A 57-year-old woman had an incidental finding of a hypervascular small bowel lesion on a contrast-enhanced CT scan performed for a suspected renal graft infection. The morphologic features of the lesion were suggestive of a neuroendocrine tumor (NET), but serum chromogranin A and urinary 5-HIAA were negative. 68 Ga-DOTATOC PET/CT showed high SSTR-2 expression in the lesion, suggesting a NET. However, pathologic examination revealed diffuse alpha-smooth muscle actin positivity, consistent with a glomus tumor. This case highlights the utility of PET/CT for in vivo molecular tumor characterization and the challenge of distinguishing between different tumor types with overlapping molecular targets.

The MYC family of transcription factors-comprising c-MYC, N-MYC, and L-MYC-plays a pivotal role in oncogenesis, driving cancer progression and resistance to therapy. While MYC proteins have long been considered challenging drug targets due to their intricate structures, recent advances have led to the development of promising inhibitors. This review explores the role of MYC overexpression in promoting radiotherapy resistance in aggressive neuroendocrine malignancies through multiple mechanisms, including increased tumor cell invasion, enhanced DNA damage repair and oxidative stress management, pro-survival autophagy, survival of circulating tumor cells, angiogenesis, awakening from dormancy, and modulation of chronic inflammation and host immunity. Paradoxically, MYC overexpression can also enhance radiosensitivity in certain cancer cells by driving pro-apoptotic pathways, such as reactive oxygen species (ROS)-induced DNA damage that overwhelms cellular repair mechanisms, ultimately leading to cell death. Additionally, we provide a comprehensive summary of direct MYC inhibitors, detailing their current stage of preclinical and clinical development as novel anti-cancer therapeutics. This review highlights MYC's role in cancer metastasis and radiotherapy resistance while examining the potential of MYC inhibitors as radiosensitizers in adult and pediatric neuroendocrine malignancies, including small cell lung cancer, large cell neuroendocrine lung cancer, Merkel cell carcinoma, neuroendocrine-differentiated prostate cancer, neuroblastoma, central nervous system embryonal tumors, and medulloblastoma.

Current guidelines lack clarity regarding the appropriate use of preoperative ultrasound-guided (EUS) biopsy and receptor positron emission tomography (SSTR PET) imaging for pancreatic neuroendocrine tumors (PNETs). This study aims to reach expert consensus on the optimal sequencing of SSTR PET and EUS biopsy in the diagnostic workup and management of patients with suspected PNETs.

A three-round modified Delphi process was used. A multidisciplinary panel of experts was recruited via snowball sampling. A set of 22 baseline statements pertaining to diagnostic workup, imaging, and biopsy was developed based on literature review and feedback obtained through a focus group. Survey rounds were conducted electronically and anonymously. A panel of international experts was asked to indicate whether they agreed, disagreed, or lacked the appropriate background to answer each statement. Of the 55 experts invited, 38 (69%) accepted to participate. Consensus was achieved with > 80% agreement.

Response rates were 97%, 100%, and 100% in rounds 1, 2, and 3, respectively. Following rounds 1 and 2, 29 final statements achieved consensus in the following three domains: diagnostic workup (15 statements), imaging (nine statements), and tissue sampling (five statements). Cronbach's alpha value, a measure of internal consistency, was 0.91 and 0.85 for rounds 1 and 2, respectively. The final set of statements achieved a 95% approval rate in round 3.

This international Delphi study provides expert consensus-based guidance on the appropriate use of EUS biopsy in the diagnostic workup of PNETs in the era of SSTR PET imaging.

The heterogeneous expression of somatostatin receptors in gastroenteropancreatic neuroendocrine tumors (GEP-NET) leads to significant intra-individual variability in tracer uptake during pre-therapeutic [68Ga]Ga-DOTATOC PET/CT for patients receiving peptide receptor radionuclide therapy (PRRT). This study aims to evaluate the lesion-based relationship between receptor-mediated tracer uptake and the functional response to PRRT.

A retrospective analysis was conducted on 32 patients with metastatic GEP-NET (12 pancreatic and 20 non-pancreatic), all treated with [177Lu]Lu-octreotate (4 cycles, with a mean of 7.9 GBq per cycle). [68Ga]Ga-DOTATOC PET/CT was performed at baseline and 3 months after the final PRRT cycle. Tumor uptake was quantified using the standardized uptake value (SUV). For each patient, 2 to 3 well-delineated tumor lesions were selected as target lesions. SUVmax, SUVmean (automated segmentation with a 50% SUVmax threshold), and corresponding tumor-to-liver ratios (SUVmaxT/L and SUVmeanT/L) were calculated. Functional tumor response was assessed based on the relative change in metabolic tumor volume (%ΔTVPET). The correlation between baseline SUV parameters and lesion-based functional response was analyzed using Spearman's rank correlation.

A total of 71 lesions were included in the analysis. The mean baseline SUVmax and SUVmean were 28.1 ± 15.9 and 13.6 ± 5.1, respectively. Three months after PRRT completion, the mean %ΔTVPET was 39.6 ± 52.1%. Baseline SUVmax and SUVmean demonstrated a poor correlation with lesion-based response (p = 0.706 and p = 0.071, respectively). In contrast, SUVmaxT/L and SUVmeanT/L were significantly correlated with lesion-based response (SUVmeanT/L: p = 0.011, r = 0.412; SUVmaxT/L: p = 0.004, r = 0.434). Among patient characteristics-including primary tumor origin, baseline tumor volume, and metastatic sites-only pancreatic origin was significantly associated with functional tumor volume reduction (ΔTVPET%: 56.8 ± 39.8 in pancreatic vs. 28.4 ± 50.1 in non-pancreatic NET; p = 0.020).

The lesion-based molecular response to PRRT correlates with pretreatment somatostatin receptor PET uptake, particularly when expressed as tumor-to-liver SUV ratios (SUVmaxT/L and SUVmeanT/L).

