Gastric Neuroendocrine Tumors Research Articles

Grade 2 gastric neuroendocrine tumours type 1: not always an indolent disease

Grade 2 gastric neuroendocrine tumours type 1: not always an indolent disease

Clinical Outcome of Patients with Gastric, Duodenal, or Rectal Neuroendocrine Tumors after Incomplete Endoscopic Resection.

Objectives: Our aim was to investigate the clinical outcome of patients with well-differentiated gastric, duodenal, and rectal neuroendocrine tumors after treatment with incomplete endoscopic resection due to the finding of microscopic positive resection margins (R1). Methods: This is a retrospective analysis of consecutive patients with type 1 gastric, non-ampullary non-functioning duodenal, or rectal neuroendocrine neoplasms with positive R1 margins after endoscopic resection. The rate of tumor recurrence and progression-free survival were considered to be the study's main endpoints. Statistical analysis was performed using MedCalc® v.17 software and a p-value of <0.05 was considered significant. A Cox proportional-hazard regression was performed to identify risk factors for disease recurrence/progression. Results: After evaluating 110 patients, a total of 58 patients were included in the final analysis (15 gastric NENs, 12 duodenal NENs, and 31 rectal NENs). After evidence of endoscopic R1 resection had been gathered, 26 patients (44.8%) underwent an endoscopic/surgical extension of the previous resection. Tumor progression (all local recurrences) occurred in five out of fifty-eight patients (8.6%) with a median PFS of 36 months. There were no tumor-related deaths. G2 grading and the gastric primary tumor site were the only features significantly associated with the risk of recurrence of the disease (HR: 11.97 [95% CI: 1.22-116.99], HR: 12.54 [95% CI: 1.28-122.24], respectively). Conclusions: Tumor progression rarely occurs in patients with microscopic positive margin excision (R1) after endoscopic resection and does not seem to affect patients' clinical outcomes.

Therapeutic efficacy analysis of endoscopic combined with serological diagnosis strategy and endoscopic in G1 and G2 gastric neuroendocrine neoplasms

Objective: To investigate the endoscopic combined serological diagnosis strategy for G1 and G2 gastric neuroendocrine neoplasms (G-NENs), and to evaluate the safety, short-term, and long-term efficacy of two endoscopic treatment procedures: endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). Methods: This study retrospectively analyzed the clinical data of 100 consecutive patients with G-NENs who were hospitalized at the Cancer Hospital of the Chinese Academy of Medical Sciences from January 2011 to October 2023. These patients underwent endoscopic treatment, and propensity score matching (PSM) was used to compare clinicopathological characteristics, as well as short-term and long-term efficacy of lesions in the EMR group and ESD group before and after treatment. Results: Among the 100 patients with G-NENs, the median age was 54 years old. Before surgery, 29 cases underwent endoscopic combined serological examination, and 24 of them (82.2%) had abnormally elevated plasma chromogranin A. The combined diagnostic strategy for autoimmune atrophic gastritis (AIG) achieved a diagnostic accuracy of 100%(22/22). A total of 235 G-NEN lesions were included, with 84 in the ESD group and 151 in the EMR group. The median size of the lesions in the ESD group (5.0 mm) was significantly larger than that in the EMR group (2.0 mm, P＜0.001). Additionally, the ESD group had significantly more lesions with pathological grade G2[23.8%(20/84) vs. 1.3%(2/151), P＜0.001], infiltration depth reaching the submucosal layer [78.6%(66/84) vs. 51.0%(77/151), P＜0.001], and more T2 stage compared to the EMR group[15.5%(13/84) vs. 0.7%(1/151), P＜0.001]. After PSM, 49 pairs of lesions were successfully matched between the two groups. Following PSM, there were no significant differences in the en bloc resection rate [100.0%(49/49) vs. 100.0%(49/49)], complete resection rate [93.9%(46/49) vs. 100.0%(49/49)], and complication rate [0(0/49) vs. 4.1%(2/49)] between the two groups. During the follow-up period, no recurrence or distant metastasis was observed in any of the lesions in both groups. Conclusions: The combination of endoscopy and serology diagnostic strategy has the potential to enhance the accuracy of diagnosing G1 and G2 stage G-NENs and their background mucosa. Endoscopic resection surgery (EMR, ESD) is a proven and safe treatment approach for G1 and G2 stage G-NENs.

