Graphical Abstract: Abstract:The incidence of adrenal tumors rises with age, but the link between adrenal aging and tumorigenesis is still not well defined. This mini-review summarizes age-related changes in both the adrenal cortex and medulla, including structural remodeling, altered steroidogenesis, and shifts in immune and cellular homeostasis. We then examine adrenocortical carcinoma (ACC), where clinical outcomes are poorer in older patients and where senescence, inflammation, and sex-specific immune differences may shape disease behavior. Limited information is available for other adrenocortical tumors, while pheochromocytomas in the elderly are described mainly in case reports, often with diagnostic and perioperative difficulties. For other rare adrenal neoplasms, data are fragmentary. Much of the mechanistic evidence summarized here derives from preclinical models, and robust clinical validation remains limited; accordingly, translational inferences should be regarded as provisional. The evidence suggests that aging influences both the biology and clinical course of adrenal tumors, but systematic studies are lacking. This review brings together what is currently known and highlights many open questions. We hope this will serve as a starting point for further work on how aging affects adrenal function and tumor development and how this knowledge might be used to improve care of older patients.

IntroductionThis study aimed to assess the prognostic values of the S-GRAS model and two of the most frequently used inflammation-based scores – neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) – and to characterise the potential interaction between the two measures.Patients and methodsIn this single-centre, retrospective, observational cohort analysis, 67 adult patients with histologically confirmed adrenocortical carcinoma (ACC) were analysed. The S-GRAS score and the inflammation-based markers were evaluated using Kaplan-Meier survival analysis with log-rank tests, univariate and multivariate Cox proportional hazards regressions. Discriminative ability was assessed using Harrell’s C-index, later compared with likelihood ratio tests. An interaction analysis was conducted by constructing a multivariate regression with mean-centred variables and their interaction term.ResultsExternal validation on the S-GRAS scoring system demonstrated the superior discriminative ability of the model (C-index=0.765) compared to its constituents. Our sub-analysis on 42 patients identified NLR as a significant predictor of mortality (HR = 3.1; p=0.008), whilst PLR failed to reach statistical significance. Our interaction analysis revealed a significant synergistic interaction between S-GRAS and NLR (HR = 1.177, p=0.009). While both S-GRAS (C-index=0.803) and NLR (C-index=0.722) was found to be a significant predictor of survival, their joint application demonstrated superior prognostic discrimination (C-index=0.822) over their individual use (p=0.006 and p<0.001).ConclusionsNLR provides independent and complementary predictive value to the well-established S-GRAS score, and their combination offers superior discrimination over each marker alone. A synergistic interaction between the two metrics is the most prominent in high-risk patient groups. External validation confirms the prognostic robustness of the S-GRAS score.

BACKGROUND:Biopsy of phaeochromocytomas and paragangliomas (PPGLs) is discouraged due to the perceived risk of catecholamine-related complications. However, a systematic review showed that this recommendation is primarily supported by case reports. We aimed to assess the safety of percutaneous biopsy in patients with PPGLs. METHODS:This international, multicentre, retrospective study included patients of any age with PPGLs referred to participating centres who had had percutaneous core-needle biopsy or fine-needle aspiration. Biopsies of head and neck paragangliomas were excluded. Participating centres completed standardised data-collection forms. The primary outcome was biopsy-related mortality rate for all patients who had biopsies performed at participating centres, given that biopsies done elsewhere that had fatal outcomes would be unlikely to be referred. Secondary outcomes included the incidence of serious catecholamine-related and non-catecholamine-related complications among all included patients. FINDINGS:Between Sep 1, 1993, and May 31, 2025, 222 patients (110 [50%] female, 112 [50%] male) underwent 234 biopsies in 19 hospitals across 11 countries. 139 (67%) of 207 patients had elevated epinephrine or norepinephrine (or metabolites) and 27 (12%) of 232 biopsies were preceded by the administration of α-adrenoceptor blockade. One (mortality rate 0·9% [95% CI 0·0-5·1]) of 106 biopsies led to death due to biopsy-related infection. Serious catecholamine-related complications occurred after four (1·7% [0·5-4·3]) of 233 biopsies and included tachyarrhythmia, hypertensive crisis, and cardiogenic shock. No serious catecholamine-related complications occurred in patients without catecholamine excess (n=59), receiving fine-needle aspiration (n=46), or after biopsy of metastatic lesions (n=114). Serious non-catecholamine-related complications occurred after ten (4·3% [2·1-7·8]) of 233 biopsies, mainly bleeding and infection. INTERPRETATION:Percutaneous biopsy of PPGLs was associated with a low mortality rate. Serious complication rates were also low, most of which were not catecholamine-related. These findings challenge current recommendations that biopsy should be avoided in suspected or confirmed PPGLs, and instead support a personalised, risk-benefit-based approach to the procedure. FUNDING:Cancerfonden. TRANSLATIONS:For the Chinese and French translations of the abstract see Supplementary Materials section.

