Incidentally discovered adrenal masses are becoming more common in clinical practice.
To review the management of the incidental adrenal mass, including initial evaluation, surveillance, medical therapy, and surgical therapy.
A literature search of English-language publications that included the keywords adrenal incidentaloma and incidental adrenal mass was performed through July 2015 using PubMed. Relevant original articles and guidelines on the management of the incidental adrenal mass were ultimately selected for analysis, with the consensus of all authors.
Data from the manuscripts included in this review were synthesized, and findings were categorized into metabolic evaluation, imaging, biopsy, surgical considerations, and follow-up recommendations.
Ideally, management of patients with adrenal incidentalomas should involve a multidisciplinary approach with experienced surgeons, radiologists, and endocrinologists to determine whether such lesions are benign or malignant and functional or nonfunctional and/or whether they require surgical resection.
Management of patients with adrenal incidentalomas should involve a multidisciplinary approach with surgeons, radiologists, and endocrinologists to determine whether such lesions are benign or malignant and functional or nonfunctional and/or whether they require surgical resection.
Keywords: Adrenal mass, Adrenal incidentaloma, Adenoma, Carcinoma.
Adrenal incidentalomas (AIs) are defined as asymptomatic masses >1 cm in diameter discovered on cross-sectional imaging studies performed for reasons unrelated to adrenal disease . The increasing use of radiologic investigations including abdominal ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) has led to an increase in the detection of such incidental adrenal lesions. The prevalence of AIs is approximately 2% on autopsies and increases with age (<1% in patients aged <30 yr and as high as 5% in those aged ≥70 yr) . More recent large contemporary imaging series reported the incidence of AIs to be as high as 4–5% in patients without prior history of malignancy .
The majority of incidentally detected adrenal lesions are benign and nonfunctional (nonsecreting) adrenal adenomas. Table 1 summarizes the differential diagnosis associated with AIs. There is remarkable variation in the reported risk of adrenocortical carcinoma in AIs. In patients with no prior history of malignancy, it is less likely for incidental adrenal masses to harbor malignant disease. In one of the largest published series of AIs detected on CT imaging involving 1049 patients with no prior history of cancer, no malignant lesions were reported . However, in patients with oncologic disease, adrenal metastases may occur in approximately 50% of incidentally detected adrenal masses . Other reports that included surgical series estimated the risk of adrenocortical carcinoma to be approximately 2% in AIs <4 cm and 25% in AIs >6 cm .
|Differential diagnosis||Biochemical abnormality||Primary screening test||Other confirmatory tests||Circumstances leading to false positives|
|Adrenal adenoma||Nonfunctional||Unenhanced CT <10-HU attenuation, <4 cm||See algorithm (Fig. 1)||Lipid poor adrenal adenomas|
|Cushing's syndrome||Hypercortisolism (secondary to excessive production by the adrenal gland)||Low-dose (1 mg) overnight dexamethasone test: failure to suppress endogenous cortisol: >1.8 μg/dl||Serum cortisol, 24-h urinary free cortisol,* late-night salivary cortisol*||Anticonvulsants, exogenous glucocorticoid use|
|Pheochromocytoma||Hypercatecholaminemia||24-h urinary fractionated metanephrines or plasma free metanephrines||Metaiodobenzylguanidine scintigraphy||Stop acetaminophen 5 d prior to urinary catecholamine testing; stop tricyclic antidepressants, phenoxybenzamine|
|Primary hyperaldosteronism||Elevated plasma aldosterone concentration and suppressed plasma renin activity||Rule out and correct hypokalemia; ratio of morning serum aldosterone (ng/dl) to renin activity (ng/ml/h) >20 and serum aldosterone >15 ng/ml||1. Normal saline infusion test|
2. Oral sodium loading test
3. Fludrocortisone suppression test
4. Captopril suppression test
|Stop potassium-sparing diuretics, mineralocorticoid receptor blockers/spironolactone, beta blockers 6 wk prior to screening|
|Adrenocortical carcinoma||Functional (as above) or nonfunctional||CT/MRI: incidentaloma (≥4 or <4 cm)||See algorithm (Fig. 1)||–|
|Metastatic disease||–||Biopsy, PET-CT||–||–|
* Repeat testing recommended.
