REVIEW
The clinical significance of adrenal incidentalomas
loannis I. Androulakis*, Gregory Kaltsas”, George Piaditist and Ashley B. Grossman+
`Department of Pathophysiology, National University of Athens, Mikras Asias, Athens, Greece, 1Department of Endocrinology and Diabetes, General Hospital of Athens ‘G. Genimatas’, Leoforos Mesogion, Athens, Greece, +Department of Endocrinology, St Bartholomew’s Hospital, Barts and the London School of Medicine, West Smithfield, London, UK
ABSTRACT
Background The term adrenal incidentaloma (AI) indicates an adrenal mass lesion > 1 cm in diameter discov- ered during testing for conditions unrelated to adrenal disease. The overall prevalence of these lesions ranges between 3% and 10%. Their incidence increases with age, and it is clinically important to identify AI associated with hormonal activity and/or malignant potential.
Design A detailed Medline search of all English language articles related to AI was carried out, and the clinical implications related to their hormonal activity and malignant potential are discussed.
Results The subclinical hypercortisolism observed in a significant percentage of patients with AI is associated with some of the detrimental effects of continuous autonomous cortisol secretion, including a higher prevalence of hypertension, dyslipidemia, impaired glucose tolerance or type 2 diabetes mellitus and an increased risk for osteoporotic fractures. However, it remains to be proven whether treatment to reverse subtle glucocorticoid excess is beneficial. Clinically silent phaeochromocytomas and primary adrenal cancer are conditions associated with significantly high morbidity and mortality and require urgent treatment, while the prevalence and clinical significance of autonomous mineralocorticoid secretion are less clearly defined. Size and radiological features are the main predictors of malignant potential.
Conclusions Patients harbouring Al should be evaluated for the possibility of malignancy and/or subclinical hypercortisolism which is associated with cardiovascular risk and bone loss. However, in the absence of prospective controlled studies correlating biochemical activity with end-organ complications, the long-term consequences of AI remain uncertain and their management remains largely pragmatic.
Keywords Adrenal incidentaloma, adrenocortical adenoma, subclinical Cushing’s syndrome. Eur J Clin Invest 2011; 41 (5): 552-560
Introduction
The term adrenal incidentaloma (AI) or a clinically inapparent adrenal mass indicates an adrenal mass lesion > 1 cm in diam- eter discovered during testing or treatment for conditions unrelated to any suspicion of adrenal disease [1]. This entity was first described 25 years ago and is the result of technological advances and broader availability of imaging technology [2].
Despite the rarity of primary adrenal cancer, adrenal masses are one of the most prevalent human tumours. The prevalence of AI detected at autopsy is < 1% in patients younger than 30 years of age, increasing to 7% in patients 70 years of age or older [3]. Data from the Mayo Clinic indicate a 3-4% prevalence of adrenal masses among 61 054 abdominal computerised tomography (CT) scans performed from 1985 to 1990 [4]. A more recent study, which utilised higher resolution scanners, the reported prevalence of AI on abdominal CT was 4.4% [5].
Adrenal incidentalomas do not constitute a single pathologi- cal entity. They can arise from the adrenal cortex or medulla and may or may not manifest autonomous hormone production or growth. After combining studies, the most common aetiolo- gies were as follows: nonfunctioning adenoma 73-9%, subclini- cal Cushing’s syndrome (CS) 7%, aldosterone-producing adenoma 1.2%, phaeochromocytoma 4-7%, adrenocortical carcinoma (ACC) 4.8% and metastases 2-3% (Table 1).
A major determinant of the prevalence of AI in both autopsy and clinical series is age. The prevalence of incidentalomas detected at autopsy peaks between the 5th and 7th decades of life [19]; consequently, as the population ages, the management of AI is becoming an increasingly important aspect of health care. Arbitrarily, the definition of incidentaloma rules out patients undergoing imaging procedures for cancer staging and work-up; in addition, there should be no clinical symptoms or
THE CLINICAL SIGNIFICANCE OF ADRENAL INCIDENTALOMAS
| Study (reference) | No. of patients | Nonfunctioning adenoma (%) | Subclinical Cushing's syndrome (%) | Aldosterone- producing adenoma (%) | Pheochromo- cytoma (%) | Adrenocortical carcinoma (%) | Metastases (%) |
|---|---|---|---|---|---|---|---|
| Herrera et al. 1991 [4] | 342 | 95-9 | 0-6 | 0 | 1.5 | 1.17 | 0-3 |
| Reincke et al. 1992 [6] | 68 | 85.3 | 11.8 | 1.5 | 1.5 | 0 | 0 |
| Bencsik et al. 1995 [7] | 63 | 50.8 | 20-6 | 0 | 0 | 1.59 | 11.1 |
| Linos et al. 1996 [8] | 57 | 84.2 | 8.8 | 0 | 7.0 | 3.51 | 3.5 |
| Kasperlik-Zaluska et al. 1997 [9] | 208 | 70-2 | 2.9 | 0 | 9.1 | 8.65 | 9.1 |
| Terzolo et al. 1997 [10] | 210 | 58.6 | 14.3 | 0.5 | 4-8 | 7.14 | 0-9 |
| Bastounis et al. 1997 [11] | 86 | 61-6 | 3.5 | 0 | 2.33 | 1.16 | 2-3 |
| Proye et al. 1998 [12] | 103 | 69.9 | 0 | 4.8 | 14.6 | 4.85 | 3.9 |
| Murai et al. 1999 [13] | 59 | 72.9 | 1.7 | 1.7 | 18.6 | 5.08 | 0 |
| Rossi et al. 2000 [14] | 65 | 58.5 | 18.5 | 0 | 7.7 | 3.08 | 3.1 |
| Favia et al. 2000 [15] | 158 | 76.6 | 5.1 | 3.8 | 2.5 | 9-49 | 1.9 |
| Mantero et al. 2000 [16] | 1004 | 71-3 | 9.2 | 1.6 | 4.2 | 4.68 | 1.2 |
| Bulow & Ahren 2002 [17] | 381 | 84-2 | 1.0 | 0-5 | 3.9 | 2.6 | 2.1 |
| Barzon et al. 2002 [18] | 284 | 64.8 | 11-3 | 2.1 | 5.9 | 8.80 | 2.8 |
| Total | 3088 | 2283 (73.9%) | 216 (7%) | 38 (1-2%) | 146 (4-7%) | 148 (4.8%) | 70 (2-3%) |
signs of adrenal disease at the time of diagnosis. In retrospect, however, patients were often found to have had signs or symp- toms of hormone oversecretion, albeit in mild forms, while arte- rial hypertension and obesity are significantly more prevalent in patients with AI [20].
