Clinical features of resected gastric neuroendocrine neoplasms

Clinical features of resected gastric neuroendocrine neoplasms | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical features of resected gastric neuroendocrine neoplasms Shunichi Ito, Kiyoaki Taniguchi, Kazuomi Suzuki, Hiroto Egawa This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1657483/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Due to improvements in diagnostic technology, the incidence of gastrointestinal neuroendocrine neoplasms has increased gradually. Therefore, it is important to understand their clinical manifestations and management. The aims of this study were to investigate the clinical features of gastrointestinal neuroendocrine neoplasms and to evaluate the outcomes of patients in our institute. Methods: Between April 1965 and December 2020, patients with a diagnosis of gastric neuroendocrine neoplasms undergoing surgery in our institute were recruited. Clinical data were collected retrospectively. Results: Twenty-four gastric neuroendocrine neoplasm patients were recruited. Ten patients had lymphovascular invasion and seven patients had lymph node metastasis. There was a significant difference in the overall survival rate between those with and without lymph node metastasis. The significant risk factor for lymph node metastasis was lymphatic invasion. Conclusions: Positive lymph node metastasis influenced overall survival. Lymphatic invasion was the most important risk factor for lymph node metastasis. gastric neuroendocrine neoplasm gastric neuroendocrine tumor gastric neuroendocrine carcinoma carcinoid stomach Figures Figure 1 Figure 2 1. Introduction Gastric neuroendocrine neoplasms (GNENs) have been known as gastric “carcinoid” since 1907. 1 In 2000, the World Health Organization (WHO) classified gastric neuroendocrine tumor (GNET) as a kind of neuroendocrine tumor (NET). In Japan, GNEN accounts for 15.1% of all neuroendocrine neoplasms (NENs). 2 Due to improvements in diagnostic technology, including endoscopic and radiological modalities and immunostaining, the incidence of NENs, especially gastrointestinal (GI) NENs, has increased gradually. 3 However, even after including progress and prognosis regarding rare GNENs, our knowledge is still very limited because the overall prevalence of GINENs is reported to be only 6.42 per 100,000 people. 4 , 5 The aims of this study were to investigate the clinical features and to evaluate the outcomes in patients with GNENs in our institute. 2. Case Series Between April 1965 and December 2020, patients with a diagnosis of histologically confirmed GNENs and undergoing surgery in our institute were recruited. We collected the clinical data retrospectively. The WHO classification system (in 1980, 2000, 2010, and 2019) was used for grading of differentiation and NEN diagnosis ( Table 1 ). 6 , 7 Clinical classification was based on the European Neuroendocrine Tumor Society (ENETS) Consensus Guidelines ( Table 2 ). 8 In total, 24 GNEN patients were recruited. Data analyzed included demographic characteristics (male vs. female, less than 70 years old vs. over 70 years old), symptoms, tumor size ( 20 mm), location (proximal vs. distal), number, depth of tumor invasion, pathological diagnosis (carcinoid vs. NET vs. neuroendocrine carcinoma (NEC) vs. others), lymphovascular invasion (positive vs. negative), tumor stages, treatment, and postoperative outcomes. To evaluate lymph node metastasis or distant organ metastases, we used radiological examinations, including computed tomography. Univariate analysis was performed using Fisher’s exact test. In the statistical calculation of the cumulative overall survival (OS) rate (OSR), the Kaplan-Meier method was employed. Variables were compared using the log-rank test. Statistical significance was accepted for p-values < 0.05. Data were expressed as means and ranges, as appropriate. Qualitative data were expressed as numbers (and percentages). All statistical analyses were performed using JMP Pro ver.13 (SAS Institute, Cary, NC, USA). Eleven patients were diagnosed with carcinoid (45.8%), three with NET (12.5%), seven with NEC (29.2%) (one of them had synchronous liver metastasis), and three with mixed-type adenoneuroendocrine carcinoma (including mixed endocrine-exocrine carcinoma, mixed acinar-endocrine carcinoma, and mixed adenoneuroendocrine carcinoma) (12.5%) (Table 3) . Fourteen patients had type 1 GNEN (77.8%) and four had type 3 GNEN (22.2%). None of the patients had type 2 GNEN. There were 19 male (79.2%) and 5 female patients (20.8%). The mean age was 65.5 years (SD: 9.3, range: 42–78); 13 patients had no symptoms (54.2%). The most common symptom was epigastralgia (29.2%), and one patient had carcinoid syndrome. The mean tumor size was 25.4 mm (SD: 17.8, range: 7–80). The tumors of 17 patients were located in the proximal (fundus, cardia, or body) stomach (73.9%). Most patients had solitary tumors (95.8%). One patient had mucosal invasion (5.6%), nine had submucosal invasion (50%), two had muscularis propria invasion (11.1%), and six had subserosa invasion (33.3%). Ten patients had lymphovascular invasion histologically (52.6%) and seven patients had lymph node metastasis (29.2%). Five patients underwent treatment before surgery and two patients underwent hepatectomy simultaneously. All patients but one did not die because of surgery. The mean follow-up period was 45.3 months (SD 43.3; range, 0.5–163). Kaplan-Meier curves for OSR according to lymph node metastasis and tumor size are shown in Fig. 1 and Fig. 2 . For OSR, there was a significant difference between patients with and without lymph node metastasis (p = 0.0407). On the other hand, there was no statistical difference in tumor size (10 mm is the cut-off) ( p = 0.3176). The risk factors for lymph node metastasis included sex, age, tumor size, tumor location, diagnosis, lymphatic invasion, vascular invasion, and recurrence on univariate analysis ( Table 4 ). A significant risk factor for lymph node metastasis was lymphatic invasion ( p = 0.0408). 