Evaluation and management of the adrenal incidentaloma

1 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 [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'.)

2 PREVALENCE

2.1 Unilateral masses — Adrenal masses may be found incidentally when computed tomography (CT) scans or magnetic resonance imaging (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]. A subsequent study, utilizing higher resolution scanners, reported a prevalence of adrenal incidentaloma on abdominal CT of 4.4 percent [4]. The prevalence of adrenal incidentaloma is higher in older patients (10 percent) [5].

In autopsy studies, the prevalence of incidentalomas is 2 percent, and it ranges from 1 to 9 percent. The prevalence is higher in obese, diabetic, and hypertensive patients [5]. 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 normotensive patients and in 12 percent of patients who had hypertension [6].

2.2 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 [7,8]. Bilateral adrenal masses can be seen with metastatic disease, congenital adrenal hyperplasia, cortical adenomas, lymphoma, infection (eg, tuberculosis, fungal), hemorrhage, corticotropin (ACTH)-dependent Cushing's, pheochromocytoma, primary aldosteronism, amyloidosis, infiltrative disease of the adrenal glands, and bilateral macronodular adrenal hyperplasia (BMAH). 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 [9].

In some patients with bilateral disease, one adrenal mass proves to be a nonfunctioning cortical adenoma, while the contralateral adrenal mass is hormone secreting [8]. 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.

3 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 [1,5,10-12]. The size and imaging characteristics ('imaging phenotype') of the mass may help determine whether the tumor is benign or malignant [1,11,13].

3.1 Size — The maximum diameter of the adrenal mass is predictive of malignancy. This was illustrated in a study of 887 patients with adrenal incidentalomas from the National Italian Study Group on Adrenal Tumors [7]. 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 [14]. (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) [7,11]. 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; 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 [15]. On multivariate analysis, older age at diagnosis, male sex, nonincidental mode of discovery, larger tumor size, and higher unenhanced computed tomography (CT) attenuation were all found to be statistically significant predictors of malignancy [15]. (See 'Imaging phenotype' below and 'Monitoring when surgery not performed' below.)

3.2 Imaging phenotype — CT or magnetic resonance imaging (MRI) with 2 to 3 mm cuts may allow prediction of the histologic type of the adrenal tumor [1,7]. As an example, the lipid-rich nature of a cortical adenoma is helpful in distinguishing this benign tumor from carcinoma (image 1).

image1  Lipid-rich benign adrenal adenoma

Unenhanced (A) and enhanced (B) axial CT images of an incidentally discovered 2.8 × 3.5 cm right adrenal mass (arrows). On the unenhanced image, the CT attenuation was 5 HU and diagnostic of a lipid-rich adrenal mass. With contrast administration, the adrenal mass was shown to be not vascular (B), enhanced homogenously, and had rapid contrast washout (>50% at 10 minutes).   CT: computed tomography; HU: Houndsfield units.

3.2.1 CT scan

Unenhanced attenuation — On computed tomography (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.

●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 [16]. 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 [17]. 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 — On delayed contrast-enhanced CT, adenomas typically exhibit rapid contrast medium washout, whereas non-adenomas have delayed contrast material washout [16]. 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 carcinomas, pheochromocytomas, and metastases [16,18,19]. 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].

3.2.2 MRI — Although CT is the recommended primary adrenal imaging procedure in most cases, magnetic resonance imaging (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.

●On gadolinium-diethylene triamine pentaacetic acid (DTPA)-enhanced MRI, adenomas demonstrate mild enhancement and a rapid washout of contrast, while malignant lesions show rapid and marked enhancement and a slower washout pattern.

●MR with chemical shift imaging (CSI) accurately distinguishes adrenal adenomas from non-adenomas based on their elevated amounts of intracytoplasmic fat [20]. 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.

3.2.3 Other — Positron emission tomography (PET) with either fludeoxyglucose F 18 (FDG) [21,22] or 11C-metomidate (MTO) [23] 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 [5]) because of their high sensitivity for detecting malignancy [1]. (See 'Clinical presentation and evaluation of adrenocortical tumors', section on 'Radiographic studies'.)

3.3 Typical imaging features

The imaging characteristics of adrenal masses are summarized here.