Factors Associated with Gastric and Duodenal Neuroendocrine Tumor Development

Factors Associated with Gastric and Duodenal Neuroendocrine Tumor Development

Multiple gastric neuroendocrine tumors in a patient with parietal cell dysfunction and adenosine triphosphatase H+/K+ transporting subunit alpha gene variant.

A 47-year-old woman presented with multiple gastric tumors, each up to 10mm in diameter, in the gastric body and fundus without mucosal atrophy. White spots and numerous transparent, light-brownish, small, and rounded spots were observed in the background gastric mucosa. Biopsy specimens obtained from the tumors revealed gastric neuroendocrine tumors. The patient exhibited hypergastrinemia and achlorhydria and tested negative for serum parietal cell antibody, intrinsic factor antibody, and Helicobacter pylori infection. Moreover, no additional lesions were detected on imaging. These findings were inconsistent with Rindi's classification. The tumor was resected via endoscopic submucosal resection. Histopathological examination revealed gastric neuroendocrine tumors G2 infiltrating the submucosa with no atrophy of the gastric mucosa, dilated fundic glands, parietal cell protrusions, and hyperplasia of enterochromaffin-like cells. Immunohistochemically, the parietal cells were negative for both α- and β-subunits of H+/K+ ATPase, suggesting parietal cell dysfunction. A genomic variant was identified in adenosine triphosphatase H+/K+ transporting subunit alpha. After 7years of treatment, there was no evidence of residual or metastatic lesions. Modification of adenosine triphosphatase H+/K+ transporting subunit alpha may be a significant factor in the pathogenesis of multiple gastric neuroendocrine tumors in the context of gastric parietal cell dysfunction.

When rare diseases crisscross within the same patient: von Hippel-Lindau and type 1 gastric neuroendocrine tumor.

Von-Hippel-Lindau (VHL) is a genetic multisystem disorder characterized by visceral cysts and benign and malignant tumors in various organs. Herein, we present the case of a 23-year-old woman with VHL presenting with multiple gastric neuroendocrine neoplasms (gNENs) type 1 in the context of chronic autoimmune gastritis (CAG). Although gNENs are not acknowledged as a typical entity in VHL patients, in the present case, gNENs were composed of neoplastic cells with clear cytoplasm usually seen in tumors related to VHL disease. We additionally performed a literature review on the presence of neuroendocrine clear cell tumors and report on further cases of clear cell NENs. The present case illustrates that clear-cell transformation in gNENs may be due to the dual genetic background of the patient; the real oncogenic stimulus may be more closely related to CAG than to VHL disease accompanied by an interplay between neoplastic and autoimmune processes. Therefore, close monitoring of patients with clear cell NENs appears to be important before excluding VHL disease, even in the context of phenotypically unrelated diseases.

Gastric neuroendocrine neoplasms.

Gastric neuroendocrine neoplasms (gNENs) display peculiar site-specific features among all NENs. Their incidence and prevalence have been rising in the past few decades. gNENscomprise gastric neuroendocrine carcinomas (gNECs) and gastricneuroendocrine 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 typeII 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.

The impact of surgical resection on prognosis in gastric neuroendocrine tumors

Aims: This study aimed to investigate the pathological factors influencing prognosis in patients undergoing surgical resection for GNETs, in the context of the World Health Organization 2010 staging system. Methods: This retrospective study included 27 patients who underwent surgical resection for GNETs diagnosis between 2001 and 2015. Patients were clinically categorized into four types based on gastric NET characteristics: type 1 tumors, which are typified by hypergastrinemia and develop on a background of atrophic gastritis; type 2 tumors, which are related with gastrinomas; type 3 tumors, which have low serum gastrin levels and no underlying mucosal pathology, and type 4, which are characterized by neuroendocrine carcinoma. Additionally, all patients were classified according to the TNM staging system. Results: The median age of the patients was 56 years (range: 33-81), and most patients were identified as type I (55.6%), with subsequent groups being type IV (25.9%) and type III (18.5%). The majority of type I patients were classified as stage I, while the majority of type III patients were in stage IIA, and most type IV patients were in stage IIIB. Type III and type IV groups exhibited a higher rate of lymph node metastasis compared to type I group (Type I: 13.3% vs. Type II: 80.0% vs. Type IV: 57.1%, p &lt; 0.001). The mortality rate was higher in the Type IV group compared to other groups (Type I: 0% vs. Type II: 20% vs. Type IV: 57.1%, p &lt; 0.001). The Ki-67 levels were higher in patients with lymph node metastasis than in those without. Conclusion: Type III and IV GNETs are at a higher risk of lymph node metastasis and mortality. The Ki-67 value assessed through preoperative endoscopic biopsy may serve as a guide for deciding on the necessity of lymph node dissection.

