Modern imaging techniques like ultrasound, computerized tomography (CT) and magnetic resonance imaging (MRI) enable the detection of adrenal tumors with high sensitivity. Already several decades ago, both collection of adrenals for anatomical studies and large autopsy series have demonstrated a high incidence of adrenal nodules in routine autopsies [1-5]. Adrenal tumors not suspected prior to radiological investigation are called ‘clinically inapparent adrenal mass’, ‘incidentally detected adrenal masses’ or ‘adrenal incidentalomas’. It is not surprising that due to the widespread use of imaging techniques these so-called “diseases of modern technology” [6] will be diagnosed more frequently, but also might put burden on the patient due to insecurity and will have increasing economic consequences for the health system [7].

In a patient with a suspected adrenal incidentaloma several questions have to be answered. The most important ones are:

The following review will focus on these and other aspects of the incidentally detected adrenal mass and will give expert guidelines for diagnostic and therapeutic evaluation of affected patients.

By common consensus, an incidentally detected adrenal mass is defined as an adrenal tumor not suspected prior to the imaging procedure which led to its discovery [8]. Thus, by definition, clinical symptoms and/or signs of an adrenal tumor must not precede the diagnosis of an incidentally detected adrenal mass. Retrospectively, patients with incidentally detected adrenal tumors observed in an abdominal CT scan performed for staging of nonadrenal malignant disease cannot be considered to have an incidentaloma, as adrenal metastases are a likely possibility prior to the investigation. In patients who have died from an extra-adrenal primary tumor the prevalence of adrenal metastases at autopsy is in the range of 25-100%, depending on the type of cancer [9]. Another example are patients with newly diagnosed arterial hypertension. They should also undergo a biochemical investigation to exclude an adrenal cause (pheochromocytoma, primary hyperaldosteronism). If this was missed, an adrenal mass detected during subsequently performed ultrasound study should not be called an incidentaloma.

The precise incidence and prevalence of adrenal nodules is not known, as no population based studies are available. However, in post mortem investigations, the frequency of adrenal tumors is 1.4 - 8.7 % of the cases [1, 3-5, 10, 11]. Most of these tumors were small adrenal adenomas. The prevalence of tumors with a diameter > 1.5 cm is 1.8 %, and that of tumors with a diameter > 6 cm is 0.025 % [5]. These data are consistent with the results using CT, where a prevalence between 0.6 and 4.4 % has been reported [12-15]. Most of these tumors are very small (diameter  1 cm) and in a study using CT, 79 % of the incidentally detected adrenal masses had a diameter < 2 cm [14]. Pooling the data of several studies representing more than 30.000 patients the mean prevalence is around 1 % (Table 1).

In some studies, a slight female preponderance has been reported [16, 17]. This might be explained by a referral bias (e. g. more imaging studies are recommended for women due to a higher prevalence of biliary disease). Probably the prevalence of adrenal masses is equal in both sexes, which is supported by autopsy studies [1, 2, 5, 18].

The frequency of incidentally detected adrenal masses increases with age [1, 5, 17-19]. In individuals > 50 years, the prevalence ranges between 3 – 7 % [20, 21].

Some studies have reported a higher prevalence of incidentalomas on the right side [16]. However, this observation can be explained by the better ultrasound visualization of the right adrenal gland. Consistent autopsies series and CT investigations indicate that both adrenals are affected equally [17]. Bilateral incidentally detected adrenal masses have been reported in 2 - 10 % of the cases [17, 22]. Table 2 shows the prevalence of adrenal tumors with regard to clinical settings [23].

Per definition, no clinical symptoms or signs of adrenal disease should be present at the time of diagnosis in patients with incidentally detected adrenal masses. However, a more detailed questioning and a careful second physical examination might reveal evidence of subtle hormone excess (such as recent weight gain, skin atrophy, episodic headaches etc.). Moreover, arterial hypertension and obesity are significantly more prevalent in patients with incidentalomas [19, 20]. The hypothesis that the higher number of incidentalomas in patients with hypertension is due to the fact that these individuals have imaging procedures more often (e. g. to screen for aortic aneurysm) is not supported by autopsy studies [11, 24]. In a study, patients with incidentalomas who were suffering from subclinical Cushing´s syndrome (SCCS) were significantly more obese [17]. In addition, patients with incidentalomas more frequently suffer from diabetes mellitus type 2 [2, 5] and it has been postulated that hyperinsulism in these individuals leads to an increased proliferation of adrenal cells [25]. Taking these findings together there seems to be an association of incidentalomas with features of the metabolic syndrome (obesity, arterial hypertension, NIDDM, dyslipidemia, dyscoagulation).

