• gastric NET
• neuroendocrine tumors
• stomach
• type 3

• Krukenberg tumors
• Neuroendocrine carcinoma
• debulking surgery
• liver metastases

• MiNEN
• small (large) cell

Gastrointestinal neuroendocrine tumors are rare slow-growing tumors with distinct histological, biological, and clinical characteristics that have increased in incidence and prevalence within the last few decades. They contain chromogranin A, synaptophysin and neuron-specific enolase which are necessary for making a diagnosis of neuroendocrine tumor. Ki-67 index and mitotic index correlate with cellular proliferation. Serum chromogranin A is the most commonly used biomarker to assess the bulk of disease and monitor treatment and is raised in both functioning and non-functioning neuroendocrine tumors. Most of the gastrointestinal neuroendocrine tumors are non-functional. World Health Organization updated the classification of neuroendocrine tumors in 2017 and renamed mixed adenoneuroendocrine carcinoma into mixed neuroendocrine neoplasm. Gastric neuroendocrine tumors arise from enterochromaffin like cells. They are classified into 4 types. Only type I and type II are gastrin dependent. Small intestinal neuroendocrine tumor is the most common small bowel malignancy. More than two-third of them occur in the terminal ileum within 60 cm of ileocecal valve. Patients with small intestinal neuroendrocrine tumors frequently show clinical symptoms and develop distant metastases more often than those with neuroendocrine tumors of other organs. Duodenal and jejuno-ileal neuroendocrine tumors are distinct biologically and clinically. Carcinoid syndrome generally occurs when jejuno-ileal neuroendocrine tumors metastasize to the liver. Appendiceal neuroendocrine tumors are generally detected after appendectomy. Colonic neuroendocrine tumors generally present as a large tumor with local or distant metastasis at the time of diagnosis. Rectal neuroendocrine tumors are increasingly being diagnosed since the implementation of screening colonoscopy in 2000. Gastrointestinal neuroendocrine tumors are diagnosed and staged by endoscopy with biopsy, endoscopic ultrasound, serology of biomarkers, imaging studies and functional somatostatin scans. Various treatment options are available for curative and palliative treatment of gastrointestinal neuroendocrine tumors.

• Gastrointestinal neuroendocrine tumors
• Gastric neuroendocrine tumors
• Small intestinal neuroendocrine tumors
• Colonic neuroendocrine tumors
• Rectal neuroendocrine tumors
• Carcinoid syndrome

• Humans
• Neuroendocrine Tumors/diagnosis
• Neuroendocrine Tumors/metabolism
• Neuroendocrine Tumors/pathology
• Neuroendocrine Tumors/therapy

• Ipsen
• Novartis
• Pfizer
• Sanofi and Shire

To date, the histopathological parameters predicting the risk of lymph node (LN) metastases and local recurrence, associated mortality and appropriateness of endoscopic or surgical resection in patients with gastric neuroendocrine neoplasms type 1 (GNENs1) have not been fully elucidated.

To determine the rate of LN metastases and its impact in survival in patients with GNEN1 in relation to certain clinico-pathological parameters.

The PubMed, EMBASE, Cochrane Library, Web of Science and Scopus databases were searched through January 2019. The quality of the included studies and risk of bias were assessed using the Newcastle-Ottawa Scale (NOS) in accordance with the Cochrane guidelines. A random effects model and pooled odds ratios (OR) with 95%CI were applied for the quantitative meta-analysis.

We screened 2933 articles. Thirteen studies with 769 unique patients with GNEN1 were included. Overall, the rate of metastasis to locoregional LNs was 3.3% (25/769). The rate of LN metastases with a cut-off size of 10 mm was 15.3% for lesions > 10 mm (vs 0.8% for lesions < 10 mm) with a random-effects OR of 10.5 (95%CI: 1.4 -80.8; heterogeneity: P = 0.126; I² = 47.5%). Invasion of the muscularis propria was identified as a predictor for LN metastases (OR: 17.2; 95%CI: 1.8-161.1; heterogeneity: P = 0.165; I² = 44.5%), whereas grade was not clearly associated with LN metastases (OR: 2; 95%CI: 0.3-11.6; heterogeneity: P = 0.304; I² = 17.4%). With regard to GNEN1 local recurrence, scarce data were available. The 5-year disease-specific survival for patients with and without LN metastases was 100% in most available studies irrespective of the type of intervention. Surgical resection was linked to a lower risk of recurrence (OR: 0.3; 95%CI: 0.1-1.1; heterogeneity: P = 0.173; I² = 31.9%). The reported complication rates of endoscopic and surgical intervention were 0.6 and 3.8%, respectively.

