Neuroendocrine tumours (NETs) are heterogeneous, biologically variable tumours arising from the diffuse neuroendocrine system. While more frequently seen in older patients, the incidence and prevalence of NETs in the younger population are increasing. In addition, because of their generally slow progression and favourable prognosis, coupled with widely available effective treatments, survival times even with metastatic tumours may often be prolonged. However, there is a paucity of data on the effect of treatment of NETs on men’s and women’s reproductive and sexual health. In this review, we have evaluated the effects of NET therapies, including somatostatin analogues (SSTAs), molecular targeted therapy (everolimus and sunitinib), peptide receptor radionuclide therapy (PRRT), and chemotherapy, on reproductive and sexual function in patients with NETs. There is a lack of evidence on the detrimental effects of SSTAs on human fertility, and indeed, many patients have conceived successfully after many years of treatment with SSTAs. Even patients who have received SSTAs during pregnancy have generally shown positive maternal and fetal outcomes. While the effects of PRRT and molecular targeted therapy on fertility are as yet poorly defined, chemotherapy has a proven negative impact on fertility; thus, family and pregnancy planning are strongly recommended before the initiation of chemotherapy. Finally, data on the effects of NET treatment on sexual function are very limited; however, neuroendocrine tumours can express oestrogen receptors/progesterone receptors (ER/PR) or testosterone receptors (TR); thus, checking tumour tissue for ER/PR/TR status prior to considering hormonal therapy for sexual dysfunction should be considered but warrants additional studies.

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.

Pheochromocytomasand paragangliomas (collectively referred as PPGLs) are highly heritable neoplasms arise from chromaffin cells of neural crest tissues; 40% of patients with PPGLs harbour germline pathogenic variants (PV), which up to 45% of patients exhibit somatic mutations in similar susceptibility genes. Endothelial PAS domain-containing protein-1 [also known as hypoxia inducible factor-2α, HIF-2α] is encoded by EPAS1, and along with other hypoxia-inducible factors (HIFs) acts as a key mediator in the cellular response to hypoxia. Gain-of-function mutations in EPAS1 have been linked to the Pacak-Zhuang syndrome, congenital cyanotic heart disease and sickle cell anaemia. Hypoxia due to chronic anaemia and/or associated nephropathy in patients with sickle cell disease (SCD) may increase the expression of genes related to HIFs, thereby increasing susceptibility to the development of PPGLs. We describe a case of young female with a history of sickle cell anaemia and sickle cell nephropathy who was found to have a para-aortic mass. Histology confirmed the diagnosis of a paraganglioma. She did not exhibit somatic mutations of the common predisposition genes but demonstrated a likely pathogenic activating somatic EPAS1 variant mutation. This case illustrates the predisposition of patients with SCD to PPGLs due to somatic EPAS1 mutations, and should increase awareness of such tumours in these patients.

OBJECTIVES:Type 1 gastric neuroendocrine tumors (T1g-NETs) are well-differentiated lesions with excellent survival but frequent recurrence. Tumor size is the main prognostic factor, yet optimal management for tumors >1cm remains uncertain. This study aimed to evaluate treatment strategies and outcomes in patients with T1g-NETs>1 cm. METHODS:We conducted a retrospective multicenter study including 106 adults with T1g-NETs>1 cm. Clinicopathologic and management data were collected. The primary outcome event was a composite unfavorable outcome (UO), defined as recurrence or progression, used to analyze progression-free survival as the main time-to-event outcome. Analyses included multinomial logistic regression, Cox models, and Kaplan-Meier curves (p<0.05). RESULTS:Among 106 patients (58.5% female; median age 59), median tumor size was 15mm. Most tumors were Grade 1 (61.4%) or Grade 2 (37.7%), with median Ki-67 of 2%. Endoscopic resection was performed in 76 patients (71.7%), surgery in 33 (31.1%, including 13 initially treated endoscopically), and 10 (9.4%) were surveilled. Over a median 61-month follow-up, 24 patients (22.6%) recurred, 8 (7.5%) progressed; only 2 deaths (1.9%) were tumor-related. Larger tumors were associated with UO (p=0.005), with lesions ≥24mm predicting shorter progression-free survival (HR 3.93;p<0.001). Endoscopic submucosal dissection (ESD) and modified-endoscopic mucosal resection (m-EMR) were associated with a significantly longer progression-free survival (p=0.004). R0 resection showed a borderline protective effect. Five-year overall survival approached 95%. CONCLUSIONS:T1g-NETs>1cm frequently recur and may exhibit aggressive potential, particularly when lesions are larger. When endoscopic resection is feasible, ESD or m-EMR should be preferred to optimize outcomes.