3. Discussion In our study, positive lymph node metastasis was found to influence OSR statistically. Lymphatic invasion was the most important risk factor for lymph node metastasis in the univariate analysis. Thus far, many prognostic factors have been proposed. For lymph node metastasis, risk factors were angiolymphatic invasion, 9 the tumor-associated neutrophil-to-lymphocyte ratio (TA-NLR), which was calculated as the average number of neutrophils (CD15-positive cells) divided by the average number of T lymphocytes (CD8-positive cells), 4 and tumor size and tumor grade in rectal NETs. 10 This study showed that lymph node metastasis was not associated with vascular invasion and tumor size but instead with lymphatic invasion. The Ki-67 index and the TA-NLR were independent prognostic factors for recurrence-free survival (RFS) and OS. 4 In this study, positive lymph node metastasis was an important factor for the OSR in the univariate analysis. This may be influenced by many censored cases, and multivariate analysis may produce different results. Furthermore, for type 3 GNETs without distant metastases, radical surgery, serum carcinoembryonic antigen (CEA) level, immunohistochemistry marker CD56, and chromogranin A (CgA) are important for prognostic evaluation. 11 In this study, unfortunately, we did not obtain enough data to determine whether prognosis was affected by angiolymphatic invasion, but we would like to consider these factors in further research. GNENs are rare neoplasms derived from the enterochromaffin-like (ECL) cells of the gastric mucosa that play a role in regulating gastric acid production. 11 , 12 GNENs are more common in male patients and the average age of onset is 55 years. The incidence of proximal gastric fundus and cardia region accounted for 69.7% of cases. The specificities of biomarkers in gastroenteropancreatic NET patients were 86% for CgA, 100% for neuron-specific enolase (NSE), 91% for CEA, and 100% for 5-hydroxyindoleacetic acid (5-HIAA). The corresponding sensitivities were 68% for CgA, 33% for NSE, 15.4% for CEA, and 35% for 5-HIAA. 11 In p53 expression, it was negative in all NETs G3 but positive in almost 78% of poorly differentiated NENs. 13 The proportions of tumor recurrence of the patients with GNEN were 72% of liver metastasis, 28% of peritoneal metastasis, and 25% of lymph node metastasis. On the other hand, the spleen, kidney, and brain are relatively rare sites of recurrence. 4 Rindi et al. described three clinicopathologic subtypes of well-differentiated ECL cell tumors of the stomach: Type 1 was associated with body-fundus chronic atrophic gastritis, Helicobacter pylori-related gastritis, autoimmune gastritis, pernicious anemia, and hypergastrinemia; Type 2 was associated with hypertrophic gastropathy and hypergastrinemia due to multiple endocrine neoplasia type 1 (MEN-1) and Zollinger-Ellison syndrome; Type 3 was sporadic. 3 , 14 , 15 ENETS reported that the overall metastatic risk is low in type 1 GNETs and has been directly correlated with tumor size (10 mm is the cut-off.), and recommended tumors > 10 mm were resected. The RFS rate of patients with type 1 GNETs for approximately 24 months is 100%. For type 2 GNETs, local resection can be recommended with or without duodenal or pancreatic NENs as part of MEN-1. For type 3 GNETs, while endoscopic management for small lesions has been proposed, surgical treatment such as gastrectomy with lymph node dissection following the strategy for gastric adenocarcinomas is recommended. 8 GI carcinoids originate as hyperplastic proliferations of endocrine cells in the basal portion of the glands, develop into extraglandular buddings, and penetrate the muscularis mucosae, resulting in the formation of a submucosal nodule. Soga reported that GI carcinoids that penetrate the muscularis mucosae and enter the submucosal layer (SM carcinoids) are indicative of malignancy without exception. 9 The previous study reported that 59 out of 381 cases (15.5%) of gastric SM carcinoids had metastases. The metastasis rates were 7.9% (carcinoids 10 mm and 20 mm), respectively. Moreover, the average size of the SM G-carcinoids was 14.4 mm, and there was a significant difference between their size with metastases (20.9 mm) and without metastases (13.2 mm). 9 In this study, there was no significant difference according to tumor size for OSR. This may be associated with insufficient data for the T category. The 5-year survival rate in patients with gastric SM carcinoids was the same as that of patients with gastric SM carcinomas (89.6% versus 82.7%). The 5-year survival rate in patients with gastric SM carcinoids with metastases was 61.7%. 9 Therefore, it is necessary to pay attention to the patients with early gastric SM carcinoid, especially those over 10 mm. In contrast, it has been reported that approximately 60% of patients with less than 20 mm type 1 NET had recurrence after endoscopic resection. 