CT = computed tomography; HU = Hounsfield units; PET = positron emission tomography.
This nonstructured review outlines the initial metabolic and radiologic work-up required for the accurate diagnosis of an AI and the evidence supporting recommendations for managing such patients conservatively or with surgical resection. With the increasing use of minimally invasive surgery, we reviewed the evidence comparing minimally invasive and open surgery for patients undergoing adrenalectomy for AIs. Last, we reviewed recommendations for appropriate follow-up for patients on surveillance.
2. Evidence acquisition
A literature search of English-language publications that included the keywords adrenal incidentaloma and incidental adrenal mass was performed through July 2015 using PubMed. Relevant original articles and guidelines on the management of the incidental adrenal mass were ultimately selected for analysis, with the consensus of all authors.
3. Evidence synthesis
3.1. Metabolic evaluation of the incidental adrenal mass
Although several guidelines exist, to date, there is no prospective validation of the suggested investigation of AIs  and . The ultimate goals in evaluation are to determine if such lesions are benign or malignant and metabolically active/functional or nonfunctional. The National Institutes of Health (NIH) consensus statement recommends metabolic work-up for all incidentally diagnosed adrenal masses, as >10% of such lesions are potentially functional . Despite the 2002 NIH guidelines, in clinical practice, up to 80% of patients are inappropriately underinvestigated and do not receive recommended endocrinology referral .
Starting with history and physical examination, symptoms and signs of adrenal hyperfunction and malignancy should be elucidated, followed by metabolic evaluation and radiologic imaging. The most frequent forms of adrenal hypersecretion include hormones derived from the adrenal cortex (cortisol, aldosterone, or androgens) or the adrenal medulla (catecholamines) . In general, all newly diagnosed AIs should be tested for cortisol and catecholamine hypersecretion and, occasionally, androgens. Furthermore, hypertensive or hypokalemic patients should also have plasma aldosterone concentration and plasma renin activity measurement.
3.1.1. Cushing's syndrome
Cushing's syndrome, also known as hypercortisolism, is a constellation of signs and symptoms associated with excessive glucocorticosteroid activity. These signs and symptoms are mostly nonspecific, but some are more suggestive of Cushing's syndrome. These patients often have classic features related to the effects of glucocorticosteroids on adipose tissue and musculoskeletal tissues (rounding of the face with plethora [moon facies], dorsocervical and supraclavicular fat pads, central obesity with thinning of the extremities, proximal muscle weakness, easy bruising, acne, and purple striae). New-onset hypertension or worsening blood pressure control can be observed in these patients. On laboratory testing, these patients may have hyperglycemia, hypokalemia, alkalosis, and leukocytosis (with increased percentage of neutrophils, lymphopenia, and eosinopenia).
Cushing's syndrome is often caused by exogenous use of glucocorticosteroids, and a minority of patients have endogenous cortisol production. Patients with endogenous Cushing's syndrome can be divided into adrenocorticotropic hormone (ACTH)–dependent Cushing's syndrome (ACTH-producing pituitary adenoma, ectopic ACTH production, and rarely ectopic corticotropin-releasing hormone production) or ACTH-independent Cushing's syndrome associated with adrenal tumors. In these patients with overt cortisol overproduction, ACTH is usually very low or near the lower end of normal reference range (usually <10 pg/ml), with evidence of hypercortisolism (elevated 24-h urinary free cortisol, elevated late-night salivary cortisol, or failure of 1 mg overnight dexamethasone suppression test). Some patients with AIs have no typical features to suggest Cushing's syndrome, but they have subtle laboratory abnormities to point to a mild case of autonomous cortisol production. The term subclinical Cushing's syndrome (SCS) was first introduced in 1981 to describe patients with AIs and autonomously producing glucocorticoids with no obvious signs of overt Cushing's syndrome . SCS can be seen in 5–8% patients with AIs . Despite the term subclinical, these patients are still are at risk due to continuous excess cortisol exposure, including hypertension, diabetes mellitus, osteoporosis, and obesity. As the majority of patients do not have overt Cushing's syndrome, 24-h urinary cortisol levels are often normal and are not sufficient for diagnosis. Autonomous cortisol hypersecretion is best assessed initially with an overnight dexamethasone (1 mg) suppression test. A patient's failure to suppress cortisol levels (<1.8 μg/dl) following low-dose dexamethasone administration (1 mg overnight dexamethasone suppression test) is indicative of Cushing's syndrome and has sensitivity >90%. If positive, further confirmatory tests are required to rule out a false-positive rate of approximately 10% . Other tests include the late-night salivary cortisol test and ACTH measurement .
