EJE
Presentation and management of patients with adrenal masses: a large tertiary centre experience
Onnicha Suntornlohanakul, 1,2(D Sumedha Mandal,3 Pratyusha Saha,3 Emre S. Saygili, 1,4 Miriam Asia,5 Wiebke Arlt, 1,6,7 [D Yasir S. Elhassan, 1,3,5[D Alessandro Prete, 1,3,5,8,+ [D and Cristina L. Ronchi1,3,5,*+ (D
1Department of Metabolism and Systems Science, College of Medicine and Health, University of Birmingham, Birmingham B152TT, United Kingdom
2Endocrinology and Metabolism Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
3Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B152TT, United Kingdom
4Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Canakkale Onsekiz Mart University, Canakkale 17020, Turkey
5Department of Endocrinology, Queen Elizabeth Hospital Birmingham, Birmingham B152GW, United Kingdom 6Medical Research Council Laboratory of Medical Sciences, London W120NN, United Kingdom
7Institute of Clinical Sciences, Imperial College London, London SW72AZ, United Kingdom
8NIHR Birmingham Biomedical Research Centre, University of Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham B152GW, United Kingdom
*Corresponding author: Department of Metabolism and Systems Science, College of Medicine and Health, University of Birmingham, Birmingham B152TT, United Kingdom. Email: c.l.ronchi@bham.ac.uk
Abstract
Background: Adrenal masses are found in up to 5%-7% of adults. The 2016 European guidelines on the management of adrenal incidentalomas have standardised the workup of these patients, but evidence of their impact on clinical practice is lacking.
Methods: Retrospective review of clinical presentation, radiological characteristics, and final diagnosis of a large cohort of patients with adrenal masses referred to a tertiary care centre 1998-2022. Sub-analysis compares outcomes before and after implementing the 2016 guidelines.
Results: A total of 1397 patients (55.7% women; median age 60 years [interquartile range {IQR}, 49-70]) were included. Incidental discovery was the most frequent mode of presentation (63.7%) and 30.6% of patients had masses ≥ 4 cm (median 2.9 cm [IQR, 1.9-4.7]). Unenhanced computed tomography Hounsfield units (HU) were available for 763 patients; of these, 32.9% had heterogeneous masses or >20 HU. The most common diagnoses were adrenocortical adenoma (56.0%), phaeochromocytoma (12.7%), adrenocortical carcinoma (10.6%), and metastases (5.7%). At multivariable analysis, significant predictors of malignancy included >20 HU or heterogeneous density (odds ratio [OR] 28.40), androgen excess (OR 27.67), detection during cancer surveillance (OR 11.34), size ≥ 4 cm (OR 6.11), and male sex (OR 3.06). After implementing the 2016 guidelines, the number of adrenalectomies decreased (6.1% pre-2016 vs 4.5% post-2016) and the number of patients discharged increased (4.4% pre-2016 vs 25.3% post-2016) for benign non-functioning adrenal masses.
Conclusion: Implementing the 2016 guidelines positively impacted clinical practice, reducing unnecessary surgeries and increasing the discharge rate for benign adrenal masses, thereby preserving healthcare resources and patient burden.
Keywords: adrenal tumour, adrenal incidentaloma guidelines, adrenocortical carcinoma, adrenocortical adenoma
Significance
Adrenal masses are mostly diagnosed incidentally and require assessment for hormone excess and malignancy. The European Society of Endocrinology, in collaboration with the European Network for the Study of Adrenal Tumours, first published guidelines for managing adrenal incidentalomas in 2016 to standardise patient care. However, evidence for the impact of these guidelines on real-world clinical practice is lacking. In this retrospective tertiary single-centre study, we provide a comprehensive overview of demographic, clinical, and radiological characteristics and outcomes of a large cohort of nearly 1400 patients newly presenting with adrenal masses. For the first time, we demonstrate that implementing these guidelines reduced unnecessary follow-up visits and surgeries-while increasing the discharge rate-for patients with benign non-functioning masses.
+ A.P. and C.L.R. jointly supervised this paper.
Introduction
Adrenal masses are found in up to 5%-7% of adults, with older individuals carrying a higher risk.1 Their incidence has been rising around 10-fold over the last 2 decades due to the frequent incidental discovery (adrenal incidentalo- mas) during abdominal cross-sectional imaging for reasons unrelated to adrenal disease.2 The vast majority of inciden- talomas are benign; however, malignancy and hormone ex- cess are observed in 2%-10% and 30%-60% of cases, respectively.2-6 Therefore, it is mandatory to exclude malig- nancy and hormone excess in all individuals with newly diag- nosed adrenal masses. The European Society of Endocrinology (ESE), in collaboration with the European Network for the Study of Adrenal Tumours (ENSAT), published guidelines for managing adrenal incidentalomas, initially released in 2016 and updated in 2023.3,6 The scope of these guidelines is to standardise the care of patients with adrenal incidenta- lomas to improve health outcomes and reduce unnecessary investigations and treatments.6,7 However, evidence of the impact of the ESE-ENSAT guidelines on real-world clinical practice is lacking.
The primary aim of this study was to evaluate the demo- graphic, clinical, and radiological characteristics, hormonal secretion patterns, and management approaches before and after implementing the 2016 ESE-ENSAT guidelines in a large cohort of patients referred to our tertiary centre. The second- ary aim was to determine the best clinical and radiological pre- dictors of malignancy.
Materials and methods
Study design
We retrospectively collected clinical data from electronic re- cords of all consecutive patients aged ≥18 with adrenal masses referred to the Adrenal Tumour Service at the Queen Elizabeth Hospital Birmingham (QEHB, Birmingham, United Kingdom) between January 1998 and December 2022. This study has
been conducted in accordance with the Declaration of Helsinki. Institutional review board approval of the study was obtained by the University Hospitals Birmingham National Health Service Foundation Trust (CARMS-18109).
Patient assessment and data collection
The collected data at baseline included demographics, the year of and reason for referral, the modality of presentation, the radiological characteristics of the adrenal mass(es), and ad- renal hormone secretion patterns. Whenever possible and in line with the 2016 ESE-ENSAT guidelines, patients underwent an unenhanced computed tomography (CT) scan of the ad- renal region (if not yet done at the time of referral) as well as standardised clinical assessment and endocrine biochemical workup (Figure 1). Our adrenal tumour multidisciplinary team (MDT), including an adrenal specialist radiologist, re- viewed the images of adrenal masses meeting 1 or more of the following criteria: adrenal masses initially reported as in- determinate or suspicious for malignancy; bilateral adrenal masses; adrenal masses in a patient with a history of cancer; and adrenal masses with adrenal hormone excess. In bilateral adrenal masses, each lesion was assessed individually.