2 In this study, two patients survived over 10 years. One patient survived for over 13 years despite recurrence due to the introduction of somatostatin analogs. In a previous study, 23% of the tumors regarded to be NET G3 were reported to be strongly somatostatin receptor 2A positive. 13 The Japan Neuroendocrine Tumor Society recommends somatostatin analogs, everolimus, and streptozocin for GNETs and somatostatin analogs, etoposide plus cisplatin, irinotecan plus cisplatin, and etoposide plus carboplatin for GNECs as chemotherapy. 16 In addition, Hainsworth et al. proposed a treatment with paclitaxel, carboplatin, and etoposide for advanced poorly differentiated neuroendocrine carcinoma because it produced an overall response rate of 53% and a complete response rate of 15%. On the other hand, they said it seems reasonable to treat patients with metastatic poorly differentiated NETs according to guidelines established for small-cell lung cancer. 17 Furthermore, long-term prognosis can be expected because of the development of new drugs. Of the 14 cases of type 1 GNETs, one patient died due to liver metastasis 1 year after surgery. Because the tumor-related death rate of type 1 GNETs is 0%, we need more histopathological reconsiderations. There are some limitations to this study. First, there are some missing data. Second, the diagnostic criteria were not standardized because of the retrospective nature of the study. Third, the small number of cases and short follow-up time may have influenced the statistically significant difference for OSR with or without lymph node metastasis. Finally, the differences in histological classification between Japan and the WHO have not been considered. We evaluated the outcomes in patients with GNEN in our institute. Positive lymph node metastasis was found to influence OSR statistically. In addition, lymphatic invasion was the most important risk factor for lymph node metastasis in the univariate analysis. Further retrospective analyses, such as resected specimens with standardized criteria, can help us further our understanding of GNENs. Declarations Ethics approval and consent to participate This study was approved by the Research Ethics Committee of Tokyo Women’s Medical University (acceptance number: 2021-0038). Consent for publication The requirement for obtaining written informed consent from each patient was waived because of the retrospective study design. Availability of data and materials All data generated or analyzed during this study are included in this published article. Competing interests The authors declare that they have no competing interests. Funding No financial support was received for this study. Authors’ contributions SI wrote the main manuscript text, and KT and KS prepared figures and tables. All authors reviewed the manuscript. Acknowledgements Not applicable. References Oberndorfer S: Karzinoide Tumoren des Dünndarms. Frankf. Zschr Pathol 1: 426–432, 1907. Sato Y, Imamura H, Kaizaki Y, Koizumi W, Ishido K, Kurahara K et al: Management and Clinical Outcomes of Type I Gastric Carcinoid Patients: Retrospective, Multicenter Study in Japan. Digestive Endoscopy 26: 377–384, 2014. Chung CS, Tsai CL, Chu YY, Chen KC, Lin JC, Chen BC et al: Clinical Features and Outcomes of Gastric Neuroendocrine Tumors after Endoscopic Diagnosis and Treatment. Medicine 97: 38, 2018. Cao LL, Lu J, Lin JX, Zheng CH, Li P, Xie JW et al: Nomogram based on Tumor-Associated Neutrophil-To-Lymphocyte Ratio to Predict Survival of Patients with Gastric Neuroendocrine Neoplasms. World J Gastroenterol 23: 8376–8386, 2017. Ito T, Igarashi H, Nakamura K, Sasao H, Okusaka T, Takano K et al: Epidemiological Trends of Pancreatic and Gastrointestinal Neuroendocrine Tumors in Japan: A Nationwide Survey Analysis. J Gastroenterol 50: 58–64, 2015. Rindi G, Arnold R, Bosman FT, Capella C, Klimstra DS, Kloppel G et al: Nomenclature and Classification of Neuroendocrine Neoplasms of the Digestive System. Bosman FT, Carneiro F, Hruban RH, et al eds. WHO Classification of Tumours of the Digestive System. Pp13-14, IARC, Lyon, 2010. Klimstra D, Klöppel G, La Rosa S, Rindi G: Classification of Neuroendocrine Neoplasm of the Digestive System. WHO Classification of Tumours Editorial Board, ed. WHO Classification of Tumours, 5th ed, Vol.1, Digestive System Tumours. Pp16–21. World Health Organization, Lyon, 2019. Delle Fave G, O’Toole D, Sundin A, Taal B, Ferolla P, Ramage JK et al: ENETS Consensus Guidelines Update for Gastroduodenal Neuroendocrine Neoplasms. Neuroendocrinology 103: 119–124, 2016. Soga J: Early-Stage Carcinoids of the Gastrointestinal Tract -An Analysis of 1914 Reported Cases-. Cancer 8: 1587–1595, 2005. Sohn B, Kwon Y, Ryoo SB, Song I, Kwon YH, Lee DW et al: Predictive Factors for Lymph Node Metastasis and Prognostic Factors for Survival in Rectal Neuroendocrine Tumors. J Gastrointest Surg 21: 2066–2074, 2017. Li Y, Bi X, Zhao J, Huang Z, Zhou J, Li Z et al: CEA Level, Radical Surgery, CD56 and CgA Expression are Prognostic Factors for Patients with Locoregional Gastrin-Independent GNET. Medicine 95: e3567, 2016. Dias AR, Azevedo BC, Alban LBV, Yagi OK, Ramos MFKP, Jacob CE et al: Gastric Neuroendocrine Tumor: Review and Update. ABCD Arq Bras Cir Dig 30: 150–154, 2017. Konukiewitz B, Schlitter AM, Jesinghaus M, Pfister D, Steiger K, Segler A et al: Somatostatin Receptor Expression Related to TP53 and RB1 Alterations in Pancreatic and Extrapancreatic Neuroendocrine Neoplasms with a Ki67-index Above 20. Mod Pathol 30: 587–598, 