Because adrenocortical carcinoma can present with mixed cortisol and adrenal androgen overproduction, careful assessment is warranted to exclude adrenocortical carcinoma. Most cortisol-producing adrenal adenomas are associated with excessive cortisol and low adrenal androgens (dehydroepiandrosterone sulfate).
Approximately 5% of all AIs are pheochromocytomas, and up to 50% of these may be clinically silent (ie, normotensive), hence biochemical assessment is warranted for all patients. First-line investigations for pheochromocytomas should include either plasma free metanephrine/normetanephrine or 24-h urine fractionated metanephrines . By itself, testing for plasma free metanephrine is associated with lower specificity (85–90%) , especially in older patients, and has higher false-positive rates if patients are taking acetaminophen, tricyclic antidepressants, or phenoxybenzamine; therefore, these medications should be withheld 5 d prior to testing . Two reviews recently addressed the topics of pheochromocytoma and metabolically active urologic tumors and included details on optimal perioperative management strategies  and .
3.1.3. Primary aldosteronism
Approximately ≤1% of AIs are aldosterone-hypersecreting tumors that clinically present as Conn's syndrome, in which patients may present with hypertension. Nearly 5% of patients with new-onset hypertension may have an underlying adrenal mass . Consequently, routing screening for hyperaldosteronism is mainly recommended in hypertensive patients. Historically, low serum potassium levels were the first-line investigation for aldosterone hypersecretion; however, up to 40% of patients exhibit normal or low serum potassium . The more appropriate first-line screening for Conn's syndrome is the ratio of morning plasma aldosterone to renin, for which a ratio of >20 and a concurrent elevated serum aldosterone level (>15 ng/ml) are suggestive of primary hyperaldosteronism and must be followed by confirmatory tests (eg, 24-h urinary aldosterone level while on a high salt diet or 4-h normal saline suppression test with plasma aldosterone measurement) (Table 1).
3.2. Imaging and size of adrenal mass
AIs are most commonly found on abdominal ultrasound, CT, or MRI, with an incidence of approximately 5%. The latter two imaging modalities form the cornerstones for further characterization and evaluation for such adrenal masses. A homogenous mass with smooth borders and attenuation of <10 Hounsfield units (HU) on unenhanced CT is strongly suggestive of a lipid-rich benign adrenal adenoma. The low attenuation on unenhanced CT corresponds to high intracytoplasmic lipid content. Overall, 98% of adrenal lesions with ≤10 HU on noncontrast CT are benign adrenal adenomas; however, attenuation alone is not diagnostic because 15–30% of adrenal adenomas are lipid poor, with ≥10 HU on noncontrast CT, and thus may be interpreted as malignant  and . In such cases, additional imaging with intravenous contrast is required. On delayed contrast-enhanced CT, adrenal adenomas exhibit rapid washout of the intravenous contrast medium. If the absolute washout of contrast is 50% after 10 min or relative washout is 40% after 15 min from administration, this is indicative of adenoma, with sensitivity and specificity of 100%  and .
Similarly, MRI can assess the differences in signal between fat and water to evaluate intracellular lipid content. This is known as chemical shift MRI, which exploits different resonant frequency rates of protons in fat and water. Adrenal adenomas exhibit loss of signal intensity on out-of-phase sequences compared with in-phase imaging, confirming the presence of intra-adrenal fat. In comparison to CT, however, contrast-enhanced MRI with gadolinium washout studies does not appear to exhibit the same diagnostic strength as its CT counterpart. Consequently, CT washout studies remain the gold standard, especially in the evaluation of lipid-poor adenomas  and . Moreover, patients with a previous history of extra-adrenal malignancy should also undergo positron emission tomography–CT with flurodeoxyglucose (FDG) and/or biopsy to rule out metastasis. In general, metastatic lesions tend to have increased FDG uptake because of increased glucose metabolism, whereas benign adenomas do not .