Somatostatin receptor (SST) positron emission tomography with computed tomography (PET/CT) is the gold standard for functional imaging of neuroendocrine tumors (NETs), but FDG PET/CT is increasingly recognized for its prognostic value, particularly for higher-grade NETs and to detect disease heterogeneity. Despite the established role of pathological grading, clinical heterogeneity within the tumor burden often complicates accurate prognostication. Evidence suggests FDG PET/CT can outperform WHO grading in predicting outcomes by identifying aggressive, undifferentiated tumor clones that influence long-term prognosis and treatment decisions. Several grading systems integrating both SST and FDG PET/CT have been proposed to better capture tumor heterogeneity and guide clinical management. Studies demonstrate that FDG PET/CT can influence management in a significant subset of patients, although variably reported. Its use remains variable across centers, also affected by different reimbursement policies and local clinical practices. This review explores the indications to FDG PET/CT in NET and the clinical impact of combined SST and FDG PET/CT imaging.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for both oncological and hormone control and is a widely accepted standard of care treatment for patients with neuroendocrine neoplasms (NEN). Its use is anticipated to increase significantly, and this demands accurate tools and paradigms to assess treatment response post PRRT. This article outlines the current role and future developments of anatomical, molecular imaging and biomarkers for response assessment to PRRT, highlighting the challenges and provides perspectives for the need to focus on a multimodality, multidisciplinary and individualised approach for patients with this complex heterogeneous disease.

Neuroendocrine tumors (NETs) can affect several organ systems and present a variety of clinical symptoms, which are difficult to diagnose by conventional methods. Somatostatin receptor (SSTR) is a group of specific receptors expressed on the well-differentiated NET cell membrane. [68Ga]-labeled somatostatin analogues (SSAs) PET/CT, endogenous ligands targeting SSTR, is widely used in currently clinical NETs diagnosis. The dual-tracer strategy ([68Ga]Ga-SSAs + [18F]FDG) allows for a more detailed evaluation of tumor metabolism and receptor expression. The NETPET score, integrating [68Ga]Ga-SSAs PET/CT and [18F]FDG PET/CT results, enhances the accuracy of predicting treatment response and prognosis. In addition, novel isotopes ([18F]/[64Cu]) labeled SSAs and SSTR antagonists outperformed [68Ga]-SSAs in lesion detection, tumor uptake, and tumor-to-background ratio. Due to undifferentiated or dedifferentiated NETs, SSTR may not be expressed. [68Ga]Ga-Pentixafor and [18F]-FDG PET/CT are applicable for SSTR-negative NET diagnosis. [18F]-MFBG and [18F]-DOPA have a higher sensitivity for identifying non-metastatic pheochromocytoma and paraganglioma (PPGL) than other radiotracers. This review addressed NET diagnosis with conventional imaging techniques, the clinical application of novel radiotracers, and the merits and limitations of the various radiotracers.

Assessing the response to systemic therapy in neuroendocrine tumors (NET) is challenging since morphological imaging response is often delayed and not necessarily reflective of clinical benefit. Peptide receptor radionuclide therapy (PRRT) has a complex mechanism of action, further complicating response assessment. In response to these challenges, the European Neuroendocrine Tumor Society (ENETS) Theranostics Task Force conducted a statement-based survey among experts to identify the current landscape and unmet needs in PRRT response assessment. The survey, presented at the 2022 ENETS Advisory Board (AB) meeting in Vienna, was completed by 70% of AB members, most of whom (81%) were from ENETS Centers of Excellence (CoE). It comprised a set of 13 questions with two substatements in three questions. Six (46%) of the statements achieved more than 75% agreement, while five (39%) additional statements reached over 60% consensus. Key points from the survey include: AB members agreed that lesions deemed equivocal on computed tomography (CT) or magnetic resonance imaging (MRI) should be characterized by somatostatin receptor (SST) positron emission tomography (PET)/CT before being designated as target lesions. It was agreed that interim response assessments should occur after the second or third PRRT cycle. Over half (54%) preferred using both conventional cross-sectional imaging (CT and/or MRI) and hybrid imaging (SST PET/CT) for this purpose. Almost all AB members supported further response assessment 3 months after the final PRRT cycle. A majority (62%) preferred using a combination of conventional cross-sectional imaging and SST PET/CT. For cases showing equivocal progression (ambiguous lesions or nontarget lesions) on CT and/or MRI, further confirmation using SST PET/CT was recommended. A significant majority (74%) preferred assessing pseudo-progression and delayed response by combining SST PET with diagnostic CT and/ or MRI. Though just below the 75% consensus threshold, there was substantial agreement on selecting target lesions based on SST PET/CT uptake intensity and homogeneity. Sixty-nine percent noted the importance of documenting and closely following heterogeneity in lesions in liver, lymph nodes, primary tumors, or other organs. As to the statement on parameters for new response criteria, AB members recommended exploring maximum standard unit value, tumor-to-background ratio, Hounsfield Unit (Choi Criteria), total tumor burden, and novel serum or molecular markers for future response evaluation criteria. Sixty-five percent supported the use of a single SST PET/CT for response assessment of NET lesions treated with PRRT. These findings highlight the importance of integrating advanced imaging techniques and recognizing the need for more nuanced criteria in assessing the efficacy of PRRT in NET patients. This approach aims to enhance the accuracy of treatment monitoring and improve patient outcomes.

Background and Objectives: At diagnosis, the initial staging of well-differentiated neuroendocrine tumors (WD NETs) aids in treatment planning. The somatostatin receptor (SSTR)-PET has been recommended for staging of WD NETs although limited data are available on its impact on non-gastroeneteropancreatic (GEP) NETs. The main purpose of this study was to compare the stage migration after the addition of SSTR-PET to the workup of patients at the initial staging of GEP NETs to those with non-GEP NETs, and its potential impact on patient management. Methods: This prospective study included patients with WD NETs at initial staging. Demographic data, results of conventional and SSTR-PET staging, and SUVmax were recorded. Three panels of experts assessed the potential impact of SSTR-PET to management. Results: There were 482 patients, including 376 with gastroenteropancreatic (GEP) NETs and 106 non-GEP NETs with a median SUVmax of 34.7 [Q1, Q3: 22.8, 59.1]) and 19.0 [Q1, Q3: 7.9, 39.8]), respectively; p < 0.001. The discordant M-stage was recorded in 111/473 patients (23.5%). PET suggested a higher stage in 78/369 GEP NETs (21.1%), including the detection of extrahepatic metastatic disease in 42/114 (36.8%) patients with liver metastases only on CI. For non-GEP NETs, PET suggested a higher stage in 10/104 (9.6%) and CI suggested a higher stage in 15/104 (14.4%), with CI detecting liver metastases more frequently. The potential impact to management for patients with discordant M-stage was scored as moderate to high between 57/101 (56.4%) and 79/101 (78.2%) of patients. Conclusions: One in five patients are upstaged following SSTR-PET, more frequently with GEP NETs than others. SSTR-PET identifies extrahepatic metastatic disease in >1/3 of patients with presumed liver-only metastases on CI. Stage migration following SSTR-PET may result in frequent moderate or significant management change.

