Evaluation and management of the adrenal incidentaloma

INTRODUCTION — An adrenal incidentaloma is a mass lesion greater than 1 cm in diameter, serendipitously discovered by radiologic examination [1]. This entity is the result of technological advances in imaging such as computed tomography (CT) and magnetic resonance imaging (MRI) and their widespread use in clinical practice. Discovery of an adrenal mass raises two questions that determine the degree of evaluation and the need for therapy, and both questions should be addressed simultaneously [2]:

●Is it malignant?

●Is it functioning?

The approach to the evaluation and management of adrenal incidentalomas is reviewed here. Detailed discussions of adrenal carcinoma and functioning adrenal tumors such as pheochromocytomas and aldosteronomas are found elsewhere. (See "Clinical presentation and evaluation of adrenocortical tumors" and "Clinical presentation and diagnosis of pheochromocytoma" and "Pathophysiology and clinical features of primary aldosteronism".)

PREVALENCE

Unilateral masses — Adrenal masses may be found incidentally when CT scans or MRI is done for other reasons. In a study of 61,054 abdominal CT scans performed from 1985 to 1990, an incidental adrenal tumor (incidentaloma >1 cm) was detected in 259 patients (0.4 percent of all CT scans) [3]. Subsequent studies, utilizing higher-resolution scanners, have reported a prevalence of adrenal incidentaloma on abdominal CT from 1.4 to 7.3 percent [4-6]. The prevalence of adrenal incidentaloma is higher in older patients (10 percent) [7].

In autopsy studies, the prevalence of incidentalomas is 2 percent, and it ranges from 1 to 9 percent. The prevalence is higher in individuals with obesity, diabetes, and hypertension [7]. As an example, in a series of 739 autopsies, adrenal masses between 2 mm and 4 cm in size were present in 9 percent of individuals without hypertension and in 12 percent of those with hypertension [8].

Bilateral masses — Analyses from two large adrenal incidentaloma studies with 887 and 202 patients showed that bilateral masses were found in 10 to 15 percent of cases [9,10]. Bilateral adrenal masses can be seen with metastatic disease, congenital adrenal hyperplasia, cortical adenomas, lymphoma, infection (eg, tuberculosis, fungal), hemorrhage, corticotropin (ACTH)-dependent Cushing syndrome, pheochromocytoma, primary aldosteronism, amyloidosis, infiltrative disease of the adrenal glands, and primary bilateral macronodular adrenal hyperplasia (PBMAH). In one study of 208 adrenal incidentaloma patients, 19 (9 percent) proved to have adrenal metastases; 10 of the 19 patients (53 percent) had bilateral disease [11].

In some patients with bilateral disease, one adrenal mass proves to be a nonfunctioning cortical adenoma, while the contralateral adrenal mass is hormone secreting [10]. In addition, adrenocortical hypofunction may occur in patients with bilateral adrenal masses. Therefore, all patients with bilateral adrenal masses should be screened for adrenocortical hyper- and hypofunction.

EVALUATION FOR MALIGNANCY — Malignancy is an uncommon cause of adrenal incidentaloma in patients without a known diagnosis of cancer. Although estimates have varied widely, the actual frequency of primary adrenal carcinoma in patients with adrenal incidentaloma is approximately 2 to 5 percent; another 0.7 to 2.5 percent have non-adrenal metastases to the adrenal gland [1,7,12-14]. The size and imaging characteristics ("imaging phenotype") of the mass may help determine whether the tumor is benign or malignant [1,13,15].

Size — The maximum diameter of the adrenal mass is predictive of malignancy [16]. This was illustrated in a study of 887 patients with adrenal incidentalomas from the National Italian Study Group on Adrenal Tumors [9]. Adrenocortical carcinomas were significantly associated with mass size, with 90 percent being more than 4 cm in diameter when discovered.

Adrenal mass size is also important because the smaller the adrenocortical carcinoma is at the time of diagnosis, the better the overall prognosis. In a retrospective review of 62 patients with adrenocortical carcinoma, five-year survival was approximately 16 percent overall, but much higher (42 percent) in patients with smaller tumors (stages I and II, confined to the adrenal gland) who were more likely to undergo curative resection [17]. (See "Clinical presentation and evaluation of adrenocortical tumors" and "Treatment of adrenocortical carcinoma".)

