Management of Adrenal Incidentalomas

Publication Date: June 15, 2023
Last Updated: August 2, 2023

General remarks

R.1.1

We recommend that patients with adrenal incidentalomas are discussed in a multidisciplinary expert team meeting, if at least one of the following criteria is met:
  • Imaging is not consistent with a benign lesion.
  • There is evidence of hormone excess (including mild autonomous cortisol secretion [MACS] in patients with clinically relevant comorbidities potentially attributable to cortisol).
  • Adrenal surgery is considered.
  • Evidence of significant tumor growth during follow-up imaging.
The core multidisciplinary team should consist of a radiologist, an endocrinologist, and a surgeon, all with significant experience in the management of adrenal tumors. (, )
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Assessment of the risk of malignancy

R.2.1

We recommend aiming to establish with the highest possible certainty if an adrenal mass is benign or malignant at the time of initial detection. (, )
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R.2.2

We recommend that all adrenal incidentalomas undergo an imaging procedure to determine if the mass is homogeneous and lipid-rich and therefore benign. (Moderate, 1 – Strong recommendation)
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For this purpose, we recommend the use of noncontrast CT as the first imaging modality if not yet performed. (Moderate, 1 – Strong recommendation)
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R.2.3

We recommend that if the noncontrast CT is consistent with a benign adrenal mass (homogenous appearance and Hounsfield units [HU] ≤ 10), no further imaging is required. (Moderate, 1 – Strong recommendation)
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R.2.4

If CT demonstrates a homogeneous adrenal mass with unenhanced HU between 11 and 20 and a tumor size < 4 cm, and the results of the hormonal work-up do not indicate significant hormone excess, we suggest an immediate additional imaging to avoid any follow-up imaging. (Very Low, 2 – Conditional recommendation)
Alternatively, interval imaging in 12 months by noncontrast CT (or MRI) could be performed.
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R.2.5

If the adrenal mass is ≥4 cm and heterogeneous or has unenhanced HU > 20, there is a relevant risk that this lesion is malignant. Therefore, we suggest discussing such cases in a multidisciplinary team meeting. In most cases, immediate surgery will be the management of choice, but in some patients, additional imaging might be an option. (Very Low, 2 – Conditional recommendation)
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Prior to surgery, we suggest completely staging the patient (including at least thoracic CT and/or FDG-PET/CT. (Very Low, 2 – Conditional recommendation)
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If surgery is not performed, follow up imaging in 6-12 months is recommended. (Very Low, 1 – Strong recommendation)
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R.2.6

In adrenal masses that do not fall in one of the categories above (eg, tumor size ≥ 4 cm with unenhanced HU 11-20; or tumor size < 4 cm with unenhanced HU > 20; or tumor size < 4 cm with heterogeneous appearance), we suggest an individualized approach with discussion in a multidisciplinary team meeting. (Very Low, 2 – Conditional recommendation)
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The likelihood of a malignant tumor is still low. Therefore, in most cases, immediate additional imaging according to the center expertise and availability is the preferred option. If the tumor is still judged as indeterminate mass and surgery is not performed, we recommend interval imaging in 6-12 months (noncontrast CT/MRI). (Very Low, 1 – Strong recommendation)
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R.2.7

We recommend against the use of an adrenal biopsy in the diagnostic work-up of patients with adrenal masses unless there is a history of extra-adrenal malignancy (see R.6.3.5). (, )
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R.2.8

We suggest measurement of sex steroids and precursors of steroidogenesis (ideally using multisteroid profiling by tandem mass spectrometry) in patients in whom by imaging or clinical features an adrenocortical carcinoma is suspected. (Low, 2 – Conditional recommendation)
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Figure 1. Diagnostic performance of unenhanced CT in adrenal incidentaloma

Figure 2. Diagnostic performance of FDG-PET/CT in adrenal incidentaloma

Figure 3. Morbidity in patients with mild autonomous cortisol secretion (MACS)

Assessment for hormone excess

R.3.1

We recommend that every patient with an adrenal incidentaloma should undergo careful assessment including clinical examination for symptoms and signs of adrenal hormone excess. (, )
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R.3.2

