Tu Vinh Luong

Mixed neuroendocrine/non‐neuroendocrine neoplasms (MiNEN) of the digestive system are rare epithelial malignancies characterised by the coexistence of neuroendocrine and non‐neuroendocrine neoplasm components within the same lesion, where each component must account for at least 30% of the total tumour cell population. Despite growing recognition, MiNEN remain diagnostically and therapeutically challenging because of marked morphological heterogeneity, biological plasticity, and limited evidence guiding management. Recent molecular studies support a common clonal origin with subsequent divergent differentiation, although the mechanisms underlying progression and treatment resistance remain incompletely understood. This ENETS position statement summarises current evidence and expert opinion regarding the diagnosis and treatment of digestive MiNEN, focusing on major controversies in pathology, molecular biology, imaging, and management. Key diagnostic issues include the arbitrary 30% cutoff defining MiNEN, sampling limitations in biopsy specimens, intra‐tumoural heterogeneity, and the distinction between amphicrine and collision neoplasms. Molecular profiling increasingly demonstrates shared genomic alterations between distinct components and may identify potentially actionable targets, including high level of microsatellite instability (MSI‐high) or deficient mismatch repair (dMMR) and V‐RAF murine sarcoma viral oncogene homolog B1 ( BRAF ) alterations in selected cases. Clinical management should be individualised according to anatomical site, stage, differentiation and proliferation of each component, and the histology of metastatic disease when available. Surgery is the main potentially curative approach for localised resectable disease. Perioperative and metastatic systemic treatments are extrapolated predominantly from site‐specific adenocarcinoma and poorly differentiated neuroendocrine carcinoma (NEC) practice; no regimen has been prospectively established as superior specifically for MiNEN. Given the rarity and complexity of MiNEN, multidisciplinary management in expert centres, centralised pathological review, and international collaborative registries are essential to improve diagnostic standardisation and optimise treatment strategies.

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.

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% of the tumor volume. The NE component must be substantiated by immunohistochemistry. MiNENs generally have a poor prognosis, with a more aggressive component dictating overall survival and prognosis. Owing to its rarity, there are no specific validated treatment guidelines available for these tumors, and they are generally treated with surgery if possible. However, surgically unresectable or advanced tumors are generally treated with chemotherapy. We report a case of an elderly woman who was referred to the neuroendocrine tumor (NET) unit following incidental findings of liver lesions found on cardiac magnetic resonance imaging (MRI) performed for an asymptomatic heart murmur. Histology from the liver biopsy revealed MiNEN with up to 60% grade 2 (Ki67: 19%) well-differentiated NET and up to 30% well-differentiated to moderately differentiated adenocarcinoma of possible pancreato-biliary origin; intrahepatic ductal primary could not be excluded. Her 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) revealed no FDG-avid lesions, and a ⁶⁸Gallium 1,4,7,10-tetraazacyclododecane-tetraacetic acid Tyr3-octreotate (⁶⁸ Ga-DOTATATE)-PET scan revealed multiple areas of intensely DOTATATE-avid liver lesions. Due to the absence of any primary imaging findings, the patient was diagnosed with MiNEN of possible pancreato-biliary origin. She was started on lanreotide 120 mg every 28 days for 6 months, with no response to the treatment. Subsequently, the patient was treated with four cycles of ¹⁷⁷Lutetium-DOTATATE (Lutathera®) peptide receptor radionuclide therapy (PRRT). She tolerated the treatment well, with no significant side effects. MRI at the end of treatment revealed a partial response to treatment. PRRT is currently not used in treatment protocols for the management of MiNENs; however, it could be considered a treatment option in patients with MiNENs, where there is a predominant component of well-differentiated NETs with ⁶⁸ Ga-DOTATATE avid lesions.