Following the demonstration of an adrenal mass, the differential diagnosis should consider adrenal CS, phaeo- chromocytoma, primary aldosteronism, primary and metastatic malignancy, myelolipoma and nonhypersecretory cortical adenoma [1,19,21-23]. Differentiating between malig- nant and benign masses is essential because metastases to the adrenal glands are common. Adenomas, comprising the vast majority of incidental asymptomatic adrenal masses, are benign, and there is no evidence that they progress into malignant lesions [24]. Adrenal cortical carcinoma is rare, but remains of great clinical concern because of its high mortality rate. The diagnostic challenge is to recognise and treat the percentage of AI that pose a significant health risk, because of either hormonal activity or risk of malignancy, and distinguish them from those that are neither hyperfunc- tioning nor malignant.
In the present review, a detailed Medline search of articles related to AI was carried out, and the clinical implications related to their hormonal activity and malignant potential are discussed.
Clinical implications of apparently nonfunctioning adrenal tumours
Patients with clinically inactive adrenal adenomas as a group exhibit insulin resistance (IR) and a variety of meta- bolic disturbances and manifestations of the metabolic syn- drome [3,16,22,25,26]. In a multi-institutional study of 1004 patients with AI, the prevalence of arterial hypertension, diabetes mellitus type 2 (DM type 2) or obesity were 41%, 10% and 28%, respectively [16]. Furthermore, a remarkably high prevalence of impaired glucose tolerance (IGT), or previously unknown DM type 2, increased visceral fat mass, and hyperinsulinaemia has been found among patients with nonfunctioning adrenal tumours [27,28]. The degree of metabolic and body fat alterations is reported to be intermediate between that of controls and patients with overt CS [28]. The limited available data suggest that most patients with AI die of causes not strictly related to the adrenal mass itself but mostly from cardiovascular events, although it still not known whether the mortality rate is higher than the general population [29,30].
This insulin-resistant state is probably associated with subtle cortisol autonomy leading to an increased incidence of several cardiovascular risk factors. Patients with AI exhibit elevated levels of D-dimers [31], interleukin-6 (IL-6), adiponectin,
resistin, tumour necrosis factor (TNF)-alpha and monocyte chemoattractant protein 1 (MCP-1) [32]. Such patients also show an impairment of cardiac morphology and function as reflected by the impairment of echocardiographic indices of left ventricular hypertrophy and diastolic dysfunction [33]. Fur- thermore, they present other subtle indices of atherosclerosis, such as increased carotid intima media thickness, which is also correlated with morning cortisol levels [34]. Finally, even slight glucocorticoid excess exerts inhibitory effects on TSH secretion, suggesting the presence of mild central hypothyroidism in patients with AI [35].
Consequences of subclinical adrenal hyperfunction
Subclinical Cushing’s syndrome (CS)
Although the majority of AI are nonhypersecretory adenomas, many patients present isolated or multiple mild hypothalamic- pituitary-adrenal (HPA) abnormalities, such as elevated or high normal urinary-free cortisol excretion, impaired cortisol rhythm, partial cortisol suppression to dexamethasone admin- istration, low plasma adrenocorticotropic hormone (ACTH) levels and/or poor responses to corticotropin-releasing hor- mone [14,26,36-38]. Adrenal insufficiency following surgical excision of presumed nonsecretory adrenal adenomas has been described in 18-20% of cases, suggesting the presence of mild hypercortisolism that is called subclinical CS (SCS) [19]. This term is used to define a condition characterised by alterations of HPA function in keeping with a subtle cortisol hypersecre- tion in the absence of signs and/or symptoms specific of overt hypercortisolism [20]. Rarely, cortisol secretion can be under the control of one or more aberrant hormone receptors in patients with unilateral adenomas or incidental bilateral ACTH-independent macronodular hyperplasia [39].
Subclinical CS is the most frequent hormonal abnormality detected in patients with AI, with a prevalence that ranges from 5% to 47% in various studies [3,14,20,23,26,29,36,40,41]. This wide variation is mainly attributed to the different work-up protocols and variable criteria used to define subclinical cortisol excess, as well as in different inclusion criteria and size of reporting series. However, it is difficult to characterise this endocrine disorder as there is a continuum from normality to autonomy, and the degree of cortisol excess may be only slightly higher than the physiological daily cortisol output [3,42]. Following the suggestion that even subclinical hormone overproduction by AI may be associated with a greater morbid- ity if left untreated, the threshold for treating SCS has been lowered in the last decade [1,3,43].