The reasons for referral were collected from referral docu- ments. The final diagnosis was recorded in the medical re- cords after the completion of a standardised workup and multidisciplinary discussion (Figure 1). Adrenal masses were classed as indeterminate in case of heterogeneous density or Hounsfield unit (HU) > 10 from unenhanced CT. Patients with adrenal incidentalomas or clinical suspicion of Cushing’s syn- drome (CS) underwent a 1-mg overnight dexamethasone sup- pression test (1mg-DST). According to the 2016 ESE-ENSAT guidelines, possible and definitive mild autonomous cortisol secretion (MACS) was defined as 1mg-DST serum cortisol 50-138 nmol/L and >138 nmol/L, respectively, without clinical signs of CS.6 Overt CS diagnosis was confirmed with 24-h urinary-free cortisol and/or late-night salivary cortisol in pa- tients with typical signs of hypercortisolism (eg, proximal
Patients with adrenal mass (N=1397) Referred to Queen Elizabeth Hospital Birmingham 1998-2022+
Standardised workup Clinical assessment Imaging: Unenhanced abdomen CT scan Endocrine workup*
+
- 1mg-DST
- Plasma or 24-hour urine metanephrines (if indicated)
Adrenal Tumour multidisciplinary team discussion
- Aldosterone/renin ratio (if indicated)
Baseline demographics Modes of presentation Reasons for referral
- DHEAS, androstenedione, 17OHP testosterone (in women), oestrogen (in men)
Additional workup (if indicated)
*21, 386, and 990 patients in the first (1998-2007), second (2008-2015), and third periods (2016-2022), respectively.
- Additional ** or interval imaging - Adrenal biopsy
Management plan (as appropriate)
- Adrenalectomy
Final diagnosis
- Follow up
- Discharge
- Other
myopathy and purple striae).6,8 Adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulphate (DHEAS) levels were measured to rule out ACTH-dependent CS. Primary al- dosteronism diagnosis relied on at least 2 paired measurements of plasma renin and aldosterone levels and confirmation by sa- line infusion test.9 Adrenal androgen excess was diagnosed based on DHEAS, androstenedione, or testosterone levels (women only) higher than the sex- and age-specific reference ranges. Phaeochromocytoma was diagnosed by plasma-free or 24-h urinary-fractionated metanephrine or normetanephrine levels at least twice over the upper limit of the reference range and, in nearly all cases, by histology after adrenalectomy.10 Metastatic phaeochromocytomas were classified separately as other malignant tumours. Primary bilateral macronodular ad- renal hyperplasia (PBMAH) was diagnosed by histology (mac- ronodular hyperplasia) after bilateral adrenalectomy or radiological features (enlarged adrenal glands with at least 2 bi- lateral nodules of more than 1 cm).11 Almost all adrenocortical carcinoma (ACC) cases were diagnosed on histology using the Weiss criteria.12 A few non-operable ACCs were diagnosed based on typical features (mass ≥4 cm with indeterminate radiological findings and severe adrenal androgen excess).
We recorded additional investigations carried out to guide the management plan, including immediate further imaging other than CT (magnetic resonance imaging, fluorodeoxyglucose- positron emission tomography, or metaiodobenzylguanidine scan), interval imaging to monitor the adrenal mass growth,6 or biopsies to differentiate primary adrenal pathology from oth- er aetiologies.
Management strategies were obtained from the adrenal tu- mour MDT discussion outcomes and included adrenalectomy, follow-up for clinical, hormonal, or radiological monitoring, additional imaging other than CT, discharge from the Adrenal Tumour Service, or other treatments such as neo-adjuvant chemotherapy (eg, for advanced non-operable ACC), and refer- ral to other departments for specific treatment according to the aetiology of the adrenal lesion (eg, metastases of extra-adrenal primary cancers). The clinical outcome at the latest available follow-up was recorded.
To assess the potential changes in demographics, presentation patterns, clinical and radiological characteristics, and treatment approaches over time, we considered 3 periods separately: 1998-2007 (first period), 2008-2015 (second period), and 2016-2022 (third period). The time intervals were determined by the introduction of adrenal tumour MDT meetings and elec- tronic medical records in 2008 and the release of ESE-ENSAT guidelines in 2016.6 Only the second and third periods were compared due to the limited number of patients and the lack of electronic medical records during the first period.
Statistical analysis
Categorical variables are presented as counts and percen- tages and differences between groups were analysed by the Fisher exact test with post hoc analysis using Bonferroni cor- rection. Continuous variables are presented as median and interquartile ranges (IQRs) and differences between groups were analysed by t-tests (for normally distributed variables) or Wilcoxon rank-sum tests (for non-normally distributed variables). When more than 2 groups were compared, ANOVA and Kruskal-Wallis rank sum tests were used in normally and non-normally distributed variables, respectively. Statistical sig- nificance was set at P <. 05.
Analyses of the predictors for adrenal malignancy were per- formed using binomial logistic regression analysis and are re- ported as odds ratio (OR) with a 95% CI. All predictors with P <. 1 in the univariable analysis were incorporated into the multivariable model. The final model was developed using stepwise backward regression analysis.
The statistical analysis was carried out using R Statistical Software (v4.3.2; https://www.r-project.org/) and IBM SPSS Statistics for Windows (Version 29.0.2.0, IBM Corp, Armonk, NY, United States). Sankey diagrams were created through the open-source SankeyMATIC (sankeymatic.com).
Results
Reasons for referral, modalities of presentation, and final diagnosis
Overall, 1397 patients with adrenal masses were referred to the QEHB Adrenal Tumour Service during the study period: 21 in the first (1998-2007), 386 in the second (2008-2015), and 990 in the third period (2016-2022). The 3 most common reasons for referral were adrenocortical adenoma (ACA; 43.2%), indeterminate lesions (27.4%), and phaeochromo- cytoma (11.0%), followed by ACC (7.4%), and metastases (4.7%) (Figure 2A). The proportion of patients referred for indeterminate adrenal lesions significantly increased from 20.2% in the second period to 30.6% in the third peri- od (P <. 001; Figure S1).
Incidental discovery was the most frequent mode of presen- tation (63.7%), followed by cancer surveillance or staging (10.0%) and symptoms of adrenal hormone excess (9.8%). Around 22% of patients had a past or current medical his- tory of extra-adrenal malignancy. During the third period, the percentage of patients with adrenal masses detected through screening for known germline mutations associated with adrenal tumours decreased from 3.4% to 0.5% (P =. 001; Table S1).