Somatostatin analogs, such as octreotide, lanreotide, and pasireotide, which function as somatostatin receptor ligands (SRLs), are the main drugs used for the treatment of acromegaly. These ligands are also used as important molecules for radiation therapy and imaging of neuroendocrine tumors. Somatostatin receptors (SSTRs) are canonical G protein-coupled proteins that play a role in metabolism, growth, and pathological conditions such as hormone disorders, neurological diseases, and cancers. Cryogenic electron microscopy combined with the protein structure prediction platform AlphaFold has been used to determine the 3-dimensional structures of many proteins. Recently, several groups published a series of papers illustrating the 3-dimensional structure of SSTR2, including that of the inactive/activated SSTR2-G protein complex bound to different ligands. The results revealed the residues that contribute to the ligand binding pocket and demonstrated that Trp8-Lys9 (the W-K motif) in somatostatin analogs is the key motif in stabilizing the bottom part of the binding pocket. In this review, we discuss the recent findings related to the structural analysis of SSTRs and SRLs, the relationships between the structural data and clinical findings, and the future development of novel structure-based therapies.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a rare and biologically diverse group of tumors that are challenging to image. 68Ga-DOTATATE PET/CT is the most sensitive imaging tool for these tumors, and while its use has increased over time, its clinical impact remains unclear, particularly for clinical scenarios involving surveillance after treatment. We sought to reassess its clinical utility across all stages.

Retrospective study of pathologically confirmed GEP-NET patients between 1/1/2020 and 9/1/2022 at a tertiary care center. Demographic, clinical, and radiographic data were analyzed. The primary objective was to determine if PET/CT use was associated with a change in clinical management. The secondary objective was to determine if PET/CT was superior in identifying primary or metastatic lesions compared to traditional imaging.

One hundred twenty-four patients with GEP-NETs underwent 207 PET/CT scans. The majority of scans were obtained for disease surveillance (70.2%) or staging (37.9%), and the remaining (3.2%) were used to aid in diagnosis or before PRRT initiation (3.2%). Following PET/CT scan, 51 patients (41.1%) had a change in clinical management, with change being higher among those with metastatic disease (44.9% vs. 14.5%). Of the 124, 72 patients had traditional imaging available for comparison. In this subgroup, 34 patients (47.2%) had new lesions identified on PET/CT that were not identified using traditional imaging resulting in a change in management in 79.4% favoring patients with M1 versus M0 disease (26.9% M0 vs. 58.7% M1, p = 0.010).

68Ga-DOTATATE PET/CT imaging is clinically most useful for initial staging and in surveillance and monitoring response to therapy in the metastatic setting. It is least useful for surveillance in the early-stage setting and does not support its use following curative intent surgery. It remains superior to unlabeled imaging in sensitivity and the additional disease burden detected is highly likely to change management.

Gastroenteropancreatic neuroendocrine tumors (NET) often metastasize to the liver. Although curative liver resection provides a favorable prognosis for patients with neuroendocrine liver metastasis (NELM), with a 5-year survival rate of 70-80%, recurrence is almost inevitable, mainly in the remnant liver. In Western countries, liver transplantation (LT) has been performed in patients with NELM, with the objective of complete removal of macro- and micro-NELMs. However, prognosis had been unsatisfactory, with 5-year overall survival and recurrence-free survival rates of approximately 50 and 30%, respectively. In 2007, the Milan criteria were proposed as indications for LT for NELM. The criteria included: (1) confirmed histology of NET-G1 or G2; (2) a primary tumor drained by the portal system and all extrahepatic diseases removed with curative resection before LT; (3) liver involvement ≤50%; (4) good response or stable disease for at least 6 months before LT; (5) age ≤ 55 years. A subsequent report demonstrated outstanding LT outcomes for NELM within the Milan criteria, with 5-year overall survival and recurrence rates of 97 and 13%, respectively. In Japan, living donor LT (LDLT) for NELM has been performed sporadically in only 16 patients by 2021 in Japan; however, no consensus has been reached on the indications or perioperative management of LDLT. This article presents the outcomes of these 16 patients who underwent LDLT in Japan and reviews the literature to clarify optimal indications and perioperative management of LDLT for NELM in the era of novel multimodal treatments.

The Iowa Neuroendocrine Tumor (NET) Clinic was founded and developed by two remarkable physicians, Thomas and Sue O'Dorisio. Tom was an Endocrinologist and close friend and colleague of Aaron Vinik. Both men were pioneers in studies of gastrointestinal hormones and the management of patients with NETs. Sue was a Pediatric Oncologist and research scientist with great expertise in new drug development and clinical trials. She and Tom were leaders in bringing somatostatin analogs and somatostatin-conjugated radioligands to the clinic for the therapy and diagnosis of NETs. All three physicians received lifetime achievement awards for their contributions to the field of NETs. This is the story of how the Iowa NET Clinic developed over the years to become a model for the multidisciplinary mantagement of patients with NETs, culminating in its designation as a European Neuroendocrine Tumor Society NET Center of Excellence, and the receipt of a Specialized Project of Research Excellence (SPORE) grant for the study of NETs from the National Institutes of Health.

Rarely, appendiceal neuroendocrine tumours (NET) are an incidental finding when an appendicectomy is undertaken for suspected appendicitis. The role of further imaging in this setting is poorly defined. Positron emission tomography (PET) using 68Ga-DOTATATE is requested to evaluate post-surgical status, however, there is little evidence to guide how it should be employed. The aims of this project are to: (i) characterize 68Ga-DOTATATE PET findings in patients with incidental appendiceal NETs and (ii) discuss how these data might inform post-surgical imaging with PET.

We reviewed 47 PET scans in 30 patients, undertaken from 2009 to 2018. Scintigraphic findings, histopathological characteristics of the initial appendiceal lesion and medical records were reviewed.

Most patients (n = 15) had small (<10 mm) appendiceal NETs with low grade (Ki67 < 2%) features. Eight patients had tumours between 10 and 20 mm, and seven had tumours >20 mm. Goblet cell features were identified in two patients. Three positive PET scans were reported in one patient with an index tumour measuring 40 mm and Ki67 < 2%. The remaining 29 patients had 44 negative scans. Clinical outcome data were available in 27 patients (mean follow-up time 57 months; range 6-123 months). There was no evidence of recurrent neuroendocrine disease at the time of the last follow-up.