Because many patients with clinically nonfunctioning inci- dentalomas are exposed to a chronic, even if only minimal to
mild, cortisol excess, it is biologically plausible to anticipate that they should suffer, at least to some extent, from the classic long-term consequences of overt CS [24,44]. Although AI patients with SCS lack many of the usual stigmata of overt CS, they may exhibit one or more of the effects of continuous auton- omous cortisol secretion [45]. Indeed, patients with SCS are more likely to have hypertension, dyslipidaemia, IGT or type 2 DM and evidence of atherosclerosis [46]. Furthermore, they exhibit increased waist-to-hip ratio, increased indices of IR and significant changes in carotid intimal-medial thickness [37]. These data are in agreement with the view that SCS may be associated with the clinical phenotype of the IR syndrome as the subtle autonomous cortisol secretion may cause IR in other- wise normoglycaemic and nonobese subjects [25]. An alterna- tive hypothesis is that AI may be a consequence rather than cause of the metabolic syndrome [47]; however, a causal link between SCS and IR remains the most plausible explanation [48]. In SCS, the cortisol secretion is probably a continuum between normal and clear-cut cortisol excess and may be inter- mittent. Therefore, this subtle cortisol hypersecretion may be not reliably revealed by the commonly employed biochemical markers [3,38,49].
Many of the features encountered in patients with AI, such as central fat deposition, hypertension and low high-density lipo- protein (HDL) levels, are important predisposing factors for the development of cardiovascular disease putting subjects with AI at greater risk than the general population. However, studies specifically designed to investigate the possible benefits from treatment of SCS are partially conflicting, although all suggested an improvement in hypertension [14,44,50-52]. Although some authors have described an improvement of all features of the metabolic syndrome in patients with SCS follow- ing the removal of the adrenal mass [14,36,52,53], others have not [44,50,51]. These discrepancies may be because of the different criteria adopted to define SCS, insufficient sample size and differences in the duration of follow-up and timing of postoperative evaluation.
Obesity in patients with SCS. Hypercortisolism is character- ised by a redistribution of adipose tissue from peripheral to central sites of the body, mainly in the truncal region and visceral depots [54]. Central abdominal obesity determined by waist-to-hip ratio and dual-energy x-ray absorptiometry is more frequent in patients with SCS [14,28]. Surgical treatment of subclinical hypercortisolism in patients with AI is associated with a significantly higher probability of improving body weight [55].
Diabetes mellitus type 2 and glucose metabolism in patients with SCS. Several observations have suggested that DM type 2 in patients with SCS may be more frequent than previously
THE CLINICAL SIGNIFICANCE OF ADRENAL INCIDENTALOMAS
appreciated [56,57]. In a controlled study, the proportion of SCS in patients with DM type 2 was estimated to be higher than con- trols [58]; however, a subsequent study failed to support the validity of screening diabetic patients without clinical features of CS [59]. The presence of SCS in diabetic patients is associated with poor metabolic control [14,25,37,58]. However, surgical treatment of SCS in patients with AI has yielded conflicting results. In some series, adrenalectomy did not seem to improve glucose metabolism [44,51], whereas in one study it was associ- ated with a significant improvement in fasting glucose levels in 52.5% of patients [52].
Hypertension in patients with SCS. Blood pressure values are higher in patients with AI compared to healthy matched individuals [28]. Furthermore, approximately 50% of patients with AI are hypertensive [28]. Surgical excision of AI in patients with SCS is associated with normalisation of blood pressure and/or a significantly higher probability of improving blood pressure levels [55].
Dyslipidaemia in patients with SCS. HDL cholesterol levels are lower, and triglyceride levels are higher, in AI patients with SCS compared to controls [28]. However, the effects of surgical treatment on lipid profile are conflicting as in one study adre- nalectomy did not show any effect [44], whereas in others it led to restoration of lipid levels to normal in 37.5% of patients [52].
Bone metabolism in patients with SCS. Overt endogenous glucocorticoid excess is a well-recognised cause of bone loss and osteoporotic fractures [60]. Cortisol excess inhibits bone formation, increases bone resorption, impairs calcium absorp- tion from the gut and affects the secretion of several hormones (particularly gonadotrophins and GH), cytokines and growth factors influencing bone metabolism [60]. Subclinical hypercor- tisolism has been shown to be associated with increased bone resorption, bone loss and a high prevalence of vertebral frac- tures [45,61,62]. The degree of clinical consequences of SCS on bone metabolism varies with the extent of hormone overpro- duction [63]. In a recent study, patients with AI and SCS exhibited reduced bone density, architectural deterioration of trabecular bone and an increased prevalence of vertebral fractures [45]. In a further study, it was shown that subclinical hypercortisolism is a common and underrated finding in patients with established osteoporosis [60]. Although no improvement in bone parameters was documented in patients with SCS after adrenalectomy [52,64], antiresorptive treatment resulted in significant increase in lumbar BMD and bone turn- over markers [65]. Further longitudinal studies of adequate statistical power are needed to estimate the risk of osteopo- rotic fractures and their attendant impact on outcome and quality of life.
Subclinical hyperaldosteronism
Primary aldosteronism is probably more common nowadays than previously reported [66]. The prevalence of mineralocorti- coid-secreting masses in hypertensive patients with AI has been estimated to range between 1.6% and 5% [23,67] More recent series that have employed more sophisticated diagnostic proce- dures have suggested that in patients with AI subclinical auto- nomous aldosterone secretion is much more common than previously appreciated and that it correlates with diastolic blood pressure [40]. However, further research in this area is needed to confirm these findings and correlate them with relevant clinical end-points.