After standardised workup, ACA was the most frequent diag- nosis (56.0%), followed by phaeochromocytoma (12.7%), ACC (10.6%), adrenal metastasis (5.7%), other benign mass (3.9%), myelolipoma (3.6%), other malignant tumour (1.1%), and PBMAH (0.5%) (Figure 2A). Among bilateral adrenal masses, the 3 most common final diagnoses were ACA (60.3%), phaeochromocytoma (13.2%), and adrenal metastasis (9.3%). There was a significant decrease between the second and third periods in the proportion of phaeochro- mocytomas (16.3%-10.2%; P =. 02) and ACC (15.3%-8.3%; P =. 002), while there was a non-significant increase in adrenal metastases (3.6%-6.6%; P = . 35; Figure S1). Considering only the incidentally detected masses (n = 890), benign lesions ac- counted for 76.5% of cases (ACA 67.8%, myelolipomas 4.3%, and other benign masses 4.4%), while ACC was diag- nosed in 3.5% of cases (Figure S2).
The adrenal mass remained indeterminate at the last avail- able visit in 83 patients: 36 were lost to follow-up or referred to other hospitals upon their request before completion of the workup, 25 were still being investigated at the time of data col- lection cut-off, and 22 died before reaching a final diagnosis.
Patient demographics
At diagnosis of the adrenal mass, the median age was 60 years (49-70); most patients were women (55.7%) (Table 1). The most common ethnicities were White (57.8%) and Asian
Reason for referral
Final diagnosis
ACA, N=603 (43.2%)
ACA, N=783 (56.0%)
Indeterminate adrenal lesion, N=83 (5.9%)
Indeterminate adrenal lesion, N=383 (27.4%)
Phaeochromocytoma, N=177 (12.7%)
Phaeochromocytoma, N=154 (11.0%)
ACC, N=148 (10.6%)
ACC, N=104 (7.4%)
Adrenal metastasis, N=79 (5.7%)
Adrenal metastasis, N=66 (4.7%)
Myelolipoma, N=50 (3.6%)
Myelolipoma, N=48 (3.4%)
Other benign mass, N=54 (3.9%) Other malignant tumour, N=16 (1.1%) PBMAH, N=7 (0.5%)
Other benign mass, N=26 (1.9%)
PBMAH, N=8 (0.6%)
Other malignant tumour, N=5 (0.4%)
B
Reason for referral
Final diagnosis
Indeterminate adrenal lesion, N=383
ACA, N=183
47.8%
Indeterminate adrenal lesion, N=69
18.0%
ACC, N=36
9.4%
Phaeochromocytoma, N=36
9.4%
Other benign mass, N=22
5.7%
Adrenal metastasis, N=22
5.7%
Myelolipoma, N=8
2.1%
Other malignant tumour, N=7
1.8%
British (6.9%). Patients referred during the third period were slightly older (median age 60 vs 58 years; P =. 02) age, sex and ethnicity distribution was similar between pe- riods 2 and 3 (Table S1).
Myelolipoma and adrenal metastasis were more prevalent in men (56.0% and 69.1% of cases, respectively). Adrenal me- tastases were mostly detected during cancer surveillance or staging (74.7%). Moreover, 96.2% of patients with adrenal
| Parameter | Value |
|---|---|
| Demographics | |
| Women, n (%) | 778 (55.7) |
| Median age at mass diagnosis (IQR), years | 60 (49-70) |
| Ethnicity, n (%) | |
| White (White British or other White) | 808 (57.8) |
| Asian British (British Indians, Pakistanis, other | 97 (6.9) |
| British Asians) | |
| Black British | 57 (4.1) |
| Any other ethnicity | 30 (2.1) |
| Unknown | 405 (29.0) |
| Modality of presentation, n (%) | |
| Incidental discovery | 890 (63.7) |
| Cancer surveillance or staging | 140 (10.0) |
| Symptoms of adrenal hormone excess | 137 (9.8) |
| Local mass symptoms | 67 (4.8) |
| Drug-resistant or severe hypertension | 57 (4.1) |
| Screening due to known genetic disease predisposing to adrenal masses | 19 (1.4) |
| Unknown | 87 (6.2) |
| Past or current medical history of extra-adrenal malignancy, n (%) | |
| Yes | 303 (21.7) |
| Unknown | 21 (1.5) |
| Radiological characteristics | |
| Mass location, n (%) | |
| Left | 730 (52.3) |
| Right | 456 (32.6) |
| Bilateral | 204 (14.6) |
| Unknown | 7 (0.5) |
| Single or multiple adrenal lesions, n (%) | |
| Single | 1163 (83.2) |
| Multiple | 227 (16.2) |
| Unknown | 7 (0.5) |
| Mass size | |
| Median maximum mass diameterª (IQR), cm | 2.9 (1.9-4.7) |
| Size ≥ 4 cm, n (%) | 428 (30.6) |
| Unknown | 90 (6.4) |
| Unenhanced CT mass attenuation | |
| Median unenhanced CT mass attenuationb (IQR), HU | 10 (0-25) |
| ≤10 HU, n (%) | 381 (27.3) |
| 11-20 HU, n (%) | 131 (9.4) |
| >20 HU, n (%) | 210 (15.0) |
| Heterogeneous, n (%) | 41 (2.9) |
| Unknown | 634 (45.4) |
Abbreviations: CT, computer tomography; HU, Hounsfield units; IQR, interquartile range; n, number.
ªFor bilateral masses, the maximum diameter of the larger adrenal mass was considered.
bCalculated from 691 patients with available data.
metastases had a diagnosis of current or past extra-adrenal malignancy at the time of referral. Among these, the majority had kidney cancer (34.2%), followed by lung and gastrointes- tinal cancer (both 14.5%) and skin malignancies (10.5%) (Table S2 and Figure S3A-E).
Radiological characteristics
The median adrenal mass diameter was 2.9 cm (1.9-4.7), with 428 patients (30.6%) having masses ≥ 4 cm (Table 1). Bilateral lesions were observed in 204 patients (14.6%). Unilateral lesions were more frequently detected in the left ad- renal (52.3%). After stratification by size, this predominance mostly originated from smaller adrenal masses (<4 cm: left 55.5%, right 28.5%, bilateral 16.1%; ≥4 cm: left 48.2%, right 42.4%, bilateral 9.3%; P <. 001). Unenhanced CT for
determination of attenuation values (HU) was available for 763 patients (54.6%), and 27.3% had heterogeneous masses or >10 HU.