These data indicate that in most cases, post-surgical 68Ga-DOTATATE PET is negative in patients with incidentally detected appendiceal NETs. Clinical outcome data suggest that 68Ga-DOTATATE PET should be reserved for patients with large tumours (>20 mm) or those displaying goblet cell features.

Evidence-based treatment decisions for advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) require individualized patient-centered decision-making that accounts for patient and cancer characteristics.

To create an accessible guidance document to educate clinicians and patients on biomarkers informing prognosis and treatment in unresectable or metastatic GEP-NENs.

A multidisciplinary panel in-person workshop was convened to define methods. English language articles published from January 2016 to January 2023 in PubMed (MEDLINE) and relevant conference abstracts were reviewed to investigate prognostic and treatment-informing features in unresectable or metastatic GEP-NENs. Data from included studies were used to form evidence-based recommendations. Quality of evidence and strength of recommendations were determined using the Grading of Recommendations, Assessment, Development and Evaluations framework. Consensus was reached via electronic survey following a modified Delphi method.

A total of 131 publications were identified, including 8 systematic reviews and meta-analyses, 6 randomized clinical trials, 29 prospective studies, and 88 retrospective cohort studies. After 2 rounds of surveys, 24 recommendations and 5 good clinical practice statements were developed, with full consensus among panelists. Recommendations focused on tumor and functional imaging characteristics, blood-based biomarkers, and carcinoid heart disease. A single strong recommendation was made for symptomatic carcinoid syndrome informing treatment in midgut neuroendocrine tumors. Conditional recommendations were made to use grade, morphology, primary site, and urinary 5-hydroxyindoleacetic levels to inform treatment. The guidance document was endorsed by the Commonwealth Neuroendocrine Tumour Collaboration and the North American Neuroendocrine Tumor Society.

The study results suggest that select factors have sufficient evidence to inform care in GEP-NENs, but the evidence for most biomarkers is weak. This article may help guide management and identify gaps for future research to advance personalized medicine and improve outcomes for patients with GEP-NENs.

For several years, oncological positron emission tomography (PET) has developed beyond 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). This umbrella review of meta-analyses aims to provide up-to-date, comprehensive, high-level evidence to support appropriate referral for a specific radiopharmaceutical PET/computed tomography (CT) or PET/magnetic resonance (MR) in the diagnosis and staging of solid cancers other than brain malignancies.

We performed a systematic literature search on the PubMed/MEDLINE and EMBASE databases for meta-analyses assessing the accuracy of PET/CT and/or PET/MRI with [18F]FDG, somatostatin- receptor-targeting 68Ga-DOTA-peptides, 18F-labelled dihydroxyphenylalanine ([18F]DOPA), prostate-specific membrane antigen (PSMA)-targeted radioligands, and fibroblast activation protein inhibitors (FAPI) in the diagnosis/disease characterisation and staging of solid cancers other than brain tumours.

The literature search yielded 449 scientific articles. After screening titles and abstracts and applying inclusion and exclusion criteria, we selected 173 meta-analyses to assess the strength of evidence. One article was selected from references. Sixty-four meta-analyses were finally considered. The current evidence corroborates the role of [18F]FDG as the main player in molecular imaging; PSMA tracers are useful in staging and re-staging prostate cancer; somatostatin-targeting peptides (e.g. [68Ga]Ga- DOTA-TOC and -TATE) or [18F]DOPA are valuable in neuroendocrine tumours (NETs). FAPI has emerged in gastric cancer assessment. According to search and selection criteria, no satisfactory meta-analysis was selected for the diagnosis/detection of oesophageal cancer, the diagnosis/detection and N staging of small cell lung cancer and hepatic cell carcinoma, the diagnosis/detection and M staging of melanoma and Merkel cell carcinoma, cervical, vulvar and penis cancers, the N and M staging of lung and gastroenteropancreatic NET, testicular cancer, and chondrosarcoma, and the M staging of differentiated thyroid, bladder and anal cancers.

The comprehensive high-level evidence synthesised in the present umbrella review serves as a guiding compass for clinicians and imagers, aiding them in navigating the increasingly intricate seascape of PET examinations.

Prostate cancer is a malignant tumor caused by the malignant proliferation of epithelial cells, which is highly heterogeneous and drug-resistant, and neuroendocrine prostate cancer (NEPC) is an essential cause of drug resistance in its late stage. Elucidating the evolution of NEPC and the resistance process of enzalutamide, a novel antiandrogen, will be of great help in improving the prognosis of patients. As a research hotspot in the field of molecular biology in recent years, the wide range of biological functions of long noncoding RNAs (lncRNAs) has demonstrated their position in the therapeutic process of many diseases, and a large number of studies have revealed their critical roles in tumor progression and drug resistance. Therefore, elucidating the involvement of lncRNAs in the formation of NEPCs and their interrelationship with enzalutamide resistance may provide new ideas for a deeper understanding of the development of this disease and the occurrence of enzalutamide resistance and give a new direction for reversing the therapeutic dilemma of advanced prostate cancer. This article focuses on lncRNAs that regulate enzalutamide resistance and the neuroendocrine transition of prostate cancer through epigenetic, androgen receptor (AR) signaling, and non-AR pathways that act as "molecular sponges" interacting with miRNAs. Some insights into these mechanisms are used to provide some help for subsequent research in this area.

The role of somatostatin receptor (SSTR) PET/CT, using 68Ga-based tracers or [64Cu]Cu-DOTATATE (64Cu-DOTATATE), in the management of patients with neuroendocrine neoplasm (NEN) is guided by appropriate use criteria (AUC). In this study, we performed systematic analyses of referral patterns and image findings of routine 64Cu-DOTATATE PET/CT scans to support AUC development. Methods: We included all clinical routine 64Cu-DOTATATE PET/CT scans performed between April 10, 2018 (start of clinical use), and May 2, 2022, at Copenhagen University Hospital-Rigshospitalet. We reviewed the referral text and image report of each scan and classified the indication according to clinical scenarios as listed in the AUC. Results: In total, 1,290 patients underwent 2,249 64Cu-DOTATATE PET/CT scans. Monitoring of patients with NEN seen both on conventional imaging and on SSTR PET without clinical evidence of progression was the most common indication (defined as "may be appropriate" in the AUC) and accounted for 703 (31.3%) scans. Initial staging after NEN diagnosis ("appropriate" in the AUC) and restaging after curative-intent surgery ("may be appropriate" in the AUC) accounted for 221 (9.8%) and 241 (10.7%) scans, respectively. Selection of patients eligible for peptide receptor radionuclide therapy ("appropriate" in the AUC) and restaging after peptide receptor radionuclide therapy completion ("appropriate" in the AUC) accounted for 95 (4.2%) and 115 (5.1%) scans, respectively. The number of scans performed for indications not defined in the AUC was 371 (16.5%). Image result analysis revealed no disease in 669 scans (29.7%), stable disease in 582 (25.9%), and progression in 461 (20.5%). In 99 of the 461 (21.5%) scans, progression was detected on PET but not on CT. Conclusion: Our study provided real-life data that may contribute to support development of 64Cu-DOTATATE/SSTR PET/CT guidelines including AUC. Some scenarios listed as "may be appropriate" in the current AUC were frequent in our data. Monitoring of patients with NEN without clinical evidence of progression was the most frequent indication for 64Cu-DOTATATE PET/CT, in which disease progression was detected in more than one third, and a large proportion was visible by PET only. We therefore conclude that this scenario could potentially be classified as appropriate.