2017. Rindi G, Luinetti O, Cornaggia M, Capella C, Solcia E: Three Subtypes of Gastric Argyrophil Carcinoids and the Gastric Neuroendocrine Carcinoma: A Clinicopathological Study. Gastroenterology 104: 994–1006, 1993. Rindi G, Azzoni C, La Rosa S, Klersy C, Paolotti D, Rappel S et al: ECL Cell Tumor and Poorly Differentiated Endocrine Carcinoma of the Stomach: Prognostic Evaluation by Pathological Analysis. Gastroenterology 116: 532–542, 1999. Japan Neuroendocrine Tumor Society: Clinical Practice Guidelines for Gastoroenteropancreatic Neuroendocrine Neoplasms 2019, pp 115–116, Kanahara Shuppan, Tokyo (2019). Hainsworth JD, Spigel DR, Litchy S, Greco FA: Phase II Trial of Paclitaxel, Carboplatin, and Etoposide in Advanced Poorly Differentiated Neuroendocrine Carcinoma: A Minnie Peral Cancer Research Network Study. J Clin Oncol 24: 3548–3554, 2006. Tables Tables 1 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.xlsx Table 1Comparison of the WHO classifications of GNENs Table2.xlsx Table 2Classification of GNENs Table3.xlsx Table 3Cases of GNENs resected in our institute Table4.xlsx Table 4The risk factors for lymph node metastasis on univariate analysis Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1657483","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":107065354,"identity":"d99e4311-6025-4220-98d6-45a642bf40a5","order_by":0,"name":"Shunichi Ito","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYBACNhDB2ABi8DAc+AAX58GjhQ1Jy8EZCURoYYBpAali5knAoxIG+OSbDzD+3HE4j4/97MHDtj8ORxscYH74gUHmDh6HsSUw8545XMzGk5dwOCfhcO6GA2zGEgw8z/Bo4TFgZmw7nNgmwWMA1HIbqIXBDOjKw3i1MP6EabEAa2H/RlALAy9MCwNYCw8hW9ISDvO2pSe28eQYHOxJ+5878zBPsUQCHr/INx8++PBnm3Xi/PYzxh9+2KTl9h1v3/jhYw/uEAOBA6hcZiBO7DmARSF+8IN0LaNgFIyCUTBsAQAfvlOeR9XJ/gAAAABJRU5ErkJggg==","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Shunichi","middleName":"","lastName":"Ito","suffix":""},{"id":107065355,"identity":"70205bdc-ec6a-4b88-a540-d3e799488c36","order_by":1,"name":"Kiyoaki Taniguchi","email":"","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kiyoaki","middleName":"","lastName":"Taniguchi","suffix":""},{"id":107065357,"identity":"f2519e6a-9727-4711-b806-cc696767211e","order_by":2,"name":"Kazuomi Suzuki","email":"","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kazuomi","middleName":"","lastName":"Suzuki","suffix":""},{"id":107065359,"identity":"7224f8cc-c353-4872-8dda-1064df248a58","order_by":3,"name":"Hiroto Egawa","email":"","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hiroto","middleName":"","lastName":"Egawa","suffix":""}],"badges":[],"createdAt":"2022-05-15 05:44:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1657483/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1657483/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":21718429,"identity":"07c17cc3-3a9c-41f4-ae56-1073823ba1fd","added_by":"auto","created_at":"2022-05-20 16:32:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":61937,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival rate in resected GNENs according to lymph node metastasis\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-1657483/v1/78a5d84db17d87feb20ae07b.png"},{"id":21718430,"identity":"5777c2e9-237c-4a00-a433-98425b2d81bd","added_by":"auto","created_at":"2022-05-20 16:32:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":65526,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival rate in resected GNENs according to tumor size\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-1657483/v1/aeb4c8c58b77dea99c01f5d5.png"},{"id":23930986,"identity":"97241ba0-e6fb-4b0d-986e-3aee4707677c","added_by":"auto","created_at":"2022-07-16 07:29:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":307953,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1657483/v1/bc31fe15-bbe4-4400-a978-58f7a778b69d.pdf"},{"id":21718432,"identity":"e0148a36-2c11-47c5-8b05-bb45fa91b7cd","added_by":"auto","created_at":"2022-05-20 16:32:16","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":12397,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1\u003c/p\u003e\u003cp\u003eComparison of the WHO classifications of GNENs\u003c/p\u003e","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-1657483/v1/8c6773802ecacbf7772dc528.xlsx"},{"id":21718434,"identity":"3f858afb-301a-4a94-ab09-f5de4c68e99d","added_by":"auto","created_at":"2022-05-20 16:32:16","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":11416,"visible":true,"origin":"","legend":"\u003cp\u003eTable 2\u003c/p\u003e\u003cp\u003eClassification of GNENs\u003c/p\u003e","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-1657483/v1/e0f89a8d1d67815a77bf5b64.xlsx"},{"id":21718902,"identity":"b4d7506d-2d59-4786-a24d-f0c4d2567699","added_by":"auto","created_at":"2022-05-20 16:37:16","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":15295,"visible":true,"origin":"","legend":"\u003cp\u003eTable 3\u003c/p\u003e\u003cp\u003eCases of GNENs resected in our institute\u003c/p\u003e","description":"","filename":"Table3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-1657483/v1/618a46771595fae20c1c6349.xlsx"},{"id":21718433,"identity":"f2e60d39-46c4-429a-bdbb-8f55cd7e9da9","added_by":"auto","created_at":"2022-05-20 16:32:16","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":12184,"visible":true,"origin":"","legend":"\u003cp\u003eTable 4\u003c/p\u003e\u003cp\u003eThe risk factors for lymph node metastasis on univariate analysis\u003c/p\u003e","description":"","filename":"Table4.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-1657483/v1/7fc853b6b07763407d931528.