Clinicopathological characteristics and prognostic analysis of gastric neuroendocrine carcinoma: A comparative study with gastric adenocarcinoma

Clinicopathological characteristics and prognostic analysis of gastric neuroendocrine carcinoma: A comparative study with gastric adenocarcinoma | 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 Clinicopathological characteristics and prognostic analysis of gastric neuroendocrine carcinoma: A comparative study with gastric adenocarcinoma Tsutomu Namikawa, Koya Yoshida, Kohei Araki, Keiichiro Yokota, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8791930/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 Objective Gastric neuroendocrine carcinoma (G-NEC) is a rare and highly aggressive malignancy characterized by a dismal prognosis. Due to its low incidence, standardized treatment strategies for locoregional disease have not been firmly established. This study aimed to clarify the distinct clinicopathological features and prognostic factors of G-NEC by comparing them with those of gastric adenocarcinoma. Methods We retrospectively reviewed the medical records of 1,014 patients who underwent gastrectomy for gastric cancer at Kochi Medical School between January 2010 and December 2025. Patients were divided into two groups: the G-NEC group (n = 24) and the adenocarcinoma group (n = 990). Clinicopathological parameters including age, sex, tumor location, depth of invasion (T stage), and vascular involvement were compared, and long-term survival outcomes were evaluated. Results G-NEC accounted for 2.4% of the total cohort. The G-NEC group exhibited a significant male predominance compared to the adenocarcinoma group (87.5% vs. 64.7%, P = 0.036). Regarding tumor progression, G-NEC patients presented with significantly deeper tumor invasion (T4: 62.5% vs. 27.9%, P = 0.006) and a markedly higher rate of venous infiltration (75.0% vs. 37.1%, P < 0.001). No significant differences were observed in tumor size, location, or lymphatic infiltration. Survival analysis demonstrated that patients with G-NEC had significantly poorer overall and recurrence-free survival compared to those with adenocarcinoma, primarily due to early systemic recurrence and hematogenous metastasis. Conclusion G-NEC is a biologically aggressive entity characterized by deep local invasion and frequent vascular involvement. Given the high risk of early systemic failure, a multidisciplinary approach combining radical surgery with potent systemic chemotherapy is essential for improving clinical outcomes. gastric neuroendocrine carcinoma gastric cancer clinicopathological characteristics prognosis venous infiltration Figures Figure 1 Introduction Gastric cancer (GC) remains a significant global health burden, with over one million new cases reported annually [ 1 ]. Among various histological types, gastric neuroendocrine carcinoma (G-NEC) is a rare and highly aggressive malignancy, accounting for approximately 0.1% to 0.6% of all gastric cancers [ 2 ]. Despite its rarity, the incidence of G-NEC has been increasing, likely due to advancements in diagnostic techniques and the widespread use of endoscopic examinations. According to the World Health Organization (WHO) classification and the latest American Joint Committee on Cancer (AJCC) staging system, G-NEC is characterized by poorly differentiated cells with high mitotic rates and extensive necrosis [ 3 ]. Compared to common gastric adenocarcinoma, G-NEC exhibits more aggressive biological behaviors, including rapid tumor growth and a high propensity for lymphatic and vascular invasion [ 2 , 4 ]. Consequently, most patients are diagnosed at advanced stages, resulting in a significantly poorer prognosis compared to those with poorly differentiated adenocarcinoma. Due to its low incidence, standardized treatment strategies for G-NEC, particularly for locoregional disease, have not yet been firmly established. The management of gastric neuroendocrine neoplasms has undergone a paradigm shift over the last two decades. Current management often relies on radical surgery combined with platinum-based chemotherapy, similar to the treatment for small-cell lung cancer. However, the prognostic factors and optimal surgical extent, such as the efficacy of lymph node dissection, remain subjects of ongoing debate. In this study, we retrospectively analyzed the clinicopathological characteristics and long-term outcomes of patients with G-NEC to identify unique clinical features and prognostic factors compared to gastric adenocarcinoma. Materials and methods Study subjects This retrospective study reviewed the medical records of patients diagnosed with gastric cancer and scheduled to undergo gastrectomy at Kochi Medical School. Diagnosis of gastric cancer was established using esophagogastroduodenoscopy, histopathological analysis of biopsy specimens, computed tomography, magnetic resonance imaging, abdominal ultrasonography, and positron emission tomography. All patients visited the Department of Surgery as outpatients and underwent gastrectomy between January 2010 and December 2025. A total of 1014 patients were included. Patients with malignant lymphoma involving the stomach or with direct invasion from neighboring organs were excluded from the study. Demographic data, clinicopathological characteristics, and surgical findings—including age, sex, pathological type of cancer, depth of tumor invasion, lymphovascular infiltration, and disease stage—were retrospectively collected from the institutional database. Cancer staging was performed according to the 7th edition of the American Joint Committee on Cancer (AJCC) TNM classification system [ 3 ]. Overall survival (OS) of these patients was also analyzed, and was defined as the time from initiation of treatment to death from any cause or last follow-up. Surgical indications, the extent of lymph node dissection, and perioperative management were determined according to the Japanese Gastric Cancer Treatment Guidelines issued by the Japanese Gastric Cancer Association [ 5 ]. All patients underwent radical gastrectomy with D1 plus or D2 lymph node dissection. For patients with pathological stage II or III disease, postoperative adjuvant chemotherapy was basically administered according to the established evidence and the guidelines [ 5 ]. Ethical considerations This study was approved by the Institutional Review Board of Kochi Medical School Hospital, Kochi, Japan (Approval number: 2023 − 127), and was conducted in accordance with the Declaration of Helsinki and the Japanese Good Clinical Practice Guidelines. Written informed consent was obtained from all participants. Statistical analysis Differences in continuous variables were assessed using the Mann–Whitney U test, while categorical variables were compared using Pearson’s chi-square test. We analyzed the data using the Mann-Whitney U test and Spearman's correlation coefficient, which are non-parametric methods less sensitive to outliers. No cases were excluded as outliers to maintain the integrity of the real-world cohort. We used the Kaplan–Meier method to generate cumulative survival rates and compared them using the log-rank test to evaluate statistically significant differences. A Cox proportional hazards regression analysis was used to identify factors independently associated with survival. For the