In the report from the National Italian Study Group, a 4 cm cutoff had a 93 percent sensitivity of detecting adrenocortical carcinoma, even though specificity was limited (76 percent of masses larger than 4 cm in diameter were benign) [9,13]. In the Mayo Clinic study cited above, all 20 adrenal carcinomas were between 4 and 6 cm in diameter [3]. Therefore, surgical removal of unilateral adrenal masses larger than 4 cm should be considered to avoid missing adrenal carcinomas, particularly in younger patients. (See 'Management' below.)

However, adrenal mass size should not be used as the only parameter to guide treatment. In a retrospective, single-center cohort of 4085 patients with adrenal tumors, 705 (17 percent) had adrenal masses measuring 4 cm or more in diameter; of these, 216 (31 percent) were adrenocortical adenomas, 158 (22 percent) were pheochromocytomas, 116 (16 percent) were other benign adrenal tumors, 88 (13 percent) were adrenocortical carcinomas, and 127 (18 percent) were other malignant tumors [18]. On multivariate analysis, older age at diagnosis, male sex, nonincidental mode of discovery, larger tumor size, and higher unenhanced CT attenuation were all found to be statistically significant predictors of malignancy [18]. (See 'Imaging phenotype' below and 'Monitoring when surgery not performed' below.)

Imaging phenotype — CT or MRI with 2 to 3 mm cuts may allow prediction of the histologic type of the adrenal tumor [1,9]. As an example, the lipid-rich nature of a cortical adenoma is helpful in distinguishing this benign tumor from carcinoma (image 1).

CT scan

Unenhanced attenuation — On CT scanning, the density of the image (black is less dense) is attributed to radiograph attenuation. The intracytoplasmic fat in adenomas results in low attenuation on unenhanced CT; non-adenomas have higher attenuation in unenhanced CT. The Hounsfield scale is a semiquantitative method of measuring radiograph attenuation. Typical precontrast Hounsfield unit (HU) values are for adipose tissue (-20 to -150 HU) and kidney (20 to 150 HU). If an adrenal mass measures <10 HU on unenhanced CT (ie, has the density of fat), the likelihood that it is a benign adenoma is nearly 100 percent. However, up to 30 percent of adenomas do not contain large amounts of lipid and may be indistinguishable from non-adenomas on nonenhanced CT scans and are termed lipid-poor adenomas. Although imaging phenotype does not predict hormonal function, it does predict underlying pathology, and surgical resection should be considered in patients with adrenal incidentalomas that have a suspicious imaging phenotype [1]. (See 'Typical imaging features' below.)

●HU<10 – A consensus panel noted that a homogeneous adrenal mass with a smooth border and an attenuation value <10 HU on unenhanced CT is very likely to be a benign adenoma [2]. This appears to be a reasonable CT HU cutoff based upon a retrospective analysis of 151 patients with adrenal masses who underwent both a noncontrast CT scan and adrenalectomy [19]. The mean HU (± standard deviation [SD]) for adrenal adenomas/hyperplasia was significantly lower than for adrenal carcinomas, metastases, and pheochromocytomas (16.2±13.6 versus 36.9±4.1, 39.2±15.2, and 38.6±8.2, respectively). The only patients in the nonadenoma groups with a noncontrast CT HU <10 were those with myelolipomas (which were all less than -40 and therefore easily distinguishable). In this series, an unenhanced CT attenuation ≤10 HU or a combination of tumor size ≤4 cm and HU ≤20 excluded non-adenomas in 100 percent of cases.

●HU>10 – In a retrospective cohort study of 353 patients with adrenal nodules who underwent adrenal biopsy and/or adrenalectomy, 80 percent of patients presented with known or suspected extra-adrenal malignancy [20]. Adrenal masses with unenhanced CT attenuation >10 HU diagnosed malignancy with a sensitivity of 100 percent, specificity of 33 percent, positive predictive value (PPV) of 72 percent, and negative predictive value (NPV) of 100 percent. Unenhanced CT attenuation of ≤10 HU excluded malignancy even in this high-risk population.

Delayed contrast-enhanced CT — Initial studies suggested that on delayed contrast-enhanced CT, the rapidity of contrast medium washout could distinguish between adrenal adenoma and non-adenomas [21]. Ten minutes after administration of contrast, an absolute contrast medium washout of more than 50 percent was reported to be 100 percent sensitive and specific for adenoma when patients with adenomas were compared with those with carcinomas, pheochromocytomas, and metastases [22,23]. However, contrast medium washout may have limited utility for excluding malignancy and pheochromocytoma in indeterminate, lipid-poor nodules. One retrospective study of adrenal nodules with an attenuation value of >10 HU found that contrast washout greater than 60 percent had substantially lower sensitivity (77.5 percent) and specificity (70 percent) for benign adenoma in adrenal masses <4 cm [24].