The histologic characterization of incidentalomas reveals many different pathologic entities as shown in Table 3. However, the exact prevalence of these entities is not known, as only a small proportion of patients require surgical removal of the tumor. By far, most of the adrenal incidentalomas are benign, hormonally inactive adrenal adenomas (> 70%) [26] Nevertheless, surgical removal of incidentalomas always has to be contemplated because adrenal cortical carcinomas are rare but highly malignant tumors, with an estimated annual incidence of 0.5 – 2 cases per million population [20, 27]. However, data on incidence are mainly based on the National Cancer Institute survey from the early 1970s and probably underestimate the true incidence [28]. Surprisingly, in some clinical studies, their frequency was reported to be even 4 - 5 % of all incidentally detected adrenal masses [16, 17, 29]. Although these findings are inconsistent, it seems that only a small percentage of adrenal cortical carcinomas present as incidentalomas. For example, a significant percentage of these patients had complained about abdominal pain and thus these tumors do not meet the above mentioned definition of incidentaloma [17]. In addition, large extra adrenal tumors, mostly primary retroperitoneal neoplasms, are sometimes misclassified as tumors of adrenal origin.

Frequency of pathological entities from the literature (second column) [8]. In the multicentre Italian study (third column) 380 of 1004 patients underwent adrenalectomy [17]. The high frequency of adrenocortical carcinomas may be explained by the fact that patients with abdominal pain (due to large tumors) were included in the Italian series.

Adrenal nodularity increases with age and usually affects both glands. This led to the hypothesis that adrenal tumors are a manifestation of the aging adrenal [11]. The additional proof of capsular arteriopathy in these subjects supports the concept that the nodules represent focal hyperplasia in response to focal ischemic loss of cortical adrenal tissue [11]. However, it has been shown by clonal analysis that the vast majority of adrenal tumors are of monoclonal origin. Therefore, adrenal tumors are the result of clonal expansion following after a somatic oncogenic mutation [30, 31]. Only some nodules arise from polyclonal focal nodular hyperplasia. These adenomas may have an oligo- or multicellular origin under the putative action of extra adrenal or local growth factors [32]. In functional hypersecreting tumors, adrenal cortical carcinomas and familial endocrine syndromes a stepwise tumorigenesis by known affected genes is partially understood [22, 27]. On the other hand, the genetic background of the “silent” adrenal tumors, which are mostly monoclonal lesions is poorly understood [27, 32, 33].

Another hypothesis of the pathogenesis of adrenal adenomas emerged from the frequent finding of macronodular adrenals (80 %) in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (Figure 1). If these patients do not receive adequate steroid therapy they are even at an increased risk of developing adrenocortical cancer [34, 35]. Macronodular adrenal hyperplasia does not only occur in homozygote individuals with 21-hydroxylase deficiency. Using abdominal CT scans in families with CAH, Jaresch et al. found adrenal nodules in 45 % of the heterozygous carriers [36]. These observations led to the concept that incidentalomas are somehow related to 21-hydroxylase deficiency. [37]. A causal relationship between adrenal enzyme defects and incidentalomas is supported by the fact that the population frequency of CAH heterocygosity (2 %) and the prevalence of incidentalomas (1-2 %) are very similar. Interestingly, it has been shown in several studies that 30 - 70 % of patients with adrenal tumors have an enhanced response of 17-hydroxyprogesterone after stimulation with ACTH as it is seen in heterozygous carriers of CAH [17, 38-40]. However, using multisteroid analysis we have found that patients with adrenal incidentaloma have also an increased secretion of multiple precursors of the mineralocorticoid and glucocorticoid pathway after ACTH challenge. This indicates an impaired 11ß-hydroxylase activity in the tumor itself rather than heterozygosity for 21-hydroxylase deficiency [41]. Additionally, a recent molecular analysis of adrenal tumors revealed that mutations in the 21-hydroxylase gene are rare and are not linked to an increase in ACTH-induced 17-hydroxyprogesterone [42]. Furthermore, after surgical removal of the tumor the elevated ACTH response disappears, which is a proof that the exaggerated 17-hydroxyprogesterone secretion is restricted to the tumor [43, 44]. In conclusion, heterozygosity for CAH does not explain the majority of adrenal incidentalomas.