Approximately 25% of patients with adrenal metastases or other malignant tumours exhibited bilateral adrenal le- sions (24.1% and 25.0%, respectively). In nearly all ACC cases (95.5%), most of other malignant tumours (76.9%), and almost half of the adrenal metastases (40.5%), the mass was ≥4 cm. Most patients with ACC (94.4%), metas- tasis (94.7%), or other malignant tumours (100%) had masses with a plain density > 20 HU or heterogeneous dens- ity; none of these patients had density ≤ 10 HU. All patients with phaeochromocytoma had mass density >10 HU (Tables S2 and 3 and Figure S3F-H).
Adrenal hormone secretion patterns
At the initial endocrine workup, 47.8% of the adrenal masses were classified as hormone producing: MACS was the most fre- quent diagnosis (20.1%) followed by catecholamine excess (11.9%) (Table 2). Almost half of the adrenal incidentalomas (47.1%) were hormonally inactive, and MACS was the most common hormonal abnormality (26.9%), followed by catechol- amine excess (8.2%). In contrast, in patients presenting with symptoms of adrenal hormone excess, adrenal CS (40.1%) was the most common diagnosis, followed by catecholamine ex- cess (22.6%) and mixed steroid excess (14.6%) (Table S4).
When considering only ACAs, around half (50.9%) were non-functioning adrenal tumours (NFAT), 32.1% had MACS, 9.8% primary aldosteronism, and 4.4% adrenal CS. After excluding primary aldosteronism cases, patients with ACAs were more frequently women (61.8%), especially if they had CS (87.1% vs 60.6% in NFAT and 60.4% in MACS; P = . 01) (Table S5). Patients with CS were also younger (median 44 years [31-55] vs 60 [52-68] in NFAT and 67 [58-74] in MACS; P <. 001) and had larger adrenal masses (me- dian 3.0 cm [2.8-3.8] vs 2.0 [1.5-2.7] in NFAT and 2.8 [2.1-3.7] in MACS; P <. 001). Patients with MACS were more likely to have bilateral adrenal lesions (26.4% vs 16.1% in CS and 10.6% in NFAT; P <. 001). Seven patients were even- tually diagnosed with PBMAH: 4 had MACS and 3 CS.
Seven out of 50 patients with adrenal myelolipoma (14.0%) failed the 1mg-DST (Table 2), with no difference in the radio- logical characteristics (laterality and mass size) of patients with abnormal 1mg-DST results (data not shown).
Among patients with ACC, 14.2% had no evidence of ster- oid excess. In the remaining ones, the most prevalent abnor- mal hormonal pattern was CS (22.3%), followed by mixed steroid secretion (21.0%), MACS (7.4%), and isolated ad- renal androgen excess (6.1%). Interestingly, men with ACC tended to have a higher frequency of CS than women (40.5% [17/42] vs 24.6% [16/65]; P =. 09), while women more frequently presented with mixed steroid excess (38.5% [25/65] vs 14.3% [6/42]; P =. 01). There was no difference in hormone excess pattern according to age (data not shown).
Management strategies
After the first standardised assessment and MDT discussion, just over half of the patients were recommended for further follow-up (56.6%). Adrenalectomy was carried out in 32.2% of patients (unilateral 30.0% and bilateral 2.2%), while 3.2% were offered other treatments. A total of 8.0% of patients were discharged (Table S2 and Figure S3I).
| Adrenal hormonal pattern, n (%) | Entire cohort N= 1397ª | Adrenocortical adenoma N=783 | Adrenocortical carcinoma N=148 | Myelolipoma N= 50 |
|---|---|---|---|---|
| Inactive | 527 (37.7) | 360 (46.0) | 21 (14.2) | 31 (62.0) |
| MACS | 280 (20.1) | 227 (29.0) | 11 (7.4) | 7 (14.0) |
| Possible MACS (1mg-DST cortisol 51-138 nmol/L) | 202 (14.5) | 170 (21.7) | 8 (5.4) | 4 (8.0) |
| Definitive MACS (1mg-DST cortisol >138 nmol/L) | 78 (5.6) | 57 (7.3) | 3 (2.0) | 3 (6.0) |
| Adrenal Cushing's syndrome | 71 (5.1) | 31 (4.0) | 33 (22.3) | 0 (0.0) |
| Primary aldosteronism | 72 (5.2) | 69 (8.8) | 1 (0.7) | 0 (0.0) |
| Excess of adrenal androgen | 15 (1.1) | 5 (0.6) | 9 (6.1) | 0 (0.0) |
| Co-secretion of aldosterone and cortisol (MACS) | 16 (1.1) | 15 (1.9) | 1 (0.7) | 0 (0.0) |
| Mixed steroid excessb | 31 (2.2) | 0 (0.0) | 31 (21.0) | 0 (0.0) |
| Catecholamine excess | 166 (11.9) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Co-secretion of catecholamine and cortisol | 16 (1.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Unknown | 203 (14.5) | 76 (9.7) | 41 (27.7) | 12 (24.0) |
| Median cortisol leveld after 1 mg-DST (IQR), nmol/L | 45 (29-93) | 46 (30-90) | 216 (76-512) | 34 (28-54) |
Abbreviations: 1mg-DST, 1-mg overnight dexamethasone suppression test; IQR, interquartile range; MACS, mild autonomous cortisol secretion; N, number. aIn the entire cohort column, a few extra cases are not listed in the ACA, ACC, and myelolipoma columns. For example, inactive hormonal secretion cases included adrenal metastases (n = 51), indeterminate adrenal lesions (n = 24), other benign masses (n = 36), and other malignant tumours (n =4). MACS cases included adrenal metastases (n = 8), primary bilateral macronodular adrenocortical hyperplasia (PBMAH, n = 4), indeterminate adrenal lesions (n = 19), other benign masses (n = 3), and other malignant tumour (n = 1). Adrenal CS cases included PBMAH (n = 3) and other benign masses (n = 4). Primary aldosteronism and excess of adrenal androgen cases included other benign masses (n = 2 and 1, respectively).
bMixed steroid excess included androgen plus oestrogen and/or cortisol and/or aldosterone.
“Co-secretion of catecholamine and cortisol included catecholamine and cortisol excess (non-suppressible 1mg-DST or CS). dCalculated from available data of 811, 602, 23, and 39 patients in the entire cohort, myelolipoma group, ACA group, and ACC group, respectively.
