Background: In the era of personalized medicine, the overall therapeutic approach has progressed throughout the years in acromegaly, but biochemical control of the disease is not achieved in a significant proportion of patients. This study aims to systematically record the journey of patients with acromegaly in the context of adenomas characteristics, therapeutic approaches and comorbidities in acromegaly with an emphasis in elderly. Method: In this retrospective study 79 patients were diagnosed with acromegaly between 1971 and 2023. Results: The dataset consisted of 43 (54%) female and 36 male (46%) with an overall mean age ± SD at diagnosis at 45 ± 13 years. 57 (73%) underwent one surgical procedure. Medical treatment with one agent was reported in 36 patients (67%), almost all by somatostatin analogs (89%). Radiotherapy was offered in 14 patients (18%). Disease remission was documented in 67 (85%) patients. IGF1/ULN at diagnosis displayed a tendency to predict non-remission. A diagnostic delay of less than five years was reported in 28 cases (65%) and patients reporting longer delays were older at diagnosis (58 ± 6 years). Patients diagnosed at or above the age of 60 were less likely to undergo a surgical procedure compared to patients diagnosed before the age of 60. Conclusions: Biochemical control was the most frequent disease outcome. A higher IGF-1/ULN ratio tends to predict non-remission. Longer diagnostic delay was reported with advancing age and older patients were less likely to follow surgical procedures.

Molecular imaging of the somatostatin receptor (SSTR) plays a key role in the management of patients with neuroendocrine neoplasms in general, and neuroendocrine tumours in particular. Over the last 2 decades, gallium-68 labelled somatostatin analogues have revolutionised SSTR imaging through the advent of SSTR positron emission tomography (PET), leading to better staging and theranostic imaging. Recent advances in the development of PET SSTR tracers continue to change the field, with novel tracers labelled with different radionuclides such as fluorine-18 and copper-64, or based on new antagonist vector molecules. The advent of these innovations generates questions, such as which tracers can be used in clinical practice, how to compare scans performed with different tracers, or can antagonists be used to select patients for peptide receptor radionuclide therapy? This 'controversy paper' from the European Neuroendocrine Tumor Society provides an overview of the relevant evidence to answer these questions, and provides guidance to clinicians and nuclear medicine physicians for contemporary use of SSTR PET.

Introduction:Pancreatic neuroendocrine tumors (pNETs) are a recognized feature of tuberous sclerosis complex (TSC). The current evidence suggests that pNETs occurring in TSC may exhibit a different clinical course from sporadic cases, but their natural history remains poorly characterized. Objective:This study aimed to characterize the demographics, clinical presentation, management, and long-term outcomes of TSC-associated-pNETs and to propose possible guidelines for surveillance and management. Materials and Methods:We conducted a multicenter retrospective review of TSC-pNET patients from 6 UK TSC specialist clinics and from 3 NET referral centers, from 2008 to 2024. Data on demographics, tumor characteristics, management, and outcomes, were collected. A systematic review of the literature from 2009 to 2026 on TSC-pNETs was also performed. Results:We identified a total of 26 consecutive cases with the TSC-pNET-association in our cohort: 21 cases of pNETs from TSC specialist clinics (1.1% of the population), and 5 cases of TSC-pNETs from the NET referral centers (0.25% of the population). An additional 80 cases were identified from the published literature. We observed a wide spectrum of clinical phenotypes, with the majority being nonfunctioning pNETs (n = 24; 92%), whereas 2 patients were diagnosed with glucagonomas. Surgical intervention was the mainstay initial treatment, the indication being either functional pNETs, or large or symptomatic nonfunctioning pNETs. Conclusion:TSC-pNETs are rare and mostly nonfunctioning tumors with variable clinical behavior. Due to their uncertain malignant potential, we suggest that baseline pancreatic imaging should be incorporated into TSC surveillance, and we emphasize the need for heightened pNET surveillance and updated management recommendations.