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical features of resected gastric neuroendocrine neoplasms","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eGastric neuroendocrine neoplasms (GNENs) have been known as gastric \u0026ldquo;carcinoid\u0026rdquo; since 1907.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e In 2000, the World Health Organization (WHO) classified gastric neuroendocrine tumor (GNET) as a kind of neuroendocrine tumor (NET). In Japan, GNEN accounts for 15.1% of all neuroendocrine neoplasms (NENs).\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Due to improvements in diagnostic technology, including endoscopic and radiological modalities and immunostaining, the incidence of NENs, especially gastrointestinal (GI) NENs, has increased gradually.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e However, even after including progress and prognosis regarding rare GNENs, our knowledge is still very limited because the overall prevalence of GINENs is reported to be only 6.42 per 100,000 people.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe aims of this study were to investigate the clinical features and to evaluate the outcomes in patients with GNENs in our institute.\u003c/p\u003e"},{"header":"2. Case Series","content":"\u003cp\u003eBetween April 1965 and December 2020, patients with a diagnosis of histologically confirmed GNENs and undergoing surgery in our institute were recruited. We collected the clinical data retrospectively. The WHO classification system (in 1980, 2000, 2010, and 2019) was used for grading of differentiation and NEN diagnosis (\u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e).\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Clinical classification was based on the European Neuroendocrine Tumor Society (ENETS) Consensus Guidelines (\u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e).\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e In total, 24 GNEN patients were recruited. Data analyzed included demographic characteristics (male vs. female, less than 70 years old vs. over 70 years old), symptoms, tumor size (\u0026lt;\u0026thinsp;20 mm vs. \u0026gt; 20 mm), location (proximal vs. distal), number, depth of tumor invasion, pathological diagnosis (carcinoid vs. NET vs. neuroendocrine carcinoma (NEC) vs. others), lymphovascular invasion (positive vs. negative), tumor stages, treatment, and postoperative outcomes. To evaluate lymph node metastasis or distant organ metastases, we used radiological examinations, including computed tomography. Univariate analysis was performed using Fisher\u0026rsquo;s exact test. In the statistical calculation of the cumulative overall survival (OS) rate (OSR), the Kaplan-Meier method was employed. Variables were compared using the log-rank test. Statistical significance was accepted for \u003cem\u003ep-values\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Data were expressed as means and ranges, as appropriate. Qualitative data were expressed as numbers (and percentages). All statistical analyses were performed using JMP Pro ver.13 (SAS Institute, Cary, NC, USA).\u003c/p\u003e \u003cp\u003eEleven patients were diagnosed with carcinoid (45.8%), three with NET (12.5%), seven with NEC (29.2%) (one of them had synchronous liver metastasis), and three with mixed-type adenoneuroendocrine carcinoma (including mixed endocrine-exocrine carcinoma, mixed acinar-endocrine carcinoma, and mixed adenoneuroendocrine carcinoma) (12.5%) \u003cb\u003e(Table\u0026nbsp;3)\u003c/b\u003e. Fourteen patients had type 1 GNEN (77.8%) and four had type 3 GNEN (22.2%). None of the patients had type 2 GNEN.\u003c/p\u003e \u003cp\u003eThere were 19 male (79.2%) and 5 female patients (20.8%). The mean age was 65.5 years (SD: 9.3, range: 42\u0026ndash;78); 13 patients had no symptoms (54.2%). The most common symptom was epigastralgia (29.2%), and one patient had carcinoid syndrome. The mean tumor size was 25.4 mm (SD: 17.8, range: 7\u0026ndash;80). The tumors of 17 patients were located in the proximal (fundus, cardia, or body) stomach (73.9%). Most patients had solitary tumors (95.8%). One patient had mucosal invasion (5.6%), nine had submucosal invasion (50%), two had muscularis propria invasion (11.1%), and six had subserosa invasion (33.3%). Ten patients had lymphovascular invasion histologically (52.6%) and seven patients had lymph node metastasis (29.2%). Five patients underwent treatment before surgery and two patients underwent hepatectomy simultaneously. All patients but one did not die because of surgery. The mean follow-up period was 45.3 months (SD 43.3; range, 0.5\u0026ndash;163).\u003c/p\u003e \u003cp\u003eKaplan-Meier curves for OSR according to lymph node metastasis and tumor size are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. For OSR, there was a significant difference between patients with and without lymph node metastasis \u003cem\u003e(p\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0407). On the other hand, there was no statistical difference in tumor size (10 mm is the cut-off) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3176). The risk factors for lymph node metastasis included sex, age, tumor size, tumor location, diagnosis, lymphatic invasion, vascular invasion, and recurrence on univariate analysis (\u003cb\u003eTable\u0026nbsp;4\u003c/b\u003e). A significant risk factor for lymph node metastasis was lymphatic invasion (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0408).