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).

Effector/Treg ratio is significantly lower in tumor tissues and CD8+ in metastatic tissue is significantly more regulated compared with other tissue types. A, The horizontal black bars indicate the median values for each compartment. The ratio of effectors to regulatory T cells was significantly lower in primary or metastatic tumor tissues compared with the normal tissue (CD8/Treg) and PBMCs (CD4eff/Treg). B, Single level expression and co-expression of B7 and TNFR superfamily co-inhibitory and co-stimulatory molecules on T-cell subsets were quantified by flow cytometry in matched peripheral blood mononuclear cells (PBMC), normal tissue, primary, and metastatic tumor tissues obtained from all patients. Displayed is a heatmap depicting the mean percentage of CD8+, CD4eff (CD4+ FoxP3–), and Treg (CD4+ FoxP3+) cells expressing individual immune checkpoint molecules and proliferating markers in each tissue sample. *, P < 0.05; **, P < 0.005; ***, P < 0.0005.

Mixed neuroendocrine and non-neuroendocrine neoplasms (MiNENs) are rare neoplasms composed of morphologically distinguishable neuroendocrine (NE) and non-neuroendocrine components, each representing at least 30

SiNET mutational load. This shows a comparison of the siNET mutational load against 33 TCGA cohorts from the Multicenter Mutation Calling in Multiple Cancers (MC3; ref. 63) project.

Introduction:177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) represents a possible therapeutic option for patients with metastatic inoperable phaeochromocytomas (PCC) and paragangliomas (PGL) who demonstrate adequate somatostatin analogue binding on molecular imaging. We describe treatment outcomes in our cohort of patients stratified according to germline pathogenic variants (PV) in succinate dehydrogenase (SDHx) subunit-encoding genes. Methods:In this retrospective analysis, we evaluated 20 patients with metastatic PCC/PGL who underwent two or more cycles of 177Lu-DOTATATE therapy. Clinical, radiological, and biochemical responses were assessed 8-12 weeks after the final PRRT cycle. We describe overall treatment efficacy at follow-up after stratifying according to the presence of germline SDHx PV. Radiological progression was quantified based on the sum of the longest diameter (SLD) of the target lesion. Progression-free survival (PFS) and overall survival were estimated using Kaplan-Meier survival analysis. We also aimed to investigate the impact of PRRT on health-related quality of life (HRQoL), as assessed using the EORTC QLQ-GINET21 questionnaire. Results:After a median follow-up of 29 months, we confirmed stable disease in 12 patients (60%), a partial response in one (5%), and progressive disease in seven patients (35%). The absolute mean difference in SLD was +5 ± 12 mm for bone lesions, -4 ± 6 mm for peritoneal, +8 ± 14 mm for liver lesions and -1 ± 5 mm for lymph nodes (paired t-test P-value 0.273, 0.741, 0.208 and 0.826, respectively). Thirteen patients (65%) had received two or more previous lines of treatment. The overall median PFS for the entire cohort, PGL patients, SDHx positive and negative groups was 24 months (95% CI: 9.9-38.1), 18 months (95% CI: 8.4-27.6), 24 months (95% CI: 11.9-36.0) and 18 months (95% CI: 0-48), respectively. No grade 3/4 cytopenia or nephrotoxicity was observed. Overall, HRQoL improved after PRRT, as evidenced by the progressive decline in overall symptom scores in the QLQ-GINET21. Conclusion:177Lu-PRRT appears to be an effective therapy with a good safety profile for patients with metastatic PPGL. It also appears to improve HRQoL in patients with metastatic PPGL. Further studies are needed to explore the most effective treatment modalities in this group of patients and their sequencing.