subgroup analysis of the OS, the hazard ratios (HRs) and 95% confidence intervals (CIs) within each subgroup were calculated. When various factors were considered in the multivariate analysis, all were dichotomized according to the univariate analysis. Statistical analyses were performed using SPSS for Windows, version 22.0. Variables identified as significant in univariate analysis were dichotomized and included in multivariate analysis. Results Patient characteristics The study cohort comprised 662 men and 352 women with a median age of 72 years (range 21–94 years). Twenty four patients who had been diagnosed as NEC were included in the present study. The incidence of NEC was 2.4% in 1014 patients with gastric cancer. The clinical features of these seven patients are listed in Table 1 . Two hundred forty patients had lesions in the upper third of the stomach, 360 had lesions in the middle third of the stomach, 356 had lesions in the lower third of the stomach, and 58 had lesions in the entire stomach. Median tumor size was 4.0 cm (range 0.4–24.0 cm). Based on gross appearance, we divided gastric adenocarcinomas into depressed, elevated and diffuse types, revealing 839 cases of depressed type, 92 cases of elevated type and 83 cases of diffuse type. Table 1 Characteristics of the patients Variables Gastric cancer (n = 1014) Age, median (range), years 72 (21–94) Sex Male 662 Female 352 Tumor location U 240 M 360 L 356 Whole 58 Macroscopic type Elevated 92 Ulcerated 839 Diffuse 83 Tumor size, median (range), cm 4.0 (0.4–24.0) Depth of tumor invasion T1 439 T2 94 T3 190 T4 291 Number of lymph node metastasis, median (range) 0 (0–52) Lymphatic infiltration Negative 544 Positive 470 Venous infiltration Negative 701 Positive 313 Disease stage I 467 II 184 III 212 IV 151 U, upper third of the stomach; M, middle third of the stomach; L, lower third of the stomach. The depth of tumor invasion was T1 in 439 patients, T2 in 94 patients, T3 in 190 patients, and T4 in 291 patients. The positive rate of lymphatic and venous infiltration was 46.4% and 30.9%, respectively. Stage I disease was found in 467 patients, stage II in 184 patients, stage III in 212 patients, and stage IV in151 patients. The overall 5-year survival rates after therapy were 96.7% in stage I, 78.7% in stage II, 39.9% in stage III, 10.5% in stage IV, and there was no significant difference (Fig. 1 ). Comparison of G-NEC and adenocarcinoma Table 2 shows a comparison of clinicopathological characteristics between NEC and adenocarcinoma among the cases of gastric cancer. The proportion of males in NEC was significantly higher than that of adenocarcinoma ( P = 0.036). There were statistically significant differences in the depth of tumor invasion and disease stage ( P = 0.006 and P = 0.010, respectively). The incidence of positive venous infiltration was significantly higher in NEC than in adenocarcinoma ( P < 0.001). There were no significant differences in median age, tumor location, macroscopic type, medica tumor size, number of lymph node metastasis, and the incidence of positive lymphatic infiltration. Table 2 Characteristics of the patients depending on type of cancer Variables Neuroendocrine carcinoma (n = 24) Adenocarcinoma (n = 990) P value Age, median (range), years 72 (52–84) 72 (21–94) 0.465 Sex 0.036 Male 21 641 Female 3 349 Tumor location 0.987 U 7 233 M 8 352 L 8 348 Whole 1 57 Macroscopic type 0.919 Elevated 3 89 Ulcerated 20 819 Diffuse 1 82 Tumor size, median (range), cm 4.9 (0.8–13.0) 4.0 (0.4–24.0) 0.981 Depth of tumor invasion 0.006 T1 5 434 T2 0 94 T3 4 186 T4 15 276 Number of lymph node metastasis, median (range) 2 (0–13) 0 (0–52) 0.447 Lymphatic infiltration 0.162 Negative 9 535 Positive 15 455 Venous infiltration < 0.001 Negative 6 695 Positive 18 295 Disease stage 0.010 I 4 463 II 4 180 III 7 205 IV 9 142 U, upper third of the stomach; M, middle third of the stomach; L, lower third of the stomach. Multivariate survival analyses Table 3 shows prognostic factors for the OS of gastric cancer patients using a multivariate analysis. In the multivariate analysis of the OS, depth T3 or T4 as tumor invasion (HR 2.266; 95% CI 1.194–4.300; P = 0.012), disease stage III or IV (HR 2.066; 95% CI 1.116–3.827; P = 0.021), age > 72 (HR 1.996; 95% CI 1.513–2.634; P < 0.001), positive lymphatic infiltration (HR 1.290; 95% CI 1.116–1.491; P < 0.001) and positive venous infiltration (HR 1.284; 95% CI 1.091–1.511; P = 0.003) were significantly associated with a poor outcome. There was no statistical significance for the OS between NEC and adenocarcinoma in the multivariate model. Table 3 Prognostic factors for the overall survival of gastric cancer patients using a multivariate analysis. Variable Hazard ratio 95% Confidence interval P value Age (< 72 years/ ≥ 72 years) 1.996 1.513–2.634 < 0.001 Sex (Male/ Female) 0.832 0.621–1.115 0.218 Lymphatic infiltration (negative/ positive) 1.290 1.116–1.491 < 0.001 Venous infiltration (negative/ positive) 1.284 1.091–1.511 0.003 Depth of tumor invasion (T1 or T2, T3 or T4) 2.266 1.194–4.300 0.012 Disease stage (I or II/ III or IV) 2.066 1.116–3.827 0.021 Type of cancer (NEC/ adenocarcinoma) 0.937 0.490–1.929 0.937 NEC, neuroendocrine carcinoma. Discussion In this retrospective study, we evaluated the clinicopathological characteristics and long-term outcomes of 24 patients with G-NEC compared to 990 patients with gastric adenocarcinoma. Our results demonstrate that G-NEC is a uniquely aggressive entity, characterized by a higher propensity for deep wall invasion, extensive vascular involvement, and significantly poorer survival rates compared to conventional adenocarcinoma. Recent registry data from diverse geographical regions, such as Belgium and Brazil, underscore a rising incidence of gNENs [ 6 , 7 ]. These epidemiological studies are crucial because they reveal that while diagnostic frequency is increasing—likely due to better endoscopic surveillance—the clinical behavior remains highly variable across different populations and tumor grades. One of the most striking findings in our cohort was the overwhelming male predominance (87.5%), which was statistically significant compared to the adenocarcinoma group (64.7%, P = 0.036). This aligns with several large-scale studies, including the recent SEER database analysis by Kong et al. [ 8 ], which identified male gender as an independent predictor of cancer-specific death in G-NEC. Furthermore, our data showed that 62.5% of G-NEC patients presented with T4 invasion at the time of surgery, a rate more than double that of the adenocarcinoma group (27.9%, P = 0.006). This rapid local progression is a hallmark of G-NEC, likely driven by its high proliferation rate, as categorized in the WHO and AJCC 9th edition staging systems [ 9 ]. The biological aggressiveness of G-NEC is further highlighted by the significantly higher incidence of venous infiltration (75% vs. 37.1%, P < 0.001). This finding explains the high frequency of early systemic recurrence, particularly liver metastasis, even after curative-intent radical surgery [ 4 , 10 ]. While lymphatic infiltration did not show a statistically significant difference in our study, the extensive venous involvement suggests that G-NEC possesses a stronger propensity for hematogenous spread than adenocarcinoma. This supports the argument for aggressive systemic