Abstract 4234: Personalized therapeutic screening in patient derived organoids for gastroenteropancreatic neuroendocrine tumors

Abstract Introduction Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) are a rare subset of cancers which nevertheless are a rising health burden. Development of new therapies suffers from several bottlenecks, including low patient accrual and poor understanding of tumor characteristics. Patient tumor organoids (PTOs) are a novel model capable of improving screening of patient tissue in an accurate, standardized, and high-throughput capacity. In this study, we utilized patient tumors for creation of high-fidelity PTOs from a variety of GEP-NEN primary origins to evaluate therapy responses. Methods Tumors from patients undergoing clinically guided surgeries were processed within two hours of resection and dissociated into single-cell suspension. Cells were encapsulated into Matrigel and cultured into two groups. The first group was grown for 10 days to assess viability then treated with a panel of clinically approved therapies and novel treatments recommended by high throughput NEN cell line screening for treatment sensitivity using the MIPE 5.0 library. The second group was grown for long-term expansion and biobanking, followed by characterization using immunohistochemistry and genetic profiling to ensure tumor cell maintenance. Results From March 2023-November 2023, 14 patients provided 30 tumors for PTO development. These included small intestine (n=5), pancreatic (n=8), and gastric (n=1) neuroendocrine tumors. Long-term culture (&amp;gt;3 passages) was successful for 23/30 (77%) specimens, with passage timing related to tumor grade. PTOs maintained immunohistochemical characteristics of the parent tumor types and demonstrated similar genetic profiles, including neuroendocrine tumor cell markers synaptophysin, chromogranin A, and matched grade-based Ki67 proliferative index. The early-stage therapeutic screening was performed for 12/14 (86%) patients, demonstrating tumor grade dependent treatment efficacy and showing clinically dose relevant sensitivity towards approved small molecule inhibitor therapies including cabozantinib and sunitinib in a patient and tumor origin-dependent manner. Testing of effective therapy classes recommended by cell line treatment panels suggested high level treatment efficacy for proteosome inhibitors, MEK inhibitors, and topoisomerase inhibitors. Conclusion Development of GEP-NEN PTOs is feasible for long term culture and standard of care therapy testing. Further study demonstrated the successful application of novel therapeutic options in PTOs for patients with GEP-NENs. Citation Format: Steven D. Forsythe, Srujana V. Yellapragada, Stephen G. Andrews, Jaydira del Rivero, Jonathan M. Hernandez, Naris Nilubol, James P. Madigan, Samira M. Sadowski. Personalized therapeutic screening in patient derived organoids for gastroenteropancreatic neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4234.

Factors associated with gastric and duodenal neuroendocrine tumors: A multicenter case-control study

Background and AimsThe incidence of gastric and duodenal neuroendocrine tumors (GNET and DNET, respectively) is increasing, however associated factors of these diseases are not well known. Here, we investigated the factors associated with GNET and DNET. MethodsPatients with GNET and DNET presenting at eight tertiary referral centers between 2001 and 2020 were included and compared with healthy controls who underwent upper endoscopic screening. Clinical factors and laboratory data were analyzed to determine associated factors of GNET and DNET. ResultsOverall, 396 patients with GNET and 193 patients with DNET were included and compared with 1725 healthy controls. Multivariate analysis showed that age (odds ratio [OR] 0.98), diabetes (OR 1.72), hypertension (OR 1.97), low serum high-density lipoprotein cholesterol (HDL-C) levels (OR 2.54), and past/present H. pylori infection (OR 1.46) were significantly associated with GNET. In contrast, DNET was significantly associated with diabetes (OR 1.80), hypertension (OR 1.68), low serum HDL-C levels (OR 2.29), and past/present H. pylori infection (OR 5.42). In the sex-based subgroup analysis in GNET, current smoking was strongly associated in women (OR 9.85), but not in men. ConclusionsThis study identified several common metabolic factors associated with GNET and DNET. Additionally, some factors had sex-specific associations.