Somatostatin receptors (SSTR) are expressed by many tumours especially those related to neuro-endocrine origin and molecular functional imaging of SSTR expression using radiolabelled somatostatin analogs have revolutionized imaging of patients with these group of malignancies. Coming a long way from the first radiolabelled somatostatin analog 123I-Tyr-3-octreotide, there has been significant developments in terms of radionuclides used, the ligands and somatostatin derivatives. 111In-Pentetreotide extensively employed for imaging NETs at the beginning has now been replaced by 68Ga-SSA based PET-CT. SSA-PET/CT performs superior to conventional imaging modalities and has evolved in the mainframe for NET imaging. The advantages were multiple: (i) superior spatial resolution of PET versus SPECT, (ii) quantitative capabilities of PET aiding in disease activity and treatment response monitoring with better precision, (iii) shorter scan time and (iv) less patient exposure to radiation. The modality is indicated for staging, detecting the primary in CUP-NETs, restaging, treatment planning (along with FDG: the concept of dual-tracer PET-CT) as well as treatment response evaluation and follow-up of NETs. SSA PET/CT has also been incorporated in the guidelines for imaging of Pheochromocytoma-Paraganglioma, Medullary carcinoma thyroid, Meningioma and Tumor induced osteomalacia. At present, there is rising interest on (a) 18F-labelled SSA, (b) 64Cu-labelled SSA, and (c) somatostatin antagonists. 18F offers excellent imaging properties, 64Cu makes delayed imaging feasible which has implications in dosimetry and SSTR antagonists bind with the SST receptors with high affinity and specificity, providing high contrast images with less background, which can be translated to theranostics effectively. SSTR have been demonstrated in non-neuroendocrine tumours as well in the peer-reviewed literature, with studies demonstrating the potential of SSA PET/CT in Neuroblastoma, Nasopharyngeal carcinoma, carcinoma prostate (neuroendocrine differentiation) and lymphoma. This review will focus on the currently available SSAs and their history, different SPECT/PET agents, SSTR antagonists, comparison between the various imaging tracers, and their utility in both neuroendocrine and non-neuroendocrine tumors.

Hybrid PET/MRI has the potential to transform neuro-oncologic imaging, particularly in diagnosis and treatment planning of somatostatin receptor-expressing tumors of the head and neck. Hybrid PET/MRI combines high-resolution MRI with functional information from PET, providing precise anatomic information and overcoming difficulties in localization inherent to PET alone. There is a range of tumors in the head and neck that overexpress somatostatin receptors and are therefore amenable to evaluation with somatostatin receptor PET/MRI. These include meningiomas, paragangliomas, olfactory neuroblastomas, pituitary neuroendocrine tumors, middle ear neuroendocrine tumors, and medullary thyroid carcinomas. The combination of PET and MRI is superior to either modality alone and can address several unique diagnostic challenges associated with these lesions. The authors discuss the superior capabilities of somatostatin receptor PET/MRI, including improved lesion localization, more sensitive demonstration of disease extent, enhanced surveillance, optimized radiation therapy planning, and accurate prediction of response to somatostatin analog therapy. Although there are only a few dedicated PET/MRI units available in clinical practice, commercial software is now available that can automatically fuse PET/CT data with recently acquired MRI data, increasing the availability of this approach. Radiologists should be aware of the advantages of somatostatin receptor PET/MRI in evaluation of head and neck tumors as well as the potential pitfalls of this approach so that they can accurately advise clinicians and better interpret these studies. ©RSNA, 2024 See the invited commentary by Shatzkes and Strauss in this issue.

This article presents updates in the surgical management of non-functional sporadic pancreas neuroendocrine tumors NET, including considerations for assessment of biologic behavior to support decision-making, indications for surgery, and surgical approaches tailored to the unique nature of neuroendocrine tumors.

Advancements in somatostatin receptor (SSTR) targeted imaging and treatment of well-differentiated neuroendocrine tumors (NETs) have revolutionized the management of these tumors. This comprehensive review delves into the current practice, discussing the use of the various FDA-approved SSTR-agonist PET tracers and the predictive imaging biomarkers, and elaborating on Lu177-DOTATATE peptide receptor radionuclide therapy (PRRT) including the evolving areas of post-therapy imaging practices, PRRT retreatment, and the potential role of dosimetry in optimizing patient treatments. The future directions sections highlight ongoing research on investigational PET imaging radiotracers, future prospects in alpha particle therapy, and combination therapy strategies.

Pancreatic neuroendocrine tumors (PNETs) are uncommon tumors which are increasing in incidence. The management of these tumors continues to evolve. This review examines the current role of surgery in the treatment of these tumors.

Studies published over the past 10 years were identified using several databases including PubMed, MEDLINE, and Science Direct. Search terms included PNETs, treatment, and surgery. Clinical practice guidelines and updates from several major groups were reviewed.

Surgery continues to have a major role in the treatment of sporadic functional and nonfunctional PNETs. Pancreas-sparing approaches are increasingly accepted as alternatives to formal pancreatic resection in selected patients. Options such as watch and wait or endoscopic ablation may be reasonable alternatives to surgery for non-functional PNETs < 2 cm in size. Surgical decision-making in multiple endocrine neoplasia type 1 patients remains complex and in some situations such as gastrinoma quite controversial. The role of surgery has significantly diminished in patients with advanced disease due to the advent of more effective systemic and liver-directed therapies. However, the optimal treatments and sequencing in advanced disease remain poorly defined, and it has been suggested that surgery is underutilized in these patients.