‘Silent’ phaeochromocytoma
Phaeochromocytoma, though usually histologically mostly benign, is a potential lethal disorder with an unpredictable course [68]. Approximately 0-01-0-1% of all hypertensive patients have been shown to harbour a pheochromocytoma but the majority lack the classic clinical triad of phaeochromocy- toma (headache, palpitations and diaphoresis), and the diagno- sis is easily overlooked or delayed [67]. Furthermore, hypertension is constant in only about half of the patients, paroxysmal in a third and absent in about 20% [69]. The mean interval between initial presentation and diagnosis is estimated to be 3-5 years with a reported delay as long as 30 years in extreme cases [70]. Imaging findings consistent with phaeo- chromocytoma include increased attenuation on unenhanced CT, prominent vascularity of the mass and delayed washout of intravenous contrast medium [69] (Fig. 1). CT can identify phaeochromocytomas above 1 cm in diameter with a 77-98% and 29-92% sensitivity and specificity, respectively [71]. CT scans of suboptimal technology confer limited diagnostic accu- racy and make biochemical evaluation mandatory. Phaeo- chromocytmas exhibit a high signal intensity on T2-weighted magnetic resonance imaging (MRI), and MRI T2-weighted imaging has a sensitivity and specificity in identifying phaeochromocytoma of approximately 92% and 88%, respectively [72].
Clinically silent phaeochromocytoma is not rare, and its prevalence in patients with AI has been estimated between 1.5% and 13% [23]. In the larger series of AI, phaeochromocy- toma was the second most prevalent form of hyperfunctioning tumour occurring in 4-2% of all masses [16]. Silent phaeochro- mocytomas can carry a significant morbidity and mortality if not diagnosed early. This is highly relevant as in autopsy series phaeochromocytoma was found in 0-13% of cases, and the tumour had not been suspected in 75% of the patients while alive, although it contributed to their death in approximately 55% of cases [68]. About half of the patients with AI that proved to harbour phaeochromocytomas were normotensive, while the others had mild-to-moderate hypertension [19].
Adrenocortical carcinoma
The most feared diagnostic possibility for AI is ACC, which has a mean survival of approximately 18 months and a 5-year overall survival of around 16% [43]. ACC is rare, with an inci- dence ranging from 0-6 to 2 cases per million population per year [43,73]. Although ACC can develop at any age, there is a bimodal age distribution, with disease peaks before the age of 5 years and in the 4th to 5th decade of life [74]. Adrenocorti- cal carcinomas are increasingly detected as incidentalomas during abdominal imaging [75]. The prevalence of primary adrenal carcinoma in clinically inapparent adrenal masses cor- relates with the size of the mass [43]. Adrenal cortical carci- noma accounts for 2% of tumours up to 4 cm in size, 6% of tumours between 4.1 cm and 6 cm and 25% of tumours that are larger than 6 cm; the larger the diameter of the mass, the greater the risk of it being malignant [23]. These tumours can be either functioning or nonfunctioning, the former account- ing for approximately 60%, with CS either alone or in associa- tion with virilisation is the most frequent presentation [75]. In a series of 1004 AI, the relative rate of malignancy was 4.6% [16].
Imaging features on adrenal CT are used to distinguish adenomas from malignant lesions. Adrenal adenomas are usually small, well-defined homogeneous lesions with clear
margins and high lipid content, whereas malignant lesions are larger, have an irregular border, vague contour, invade into surrounding structures and exhibit high signal intensity [21]. Signal intensity lower than 10 Hounsfield units is highly indicative of a benign adrenal lesion [76] (Fig. 2). Benign ade- nomas are also characterised by rapid absolute and relative washout of intravenous contrast; a relative washout value of more than 40% has a sensitivity and specificity of 96% and 100%, respectively, in identifying adenomas [77,78]. The com- bination of unenhanced CT intensity and washout values can distinguish adenomas from other adrenal tumours with 98% sensitivity and 92% specificity [77,79]. The accuracy of MRI in the differentiation between benign and malignant tumours is comparable to that of CT scanning, particularly using in- and out-of-phase imaging [80]. Normal adrenal glands have T1 and T2 signal intensity equal or slightly lower than that of the normal liver, whereas malignant masses are hypointense on T1 and hyperintense on T2-weighted images and exhibit strong enhancement after contrast injection and delayed washout [81]. Most ACCs accumulate and retain [18F]- fluorodeoxyglucose (FDG) and thus can be visualised by FDG positron emission tomography (FDG PET) [82]. In a recent prospective multicenter study that included 77 patients who underwent surgery, the degree of preoperative FDG PET uptake predicted with high precision the pathological findings [83]. Using a cut-off value above 1-45 for adrenal to liver maximum standardised uptake value (maxSUV) ratio, the sensitivity and specificity to distinguish adrenocortical adenomas from ACCs were 100% and 88%, respectively [83]. Although the imaging phenotype does not predict hormonal
THE CLINICAL SIGNIFICANCE OF ADRENAL INCIDENTALOMAS
Adrenal incidentaloma
Imaging phenotype clinical examination
Malignant lesion
Benign lesion
Biochemical screening
Primary adrenocortical carcinoma
Metastasis
Pheo- chromocytoma
Adrenocortical adenoma
Myelolipoma adrenal cysts
No clinical implications
High morbidity and mortality
High morbidity and mortality if untreated
Hypersecreting
Endocrine testing
Non secreting
Subclinical autonomous cortisol secretion (SCS)
Subclinical autonomous aldosterone secretion
Evidence for insulin resistance and increased cardiovascular risk
Metabolic syndrome cardiovascular risk osteoporosis
Hypertension cardiovascular risk
function, it does not necessarily predict the underlying pathology either, and therefore, surgical resection should be considered for patients who have AI with a suspicious imaging phenotype.
Evolution of a nonfunctioning adrenal mass
Follow-up of patients with nonfunctioning adrenal masses sug- gests that although 5-25% may increase in size by at least 1 cm and 3-4% may decrease, the majority remain stable [9,30,84,85]. The threshold for clinically significant increases in size is unknown, particularly because the reproducibility of size deter- mination by imaging procedures is poorly defined [81].