We recommend that patients with adrenal incidentalomas undergo a 1-mg overnight dexamethasone suppression test to exclude autonomous cortisol secretion. (Moderate, 1 – Strong recommendation)
In frail patients with limited life expectancy, this test may not be warranted.
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R.3.3

We recommend interpretation of the results of the 1-mg overnight dexamethasone test as a continuous rather than categorical (yes/no) variable. (Very Low, 1 – Strong recommendation)
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However, we recommend using serum cortisol levels post dexamethasone ≤50 nmol/L (≤1.8 µg/dL) as a diagnostic criterion for the exclusion of autonomous cortisol secretion. (Low, 1 – Strong recommendation)
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R.3.4

We recommend that in patients without signs and symptoms of overt Cushing's syndrome a postdexamethasone serum cortisol concentration above 50 nmol/L (> 1.8 µg/dL) should be considered as MACS without any further stratification based on the degree of cortisol nonsuppressibility. (Low, 1 – Strong recommendation)
In these patients, we recommend that ACTH-independency should be confirmed. Conditions that alter the results of the 1 mg DST should be considered for the interpretation of the results of the test. A repeat DST to confirm cortisol secretory autonomy is recommended. Additional biochemical tests to assess the degree of cortisol secretion might be useful. However, for clinical management the presence of comorbidities potentially attributable to cortisol excess, age, and the general condition of the patient are major factors for clinical decision-making.
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R.3.5

We recommend against considering patients with MACS (per definition without specific clinical signs of Cushing's syndrome) as being at high risk for development of overt Cushing's syndrome. (Moderate, 1 – Strong recommendation)
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R.3.6

We recommend screening patients with adrenal incidentaloma and MACS for hypertension and type 2 diabetes mellitus and suggest offering appropriate treatment of these conditions. (Low, 1 – Strong recommendation)
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R.3.7

We suggest screening patients with adrenal incidentaloma and MACS for vertebral fractures. (Very Low, 2 – Conditional recommendation)
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and we suggest to consider appropriate treatment of these conditions. (Very Low, 2 – Conditional recommendation)
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R.3.8

We recommend discussing the option of surgery with the patient who has MACS in addition to relevant comorbidities and a unilateral adrenal mass. (Very Low, 1 – Strong recommendation)
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Age, sex, general health, degree and persistence of nonsuppressible cortisol after dexamethasone, severity of comorbidities, and patient's preference should be taken into account. (Very Low, 1 – Strong recommendation)
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In all cases, the proposal to perform surgery should be established within an expert multidisciplinary group.

R.3.9

We recommend excluding pheochromocytoma by measurement of plasma free metanephrines or urinary fractionated metanephrines in all patients with adrenal lesions with features not typical for a benign adenoma. (, 1 – Strong recommendation)
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R.3.10

In patients with concomitant hypertension or unexplained hypokalemia, we recommend use of the aldosterone/renin ratio to evaluate primary aldosteronism. (, 1 – Strong recommendation)
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Surgical treatment

R.4.1

We recommend adrenalectomy as the standard of care for unilateral adrenal tumors with clinically significant hormone excess. In patients with MACS, surgery can be considered in patients with relevant co-morbidities, taking into account individual factors (detailed in R.3.8). (, )
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R.4.2

We recommend against performing surgery in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. (Low, 1 – Strong recommendation)
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R.4.3 

If surgery is indicated for a benign adrenal mass causing hormone excess (including MACS), we recommend that a minimally invasive approach is used. (Very Low, 1 – Strong recommendation)
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R.4.4 

We suggest that minimally invasive adrenalectomy is performed by an expert high-volume adrenal surgeon in patients with unilateral adrenal masses with radiological findings suspicious of malignancy (R2.4-6) and a diameter ≤6 cm, but without evidence of local invasion. (Very Low, 2 – Conditional recommendation)
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R.4.5 