The use of functional imaging such as iodine 131 metaiodobenzylguanidine (MIBG) imaging for the diagnosis for pheochromocytomas is limited, given that most pheochromocytomas can be accurately diagnosed with cross-sectional imaging and metabolic evaluation for catecholamines; however, this modality can be useful for detection of metastatic disease. MIGB is a structural analog of norepinephrine, and increased uptake of MIGB suggests the presence of chromaffin cells found in tumors such as pheochromocytomas. Previous series suggest sensitivities and specificities of 100% and 94%, respectively, in identifying pheochromocytomas with MIGB imaging .
Regardless of the initial imaging modality used for diagnosis of an adrenal mass, size of the mass is one of the most important parameters that helps distinguish malignant and nonmalignant adrenal lesions, in which larger masses are more likely to exhibit adverse clinical and pathologic features. In a large Italian multi-institutional retrospective analysis of 887 patients with AIs, tumor diameter was highly correlated with the risk of malignancy. Adrenal masses with tumor diameter >4 cm were associated with 90% sensitivity in adrenal cortical carcinoma (ACC) detection .
Another review of >1300 patients with AIs showed that the incidence of malignant neoplasms significantly increased for masses >6 cm in diameter and should be considered malignant until proven otherwise, almost always requiring definitive resection . Similarly, increasing size is associated with increasing incidence of adrenal hypersecretion . Consequently, almost all nonfunctioning lesions <4 cm are benign and may be observed in the absence of worrisome radiologic features or clinical suspicion for malignancy based on history. In contrast, the optimal diagnosis for adrenal masses between 4 and 6 cm is not established and remains controversial. If such lesions are hormonally inactive and exhibit benign radiologic appearance, they also may be considered for observation .
Occasionally bilateral adrenal masses are noted, and these should be interpreted and investigated in the context of the whole clinical picture, as they could be related to a neoplastic (malignant or benign), infectious, or immune process .
3.3. The role of biopsy
Histologically, adrenal adenomas cannot always be reliably differentiated from ACC on fine needle aspiration (FNA) or biopsy . FNA and biopsies are usually reserved for patients with known extra-adrenal malignancies when histologic diagnosis will assist in distinguishing between adrenal versus nonadrenal origin of the lesion. Furthermore, biopsy should be considered only after pheochromocytoma has been ruled out, when radiologic investigation has reached its limit, and results of biopsy will ultimately change or influence clinical management. A recent study by Villeli et al.  reported specificity of 88%, sensitivity of 86%, positive predictive value of 97%, and a much lower negative predictive value of 58% for diagnoses using adrenal core biopsy specimens.
Image-guided FNA or biopsy is safe overall, and complication rates are low (<3%) . When indicated, FNA or biopsy should always be carried out after biochemical investigation has excluded pheochromocytomas, which have been reported to lead to life-threatening hypertensive crisis . Other complications include adrenal/abdominal hematoma, infection, pneumothorax, pancreatitis, tumor seeding along the needle track, and hemorrhage  and .
3.4. Indications for surgery and patient selection
Indications for surgery for AIs should consider factors that involve both tumor functionality and radiologic criteria that may suggest malignancy. History and physical examination of patients at presentation will highlight signs and symptoms that reflect glucocorticoid, mineralocorticoid, adrenal sex hormone, or catecholamine excess. If present, these must be confirmed with further biochemical investigations, as outlined (Fig. 1). Surgery should be considered in all patients with functional adrenal cortical tumors. Similarly, all patients with biochemical evidence of pheochromocytomas should undergo adrenal resection.