CD8+ in metastatic tissue is more regulated compared with other tissue types. Co-expressions of key B7 and TNFR superfamily co-inhibitory and co-stimulatory molecules on T-cell subsets were quantified by flow cytometry with matched PBMCs, normal tissue, and tumors from primary and metastatic sites. A, SPICE analysis of all CD8+ and CD4eff T cells displaying the mean co-expression of checkpoint molecules across tissue types. B, Unsupervised FlowSOM of CD8 and CD4eff clustering demonstrates that PBMCs (red box) are distinctly different to other tissues types. C, UMAP distribution of each FlowSOM CD8 and CD4eff population (blue) on each tissue subtype (orange).

BACKGROUND:Type 1 gastric neuroendocrine tumors (T1-gNETs) are typically indolent. Current guidelines suggest endoscopic surveillance for lesions ≤10 mm, mainly based on expert consensus. AIM:To evaluate outcomes in patients with T1-gNETs ≤10 mm managed by endoscopic surveillance. METHODS:This dual-center retrospective study (2000-2023) included patients from two Western ENETS Centers of Excellence with T1-gNETs ≤10 mm under surveillance. Primary endpoints were disease progression rate and progression-free survival (PFS); p < 0.05 was considered significant. RESULTS:A total of 125 patients (66.4 % female; median age 59.5 years) with a median tumor size of 3 mm were analyzed. Most tumors were G1 (92.8 %), and 75.2 % had ≤5 lesions. Over a median follow-up of 72 months, progression occurred in 5 patients (4 %), with no metastases. Low-grade dysplasia was found in 2.4 % and early gastric cancer in 1.6 %. Eleven patients (8.8 %) died, none from tumor-related causes. Restricted mean survival time was 266.5 months. The 5-year PFS rate was 97.8 %. Having ≤5 lesions was significantly associated with lower progression risk (HR = 0.14, 95 % CI: 0.014-0.76, p = 0.022). CONCLUSIONS:T1-gNETs ≤10 mm show low progression risk and can be safely managed with lifelong surveillance. In patients with solitary or few lesions, extended intervals may be appropriate.

Purpose:To evaluate the added benefit and accuracy of 68Ga-DOTA-TATE PET/CT scans in detecting duodeno-pancreatic neuroendocrine tumours (dpNETs) compared to conventional cross-sectional imaging with CT or MRI scans in patients with multiple endocrine neoplasia type 1 (MEN-1), and whether the results from the 68Ga-DOTA-TATE PET/CT produce a change in management plans for patients with MEN-1 and dpNETs. Methods:A retrospective analysis was performed comparing the initial 68Ga-DOTA-TATE PET/CT to the respective contemporary CT or MRI imaging in patients with MEN-1 under the care of a tertiary neuroendocrine centre. Imaging and electronic patient records were analysed to identify treatment plans and the records of multidisciplinary team discussions. Results:In total, 85% (n = 39/46) of patients with MEN-1 had a 68Ga-DOTA-TATE PET/CT study in the electronic patient record; 23 of those with duodeno-pancreatic lesions detected also had contemporaneous contrast-enhanced CT scans, while 18 had MRI scans. 68Ga-DOTA-TATE PET/CT detected a total of 47 pancreatic lesions compared to 25 on CT, while 68Ga-DOTA-TATE PET/CT detected 32 pancreatic lesions compared to 25 on MRI. There were no duodenal lesions detected on conventional CT or MRI, but in comparison to CT and MRI, 68Ga-DOTA-TATE PET/CT detected eight and one duodenal lesions respectively. While 68Ga-DOTA-TATE PET/CT detected more liver metastases compared to CT (n: 31 vs 21) and similar numbers compared to MRI (n: 11 vs 11), these differences were not statistically significant. As a result of findings on 68Ga-DOTA-TATE PET/CT, a change of management was indicated in 69% (n = 27/39) of patients. Of these, 14 patients were offered somatostatin analogues (SSTA), eight patients were offered surgical intervention, three patients were offered peptide receptor radionuclide therapy, and one patient was offered ablation of liver metastases. Conclusions:In patients with MEN-1, 68Ga-DOTA-TATE PET/CT was shown to detect a greater number of duodeno-pancreatic lesions compared to conventional cross-sectional CT or MRI imaging. Management plans were changed in most patients following their initial 68Ga-DOTA-TATE PET/CT. Therefore, we suggest that somatostatin receptor-targeted PET/CT scans should be an integral part of the investigation of patients with MEN-1 for staging of suspected duodeno-pancreatic NETs.