Langerhans cell histiocytosis (LCH) is a rare disease involving multiple organs, including the endocrine system. This multicenter study aimed to characterize patients with hypothalamic- pituitary involvement in LCH. The Hypopituitarism European NeuroEndocrine Association (ENEA) Rare Etiologies Observational Study (HEROS) platform invited ENEA members to include patients with rare pituitary diseases like LCH. Demographic data, presenting symptoms, hormonal profile, imaging tests, treatment, and prognosis were retrieved. Forty-eight patients (58

Orbital metastases (OM) are uncommon but clinically significant manifestations of systemic malignancy. Endocrine tumours represent a rare source of OM, often posing diagnostic and therapeutic challenges due to their variable presentation and indolent course. OM from endocrine tumours most commonly originate from differentiated thyroid carcinoma and neuroendocrine neoplasms. Presenting symptoms include proptosis, diplopia, pain and visual impairment, frequently mimicking inflammatory or primary orbital disorders. Imaging typically demonstrates mass-like orbital lesions, while in some cases definitive diagnosis based on histopathology may be required. Management is individualized and may include radiotherapy and/or surgical excision combined with systemic therapy in case of disseminated disease. Prognosis largely depends on the extent of systemic disease and tumour biology rather than orbital involvement alone. Although rare, OM should be considered in patients with endocrine malignancies presenting with orbital symptoms. Early recognition and multidisciplinary approach are essential to optimize visual outcomes, alleviate symptoms and guide systemic disease management.

To evaluate the metabolic dysregulation of patients with pheochromocytoma and their metabolic evolution after tumor resection. This multicenter, retrospective study included individuals diagnosed and treated for pheochromocytoma at four Greek tertiary hospitals over the past twenty-five years. Clinical data were collected from medical records and compared according to catecholamine phenotypes, incidentaloma diagnosis and hypertensive status. Correlation analysis was performed between metabolic and pheochromocytoma-related characteristics. The evolution of metabolic profiles was assessed before and after adrenalectomy. A total of 117 patients were included (median age 51 years, 59.0

Abstract:Pheochromocytomas and paragangliomas, collectively known as paragangliomas (PGLs), are rare neuroendocrine tumors originating from chromaffin cells. Surgical resection is the treatment of choice, with preoperative α-adrenoceptor blockade being consistently used prior to any surgical intervention; however, this approach has recently been challenged. This comprehensive systematic review of the literature was conducted across PubMed, Embase, and the Cochrane Library up to December 2025 to address the necessity and potential indications of α-adrenoceptor blockade in the pre-, peri-, and postoperative phase of PGL management. Papers were categorized into guidelines/consensus, meta-analyses, and clinical studies. All international guidelines uniformly recommend preoperative α-adrenoceptor blockade for functional PGLs, albeit there is no substantial evidence to support abandoning this long-standing practice. Therefore, both for medicolegal considerations and for alignment with current clinical practice, the recommendation for preoperative α-adrenoceptor blockade is still widely utilized. However, recent meta-analyses and patient cohort studies indicate no significant benefits in terms of mortality, intraoperative, or postoperative outcomes using such agents in selective patient populations. The paucity of randomized controlled trials and the recent progress in clinical practice and surgical/anesthetic techniques underscore the need for a reevaluation of the routine use of α-adrenoceptor blockade during PGL surgical resections to resolve this issue.

This ENETS guidance paper, developed by a multidisciplinary working group, provides up-to-date and practical advice on the diagnosis and management of lung and thymic carcinoids, based on recent developments and study results. These recommendations aim to provide practical recommendations for the diagnosis, treatment and follow-up of these tumours, and pave the road for more standardised care for our patients expecting improved outcomes. This paper is structured on a question-answer format in order to address common dilemmas encountered in clinical practice, including controversial issues and areas of uncertainty, based on the best available evidence and expert opinion when good quality evidence is not available. Each recommendation will provide a level of evidence and grade of recommendation as per the GRADE system (adapted from the Infectious Disease Society of United States Public Health Service grading system).