Further follow-up investigations: additional or interval imaging
22.4% and 35.1% of patients received additional and interval imaging, respectively, with no differences between the second and third periods (Table S6). The median interval time for the repeat imaging was 9 months (6-18). Among patients with in- determinate lesions or size ≥ 4 cm, 28.9% received additional imaging and 42.5% had interval imaging.
Further follow-up investigations: adrenal biopsy
After biochemical exclusion of phaeochromocytoma and MDT discussion, 3.9% of patients underwent an adrenal bi- opsy, of whom 38.5% had history of extra-adrenal malig- nancy and 80% had masses ≥ 4 cm. Most of them were initially referred for an indeterminate adrenal lesion (59.6%) or suspected adrenal metastasis (11.5%). There was no differ- ence in the number of adrenal biopsies carried out during the second and third periods (Table S6).
Recommended management
Considering all adrenal masses, there was a significant differ- ence in the recommended management in the third compared with the second period (Table S6), with a decline in adrenalec- tomies (40.5% vs 27.7%; P <. 001) and an increase in dis- charged patients (2.3% vs 10.3%; P <. 001). When focusing only on the 427 patients with benign disease (myelolipomas, ACA, and other benign masses) without evidence of adrenal hormone hypersecretion, 322 patients (75.4%) were initially recommended to undergo longitudinal monitoring (ie, 209 pa- tients for interval imaging or adrenal biopsy and 113 patients to repeat hormonal workup), 84 (19.7%) were directly dis- charged, and 21 (4.9%) underwent adrenalectomy. In this group (88.3% adrenal incidentalomas), we observed a sub- stantial decrease from the second to third period in the propor- tion of patients requiring active longitudinal follow-up or adrenalectomy, that is, from 89.6% to 70.2% and from 6.1% to 4.5%, respectively. On the contrary, the number of patients directly discharged increased from 4.4% to 25.3%
(overall P <. 001; Figure 3A). We also observed similar find- ings in non-functioning benign adrenal incidentalomas (n = 377; Figure 3B).
Relationship between the initial reason for referral and final diagnosis
The final diagnosis changed compared with the reason for referral in 383 patients (27.4% of the entire cohort; Figure 2A). Most of these were initially referred for indeter- minate adrenal lesions (n = 314): almost half were eventual- ly diagnosed with ACA (47.8%), followed by ACC (9.4%), phaeochromocytoma (9.4%), other benign mass (5.7%), metastasis (5.7%), myelolipoma (2.1%), and other malig- nant tumour (1.8%) (Figure 2B).
Predictors of adrenal malignancy
For discriminating any malignant adrenal mass (ACC, adrenal metastases, and other malignant tumours) from any benign le- sion (ACA, myelolipomas, phaeochromocytomas, PBMAH, and other benign masses), significant predictors were >20 HU/heterogeneous density (OR 28.40; 95% CI, 5.87-137.56), androgen excess/mixed steroid hypersecretion (OR 27.67; 95% CI, 4.05-189.00), detection during cancer surveillance or staging (OR 11.34; 95% CI, 3.32-38.70), size ≥ 4 cm (OR 6.11; 95% CI, 2.22-16.86), and male sex (OR 3.06; 95% CI, 1.12-8.34). Predictors of ACC compared with ACA included >20 HU/heterogeneous density (OR 17.81; 95% CI, 2.02-156.79), androgen excess/mixed steroid hyper- secretion (OR 17.07; 95% CI, 1.71-170.48), non-incidental presentation (OR 10.80; 95% CI, 2.36-49.39), and size (OR 1.57 for each 1-cm increase; 95% CI, 1.24-1.99) (Table 3).
Discussion
We present a comprehensive analysis of the demographic, clinic- al, hormonal, and radiological characteristics as well as initial management and final diagnosis of a large cohort of patients with adrenal masses referred to a tertiary UK centre over
A
n=115
n=312
100
75
Percentage
Agreed management
Adrenalectomy 6.1% > 4.5%
50
Discharge
4.4% → 25.3%
p<0.001
Follow-up
89.6% > 70.2%
25
0
Before 2016
After 2016
Period
B
n=102
n=275
100
75
Percentage
Agreed management
Adrenalectomy 4.9% - 4.3%
50
Discharge
4.9% - 25.1%
p<0.001
Follow-up
90.2% > 70.6%
25
0
Before 2016
After 2016
Period
25-year period. We also investigated potential changes recorded before and after implementing the ESE-ENSAT 2016 guidelines.6
The 3 most frequent aetiologies of adrenal masses were ACA, phaeochromocytoma, and ACC. Incidental discovery was the most common mode of presentation. Interestingly, nearly half of the patients referred for indeterminate adrenal lesions were finally diagnosed with ACA after standardised workup. Significant predictors to identify malignant adrenal masses include an attenuation value >20 HU or a heteroge- neous appearance on unenhanced CT, androgen excess, de- tection during cancer surveillance or staging, size ≥ 4 cm, and male sex. After implementing the ESE-ENSAT 2016 guidelines, the proportion of patients with benign non- functioning adrenal masses discharged after initial workup significantly increased.
We found that ACA was the most common aetiology, similar to other studies.2,3,13-15 However, we observed a higher preva- lence of phaeochromocytoma (12.7%) and ACC (10.6%) compared with previous studies,2,13,14 possibly due to the differences in study settings and inclusion criteria. The EURINE-ACT, a prospective cross-sectional study from 14
European and American specialist centres for adrenal tumours, found that 83.6% were discovered incidentally, and the preva- lence of ACC was 4.9%.13 When focusing on incidentalomas only, the prevalence of ACAs and ACCs was 89.7% and 2.6% in EURINE-ACT,13 compared with 67.8% and 3.5% in our study. A population-based study from the United States found that the majority of patients were asymptomatic, with fewer cases of ACC (0.3%) or phaeochromocytoma (1.1%).2 Another study, which did not identify any ACC or phaeochro- mocytoma cases, was performed in a large cohort of asymptom- atic individuals from Southwest China who underwent cross-sectional adrenal imaging.14 It is worth considering that, as a tertiary referral centre, we receive a higher number of refer- rals for complicated cases and fewer incidentally discovered ad- renal masses than other centres, which potentially explains the higher prevalence of malignancy in our cohort.