Evolution of silent hypercortisolism to overt CS occurs rarely, while the appearance of silent biochemical alterations is found in 0-11% in different studies [41]. Masses of 3 cm in size or greater are more likely to develop silent hyperfunction than smaller tumours, and this risk seems to plateau 3-4 years after the diagnosis [84]. In some series, no case of evolution from subclinical to overt CS was observed, even if several endocrine modifications occurred during follow-up [85,86]. In selected cases, spontaneous regression of the alterations of the HPA axis may be observed, and this finding suggests that cortisol hypersecretion may have a cyclical pattern [86]. In a prospec- tive study of 229 patients with AI that were followed for up to 108 months (median period of 25, range from 3 to 108 months), two patients were diagnosed with CS within the first 48 months, one patient was found to have a phaeochromocy-
toma after the 4th year of observation, while none developed primary hyperaldosteronism or malignancy [87].
The presence of intermittent subclinical autonomous cortisol hypersecretion in a significant percentage of patients supports the wide range of variability in adrenal adenomas, from nonfunctioning to autonomous cortisol secretion [88]. Mass enlargement and the presence or occurrence over time of sub- clinical endocrine activity are frequent and not correlated, may appear at any time, are not associated with any basal clinical, biochemical or morphological predictors, and are not necessar- ily indicative of malignant transformation or of progression to overt disease [86]. However, a recent review of all published series of AI suggested that the prevalence of malignant and functional lesions in AI is likely to have been overestimated as the possibility of development of functionality or malignancy during follow-up was ≤ 1% and 0.2%, respectively [89]. Fur- thermore, exposure to ionising radiation during the recom- mended CT scan follow-up confers a one in 430-2170 chance of causing fatal cancer that is similar to the chance of developing adrenal malignancy during a 3-year follow-up period of an AI [89]. Until additional information from large prospective studies is available, it is reasonable to repeat imaging studies 6 months after the diagnosis and then annually and the hormonal screening annually for 4 years, as suggested by the National Institutes of Health (NIH) state-of-the-science state- ment [3]. However, with smaller nonfunctioning masses which show no sinister imaging characteristics, it is probable that follow-up beyond 6-12 months is unnecessary.
Conclusions
Adrenal incidentalomas that are found to be adrenal carcino- mas, metastatic deposits or phaeochromocytomas are life- threatening and need immediate management. However, it is unclear whether nonsecreting or subclinically secreting adreno- cortical adenomas pose potential harm to patient health, partic- ularly as information from randomised trials to guide their optimal management are lacking (Fig. 3). Even though SCS, which is the most common functioning state of an AI, may lead to IR, it is presently unknown whether overall mortality is increased in such patients. The reported high prevalence of autonomous aldosterone secretion in hypertensive patients with AI is an interesting suggestion that requires further study. Prospective adequately powered studies to address disease- specific or all-cause mortality are needed to evaluate the poten- tial cardiovascular morbidity linked with AI, substantiate whether adrenalectomy is beneficial and select patients that are the best candidates for this approach.
Address
Department of Pathophysiology, National University of Ath- ens, Mikras Asias 75, 11527, Athens, Greece (I. I. Androulakis, G. Kaltsas); Department of Endocrinology and Diabetes, General Hospital of Athens ‘G. Genimatas’, Leoforos Mesogion, 154, Athens, Greece (G. Piaditis); Department of Endocrinology, St Bartholomew’s Hospital, Barts and the London School of Medicine, West Smithfield, EC1A 7BE, London, UK (A. B. Grossman).
Correspondence to: Gregory Kaltsas, Department of Patho- physiology, National University of Athens, Mikras Asias 75, 11527, Athens, Greece. Tel .: +30 210 7462513; fax: +30 210 7462664; e-mail: gkaltsas@endo.gr
Received 11 August 2010; accepted 27 October 2010
References
1 Young WF Jr. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med 2007;356:601-10.
2 Griffing GT. A-I-D-S: the new endocrine epidemic. J Clin Endocrinol Metab 1994;79:1530-1.
3 Grumbach MM, Biller BM, Braunstein GD, Campbell KK, Carney JA, Godley PA et al. Management of the clinically inapparent adrenal mass (‘incidentaloma’). Ann Intern Med 2003; 138:424-9.
4 Herrera MF, Grant CS, van Heerden JA, Sheedy PF, Ilstrup DM. Incidentally discovered adrenal tumors: an institutional perspective. Surgery 1991;110:1014-21.
5 Bovio S, Cataldi A, Reimondo G, Sperone P, Novello S, Berruti A et al. Prevalence of adrenal incidentaloma in a contemporary computerized tomography series. J Endocrinol Invest 2006;29: 298-302.
6 Reincke M, Nieke J, Krestin GP, Saeger W, Allolio B, Winkelmann W. Preclinical Cushing’s syndrome in adrenal “incidentalomas”’:
comparison with adrenal Cushing’s syndrome. J Clin Endocrinol Metab 1992;75:826-32.
7 Bencsik Z, Szabolcs I, Goth M, Voros A, Kaszas I, Gonczi J et al. Incidentally detected adrenal tumours (incidentalomas): histological heterogeneity and differentiated therapeutic approach. J Intern Med 1995;237:585-9.
8 Linos DA, Stylopoulos N, Raptis SA. Adrenaloma: a call for more aggressive management. World J Surg 1996;20:788-92.
9 Kasperlik-Zeluska AA, Roslonowska E, Slowinska-Srzednicka J, Migdalska B, Jeske W, Makowska A et al. Incidentally discovered adrenal mass (incidentaloma): investigation and management of 208 patients. Clin Endocrinol (Oxf) 1997;46:29-37.
10 Terzolo M, Ali A, Osella G, Mazza E. Prevalence of adrenal carci- noma among incidentally discovered adrenal masses. A retrospec- tive study from 1989 to 1994. Gruppo Piemontese Incidentalomi Surrenalici. Arch Surg 1997;132:914-9.