MRI — Although CT is the recommended primary adrenal imaging procedure in most cases, MRI has advantages in certain clinical situations. For example, follow-up imaging with MRI avoids the radiation exposure of repeated CT imaging.

●Conventional spin-echo MRI is the most frequently used technique. Using low or mid-field-strength magnets, T1- and T2-weighted imaging can distinguish benign adenomas from malignancy and pheochromocytoma.

●MR with chemical shift imaging (CSI) accurately distinguishes adrenal adenomas from non-adenomas based on their elevated amounts of intracytoplasmic fat [25]. In a meta-analysis of 1280 lesions (859 adenomas), CSI demonstrated a sensitivity of 94 percent (95% CI 88-97 percent) and a specificity of 95 percent (95% CI 89-97 percent). No difference in diagnostic performance was seen when quantitative versus qualitative image analysis was compared.

Other — Positron emission tomography (PET) with either fludeoxyglucose F 18 (FDG) [26,27] or 11C-metomidate (MTO) [28] can be helpful in selected patients (eg, those with a prior history of malignancy or those in which unenhanced CT attenuation or washout analysis is inconclusive or suspicious for malignancy [7]) because of their high sensitivity for detecting malignancy [1]. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Radiographic studies'.)

Typical imaging features — The imaging characteristics of adrenal masses are summarized here.

Benign adenomas

●Round and homogeneous density, smooth contour, and sharp margination [29]

●Diameter less than 4 cm, unilateral location

●Low unenhanced CT attenuation values (≤10 HU) (image 1)

●Isointensity with liver on both T1- and T2-weighted MRI sequences

●Chemical shift evidence of lipid on MRI

Pheochromocytomas

●Increased attenuation on unenhanced CT (>20 HU) [30]

●Increased mass vascularity (image 2)

●High signal intensity on T2-weighted MRI (image 3)

●Cystic and hemorrhagic changes

●Variable size and may be bilateral

Adrenocortical carcinoma

●Irregular shape

●Inhomogeneous density because of central areas of low attenuation due to tumor necrosis (image 4)

●Tumor calcification

●Diameter usually >4 cm

●Unilateral location

●High unenhanced CT attenuation values (>20 HU)

●Inhomogeneous enhancement on CT with intravenous contrast

●Hypointensity compared with liver on T1-weighted MRI and high to intermediate signal intensity on T2-weighted MRI

●High standardized uptake value (SUV) on FDG-PET-CT study

●Evidence of local invasion or metastases (see "Clinical presentation and evaluation of adrenocortical tumors", section on 'Radiographic studies')

Adrenal metastases

●Irregular shape and inhomogeneous nature (image 5)

●Tendency to be bilateral

●High unenhanced CT attenuation values (>20 HU) and enhancement with intravenous contrast on CT

●Isointensity or slightly less intense than the liver on T1-weighted MRI and high to intermediate signal intensity on T2-weighted MRI (representing an increased water content)

●Elevated SUV on FDG-PET scan

Other — Adrenal cysts, adrenal hemorrhage, and myelolipoma (image 6) are usually easily characterized because of their distinctive imaging characteristics.

Fine-needle aspiration biopsy — Cytology from a specimen obtained by fine-needle aspiration (FNA) biopsy cannot distinguish a benign cortical adrenal mass from the less common adrenal carcinoma. It can, however, distinguish between an adrenal tumor and a metastatic tumor [31]. In a patient with a known primary malignancy elsewhere who has a newly discovered adrenal mass that has an imaging phenotype consistent with metastatic disease, performing a diagnostic CT-guided FNA biopsy may be indicated, but only after excluding pheochromocytoma with biochemical testing. Adrenal biopsy would not be needed if the patient was already known to have widespread metastatic disease [32,33].

One report, as an example, evaluated patients with known lung cancer and an adrenal mass; FNA biopsy revealed a benign adrenal lesion in two-thirds of cases [29]. When the non-adrenal cancer is occult, most adrenal masses are incidentaloma cortical adenomas (91 of 95 in one study [34]). Thus, FNA biopsy is not useful in the routine evaluation of incidentalomas in patients suspected to have small non-adrenal cancers.

Image-guided FNA biopsy is relatively safe; the complication rate was 2.8 percent in one series of 277 biopsies [35]. The risks of this procedure include adrenal and liver hematoma, abdominal pain, hematuria, pancreatitis, pneumothorax, formation of an adrenal abscess, and tumor recurrence along the needle track [35,36]. The FNA biopsy of a pheochromocytoma may result in hemorrhage and hypertensive crisis [37]. Therefore, the possibility of pheochromocytoma should always be ruled out by biochemical testing before FNA biopsy is undertaken [37-39].