Figure 1. MRI of a 36 year old male patient with salt loosing 21-hydroxylase deficiency and poor compliance to medical therapy. The scan shows massive bilateral macronodular hyperplasia (arrows).

Recent investigations of hormon-hypersecreting adrenal tumors showed that aberrant expression and pathologic activation of several G-protein coupled receptors such as those of vasopressin [45], gastric-inhibitory peptide [46], vasoactive intestinal polypeptide [47], luteinizing hormone [48] and catecholamines [49] could trigger or promote some adrenal tumors. Apparently, hypersecretion of neuropeptides, neurotransmitters, growth factors and cytokines that normally participate in the paracrine regulation of the adrenal cortex constitute an unregulated trophic stimulus [27].

It was mentioned before that a significant proportion of adrenal nodules may be regarded as a manifestation of the metabolic syndrome [20]. In a recent prospective series of patients with adrenal incidentalomas we found that all 13 consecutive cases exhibited elevated insulin in the fasting state or after a glucose challenge [25]. Pathogenetically, this is probably explained by the potent cell growth promoting activity of insulin. Through both insulin and IGF-I receptors insulin acts specifically on the adrenal cortex and stimulates steroidogenesis and cell proliferation [50-52].

Most lesions of the adrenal gland are benign and hormonally silent. Therefore, it is important to limit costs and risks for the patient by avoiding all unnecessary diagnostic interventions. On the other hand, careful diagnostic evaluation holds the potential of early detection of a harmful disease and can lead to a curative therapy e.g. in pheochromocytoma or adrenal cortical carcinoma. Therefore, diagnostic evaluation has to focus on two main questions:

Is their any pathologic hormone secretion, even in the absence of “typical” clinical signs and how high is the risk of malignancy in the individual case?

Endocrinologic investigation

The proportion of incidentalomas with significant endocrine activity increases with tumor size (Figure 2). Thus significant hypersecretion of adrenal masses with a diameter < 1 cm is exceptionally rare. However, aldosterone producing adenomas have to be considered even when the tumor is small, which may cause severe hypertension. At the time of diagnosis up to 20 % of all incidentalomas are significantly hormonal active and little is known about the long term-course of the remainder (Figure 3) [17, 20, 43, 44]. In a recent study by Barzon et al., follow-up of 75 patients with "silent" incidentalomas showed that approximately 10 % of these individuals developed endocrine hypersecretion within 2 years. According to these results, both mass size of 3 cm or more at diagnosis and exclusive radiocholesterol uptake, indicating higher risks to develop hyperfunction, should prompt to plan a more thorough endocrine follow-up [53]. Similar conclusions were made from Ambrosi and coworkers [54]. These results emphasize the necessity of regular reevaluation; we would like to suggest a period within two years.

Figure 2. Endocrine activity and tumor size in 68 patients with incidentally detected adrenal masses. The percentage of patients with hormonally active tumors (pheochromocytoma, subclinical Cushing´s syndrome, and aldosterone producing tumors) increases with the size of the tumor. Shaded bar = hormonally active, solid bar = hormonally inactive. (From Allolio, B., Adrenal Incidentalomas. Adrenal Disorders, ed. C.G. Margioris AN. 2001, Totowa: Humana Press Inc. 249 - 261; with permission.)

Figure 3. Prevalence of endocrine activity in incidentally detected adrenal masses.