Protocolo de evaluación de las lesiones premalignas gástricas

Gastric carcinogenesis is associated with Helicobacter pylori(H. pylori) infection and occurs through histologic gastric cancer precursor lesions (GCPL). This protocol will discuss intestinal gastric cancer. It does not cover prevention of diffuse and cardia gastric cancer, neuroendocrine tumors, or hereditary syndromes. The most significant factors that cause an increased risk of gastric cancer are family history of the disease and the presence of GCPL. The two strategies evaluated to reduce the incidence and/or mortality of gastric cancer are eradication of H. pylori and monitoring and/or endoscopic treatments.

Clinicopathological characteristics of gastric neuroendocrine neoplasms: A comprehensive analysis.

This study aimed to explore the clinicopathological characteristics and prognostic implications of gastric neuroendocrine neoplasms (g-NENs). A retrospective enrollment of 142 patients diagnosed with g-NENs was conducted at Zhejiang Cancer Hospital between January 1, 2007 and December 31, 2021. The study compared essential clinicopathological features and survival rates. Additionally, the prognosis of gastric neuroendocrine carcinomas/mixed neuroendocrine-non-neuroendocrine neoplasms (g-NEC/MiNEN) were contrasted with those of gastric adenocarcinoma (GAC) and signet ring cell carcinoma (SRCC). The study comprised a total of 142 g-NENs cases, with a male-to-female ratio of approximately 2:1. The 5-year survival rates for g-NEC and g-MiNEN were 26.7% and 35.2%, respectively. Corresponding 5-year survival rates for G1 and G2 were observed at 100% and 80.0%, respectively. g-NEC/MiNEN showed a significantly worse prognosis compared to g-NET (p < 0.001). g-NEC/MiNEN exhibited a poor prognosis compared to GAC (p < 0.001), and within poorly differentiated GAC, g-NEC/MiNEN demonstrated a worse prognosis (p = 0.007). Additionally, patients receiving postoperative adjuvant therapy exhibited notably prolonged overall survival (OS) in the case of g-NEC/MiNEN (p = 0.010). In short, the prognosis of g-NEC/MiNEN was worse than that of g-NET, GAC and poorly differentiated GAC, but this group benefit from postoperative adjuvant therapy.

Antral smooth muscle proliferation in the lamina propria of a patient with a history of chronic atrophic gastritis and multiple gastric neuroendocrine tumours

Antral smooth muscle proliferation in the lamina propria of a patient with a history of chronic atrophic gastritis and multiple gastric neuroendocrine tumours

Type 3 gastric neuroendocrine neoplasms: the rising promise of conservative endoscopic management.

Gastric neuroendocrine neoplasms (g-NENs) are rare tumors arising from the gastric enterochromaffin-like cells. Recent data suggests an increased detection rate, attributed to more frequent esophagogastroduodenoscopies. While type 3 g-NENs were historically deemed aggressive, emerging research indicates potential for conservative management, especially endoscopic resection, in well-differentiated, small tumors. European guidelines now advocate for endoscopic intervention in selected cases, but North American guidelines remain more conservative. Key factors influencing outcomes are tumor size, grading, and depth of gastric wall infiltration. Endoscopic resection has shown promise for tumors confined to submucosal layers without lymphovascular invasion. Given the complexities, a multidisciplinary team approach is essential for management decisions. Current insights are largely based on retrospective studies, underscoring the need for prospective research to optimize endoscopic approaches.

Global Publication Trends and Research Hotspots of The Gastric Neuroendocrine Neoplasms: A Bibliometric Analysis of The Current Situation

Objective: Gastric neuroendocrine neoplasms (gNENs) are uncommon tumors, with growing understandings about the disease. Bibliometric analyzes have the advantage of visually depicting the dynamic evaluation of scientific knowledge of a specific topic. The aim of this study was to perform and report bibliometric analysis of gNENs, which was not formerly studied in the literature. Methods: Articles published between 1980 and 2022 within the database of Web of Science Core Collection were included in this bibliometric analysis. Vosviewer package program and Datawrapper were used for bibliometric data interpretation. Results: A total of 2270 articles about gNENs was detected with 63240 citations and an H index of 103. A remarkable increase was detected among the articles for years. Research have focused on gastroenterology and hepatology, endocrinology and metabolism, oncology, general medicine, pathology and surgery areas. Norwegian University of Science Technology was the leading institution about gNENs literature. Modlin IM, had the highest number of articles and citations among the authors. United States, Japan and Italy were the top three countries with the most published articles. Conclusion: This bibliometric study provides an engrossing, insightful conclusion to the research and development trajectory in gNENs with a future perspective.