EVALUATION FOR HORMONAL SECRETION — While most adrenal incidentalomas are nonfunctional, 10 to 15 percent secrete excess amounts of hormones [13,14]. The most complete analysis of this issue comes from a review of all 828 published articles on adrenal incidentalomas from 1980 to 2008 [14]. Only 20 of the 828 articles were selected as having met the strict criteria for a "true" adrenal incidentaloma; of these, only nine had adequate data on both diagnosis and follow-up. Patients who were suspected as having cancer were excluded. Among the 1800 patients in these nine series, these overall mean percentages of diagnoses were reported:

●Malignant – Primary adrenal carcinoma 1.9 percent, metastases 0.7 percent

●Benign – Nonfunctioning 89.7 percent, subclinical Cushing syndrome 6.4 percent, pheochromocytoma 3.1 percent, primary aldosteronism 0.6 percent

Three forms of adrenal hyperfunction should be considered in all patients who are diagnosed with an adrenal incidentaloma (algorithm 1):

●Subclinical glucocorticoid secretory autonomy (subclinical Cushing syndrome), assuming that another diagnosis (eg, pheochromocytoma) is not present

●Pheochromocytoma if the unenhanced CT attenuation is >10 HU

●Primary aldosteronism if the patient is hypertensive or has hypokalemia

Subclinical Cushing syndrome — Subclinical Cushing syndrome (or mild autonomous cortisol secretion [MACS], cortisol hypersecretion without clinical manifestations of Cushing syndrome) is the most frequent hormonal abnormality detected in patients with adrenal incidentalomas. Some adrenal incidentalomas secrete cortisol independently of corticotropin (ACTH) [40], which may have clinically important consequences [41]. Cortisol secretion can be under the control of one or more aberrant hormone receptors in patients with unilateral adenomas or incidental primary bilateral macronodular adrenal hyperplasia (PBMAH) [42,43]. (See "Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia", section on 'Aberrant hormone receptors'.)

Clinical manifestations — Although these patients lack many of the usual stigmata of overt Cushing syndrome, they may have one or more of the effects of continuous ACTH-independent cortisol secretion, including hypertension, dyslipidemia, diabetes, weight gain, osteoporosis, and evidence of atherosclerosis [41,44-46].

In a meta-analysis of 47 observational studies in 17,156 participants with adrenal incidentaloma, individuals with MACS (defined as serum cortisol >1.8 mcg/dL after a 1 mg overnight dexamethasone suppression test) exhibited a higher prevalence of diabetes (20 studies; relative risk [RR] 1.44, 95% CI 1.23-1.69), hypertension (31 studies; RR 1.24, 95% CI 1.16-1.32), and dyslipidemia (22 studies; RR 1.23, 95% CI 1.13-1.34) compared with participants with nonfunctioning adrenal adenomas [47]. In 10 studies that reported fracture data, study design and findings were heterogeneous; nonetheless, two cohort studies identified higher incidence of vertebral fractures or all clinical fractures in individuals with MACS compared with those with nonfunctioning adenomas [48,49]. For example, in a two-year longitudinal study of 103 consecutive patients with adrenal incidentaloma, the incidence of new vertebral fractures was higher in patients with MACS (48 percent) than in those without MACS (13 percent) [48].

Atrial fibrillation (AF) is more common in patients with MACS when compared with those with nonsecreting adenomas. In a retrospective study of patients with MACS or nonsecreting adenomas (n = 632), the prevalence of AF was higher at baseline in the ACS patients (8.5 percent, 18 of 212) compared with the nonsecreting group (3.1 percent, 13 of 420) [50]. At the completion of the study (median follow-up of 7.7 years), the AF rate remained higher in the MACS group: 20 percent (22 of 108) versus the nonsecreting group, 12 percent (30 of 249). Given these rates, patients with MACS should be monitored for AF.

Diagnosis — Subclinical Cushing syndrome should be ruled out by obtaining a baseline serum dehydroepiandrosterone sulfate (DHEAS) and performing the 1 mg overnight dexamethasone suppression test (DST) (algorithm 1) [51]. Of note, the overnight DST should not be performed if the patient is thought to have a pheochromocytoma based upon the initial imaging study (unenhanced CT attenuation >10 HU). Reports of catecholaminergic crisis (some fatal) during DSTs have been described in patients with pheochromocytoma. Although most have been with high-dose DST, cases with low-dose DST have also been described [52,53].