This meta-analysis confirms that tumor size ≥ 10 mm and invasion of the muscularis propria are linked to a higher risk of LN metastases in patients with GNEN1. Overall, the metastatic propensity of GNEN1 is low with favorable 5-year disease-specific survival rates reported; hence, no clear evidence of the prognostic value of LN positivity is available. Additionally, there is a lack of evidence supporting the prediction of local recurrence in GNEN1, even if surgery was more often a definitive treatment.

• Gastric neuroendocrine neoplasms type 1
• Meta-analysis
• Lymph node metastasis
• Tumor size
• Invasion
• Endoscopy
• Surgery

• Disease-Free Survival
• Endoscopic Mucosal Resection
• Gastrectomy
• Humans
• Lymph Node Excision
• Lymphatic Metastasis/pathology
• Neoplasm Grading
• Neoplasm Invasiveness/pathology
• Neoplasm Recurrence, Local/diagnosis
• Neoplasm Recurrence, Local/epidemiology
• Neoplasm Recurrence, Local/prevention & control
• Neuroendocrine Tumors/mortality
• Neuroendocrine Tumors/pathology
• Neuroendocrine Tumors/surgery
• Patient Selection
• Prognosis
• Stomach/pathology
• Stomach Neoplasms/mortality
• Stomach Neoplasms/pathology
• Stomach Neoplasms/surgery
• Survival Rate
• Treatment Outcome
• Tumor Burden

Evaluate the predictive value of the preoperative blood neutrophil-to-lymphocyte ratio (NLR) on the clinical outcomes of patients with gastric neuroendocrine neoplasms (g-NENs) after radical surgery.

The NLR was significantly higher in patients with g-NENs than in matched normal volunteers (P < 0.05). A higher blood NLR was not significantly associated with clinical characteristics (all P > 0.05). According to the multivariate analysis, the NLR was an independent prognostic factor of RFS and OS. Nomograms, including the NLR, Ki-67 index and lymph node ratio, had superior discriminative abilities to predict clinical outcomes. The recurrence rate was 37% (55/147). The median time to recurrence was 9 months; 48 (87%) patients experienced recurrence within the first 2 years. Both the NLR and Ki-67 index were correlated with liver metastases (both P < 0.05) and were also negatively correlated with recurrence time (both P < 0.05).

We enrolled 147 patients who were diagnosed with g-NENs and underwent radical surgery. Receiver operating characteristic curve analysis was used to identify the optimal value for blood NLR. Univariate and multivariate survival analysis were used to identify prognostic factors for g-NENs. A nomogram was adopted to predict RFS and OS after surgery.

As an independent prognostic factor for g-NENs, blood NLR can improve the predictability of RFS and OS. We recommend that g-NEN patients with a high blood NLR or high Ki-67 index undergo surveillance during the first month and then every 3 months for 2 years post-surgery.

• gastric neuroendocrine neoplasms
• preoperative blood neutrophil-to-lymphocyte ratio
• prognosis
• surveillance strategy
• tumor recurrence

• carcinoid tumor
• gastric neoplasms
• neuroendocrine tumor
• recurrence
• survival

• Female
• Humans
• Incidence
• Male
• Middle Aged
• Neoplasm Staging
• Neuroendocrine Tumors/classification
• Neuroendocrine Tumors/diagnosis
• Neuroendocrine Tumors/epidemiology
• Prognosis
• Republic of Korea/epidemiology
• Retrospective Studies
• Stomach Neoplasms/classification
• Stomach Neoplasms/diagnosis
• Stomach Neoplasms/epidemiology

Type I gastric neuroendocrine tumors (TI-GNETs) are related to chronic atrophic gastritis with hypergastrinemia and enterochromaffin-like cell hyperplasia. The incidence of TI-GNETs has significantly increased, with the great majority being TI-GNETs. TI-GNETs present as small (< 10 mm) and multiple lesions endoscopically and are generally limited to the mucosa or submucosa. Narrow band imaging and high resolution magnification endoscopy may be helpful for the endoscopic diagnosis of TI-GNETs. TI-GNETs are usually histologically classified by World Health Organization criteria as G1 tumors. Therefore, TI-GNETs tend to display nearly benign behavior with a low risk of progression or metastasis. Several treatment options are currently available for these tumors, including surgical resection, endoscopic resection, and endoscopic surveillance. However, debate persists about the best management technique for TI-GNETs.