3.3.1 Benign adenomas

●Round and homogeneous density, smooth contour, and sharp margination [24]

●Diameter less than 4 cm, unilateral location

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

●Rapid contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of more than 50 percent)

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

●Chemical shift evidence of lipid on MRI

3.3.2 Pheochromocytomas

●Increased attenuation on unenhanced CT (>20 HU) [25]

●Increased mass vascularity (image 2)

●Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent)

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

●Cystic and hemorrhagic changes

●Variable size and may be bilateral

image2 Biochemically detectable pheochromocytoma

Unenhanced (A) and enhanced (B) axial CT images of an incidentally discovered 4.5 × 3.8 × 3.5 cm left adrenal mass (arrows). On the unenhanced image, the CT attenuation was 25 HU and diagnostic of a lipid-poor adrenal mass. With contrast administration, the adrenal mass was shown to be vascular and partially cystic (B), enhanced inhomogenously, and had slow contrast washout (<50% at 10 minutes). Biochemical evaluation was diagnostic of a noradrenergic pheochromocytoma with 24-hour urine normetanephrine of 4319 mcg (normal <900 mcg) and metanephrine of 250 mcg (normal <400 mcg).

CT: computed tomography; HU: Houndsfield units.

image3 MRI of pheochromocytoma

MRI of the abdomen shows a 4.5 cm right adrenal pheochromocytoma (arrows).
Upper panel: T1-weighted image.
Lower panel: T2-weighted image shows increased signal intensity typical of a pheochromocytoma.

MRI: magnetic resonance imaging.

3.3.3 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

●Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent)

●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')

image4 Nonfunctioning adrenocortical carcinoma

Unenhanced (A) and enhanced (B) axial CT images from a 22-year-old female who presented with left lower quadrant abdominal pain. An 8 cm right adrenal mass was discovered (arrows). On the unenhanced image, the CT attenuation was 34 HU and diagnostic of a lipid-poor adrenal mass. With contrast administration, the adrenal mass was shown to be vascular (B), enhanced inhomogenously, and had slow contrast washout (<50% at 10 minutes). All adrenal function tests were normal. At surgery, this tumor proved to be a 269 gram adrenal cortical carcinoma measuring 12 × 8 × 5.5 cm.

CT: computed tomography; HU: Houndsfield units.

3.3.4 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

●Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent)

●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

image5 Bilateral adrenal masses due to metastatic renal cell carcinoma

Unenhanced (A) and enhanced (B) axial CT images from a 54-year-old woman who presented with shortness of breath. A chest CT scan had been performed to screen for pulmonary embolus and incidentally detected bilateral adrenal masses (arrows). In a subsequent abdominal CT scan, the right adrenal mass measured 11.7 × 8.6 × 9.1 cm with an unenhanced CT attenuation of 35 HU. The left adrenal mass measured 5.4 cm in maximum diameter and had an unenhanced CT attenuation of 39 HU. With contrast administration, both adrenal masses enhanced markedly and inhomogenously (B), and both had slow contrast washout (<50% at 10 minutes). The abdominal CT scan also detected a large right renal mass, which proved to be renal cell carcinoma. After excluding pheochromocytoma, biopsy of the right adrenal mass documented metastatic renal cell carcinoma.

CT: computed tomography; HU: Houndsfield units.

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

image6 Adrenal myelolipoma

(A) Axial image from abdominal CT scan shows an 11 x 15 cm mixed signal intensity right adrenal mass (arrow) with large amounts of macroscopic fat consistent with adrenal myelolipoma.
(B) Gross pathology cut section showing a 19 x 12 x 9.5 1030 gm adrenal myelolipoma.

CT: computed tomography.

3.4 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 [26]. 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 [27,28].

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 [24]. When the non-adrenal cancer is occult, most adrenal masses are incidentaloma cortical adenomas (91 of 95 in one study [29]). 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 [30]. 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 [30,31]. The FNA biopsy of a pheochromocytoma may result in hemorrhage and hypertensive crisis [32]. Therefore, the possibility of pheochromocytoma should always be ruled out by biochemical testing before FNA biopsy is undertaken [32-34].