The differentiation of benign and malignant adrenocortical tumors is of major clinical relevance. Circulating microRNAs (miRNAs) hold promise as blood-borne biomarkers of adrenocortical cancer (ACC). There are, however, many difficulties with their use, including technical and biological standardization challenges. Our aim was to evaluate the interchangeability of quantitative polymerase chain reaction (qPCR) and digital PCR (dPCR) for measuring circulating miRNAs and to investigate whether K2- and K3-EDTA as anticoagulants influence the measurements. Blood samples were drawn simultaneously from 20 participants into K2- and K3-EDTA tubes. Three miRNAs shown to be associated with ACC (miR-483-5p, miR-210-3p, miR-21-5p), together with two controls (miR-16-5p, cel-miR-39-3p), were analyzed using RT-qPCR and dPCR. qPCR and dPCR results showed different correlations in K2- and K3-EDTA samples, with K2 performing better regarding ΔCt values. Moreover, proportional biases related to low or high miRNA expressions between the two methods were observed. In qPCR measurements, K3-EDTA samples showed larger standard deviations, particularly for cel-miR-39. While raw Ct values differed between K2- and K3-EDTA only for miR-483-5p, ΔCt values showed statistically significant differences across all miRNAs except for miR-483-5p. dPCR results were not affected by the choice of anticoagulant. In conclusion, this is the first study demonstrating that dPCR and qPCR results are not easily interchangeable for circulating miRNA, particularly for abundant or rare miRNAs, making cross-validation studies challenging. K2- and K3-EDTA could potentially influence qPCR outcomes, underscoring the need for standardized protocols. A consensus-based methodology could improve reproducibility, enhancing miRNA-based biomarker utility in adrenocortical tumor diagnostics.

Adrenocortical carcinoma (ACC) is an aggressive cancer with a poor prognosis. Mitotane, the only FDA-approved treatment for ACC, targets adrenocortical cells and reduces cortisol levels. Although it remains the cornerstone of systemic therapy, its overall impact on long-term outcomes is still a matter of ongoing clinical debate. Drug repurposing is a cost-effective way to identify new therapies, and defactinib, currently in clinical trials as part of combination therapies for various solid tumours, may enhance ACC treatment. We aimed to assess its efficacy in combination with mitotane. We tested the combination of mitotane and defactinib in H295R, SW13, and mitotane-sensitive and -resistant HAC15 cells, using functional assays, transcriptomic profiling, 2D and 3D cultures, bioprinted tissues, and xenografts. We assessed drug interactions with NMR and toxicity in vivo, as mitotane and defactinib have never been previously administered together. Genomic data from 228 human ACC and 158 normal adrenal samples were also analysed. Transcriptomic analysis revealed dysregulation of focal adhesion along with mitotane-related pathways. Focal adhesion kinase (FAK) signalling was enhanced in ACC compared to normal adrenal glands, with PTK2 (encoding FAK) upregulated in 44% of tumour samples due to copy number alterations. High FAK signature scores correlated with worse survival outcomes. FAK inhibition by defactinib, both alone and in combination with mitotane, showed effective anti-tumour activity in vitro. No toxicity or drug—drug interactions were observed in vivo. Combination treatment significantly reduced tumour volume and the number of macrometastases compared to those in the mitotane and control groups, with defactinib-treated tumours showing increased necrosis in xenografts. Defactinib combined with conventionally used mitotane shows promise as a novel combination therapy for ACC and warrants further investigation.