We recommend open adrenalectomy is performed by an expert high-volume adrenal surgeon for unilateral adrenal masses with radiological findings suspicious of malignancy and signs of local invasion. (Very Low, 1 – Strong recommendation)
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R.4.6

We recommend discussion of an individualized surgical approach by an expert high-volume adrenal surgeon in patients that do not fall in one of the above-mentioned categories in a multidisciplinary expert team meeting. (Very Low, 1 – Strong recommendation)
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R.4.7

We recommend perioperative glucocorticoid treatment at surgical stress doses in all patients undergoing surgery and a preoperative morning serum cortisol >50 nmol/L (1.8 µ/dL) after a 1 mg overnight dexamethasone test. (, )
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R.4.8

We suggest that patients with MACS (similarly to patients with adrenal Cushing's syndrome) that underwent surgery should be followed by an endocrinologist until recovery of hypothalamic-pituitary-adrenal axis function has been documented. (, )
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Follow-up of patients not undergoing adrenal surgery after initial assessment

R.5.1

We recommend against further imaging during follow-up in patients with an adrenal lesion with clear benign features on imaging studies. (Moderate, 1 – Strong recommendation)
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R.5.2

In patients with an indeterminate adrenal mass (by imaging), opting not to undergo adrenalectomy following initial assessment, we suggest one repeat noncontrast CT or MRI after 6-12 months to exclude significant growth. (Very Low, 2 – Conditional recommendation)
We suggest surgical resection if the lesion enlarges by more than 20% in maximum diameter (in addition to at least a 5 mm increase in maximum diameter) during this period. If there is growth of the lesion below this threshold, additional imaging again after 6-12 months might be considered.
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R.5.3 

We recommend against repeated hormonal work-up in patients with hormonal work-up results within the reference range at initial evaluation unless new clinical signs of endocrine activity appear or there is worsening of comorbidities (eg, hypertension, type 2 diabetes). (Low, 1 – Strong recommendation)
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R.5.4

In patients with MACS, who do not undergo an adrenalectomy, we recommend only annual reassessment of comorbidities potentially attributable to cortisol. (Low, 1 – Strong recommendation)
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For this purpose, we suggest that discharge from specialized endocrine follow-up be considered and that monitoring of comorbidities potentially attributable to cortisol could be undertaken by primary health care providers, if adequate surveillance for comorbidities is available in the community. (Very Low, 2 – Conditional recommendation)
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If these comorbidities develop or worsen, referral to an endocrinologist is suggested to reassess the endocrine status and reconsider the potential benefit of intervention.

Special circumstances

Patients with bilateral adrenal incidentalomas

R.6.1.1 

We recommend that for patients with bilateral or multiple adrenal masses each adrenal lesion is assessed individually at the time of initial detection according to the same imaging protocol as for unilateral adrenal masses to establish whether each nodule is benign or malignant. (, )
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R.6.1.2

We recommend that all patients with bilateral adrenal incidentalomas should undergo clinical and hormonal assessment identical to that in patients with unilateral adrenal incidentaloma. (, )
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R.6.1.3 

We suggest approaching bilateral disease according to the following 4-option schema based on the results of the imaging and hormonal work-up (1) bilateral (macronodular) hyperplasia, (2) bilateral adrenal adenomas, (3) 2 morphologically similar, but nonadenoma-like adrenal masses, and (4) 2 morphologically different adrenal masses. In patients who do not fall in one of these categories, an individualized management plan is needed. (, )
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R.6.1.4 

For patients with bilateral hyperplasia without autonomous cortisol secretion, we suggest measuring 17-hydroxyprogesterone to exclude congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. (, )
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R.6.1.5 

For patients with bilateral (macronodular) hyperplasia or bilateral adenomas, we recommend assessment of comorbidities that are potentially attributable to MACS. (, )
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R.6.1.6 

In patients with bilateral metastases, lymphoma, infiltrative inflammatory disease, and hemorrhages, we recommend assessment for adrenal insufficiency. (, )
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R.6.1.7 