Netazepide, an Antagonist of Cholecystokinin Type 2 Receptor, Prevents Vincristine-Induced Sensory Neuropathy in Mice.

Among the vinca-alkaloid class, vincristine is a potent chemotherapeutic agent with significant neurotoxic effects and is employed to address a wide spectrum of cancer types. Recently, the therapeutic potential of the cholecystokinin type 2 receptor (CCK2R) as a target for vincristine-induced peripheral neuropathy (VIPN) was demonstrated. In this study, the impact of preventive CCK2R blockade using netazepide (Trio Medicines Ltd., London, UK) was investigated in a mouse model of vincristine-induced peripheral neuropathy. Netazepide is a highly selective CCK2R antagonist under development for the treatment of patients with gastric neuroendocrine tumors caused by hypergastrinemia secondary to chronic autoimmune atrophic gastritis. Vincristine-induced peripheral neuropathy was induced by intraperitoneal injections of vincristine at 100 µg/kg/d for 7 days (D0 to D7). Netazepide (2 mg/kg/d or 5 mg/kg/d, per os) was administered one day before vincristine treatment until D7. Vincristine induced a high tactile allodynia from D1 to D7. VIPN was characterized by dorsal root ganglion neuron (DRG) and intraepidermal nerve fiber (IENF) loss, and enlargement and loss of myelinated axons in the sciatic nerve. Netazepide completely prevented the painful symptoms and nerve injuries induced by vincristine. In conclusion, the fact that netazepide protected against vincristine-induced peripheral neuropathy in a mouse model strongly supports the assessment of its therapeutic potential in patients receiving such chemotherapy.

Classification of gastric neuroendocrine tumors and associations with survival.

597 Background: The World Health Organization (WHO) classification of gastric body neuroendocrine tumors (GNETs) includes type 1 tumors characterized by hypergastrinemia and arising in a background of atrophic gastritis, type 2 tumors associated with gastrinomas, and type 3 tumors with low serum gastrin level and no background mucosal pathology. However, certain tumors remain unclassified, and the prognostic significance of these tumors is currently unknown. The purpose of this study was to better characterize GNET types and to determine associations with distant metastasis and disease-specific survival (DSS). Methods: Patients diagnosed with GNET (1986-2021) were retrospectively identified and tumors classified as type 1, 2, or 3. Unclassified tumors were reviewed for background gastric mucosal changes associated with chronic proton pump inhibitor (PPI) use. Tumors were categorized as PPI-associated if there were prominent parietal and neuroendocrine cell hyperplasia in the background mucosa, in the absence of a gastrinoma and a positive history of chronic PPI use. WHO grade was determined using mitotic index or Ki-67 proliferative index when available. Characteristics by tumor type, associations with distant metastasis at initial diagnosis, and DSS were determined using standard statistical methods. Results: Of 246 patients, 164 (66.7%) had type 1, 5 (2.0%) had type 2, 52 (21.1%) had type 3, 18 (7.3%) were PPI-associated, and 7 (2.8%) remained unclassified. Multifocal disease was more common for types 1 (56.1%) and 2 (40.0%) than type 3 (13.5%) and PPI-associated tumors (27.8%, P&lt;0.001). Patients with type 3 GNET were also less likely to have WHO grade 1 tumors (26.9%) compared to other GNETs (type 1 37.2%, type 2 40.0%, PPI-associated 50.0%, P&lt;0.001). Additionally, distant metastases at presentation occurred more frequently with type 3 (38.5%) than type 1 (1.2%), type 2 (20.0%), and PPI-associated tumors (11.1%, P&lt;0.001). GNET type (type 1 vs 3, odds ratio [OR] 0.005 [95% confidence interval [CI] 0.001-0.050; PPI-associated vs type 3, OR 0.040 [95% CI 0.004-0.45]), race (non-white vs white, OR 0.17 [95% CI 0.040-0.73]), and WHO grade (2/3 vs 1, OR 10.5 [95% CI 1.93-57.2]) were associated with distant metastasis at presentation. Five-year DSS rates were 100.0% for type 1, 59.7% (95% CI 42.7-73.2%) for type 3, and 90.9% (95% CI 50.8-98.7%) for PPI-associated (log-rank P&lt;0.001). By multivariable analysis, multifocality of primary tumors (hazard ratio [HR] 0.070 [95% CI 0.010-0.46]) and distant metastasis at diagnosis (HR 44.9, 95% CI 6.21-324.8) were independently associated with DSS, while tumor type was not (type 1 vs 3, HR 0.18 [95% CI 0.010-2.44); PPI-associated vs type 3, HR 0.13 [95% CI 0.010-1.33]). Conclusions: PPI-associated tumors may represent a distinct GNET type with intermediate outcomes compared to type 1 and type 3 tumors. However, factors other than tumor type must be considered in determining survival.