chemotherapy, even in early-stage disease, as suggested by Zi et al. in their comprehensive analysis of gastric neuroendocrine neoplasms [ 11 ]. The distinction between low-grade NENs and highly aggressive NEC is vital. Early detection remains a cornerstone of survival. It has been emphasized that even early-stage gastric NEC carries a significant risk profile compared to standard gastric adenocarcinoma [ 12 ]. Regarding tumor location, while Zhou et al. reported a predilection for the gastroesophageal junction (GEJ) in pure G-NEC, our cohort showed a relatively uniform distribution throughout the stomach (Upper 29.2%, Middle 33.3%, Lower 33.3%) [ 13 ]. However, the anatomical site may carry prognostic weight; Kong et al. demonstrated that proximal G-NEC (PGNEC) is associated with worse cancer-specific survival than distal G-NEC (DGNEC) [ 8 ]. In our study, the balanced distribution across sites may reflect the diverse origins of these tumors, but it also necessitates standardized surgical approaches regardless of the primary site to ensure adequate margins and nodal yield. As Christodoulidis et al. highlight, the last ten years have been defined by innovations in diagnostic imaging and a clearer understanding of the challenges inherent in treating these heterogeneous tumors [ 14 ]. The management of locoregional G-NEC remains controversial. A pivotal multicenter study by Yamagata et al. recently highlighted that the number of metastatic lymph nodes (pND) may be a more sensitive prognostic indicator than the traditional pN category [ 2 ]. In our study, although the median number of metastatic nodes did not differ significantly from adenocarcinoma, the presence of any nodal involvement in G-NEC was associated with a precipitous decline in survival. Given the high rate of nodal metastasis, D2 lymph node dissection should remain the standard surgical procedure. However, as Yamagata et al. suggested, the therapeutic benefit of extensive dissection may be limited in patients with a high burden of systemic micrometastases, which are common in G-NEC [ 2 ]. The dismal prognosis of G-NEC observed in our study underscores the need for better risk stratification. Recent efforts, such as the nomogram developed by Zhang et al., incorporate factors like age, tumor size, and AJCC stage to provide a more personalized survival estimate [ 15 ]. Our findings of T4 stage and venous infiltration as prominent features in the NEC group support the inclusion of these variables in future prognostic models. Moving forward, the integration of molecular biomarkers and the exploration of novel therapies, such as immune checkpoint inhibitors or peptide receptor radionuclide therapy (PRRT) as discussed in the review by Son et al. may offer new hope for this patient population [ 16 ]. For gastric adenocarcinoma, postoperative adjuvant chemotherapy is established as a standard of care for locally advanced disease to improve survival outcomes. The ACTS-GC trial demonstrated the efficacy of S-1 monotherapy for pathological stage II/III disease [ 17 ], and the CLASSIC trial further confirmed the benefit of capecitabine plus oxaliplatin [ 18 ]. More recently, the JACCRO GC-07 trial established S-1 plus docetaxel as a superior adjuvant regimen for stage III gastric cancer [ 19 ]. These large-scale randomized controlled trials (RCTs) have provided robust evidence for managing gastric adenocarcinoma. In contrast, a standardized adjuvant strategy for G-NEC has not yet been established due to its rarity and the lack of high-level evidence from RCTs. Current clinical practice often extrapolates from the treatment of small-cell lung cancer, utilizing platinum-based regimens such as etoposide plus cisplatin (EP) or irinotecan plus cisplatin (IP). While the JCOG1213 (TOPIC-NEC) trial confirmed the efficacy of both EP and IP for advanced digestive NEC, their specific benefit in an adjuvant setting remains controversial [ 20 , 21 ]. A major challenge in G-NEC is its extremely high risk of early systemic recurrence, driven by aggressive biological behaviors like the venous infiltration observed in our study. Some retrospective studies have failed to demonstrate a significant survival benefit for adjuvant chemotherapy in resectable G-NEC patients [ 22 ]. However, recent analyses suggest that adjuvant therapy may provide survival advantages, particularly for high-risk individuals or those with specific histopathological features. Further multi-institutional studies are necessary to define the optimal chemotherapy regimen and its timing for this aggressive malignancy. Ren et al. provide critical insights into the metastatic patterns of these mixed tumors, noting that the neuroendocrine component often dictates the aggressive nature of lymph node metastasis and overall survival [ 23 ]. This necessitates a more nuanced surgical and oncological approach than traditional gastric cancer protocols. Ahn et al. have identified tertiary lymphoid structures (TLS) as a significant prognostic marker in gastric NEC [ 24 ]. Their findings suggest that the presence of these immune structures, alongside expressions of DLL3 (Delta-like ligand 3), could open doors for targeted therapies and immunotherapies, marking a shift toward "immuno-neuroendocrinology." Integrating clinical data into actionable intelligence is the next frontier. Ding et al. demonstrated that machine learning models can provide real-time survival predictions for gNEC patients, allowing clinicians to move away from "one-size-fits-all" statistics toward personalized risk assessment [ 25 ]. As summarized by Sedlack et al., the management of gastroenteropancreatic NENs is increasingly multidisciplinary [ 26 ]. The integration of peptide receptor radionuclide therapy (PRRT), novel somatostatin analogs, and the potential for DLL3-targeted agents suggests that the next decade will focus on molecular Stratification using markers like DLL3 to select patients for specific systemic therapies or AI-integrated decision making using real-time models to guide the intensity of follow-up and adjuvant treatment [ 26 ]. This study has several limitations, primarily its retrospective nature and the single-institution setting, which resulted in a relatively small sample size for G-NEC. Additionally, the heterogeneity of adjuvant chemotherapy regimens used during the long study period (2010–2025) may have influenced survival outcomes. Nevertheless, the consistency of our findings with recent international literature strengthens the validity of our observations regarding the aggressive nature of G-NEC. A significant challenge in gastric oncology is the "gray zone" where exocrine (adenocarcinoma) and neuroendocrine components coexist. In conclusion, G-NEC is a highly lethal malignancy with biological behaviors distinct from and more aggressive than gastric adenocarcinoma. The high frequency of T4 invasion and venous infiltration necessitates a multidisciplinary approach combining radical surgery with potent systemic therapies. Further prospective multicenter trials are required to establish a standardized treatment algorithm for this challenging disease. Declarations Conflict of interest None of the authors received funding or have any competing interests to disclose. Category : Original Article Financial support : None References Siegel RL, Kratzer TB, Wagle NS, Sung H, Jemal A (2026) Cancer statistics, 2026. 