Management of adrenal incidentalomas: European society of endocrinology clinical practice guideline in collaboration with the European network for the study of adrenal tumors
Open accessAbstract
By definition, an adrenal incidentaloma is an asymptomatic adrenal mass detected on imaging not performed for suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas, but may also represent conditions requiring therapeutic intervention (e.g. adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastasis). The purpose of this guideline is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with adrenal incidentalomas based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions crucial for the management of adrenal incidentaloma patients, addressing these four with systematic literature searches: (A) How to assess risk of malignancy?; (B) How to define and manage low-level autonomous cortisol secretion, formerly called ‘subclinical’ Cushing’s syndrome?; (C) Who should have surgical treatment and how should it be performed?; (D) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? Selected recommendations: (i) At the time of initial detection of an adrenal mass establishing whether the mass is benign or malignant is an important aim to avoid cumbersome and expensive follow-up imaging in those with benign disease. (ii) To exclude cortisol excess, a 1mg overnight dexamethasone suppression test should be performed (applying a cut-off value of serum cortisol ≤50nmol/L (1.8µg/dL)). (iii) For patients without clinical signs of overt Cushing’s syndrome but serum cortisol levels post 1mg dexamethasone >138nmol/L (>5µg/dL), we propose the term ‘autonomous cortisol secretion’. (iv) All patients with ‘(possible) autonomous cortisol’ secretion should be screened for hypertension and type 2 diabetes mellitus, to ensure these are appropriately treated. (v) Surgical treatment should be considered in an individualized approach in patients with ‘autonomous cortisol secretion’ who also have comorbidities that are potentially related to cortisol excess. (vi) In principle, the appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health and patient preference. (vii) Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. Furthermore, we offer recommendations for the follow-up of patients with adrenal incidentaloma who do not undergo adrenal surgery, for those with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses and for young and elderly patients with adrenal incidentalomas
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Most studies have found that late-night salivary cortisol (LNSC), regardless of assay method, has poor sensitivity in patients with mild cortisol excess (formerly subclinical Cushing syndrome).
“most studies have found that LNSC (regardless of assay method) has a poor sensitivity in patients with mild cortisol excess (formerly known as subclinical CS) [20, 56, 62-76]”
From Prospective Evaluation of Late-Night Salivary Cortisol and Cortisone by EIA and LC-MS/MS in Suspected Cushing Syndrome (2020) · cites this paper as [64]
The Reasoning section says that a few studies suggest poor performance of late-night salivary cortisol in patients with adrenal incidentalomas. It does not say that most studies found poor sensitivity, or that the finding holds regardless of assay method; a response to comment #28 describes the data as conflicting. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDiagnosing CS and ACS in patients with adrenal incidentaloma remains a challenge, partly due to a lack of biochemical tests with high diagnostic accuracy.
“Diagnosing Cushing’s syndrome (CS) and autonomous cortisol secretion (ACS) in patients with adrenal incidentaloma remains a challenge, partly due to a lack of biochemical tests with high diagnostic accuracy (1, 2).”
From The diagnostic value of salivary cortisol and salivary cortisone in patients with suspected hypercortisolism (2022) · cites this paper as [1]
In general, p-cortisol following DST <50 nmol/L was considered to exclude hypercortisolism.
“In general, p-cortisol following DST <50 nmol/L was considered to exclude hypercortisolism, while values >138 nmol/L were considered to be highly suggestive for hypercortisolism (1, 2).”
From The diagnostic value of salivary cortisol and salivary cortisone in patients with suspected hypercortisolism (2022) · cites this paper as [1]
For patients with adrenal incidentaloma, DST is the most commonly recommended first-line screening test for ACS.
“For patients with adrenal incidentaloma, DST is the most commonly recommended first-line screening test for ACS (1–5).”
From The diagnostic value of salivary cortisol and salivary cortisone in patients with suspected hypercortisolism (2022) · cites this paper as [1]
In general, p-cortisol following DST >138 nmol/L was considered highly suggestive for hypercortisolism.
“In general, p-cortisol following DST <50 nmol/L was considered to exclude hypercortisolism, while values >138 nmol/L were considered to be highly suggestive for hypercortisolism (1, 2).”
From The diagnostic value of salivary cortisol and salivary cortisone in patients with suspected hypercortisolism (2022) · cites this paper as [1]
There is no international consensus on how ACS in patients with adrenal incidentalomas should be diagnosed, and different recommendations have been provided.
“Currently, there is no international consensus on how ACS in patients with adrenal incidentalomas should be diagnosed, and different recommendations have been provided (1–5, 21–23).”
From The diagnostic value of salivary cortisol and salivary cortisone in patients with suspected hypercortisolism (2022) · cites this paper as [1]
There has been an increase in knowledge concerning the natural history of untreated adrenal lesions, and recent development of international evidence-based management guidelines reflect this.
“There has also been an increase in our knowledge concerning the natural history of untreated adrenal lesions and the recent development of international evidence-based management guidelines reflect this (4,6).”
