537-1544. doi:10.1002/cncr. 20555