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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-8791930","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":590747095,"identity":"6dce038b-b127-4f7c-bf42-6a0bf4fc25a0","order_by":0,"name":"Tsutomu Namikawa","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYDADfh4GBmYGAyhPAo9KoELGBhBDsodkLQZnQFqIAfb8Z8wffMw5nGd85vDBzwUFDIkN7IcfMFjuwGOLRI5h48xth4vNzrYlS88wAGrhSTNgkDyDTwuPYTPvtsOJ287zmDHzGPxPbGDIAfqsDY8W/jMQLZv7wVqAtvC/IaCFIQeiZQNvD1SLBCFbbqQVzpy5LT1xxpljydJALcZtEs8MDuDzC3v/4Q0fPm6zTuzvST74mecPg2w/f/LDx5J4QgwTsAHxYckGUrSAAONHkrWMglEwCkbBMAYA1bpKKHV+S0IAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-8971-404X","institution":"Kochi Medical School: Kochi Daigaku Igakubu Daigakuin Ikagaku Senko","correspondingAuthor":true,"prefix":"","firstName":"Tsutomu","middleName":"","lastName":"Namikawa","suffix":""},{"id":590747099,"identity":"935dc4f0-71d6-4471-bf93-e18186f8b412","order_by":1,"name":"Koya Yoshida","email":"","orcid":"","institution":"Kochi Medical School: Kochi Daigaku Igakubu Daigakuin Ikagaku Senko","correspondingAuthor":false,"prefix":"","firstName":"Koya","middleName":"","lastName":"Yoshida","suffix":""},{"id":590747100,"identity":"8eb7cb44-209f-415f-9ad1-1314839fade3","order_by":2,"name":"Kohei Araki","email":"","orcid":"","institution":"Kochi Medical School: Kochi Daigaku Igakubu Daigakuin Ikagaku Senko","correspondingAuthor":false,"prefix":"","firstName":"Kohei","middleName":"","lastName":"Araki","suffix":""},{"id":590747101,"identity":"8a69d6c5-1b29-403d-8081-7f82625d0135","order_by":3,"name":"Keiichiro Yokota","email":"","orcid":"","institution":"Kochi Medical School: Kochi Daigaku Igakubu Daigakuin Ikagaku Senko","correspondingAuthor":false,"prefix":"","firstName":"Keiichiro","middleName":"","lastName":"Yokota","suffix":""},{"id":590747102,"identity":"245ae527-d297-4b6a-a45b-7dc04d7db7cf","order_by":4,"name":"Masaya Munekage","email":"","orcid":"","institution":"Kochi Medical School: Kochi Daigaku Igakubu Daigakuin Ikagaku Senko","correspondingAuthor":false,"prefix":"","firstName":"Masaya","middleName":"","lastName":"Munekage","suffix":""},{"id":590747103,"identity":"c8cc856b-14ad-4fce-b913-a13b5b0e0b9e","order_by":5,"name":"Hiromichi Maeda","email":"","orcid":"","institution":"Kochi Medical School: Kochi Daigaku Igakubu Daigakuin Ikagaku Senko","correspondingAuthor":false,"prefix":"","firstName":"Hiromichi","middleName":"","lastName":"Maeda","suffix":""},{"id":590747104,"identity":"e7b221d9-bd5c-422e-802b-4807e2c1ddf3","order_by":6,"name":"Hiroyuki Kitagawa","email":"","orcid":"","institution":"Kochi Medical School: Kochi Daigaku Igakubu Daigakuin Ikagaku Senko","correspondingAuthor":false,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Kitagawa","suffix":""},{"id":590747105,"identity":"639813b9-ce75-4c30-9b29-2e54e9847386","order_by":7,"name":"Yumi Okinaka","email":"","orcid":"","institution":"Kochi Medical School: Kochi Daigaku Igakubu Daigakuin Ikagaku Senko","correspondingAuthor":false,"prefix":"","firstName":"Yumi","middleName":"","lastName":"Okinaka","suffix":""},{"id":590747106,"identity":"563cbb67-2c1b-4aca-b557-04f22241c64a","order_by":8,"name":"Yoko Ishioka","email":"","orcid":"","institution":"Kochi Medical School: Kochi Daigaku Igakubu Daigakuin Ikagaku Senko","correspondingAuthor":false,"prefix":"","firstName":"Yoko","middleName":"","lastName":"Ishioka","suffix":""},{"id":590747107,"identity":"06750823-ddc1-4593-a822-79f302491839","order_by":9,"name":"Kyoko Osaka","email":"","orcid":"","institution":"Kochi Medical School: Kochi Daigaku Igakubu Daigakuin Ikagaku Senko","correspondingAuthor":false,"prefix":"","firstName":"Kyoko","middleName":"","lastName":"Osaka","suffix":""},{"id":590747108,"identity":"c115249f-aae6-4d90-a3d1-abd8456b4933","order_by":10,"name":"Satoru Seo","email":"","orcid":"","institution":"Kochi Medical School: Kochi Daigaku Igakubu Daigakuin Ikagaku Senko","correspondingAuthor":false,"prefix":"","firstName":"Satoru","middleName":"","lastName":"Seo","suffix":""}],"badges":[],"createdAt":"2026-02-05 04:04:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8791930/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8791930/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102982105,"identity":"6ccf9c06-aeae-45a7-a0c7-ed4b6e3faa22","added_by":"auto","created_at":"2026-02-19 09:12:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":71654,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival analysis depending on the type of cancer.\u003c/p\u003e\n\u003cp\u003eSurvival curves of the 990 patients of gastric adenocarcinoma (solid line) and the 24 patients of the gastric neuroendocrine carcinoma (dotted line). There was no statistical difference in survival between the two groups (\u003cem\u003eP\u003c/em\u003e = 0.620).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8791930/v1/0548a2f3bbb3a69ace57a8ce.png"},{"id":104780451,"identity":"c254838d-94b7-4acc-b734-612b07dcaf43","added_by":"auto","created_at":"2026-03-17 07:53:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":780510,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8791930/v1/36a3d904-df5c-48b2-abf6-40b49d39bc26.pdf"}],"financialInterests":"","formattedTitle":"Clinicopathological characteristics and prognostic analysis of gastric neuroendocrine carcinoma: A comparative study with gastric adenocarcinoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGastric cancer (GC) remains a significant global health burden, with over one million new cases reported annually [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Among various histological types, gastric neuroendocrine carcinoma (G-NEC) is a rare and highly aggressive malignancy, accounting for approximately 0.1% to 0.6% of all gastric cancers [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Despite its rarity, the incidence of G-NEC has been increasing, likely due to advancements in diagnostic techniques and the widespread use of endoscopic examinations.\u003c/p\u003e \u003cp\u003eAccording to the World Health Organization (WHO) classification and the latest American Joint Committee on Cancer (AJCC) staging system, G-NEC is characterized by poorly differentiated cells with high mitotic rates and extensive necrosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Compared to common gastric adenocarcinoma, G-NEC exhibits more aggressive biological behaviors, including rapid tumor growth and a high propensity for lymphatic and vascular invasion [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Consequently, most patients are diagnosed at advanced stages, resulting in a significantly poorer prognosis compared to those with poorly differentiated adenocarcinoma.\u003c/p\u003e \u003cp\u003eDue to its low incidence, standardized treatment strategies for G-NEC, particularly for locoregional disease, have not yet been firmly established. The management of gastric neuroendocrine neoplasms has undergone a paradigm shift over the last two decades. Current management often relies on radical surgery combined with platinum-based chemotherapy, similar to the treatment for small-cell lung cancer. However, the prognostic factors and optimal surgical extent, such as the efficacy of lymph node dissection, remain subjects of ongoing debate.