Gastric, duodenal and rectal neuroendocrine tumours (NETs) are increasingly detected due to advances in endoscopic imaging. While international guidelines provide criteria for endoscopic management, several aspects remain controversial due to limited high‐quality evidence. This position paper, developed by an expert panel, aims to clarify these unresolved issues and provide consensus‐based recommendations. The primary objective of this position paper is to critically analyse and address key controversies in the endoscopic management of gastro‐duodenal‐rectal NETs. These include the optimal selection of endoscopic resection techniques, the significance of R1 resections, pathological assessment and surveillance strategies. Special attention is given to site‐specific challenges, including the role of Ki‐67 in type 1 gastric NETs, the management of multiple gastric lesions, the feasibility of endoscopic resection for type 3 gastric NETs and the limitations of advanced endoscopic techniques in the duodenum. This position paper was developed using an Expert Panel Consensus methodology. Topics were identified during the 2024 ENETS Advisory Board meeting and addressed through a structured literature review. Evidence was critically appraised, and expert discussions were conducted to identify key points. By reviewing controversial aspects of endoscopic management, this position paper will provide practical guidance to optimise decision‐making and improve outcomes for patients with gastro‐duodenal‐rectal NETs. Multidisciplinary evaluation remains crucial to tailoring treatment strategies based on tumour characteristics, patient factors and procedural risks.

Neuroendocrine neoplasms (NENs) arise from the diffuse endocrine system and have been considered to be rare. However, the incidence and prevalence of these tumours have increased in recent years, and they are being seen in younger patients including women in the reproductive age group. Due to the paucity of data, diagnostic and therapeutic strategies in managing such tumours during pregnancy can be challenging to both treating physicians and patients. This article describes the experience and outcomes of managing pregnant women with NEN at a European Neuroendocrine Tumour Society (ENETS) Centre of Excellence. In this retrospective analysis, we evaluated a total of 22 pregnancies in 18 pregnant women with concurrent diagnoses of NENs who were managed at Royal Free Hospital ENETS Centre of Excellence throughout their pregnancy. These were identified from our tumour registry of 3500 NEN patients between 2015 and 2023. Cross‐sectional imaging (computed tomography (CT)/magnetic resonance imaging (MRI)), pre‐ and post‐pregnancy, for each patient was reviewed by an experienced radiologist. Tumour growth rate (TGR) was calculated using the formula: TGR = 100 × [exp (TG) − 1]; TG. [3 × log (D2/D1)]/time (months), where D1 is the tumour size at date 1; D2 is the tumour size at date 2; and time (months) = (Date 2 − Date 1 + 1)/30.44. Tumour growth rate pre‐conception (TGRpc) and tumour growth rate post‐partum (TGRpp) were calculated for each patient. In a sub‐group of patients, positivity for oestrogen and progesterone receptors were analysed on the tumour tissue to evaluate whether the presence of these receptors affected tumour progression during the pregnancy. We also reviewed the pregnancy outcome in patients treated with somatostatin analogues during pregnancy. We analysed the data of a total 22 pregnancy encounters in 18 women: 15 pregnancies (68%) preceded the diagnosis of the NEN, whereas the diagnosis of NEN was made during pregnancy or in the post‐partum period in 5 (23%) and 2 (9%) pregnancies respectively. Eight patients (44%) had a diagnosis of a pancreatic NEN, whereas 5 (28%) were diagnosed with mid‐gut NENs, and a further 5 at other sites. The majority of the patients (n = 12, 67%) had evidence of metastatic disease at the time of diagnosis. Most pregnancies had a successful outcome (n = 19, 86%), whereas 3 patients (14%) had miscarriages in the 1st trimester. Five patients in total of 6 pregnancies were treated with somatostatin analogues as monotherapy during the pregnancy, and all of them had stable disease after pregnancy. All of them delivered healthy babies without any side effects or complications due to therapy. The average TGRpc was −0.8% (n = 5) and the average TGRpp was +0.96% (n = 6); 2 patients who did not have suitable targets for calculation of TGRpc developed new lesions suggesting disease progression. Moreover, 2 of the 4 patients who have had both pre‐conception and post‐pregnancy scans showed an increase in TGRpp compared to TGRpc. The management of NENs during pregnancy should be multidisciplinary with an individualised approach to each patient. Somatostatin analogues appear to be safe during pregnancy, though further robust studies are needed. Pregnancy per se may accelerate tumour progression, and patients should be counselled regarding this possibility.