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eIn our study, positive lymph node metastasis was found to influence OSR statistically. Lymphatic invasion was the most important risk factor for lymph node metastasis in the univariate analysis.\u003c/p\u003e \u003cp\u003eThus far, many prognostic factors have been proposed. For lymph node metastasis, risk factors were angiolymphatic invasion,\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e the tumor-associated neutrophil-to-lymphocyte ratio (TA-NLR), which was calculated as the average number of neutrophils (CD15-positive cells) divided by the average number of T lymphocytes (CD8-positive cells),\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e and tumor size and tumor grade in rectal NETs.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e This study showed that lymph node metastasis was not associated with vascular invasion and tumor size but instead with lymphatic invasion. The Ki-67 index and the TA-NLR were independent prognostic factors for recurrence-free survival (RFS) and OS.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e In this study, positive lymph node metastasis was an important factor for the OSR in the univariate analysis. This may be influenced by many censored cases, and multivariate analysis may produce different results. Furthermore, for type 3 GNETs without distant metastases, radical surgery, serum carcinoembryonic antigen (CEA) level, immunohistochemistry marker CD56, and chromogranin A (CgA) are important for prognostic evaluation.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e In this study, unfortunately, we did not obtain enough data to determine whether prognosis was affected by angiolymphatic invasion, but we would like to consider these factors in further research.\u003c/p\u003e \u003cp\u003eGNENs are rare neoplasms derived from the enterochromaffin-like (ECL) cells of the gastric mucosa that play a role in regulating gastric acid production.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e GNENs are more common in male patients and the average age of onset is 55 years. The incidence of proximal gastric fundus and cardia region accounted for 69.7% of cases. The specificities of biomarkers in gastroenteropancreatic NET patients were 86% for CgA, 100% for neuron-specific enolase (NSE), 91% for CEA, and 100% for 5-hydroxyindoleacetic acid (5-HIAA). The corresponding sensitivities were 68% for CgA, 33% for NSE, 15.4% for CEA, and 35% for 5-HIAA.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e In p53 expression, it was negative in all NETs G3 but positive in almost 78% of poorly differentiated NENs.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e The proportions of tumor recurrence of the patients with GNEN were 72% of liver metastasis, 28% of peritoneal metastasis, and 25% of lymph node metastasis. On the other hand, the spleen, kidney, and brain are relatively rare sites of recurrence.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Rindi et al. described three clinicopathologic subtypes of well-differentiated ECL cell tumors of the stomach: Type 1 was associated with body-fundus chronic atrophic gastritis, \u003cem\u003eHelicobacter pylori-related\u003c/em\u003e gastritis, autoimmune gastritis, pernicious anemia, and hypergastrinemia; Type 2 was associated with hypertrophic gastropathy and hypergastrinemia due to multiple endocrine neoplasia type 1 (MEN-1) and Zollinger-Ellison syndrome; Type 3 was sporadic.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e ENETS reported that the overall metastatic risk is low in type 1 GNETs and has been directly correlated with tumor size (10 mm is the cut-off.), and recommended tumors\u0026thinsp;\u0026gt;\u0026thinsp;10 mm were resected. The RFS rate of patients with type 1 GNETs for approximately 24 months is 100%. For type 2 GNETs, local resection can be recommended with or without duodenal or pancreatic NENs as part of MEN-1. For type 3 GNETs, while endoscopic management for small lesions has been proposed, surgical treatment such as gastrectomy with lymph node dissection following the strategy for gastric adenocarcinomas is recommended.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e GI carcinoids originate as hyperplastic proliferations of endocrine cells in the basal portion of the glands, develop into extraglandular buddings, and penetrate the muscularis mucosae, resulting in the formation of a submucosal nodule. Soga reported that GI carcinoids that penetrate the muscularis mucosae and enter the submucosal layer (SM carcinoids) are indicative of malignancy without exception.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e The previous study reported that 59 out of 381 cases (15.5%) of gastric SM carcinoids had metastases. The metastasis rates were 7.9% (carcinoids\u0026thinsp;\u0026lt;\u0026thinsp;10 mm), 13.4% (\u0026gt;\u0026thinsp;10 mm and \u0026lt;\u0026thinsp;20 mm), and 26.7% (\u0026gt;\u0026thinsp;20 mm), respectively. Moreover, the average size of the SM G-carcinoids was 14.4 mm, and there was a significant difference between their size with metastases (20.9 mm) and without metastases (13.2 mm).\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e In this study, there was no significant difference according to tumor size for OSR. This may be associated with insufficient data for the T category.