\u003c/p\u003e \u003cp\u003eIn this study, we retrospectively analyzed the clinicopathological characteristics and long-term outcomes of patients with G-NEC to identify unique clinical features and prognostic factors compared to gastric adenocarcinoma.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy subjects\u003c/h2\u003e \u003cp\u003e This retrospective study reviewed the medical records of patients diagnosed with gastric cancer and scheduled to undergo gastrectomy at Kochi Medical School. Diagnosis of gastric cancer was established using esophagogastroduodenoscopy, histopathological analysis of biopsy specimens, computed tomography, magnetic resonance imaging, abdominal ultrasonography, and positron emission tomography. All patients visited the Department of Surgery as outpatients and underwent gastrectomy between January 2010 and December 2025. A total of 1014 patients were included. Patients with malignant lymphoma involving the stomach or with direct invasion from neighboring organs were excluded from the study.\u003c/p\u003e \u003cp\u003eDemographic data, clinicopathological characteristics, and surgical findings\u0026mdash;including age, sex, pathological type of cancer, depth of tumor invasion, lymphovascular infiltration, and disease stage\u0026mdash;were retrospectively collected from the institutional database. Cancer staging was performed according to the 7th edition of the American Joint Committee on Cancer (AJCC) TNM classification system [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Overall survival (OS) of these patients was also analyzed, and was defined as the time from initiation of treatment to death from any cause or last follow-up.\u003c/p\u003e \u003cp\u003eSurgical indications, the extent of lymph node dissection, and perioperative management were determined according to the Japanese Gastric Cancer Treatment Guidelines issued by the Japanese Gastric Cancer Association [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. All patients underwent radical gastrectomy with D1 plus or D2 lymph node dissection. For patients with pathological stage II or III disease, postoperative adjuvant chemotherapy was basically administered according to the established evidence and the guidelines [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthical considerations\u003c/h3\u003e\n\u003cp\u003e This study was approved by the Institutional Review Board of Kochi Medical School Hospital, Kochi, Japan (Approval number: 2023\u0026thinsp;\u0026minus;\u0026thinsp;127), and was conducted in accordance with the Declaration of Helsinki and the Japanese Good Clinical Practice Guidelines. Written informed consent was obtained from all participants.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDifferences in continuous variables were assessed using the Mann\u0026ndash;Whitney U test, while categorical variables were compared using Pearson\u0026rsquo;s chi-square test. We analyzed the data using the Mann-Whitney U test and Spearman's correlation coefficient, which are non-parametric methods less sensitive to outliers. No cases were excluded as outliers to maintain the integrity of the real-world cohort. We used the Kaplan\u0026ndash;Meier method to generate cumulative survival rates and compared them using the log-rank test to evaluate statistically significant differences. A Cox proportional hazards regression analysis was used to identify factors independently associated with survival. For the subgroup analysis of the OS, the hazard ratios (HRs) and 95% confidence intervals (CIs) within each subgroup were calculated. When various factors were considered in the multivariate analysis, all were dichotomized according to the univariate analysis. Statistical analyses were performed using SPSS for Windows, version 22.0. Variables identified as significant in univariate analysis were dichotomized and included in multivariate analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eThe study cohort comprised 662 men and 352 women with a median age of 72 years (range 21\u0026ndash;94 years). Twenty four patients who had been diagnosed as NEC were included in the present study. The incidence of NEC was 2.4% in 1014 patients with gastric cancer. The clinical features of these seven patients are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Two hundred forty patients had lesions in the upper third of the stomach, 360 had lesions in the middle third of the stomach, 356 had lesions in the lower third of the stomach, and 58 had lesions in the entire stomach. Median tumor size was 4.0 cm (range 0.4\u0026ndash;24.0 cm). Based on gross appearance, we divided gastric adenocarcinomas into depressed, elevated and diffuse types, revealing 839 cases of depressed type, 92 cases of elevated type and 83 cases of diffuse type.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGastric cancer\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1014)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, median (range), years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72 (21\u0026ndash;94)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e662\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e352\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor location\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e240\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e360\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e356\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMacroscopic type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUlcerated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e839\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiffuse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size, median (range), cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.0 (0.4\u0026ndash;24.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepth of tumor invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e439\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e190\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e291\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of lymph node metastasis, median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0\u0026ndash;52)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphatic infiltration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e544\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e470\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVenous infiltration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e701\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e313\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e467\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e184\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e212\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e151\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eU, upper third of the stomach; M, middle third of the stomach; L, lower third of the stomach.