• Gastric neuroendocrine tumor
• Narrow band imaging
• Magnifying endoscopy
• Endoscopic submucosal dissection
• Endoscopic surveillance

To date, empirical literature has generally been considered lacking in relation to neuroendocrine carcinomas (NECs), the highly malignant subgroup of neuroendocrine neoplasms. NECs are often found in the lungs or the gastroenteropancreatic (GEP) system and can be of small or large cell type. Concentrating on GEP-NECs, we can conclude that survival times are poor, with a median of only 4–16 months depending on disease stage and primary site. Further, this aggressive disease appears to be on the rise, with incidence numbers increasing while survival times are stagnant. Treatment strategies concerning surgery are often undecided and second-line chemotherapy is not yet established. After an analysis of over 2600 articles, we can conclude that there is indeed more empirical literature concerning GEP-NECs available than previously assumed. This unique review is based on 333 selected articles and contains detailed information concerning all aspects of GEP-NECs. Namely, the classification, histology, genetic abnormalities, epidemiology, origin, biochemistry, imaging, treatment and survival of GEP-NECs are described. Also, organ-specific summaries with more detail in relation to disease presentation, diagnosis, treatment and survival are presented. Finally, key points are discussed with directions for future research priorities.

• Ki-67 index
• colo-rectal
• large cell carcinomas
• neuroendocrine carcinomas
• neuroendocrine neoplasms
• neuroendocrine tumours
• oesophagus
• pancreas
• small cell carcinomas
• stomach

AIM: To evaluate the clinical characteristics and prognostic factors of gastric neuroendocrine carcinoma (GNEC).

METHODS: The clinical data for 50 GNEC patients treated at our hospital between November 1, 2007 and March 31, 2014 were reviewed and analyzed retrospectively. Kaplan-Meier survival curves were plotted, and log-rank tests and Cox proportional hazards analysis were used for univariate and multivariate comparisons of overall survival (OS).

RESULTS: There were 44 neuroendocrine carcinoma (NEC) (G3) and 6 mixed adenoneuroendocrine carcinoma (MANEC) (G2-3) patients enrolled in this study. Among them, 39 were male and 11 were female, with a median age of 61.32±10.48 years. At presentation, 6 (12.0%) cases were diagnosed with stage Ⅱ, and the percentages of stage Ⅲ and Ⅳ patients was 68.0% and 20.0%, respectively. All of the cases received radical surgery for the primary and metastatic masses. 36 (72.0%) cases had lymph node metastasis and intravascular tumor thrombi were found in 17 (34.0%) cases. The percentage of patients receiving chemotherapy was 50.0% (25/50). The follow-up duration was 1 to 50 mo. 15 cases developed relapse and 18 patients died. Univariate analysis revealed that the ratio of neutrophils to lymphocytes (NLR), Ki67 and chemotherapy were significant prognostic factors (P < 0.05). Cox regression analysis showed that Ki67 was an independent prognostic factor.

CONCLUSION: GNEC is a relatively uncommon and highly aggressive malignancy, and Ki67 is an important independent prognostic factor.

• Neuroendocrine carcinoma
• Gastric
• Prognosis

Neuroendocrine carcinoma (NEC) is a rare tumor, comprising < 1% of stomach cancers. A 55-year-old woman was referred to our hospital with biopsy-proven gastric cancer. A shallow ulcerative lesion was detected in the lesser curvature of the lower body. It was suspected to be early gastric cancer IIA + IIC type. Thus, endoscopic submucosal dissection was performed. She was subsequently diagnosed with NEC, which is aggressive and carries a poor prognosis. We conducted a radical resection and a laparoscopic-assisted distal gastrectomy. The tumor had infiltrated the subserosal layer and 6/42 lymph nodes were involved. The mitotic index was 16/10 high power fields and the Ki-67 labeling index was 26%-50%. The final diagnosis of NEC was made according to the World Health Organization 2010 criteria. She was suspected of having jumping metastasis to the proximal margin. The patient was treated with an oral anticancer drug (5-flurouracil based drug) for 2 years. The patient has been followed up for 3 years without recurrence.

