Search

Gastrointestinal neuroendocrine tumors are increasingly common. Practitioners should examine these lesions carefully found on routine endoscopy. Obtaining accurate neuroendocrine tumors stage and grade is critical to patient assessment and management, and assistance from advanced endoscopists may be needed., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Objectives: This study aimed to understand if resection (RS) for nonmetastatic small bowel neuroendocrine tumors (SBNETs) prolongs 5-year overall survival., Methods: Patients from National Cancer Data Base with primary histologically confirmed SBNETs from 2007 to 2016 were included. Patients younger than 18 years, with the disease in the duodenum/Meckel diverticulum or metastatic disease were excluded. We assessed 5-year survival rates using Kaplan-Meier curves and multivariate Cox proportional hazards regression after RS, nonresection surgical management (NRS), or no resection (NR). Multivariate models were adjusted with age, sex, race, insurance, Charlson-Deyo comorbidity score, academic facility, primary tumor location, clinical T, clinical N, stage, and grade., Results: We identified 4180 patients. On average, patients were 64 years old (standard deviation, 12 years), male (53%), and White (84%). The majority received RS (91.8%) as opposed to NRS (4.0%) or NR (4.2%). Patients who received RS versus NR had increased survival rates (84.2% vs 73.9%; univariate log-rank, P < 0.0001; multivariate hazard ratio, 0.73; 95% confidence interval, 0.53-0.99; P = 0.04). No statistical difference in survival was observed for NRS versus NR., Conclusions: To our knowledge, this is the first national study to evaluate survival after RS for nonmetastatic SBNETs. Results suggest that RS of SBNETs may prolong 5-year survival., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Diabetes mellitus (DM) is associated with an increased risk of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), but the association between DM and GEP-NET survival is unknown. We evaluated disease characteristics and survival in individuals with DM and GEP-NETs., Methods: Using the Surveillance, Epidemiology, and End Results registry linked to Medicare (SEER-Medicare) claims database, we examined sociodemographics, GEP-NET characteristics, and treatment in patients with and without DM before GEP-NET diagnosis. We compared survival using univariate and multivariate analyses., Results: We identified 1858 individuals with GEP-NETs: 478 (25.7%) with DM and 1380 (74.3%) without. Significant differences in race (P = 0.002) were found between the DM and non-DM groups. Compared with individuals without DM, those with DM had more gastric (9.7% vs 14.9%), duodenal (6.5% vs 10.0%), and pancreatic (17.0% vs 21.8%), and less jejunal/ileal (18.1% vs 12.8%) NETs (P < 0.0001). Patients with DM had earlier stages (stage I, 37.0%; stage IV, 30.8%) than those without (stage I, 30.6%; stage IV, 36.4%; P = 0.0012). We found no difference in survival (multivariate hazard ratio, 0.97; 95% confidence interval, 0.76-1.23) between groups., Conclusions: Among patients with and without DM before GEP-NET diagnosis, we found differences in tumor location and stage, but not survival., Competing Interests: E.J.G. has served on an advisory board for Novartis and as a consultant for Seattle Genetics and SynDevRx for work unrelated to this project. S.T., K.B., and M.K.K. have no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are increasingly common malignancies and tend to have favorable long-term prognoses. Somatostatin analogues (SSA) are a first-line treatment for many NETs. Short-term experiments suggest an association between SSAs and hyperglycemia. However, it is unknown whether there is a relationship between SSAs and clinically significant hyperglycemia causing development of diabetes mellitus (DM), a chronic condition with significant morbidity and mortality., Aim: In this study, we aimed to compare risk of developing DM in patients treated with SSA vs no SSA treatment., Methods and Results: Using the Surveillance, Epidemiology, and End Results (SEER) database and linked Medicare claims (1991-2016), we identified patients age 65+ with no prior DM diagnosis and a GEP-NET in the stomach, small intestine, appendix, colon, rectum, or pancreas. We used χ 2 tests to compare SSA-treated and SSA-untreated patients and multivariable Cox regression to assess risk factors for developing DM. Among 8464 GEP-NET patients, 5235 patients had no prior DM and were included for analysis. Of these, 784 (15%) patients received SSAs. In multivariable analysis, the hazard ratio of developing DM with SSA treatment was 1.19, which was not statistically significant (95% CI 0.95-1.49). Significant risk factors for DM included black race, Hispanic ethnicity, prior pancreatic surgery, prior chemotherapy, tumor size >2 cm, pancreas tumors, and higher Charlson scores., Conclusion: DM was very common in GEP-NET patients, affecting 53% of our cohort. Despite prior studies suggesting an association between SSAs and hyperglycemia, our analysis found similar risk of DM in SSA-treated and SSA-untreated GEP-NET patients. Further studies are needed to better understand this relationship. As NET patients have increasingly prolonged survival, it is crucial to identify chronic conditions such as DM that these patients may be at elevated risk for., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background & Aims: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous neoplasms. Although some have a relatively benign and indolent natural history, others can be aggressive and ultimately fatal. Somatostatin analogues (SSAs) improve both quality of life and survival for these patients once they develop metastatic disease. However, these drugs are costly and their cost-effectiveness is not known., Methods: A decision-analytic model was developed and analyzed to compare two treatment strategies for patients with Stage IV GEP-NETs. The first strategy had all patients start SSA immediately while the second strategy waited, reserving SSA initiation until the patient showed signs of progression. Sensitivity analysis was performed to explore model parameter uncertainty., Results: Our model of patients age 60 with metastatic GEP-NETs suggests empiric initiation of SSA led to an increase 0.62 unadjusted life-years and incremental increase in quality-adjusted life years (QALYs) of 0.44. The incremental costs were $388,966 per QALY and not cost-effective at a willingness-to-pay threshold of $100,000. Death was attributed to GEP-NETs for 94.1% of patients in the SSA arm vs. 94.9% of patients in the DELAY SSA arm. Sensitivity analysis found that the model was most sensitive to costs of SSAs. Using probabilistic sensitivity analysis, the SSA strategy was only cost-effective 1.4% of the time at a WTP threshold of $100,000 per QALY., Conclusions: Our modeling study finds it is not cost-effective to initiate SSAs at time of presentation for patients with metastatic GEP-NETs. Further clinical studies are needed to identify the optimal timing to initiate these drugs.