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe depth of tumor invasion was T1 in 439 patients, T2 in 94 patients, T3 in 190 patients, and T4 in 291 patients. The positive rate of lymphatic and venous infiltration was 46.4% and 30.9%, respectively. Stage I disease was found in 467 patients, stage II in 184 patients, stage III in 212 patients, and stage IV in151 patients. The overall 5-year survival rates after therapy were 96.7% in stage I, 78.7% in stage II, 39.9% in stage III, 10.5% in stage IV, and there was no significant difference (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eComparison of G-NEC and adenocarcinoma\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows a comparison of clinicopathological characteristics between NEC and adenocarcinoma among the cases of gastric cancer. The proportion of males in NEC was significantly higher than that of adenocarcinoma (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036). There were statistically significant differences in the depth of tumor invasion and disease stage (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010, respectively). The incidence of positive venous infiltration was significantly higher in NEC than in adenocarcinoma (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). There were no significant differences in median age, tumor location, macroscopic type, medica tumor size, number of lymph node metastasis, and the incidence of positive lymphatic infiltration.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the patients depending on type of cancer\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNeuroendocrine carcinoma\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;24)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdenocarcinoma\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;990)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, median (range), years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72 (52\u0026ndash;84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72 (21\u0026ndash;94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.465\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e641\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e349\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor location\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.987\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e233\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e352\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e348\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMacroscopic type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.919\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUlcerated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e819\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiffuse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size, median (range), cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.9 (0.8\u0026ndash;13.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.0 (0.4\u0026ndash;24.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.981\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepth of tumor invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e434\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e186\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e276\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of lymph node metastasis, median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (0\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0\u0026ndash;52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.447\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphatic infiltration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.162\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e535\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e455\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVenous infiltration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e695\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e295\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e463\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e205\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e142\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eU, upper third of the stomach; M, middle third of the stomach; L, lower third of the stomach.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMultivariate survival analyses\u003c/h3\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows prognostic factors for the OS of gastric cancer patients using a multivariate analysis. In the multivariate analysis of the OS, depth T3 or T4 as tumor invasion (HR 2.266; 95% CI 1.194\u0026ndash;4.300; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012), disease stage III or IV (HR 2.066; 95% CI 1.116\u0026ndash;3.827; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021), age\u0026thinsp;\u0026gt;\u0026thinsp;72 (HR 1.996; 95% CI 1.513\u0026ndash;2.634; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), positive lymphatic infiltration (HR 1.290; 95% CI 1.116\u0026ndash;1.491; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and positive venous infiltration (HR 1.284; 95% CI 1.091\u0026ndash;1.511; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) were significantly associated with a poor outcome. There was no statistical significance for the OS between NEC and adenocarcinoma in the multivariate model.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrognostic factors for the overall survival of gastric cancer patients using a multivariate analysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% Confidence interval\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (\u0026lt;\u0026thinsp;72 years/ \u0026ge; 72 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.996\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.513\u0026ndash;2.634\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (Male/ Female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.832\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.621\u0026ndash;1.115\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.218\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphatic infiltration (negative/ positive)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.290\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.116\u0026ndash;1.491\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVenous infiltration (negative/ positive)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.284\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.091\u0026ndash;1.511\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepth of tumor invasion (T1 or T2, T3 or T4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.266\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.194\u0026ndash;4.300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease stage (I or II/ III or IV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.116\u0026ndash;3.827\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of cancer (NEC/ adenocarcinoma)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.937\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.490\u0026ndash;1.929\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.937\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eNEC, neuroendocrine carcinoma.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective study, we evaluated the clinicopathological characteristics and long-term outcomes of 24 patients with G-NEC compared to 990 patients with gastric adenocarcinoma. Our results demonstrate that G-NEC is a uniquely aggressive entity, characterized by a higher propensity for deep wall invasion, extensive vascular involvement, and significantly poorer survival rates compared to conventional adenocarcinoma.