Random, morning, or late-night serum cortisol levels are not useful for diagnosis of subclinical Cushing syndrome. In addition, most ACTH assays lack sensitivity at the lower part of the reference range and cannot be relied on to identify autonomous cortisol secretion.

●DHEAS – A low DHEAS reflects chronic suppression of ACTH secretion. In a study of 185 patients with adrenal incidentaloma, 29 patients (16 percent) were diagnosed with subclinical Cushing syndrome [54]. An age- and sex-specific DHEAS ratio (derived by dividing the DHEAS by the lower limit of the respective reference range for age and sex) of <1.12 was sensitive (>99 percent) and specific (91.9 percent) for the diagnosis of subclinical Cushing syndrome [54].

In a retrospective study of 256 patients with adrenal incidentaloma and MACS, a serum DHEAS concentration <40 mcg/dL was 84 percent specific for MACS, whereas an ACTH concentration <10 pg/mL was only 75 percent specific for MACS [55]. In addition, a serum DHEAS concentration >100 mcg/dL combined with an ACTH concentration >15 pg/mL was 96 percent specific for excluding MACS [55].

●DST – An abnormal 1 mg overnight DST (cortisol >1.8 mcg/dL [>50 nmol/L]) is consistent with ACTH-independent autonomous cortisol production. Some centers use a higher dose of dexamethasone (eg, 3 mg rather than the standard 1 mg) to reduce false-positive results [56]. Positive findings on the initial DST should be further evaluated with 24-hour urinary free cortisol, serum ACTH concentration, and a high-dose (8 mg) overnight DST. Clinically significant glucocorticoid secretory autonomy is confirmed by a post-overnight 8 mg DST 8 AM serum cortisol concentration >1.8 mcg/dL (>50 nmol/L). (See "Establishing the diagnosis of Cushing syndrome".)

A study of the two-day, low-dose DST [57] showed a gradation between subnormal and complete suppression of serum cortisol concentrations in 57 patients with adrenal incidentalomas (21 percent had undetectable serum levels of cortisol, 67 percent had values between 1 and 5 mcg/dL, and 12 percent had values between 5.0 and 7.8 mcg/dL). Thus, the question for the clinician when glucocorticoid secretory activity is found is whether the cortical adenoma has clinically significant glucocorticoid secretory activity.

Bilateral adrenal masses and subclinical Cushing syndrome — This clinical scenario is being increasingly recognized. When the bilateral adrenal masses are consistent with solitary bilateral adenomas on cross-sectional computed imaging, consideration should be given to adrenal venous sampling [58-60] (see "Diagnosis of primary aldosteronism", section on 'Adrenal vein sampling'). In this setting, adrenal venous sampling is performed without cosyntropin administration, and successful adrenal vein catheterization is confirmed with either catecholamine or metanephrine gradients between the adrenal veins and the inferior vena cava [60].

In a study of 14 patients with bilateral adrenal nodules and ACTH-independent subclinical or clinical Cushing syndrome, 10 had bilateral and 4 had unilateral cortisol overproduction [59]. In patients where the computed images of the primary adrenal glands are consistent with PBMAH (image 7), adrenal vein sampling is not needed, because this is a bilateral adrenal disorder. (See "Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia", section on 'Initial evaluation'.)

Pheochromocytoma — Approximately 3 percent of adrenal incidentalomas prove to be pheochromocytomas [14]. In the past, it was thought that all patients with pheochromocytoma are symptomatic. However, with widespread use of computed imaging, pheochromocytomas are being discovered in the presymptomatic stage [61,62]. In a study of 271 consecutive patients with pheochromocytoma treated from 2005 to 2016, 61 percent were discovered as an incidental finding on cross-section imaging, 27 percent due to pheochromocytoma-related symptoms, and 12 percent due to mutation-based testing [63]. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Approach to initial evaluation'.)

Biochemical testing for pheochromocytoma should be performed if the unenhanced CT attenuation is ≥10 HU, but not if it is <10 HU (algorithm 1) [30]. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Imaging'.)

Small pheochromocytomas (eg, <1.5 cm) may have normal biochemical testing (image 8). Pheochromocytomas need a critical mass before they can become biochemically detectable. Surgical resection of apparent nonfunctioning lipid-poor and vascular adrenal masses should be considered (algorithm 1).