11 Bastounis EA, Karayiannakis AJ, Anapliotou ML, Nakopoulou L, Makri GG, Papalambros EL. Incidentalomas of the adrenal gland: diagnostic and therapeutic implications. Am Surg 1997;63:356-60.
12 Proye C, Jafari MM, Combemale F, Pattou F, Ernst O, Carnaille B et al. Experience gained from operation of 103 adrenal incident- alomas. Langenbecks Arch Surg 1998;383:330-3.
13 Murai M, Baba S, Nakashima J, Tachibana M. Management of incidentally discovered adrenal masses. World J Urol 1999;17:9-14.
14 Rossi R, Tauchmanova L, Luciano A, Di MM, Battista C, Del VL et al. Subclinical Cushing’s syndrome in patients with adrenal inci- dentaloma: clinical and biochemical features. J Clin Endocrinol Metab 2000;85:1440-8.
15 Favia G, Lumachi F, Basso S, D’ Amico DF. Management of inciden- tally discovered adrenal masses and risk of malignancy. Surgery 2000;128:918-24.
16 Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Ali A 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;85:637-44.
17 Bulow B, Ahren B. Adrenal incidentaloma-experience of a standardized diagnostic programme in the Swedish prospective study. J Intern Med 2002;252:239-46.
18 Barzon L, Fallo F, Sonino N, Boscaro M. Development of overt Cushing’s syndrome in patients with adrenal incidentaloma. Eur J Endocrinol 2002;146:61-6.
19 Mantero F, Albiger N. A comprehensive approach to adrenal incidentalomas. Arq Bras Endocrinol Metabol 2004;48:583-91.
20 Terzolo M, Reimondo G, Bovio S, Angeli A. Subclinical Cushing’s syndrome. Pituitary 2004;7:217-23.
21 Angeli A, Osella G, Ali A, Terzolo M. Adrenal incidentaloma: an overview of clinical and epidemiological data from the National Italian Study Group. Horm Res 1997;47:279-83.
22 Kloos RT, Gross MD, Francis IR, Korobkin M, Shapiro B. Inciden- tally discovered adrenal masses. Endocr Rev 1995;16:460-84.
23 Mansmann G, Lau J, Balk E, Rothberg M, Miyachi Y, Bornstein SR. The clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev 2004;25:309-40.
24 Kjellman M, Larsson C, Backdahl M. Genetic background of adreno- cortical tumor development. World J Surg 2001;25:948-56.
25 Terzolo M, Pia A, Ali A, Osella G, Reimondo G, Bovio S et al. Adre- nal incidentaloma: a new cause of the metabolic syndrome? J Clin Endocrinol Metab 2002;87:998-1003.
26 Terzolo M, Bovio S, Reimondo G, Pia A, Osella G, Borretta G et al. Subclinical Cushing’s syndrome in adrenal incidentalomas. Endocri- nol Metab Clin North Am 2005;34:423-39.
THE CLINICAL SIGNIFICANCE OF ADRENAL INCIDENTALOMAS
27 Fernandez-Real JM, Engel WR, Simo R, Salinas I, Webb SM. Study of glucose tolerance in consecutive patients harbouring incidental adrenal tumours. Study Group of Incidental Adrenal Adenoma. Clin Endocrinol (Oxf) 1998;49:53-61.
28 Garrapa GG, Pantanetti P, Arnaldi G, Mantero F, Faloia E. Body composition and metabolic features in women with adrenal inci- dentaloma or Cushing’s syndrome. J Clin Endocrinol Metab 2001;86:5301-6.
29 Barzon L, Scaroni C, Sonino N, Fallo F, Gregianin M, Macri C et al. Incidentally discovered adrenal tumors: endocrine and scintigraphic correlates. J Clin Endocrinol Metab 1998;83:55-62.
30 Siren J, Tervahartiala P, Sivula A, Haapiainen R. Natural course of adrenal incidentalomas: seven-year follow-up study. World J Surg 2000;24:579-82.
31 Yener S, Comlekci A, Akinci B, Secil M, Demir T, Ertilav S et al. Non-functioning adrenal incidentalomas are associated with elevated D-dimer levels. J Endocrinol Invest 2009;32:338-43.
32 Ermetici F, Malavazos AE, Corbetta S, Morricone L, Dall’Asta C, Corsi MM et al. Adipokine levels and cardiovascular risk in patients with adrenal incidentaloma. Metabolism 2007;56:686-92.
33 Ermetici F, Dall’ Asta C, Malavazos AE, Coman C, Morricone L, Montericcio V et al. Echocardiographic alterations in patients with non-functioning adrenal incidentaloma. J Endocrinol Invest 2008;31:573-7.
34 Yener S, Genc S, Akinci B, Secil M, Demir T, Comlekci A et al. Caro- tid intima media thickness is increased and associated with morning cortisol in subjects with non-functioning adrenal incidentaloma. Endocrine 2009;35:365-70.
35 Coiro V, Volpi R, Capretti L, Manfredi G, Magotti MG, Bianconcini M et al. The nocturnal serum thyrotropin surge is inhibited in patients with adrenal incidentaloma. J Investig Med 2002;50:350-4.
36 Emral R, Uysal AR, Asik M, Gullu S, Corapcioglu D, Tonyukuk V et al. Prevalence of subclinical Cushing’s syndrome in 70 patients with adrenal incidentaloma: clinical, biochemical and surgical outcomes. Endocr J 2003;50:399-408.
37 Tauchmanova L, Rossi R, Biondi B, Pulcrano M, Nuzzo V, Palmieri EA et al. Patients with subclinical Cushing’s syndrome due to adre- nal adenoma have increased cardiovascular risk. J Clin Endocrinol Metab 2002;87:4872-8.