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.

Over 80% of patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed at a late stage and are locally advanced or with concurrent metastases. The aggressive phenotype and relative chemo- and radiotherapeutic resistance of PDAC is thought to be mediated largely by its prominent stroma, which is supported by an extracellular matrix (ECM). Therefore, we investigated the impact of tissue-matched human ECM in driving PDAC and the role of the ECM in promoting chemotherapy resistance. Decellularized human pancreata and livers were recellularized with PANC-1 and MIA PaCa-2 (PDAC cell lines), as well as PK-1 cells (liver-derived metastatic PDAC cell line). PANC-1 cells migrated into the pancreatic scaffolds, MIA PaCa-2 cells were able to migrate into both scaffolds, whereas PK-1 cells were able to migrate into the liver scaffolds only. These differences were supported by significant deregulations in gene and protein expression between the pancreas scaffolds, liver scaffolds, and 2D culture. Moreover, these cell lines were significantly more resistant to gemcitabine and doxorubicin chemotherapy treatments in the 3D models compared to 2D cultures, even after confirmed uptake by confocal microscopy. These results suggest that tissue-specific ECM provides the preserved native cues for primary and metastatic PDAC cells necessary for a more reliable in vitro cell culture.

Summary Insulinomas are rare pancreatic neuroendocrine neoplasms (NENs) that are typically sporadic and solitary, with the majority being 68Gallium-DOTATATE PET scan. Accordingly, he was initiated on diazoxide and referred to the surgical team for distal pancreatectomy: histology confirmed a 4.4-cm well-differentiated pancreatic NEN of intermediate grade (NEN G2, Grade 2, 2017 World Health Organization (WHO) pancreatic-NEN classification), with positive immunohistochemistry for insulin. His hypoglycaemia episodes have ceased, and he remains under active surveillance. Our case demonstrates the possibility of dietary control of insulinoma-induced hypoglycaemia, and the likelihood that such a prolonged delay in diagnosis has led to the uncommonly large size of the apparently benign tumour which is usually ‘small and indolent’. Learning points Most patients with insulinomas have lesions that are 1–2 cm in size, with 96% being less than 3 cm. The mean tumour size of insulinomas found in 3 of the largest reported series was 1.5 cm, with a range of 0.1–7.0 cm. It is not uncommon for patients to have symptoms for several months to years before diagnosis; however, no reported cases had the symptoms such long for 25 years, and the large size of the tumour in this case may reflect the very long history. Abstract Summary Insulinomas are rare pancreatic neuroendocrine neoplasms (NENs) that are typically sporadic and solitary, with the majority being 68Gallium-DOTATATE PET scan. Accordingly, he was initiated on diazoxide and referred to the surgical team for distal pancreatectomy: histology confirmed a 4.4-cm well-differentiated pancreatic NEN of intermediate grade (NEN G2, Grade 2, 2017 World Health Organization (WHO) pancreatic-NEN classification), with positive immunohistochemistry for insulin. His hypoglycaemia episodes have ceased, and he remains under active surveillance. Our case demonstrates the possibility of dietary control of insulinoma-induced hypoglycaemia, and the likelihood that such a prolonged delay in diagnosis has led to the uncommonly large size of the apparently benign tumour which is usually ‘small and indolent’. Learning points Most patients with insulinomas have lesions that are 1–2 cm in size, with 96% being less than 3 cm. The mean tumour size of insulinomas found in 3 of the largest reported series was 1.5 cm, with a range of 0.1–7.0 cm. It is not uncommon for patients to have symptoms for several months to years before diagnosis; however, no reported cases had the symptoms such long for 25 years, and the large size of the tumour in this case may reflect the very long history.