Aldosteronomas — Aldosteronomas are rare (less than 1 percent) causes of an adrenal incidentaloma. However, because the majority of patients with primary aldosteronism are not hypokalemic, all patients with hypertension and an adrenal incidentaloma should be evaluated by measurements of plasma aldosterone concentration and plasma renin activity [1,2]. In addition, patients who are normotensive but have spontaneous hypokalemia should also be tested for primary aldosteronism (algorithm 1). (See "Diagnosis of primary aldosteronism" and "Pathophysiology and clinical features of primary aldosteronism".)

Confirmatory testing — The diagnosis and confirmation of clinically important subclinical Cushing syndrome is described above (see 'Subclinical Cushing syndrome' above). If there is biochemical evidence of either a pheochromocytoma or aldosterone-secreting adenoma on initial testing, confirmatory testing is required before treatment is considered. Confirmatory testing for these disorders is described elsewhere. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Indeterminate case-detection test' and "Diagnosis of primary aldosteronism", section on 'Confirmation of the diagnosis'.)

MANAGEMENT — Our approach to management is largely consistent with guidelines from the American Association of Endocrine Surgeons [64].

Unilateral adrenal masses

●Pheochromocytoma and adrenocortical cancer – All patients with documented pheochromocytoma and adrenocortical cancer should undergo prompt surgical intervention because untreated pheochromocytoma may result in significant cardiovascular complications. Alpha-adrenergic blockade should be given before patients undergo adrenalectomy. (See "Treatment of pheochromocytoma in adults".)

Patients with adrenocortical cancer or lesions suspicious for adrenocortical cancer should also undergo prompt adrenalectomy as their disease may progress rapidly. (See "Treatment of adrenocortical carcinoma".)

●Aldosterone-producing adenomas – Patients with aldosterone-producing adenomas should be offered surgery to cure aldosterone excess. (See "Treatment of primary aldosteronism".)

●Subclinical Cushing syndrome – Should all patients with this diagnosis undergo unilateral adrenalectomy? In the absence of a prospective, randomized study, it is reasonable to consider younger patients as candidates for adrenalectomy. Patients who have disorders potentially attributable to autonomous glucocorticoid secretion (eg, recent onset of hypertension, diabetes, obesity, and/or low bone mass) with well-documented glucocorticoid secretory autonomy (ie, suppressed dehydroepiandrosterone sulfate [DHEAS], failure to suppress cortisol normally on 1 mg overnight dexamethasone test [DST], low serum corticotropin [ACTH] concentration, lack of suppression to high-dose overnight DST [8 AM serum cortisol >1.8 mcg/dL]) are also candidates for adrenalectomy.

In a meta-analysis of 47 studies in participants with adrenal incidentaloma, participants with subclinical Cushing syndrome who underwent adrenalectomy showed greater improvement in cardiometabolic parameters compared with those who did not undergo surgery (11 studies) [47]; however, these data were predominantly observational.

If adrenalectomy is performed, a postoperative ACTH stimulation test should be done to confirm adequate adrenocortical function. If this test is not performed or demonstrates inadequate adrenocortical function, perioperative glucocorticoid coverage should be administered because of the risk of adrenal insufficiency, hemodynamic crisis, and death. Patients should be sent home from the hospital on glucocorticoid replacement and monitored for recovery of the hypothalamic-pituitary-adrenal axis [65]. Weight loss, improvement in hypertension and/or glycemic management, and normalization of markers of bone turnover are frequently found following unilateral adrenalectomy in patients with subclinical Cushing syndrome [66-68].

●Lipid-poor adrenal masses – Adrenal masses with either suspicious imaging phenotype or size larger than 4 cm should be considered for resection because a substantial fraction will be adrenocortical carcinomas [2,17]. The clinical scenario and patient age frequently guide the management decisions in patients who have adrenal incidentalomas that fall on either side of the 4 cm diameter cutoff. As an example, most clinicians would advise resecting a lipid-poor (29 HU) 3.2 cm adrenal incidentaloma in a 23-year-old woman, whereas most clinicians would choose serial imaging follow-up in an 83-year-old woman with a lipid-rich (9 HU) 4.7 cm adrenal incidentaloma. Before surgery, all patients should undergo appropriate testing for functional tumors. (See 'Evaluation for hormonal secretion' above.)

●Adrenal myelolipoma – This is a benign tumor composed of mature fat and interspersed hematopoietic elements that resemble bone marrow. On computed imaging, the presence of large amounts of macroscopic fat in an adrenal mass is diagnostic of a myelolipoma (image 6) [69]. Although adrenal myelolipomas may grow over time, they can usually be followed without surgical excision. However, when larger than 6 cm in diameter or when causing local mass-effect symptoms, surgical removal should be considered. When adrenal myelolipomas are bilateral, the clinician should consider the diagnosis of congenital adrenal hyperplasia [70].