\u003c/p\u003e \u003cp\u003eThe 5-year survival rate in patients with gastric SM carcinoids was the same as that of patients with gastric SM carcinomas (89.6% versus 82.7%). The 5-year survival rate in patients with gastric SM carcinoids with metastases was 61.7%.\u003csup\u003e9\u003c/sup\u003e Therefore, it is necessary to pay attention to the patients with early gastric SM carcinoid, especially those over 10 mm. In contrast, it has been reported that approximately 60% of patients with less than 20 mm type 1 NET had recurrence after endoscopic resection.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn this study, two patients survived over 10 years. One patient survived for over 13 years despite recurrence due to the introduction of somatostatin analogs. In a previous study, 23% of the tumors regarded to be NET G3 were reported to be strongly somatostatin receptor 2A positive.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e The Japan Neuroendocrine Tumor Society recommends somatostatin analogs, everolimus, and streptozocin for GNETs and somatostatin analogs, etoposide plus cisplatin, irinotecan plus cisplatin, and etoposide plus carboplatin for GNECs as chemotherapy.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e In addition, Hainsworth et al. proposed a treatment with paclitaxel, carboplatin, and etoposide for advanced poorly differentiated neuroendocrine carcinoma because it produced an overall response rate of 53% and a complete response rate of 15%. On the other hand, they said it seems reasonable to treat patients with metastatic poorly differentiated NETs according to guidelines established for small-cell lung cancer.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Furthermore, long-term prognosis can be expected because of the development of new drugs. Of the 14 cases of type 1 GNETs, one patient died due to liver metastasis 1 year after surgery. Because the tumor-related death rate of type 1 GNETs is 0%, we need more histopathological reconsiderations.\u003c/p\u003e \u003cp\u003eThere are some limitations to this study. First, there are some missing data. Second, the diagnostic criteria were not standardized because of the retrospective nature of the study. Third, the small number of cases and short follow-up time may have influenced the statistically significant difference for OSR with or without lymph node metastasis. Finally, the differences in histological classification between Japan and the WHO have not been considered.\u003c/p\u003e \u003cp\u003eWe evaluated the outcomes in patients with GNEN in our institute. Positive lymph node metastasis was found to influence OSR statistically. In addition, lymphatic invasion was the most important risk factor for lymph node metastasis in the univariate analysis. Further retrospective analyses, such as resected specimens with standardized criteria, can help us further our understanding of GNENs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cul\u003e\n\u003cli\u003eEthics approval and consent to participate\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThis study was approved by the Research Ethics Committee of Tokyo Women\u0026rsquo;s Medical University (acceptance number: 2021-0038).\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eConsent for publication\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe requirement for obtaining written informed consent from each patient was waived because of the retrospective study design.\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eAvailability of data and materials\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eCompeting interests\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eFunding\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eNo financial support was received for this study.\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eAuthors\u0026rsquo; contributions\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eSI wrote the main manuscript text, and KT and KS prepared figures and tables. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eAcknowledgements\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOberndorfer S: Karzinoide Tumoren des D\u0026uuml;nndarms. Frankf. Zschr Pathol 1: 426\u0026ndash;432, 1907.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSato Y, Imamura H, Kaizaki Y, Koizumi W, Ishido K, Kurahara K et al: Management and Clinical Outcomes of Type I Gastric Carcinoid Patients: Retrospective, Multicenter Study in Japan. Digestive Endoscopy 26: 377\u0026ndash;384, 2014.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChung CS, Tsai CL, Chu YY, Chen KC, Lin JC, Chen BC et al: Clinical Features and Outcomes of Gastric Neuroendocrine Tumors after Endoscopic Diagnosis and Treatment. Medicine 97: 38, 2018.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCao LL, Lu J, Lin JX, Zheng CH, Li P, Xie JW et al: Nomogram based on Tumor-Associated Neutrophil-To-Lymphocyte Ratio to Predict Survival of Patients with Gastric Neuroendocrine Neoplasms. World J Gastroenterol 23: 8376\u0026ndash;8386, 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIto T, Igarashi H, Nakamura K, Sasao H, Okusaka T, Takano K et al: Epidemiological Trends of Pancreatic and Gastrointestinal Neuroendocrine Tumors in Japan: A Nationwide Survey Analysis. J Gastroenterol 50: 58\u0026ndash;64, 2015.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRindi G, Arnold R, Bosman FT, Capella C, Klimstra DS, Kloppel G et al: Nomenclature and Classification of Neuroendocrine Neoplasms of the Digestive System. Bosman FT, Carneiro F, Hruban RH, et al eds. WHO Classification of Tumours of the Digestive System. Pp13-14, IARC, Lyon, 2010.