Subclinical Cushing’s Syndrome (SCCS)

Autonomous cortisol secretion by adrenal incidentaloma is reported in 5 – 20 % of all patients [16, 17, 20, 25, 39, 55-61] (Figure 4). For this entity, the term subclinical Cushing’s syndrome has been established. Depending on the amount of glucocorticoids secreted by the tumor, the clinical significance ranges from only slight attenuated diurnal cortisol rhythm to complete atrophy of the contralateral gland with long-lasting adrenocortical insufficiency after adrenalectomy [60, 62]. Thus, subclinical Cushing´s syndrome must be excluded in every patient scheduled for surgery to avoid a postoperative adrenal crisis [62]. The best means to uncover autonomous cortisol secretion is the short (1 mg, overnight) dexamethasone suppression test, which rarely fails to detect subclinical Cushing´s syndrome [63]. A suppressed serum cortisol concentration (< 3 µg/dl or 80 nmol/l; apparently this threshold is dependent on the cortisol assay) excludes significant cortisol secretion by the tumor. In a second step, serum cortisol > 3 µg/dl requires a confirmatory high-dose dexamethasone suppression test (8 mg). If serum cortisol concentrations are again not suppressible, subclinical Cushing`s syndrome is diagnosed. To facilitate therapeutic decisions, a corticotropin-releasing hormone (CRH) test, the analysis of the diurnal cortisol rhythm and the measurement of urinary free cortisol should be performed. Patients with low ACTH concentrations not responding to CRH may develop adrenal insufficiency after surgery and require adequate substitution therapy (Figure 5) [60]. Increased values of urinary free cortisol are a late finding usually associated with emerging clinical signs of Cushing´s syndrome. Thus, diagnosis of SCCS should not exclusively be established by urine analysis [60].

Figure 4. Preoperative figure of a 45-year woman with an incidentally detected adrenal mass measuring 3 cm and SCCS. The patient had a 15 year history of obesity and suffered from hypertension requiring triple drug therapy. After adrenalectomy, the patient required glucocorticoid replacement therapy for 9 month because of adrenocortical insufficiency.

Figure 5. Plasma ACTH and serum cortisol response to stimulation with human CRH (100 µg IV) in normal control subjects (mean  SEM; shaded area), in 6 patients with subclinical Cushing´s syndrome, and in 6 patients with overt adrenal Cushing´s syndrome. Circles = subclinical Cushing´s syndrome; diamonds = adrenal Cushing´s syndrome; shaded areas = normal subjects. (From Allolio, B., Adrenal Incidentalomas. Adrenal Disorders, ed. C.G. Margioris AN. 2001, Totowa: Humana Press Inc. 249 - 261; with permission.)

Pheochromocytoma

The proportion of pheochromocytoma among adrenal incidentalomas has been reported to range from 0 to 11 % [16, 17, 20, 21, 39, 55, 56, 64, 65]. As many of these individuals have no typical clinical symptoms, like hypertension or tachycardia, a careful biochemical evaluation is necessary [17]. Diagnosis should be confirmed or excluded in all incidentally detected adrenal masses, by determination of 24 h urinary catecholamines or metanephrines which have the highest sensitivity (96 %) [66]. Measurement of plasma free metanephrine seems to be superior, but is still not widely available [67]. A suppression test (clonidine test) is rarely required. In patients with elevated catecholamine secretion we advocate a I-metaiodobenzylguanidine (I-MIBG) scintigraphy for preoperative detection of possible metastases [68]. 123I-MIBG seems to have better imaging qualities than 131I-MIBG. However, because the low availability and clinical usefulness is considered debatable, this imaging technique has not been recommended by the NHI-State-of-the-science conference statement [26]. Proper precautionary medication during surgery is necessary because patients with pheochromocytoma may develop life threatening hypertensive crisis [68, 69].

Conn’s syndrome

Recently, a high prevalence of normokalaemic Conn´s syndrome of 6 – 10 % was reported in non-selected series of hypertensive individuals by means of an elevated plasma aldosterone to renin ratio [70, 71]. Probably due to the exclusion of individuals with hypertension per definition this entity seems to be rare among individuals with incidentally detected adrenal masses [17, 20]. Hypertension and only slightly decreased potassium (< 3.9 mmol/l) levels raises suspicion of primary hyperaldosteronism. In a recently published multicenter Italian study, 60 % of the individuals with aldosterone producing-adenoma had potassium levels in this range, the remainder were normokalaemic [17]. In patients with adrenal incidentaloma, who are normotensive and have a serum potassium above 3.9 mmol/l, no further evaluation is necessary [72]. Otherwise, determination of plasma renin activity (PRA) together with plasma aldosterone concentration (PAC) is required.