Surgery remains a major treatment modality for PNETs. Given the plethora of available treatments, ongoing controversies and the changing landscape, management has become increasingly complex. An experienced multidisciplinary team which includes surgery is essential to manage these patients.

Molecular imaging moves forward with the development of new imaging agents, and among these are new radiotracers for nuclear medicine applications, particularly positron emission tomography (PET). A number of new targets are becoming accessible for use in oncologic applications. In this review, major new radiotracers in clinical development are discussed. Prominent among these is the family of fibroblast-activation protein-targeted agents that interact with the tumor microenvironment and may show superiority to 2-deoxy-2-[18F]fluoro-d-glucose in a subset of different tumor histologies. Additionally, carbonic anhydrase IX (CAIX) inhibitors are directed at clear cell renal cell carcinoma, which has long lacked an effective PET imaging agent. Those CAIX agents may also have utility in hypoxic tumors. Pentixafor, which binds to a transmembrane receptor, may similarly allow for visualization by PET of low-grade lymphomas, as well as being a second agent for multiple myeloma that opens theranostic possibilities. There are new adrenergic agents aimed at providing a PET-visible replacement to the single-photon-emitting radiotracer meta-[123I]iodobenzylguanidine (MIBG). Finally, in response to a major development in oncologic chemotherapy, there are new radiotracers targeted at assessing the suitability or use of immunotherapeutic agents. All of these and the existing evidence for their utility are discussed.

Theranostics refers to the combination of diagnostic biomarkers with therapeutic agents that share a specific target expressed by diseased cells and tissues. Nuclear medicine is an exciting component explored for its applicability in theranostic concepts in clinical and research investigations. Nuclear theranostics is based on the employment of radioactive compounds delivering ionizing radiation to diagnose and manage certain diseases employing binding with specifically expressed targets. In the realm of personalized medicine, nuclear theranostics stands as a beacon of potential, potentially revolutionizing disease management. Studies exploring the theranostic profile of radioactive compounds have been presented in this review along with a detailed explanation of radioactive compounds and their theranostic applicability in several diseases. It furnishes insights into their applicability across diverse diseases, elucidating the intricate interplay between these compounds and disease pathologies. Light is shed on the important milestones of nuclear theranostics beginning with radioiodine therapy in thyroid carcinomas, MIBG labelled with iodine in neuroblastoma, and several others. Our perspectives have been put forth regarding the most important theranostic agents along with emerging trends and prospects.

Rationale: Positron Emission Tomography (PET) using the somatostatin receptor 2 (SSTR2)-antagonist satoreotide trizoxetan (68Ga-SSO120) is a novel, promising imaging modality for small-cell lung cancer (SCLC), which holds potential for theranostic applications. This study aims to correlate uptake in PET imaging with SSTR2 expression in immunohistochemistry (IHC) and to assess the prognostic value of 68Ga-SSO120 PET at initial staging of patients with SCLC. Methods: We analyzed patients who underwent 68Ga-SSO120 PET/CT during initial diagnostic workup of SCLC as part of institutional standard-of-care. SSTR2 expression in IHC was evaluated on a 4-level scale and correlated with normalized standardized uptake values and tumor-to-liver ratios (SUVmax and TLRpeak) in 68Ga-SSO120 PET on a lesion level. Highest lesion SUVmax/TLRpeak per patient, SSTR2 score in IHC, M status according to TNM classification, and other parameters were analyzed for association with overall survival (OS) and time to treatment failure (TTF) by univariate, multivariate (cut-off values were identified on data for best separation), and stratified Cox regression. Results: We included 54 patients (24 men/30 women, median age 65 years, 21 M0/33 M1 according to TNM classification). In 43 patients with available surplus tumor tissue samples, hottest lesion SUVmax/TLRpeak showed a significant correlation with the level of SSTR2-expression by tumor cells in IHC (Spearman's rho 0.86/0.81, both p < 0.001; ANOVA p < 0.001). High SSTR2 expression in IHC, 68Ga-SSO120 SUVmax and TLRpeak of the hottest lesion per patient, whole-body TLRmean, MTV, TLG, M status, and serum LDH showed a significant association with inferior TTF/OS in univariate analysis. In separate multivariate Cox regression (including sex, age, M stage, and LDH) higher hottest-lesion TLRpeak showed a significant association with shorter OS (HR = 0.26, 95%CI: 0.08-0.84, p = 0.02) and SSTR2 expression in IHC with significantly shorter TTF (HR = 0.24, 95%CI: 0.08-0.71, p = 0.001) and OS (HR = 0.22, 95%CI: 0.06-0.84, p = 0.03). In total, 12 patients (22.2%) showed low (< 1), 21 (38.9%) intermediate (≥ 1 but < 2), 14 (25.9%) high (≥ 2 but < 5), and 7 (13.0%) very high (≥ 5) whole-body mean TLRmean. Conclusion: In patients with SCLC, SSTR2 expression assessed by 68Ga-SSO120 PET and by IHC were closely correlated and associated with shorter survival. More than 75% of patients showed higher whole-body 68Ga-SSO120 tumor uptake than liver uptake and almost 40% high or very high uptake, possibly paving the way towards theranostic applications.

Pancreatic neuroendocrine tumors originate from hormone-producing islet cells and have a propensity to metastasize to the liver once they reach 2 cm in size. Their diagnosis relies upon a combination of computed tomography, MRI, DOTATATE PET, and endoscopic ultrasound with or without tissue biopsy. Biochemical work-up is driven by patient symptoms of hormone excess.

