Small growths on the adrenal glands (called adrenal incidentalomas) are often found by chance during scans performed for other reasons. Many of these growths produce small amounts of the stress hormone cortisol, even though people do not have obvious symptoms. This condition, known as mild autonomous cortisol secretion (MACS), has been linked to a higher risk of conditions such as high blood pressure, diabetes, and heart disease.

In this study, we examined the medical records of more than 2,500 adults from 25 specialist centres across Europe to understand how cortisol levels change over time and whether repeated hormone testing can better predict future health problems.

We found that about one in five patients had changes in their hormone test results over time, most within the first three years after diagnosis. People whose cortisol levels remained consistently high were generally older, had more health problems affecting the heart and metabolism, and were more likely to experience worsening high blood pressure than those whose cortisol levels remained normal.

However, after taking into account factors such as age and existing cardiovascular risk, repeated cortisol test results were not independently associated with a higher risk of death, heart disease, or blood clots.

These findings suggest that people with persistently increased cortisol production should be monitored carefully, particularly for treatable cardiovascular risk factors such as high blood pressure, diabetes, and high cholesterol. Further research is needed to determine whether repeating cortisol tests over time helps doctors better identify patients at greatest risk and improve their long-term care.

Adrenal tumours are increasingly diagnosed, yet their impact on patients’ well-being remains under-recognized in routine care. We provide a comprehensive synthesis of health-related quality of life and neuropsychiatric outcomes across the spectrum of adrenal tumours. We demonstrate a graded and heterogeneous burden that extends beyond overt hormone excess to include tumours traditionally considered non-functioning. Importantly, we show that biochemical control or oncological success does not reliably translate into full functional recovery. Our findings expose major gaps in current research—most notably the absence of tumour-specific neuropsychiatric outcome measures—and underscore the need to embed patient-reported outcomes into both clinical practice and future trials. This work reframes adrenal tumours as chronic conditions with lasting patient-centred consequences, informing more holistic, long-term models of care. 

Currently, there is limited information on referral patterns, diagnostic workup, and management of adrenal tumours (ATs) across secondary and tertiary endocrine centres in the UK. We aimed to evaluate current practices in assessing and managing ATs across the country, including diagnostic pathways and adherence to international guidelines.

A 12-item web-based survey was distributed to members of the Society for Endocrinology, UK (approximately 1,600 contacts), capturing centre characteristics, number of patients with ATs, and diagnostic strategies.

In total, 85 responses representing 80 centres were analysed. Over 45% of respondents, mainly from tertiary centres, reported more than 100 annual referrals. Malignancy rates were <5% in 89.5% of centres. Nearly all centres (99.8%) reported full or partial adherence to 2023 ESE-ENSAT guidelines. However, only 55% held regular adrenal-specific multidisciplinary meetings and 24% reported referral-to-diagnosis times exceeding 6 months. Steroid profiling (urinary or serum) was incorporated into diagnostic workup by 71.8% of centres.

This survey provides the first national overview of AT management pathways in the UK. Findings highlight strong guideline adherence but variability in multidisciplinary practice and diagnostic timelines. These data offer a foundation for policy development and future research, particularly as increasing incidental detections from cross-sectional imaging place growing demands on NHS resources.

Advanced adrenocortical carcinoma (ACC) is treated with mitotane alone or combined with cytotoxic chemotherapy, yet outcomes remain poor and prognostic models in this setting are lacking. This study aimed to evaluate the prognostic value of clinical parameters in a large cohort of patients with advanced ACC undergoing systemic therapy.

Multicenter, international cohort study investigating 418 patients with advanced ACC from 11 centers. Patients received mitotane monotherapy (n = 161), etoposide + doxorubicin + cisplatin ± mitotane (n = 178), or second-line regimens (gemcitabine + capecitabine ± mitotane or temozolomide + mitotane, n = 79). Variables included age, cortisol excess, performance status (ECOG-PS), tumor burden, and neutrophil-to-lymphocyte ratio (NLR) at start of therapy. Outcomes were overall survival (OS), time to progression (TTP), and best objective response.

Tumor burden, cortisol excess, ECOG-PS, and NLR ≥5 independently predicted shorter OS (hazard ratio [HR] 1.55-2.68). We developed an integrated ENSAT Risk Score for Advanced ACC combining these variables: tumor burden (0-2), cortisol excess (0/1), ECOG-PS (0-2), and NLR (0/1). A score >2 (poor-risk) was significantly associated with worse OS and TTP across all treatment groups (HRs for OS: 3.05-3.96; TTP: 2.53-3.08). It also predicted poorer response to mitotane (P < .01) and second-line therapies (P = .04).