As antihypertensive medication is reported to interfere with mineralocorticoid regulation the discontinuation of these substances is recommended, to allow interpretation of the measurement [72, 73]. However, recently it was observed that the impact of ACE-inhibitors and thiazide diuretics is minimal and does not preclude determination of the PAC/PRA ratio. An exception is spironolactone which should be withdrawn prior to the evaluation for at least 3 weeks [73, 74]. If the PAC is elevated and the PAC (ng/100 ml) / PRA (ng/ml per h) ratio is higher than 20 in two independent samples, hyperaldosteronism should be suspected [70, 71]. The diagnosis of primary hyperaldosteronism has to be confirmed by either the failure of fludrocortisone to suppress aldosterone (0.1 mg fludrocortison every 6 hrs. for 4 days, PAC on day 5 greater than 50 ng/ml, sampling mid-morning after 2 hours upright position) or after acute saline suppression (2 liters of 0.9 % NaCl solution infused i. v. over a period of 4 h; failure to suppress PAC < 6 ng/dl) [71, 73, 75]. Patients with an elevated PAC and PAC/PRA ratio require further evaluation in a specialized center. Investigations may even include bilateral adrenal vein catheterization to prove that the incidentaloma is indeed the source of the mineralocorticoid excess and to determine whether aldosterone is produced by one or both adrenals [76].

DHEA-S secretion

Measurement of DHEAS has been recommended in the work-up of incidentalomas. In a high percentage of patients with adrenal tumors low serum dehydroepiandrosterone-sulfate (DHEA-S) has been reported. This may be used as evidence of an adrenocortical origin of the tumor [39, 56, 77]. Otherwise, high DHEA-S concentrations are found in a substantial proportion of adrenocortical carcinomas [28]. In a recently published retrospective study DHEA-S values were elevated in 17 % of all patients with cortical carcinoma (28 % in younger individuals, age < 50 years). The sensitivity and specificity were 17 % and 93 %, respectively; negative and positive predictive values were 95 % and 10 %, respectively [17]. The pathogenesis of low DHEA-S levels in adrenal adenomas has not been elucidated yet. Suppression of ACTH by silent hypercortisolism has been suggested but remains to be proven [39]. Unpublished results of our own group in 3 patients with a Conn´s adenoma indicate that low DHEA-S secretion is not confined to the tumor bearing side. This argues against altered enzyme activity in the tumor or a paracrine action of the neoplastic tissue. Possibly low DHEA-S merely indicates premature adrenal aging which favors the development of adrenal nodules [11]. The value of DHEA-S in the assessment of adrenal tumors is low, because DHEA-S shows a steep age-related decrease in normal subjects with wide intersubject variation [78]. Moreover, some adrenocortical cancers may also exhibit decreased serum DHEAS, which is suggestive of a benign adenoma [16].

Stepwise diagnostic approach

The authors perform a stepwise endocrinologic investigation in patients with incidentalomas as follows:

Table 4. Stepwise endocrinological investigation in adrenal incidentaloma (modified after Allolio [8], with permission)

Step I: screening test 24-h urinary catecholamine excretion or free metanephrines (if available) Serum cortisol after dexamethasone suppression (1 mg at 11 PM orally) Serum potassium and repeated blood pressure measurements. In case of spontaneous hypokalemia or arterial hypertension measurement of serum aldosterone and plasma renin activity

Step II: confirmatory test (only if the corresponding test results are abnormal) 123-I-MIBG scintigraphy (or 131 I-MIBG) high-dose dexamethasone (8 mg) suppression test. If pathologic: CRH test, analysis of diurnal cortisol secretion, 24 h cortisol excretion (see Tab. 5) Fludrocortisone suppression test or saline infusion test, orthostasis test with measurement of aldosterone and PRA, 24-h excretion of aldosterone metabolites (i.e. 18-glucuronide aldosterone). In selected cases bilateral adrenal vein catheterization with determination of aldosterone and cortisol

Step III: reevaluation repeat screening tests after 2 years in patients with a tumor size of  3 cm

In summary, the most important questions in a given patient with an adrenal incidentaloma (section 2) may be answered as follows (Figure 6).