4 EVALUATION FOR HORMONAL SECRETION

While most adrenal incidentalomas are nonfunctional, 10 to 15 percent secrete excess amounts of hormones [11,12]. The most complete analysis of this issue comes from a review of all 828 published articles on adrenal incidentalomas from 1980 to 2008 [12]. 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's 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's syndrome), assuming that another diagnosis (eg, pheochromocytoma) is not present

●Pheochromocytoma if the unenhanced computed tomography (CT) attenuation is >10 HU

●Primary aldosteronism if the patient is hypertensive or has hypokalemia

4.1 Subclinical Cushing's syndrome — Subclinical Cushing's syndrome (or autonomous cortisol secretion [ACS]; cortisol secretion without clinical manifestations of Cushing's syndrome) is the most frequent hormonal abnormality detected in patients with adrenal incidentalomas. Some adrenal incidentalomas secrete cortisol independently of corticotropin (ACTH) [35], which may have clinically important consequences. Cortisol secretion can be under the control of one or more aberrant hormone receptors in patients with unilateral adenomas or incidental bilateral macronodular adrenal hyperplasia (BMAH) [36,37]. (See 'Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia', section on 'Aberrant hormone receptors'.)

4.1.1 Clinical manifestations — Although these patients lack many of the usual stigmata of overt Cushing's 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 [38-40].

In a two-year longitudinal study of 103 consecutive patients with adrenal incidentaloma, the incidence of new vertebral fractures was higher in the group with subclinical Cushing's syndrome (48 percent) than the adrenal incidentaloma group without subclinical Cushing's (13 percent) [41].

Atrial fibrillation (AF) is more common in patients with ACS when compared with those with nonsecreting adenomas. In a retrospective study of patients with ACS 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) [42]. At the completion of the study (median follow-up of 7.7 years), the AF rate remained higher in the ACS group: 20 percent (22 of 108) versus the nonsecreting group, 12 percent (30 of 249). Given these rates, patients with ACS should be monitored for AF.

4.1.2 Diagnosis — Subclinical Cushing's 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) [43]. 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 [44,45].

algorithm1  Approach to the patient with an adrenal incidentaloma

This algorithm must be used in conjunction with the UpToDate topic on the evaluation and management of the adrenal incidentaloma that describes biochemical evaluation followed by confirmatory testing if needed, as well as imaging features.

DHEAS: dehydroepiandrosterone sulfate; DST: dexamethasone suppression test; CT: computed tomography; HU: Houndsfield units; PAC: plasma aldosterone concentration; PRA: plasma renin activity; FNA: fine-needle aspiration.
* The initial biochemical testing is to determine if the incidentaloma is hormonally active. Testing is performed for subclinical hypercortisolism, pheochromocytoma, and primary aldosteronism.
¶ If there is evidence of hormonal hypersecretion, additional confirmatory testing is performed (refer to related UpToDate content on the evaluation and management of the adrenal incidentaloma).

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's syndrome [46]. 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's syndrome [46].

An abnormal 1 mg overnight DST (cortisol >1.8 mcg/dL [>50 nmol/L]) is consistent with ACTH-independent autonomous cortisol production, a finding that 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's syndrome'.)

Because of a lack of sensitivity of most ACTH assays at the lower part of the reference range, most centers rely on an alternate measure of autonomous cortisol secretion: baseline DHEAS and the overnight 1 mg DST. Some centers use a higher dose of dexamethasone (eg, 3 mg rather than the standard 1 mg) to reduce false-positive results [47].

A study of the two-day, low-dose DST [48] 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.

4.1.3 Bilateral adrenal masses and subclinical Cushing's 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 [49,50] (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.

In a study of 14 patients with bilateral adrenal nodules and ACTH-independent subclinical or clinical Cushing's syndrome 10 had bilateral and 4 had unilateral cortisol overproduction [50]. In patients where the computed images of the adrenal glands are consistent with BMAH (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'.)

image7 Bilateral macronodular adrenocortical hyperplasia

Contrast-enhanced axial CT image demonstrating massively enlarged adrenal glands (arrows) that are multinodular and adreniform in shape. This image is diagnostic of BMAH.

CT: computed tomography; BMAH: bilateral macronodular adrenocortical hyperplasia.

4.2 Pheochromocytoma

Approximately 3 percent of adrenal incidentalomas prove to be pheochromocytomas [12]. 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 [51,52]. 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 [53]. (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) [25]. (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).

image8 Small prebiochemical pheochromocytoma

Unenhanced (A) and enhanced (B) axial CT images from a 49-year-old man who presented with right-sided abdominal discomfort. A 1.6 cm left adrenal mass was incidentally discovered (arrows). On the unenhanced image, the CT attenuation was 40 HU and diagnostic of a lipid-poor mass. With contrast administration, the adrenal nodule was very vascular (B) and had slow contrast washout (<50% at 10 minutes). The patient was normotensive and had no signs or symptoms of adrenal-related disease. The plasma fractionated metanephrines and 24-hour urine fractionated metanephrines and catecholamines were normal. However, in view of the suspicious imaging phenotype and the patient's young age, surgical resection after alpha-adrenergic blockade was advised. On pathology, it proved to be a 2.1 × 1.7 × 1.3 cm pheochromocytoma.