Az elmúlt évtizedekben a klinikai endokrinológia jelentős fejlődésen ment át hazánkban. E rövid áttekintésben e fejlődés néhány fő elemét mutatom be, saját szakterületemre, a mellékvese betegségeire és a neuroendokrin daganatokra, valamint az öröklődő daganatszindrómákra összpontosítva. A diagnosztika és kezelés fejlődésének fő elemeit, a várható kihívásokat és további fejlődési irányokat is tárgyaljuk.

OBJECTIVE:Individual patients' data sharing requires interoperability, security, ethical, and legal compliance. The aim was to assess the landscape and sharing capacities between endocrine researchers. DESIGN:A standardized survey (SurveyMonkey®) with 67 questions was sent to European Network for the Study of Adrenal Tumors centers. METHODS:Answers were counted as absolute numbers and percentages. Comparisons between inclusiveness target countries (ITC) and non-ITC (defined by Cooperation in Science & Technology Action) were performed using Fisher's exact test. RESULTS:Seventy-three centers from 34 countries answered the survey. Electronic health record (EHR) systems are now the main source of data (90%). However, significant variability was reported, entailing >35 EHR providers, and variable data collected. Variable stakeholders' implication for enabling data sharing was reported, with more lawyers (P = .023), patient representatives (P < .001), ethicists (P = .002), methodologists (P = .023), and information technology experts (P < .001) in non-ITC centers. Implication of information technologies experts for data collection and sharing was underwhelming (33%). Funding for clinical research was higher in non-ITC than in ITC for clinical trials (P = .01) and for registry-based and cohort studies (P = .05). However, for retrospective studies addressing a specific clinical question, the funding was either very low (<10%) or nonexistent for both ITC and non-ITC (37% and 46%, respectively), with no dedicated funding for information technology (86%) and ethical and regulatory aspects (88%). CONCLUSIONS:In the absence of dedicated funding for retrospective research, current requirements for data sharing are obstacles.

BACKGROUND:Cyclic Cushing's syndrome (cCS) features fluctuating cortisol secretion, often causing diagnostic errors or delays, and possibly poorer outcomes. We aimed to identify unpublished cCS cases to characterise clinical challenges and guide strategies for improving outcomes by characterising cycle patterns, peak frequency, and evaluating complications. METHODS:This was a retrospective observational study at 43 endocrine centres in 21 countries, including patients with confirmed Cushing's syndrome showing two or more hypercortisolaemic peaks and one or more spontaneous eucortisolaemic or hypocortisolaemic trough. Data included both clinical (eg, comorbidities and physical signs of cortisol excess) and biochemical (eg, screening and confirmatory tests) parameters, imaging, treatment, complications, and outcomes. FINDINGS:Between Dec 1, 2023 and Feb 2, 2025, 116 potentially eligible patients were identified and 110 were included. Most patients were female (84 [76%] of 110 patients), with a median age at diagnosis of 44·0 years (IQR 31·8-58·3). cCS origin was pituitary in 70 (64%), ectopic in 25 (23%), adrenal in three (3%), and occult in 12 (11%). Cyclicity was primarily determined by 24 h urinary free cortisol, with median peaks of 7·40 × ULN (range 0·44-299) and troughs of 0·31 × ULN (0·02-0·98). The median peak count was 3·0 (IQR 2·0-4·0), mostly (55 [86%] of 64 patients) occurring at irregular intervals, and was most frequent and pronounced in ectopic cCS. Symptoms worsened in 87 (81%) of 108 patients during peaks and improved in 79 (74%) of 107 patients during troughs; 31 (28%) of 110 patients had spontaneous adrenal insufficiency. Bilateral inferior petrosal sinus sampling (BIPSS) was performed during troughs in 14 patients (18% of the 78 procedures done). Imaging missed tumours in 35 (32%) of the 110 patients, and nine (8%) underwent unwarranted surgeries at the wrong anatomical site due to misclassification. After 5·8 years (IQR 2·6-10·5) median follow-up, 55 (50%) of 110 patients had complete biochemical surgical remission, seven (6%) had spontaneous remission, 22 (20%) were medically controlled, six (5%) had partial remission, 11 (10%) remained uncontrolled, nine (8%) were lost to follow-up. During the entire observation period, 3% (3/110) died. Delayed diagnosis (45 [41%] of 110 patients) and therapy (47 [43%]) were also observed. INTERPRETATION:Even in specialised centres, cCS diagnosis and management remain challenging with high rates of spontaneous adrenal insufficiency, inappropriate surgeries, and poor outcomes. Ectopic cCS showed the most frequent and severe peaks. These findings might help to guide imaging localisations or the timing of BIPSS in patients with active occult ACTH-dependent cCS. Hypercortisolism needs to be biochemically confirmed before BIPSS to enable correct tumour localisation. Patients with suspected or proven cCS should be equipped with salivary cortisol collection kits to capture dynamic changes as well as being prescribed glucocorticoids to be used as a precaution. FUNDING:None.