From Adrenal incidentaloma (2020) · cites this paper as [4]
Adrenalectomy improves cardiovascular outcome and mortality in ACS patients.
“A recent systematic review addressed cardiovascular benefit in ACS patients (247) with adrenalectomy improving cardiovascular outcome and mortality (4,247).”
From Adrenal incidentaloma (2020) · cites this paper as [4]
Both adrenocortical cancers and metastases usually demonstrate rapid growth over months, in contrast to a benign adenoma.
“Both adrenocortical cancers and metastases usually demonstrate rapid growth over months, in contrast to a benign adenoma.”
From Adrenal incidentaloma (2020) · cites this paper as [4]
Adrenocortical carcinoma is a rare but aggressive malignancy that accounts for 2% to 11% of adrenal tumors.
“ACC is a rare but aggressive malignancy, which accounts for 2% to 11% of adrenal tumors (185).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [185]
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Cohort study of patients with adrenal lesions discovered incidentally
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“An adrenal incidentaloma (AI) is defined as a clinically unapparent adrenal mass greater than 1 cm in diameter detected during imaging performed for reasons other than for suspected adrenal disease (4).”
BackgroundMethodInfluentialSteroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism
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Self-citationApproach to the Patient With Adrenal Incidentaloma
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Clinical guidelines for the management of adrenal incidentaloma
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Self-citationCT characteristics of pheochromocytoma: relevance for the evaluation of adrenal incidentaloma
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Diagnosis of Cushing’s Syndrome in the Modern Era
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Plasma steroid metabolome profiling for the diagnosis of adrenocortical carcinoma
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Self-citationUnenhanced CT imaging is highly sensitive to exclude pheochromocytoma: a multicenter study
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Adrenocortical hyperplasia: A multifaceted disease
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Modern management of mild autonomous cortisol secretion
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The lateralizing asymmetry of adrenal adenomas
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Self-citationDaily salivary cortisol and cortisone rhythm in patients with adrenal incidentaloma
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Diagnostic testing of autonomous cortisol secretion in adrenal incidentalomas
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“This is not surprising, since most studies have found that LNSC (regardless of assay method) has a poor sensitivity in patients with mild cortisol excess (formerly known as subclinical CS) [20, 56, 62-76].”
BackgroundZhang, C. D., Li, D., Singh, S., Suresh, M., Thangamuthu, K., Nathani, R., Achenbach, S. J., Atkinson, E. J., Van Gompel, J. J., Young, W. F., et al. (2023) · European Journal of Endocrinology · doi:10.1093/ejendo/lvad073 · Cited by 29 · see citing works
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“Whereas the most recent clinical guidelines regarding diagnosis of hypercortisolism in patients with adrenal incidentalomas, from 2016, suggest that patients undergo screening with the ODST [8], a recent study of 57 centers from 26 European countries found that testing protocols varied considerably across practices [5…”
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Primary aldosteronism in patients with adrenal incidentaloma: is screening appropriate for everyone?
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Association between thyroid function and serum cortisol in cortisol-producing adenoma patients
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Goh, Z., Phillips, I., Hunt, P. J., Soule, S., & Cawood, T. J. (2020) · Internal Medicine Journal · doi:10.1111/imj.14332 · Cited by 14 · see citing works
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Adrenopause – does it really exist?
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- Authors
- Fassnacht, M., Arlt, W., Bancos, I., Dralle, H., Newell-Price, J., Sahdev, A., Tabarin, A., Terzolo, M., Tsagarakis, S., & Dekkers, O. M.
- Affiliations
- University of Würzburg (DE)
- University of Birmingham (GB)
- Mayo Clinic (US)
- Martin Luther University Halle-Wittenberg (DE)
- Royal Hallamshire Hospital (GB)
- St Bartholomew's Hospital (GB)
- Inserm (FR)
- University of Turin (IT)
- Evangelismos Hospital (GR)
- Aarhus University (DK)
- Corresponding author
- Fassnacht, Martin
- ORCID
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-08
- Volume
- 175
- Issue
- 2
- Pages
- G1-G34
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- OpenAlex
- W2469640494
- Cited by
- 1,566
- References
- 228
- Citations by year
- 2026: 69 · 2025: 116 · 2024: 126 · 2023: 199 · 2022: 265 · 2021: 209 · 2020: 190 · 2019: 137 · 2018: 139 · 2017: 94 · 2016: 17 · 2015: 2
- FWCI
- 142.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- European Journal of Endocrinology (publishedVersion, other-oa)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (publishedVersion, other-oa)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Scopus (Elsevier) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- European Society of Endocrinology
- Cancer Research UK (15622)
- European Science Foundation
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- adrenal incidentaloma, adrenal adenoma, adrenocortical carcinoma, pheochromocytoma, autonomous cortisol secretion, subclinical Cushing's syndrome, dexamethasone suppression test, cancer risk, adrenalectomy, follow-up imaging, hypertension, type 2 diabetes, adrenal metastasis
- MeSH terms
- Adrenal Gland Neoplasms, Humans, Hydrocortisone, Incidental Findings
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