Grade 3 neuroendocrine tumours (NET G3) represent approximately 20% of high-grade neuroendocrine neoplasms, and the recent identification of this entity has given rise to many unanswered questions relating to clinical management. The prognosis for these patients is worse than for those with Grade 1-2 well-differentiated NET, but better than for those with Grade 3 poorly differentiated neuroendocrine carcinoma. This consensus statement aims to address some uncertainties and explore unmet needs in the management of patients with NET G3. Firstly, the role of surgery in localised disease will be discussed as well as the dilemma in relation to the use of neo-adjuvant and/or adjuvant treatment in this setting. Treatment of oligometastatic digestive NET G3 will also be examined, including the positioning of surgery and ablative therapy. In the advanced setting, traditionally, chemotherapy in the form of temozolomide/capecitabine or 5-fluorouracil-based therapies, rather than platinum/etoposide, is considered a first-line treatment option, with second-line therapy dependent on what was used first-line. More recently, following the results of the NETTER-2 trial, Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE may be an option for selected patients with somatostatin receptor positive NET G3. There is limited data on the use of immunotherapy and targeted therapy in this disease group to date, and some available evidence will be presented. The role for re-biopsy to guide treatment decision-making in patients with digestive NET G3 and whether NET G3 outside of the digestive tract should be treated similarly will also be scrutinised. Prospective studies with translational end-points are required to enable a better understanding of this diagnosis and to facilitate more optimal treatment discoveries.

IntroductionAdrenal tumors (ATs) encompass a wide differential diagnosis, necessitating a multi-step process for accurate identification. Liquid biopsy emerges as a promising non-invasive technique for distinguishing between malignant and benign, as well as hyperfunctioning and non-functioning cases. Recent studies have highlighted the potential of microRNAs as circulating biomarkers; however, their clinical utility remains underexplored. This study aims to validate the diagnostic performance of selected circulating microRNAs, (miR-483-5p, miR-210, miR-335 and miR-22-3p), identified through microRNA profiling studies, as markers of malignancy or cortisol hypersecretion in a cohort of patients with ATs.MethodsWe collected serum samples from 75 patients with ATs, including 50 cases of adrenocortical adenomas (ACA) and 25 cases of adrenocortical carcinomas (ACC), along with 15 controls. In the ACC subgroup, 16 samples were obtained preoperatively or upon detection of recurrence (active ACC group), while the remaining from disease-free patients with long-term follow-up. Among the 56 patients with ATs evaluated preoperatively (50 with ACAs and 6 with ACC), 26 had non-functioning tumors, 22 exhibited mild autonomous cortisol secretion, and 8 had Cushing syndrome. Quantitative real-time polymerase chain reaction was employed to analyze microRNA expression.ResultsCirculating levels of miR-483-5p and miR-210 were significantly elevated in patients with active ACC compared to both ACAs (p<0.001 and p=0.004, respectively) and controls (p=0.02 and p = 0.03, respectively). Notably, miR-483-5p serum levels were higher in patients with active ACC compared to disease-free ACC patients (p = 0.01). MiR-483-5p demonstrated the best diagnostic accuracy for distinguishing active ACC cases from ACAs, achieving a sensitivity of 81.3% and a specificity of 88%, and from disease-free ACC patients, reaching sensitivity of 81.3% and specificity of 89%. MiR-22-3p serum levels successfully differentiated patients with Cushing syndrome from those with non-functioning ATs (area under the curve=AUC=0.800, 95% CI: 0.653–0.953, p=0.01) and controls (AUC= 0.800, 95% CI: 0.610–0.990, p=0.02). Additionally, circulating miR-22-3p levels exhibited a significant correlation with traditional diagnostic tests for hypercortisolism.ConclusionThis study supports the potential of a liquid biopsy approach as an innovative method for diagnosing and monitoring patients with ATs, offering a complementary tool to existing diagnostic methods.