• Neuroendocrine carcinoma
• Mitosis
• Ki-67
• Gastrectomy
• Prognosis

Gastric neuroendocrine tumors (GNETs) are rare lesions characterized by hypergastrinemia that arise from enterochromaffin-like cells of the stomach. GNETs consist of a heterogeneous group of neoplasms comprising tumor types of varying pathogenesis, histomorphologic characteristics, and biological behavior. A classification system has been proposed that distinguishes four types of GNETs; the clinicopathological features of the tumor, its prognosis, and the patient’s survival strictly depend on this classification. Thus, correct management of patients with GNETs can only be proposed when the tumor has been classified by an accurate pathological and clinical evaluation of the patient. Recently developed cancer therapies such as inhibition of angiogenesis or molecular targeting of growth factor receptors have been used to treat GNETs, but the only definitive therapy is the complete resection of the tumor. Here we review the literature on GNETs, and summarize the classification, clinicopathological features (especially prognosis), clinical presentations and current practice of management of GNETs. We also present the latest findings on new gene markers for GNETs, and discuss the effective drugs developed for the diagnosis, prognosis and treatment of GNETs.

• Gastric neuroendocrine tumor
• Classification
• Clinicopathological significance
• Diagnosis
• Prognosis
• Treatment

• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/blood
• Biomarkers, Tumor/genetics
• Gastrectomy
• Humans
• Molecular Targeted Therapy
• Neuroendocrine Tumors/blood
• Neuroendocrine Tumors/classification
• Neuroendocrine Tumors/genetics
• Neuroendocrine Tumors/pathology
• Neuroendocrine Tumors/therapy
• Precision Medicine
• Predictive Value of Tests
• Stomach Neoplasms/blood
• Stomach Neoplasms/classification
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Stomach Neoplasms/therapy
• Treatment Outcome

• Aged
• Aged, 80 and over
• Biomarkers, Tumor/metabolism
• Carcinoma, Neuroendocrine/pathology
• Carcinoma, Neuroendocrine/surgery
• Chromogranin A/metabolism
• Female
• Gastrectomy
• Humans
• Immunohistochemistry
• Japan
• Male
• Microscopy, Electron, Transmission
• Middle Aged
• Phosphopyruvate Hydratase/metabolism
• Stomach Neoplasms/pathology
• Stomach Neoplasms/surgery
• Synaptophysin/metabolism
• Tumor Suppressor Protein p53/metabolism

Gastric carcinoid tumors (GCs) are rare lesions representing less than 10% of carcinoid tumors and less than 1% of all stomach neoplasms. There are three distinct types of gastric carcinoids; type I includes the vast majority (70–85%) of these neoplasms that are closely linked to chronic atrophic gastritis. Type II which accounts for 5–10 %, is associated with Zollinger-Ellison syndrome and often occurs in the context of multiple endocrine neoplasia type 1. Type III, finally, represents 15–25% of gastric carcinoids and is characterized by a far more aggressive course. The optimal clinical approach to GCs remains to be elucidated, depending upon type, size, and number of carcinoids. While there is universal agreement about the surgical treatment of type III GCs, current options for type I and II include simple surveillance, endoscopic polypectomy, surgical excision associated with or without surgical antrectomy, or total gastrectomy. Moreover, the introduction of somatostatin analogues could represent another therapeutic option.

• Carcinoid Tumor/classification
• Carcinoid Tumor/epidemiology
• Carcinoid Tumor/pathology
• Carcinoid Tumor/therapy
• Carcinoma, Neuroendocrine/classification
• Carcinoma, Neuroendocrine/epidemiology
• Carcinoma, Neuroendocrine/pathology
• Carcinoma, Neuroendocrine/therapy
• Cell Transformation, Neoplastic
• Enterochromaffin-like Cells/pathology
• Enterochromaffin-like Cells/physiology
• Gastroscopy
• Humans
• Incidence
• Neoplasm Invasiveness
• Neoplasm Staging
• Neuroendocrine Tumors/classification
• Neuroendocrine Tumors/epidemiology
• Neuroendocrine Tumors/pathology
• Neuroendocrine Tumors/therapy
• Prognosis
• Stomach Neoplasms/classification
• Stomach Neoplasms/epidemiology
• Stomach Neoplasms/pathology
• Stomach Neoplasms/therapy

• DK080871 NIDDK NIH HHS