In patients with bilateral hyperplasia or bilateral adenomas and MACS, we suggest individualization of specific treatment options based on age, sex, degree of cortisol autonomy, general condition, comorbidities, and patient preference. (, )
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R.6.1.8

We suggest against bilateral adrenalectomy in patients without clinical signs of overt Cushing's syndrome. (, )
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Adrenal incidentalomas in young or elderly patients

R.6.2.1 

We recommend urgent assessment of an adrenal mass in pregnant women and individuals <40 years of age because of a higher likelihood of malignancy as well as and clinically significant hormone excess. (, )
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R.6.2.2

We suggest the use of MRI rather than CT in children, adolescents, and pregnant women if dedicated adrenal imaging is required. (, )
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R.6.2.3

We suggest surgical resection if an adrenal mass is indeterminate on imaging in children, adolescents, pregnant women, and adults < 40 years of age. (, )
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R.6.2.4 

We recommend that investigation and management of patients with poor general health and a high degree of frailty be kept in proportion to potential clinical gain. (, )
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Patients with newly diagnosed adrenal mass and a history of extra-adrenal malignancy

R.6.3.1

We recommend measurement of plasma or urinary metanephrines to exclude pheochromocytoma in patients with extra-adrenal malignancy with an indeterminate mass, even if the adrenal mass is likely to be a metastasis. We suggest additional hormonal work-up based on an individualized approach. (, )
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R.6.3.2

We recommend that in patients with a history of extra-adrenal malignancy, adrenal lesions characterized as benign by noncontrast CT require no further specific adrenal imaging follow-up. (, )
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R.6.3.3

In patients with a history of extra-adrenal malignancy, strong FDG uptake in the adrenal gland(s) on PET-CT is suggestive of metastasis. In case of moderate or no FDG uptake, further work-up with at least unenhanced CT is recommended. (, )
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R.6.3.4

For indeterminate lesions in patients with a history of extra-adrenal malignancy, in whom the clinical management will be altered by the demonstration that the adrenal lesion is malignant, we suggest performing either an FDG-PET/CT (if not done already), surgical resection, or a biopsy (see also R.6.3.5). In all other patients, we recommend imaging follow-up at the same interval as imaging for the primary malignancy. (, )
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R.6.3.5

We recommend that 3 key criteria be fulfilled before adrenal biopsy is considered: (1) the lesion is hormonally inactive (in particular, a pheochromocytoma has been excluded), (2) the lesion has not been conclusively characterized as benign by imaging, and (3) clinical management of the patient would be altered by knowledge of the histology. (, )
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R.6.3.6 

We recommend assessment of residual adrenal function in patients with large bilateral metastases. (, )
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Recommendation Grading

Disclaimer

The information in this patient summary should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.

Overview

Title

Management of Adrenal Incidentalomas

Authoring Organization

European Society of Endocrinology

Publication Month/Year

June 15, 2023

Last Updated Month/Year

April 1, 2024

Supplemental Implementation Tools

Document Type

Guideline

Country of Publication

European

Document Objectives

Adrenal incidentalomas are adrenal masses detected on imaging performed for reasons other than suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas but may also require therapeutic intervention including that for adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma, or metastases. Here, we provide a revision of the first international, interdisciplinary guidelines on incidentalomas. We followed the Grading of Recommendations Assessment, Development and Evaluation system and updated systematic reviews on 4 predefined clinical questions crucial for the management of incidentalomas: (1) How to assess risk of malignancy?; (2) How to define and manage mild autonomous cortisol secretion?; (3) Who should have surgical treatment and how should it be performed?; and (4) What follow-up is indicated if the adrenal incidentaloma is not surgically removed?

Inclusion Criteria

Male, Female, Adolescent, Adult, Child, Older adult

Health Care Settings

Ambulatory, Outpatient, Operating and recovery room

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Diagnosis, Assessment and screening, Treatment, Management

Keywords

Adrenal Incidentalomas

Source Citation

Martin Fassnacht and others, European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors, European Journal of Endocrinology, Volume 189, Issue 1, July 2023, Pages G1–G42, https://doi.org/10.1093/ejendo/lvad066