OBJECTIVE:To study cardiovascular morbidity in patients with biochemically inactive pheochromocytomas/paragangliomas. METHODS:PubMed, Cochrane, and Scopus databases were searched by two independent reviewers to identify relevant studies. Twenty-four case reports ( n  = 24 patients) met the inclusion criteria providing data on the cardiovascular status of biochemically negative pheochromocytomas/paragangliomas patients. Methodological quality was assessed by the Grading of Recommendations, Assessment, Development and Evaluations system, and all included studies were assessed for the risk of bias. This systematic review was conducted in conformance with the PRISMA statement and registered to PROSPERO (ID: CRD42024530601). RESULTS:Almost half of patients (46%) presented objective abnormal findings on noninvasive cardiovascular examination performed routinely before surgery, whereas 67% complained of pheochromocytoma/paraganglioma-related symptoms (angina, headache, diaphoresis, shortness of breath, palpitations) and exhibited relevant clinical signs (hypertension, tachycardia, tachypnea, pallor). Preoperatively, only 38% of patients with biochemically negative pheochromocytomas/paragangliomas were treated with alpha-blockers, 25% did not receive any pharmaceutical preparation whereas data were not available for the remaining 37% of patients. Following an uneventful surgery, 70% of patients exhibited resolution of the preoperatively detected cardiovascular symptoms and signs. CONCLUSION:The high occurrence of cardiovascular abnormalities in patients with pheochromocytomas/paragangliomas characterized as "biochemically negative" based on routine biochemical analyses highlights the difficulty in the appropriate classification of these tumors regarding their secretory profile and thus the risk of missing cardiovascular system involvement with potentially deleterious effects.

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 adrenocorticotropic hormone (ACTH)-secreting neuroendocrine neoplasms (NENs) represent a rare but frequently severe disease that is associated with poor prognosis, if not adequately managed. Treatment strategies vary according to the characteristics of the tumor and the severity of hypercortisolism. The optimal treatment is surgical resection of the NEN with a curative intent. In unresectable or metastatic tumors, medical control of hypercortisolism with concomitant treatment of NENs based on current guidelines is suggested. Steroidogenesis inhibitors are the principal choice to control hypercortisolism while bilateral adrenalectomy should be considered in cases of failure to control severe life-threatening hypercortisolism. Additionally, amongst the various anti-tumor systemic treatment options, peptide receptor radionuclide therapy (PRRT) seems to also be an effective option for the control of hypercortisolism. Preventive and curative treatment of cortisol-induced complications and comorbidities is also important to reduce morbidity and mortality. Overall, the management of ACTH secreting NENs may be very complex and requires an individualized approach in a multidisciplinary context to achieve the best and timely outcome for the patient.

Background:Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with variable behavior and metastatic potential. Reliable prognostic biomarkers are needed to improve risk stratification and long-term management. Emerging data suggest a role for microRNAs (miRNAs) and immune checkpoint pathways (or inhibitors) in tumor aggressiveness. Objective:To evaluate the expression of five candidate miRNAs (miR-15a, miR-16, miR-101, miR-183, and miR-483-5p) and programmed death ligand-1 (PD-L1) in PPGL tissues, and assess their associations with clinicopathological features, genetic status and outcomes. Methods:A retrospective cohort of 130 patients with PPGLs was analyzed, including 53 PPGL tumor and 20 normal adrenal medulla tissues (controls). MiRNA expression was assessed by RT-qPCR in 53 formalin-fixed paraffin-embedded samples (FFPE). PD-L1 and microsatellite instability (MSI) were evaluated by immunohistochemistry in FFPE samples. Associations with tumor type and size, functionality, Ki-67 index, grading scores (PASS, GAPP), metastatic status, localization, and genotype were examined. Results:Overall, 21.5% (28/130) of patients developed metastases during a median period of follow-up of 45 months and 35 out of the 61 tested (57.4%), harbored pathogenic germline mutations. In tumor samples (n=53), PD-L1 expression was observed in 18.9% (10/53) whereas no MSI expression was detected. MiR-483-5p was the most consistently upregulated marker in biochemically negative and in high-Ki-67 tumors along with significant up regulation in metastatic PPGL, supporting its role in cellular proliferation and metastatic potential. MiR-183 and miR-101 were overexpressed in pheochromocytomas (PHEOs) with high PASS and Ki-67 indices, while miR-15a and miR-16 displayed higher levels in non-metastatic tumors. Conclusion:MiR-483-5p emerges as a promising biomarker of aggressive PPGL behavior, while other miRNAs reflect distinct biological behaviors. PD-L1 expression in a subset of cases highlights immune checkpoint inhibition as a potential therapeutic strategy. Prospective validation is warranted.