Conclusions: The ENSAT Risk Score for Advanced ACC is a practical, prognostic tool for patients with advanced ACC receiving systemic therapy. Based on accessible clinical and biochemical markers, it can support treatment decisions and facilitate informed discussions in routine care.

Adrenocortical adenomas are frequent in the general population and can be associated with autonomous cortisol excess, which comes with increased morbidity and mortality. Altered cAMP/PKA signalling is common in sporadic cortisol-producing adenomas, typically due to somatic mutations in the catalytic subunit α of PKA or the G-protein α subunit, Gαs (GNAS), which activate cAMP signalling. We previously identified a novel p.Lys58Gln GNAS somatic variant in a patient with an adenoma and overt Cushing's syndrome that provided enough evidence to warrant further investigation.

We established cel lines with and without the p.Lys58Gln GNAS variant and evaluated adrenocorticotropic hormone (ACTH) receptor signalling using different downstream methods, and assessed cell viability and apoptosis. The Lys58Gln variant showed a significantly higher basal cAMP, pCREB and CRE luciferase reporter concentration and a greater response to ACTH compared to non mutated GNAS. There was also significantly enhanced cell viability and apoptosis in cells with the Lys58Gln variant.

Our study demonstrated that the Lys58Gln variant is associated with constitutive activation of GNAS signalling, similar to other known mutations in adrenocortical adenomas, potentially representing a new pathogenic mechanism in a subset of patients with adrenal Cushing syndrome. 

Somatic alterations are commonly observed in adrenocortical adenomas including cortisol-producing (CPA) [overt Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS)], aldosterone-producing (APA), and non-functioning (NFAT) tumors. 

Aim of the staudy was to test whether somatic variants could be detected in circulating cell-free DNA (ccfDNA) from patients with adenomas and potentially contribute to management strategies.

• We investigated 44 patients and 23 healthy subjects that served as controls. 

• ccfDNA was extracted from blood samples and quantified with fluorimeter. Tumor DNA was isolated from paraffin embedded tissue in 17/44 cases. 

• Matched ccfDNA/T-DNA were sequenced using a customized panel including 32 genes. 

• Leucocyte DNA was used to filter out germline variants.

Patients with adenomas had higher total ccfDNA concentrations than healthy subjects, with CPA-CS showing the highest ccfDNA levels. Within T-DNA, somatic variants were identified in 53% of adenomas: PRKACA in 2/7 CPA-CS, CTNNB1 in 3/5 CPA-MACS and 1/7 CPA-CS, KCNJ5 in 2/5 APA and CACNA1D in 1/5 APA. Somatic mutations were not detected in any of the investigated ccfDNA samples.

In conclusion, ccfDNA concentrations are higher in patients with CPA-CS. Despite the presence of somatic variants in half of tumor samples, we did not detect any at ccfDNA level. Therefore, this approach appears ineffective for pre-operative detection of genetic alterations.

Serum inflammation-based scores can predict clinical outcome in several cancer types, including adrenocortical carcinoma (ACC). It is however unclear whether the extent of inflammation-based scores alterations in ACC reflects malignancy, steroid excess, or both. We investigated a large retrospective cohort of adrenocortical adenomas (ACA, n = 429) and ACC (n = 61) with available baseline full blood count and hormonal evaluation. We examined the relationship between different inflammation-based scores [neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), and prognostic nutrition index (PNI)] and both malignancy and steroid secretion patterns. All inflammation-based scores differed between ACC and ACA: patients with ACC had higher NLR, PLR, SII and lower LMR and PNI levels compared to ACA. NLR showed a positive correlation with cortisol levels after overnight 1 mg-dexamethasone suppression test, both in ACC and ACA. At multivariable analysis, NLR > 2.6 was independently associated with ACC, 1 mg-DST cortisol levels and age, but not with tumour size. Considering the ACC, NLR and SII were higher and PNI was lower in patients with cortisol excess compared to those without cortisol excess. Finally, LMR and NLR differed between inactive-ACC (n = 10) and inactive-ACA (n = 215). 

Inflammation-based scores are related to steroid secretion both in ACC and ACA. ACCs present a higher grade of inflammation regardless of their hormonal secretion, likely as a feature of malignancy itself.