Objective: Glucagonomas are rare islet cell tumours, accounting for 2% of such tumours, with an annual incidence of 0.01–0.1 per million. This study aimed to describe diagnostic characteristics and treatment outcomes in patients with glucagonoma from a major referral centre. Design: A retrospective case series included patients diagnosed with glucagonoma at the ENETS Centre of Excellence, Royal Free Hospital, London, UK. Methods: Electronic patient records were reviewed to document baseline disease characteristics and treatment outcomes. Disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) were calculated using the Kaplan–Meier method. Results: Twenty patients (75% male, age 56.6 ± 11.6 years, mean Ki-67 index 7.3 ± 7, mean ± SD) were included; 50% had liver metastases at diagnosis. The median OS was 34 months (95% CI: 30.3–37.7). Median OS was 34, 9, and 71 months for patients with liver, lung, and skeletal metastases, respectively. At diagnosis, migratory necrolytic erythema was linked to poorer OS (22 months, 95% CI: 14.3–29.7). Median DFS following surgery was 25 months (95% CI: 3.5–46.5). For inoperable disease, Lutetium-177 (177Lu)-DOTATATE peptide receptor radionuclide therapy (PRRT) demonstrated efficacy in disease control. Other treatments included somatostatin analogues, chemotherapy, and molecular-targeted agents. Conclusion: Tumour grade, metastases, and NME at diagnosis influence OS in glucagonoma. Surgery is associated with the best PFS as first-line therapy, while 177Lu-DOTATATE PRRT effectively controls disease progression. Further studies are needed to optimise treatment sequencing for advanced glucagonoma.

Small intestinal neuroendocrine tumours (SI-NETs) are associated with mesenteric fibrosis, which causes significant morbidity and mortality. Telotristat ethyl was developed to treat carcinoid syndrome in SI-NET patients. Recent studies indicated telotristat ethyl could have anti-tumour activity; however, the mechanism remains unclear. This study aimed to investigate the effects of telotristat ethyl on SI-NET-fibroblast crosstalk in tumour progression and mesenteric fibrosis. A co-culture paracrine model with GOT1 (tumour) cells and LX2 (stromal) cells was optimized. Cells were treated with conditioned medium with/without telotristat ethyl followed by RNA sequencing and Gene Set Enrichment Analysis. Quantitative RT-PCR, immunohistochemistry, and Western blot were performed on first and second tier targets in tissue from 34 SI-NET patients grouped into categories of mesenteric fibrosis severity. Telotristat ethyl significantly decreased proliferation and serotonin secretion in a dose-dependent manner in GOT1 cells. GSEA data indicated ECM-related reactomes were downregulated in GOT1 cells grown in conditioned medium of LX2 cells with telotristat ethyl. LAMA5, COL6A2, and COL12A1 expression was significantly increased in mild and severely fibrotic patients. Immunohistochemistry determined the localization of proteins such as COL4A2 in the stroma and ADAM12 in tumour cells. Protein analysis of second tier targets showed differences in expression, including β-catenin, which was significantly upregulated, and pAKT/AKT, which tended to increase in primary tumour compared to normal SI. Telotristat ethyl affects the expression of genes associated with the ECM and interferes with SI-NET-fibroblast crosstalk. Further analysis is required; however, this study represents an important step in understanding the mechanisms of telotristat ethyl when treating SI-NET patients.

The geographical immune landscape in siNET shows predominantly peri-tumoral T cells. A and B, IHC staining of siNET. T-cell subsets stained are CD8+ T cells (red), CD4+ T cells (brown), and FoxP3+ (blue), and tumor cells are stained for Cytokeratin (green). These images of two siNET show examples of a tumor with intra-tumoral T cells (A) or with mainly peri-tumoral T cells (B). Examples of intra-tumoral or peri-tumoral T cells are circled in black in A and B, respectively. C, Plots of T-cell counts per mm2 showing that T cells are predominantly peri-tumoral rather than intra-tumoral in these tumors. D, Respective CD8/Treg ratio (Log10) in primary versus metastatic, peri-tumoral, and intra-tumoral. Horizontal bars represent the mean; error bars show ± standard error of the mean (SEM). *, P < 0.05; ****, P < 0.0001.

Clinicopathological features of siNET cohort.