CT: computed tomography; HU: Houndsfield units.

4.3 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'.)

4.4 Confirmatory testing

The diagnosis and confirmation of clinically important subclinical Cushing's syndrome is described above (see 'Subclinical Cushing's 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'.)

5 MANAGEMENT

5.1 Unilateral adrenal masses

●Pheochromocytoma and adrenal 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's syndrome – Should all patients with this diagnosis undergo unilateral adrenalectomy? In the absence of a prospective, randomized study, it is reasonable to consider that younger patients and those who have disorders potentially attributable to autonomous glucocorticoid secretion (eg, recent onset of hypertension, diabetes, obesity, and low bone mass) and have 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 candidates for adrenalectomy.

If adrenalectomy is performed, 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 [54]. Weight loss, improvement in hypertension and/or glycemic control, and normalization of markers of bone turnover are frequently found following unilateral adrenalectomy in patients with subclinical Cushing's syndrome [55-57].

●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 [2,14]. 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) [58]. 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 [59].

5.2 Bilateral adrenal masses — The management of bilateral adrenal masses is different from that for unilateral masses. As an example, in cases of bilateral macronodular adrenal hyperplasia (BMAH) (image 7), size is not an indication for surgery, whereas the degree of cortisol secretory autonomy should guide surgical decision-making. Patients with BMAH and clinical Cushing's syndrome usually are best treated with bilateral adrenalectomy, whereas patients with BMAH and subclinical Cushing's 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's syndrome or subclinical Cushing's syndrome in the setting of solitary bilateral adrenal adenomas [49,50].

5.3 Adrenalectomy — Adrenalectomy for patients with aldosteronomas, pheochromocytoma, cortisol-secreting tumors, and adrenal incidentalomas is safe and effective [60]. 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 [61]. 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 [62,63]. 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 [62,64-67]. (See 'Imaging phenotype' above and 'Adrenalectomy techniques', section on 'Approach by indication'.)

5.4 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 [5]. 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, computed tomography [CT] or magnetic resonance imaging [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 [12]. (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. However, 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) not present at baseline may be detected at follow-up testing [68-70] has led to the recommendation for repeating the baseline DHEAS and the overnight DST annually for four years in cases where initial evaluation is negative [1,69,70]; however, the yield and cost effectiveness of such testing is also unknown [5,12].

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's syndrome' and 'Society guideline links: Adrenal incidentaloma'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, 'The Basics' and 'Beyond the Basics.' The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on 'patient info' and the keyword(s) of interest.)

●Basics topic (see 'Patient education: Adrenal cancer (The Basics)')

SUMMARY AND RECOMMENDATIONS 

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 computed tomography (CT) and magnetic resonance imaging (MRI).

All patients with adrenal incidentalomas should be evaluated for the possibility of malignancy and subclinical hormonal hyperfunction:

●A homogeneous adrenal mass <4 cm in diameter, with a smooth border, and an attenuation value <10 Hounsfield unit (HU) on unenhanced CT, and rapid contrast medium washout (eg, >50 percent at 10 minutes) is very likely to be a benign cortical adenoma. (See 'CT scan' above.)

●The imaging characteristics that suggest adrenal carcinoma or metastases include: irregular shape, inhomogeneous density, high unenhanced CT attenuation values (>20 HU), delayed contrast medium washout (eg, <50 percent at 10 minutes), diameter >4 cm, and tumor calcification. Other characteristics are described above. (See 'Adrenocortical carcinoma' above.)

●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's 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's syndrome' above.)

●If the adrenal incidentaloma patient is hypertensive or is hypokalemic, a plasma aldosterone and plasma renin activity should be obtained to screen for primary aldosteronism. (See 'Aldosteronomas' above.)

●We recommend surgery for all patients with biochemical documentation of pheochromocytoma. The preoperative management and surgical approach of patients with pheochromocytoma is reviewed elsewhere. (See 'Treatment of pheochromocytoma in adults'.)

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

●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.)

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

●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.)

●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.)

●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.)

●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.)

●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) not present at baseline may be detected at follow-up testing. (See 'Monitoring when surgery not performed' above.)

DISCLOSURE — 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.

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Norman M Kaplan, MD, who contributed to earlier versions of this topic review.

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