Autoimmune gastritis

Diagnosis of autoimmune gastritis (AIG) is often challenging because of the absence of typical symptoms. Clinical guidelines are lacking, which results in inadequate treatment and poor cancer screening. This work presents an overview of current management options and aims at raising awareness for this disease. The paper also describes a clinical case of the full-scale course of AIG with all its complications. Autoimmune gastritis is mostly considered as a disease of elderly with vitamin B12 deficiency and pernicious anaemia. Today it is recognized that AIG is found with a similar prevalence in all age groups, with iron deficiency being a frequent symptom. Conventional therapy consists of adequate iron and vitamin B12 supplementation, as well as symptomatic approaches. The associated risk for gastric adenocarcinoma and gastric neuroendocrine tumours requires regular endoscopic follow-up. New treatments aiming to reduce gastric atrophy and cancer risk are currently under development. Thus, treatment of autoimmune gastritis should focus on optimizing supplementation of vitamin and macronutrient deficiencies, symptomatic therapy that improves quality of life, and include cancer prevention measures. Clinical studies should address the possibility to arrest the inflammation process and to prevent progression of AIG. The author of the article suggests that itopride hydrochloride and rebamipide will be used for symptomatic and pathogenetic therapy. The problem facing gastroenterologists today is to develop domestic guidelines for the management and screening endoscopic intervals of patients with AIG.

Infiltrating characteristics and prognostic value of tertiary lymphoid structures in resected gastric neuroendocrine neoplasm patients.

Tertiary lymphoid structures (TLSs) are lymphocyte aggregates that play an anti-tumor role in most solid tumors. However, the functions of TLS in gastric neuroendocrine neoplasms (GNENs) remain unknown. This study aimed to determine the characteristics and prognostic values of TLS in resected GNEN patients. Haematoxylin-eosin, immunohistochemistry (IHC) and multiple fluorescent IHC staining were used to assess TLS to investigate the correlation between TLSs and clinicopathological characteristics and its prognostic value. Tertiary lymphoid structures were identified in 84.3% of patients with GNEN. They were located in the stromal area or outside the tumor tissue and mainly composed of B and T cells. A high density of TLSs promoted an anti-tumor immune response in GNEN. CD15+ TANs and FOXP3+ Tregs in TLSs inhibited the formation of TLSs. High TLS density wassignificantly associated with prolonged recurrence-free survival(RFS) and overall survival (OS) of GNENs. Univariate and multivariate Cox regression analyses revealed that TLS density, tumor size, tumor-node-metastasis (TNM) stage and World Health Organisation (WHO) classification were independent prognostic factors for OS, whereas TLS density, tumor size and TNM stage were independent prognostic factors for RFS. Finally, OS and RFS nomograms were developed and validated, which were superior to the WHO classification and the TNM stage. Tertiary lymphoid structures were mainly located in the stromal area or outside the tumor area, and high TLS density was significantly associated with the good prognosis of patients with GNEN. Incorporating TLS density into a nomogram may improve survival prediction in patients with resected GNEN.

Gastric neuroendocrine tumor presenting with carcinoid syndrome.

Carcinoid tumors are rare neoplasms, most frequently found in the gastrointestinal tract, responsible for the production of neuroendocrine mediators. Carcinoid syndrome is even rarer and consists of a set of symptoms characteristic of the release of these mediators into the systemic circulation. We present an interesting case of a patient with carcinoid syndrome as a late manifestation of a gastric neuroendocrine tumor with, highlighting the importance of knowing how to identify the carcinoid syndrome.