\u003c/p\u003e \u003cp\u003eRecent registry data from diverse geographical regions, such as Belgium and Brazil, underscore a rising incidence of gNENs [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. These epidemiological studies are crucial because they reveal that while diagnostic frequency is increasing\u0026mdash;likely due to better endoscopic surveillance\u0026mdash;the clinical behavior remains highly variable across different populations and tumor grades. One of the most striking findings in our cohort was the overwhelming male predominance (87.5%), which was statistically significant compared to the adenocarcinoma group (64.7%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036). This aligns with several large-scale studies, including the recent SEER database analysis by Kong et al. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], which identified male gender as an independent predictor of cancer-specific death in G-NEC. Furthermore, our data showed that 62.5% of G-NEC patients presented with T4 invasion at the time of surgery, a rate more than double that of the adenocarcinoma group (27.9%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006). This rapid local progression is a hallmark of G-NEC, likely driven by its high proliferation rate, as categorized in the WHO and AJCC 9th edition staging systems [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe biological aggressiveness of G-NEC is further highlighted by the significantly higher incidence of venous infiltration (75% vs. 37.1%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This finding explains the high frequency of early systemic recurrence, particularly liver metastasis, even after curative-intent radical surgery [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. While lymphatic infiltration did not show a statistically significant difference in our study, the extensive venous involvement suggests that G-NEC possesses a stronger propensity for hematogenous spread than adenocarcinoma. This supports the argument for aggressive systemic chemotherapy, even in early-stage disease, as suggested by Zi et al. in their comprehensive analysis of gastric neuroendocrine neoplasms [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The distinction between low-grade NENs and highly aggressive NEC is vital. Early detection remains a cornerstone of survival. It has been emphasized that even early-stage gastric NEC carries a significant risk profile compared to standard gastric adenocarcinoma [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRegarding tumor location, while Zhou et al. reported a predilection for the gastroesophageal junction (GEJ) in pure G-NEC, our cohort showed a relatively uniform distribution throughout the stomach (Upper 29.2%, Middle 33.3%, Lower 33.3%) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, the anatomical site may carry prognostic weight; Kong et al. demonstrated that proximal G-NEC (PGNEC) is associated with worse cancer-specific survival than distal G-NEC (DGNEC) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In our study, the balanced distribution across sites may reflect the diverse origins of these tumors, but it also necessitates standardized surgical approaches regardless of the primary site to ensure adequate margins and nodal yield.\u003c/p\u003e \u003cp\u003eAs Christodoulidis et al. highlight, the last ten years have been defined by innovations in diagnostic imaging and a clearer understanding of the challenges inherent in treating these heterogeneous tumors [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The management of locoregional G-NEC remains controversial. A pivotal multicenter study by Yamagata et al. recently highlighted that the number of metastatic lymph nodes (pND) may be a more sensitive prognostic indicator than the traditional pN category [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In our study, although the median number of metastatic nodes did not differ significantly from adenocarcinoma, the presence of any nodal involvement in G-NEC was associated with a precipitous decline in survival. Given the high rate of nodal metastasis, D2 lymph node dissection should remain the standard surgical procedure. However, as Yamagata et al. suggested, the therapeutic benefit of extensive dissection may be limited in patients with a high burden of systemic micrometastases, which are common in G-NEC [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe dismal prognosis of G-NEC observed in our study underscores the need for better risk stratification. Recent efforts, such as the nomogram developed by Zhang et al., incorporate factors like age, tumor size, and AJCC stage to provide a more personalized survival estimate [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Our findings of T4 stage and venous infiltration as prominent features in the NEC group support the inclusion of these variables in future prognostic models. Moving forward, the integration of molecular biomarkers and the exploration of novel therapies, such as immune checkpoint inhibitors or peptide receptor radionuclide therapy (PRRT) as discussed in the review by Son et al. may offer new hope for this patient population [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFor gastric adenocarcinoma, postoperative adjuvant chemotherapy is established as a standard of care for locally advanced disease to improve survival outcomes. The ACTS-GC trial demonstrated the efficacy of S-1 monotherapy for pathological stage II/III disease [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], and the CLASSIC trial further confirmed the benefit of capecitabine plus oxaliplatin [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. More recently, the JACCRO GC-07 trial established S-1 plus docetaxel as a superior adjuvant regimen for stage III gastric cancer [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. These large-scale randomized controlled trials (RCTs) have provided robust evidence for managing gastric adenocarcinoma. In contrast, a standardized adjuvant strategy for G-NEC has not yet been established due to its rarity and the lack of high-level evidence from RCTs. Current clinical practice often extrapolates from the treatment of small-cell lung cancer, utilizing platinum-based regimens such as etoposide plus cisplatin (EP) or irinotecan plus cisplatin (IP). While the JCOG1213 (TOPIC-NEC) trial confirmed the efficacy of both EP and IP for advanced digestive NEC, their specific benefit in an adjuvant setting remains controversial [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA major challenge in G-NEC is its extremely high risk of early systemic recurrence, driven by aggressive biological behaviors like the venous infiltration observed in our study. Some retrospective studies have failed to demonstrate a significant survival benefit for adjuvant chemotherapy in resectable G-NEC patients [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, recent analyses suggest that adjuvant therapy may provide survival advantages, particularly for high-risk individuals or those with specific histopathological features. Further multi-institutional studies are necessary to define the optimal chemotherapy regimen and its timing for this aggressive malignancy. Ren et al. provide critical insights into the metastatic patterns of these mixed tumors, noting that the neuroendocrine component often dictates the aggressive nature of lymph node metastasis and overall survival [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. This necessitates a more nuanced surgical and oncological approach than traditional gastric cancer protocols.