Figure 6. Probability of location, biochemical activity and dignity of the incidentally detected adrenal mass

To prevent serious morbidity, all hormonally active incidentalomas must be surgically removed [17, 19, 104]. This strategy is undisputed for Conn´s adenomas and pheochromocytomas. However, it remains controversial whether all patients with subclinical Cushing´s syndrome benefit from adrenal surgery [23], as progress from subclinical disease to overt Cushing´s syndrome may occur only in a minority of cases [53, 60]. As autonomous cortisol secretion by the tumor may range from a small percentage of the daily requirements to borderline hypersecretion with suppression of the contralateral adrenal, metabolic benefits of surgery will vary accordingly. In patients with subclinical Cushing´s syndrome undergoing unilateral adrenalectomy, a permanent weight loss in obese individuals, a reduction of hypertension and an improvement of glycemic control in diabetics are frequent findings [43, 44, 60]. Moreover, recently a decrease in bone mineral density and altered bone metabolism in patients with SCCS (diagnosed by elevated urinary free cortisol) was shown, which indicates that these individuals are at higher risk of osteoporosis [105-108]. Although these results were not obtained in large prospective studies, they indicate that surgical therapy should be advocated in more patients.

Adrenal surgery has a significant morbidity and mortality [109] which have to be taken into account if an operation is considered. As there are no prospective, randomized trials comparing open with laparoscopic adrenalectomy both approaches are acceptable [23]. The newly developed endoscopic adrenalectomy [110-112] with its low morbidity (5 – 10 %) and mortality (1 – 2 %) may justify earlier intervention. However, it has to be emphasized that these operations are mostly performed in specialized centers by surgeons experienced in laparoscopic techniques [113]. There are no studies that demonstrate a consistent benefit of one laparoscopic approach (transabdominal or retroperitoneal) over another [23].

Generally, surgery should be considered in patients with SCCS who have suppressed plasma ACTH and elevated urinary free cortisol because progression to overt Cushing`s syndrome is imminent. When the diagnosis of subclinical Cushing`s syndrome is established by high-dose dexamethasone suppression, adrenalectomy is recommended in younger individuals (age < 50 years), in patients who have metabolic disease of recent onset possibly related to the incidentaloma (e. g., obesity, hypertension, diabetes), or if they have osteopenia or osteoporosis (Table 5) [61].

Because of the increasing risk of malignancy, tumors with a diameter 6 > cm are surgically removed after adequate endocrinologic investigation. Smaller tumors (4 – 6 cm) may also be removed, if there is strong suspicion of malignancy after adrenal imaging and scintigraphy [20, 92]. Additionally, in the case of clearly elevated serum DHEAS, surgical therapy should be considered, especially in patients younger than 50 years [17]. All tumors demonstrating significant growth during follow-up should also be removed.

In February 2002 a NIH state-of-the-science conference on “Management of Clinically Inapparent Adrenal Mass” (“Incidentaloma”) developed recommendations for the work-up and treatment of patients with adrenal incidentalomas (http://consensus.nih.gov/ta/021/021_intro.htm) [23, 26]. A summary of these recommendations is shown in Figure 7.

Figure 7. Diagnostic and therapeutic approach to the patient with an incidentally detected adrenal mass, according to the NIH state-of-the-science conference statement . We recommend an endocrinologic reevaluation after 2 years in patients with a tumor size  3 cm .

Due to the advances and broader use of modern imaging, adrenal incidentalomas are detected with increasing frequency. Their prevalence peaks between the 50th and 60th year (3 – 7 %) and is particularly high in patients with features of the metabolic syndrome (arterial hypertension, obesity, insulin resistance). A biochemical investigation (24 h urinary catecholamines, dexamethasone suppression test, plasma aldosterone/renin activity) reveals a subtle, but significant endocrine activity of these tumors in up to 20 % (e. g. pheochromocytoma and subclinical Cushing´s syndrome). The risk of malignancy is low, but it increases with the size of the mass. Therefore, the diameter of the tumor remains the most useful parameter for clinical decision making. Hormonal significantly active incidentalomas and all tumors > 6 cm should be surgically removed. The newly developed endoscopic adrenalectomy with its low morbidity and mortality may justify earlier intervention. Smaller tumors require both imaging and endocrine follow-up. If tumor growth is detected, the adrenal mass must be surgically removed. Imaging studies beyond 12 month in a stable adrenal mass are not recommended. Fine-needle aspiration should be restricted to oncologic patients, in whom the adrenal mass is the only evidence of possible metastasis. The utility of adrenal scintigraphy remains controversial.