The hyperinsulinemic hypoglycemic syndrome is typically caused by insulinoma, a neuroendocrine tumor of the pancreas. Beyond the diagnosis, the most difficult part is the accurate localization of the tumor, which is essential to the curative surgical therapy. A 36-year-old woman with several episodes of loss of consciousness was diagnosed with endogenous hyperinsulinemia causing hypoglycemia. The MRI raised the possibility of a 5-mm lesion in the tail of the pancreas, however, neither the CT, nor the endoscopic ultrasound was able to confirm it. The somatostatin-receptor scintigraphy was also negative. The 68Ga-exendin PET/CT showed tracer enhancement in the tail of the pancreas in the same region as in the MRI. Based on these results, a distal pancreas resection was made. After the surgery, the hypoglycemic episodes of the patient disappeared and histology confirmed the diagnosis. Conventional imaging techniques are often not sensitive enough for the localization of insulinoma, mostly in cases of small, hypovascularized tumors. Somatostatine-receptor targeted modalities which are widely used in the imaging of neuroendocrine tumors could be negative because of the lower expression of somatostatine receptors. In our case, the novel, functional imaging 68Ga-exendin PET/CT was efficiently used, which can localize insulinomas with high sensitivity. Orv Hetil. 2025; 166(6): 228–233.

Neuroendocrine neoplasms (NEN) themselves and also their treatment may cause malnutrition, inducing changes in physiological behaviour and eventually leading to increased rates of morbidity and mortality. Malnutrition is a common, under-recognised and under-treated condition in patients with NEN, and there are limited data available on the role of optimising nutrition in this setting. There are no formal evidence-based European Neuroendocrine Tumor Society (ENETS) guidelines on nutrition evaluation and management in patients with NEN to date. This manuscript was initiated during the 2024 ENETS Advisory Board meeting by using an expert panel consensus methodology and specific structured questions, which were identified and addressed through a structured review of the literature. The manuscript aims to identify the presence of specific nutrient deficits and define unmet needs and controversies regarding nutrition and NEN in a succinct manner, to promote collaborative and multidisciplinary research in the field, and to offer practical guidance in terms of how to assess malnutrition and dietary interventions by means of formulating a structured questionnaire.