We observed a predominance of left-sided adrenal masses among those <4 cm. This could be explained by the more dif- ficult visualisation of the right adrenal gland (detection bias). In line with our findings, previous studies showed no asym- metry in the location when considering larger masses.
| Predictors for malignant adrenal masses (n = 243) compared with benign adrenal lesions (n = 1071)ª | Univariable logistic regression analysis | Multivariable logistic regression analysis | ||
|---|---|---|---|---|
| OR (95% CI) | P-value | Adjusted OR (95% CI) | P-value | |
| Male sex | 1.58 (1.19-2.09) | .001 | 3.06 (1.12-8.34) | .03 |
| Age increased by 5 years | 0.95 (0.91-1.00) | .035 | ||
| White ethnicity | 2.32 (1.36-3.94) | .002 | ||
| Incidental discovery | 0.12 (0.09-0.17) | <. 001 | ||
| Detection of mass from cancer surveillance or staging | 8.24 (5.60-12.14) | <. 001 | 11.34 (3.32-38.70) | <. 001 |
| Non-incidental presentationb | 2.77 (2.01-3.81) | <. 001 | ||
| Mass density >20 HU from plain CT or heterogeneous mass density | 48.82 (11.64-204.78) | <. 001 | 28.40 (5.87-137.56) | <. 001 |
| Multiple adrenal lesion | 0.63 (0.41-0.97) | .035 | ||
| Mass size ≥ 4 cm | 10.62 (7.60-15.07) | <. 001 | 6.11 (2.22-16.86) | <. 001 |
| Mild autonomous cortisol secretion and adrenal Cushing's syndrome | 0.70 (0.50-0.98) | .035 | ||
| Androgen(s) or mixed steroid secretion | 34.98 (14.64-83.58) | <. 001 | 27.67 (4.05-189.00) | <. 001 |
| Predictors for ACC (n = 148) compared with adrenocortical adenoma (n =783) | Univariable logistic regression analysis | Multivariable logistic regression analysis | ||
|---|---|---|---|---|
| OR (95% CI) | P-value | Adjusted OR (95% CI) | P-value | |
| Male sex | 1.26 (0.89-1.79) | .200 | ||
| Age increased by 5 years | 0.84 (0.79-0.89) | <. 001 | ||
| White ethnicity | 2.16 (1.09-4.29) | .028 | ||
| Incidental discovery | 0.09 (0.06-0.15) | <. 001 | ||
| Detection of mass from cancer surveillance or staging | 1.50 (0.71-3.17) | .292 | ||
| Non-incidental presentationb | 10.56 (6.87-16.24) | <. 001 | 10.80 (2.36-49.39) | .002 |
| Mass density > 20 HU from plain CT or heterogeneous mass density | 64.52 (8.51-489.25) | <. 001 | 17.81 (2.02-156.79) | .01 |
| Multiple adrenal lesion | 0.13 (0.05-0.35) | <. 001 | ||
| Mass size increased by 1 cm | 2.56 (2.15-3.06) | <. 001 | 1.57 (1.24-1.99) | <. 001 |
| Mild autonomous cortisol secretion | 0.20 (0.11-0.36) | <. 001 | ||
| Adrenal Cushing's syndrome | 6.95 (4.10-11.79) | <. 001 | ||
| Androgen(s) or mixed steroid secretion | 57.56 (22.23-149.01) | <. 001 | 17.07 (1.71-170.48) | .02 |
Abbreviations: CT, computer tomography; HU, Hounsfield units; OR, odds ratio; CI, confidence interval.
ªMalignant adrenal masses included ACC, adrenal metastases, and other malignant tumours. Benign adrenal lesions included ACAs, myelolipomas, other benign masses, phaeochromocytomas, and PBMAH.
“Non-incidental presentation included local mass symptoms, symptoms of adrenal hormone excess, drug-resistant or severe hypertension, screening due to known genetic disease predisposing to adrenal masses.
All variables with P <. 1 were included in multivariable regression analysis except non-incidental presentation in predictors for malignant adrenal masses due to collinearity with other variables and White ethnicity in predictor for ACC to increase model stability.
After excluding aldosterone- and androgen-producing ad- enomas, cortisol excess was diagnosed in just over 40% of pa- tients with ACA: 36.7% had MACS and 5.0% CS. Consistent with previous studies, patients with MACS were predomin- antly women of post-menopausal age (90.3%, >50 years), while patients with CS were mostly younger women (67.7%, <50 years).4,19-21 Bilateral masses were observed in 26.4% of MACS cases, compared with only 10.6% of NFAT and 16.1% of CS. The reason behind the higher prevalence of the female sex in patients with cortisol excess remains uncertain; possible contributing factors include prolonged luteinizing hormone stimulation on the adrenal cortex during menopause in MACS and oestrogen/progesterone signalling in CS.22-24 The high prevalence of MACS in bilateral ACAs was consistent with other studies4,19 and might be linked to undiagnosed PBMAH cases due to ARMC5 mutations. Distinguishing bilat- eral ACAs from PBMAH based on imaging are difficult; a large series showed that up to 19% of patients with bilateral adrenal lesions and MACS carried ARMC5 mutations.25
We also looked at abnormal hormone secretion in patients with myelolipomas. A large retrospective longitudinal study found that 3.3% of patients with myelolipoma could have MACS-mostly due to concomitant ipsi- or contralateral ad- enomas.26 However, our finding and another study27 found that 14%-20% of myelolipomas can have MACS. This might be due to false-positive 1mg-DST results; however,
even considering a false-positive rate of 3%-20%,28 the pro- portion of patients with abnormal results is still relatively high. Myelolipomas should not contain any adrenal cortical or medullary components; nevertheless, a small case series found adrenal cortical hyperplasia concomitant with mature adipose tissues haematopoietic elements in patients with mye- lolipoma and endocrine hyperfunction undergoing adrenalec- tomy,29 but the reason for this is unclear. Another possible explanation could be due to an adrenal collision tumour, that is, when 2 adjacent tumours (eg, myelolipoma and aden- oma) appearing as a single mass on imaging.3º Based on our findings, we suggest that all patients with myelolipoma should be tested with 1mg-DST at least once.
Across different time periods, there were minor differences in patients’ demographics, as well as in clinical and radiologic- al characteristics of adrenal masses, in line with a previous study comparing adrenal tumour characteristics before and after 2010.15 There was no significant difference in the add- itional investigations recommended over time, for example, imaging or adrenal biopsy.