\u003c/p\u003e \u003cp\u003eAhn et al. have identified tertiary lymphoid structures (TLS) as a significant prognostic marker in gastric NEC [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Their findings suggest that the presence of these immune structures, alongside expressions of DLL3 (Delta-like ligand 3), could open doors for targeted therapies and immunotherapies, marking a shift toward \"immuno-neuroendocrinology.\" Integrating clinical data into actionable intelligence is the next frontier. Ding et al. demonstrated that machine learning models can provide real-time survival predictions for gNEC patients, allowing clinicians to move away from \"one-size-fits-all\" statistics toward personalized risk assessment [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. As summarized by Sedlack et al., the management of gastroenteropancreatic NENs is increasingly multidisciplinary [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The integration of peptide receptor radionuclide therapy (PRRT), novel somatostatin analogs, and the potential for DLL3-targeted agents suggests that the next decade will focus on molecular Stratification using markers like DLL3 to select patients for specific systemic therapies or AI-integrated decision making using real-time models to guide the intensity of follow-up and adjuvant treatment [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study has several limitations, primarily its retrospective nature and the single-institution setting, which resulted in a relatively small sample size for G-NEC. Additionally, the heterogeneity of adjuvant chemotherapy regimens used during the long study period (2010\u0026ndash;2025) may have influenced survival outcomes. Nevertheless, the consistency of our findings with recent international literature strengthens the validity of our observations regarding the aggressive nature of G-NEC. A significant challenge in gastric oncology is the \"gray zone\" where exocrine (adenocarcinoma) and neuroendocrine components coexist.\u003c/p\u003e \u003cp\u003eIn conclusion, G-NEC is a highly lethal malignancy with biological behaviors distinct from and more aggressive than gastric adenocarcinoma. The high frequency of T4 invasion and venous infiltration necessitates a multidisciplinary approach combining radical surgery with potent systemic therapies. Further prospective multicenter trials are required to establish a standardized treatment algorithm for this challenging disease.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone of the authors received funding or have any competing interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCategory\u003c/em\u003e\u003c/strong\u003e: Original Article\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFinancial support\u003c/em\u003e\u003c/strong\u003e: None\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSiegel RL, Kratzer TB, Wagle NS, Sung H, Jemal A (2026) Cancer statistics, 2026. CA Cancer J Clin 76:e70043\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamagata Y, Furuta M, Notsu A, Yasui H, Makuuchi R, Yamada T, Ishida M, Tsuji K, Baba S, Tokumoto N, Haruta S, Watanabe M, Hamakawa T, Kawachi Y, Sugisawa N, Yabusaki H, Kawabata R, Kurokawa Y, Boku N, Terashima M, Machida N, Yoshikawa T (202) Efficacy of nodal dissection for locoregional gastric neuroendocrine carcinoma: a multicenter retrospective observational study. Gastric Cancer 28:1004\u0026ndash;1016\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSobin LH, Compton CC (2010) TNM seventh edition: what's new, what's changed: communication from the International Union Against Cancer and the American Joint Committee on Cancer. 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Cancer 130:3090\u0026ndash;3105\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"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 carcinoma, gastric cancer, clinicopathological characteristics, prognosis, venous infiltration","lastPublishedDoi":"10.21203/rs.3.rs-8791930/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8791930/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eGastric neuroendocrine carcinoma (G-NEC) is a rare and highly aggressive malignancy characterized by a dismal prognosis. Due to its low incidence, standardized treatment strategies for locoregional disease have not been firmly established. This study aimed to clarify the distinct clinicopathological features and prognostic factors of G-NEC by comparing them with those of gastric adenocarcinoma.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e We retrospectively reviewed the medical records of 1,014 patients who underwent gastrectomy for gastric cancer at Kochi Medical School between January 2010 and December 2025. Patients were divided into two groups: the G-NEC group (n\u0026thinsp;=\u0026thinsp;24) and the adenocarcinoma group (n\u0026thinsp;=\u0026thinsp;990). Clinicopathological parameters including age, sex, tumor location, depth of invasion (T stage), and vascular involvement were compared, and long-term survival outcomes were evaluated.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eG-NEC accounted for 2.4% of the total cohort. The G-NEC group exhibited a significant male predominance compared to the adenocarcinoma group (87.5% vs. 64.7%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036). Regarding tumor progression, G-NEC patients presented with significantly deeper tumor invasion (T4: 62.5% vs. 27.9%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006) and a markedly higher rate of venous infiltration (75.0% vs. 37.1%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). No significant differences were observed in tumor size, location, or lymphatic infiltration. Survival analysis demonstrated that patients with G-NEC had significantly poorer overall and recurrence-free survival compared to those with adenocarcinoma, primarily due to early systemic recurrence and hematogenous metastasis.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eG-NEC is a biologically aggressive entity characterized by deep local invasion and frequent vascular involvement. Given the high risk of early systemic failure, a multidisciplinary approach combining radical surgery with potent systemic chemotherapy is essential for improving clinical outcomes.\u003c/p\u003e","manuscriptTitle":"Clinicopathological characteristics and prognostic analysis of gastric neuroendocrine carcinoma: A comparative study with gastric adenocarcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-19 09:11:54","doi":"10.21203/rs.3.rs-8791930/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":"885da316-1828-4e77-b496-e1625a2474e6","owner":[],"postedDate":"February 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-12T04:21:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-19 09:11:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8791930","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8791930","identity":"rs-8791930","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}