A hyperinsulinaemiás hypoglykaemiás tünetegyüttes fő oka a pancreas neuroendokrin daganata, az insulinoma. A nehézséget a diagnózis felállításán túl a tumor pontos lokalizációja adja, mely elsődleges a kuratív műtét elvégzéséhez. 36 éves nőbetegünk esetében zavartság, eszméletvesztéssel járó rosszullétek hátterében igazolódott hypoglykaemiát okozó endogén hyperinsulinaemia. Az MRI felvetette a pancreas farki részén 5 mm-es eltérés jelenlétét, mely ezt követően sem a hasi CT-vizsgálaton, sem az insulinoma diagnózisában nagy jelentőséggel bíró endoszkópos ultrahangvizsgálaton nem ábrázolódott. Szintén nem igazolódott szomatosztatinreceptor-pozitivitás a hasnyálmirigy területén az elvégzett szomatosztatinreceptor-szcintigráfia során. A 68 Ga-exendin-PET/CT ugyanakkor az MRI-n leírt laesiónak megfelelő dúsulást jelzett a pancreas farki régiójában. A vizsgálat eredménye alapján distalis pancreasresectio történt, melyet követően a beteg hypoglykaemiás rosszullétei megszűntek, és a szövettani vizsgálat a diagnózist megerősítette. A hagyományos képalkotó diagnosztikai módszerek gyakran nem informatívak az insulinoma lokalizálásában, elsősorban a kis méretű, hipovaszkularizált laesiók esetében. A neuroendokrin daganatoknál széleskörűen alkalmazott szomatosztatin-receptor kimutatását célzó képalkotó vizsgálatok az insulinomák esetében negatív eredményt adhatnak az alacsony szomatosztatinreceptor-expresszió miatt. Esetünkben a legújabb funkcionális képalkotó módszert, a 68 Ga-exendin-PET/CT-t hatékonyan alkalmaztuk, mely specifikusan képes kimutatni még a kis méretű insulinomákat is. Orv Hetil. 2025; 166(6): 228–233.

Circulating non-coding RNA (ncRNA) molecules are being investigated as biomarkers of malignancy, prognosis and follow-up in several neoplasms, including endocrine tumours of the pituitary, parathyroid, pancreas and adrenal glands. Most of these tumours are classified as neuroendocrine neoplasms (comprised of neuroendocrine tumours and neuroendocrine carcinomas) and include tumours of variable aggressivity. We consider them together here in this Review owing to similarities in their clinical presentation, pathomechanism and genetic background. No preoperative biomarkers of malignancy are available for several forms of these endocrine tumours. Moreover, biomarkers are also needed for the follow-up of tumour progression (especially in hormonally inactive tumours), prognosis and treatment efficacy monitoring. Circulating blood-borne ncRNAs show promising utility as biomarkers. These ncRNAs, including microRNAs, long non-coding RNAs and circular RNAs, are involved in several aspects of gene expression regulation, and their stability and tissue-specific expression could make them ideal biomarkers. However, no circulating ncRNA biomarkers have yet been introduced into routine clinical practice, which is mostly owing to methodological and standardization problems. In this Review, following a brief synopsis of these endocrine tumours and the biology of ncRNAs, the major research findings, pathomechanisms and methodological questions are discussed along with an outlook for future studies. Circulating non-coding RNA (ncRNA) molecules are being investigated as biomarkers of endocrine tumours of the pituitary, parathyroid, pancreas and adrenal glands. This Review outlines ncRNA biology, before discussing research findings on ncRNAs in endocrine tumours and their potential utility as biomarkers, ending with an outlook for future studies. Endocrine tumours, including pituitary, pancreatic and parathyroid neuroendocrine tumours, adrenocortical cancer and phaeochromocytoma-paraganglioma, share common features in their pathogenesis, genetic background and associated clinical challenges.Non-coding RNAs (ncRNAs) can be exploited as tissue-specific biomarkers of malignancy, prognosis and follow-up, and their circulating counterparts can be measured in blood samples as a form of liquid biopsy.Circulating microRNAs show promising utility as biomarkers of malignancy and prognosis in adrenocortical tumours, and several other differentially expressed ncRNAs were reported in other endocrine tumours.Apart from circulating and , few overlaps are observed in the circulating ncRNA molecules expressed from different types of endocrine tumour.None of these biomarkers has yet been introduced into clinical practice, which is mainly owing to difficulties in standardization and methodology.