Bilateral adrenal masses — The management of bilateral adrenal masses is different from that for unilateral masses. As an example, in cases of primary bilateral macronodular adrenal hyperplasia (PBMAH) (image 7), size is not an indication for surgery, whereas the degree of cortisol secretory autonomy should guide surgical decision-making. Patients with PBMAH and clinical Cushing syndrome usually are best treated with bilateral adrenalectomy, whereas patients with PBMAH and subclinical Cushing syndrome may be managed by resecting the larger adrenal gland.

Surgical management should be guided by the findings on adrenal venous sampling in patients with ACTH-independent Cushing syndrome or subclinical Cushing syndrome in the setting of solitary bilateral adrenal adenomas [58-60].

Adrenalectomy — Adrenalectomy for patients with aldosteronomas, pheochromocytoma, cortisol-secreting tumors, and adrenal incidentalomas is safe and effective [71]. An adrenalectomy may be done laparoscopically, endoscopically via the posterior approach, or as an open procedure. Laparoscopic adrenalectomy, compared with open adrenalectomy, is associated with less pain, shorter hospitalization time, less blood loss, and faster recovery [72]. The laparoscopic approach is used for most adrenal masses [64].

In patients with known or suspected adrenal carcinoma, the laparoscopic approach should only be considered if the adrenal mass is <10 cm and does not appear to be locally invasive [73,74]. An open adrenalectomy is recommended for all large (>10 cm) adrenal masses, including those benign imaging features, as the adrenal mass may be diagnosed as malignant on a definitive histologic review [73,75-78]. (See 'Imaging phenotype' above and "Adrenalectomy techniques", section on 'Approach by indication'.)

Monitoring when surgery not performed — For incidentalomas with a benign appearance on imaging, repeat imaging after 12 months should be performed to reconfirm the initial diagnosis of a benign adrenal mass [7]. The decision to obtain additional images (eg, at 3, 6, 12, and 24 months after the initial image) and the type of image obtained (eg, CT or MRI) should be guided by the individual clinical circumstance, imaging phenotype, and clinical judgment (algorithm 1).

As an example, a single repeat image is reasonable in patients who have no history of malignancy and who have small (less than 2 cm), uniform, low unenhanced CT attenuation cortical nodules (ie, benign imaging phenotype). There are no prospective studies of the optimal frequency and duration of follow-up for adrenal incidentalomas. In addition, the radiation exposure related to CT should be considered [14]. (See "Radiation-related risks of imaging", section on 'Clinical decision-making and informing patients'.)

Most experts would consider resecting any tumor that enlarges by more than 1 cm in diameter during the follow-up period (algorithm 1). However, most adrenal masses that grow are not malignant. Nonetheless, surgical removal should be considered for masses ≥4 cm to avoid missing adrenal carcinomas, particularly in younger patients. (See 'Size' above.)

The observation that autonomous function (glucocorticoid hypersecretion) not present at baseline may be detected at follow-up testing [79-81] has led to the recommendation for repeating the baseline DHEAS measurement and the overnight DST annually for four years in cases where initial evaluation is negative [1,80,81]; however, the yield and cost effectiveness of such testing is also unknown [7,14].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of Cushing syndrome" and "Society guideline links: Adrenal incidentaloma".)

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SUMMARY AND RECOMMENDATIONS

●Adrenal incidentaloma definition – An adrenal incidentaloma is a mass lesion greater than 1 cm in diameter, serendipitously discovered by radiologic examination. This entity is the result of technological advances in imaging such as CT and MRI. (See 'Introduction' above.)

●Imaging phenotype – All patients with adrenal incidentalomas should be evaluated for the possibility of malignancy. The size and imaging characteristics ("imaging phenotype") of the mass may help determine whether the tumor is benign or malignant. (See 'Evaluation for malignancy' above.)

•Benign cortical adenoma – A homogeneous adrenal mass <4 cm in diameter, with a smooth border, and an attenuation value <10 Hounsfield unit (HU) on unenhanced CT is very likely to be a benign cortical adenoma. (See 'CT scan' above.)

•Adrenal carcinoma or metastases – The imaging characteristics that suggest adrenal carcinoma or metastases include irregular shape, inhomogeneous density, high unenhanced CT attenuation values (>20 HU), diameter >4 cm, and tumor calcification. Other characteristics are described above. (See 'Adrenocortical carcinoma' above.)