[18F]AlF-NOTA-octreotide ([18F]AlF-OC) is a promising alternative for [68Ga]Ga-DOTA-somatostatin analogs (SSAs) in positron emission tomography (PET) imaging of the somatostatin receptor (SSTR). Our aim is to assess changes in TNM staging and differences in patient management between [18F]AlF-OC PET/CT and [68Ga]Ga-DOTA-SSA PET/CT in the work-up of neuroendocrine tumor (NET) patients. Patients who underwent both [18F]AlF-OC and [68Ga]Ga-DOTA-TATE or [68Ga]Ga-DOTA-NOC PET/CT in our multicenter study (Pauwels et al., J Nucl Med.2023;63:632-638) with a NET were included for analysis. TNM staging was determined and compared for both tracers. For each patient, the blinded [68Ga]Ga-DOTA-SSA or [18F]AlF-OC PET/CT images were presented in random order at a multidisciplinary team board. The images were presented together with clinical information and compared with previous SSTR and [18F]FDG PET/CT imaging. After a consensus decision for patient management was recorded, the board was presented with the PET/CT images from the other SSTR tracer and a decision was made for the second tracer. Differences in management were classified as major if it entailed an intermodality change and minor if it led to an intramodality change. Compared with [68Ga]Ga-DOTA-SSA, the use of [18F]AlF-OC led to a change in 16/75 patients: TNM staging changes in 10/75 patients (13.3%; downstaging in 3/10, upstaging in 7/10) and differences in clinical management were seen in 10/75 patients (13.3%), leading to a major difference in 7/10 cases and a minor change in 3/10 cases. All 10 cases with a difference in patient management between both PET tracers were caused by additional lesion detection by [18F]AlF-OC. The use of [18F]AlF-OC did not impact TNM staging or clinical management in the large majority of the patients (86.7%), further validating the potential for routine clinical use of [18F]AlF-OC PET/CT as an alternative for [68Ga]Ga-DOTA-SSA PET/CT. The trial is registered under ClinicalTrials.gov identifier NCT04552847 and EudraCT 2020-000549-15.

Carcinoid syndrome is a constellation of signs and symptoms caused by different hormones produced by carcinoid tumors. Very rarely, those tumors can metastasize to the heart and cause cardiac involvement of the tumor. This study presents a very rare case of secondary cardiac tumor affecting the left ventricle from a metastatic carcinoid tumor originating from the small intestine without carcinoid valvular heart disease.

Neuroendocrine neoplasms (NENs) are a diverse group of tumors that express neuroendocrine markers and primarily affect the lungs and digestive system. The incidence of NENs has increased over time due to advancements in imaging and diagnostic techniques. Effective management of NENs requires a multidisciplinary approach, considering factors such as tumor location, grade, stage, symptoms, and imaging findings. Treatment strategies vary depending on the specific subtype of NEN. In this review, we will focus on treatment strategies and therapies including the information relevant to clinicians in order to undertake optimal management and treatment decisions, the implications of different therapies on imaging, and how to ascertain their possible complications and treatment effects.

Neuroendocrine neoplasms (NENs) may be challenging to diagnose due to their small size and diverse anatomical locations. Hybrid imaging techniques, specifically positron emission tomography/computed tomography (PET/CT) and positron emission tomography/magnetic resonance imaging (PET/MRI), represent the current state-of-the-art for evaluating NENs. The preferred radiopharmaceuticals for NEN PET imaging are gallium-68 (68Ga) DOTA-peptides, which target somatostatin receptors (SSTR) overexpressed on NEN cells. Clinical applications of [68Ga]Ga-DOTA-peptides PET/CT include diagnosis, staging, prognosis assessment, treatment selection, and response evaluation. Fluorodeoxyglucose-18 (18F-FDG) PET/CT aids in detecting low-SSTR-expressing lesions and helps in patient stratification and treatment planning, particularly in grade 3 neuroendocrine tumors (NETs). New radiopharmaceuticals such as fluorine-labeled SSTR agonists and SSTR antagonists are emerging as alternatives to 68Ga-labeled peptides, offering improved detection rates and favorable biodistribution. The maturing of PET/MRI brings advantages to NEN imaging, including simultaneous acquisition of PET and MRI images, superior soft tissue contrast resolution, and motion correction capabilities. The PET/MRI with [68Ga]Ga-DOTA-peptides has demonstrated higher lesion detection rates and more accurate lesion classification compared to PET/CT. Overall, hybrid imaging offers valuable insights in the diagnosis, staging, and treatment planning of NENs. Further research is needed to refine response assessment criteria and standardize reporting guidelines.

Neuroendocrine tumors (NETs) are relatively uncommon heterogeneous neoplasms arising from endocrine and neuronal origin cells showing highly variable clinical behavior. By the time these tumors are discovered, up to 14% of patients with histologically proven NETs have metastasis, with the liver as the most frequently affected organ. Sometimes, no known primary site can be identified via routine imaging. Neuroendocrine tumors of unknown origin carry a poorer prognosis (compared with metastatic NETs with a known primary site) because of a lack of tailored surgical intervention and appropriate medical therapy (eg, chemotherapy or targeted therapy). A multimethod approach is frequently used in the trial to accurately determine the primary site for NETs of unknown primary sites and may include clinical, laboratory, radiological, histopathological, and surgical data. New molecular techniques using the genomic approach to identify the molecular signature have shown promising results. Various imaging modalities include ultrasound, computed tomography (CT), dual-energy CT, magnetic resonance imaging, and functional and hybrid imaging (positron emission tomography/CT, positron emission tomography/magnetic resonance imaging); somatostatin receptor imaging with new tracers is frequently used in an attempt for localization of the primary site.

Molecular imaging of thyroid and parathyroid diseases has changed in recent years due to the introduction of new radiopharmaceuticals and new imaging techniques. Accordingly, we provided an clinicians-oriented overview of such techniques and their indications.

A review of the literature was performed in the PubMed, Web of Science, and Scopus without time or language restrictions through the use of one or more fitting search criteria and terms as well as through screening of references in relevant selected papers. Literature up to and including December 2023 was included. Screening of titles/abstracts and removal of duplicates was performed and the full texts of the remaining potentially relevant articles were retrieved and reviewed.

Thyroid and parathyroid scintigraphy remains integral in patients with thyrotoxicosis, thyroid nodules, differentiated thyroid cancer and, respectively, hyperparathyroidism. In the last years positron-emission tomography with different tracers emerged as a more accurate alternative in evaluating indeterminate thyroid nodules [18F-fluorodeoxyglucose (FDG)], differentiated thyroid cancer [124I-iodide, 18F-tetrafluoroborate, 18F-FDG] and hyperparathyroidism [18F-fluorocholine]. Other PET tracers are useful in evaluating relapsing/advanced forms of medullary thyroid cancer (18F-FDOPA) and selecting patients with advanced follicular and medullary thyroid cancers for theranostic treatments (68Ga/177Ga-somatostatin analogues).

Neuroendocrine neoplasms (NEN) are rare tumors arising from neuroendocrine cells. NEN are ideally suited for a theragnostic approach due to their specific expression of somatostatin receptors (SSTR). SSTR imaging of NEN dates back to the 1980s, but has evolved recently due to the introduction of more sensitive SSTR PET radiotracers. SSTR PET is a primary imaging modality for identifying NEN and characterizing SSTR expression. SSTR PET is complementary to anatomic imaging for assessing tumor response to treatment. SSTR PET is mandated to determine eligibility for peptide receptor radionuclide therapy. Here, the role of imaging to aid management of NEN is reviewed.