More than 60% of incidentalomas <4 cm are benign adenomas. Of these, <2% represent ACC and are almost always benign lesions if nonfunctional. In contrast, if the adrenal mass is >6 cm, ACC accounts for >25% cases, of which only ≤15% are benign adenomas . For lesions 4–6 cm, closer follow-up or surgery should be considered, taking into account other imaging parameters including attenuation >10 HU, irregular boarders, or inconclusive percentage of contrast-enhanced washout on CT or MRI. Rapid growth rate in adrenal masses has also been advocated as a potential indicator of malignancy, even though a reliable adrenal mass growth cutoff value is not well established to confirm or exclude a malignant lesion . Furthermore, almost all lesions resected due to increased growth kinetics are benign. In a prospective multi-institutional Swedish study, 29 of 229 patients (12.6%) undergoing surveillance of AIs underwent resection due to an increase in size of adrenal lesions ranging between 5 and 10 mm, all exhibiting benign pathology. Another study reviewing 873 patients with AIs showed that up to 9% of lesions grew at least 1 cm at mean follow-up of 3 yr, with only one lesion proving malignant. The authors concluded that the rate of malignant transformation is approximately 1 in 1000 . Although such reports suggest that growth kinetics in conservatively managed adrenal lesions correlate poorly with malignancy rates, growth rates of ≥1 cm often prompt surgical resection; therefore, change in adrenal mass size should be used in conjunction with other imaging and clinical characteristics when surgical resection is being considered.
Metastases are common in patients with an adrenal mass and a history of malignancy. Work-up of these masses should always exclude the possibility of other adrenal tumors, with proper imaging, serologic testing, and sometimes biopsy. Adrenalectomy can be a viable treatment option for well-selected patients with adrenal metastases. In general, operative intervention is best reserved for patients in whom the adrenal gland is the solitary site or in the presence of oligometastatic disease for which complete resection is feasible. The absence of local invasion into contiguous structures and a disease-free interval >6 mo from the original cancer diagnosis are also suggestive of favorable tumor biology and better survival outcomes after adrenalectomy .
Historically, open adrenalectomy (OA) was considered the standard of care for surgical excision of the majority of adrenal tumors; however, contemporary studies show that minimally invasive laparoscopic adrenalectomy (LA), done with a transperitoneal or retroperitoneal approach, can be offered safely to carefully selected patients. Relative contraindications for LA continue to include tumor size, obesity, and ACC; however, the increasing use of minimally invasive surgery in adrenalectomy reflects the increasing skill sets of surgeons that attain oncologic outcomes similar to open surgery while offering improved postoperative pain levels, decreased morbidity, less or equivalent operative blood loss, shorter hospital stay, and faster recovery .
Despite the obvious advantages of LA, the underlying adrenal pathology is paramount in planning the optimal surgical approach, as it may significantly affect oncologic and survival outcomes for the patient if complete resection is compromised. Most important, cancer control, especially in ACC, is highly dependent on wide local excision with negative margins and meticulous attention to prevent tumor spillage in these friable tumors. ACC tends to be an aggressive disease in which locoregional recurrence can be as high as 60% . Consequently, known adrenal vein or vena caval involvement are still regarded as absolute contraindications to laparoscopic surgery. Furthermore, to obtain an R0 resection of a locally advanced ACC, it is often mandatory to resect adjacent organs such as the wall of the vena cava, liver, spleen, colon, pancreas, and/or stomach, mandating an OA approach  and .
The Society of American Gastrointestinal and Endoscopic Surgeons guidelines for the minimally invasive treatment of adrenal pathology state that large adrenal tumors without pre- or intraoperative evidence of primary ACC can be approached by LA by a skilled laparoscopic surgeon; however, such cases may be associated with longer operating room time, more blood loss, and a higher rate of conversion to open surgery. If any evidence for metastatic carcinoma is found intraoperatively, conversion to an open approach is warranted and should be strongly considered . Of great concern is that previous studies have shown significant differences in recurrence-free and overall survival favoring OA compared with LA in patients with ACC, with significantly higher rates of peritoneal carcinomatosis within the LA group, strongly supporting the oncologic benefits of OA in ACC .