Hounsfield units > 20 from unenhanced CT, non-incidental discovery, size ≥ 4 cm, and male sex were predictors of ad- renal malignancy, similar to a previous study focusing on large adrenal masses.18 We propose that male sex is linked to the higher prevalence of adrenal metastases31,32; in fact, we did not find this to be predictive of ACC. Conversely, androgen
excess was highly predictive of ACC, in line with previous stud- ies. 3,6,31,33-35 Hounsfield units > 20 to predict adrenal malig- nancy is supported by previous studies: compared with the >10 cut-off, HU> 20 provided better specificity (67%-80% vs 45%-64%) with nearly similar sensitivity (94%-100% vs 100%) both when considering all adrenal masses or adrenal in- cidentalomas only. 13,36,37
Implementing the 2016 ESE-ENSAT guidelines significant- ly decreased the rate of active follow-up and adrenalectomies in patients with benign non-functioning adrenal masses (Figure 3A and B). According to the guidelines, patients with homogeneous masses < 4 cm and HU ≤ 10 do not require fur- ther imaging and can be discharged, provided they do not have hormone excess.6 Therefore, following the guidelines reduced unnecessary follow-ups and healthcare costs. The impact of the 2023 ESE-ENSAT guidelines update3 on clinical care needs to be addressed by future studies.
A limitation of our study is its retrospective design. Additionally, our tertiary referral setting likely overestimates the prevalence of malignant adrenal masses, which limits the generalisability of our findings to population-based settings. The strengths of this study include the very large number of patients who underwent a standardised workup, MDT man- agement, and long-term longitudinal follow-up.
In conclusion, in our large cohort, including a high proportion of large and heterogeneous adrenal lesions, ACA was still the most common aetiology. Sex, mode of presentation, hormonal secretion patterns, and imaging characteristics, including mass size and pre-contrast density, were significant predictors for malignant adrenal masses. Adopting the 2016 ESE-ENSAT guidelines positively impacted real-world practice, reducing unnecessary investigations and surgeries for patients with be- nign, non-functioning adrenal masses.
Acknowledgements
We thank all the core members of the UHB Adrenal MDT and the medical students (Shadman Ahmed and Jessica Parkin-Crawshaw) who helped us collect the data. We also thank the EU COST Action CA20122 Harmonisation for supportive networking (www.goharmonisation.com).
Supplementary material
Supplementary material is available at European Journal of Endocrinology online.
Funding
This work has been supported by the European Reference Network on Rare Endocrine Conditions (Endo-ERN) and the Horizon Europe 2022 Work Program under grant agree- ment 101095407 (HT-ADVANCE, to A.P. and W.A.). This study has been delivered through the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre (BRC) (Grant Reference Number NIHR203326). C.L.R. receives support from HRA Pharma Rare Disease (research grant). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The views ex- pressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care UK.
Authors’ contributions
Onnicha Suntornlohanakul (Data curation [equal], Formal analysis [equal], Validation [equal], Writing-original draft [equal], Writing-review & editing [equal]), Sumedha Mandal (Data curation [equal], Validation [equal], Visualization [equal]), Pratyusha Saha (Data curation [equal], Validation [equal], Visualization [equal]), Emre Saygili (Formal analysis [equal], Validation [equal], Visualization [equal]), Miriam Asia (Data curation [equal], Validation [equal], Visualization [equal]), Wiebke Arlt (Supervision [equal], Validation [equal], Visualization [equal], Writing-review & editing [equal]), Yasir Elhassan (Supervision [equal], Validation [equal], Visualization [equal], Writing-review & editing [equal]), Alessandro Prete (Conceptualization [equal], Supervision [equal], Validation [equal], Visualization [equal], Writing-original draft [equal], Writing-review & editing [equal]), and Cristina Ronchi (Conceptualization [equal], Supervision [equal], Validation [equal], Visualization [equal], Writing-original draft [equal], Writing-review & editing [equal])
Conflict of interest: C.L.R. and A.P. have received a research grant from HRA Pharma Rare Disease. All other authors have nothing to disclose.
Data availability
The data sets generated during and/or analysed during the cur- rent study are available from the corresponding author on rea- sonable request.
References
1. Bancos I, Prete A. Approach to the patient with adrenal incidenta- loma. J Clin Endocrinol Metab. 2021;106(11):3331-3353. https:/ doi.org/10.1210/clinem/dgab512
2. Ebbehoj A, Li D, Kaur RJ, et al. Epidemiology of adrenal tumours in Olmsted County, Minnesota, USA: a population-based cohort study. Lancet Diabetes Endocrinol. 2020;8(11):894-902. https:/ doi.org/10.1016/S2213-8587(20)30314-4
3. Fassnacht M, Tsagarakis S, Terzolo M, et al. 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. Eur J Endocrinol. 2023;189(1):G1-G42. https://doi.org/10.1093/ejendo/lvad066
4. Prete A, Subramanian A, Bancos I, et al. Cardiometabolic disease burden and steroid excretion in benign adrenal tumors: a cross- sectional multicenter study. Ann Intern Med. 2022;175(3): 325-334. https://doi.org/10.7326/M21-1737
5. Reimondo G, Castellano E, Grosso M, et al. Adrenal incidentalo- mas are tied to increased risk of diabetes: findings from a prospect- ive study. J Clin Endocrinol Metab. 2020;105(4):e973-e981. https://doi.org/10.1210/clinem/dgz284
6. Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal inci- dentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the study of adrenal tumors. Eur J Endocrinol. 2016;175(2):G1-G34. https://doi.org/10.1530/EJE-16-0467
7. Woolf SH, Grol R, Hutchinson A, Eccles M, Grimshaw J. Clinical guidelines: potential benefits, limitations, and harms of clinical guidelines. BMJ. 1999;318(7182):527-530. https://doi.org/10. 1136/bmj.318.7182.527
8. Nieman LK, Biller BMK, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guide- line. J Clin Endocrinol Metab. 2008;93(5):1526-1540. https://doi. org/10.1210/jc.2008-0125