Introduction: Earlier detection and improved treatment of neuroendocrine tumors (NETs) have prolonged survivorship in NET patients. We undertook this study to understand the prevalence of NET-related posttraumatic stress disorder (PTSD) and the factors and cancer-related illness beliefs associated with PTSD., Methods: We recruited patients with a diagnosis of NET from a large NET center in New York City. Cancer-related PTSD was assessed using the Revised Impact of Events scale (IES), with probable PTSD as ≥ 33. We used the Brief Illness Perception Questionnaire (BIPQ) to assess NET-related beliefs. Data on baseline patient characteristics were collected. Comparisons used chi-squares and Fisher exact tests, as appropriate., Results: Of the 73 participants, 48 (66%) were female and the mean age was 60 years (standard deviation (SD) 11.7, see Table 1). Twelve patients (16%) met criteria for probable NET-related PTSD. Women were more likely to meet criteria for probable PTSD (15% vs. 1%, p = 0.04). Those who met criteria for probable PTSD were more likely to have higher overall scores on the BIPQ (64 vs. 57, p = 0.03), report constantly feeling unwell due to their cancer (4 vs. 1, p = 0.04), as well as report more physical and emotional symptoms from their cancer (5 vs. 1, p = 0.03, and 7 vs. 4, p = 0.02, respectively)., Conclusion: NET patients with probable PTSD were more likely to be women with greater physical and emotional burden due to their cancer. Our findings suggest that specific threatening cancer-related beliefs, not disease characteristics, predict a higher risk of PTSD among NET survivors.

Background: Medical centers with varying levels of expertise treat gastroenteropancreatic neuroendocrine tumors (GEP-NETs), which are relatively rare tumors. This study assesses the impact of center volume on GEP-NET treatment outcomes., Methods: We used the Surveillance, Epidemiology, and End Results (SEER) registry linked to Medicare claims data. The data includes patients diagnosed between 1995 and 2010 who had no health maintenance organization (HMO) coverage, participated in Medicare parts A and B, were older than 65 at diagnosis, had tumor differentiation information, and had no secondary cancer. We identified medical centers at which patients received GEP-NET treatment (surgery, chemotherapy, somatostatin analogues, or radiation therapy) using Medicare claims data. Center volume was divided into 3 tiers - low, medium, and high - based on the number of unique GEP-NET patients treated by a medical center over 2 years. We used Kaplan-Meier curves and Cox regression to assess the association between volume and disease-specific survival., Results: We identified 899 GEP-NET patients, of whom 37, 45, and 18% received treatment at low, medium volume, and high-volume centers, respectively. Median disease-specific survival for patients at low and medium tiers were 1.4 years and 5.3 years, respectively, but was not reached for patients at high volume centers. Results showed that patients treated at high volume centers had better survival than those treated in low volume centers (HR: 0.63, 95% CI: 0.4-0.9), but showed no difference in outcomes between medium and high-volume centers., Conclusions: Our results suggest that for these increasingly common tumors, referral to a tertiary care center may be indicated. Physicians caring for GEP-NET patients should consider early referral to high volume centers.