The advent of robotic surgery has rapidly increased in popularity worldwide, including robotic adrenalectomy (RA), which was first described in 2001 . Brunaud et al. reported that RA might be especially useful for patients with high body mass index (BMI; >30) and for large tumors (>5.5 cm)  and . Nevertheless, in a recent systematic review and meta-analysis comparing LA and RA, patients undergoing RA had lower BMI, highlighting a significant selection bias for RA. Furthermore, RA was shown to have no significant difference in operative time or complication rate compared with LA . In the same meta-analysis, although RA had less hospitalization (0.5 d less) and blood loss (25 ml) compared with LA, these differences were not clinically significant. Given the increased cost of RA compared with LA  and the lack of clear patient outcomes with RA, further high-quality evidence is needed before firm recommendations can be provided. Other minimally invasive technical modifications of minimally invasive adrenalectomy include laparoendoscopic single-site surgery and minilaparoscopy.
3.5. Follow-up for the incidental adrenal mass
There is currently no national or international consensus for the follow-up of AIs. The 2003 NIH statement for follow-up for nonresected adrenal masses recommends repeat CT in 6–12 mo. For lesions that do not increase in size, further radiologic evaluation is not supported within the literature. A summary of 21 studies involving >1690 patients with median follow-up ranging from 2 to 7 yr attributed the risk of developing malignancy, hyperfunction, or overt disease to be very low at 0.05%, 1.2%, and 0.9%, respectively. Similarly, in the same review, of the 212 of 1690 lesions (12.5%) that increased in size, only 1 was observed to be malignant .
Furthermore, Cawood and colleagues highlighted that during follow-up, false-positive rates of recommended investigations may be 50 times greater than true-positive rates . The average CT scan for follow-up exposes each patient to 23 mSv of ionizing radiation, which equates to a 1 in 430–2170 chance of causing fatal cancer; this is similar to the chance of developing adrenal malignancy during the 3-yr follow-up of AI .
With regard to abnormal adrenal hypersecretion of glucocorticoids and catecholamines, the observation that autonomous function not present at baseline may be subsequently detected at follow-up testing has led to the recommendation of repeating hormonal testing annually for at least 4 yr , , and . The rationale for annual screening is that development of subtle hypercortisolism may have detrimental effects on cardiovascular risk profile and bone health . In one study, the overall risk of developing additional endocrine abnormalities was 47% at 5 yr. When participants were divided by mass size at diagnosis, the risk of further endocrine changes in the first 2 yr of follow-up was higher in patients with adrenal lesions >3 versus <3 cm . It is important to note in the same study, however, that of the 82% patients that had hormonal irregularities noted at initial diagnosis, none went on to develop subclinical or overt Cushing's syndrome on follow-up.
In conclusion, standardized follow-up protocols or guidelines are controversial, and evidence to date suggests that small radiographically benign lesions (<4 cm) that are functionally inactive do not require further (or require less frequent) investigation. Outside of these parameters, even though radiologic and hormonal follow-up is recommended, the yield and cost-effectiveness of such testing is unknown  and .
AIs are becoming more common due to increased use of body imaging. Ideally, management of patients with AIs should involve a multidisciplinary approach with surgeons, radiologists, and endocrinologists to determine whether such lesions are benign or malignant and functional or nonfunctional and/or whether they require surgical resection.
Author contributions: Jose A. Karam had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Thomas, Karam.
Acquisition of data: Thomas, Blute, Seitz, Habra, Karam.
Analysis and interpretation of data: Thomas, Blute, Seitz, Habra, Karam.
Drafting of the manuscript: Thomas, Karam.
Critical revision of the manuscript for important intellectual content: Thomas, Blute, Seitz, Habra, Karam.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: Karam.
Other (specify): None.
Financial disclosures: Jose A. Karam certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
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a Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
b Department of Urology, Massachusetts General Hospital, Boston, MA, USA
c Department of Urology, Medical University of Vienna, Vienna, Austria
d Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Corresponding author. The University of Texas MD Anderson Cancer Center, Department of Urology, 1515 Holcombe Blvd, Unit 1373, Houston, TX 77030, USA. Tel. +1 713 792 3250; Fax: +1 713 794 4824.
© 2015 European Association of Urology, Published by Elsevier B.V.