9. Funder JW, Carey RM, Mantero F, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916. https://doi.org/10.1210/jc.2015-4061
10. Lenders JWM, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guide- line. J Clin Endocrinol Metab. 2014;99(6):1915-1942. https://doi. org/10.1210/jc.2014-1498
11. Bouys L, Chiodini I, Arlt W, Reincke M, Bertherat J. Update on pri- mary bilateral macronodular adrenal hyperplasia (PBMAH). Endocrine. 2021;71(3):595-603. https://doi.org/10.1007/s12020- 021-02645-w
12. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol. 1984;8(3):163-169. https://doi.org/10.1097/00000478-198403000- 00001
13. Bancos I, Taylor AE, Chortis V, et al. Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study. Lancet Diabetes Endocrinol. 2020;8(9):773-781. https://doi.org/10.1016/ S2213-8587(20)30218-7
14. Jing Y, Hu J, Luo R, et al. Prevalence and characteristics of adrenal tumors in an unselected screening population: a cross-sectional study. Ann Intern Med. 2022;175(10):1383-1391. https://doi.org/ 10.7326/M22-1619
15. Saydam BO, Baris M, Adiyaman SC, et al. Many faces of adrenal lesions in a large patient cohort: what has changed over the last two decades? Exp Clin Endocrinol Diabetes. 2023;131(4): 242-250. https://doi.org/10.1055/a-2035-6091
16. Bechmann N, Moskopp ML, Constantinescu G, et al. Asymmetric adrenals: sexual dimorphism of adrenal tumors. J Clin Endocrinol Metab. 2024;109(2):471-482. https://doi.org/10.1210/clinem/ dgad515
17. Hao M, Lopez D, Luque-Fernandez MA, et al. The lateralizing asymmetry of adrenal adenomas. J Endocr Soc. 2018;2(4): 374-385. https://doi.org/10.1210/js.2018-00034
18. Iñiguez-Ariza NM, Kohlenberg JD, Delivanis DA, et al. Biochemical, and radiological characteristics of a single-center retrospective cohort of 705 large adrenal tumors. Mayo Clin Proc Innov Qual Outcomes 2018;2(1):30-39. https://doi.org/10.1016/j. mayocpiqo.2017.11.002
19. Deutschbein T, Reimondo G, Dalmazi GD, et al. Age-dependent and sex-dependent disparity in mortality in patients with adrenal inciden- talomas and autonomous cortisol secretion: an international, retro- spective, cohort study. Lancet Diabetes Endocrinol. 2022;10(7): 499-508. https://doi.org/10.1016/S2213-8587(22)00100-0
20. Elhassan YS, Alahdab F, Prete A, et al. Natural history of adrenal in- cidentalomas with and without mild autonomous cortisol excess: a systematic review and meta-analysis. Ann Intern Med. 2019;171(2): 107. https://doi.org/10.7326/M18-3630
21. Prete A, Bancos I. Mild autonomous cortisol secretion: pathophysi- ology, comorbidities and management approaches. Nat Rev Endocrinol. 2024;20(8):460-473. https://doi.org/10.1038/s41574- 024-00984-y
22. Pabon JE, Li X, Lei ZM, Sanfilippo JS, Yussman MA, Rao CV. Novel presence of luteinizing hormone/chorionic gonadotropin receptors in human adrenal glands. J Clin Endocrinol Metab. 1996;81(6): 2397-2400. https://doi.org/10.1210/jcem.81.6.8964884
23. Caticha O, Odell WD, Wilson DE, et al. Estradiol stimulates corti- sol production by adrenal cells in estrogen-dependent primary adre- nocortical nodular dysplasia. J Clin Endocrinol Metab. 1993;77(2): 494-497. https://doi.org/10.1210/jcem.77.2.8345057
24. de Cremoux P, Rosenberg D, Goussard J, et al. Expression of pro- gesterone and estradiol receptors in normal adrenal cortex, adreno- cortical tumors, and primary pigmented nodular adrenocortical disease. Endocr Relat Cancer. 2008;15(2):465-474. https://doi. org/10.1677/ERC-07-0081
25. Bouys L, Vaczlavik A, Jouinot A, et al. Identification of predictive criteria for pathogenic variants of primary bilateral macronodular adrenal hyperplasia (PBMAH) gene ARMC5 in 352 unselected pa- tients. Eur J Endocrinol. 2022;187(1):123-134. https://doi.org/10. 1530/EJE-21-1032
26. Hamidi O, Raman R, Lazik N, et al. Clinical course of adrenal mye- lolipoma: a long-term longitudinal follow-up study. Clin Endocrinol. 2020;93(1):11-18. https://doi.org/10.1111/cen.14188
27. Campbell MJ, Obasi M, Wu B, Corwin MT, Fananapazir G. The radiographically diagnosed adrenal myelolipoma: what do we real- ly know? Endocrine. 2017;58(2):289-294. https://doi.org/10.1007/ s12020-017-1410-6
28. Genere N, Kaur RJ, Athimulam S, et al. Interpretation of abnormal dexamethasone suppression test is enhanced with use of synchron- ous free cortisol assessment. J Clin Endocrinol Metab. 2022;107(3): e1221-e1230. https://doi.org/10.1210/clinem/dgab724
29. Su H-C, Huang X, Zhou W-L, et al. Pathologic analysis, diagnosis and treatment of adrenal myelolipoma. Can Urol Assoc J. 2014;8(9-10):637. https://doi.org/10.5489/cuaj.422
30. Zhou C, Fananapazir G, Campbell MJ. Functional adrenal collision tumor in a patient with Cushing’s syndrome. Case Rep Endocrinol. 2020 ; 2020:1-5. https://doi.org/10.1155/2020/7415762
31. Ichijo T, Ueshiba H, Nawata H, Yanase T. A nationwide survey of adrenal incidentalomas in Japan: the first report of clinical and epi- demiological features. Endocr J. 2020;67(2):141-152. https://doi. org/10.1507/endocrj.EJ18-0486
32. Mao JJ, Dages KN, Suresh M, Bancos I. Presentation, disease progression and outcomes of adrenal gland metastases. Clin Endocrinol. 2020;93(5):546-554. https://doi.org/10.1111/cen. 14268
33. Arlt W, Biehl M, Taylor AE, et al. Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors. J Clin Endocrinol Metab. 2011;96(12):3775-3784. https://doi.org/10. 1210/jc.2011-1565
34. Fassnacht M, Kroiss M, Allolio B. Update in adrenocortical carcin- oma. J Clin Endocrinol Metab. 2013;98(12):4551-4564. https:// doi.org/10.1210/jc.2013-3020
35. Puglisi S, Calabrese A, Ferraù F, et al. New findings on presentation and outcome of patients with adrenocortical cancer: results from a national cohort study. J Clin Endocrinol Metab. 2023;108(10): 2517-2525. https://doi.org/10.1210/clinem/dgad199
36. Hong AR, Kim JH, Park KS, et al. Optimal follow-up strategies for adrenal incidentalomas: reappraisal of the 2016 ESE-ENSAT guide- lines in real clinical practice. Eur J Endocrinol. 2017;177(6): 475-483. https://doi.org/10.1530/EJE-17-0372
37. Kahramangil B, Kose E, Remer EM, et al. A modern assessment of cancer risk in adrenal incidentalomas: analysis of 2219 patients. Ann Surg. 2022;275(1):e238-e244. https://doi.org/10.1097/SLA. 0000000000004048