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlimstra D, Kl\u0026ouml;ppel G, La Rosa S, Rindi G: Classification of Neuroendocrine Neoplasm of the Digestive System. WHO Classification of Tumours Editorial Board, ed. WHO Classification of Tumours, 5th ed, Vol.1, Digestive System Tumours. Pp16\u0026ndash;21. World Health Organization, Lyon, 2019.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDelle Fave G, O\u0026rsquo;Toole D, Sundin A, Taal B, Ferolla P, Ramage JK et al: ENETS Consensus Guidelines Update for Gastroduodenal Neuroendocrine Neoplasms. Neuroendocrinology 103: 119\u0026ndash;124, 2016.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoga J: Early-Stage Carcinoids of the Gastrointestinal Tract -An Analysis of 1914 Reported Cases-. Cancer 8: 1587\u0026ndash;1595, 2005.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSohn B, Kwon Y, Ryoo SB, Song I, Kwon YH, Lee DW et al: Predictive Factors for Lymph Node Metastasis and Prognostic Factors for Survival in Rectal Neuroendocrine Tumors. J Gastrointest Surg 21: 2066\u0026ndash;2074, 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi Y, Bi X, Zhao J, Huang Z, Zhou J, Li Z et al: CEA Level, Radical Surgery, CD56 and CgA Expression are Prognostic Factors for Patients with Locoregional Gastrin-Independent GNET. Medicine 95: e3567, 2016.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDias AR, Azevedo BC, Alban LBV, Yagi OK, Ramos MFKP, Jacob CE et al: Gastric Neuroendocrine Tumor: Review and Update. ABCD Arq Bras Cir Dig 30: 150\u0026ndash;154, 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKonukiewitz B, Schlitter AM, Jesinghaus M, Pfister D, Steiger K, Segler A et al: Somatostatin Receptor Expression Related to TP53 and RB1 Alterations in Pancreatic and Extrapancreatic Neuroendocrine Neoplasms with a Ki67-index Above 20. Mod Pathol 30: 587\u0026ndash;598, 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRindi G, Luinetti O, Cornaggia M, Capella C, Solcia E: Three Subtypes of Gastric Argyrophil Carcinoids and the Gastric Neuroendocrine Carcinoma: A Clinicopathological Study. Gastroenterology 104: 994\u0026ndash;1006, 1993.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRindi G, Azzoni C, La Rosa S, Klersy C, Paolotti D, Rappel S et al: ECL Cell Tumor and Poorly Differentiated Endocrine Carcinoma of the Stomach: Prognostic Evaluation by Pathological Analysis. Gastroenterology 116: 532\u0026ndash;542, 1999.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJapan Neuroendocrine Tumor Society: Clinical Practice Guidelines for Gastoroenteropancreatic Neuroendocrine Neoplasms 2019, pp\u0026nbsp;115\u0026ndash;116, Kanahara Shuppan, Tokyo (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHainsworth JD, Spigel DR, Litchy S, Greco FA: Phase II Trial of Paclitaxel, Carboplatin, and Etoposide in Advanced Poorly Differentiated Neuroendocrine Carcinoma: A Minnie Peral Cancer Research Network Study. J Clin Oncol 24: 3548\u0026ndash;3554, 2006.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"Tables 1 to 4 are available in the Supplementary Files section."}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"gastric neuroendocrine neoplasm, gastric neuroendocrine tumor, gastric neuroendocrine carcinoma, carcinoid, stomach","lastPublishedDoi":"10.21203/rs.3.rs-1657483/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1657483/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBackground:\u003c/em\u003e\u003c/strong\u003e Due to improvements in diagnostic technology, the incidence of gastrointestinal neuroendocrine neoplasms has increased gradually. Therefore, it is important to understand their clinical manifestations and management. The aims of this study were to investigate the clinical features of gastrointestinal neuroendocrine neoplasms and to evaluate the outcomes of patients in our institute.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMethods:\u003c/em\u003e\u003c/strong\u003e Between April 1965 and December 2020, patients with a diagnosis of gastric neuroendocrine neoplasms undergoing surgery in our institute were recruited. Clinical data were collected retrospectively.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eResults:\u003c/em\u003e\u003c/strong\u003e Twenty-four gastric neuroendocrine neoplasm patients were recruited. Ten patients had lymphovascular invasion and seven patients had lymph node metastasis. There was a significant difference in the overall survival rate between those with and without lymph node metastasis. The significant risk factor for lymph node metastasis was lymphatic invasion.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConclusions:\u003c/em\u003e\u003c/strong\u003e Positive lymph node metastasis influenced overall survival. Lymphatic invasion was the most important risk factor for lymph node metastasis.\u003c/p\u003e","manuscriptTitle":"Clinical features of resected gastric neuroendocrine neoplasms","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-05-20 16:32:14","doi":"10.21203/rs.3.rs-1657483/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3978f141-6085-411a-9627-e69a7228a3a7","owner":[],"postedDate":"May 20th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-08-02T10:59:15+00:00","versionOfRecord":[],"versionCreatedAt":"2022-05-20 16:32:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1657483","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1657483","identity":"rs-1657483","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}