38 Tsagarakis S, Vassiliadi D, Thalassinos N. Endogenous subclinical hypercortisolism: diagnostic uncertainties and clinical implications. J Endocrinol Invest 2006;29:471-82.
39 Reznik Y, Lefebvre H, Rohmer V, Charbonnel B, Tabarin A, Rodien P et al. Aberrant adrenal sensitivity to multiple ligands in unilateral incidentaloma with subclinical autonomous cortisol hypersecretion: a prospective clinical study. Clin Endocrinol (Oxf) 2004;61:311-9.
40 Piaditis GP, Kaltsas GA, Androulakis II, Gouli A, Makras P, Papado- gias D et al. High prevalence of autonomous cortisol and aldoste- rone secretion from adrenal adenomas. Clin Endocrinol (Oxf) 2009;71:772-8.
41 Barzon L, Sonino N, Fallo F, Palu G, Boscaro M. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol 2003;149:273-85.
42 Reincke M. Subclinical Cushing’s syndrome. Endocrinol Metab Clin North Am 2000;29:43-56.
43 Nawar R, Aron D. Adrenal incidentalomas-a continuing manage- ment dilemma. Endocr Relat Cancer 2005;12:585-98.
44 Erbil Y, Ademoglu E, Ozbey N, Barbaros U, Yanik BT, Salmaslioglu A et al. Evaluation of the cardiovascular risk in patients with
subclinical Cushing syndrome before and after surgery. World J Surg 2006;30:1665-71.
45 Chiodini I, Morelli V, Masserini B, Salcuni AS, Eller-Vainicher C, Viti R et al. Bone mineral density, prevalence of vertebral fractures, and bone quality in patients with adrenal incidentalomas with and without subclinical hypercortisolism: an Italian multicenter study. J Clin Endocrinol Metab 2009;94:3207-14.
46 Sereg M, Szappanos A, Toke J, Karlinger K, Feldman K, Kaszper E et al. Atherosclerotic risk factors and complications in patients with non-functioning adrenal adenomas treated with or without adrenalectomy: a long-term follow-up study. Eur J Endocrinol 2009;160:647-55.
47 Reincke M, Fassnacht M, Vath S, Mora P, Allolio B. Adrenal incidentalomas: a manifestation of the metabolic syndrome? Endocr Res 1996;22:757-61.
48 Angeli A, Terzolo M. Adrenal incidentaloma-a modern disease with old complications. J Clin Endocrinol Metab 2002;87:4869-71.
49 NIH state-of-the-science statement on management of the clinically inapparent adrenal mass (‘incidentaloma’). NIH Consens State Sci Statements 2002;19:1-25.
50 Midorikawa S, Sanada H, Hashimoto S, Suzuki T, Watanabe T. The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection. Clin Endocrinol (Oxf) 2001;54:797-804.
51 Bernini G, Moretti A, Iacconi P, Miccoli P, Nami R, Lucani B et al. Anthropometric, haemodynamic, humoral and hormonal evaluation in patients with incidental adrenocortical adenomas before and after surgery. Eur J Endocrinol 2003;148:213-9.
52 Toniato A, Merante-Boschin I, Opocher G, Pelizzo MR, Schiavi F, Ballotta E. Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study. Ann Surg 2009;249:388-91.
53 Mitchell IC, Auchus RJ, Juneja K, Chang AY, Holt SA, Snyder WH, III et al. ‘Subclinical Cushing’s syndrome’ is not subclinical: improvement after adrenalectomy in 9 patients. Surgery 2007;142:900-5.
54 Pasquali R, Vicennati V, Cacciari M, Pagotto U. The hypothalamic- pituitary-adrenal axis activity in obesity and the metabolic syndrome. Ann N Y Acad Sci 2006;1083:111-28.
55 Chiodini I, Morelli V, Salcuni AS, Eller-Vainicher C, Torlontano M, Coletti F et al. Beneficial metabolic effects of prompt surgical treat- ment in patients with an adrenal incidentaloma causing biochemical hypercortisolism. J Clin Endocrinol Metab 2010;95:2736-45.
56 Catargi B, Rigalleau V, Poussin A, Ronci-Chaix N, Bex V, Vergnot V et al. Occult Cushing’s syndrome in type-2 diabetes. J Clin Endocrinol Metab 2003;88:5808-13.
57 Leibowitz G, Tsur A, Chayen SD, Salameh M, Raz I, Cerasi E et al. Pre-clinical Cushing’s syndrome: an unexpected frequent cause of poor glycaemic control in obese diabetic patients. Clin Endocrinol (Oxf) 1996;44:717-22.
58 Chiodini I, Torlontano M, Scillitani A, Arosio M, Bacci S, Di LS et al. Association of subclinical hypercortisolism with type 2 diabetes mellitus: a case-control study in hospitalized patients. Eur J Endocri- nol 2005;153:837-44.
59 Mullan K, Black N, Thiraviaraj A, Bell PM, Burgess C, Hunter SJ et al. Is there value in routine screening for Cushing’s syndrome in patients with diabetes? J Clin Endocrinol Metab 2010;95:2262-5.
60 Chiodini I, Torlontano M, Carnevale V, Trischitta V, Scillitani A. Skeletal involvement in adult patients with endogenous hypercortisolism. J Endocrinol Invest 2008;31:267-76.
61 Torlontano M, Chiodini I, Pileri M, Guglielmi G, Cammisa M, Modoni S et al. Altered bone mass and turnover in female patients with adrenal incidentaloma: the effect of subclinical hypercortiso- lism. J Clin Endocrinol Metab 1999;84:2381-5.
62 Hadjidakis D, Tsagarakis S, Roboti C, Sfakianakis M, Iconomidou V, Raptis SA et al. Does subclinical hypercortisolism adversely affect the bone mineral density of patients with adrenal incidentalomas? Clin Endocrinol (Oxf) 2003;58:72-7.