Neuroendocrine neoplasms (NEN) are heterogenous with an increasing incidence in recent years.

Overview on incidence, symptoms, diagnostics, grading, imaging and prognostic determinants, including factors having an impact on therapeutic management.

Review on current literature, including original articles, reviews, guidelines and expert opinions.

NEN are mainly located in the gastrointestinal tract and their incidence has increased in recent years, mainly due to improved diagnostics, e.g., cross-sectional imaging. Clinical characteristics include hormone excess syndromes (carcinoid syndrome). Laboratory markers such as chromogranin A are commonly used as part of routine diagnostics, followed by endoscopic and endosonographic procedures, which also allow biopsies to be obtained. Tumor spread can be determined by contrast-enhanced computed tomography/magnetic resonance imaging (CT/MRI) or somatostatin receptor (SSRT)-PET/CT (positron emission tomography). Prognostic factors include Ki67 index, type, and grading. Resection with curative intent is the therapy of choice. In a metastasized setting, SSRT-directed treatment approaches are favored, while in dedifferentiated NEN, conventional chemotherapy is needed.

A broad diagnostic armamentarium can be offered to NEN patients and the improved diagnostic procedures have most likely caused a raising incidence in recent years. Among others, prognostic factors are Ki67 and NEN subtypes; these clinical determinants also have an impact on patient management.

Somatostatin receptor (SSTR)-targeted PET imaging has emerged as a common approach to evaluating those patients with well-differentiated neuroendocrine tumors (NETs). The SSTR reporting and data system (SSTR-RADS) version 1.0 provides a means of categorizing lesions from 1 to 5 according to the likelihood of NET involvement, with SSTR-RADS-3A (soft-tissue) and SSTR-RADS-3B (bone) lesions being those suggestive of but without definitive NET involvement. The goal of the present study was to assess the ability of 68Ga-DOTATATE PET/MR imaging data to predict outcomes for indeterminate SSTR-RADS-3A and 3B lesions.

NET patients with indeterminate SSTR-RADS-3A or SSTR-RADS-3B lesions who underwent 68Ga-DOTATATE PET/MR imaging from April 2020 through August 2023 were retrospectively evaluated. All patients underwent follow-up through December 2023 (median, 17 months; (3-31 months)), with imaging follow-up or biopsy findings ultimately being used to classify lesions as malignant or benign. Lesion maximum standardized uptake value (SUVmax) along with minimum and mean apparent diffusion coefficient (ADCmin and ADCmean) values were measured and assessed for correlations with outcomes on follow-up.

In total, 33 indeterminate SSTR-RADS-3 lesions from 22 patients (19 SSTR-RADS-3A and 14 SSTR-RADS-3B) were identified based upon baseline 68Ga-DOTATATE PET/MR findings. Over the course of follow-up, 16 of these lesions (48.5%) were found to exhibit true NET positivity, including 9 SSTR-RADS-3A and 7 SSTR-RADS-3B lesions. For SSTR-RADS-3A lymph nodes, a diameter larger than 0.7 cm and an ADCmin of 779 × 10-6mm2/s or lower were identified as being more likely to be associated with metastatic lesions. Significant differences in ADCmin and ADCmean were identified when comparing metastatic and non-metastatic SSTR-RADS-3B bone lesions (P < 0.05), with these parameters offering a high predictive ability (AUC = 0.94, AUC = 0.86).

Both diameter and ADCmin can aid in the accurate identification of the nature of lesions associated with SSTR-RADS-3A lymph nodes, whereas ADCmin and ADCmean values can inform the accurate interpretation of SSTR-RADS-3B bone lesions.

Neuroendocrine tumors (NETs) are rare tumors that develop from cells of the neuroendocrine system and can originate in multiple organs and tissues such as the bowels, pancreas, adrenal glands, ganglia, thyroid, and lungs. This review will focus on gastroenteropancreatic NETs (more commonly called NETs) characterized by frequent somatostatin receptor (SSTR) overexpression and pheochromocytomas/paragangliomas (PPGLs), which typically overexpress norepinephrine transporter. Advancements in SSTR-targeted imaging and treatment have revolutionized the management of patients with NETs. This comprehensive review delves into the current practice, discussing the use of the various Food and Drug Administration-approved SSTR-agonist positron emission tomography tracers and the predictive imaging biomarkers, and elaborating on 177Lu-DOTATATE peptide receptor radionuclide therapy including the evolving areas of posttherapy imaging practices and peptide receptor radionuclide therapy retreatment. SSTR-targeted imaging and therapy can also be used in patients with PPGL; however, this patient population has demonstrated the best outcomes from norepinephrine transporter-targeted therapy with 131I-metaiodobenzylguanidine. Metaiodobenzylguanidine theranostics for PPGL will be discussed, noting that in 2024 it became commercially unavailable in the United States. Therefore, the use and reported success of SSTR theranostics for PPGL will also be explored.

Gastric neuroendocrine neoplasms (gNENs) display peculiar site-specific features among all NENs. Their incidence and prevalence have been rising in the past few decades. gNENs comprise gastric neuroendocrine carcinomas (gNECs) and gastric neuroendocrine tumours (gNETs), the latter further classified into three types. Type I anatype II gNETs are gastrin-dependent and develop in chronic atrophic gastritis and as part of Zollinger-Ellison syndrome within a multiple endocrine neoplasia type 1 syndrome (MEN1), respectively. Type III or sporadic gNETs develop in the absence of hypergastrinaemia and in the context of a near-normal or inflamed gastric mucosa. gNECs can also develop in the context of variable atrophic, relatively normal or inflamed gastric mucosa. Each gNEN type has different clinical characteristics and requires a different multidisciplinary approach in expert dedicated centres. Type I gNETs are managed mainly by endoscopy or surgery, whereas the treatment of type II gNETs largely depends on the management of the concomitant MEN1. Type III gNETs may require both locoregional approaches and systemic treatments; NECs are often metastatic and therefore require systemic treatment. Specific data regarding the systemic treatment of gNENs are lacking and are derived from the treatment of intestinal NETs and NECs. An enhanced understanding of molecular and clinical pathophysiology is needed to improve the management and outcomes of patients' gNETs.