●Evaluation for hormonal secretion – All patients with adrenal incidentalomas should be evaluated for the possibility of subclinical hormonal hyperfunction.

•Pheochromocytoma – Pheochromocytoma should be excluded in all patients with adrenal incidentalomas with unenhanced CT attenuation >10 HU by measuring 24-hour urinary fractionated metanephrines and catecholamines or plasma fractionated metanephrines. (See 'Pheochromocytoma' above.)

•Subclinical Cushing syndrome – Subclinical Cushing syndrome should be ruled out by measuring baseline dehydroepiandrosterone sulfate (DHEAS) and performing the 1 mg overnight dexamethasone suppression test (DST). To detect clinically significant glucocorticoid secretory autonomy, the post-overnight 1 mg DST 8 AM serum cortisol concentration cutoff is >1.8 mcg/dL (>50 nmol/L). An abnormal 1 mg overnight DST is consistent with corticotropin (ACTH)-independent cortisol production, a finding that should be confirmed with 24-hour urinary free cortisol, serum ACTH concentration, and a high-dose (8 mg) overnight DST. (See 'Subclinical Cushing syndrome' above.)

•Primary aldosteronism (selected patients) – If the adrenal incidentaloma patient has hypertension or hypokalemia, a plasma aldosterone level and plasma renin activity should be measured to screen for primary aldosteronism. (See 'Aldosteronomas' above.)

●Management

•Pheochromocytoma – We recommend surgery for all patients with biochemical documentation of pheochromocytoma. The preoperative management and surgical approach of patients with pheochromocytoma are reviewed elsewhere. (See "Treatment of pheochromocytoma in adults".)

•Subclinical Cushing syndrome – We suggest surgical resection for patients with subclinical Cushing syndrome who are good surgical candidates and who have disorders potentially attributable to excess glucocorticoid secretion (eg, recent onset of hypertension, diabetes, obesity, and/or low bone mass) (Grade 2C). (See 'Unilateral adrenal masses' above.)

•Suspected metastatic disease – In a patient with a known primary malignancy elsewhere who has a newly discovered adrenal mass that has an imaging phenotype consistent with metastatic disease, performing a diagnostic CT-guided fine-needle aspiration (FNA) biopsy may be indicated, but only after excluding pheochromocytoma with biochemical testing. Adrenal biopsy is not needed if the patient is already known to have widespread metastatic disease. (See 'Fine-needle aspiration biopsy' above.)

•Suspected carcinoma – We suggest excision of a tumor if the initial imaging phenotype is suspicious (Grade 2C). (See 'Unilateral adrenal masses' above.)

•Masses >4 cm – In patients with adrenal masses greater than 4 cm in diameter, we consider surgical resection. However, the clinical scenario, imaging characteristics, and patient age frequently guide the management decisions in patients who have adrenal incidentalomas that fall on either side of the 4 cm diameter cutoff. (See 'Size' above and 'Unilateral adrenal masses' above.)

●Adrenalectomy – The laparoscopic approach is used for most adrenal masses. In patients with known or suspected adrenal carcinoma, the laparoscopic approach should only be considered if the adrenal mass is <10 cm and does not appear to be locally invasive. For all adrenal masses larger than 10 cm, including those masses with benign imaging phenotypes, we suggest an open adrenalectomy rather than a laparoscopic procedure (Grade 2C). (See 'Adrenalectomy' above.)

●Monitoring when surgery not performed

•Repeat imaging – For incidentalomas with a benign appearance on imaging, we suggest a repeat imaging study at 12 months after initial discovery. The rationale is that many malignant lesions will grow in this interval, leading to earlier intervention. Whether to obtain additional images (eg, at 6, 12, and 24 months after initial discovery) and the type of image obtained (eg, CT, MRI, or ultrasound) should be guided by clinical judgment and imaging phenotype. The yield and cost-effectiveness of such a strategy are not known. (See 'Monitoring when surgery not performed' above.)

•Tumors with interim growth – We suggest removal of any tumor that enlarges by more than 1 cm in diameter during the follow-up period (Grade 2C). (See 'Monitoring when surgery not performed' above.)

•Biochemical monitoring – We suggest that baseline DHEAS and an overnight DST be repeated annually for four years in cases where initial evaluation is negative, although the yield and cost effectiveness of such testing is also unknown. Autonomous function (glucocorticoid hypersecretion) not present at baseline may be detected at follow-up testing. (See 'Monitoring when surgery not performed' above.)

ACKNOWLEDGMENTS — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.

The UpToDate editorial staff acknowledges Norman M Kaplan, MD, who contributed to earlier versions of this topic review.