63 Francucci CM, Caudarella R, Rilli S, Fiscaletti P, Ceccoli L, Boscaro M. Adrenal incidentaloma: effects on bone metabolism. J Endocrinol Invest 2008;31:48-52.
64 Guerrieri M, Campagnacci R, Patrizi A, Romiti C, Arnaldi G, Boscar- o M. Primary adrenal hypercortisolism: minimally invasive surgical treatment or medical therapy? A retrospective study with long-term follow-up evaluation. Surg Endosc 2010.
65 Tauchmanova L, Guerra E, Pivonello R, De Martino MC, De LM, Caggiano F et al. Weekly clodronate treatment prevents bone loss and vertebral fractures in women with subclinical Cushing’s syndrome. J Endocrinol Invest 2009;32:390-4.
66 Stowasser M. Primary aldosteronism: revival of a syndrome. J Hypertens 2001;19:363-6.
67 Cicala MV, Sartorato P, Mantero F. Incidentally discovered masses in hypertensive patients. Best Pract Res Clin Endocrinol Metab 2006;20:451-66.
68 Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma. Review of a 50-year autopsy series. Mayo Clin Proc 1981;56:354-60.
69 Motta-Ramirez GA, Remer EM, Herts BR, Gill IS, Hamrahian AH. Comparison of CT findings in symptomatic and incidentally discovered pheochromocytomas. AJR Am J Roentgenol 2005;185:684-8.
70 Mannelli M, Ianni L, Cilotti A, Conti A. Pheochromocytoma in Italy: a multicentric retrospective study. Eur J Endocrinol 1999;141:619-24.
71 Ilias I, Pacak K. Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocri- nol Metab 2004;89:479-91.
72 Kievit J, Haak HR. Diagnosis and treatment of adrenal incidentalo- ma. A cost-effectiveness analysis. Endocrinol Metab Clin North Am 2000;29:69-90.
73 Latronico AC, Chrousos GP. Extensive personal experience: adreno- cortical tumors. J Clin Endocrinol Metab 1997;82:1317-24.
74 Ng L, Libertino JM. Adrenocortical carcinoma: diagnosis, evaluation and treatment. J Urol 2003;169:5-11.
75 Allolio B, Fassnacht M. Clinical review: adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 2006;91:2027-37.
76 Hamrahian AH, Ioachimescu AG, Remer EM, Motta-Ramirez G, Bogabathina H, Levin HS et al. Clinical utility of noncontrast
computed tomography attenuation value (hounsfield units) to dif- ferentiate adrenal adenomas/hyperplasias from nonadenomas: cleveland clinic experience. J Clin Endocrinol Metab 2005;90:871-7.
77 Caoili EM, Korobkin M, Francis IR, Cohan RH, Platt JF, Dunnick NR et al. Adrenal masses: characterization with combined unenhanced and delayed enhanced CT. Radiology 2002;222:629-33.
78 Boland GW, Hahn PF, Pena C, Mueller PR. Adrenal masses: characterization with delayed contrast-enhanced CT. Radiology 1997;202:693-6.
79 Sahdev A, Reznek RH. Imaging evaluation of the non-functioning indeterminate adrenal mass. Trends Endocrinol Metab 2004;15: 271-6.
80 Ilias I, Sahdev A, Reznek RH, Grossman AB, Pacak K. The optimal imaging of adrenal tumours: a comparison of different methods. Endocr Relat Cancer 2007;14:587-99.
81 Lockhart ME, Smith JK, Kenney PJ. Imaging of adrenal masses. Eur J Radiol 2002;41:95-112.
82 Mackie GC, Shulkin BL, Ribeiro RC, Worden FP, Gauger PG, Mody RJ et al. Use of [18F]fluorodeoxyglucose positron emission tomogra- phy in evaluating locally recurrent and metastatic adrenocortical carcinoma. J Clin Endocrinol Metab 2006;91:2665-71.
83 Groussin L, Bonardel G, Silvera S, Tissier F, Coste J, Abiven G et al. 18F-Fluorodeoxyglucose positron emission tomography for the diagnosis of adrenocortical tumors: a prospective study in 77 operated patients. J Clin Endocrinol Metab 2009;94:1713-22.
84 Barzon L, Scaroni C, Sonino N, Fallo F, Paoletta A, Boscaro M. Risk factors and long-term follow-up of adrenal incidentalomas. J Clin Endocrinol Metab 1999;84:520-6.
85 Libe R, Dall’Asta C, Barbetta L, Baccarelli A, Beck-Peccoz P, Ambrosi B. Long-term follow-up study of patients with adrenal incidentalomas. Eur J Endocrinol 2002;147:489-94.
86 Bernini GP, Moretti A, Oriandini C, Bardini M, Taurino C, Salvetti A. Long-term morphological and hormonal follow-up in a single unit on 115 patients with adrenal incidentalomas. Br J Cancer 2005;92:1104-9.
87 Bulow B, Jansson S, Juhlin C, Steen L, Thoren M, Wahrenberg H et al. Adrenal incidentaloma - follow-up results from a Swedish prospective study. Eur J Endocrinol 2006;154:419-23.
88 Vassilatou E, Vryonidou A, Michalopoulou S, Manolis J, Caratzas J, Phenekos C et al. Hormonal activity of adrenal incidentalomas: results from a long-term follow-up study. Clin Endocrinol (Oxf) 2009;70:674-9.
89 Cawood TJ, Hunt PJ, O’Shea D, Cole D, Soule S. Recommended evaluation of adrenal incidentalomas is costly, has high false- positive rates and confers a risk of fatal cancer that is similar to the risk of the adrenal lesion becoming malignant; time for a rethink? Eur J Endocrinol 2009;161:513-27.