Objectives: The objective of this study was to evaluate racial differences in cancer treatment and survival in gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients., Methods: Using the Surveillance, Epidemiology, and End Results Registry, we identified patients with GEP-NETs of the stomach, small intestine (SI), colon, rectum, appendix, and pancreas diagnosed between 1973 and 2014. Demographic, cancer, and treatment information were collected and compared using χ2 tests. Multivariable logistic and Cox regression were used to determine disparities in receiving treatment and overall survival., Results: We identified 19,031 GEP-NET patients: 2839 were non-Hispanic Blacks, 12,832 non-Hispanic Whites, 2098 Hispanics, and 1262 Asians. African Americans and Hispanics with SI and pancreatic NETs were less likely to be treated with surgery (odds ratio, 0.6; 95% confidence interval [CI], 0.46-0.69; odds ratio, 0.71; 95% CI, 0.51-0.99, respectively). African American race was not an independent predictor of survival; there was a strong trend in stomach, SI, and pancreas NETs (hazard ratio [HR], 1.31; 95% CI, 1-1.7; HR, 1.2; 95% CI, 0.99-1.45; HR, 1.22; 95% CI, 1-1.48, respectively)., Conclusions: Our study provides evidence of racial disparities in treatment and survival across GEP-NET primary sites and racial groups. Further studies should be performed to improve our understanding of the reason for these disparities., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Neuroendocrine tumors represent approximately 40% of primary small bowel malignancies. However, factors predictive of progression after multimodal surgical therapy have not been well described. We evaluated the characteristics of small bowel neuroendocrine tumor patients associated with progression after multimodal surgical resection., Methods: A retrospective chart review identified 99 stage III and stage IV small bowel neuroendocrine tumor patients at Mount Sinai diagnosed and treated with surgery between 2005 and 2019. Progression-free survival (PFS) was defined as time from surgery until progression in surveillance radiologic imaging. Kaplan-Meier method was used to calculate PFS. Cox proportional hazard models were used to study the prognostic factors for PFS., Results: Of 99 patients, 48 had tumor progression during the follow-up period. Median PFS was 5.7 years (95% confidence interval [CI], 3.73-8.66) for the entire cohort. Prognostic factors for PFS were age at diagnosis (hazard ratio [HR], 1.04; 95% CI, 1.01-1.07), perineural invasion (HR, 2.19; 95% CI, 1.13-4.23), and elevated preoperative chromogranin level (HR, 2.31; 95% CI, 1.01-5.27)., Conclusions: Age at diagnosis, perineural invasion, and elevated preoperative chromogranin level may play a prognostic role in PFS.

Objective: Given the lack of consensus on surveillance guidelines after pancreatic neuroendocrine tumor (PanNET) resection, we assessed outcomes in a large cohort of patients with nonmetastatic, surgically resected PanNETs., Methods: Data of patients with PanNETs resected between 1990 and 2017 were retrospectively collected using databases at 3 academic institutions. The National Death Index was queried to determine vital status. Kaplan-Meier analysis was used to estimate recurrence-free survival (RFS) and disease-specific survival (DSS) rates. Variables associated with recurrence and disease-related death were identified through Cox multivariate analyses., Results: Of 307 patients with PanNET who underwent resection, recurrence occurred in 79 (26%) of patients. For stage I and II disease, 5-year RFS rates were 90% and 43%, whereas 5-year DSS rates were 98% and 86% (P < 0.0001 and P = 0.0038, respectively). For grades 1, 2, and 3 disease, 5-year RFS rates were 87%, 49%, and 18%, and 5-year DSS rates were 98%, 89%, and 51% (P < 0.0001 for both). Stage II, grade 2, and grade 3 disease were each associated with increased recurrence and disease-specific death., Conclusions: Stage and grade are important prognostic factors that should be utilized to tailor postsurgical surveillance after curative resection of PanNET.

This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the surgical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The group reviewed a series of questions of specific interest to surgeons taking care of patients with pancreatic neuroendocrine tumors, and for each, the available literature was reviewed. What follows are these reviews for each question followed by recommendations of the panel.

Objective: The aim of the study was to assess treatment patterns, healthcare resource utilization, and healthcare costs among patients with neuroendocrine tumors (NETs) receiving long-acting octreotide versus lanreotide, overall and in patients with carcinoid syndrome (CS)., Methods: A provider-based claims database was used to identify NET patients who first initiated long-acting octreotide or lanreotide (index date) from January 2015 to November 2017. Propensity-score matching 1:1 was used. Patients with CS were identified from the previously mentioned matched cohorts. Time-to-treatment discontinuation (TTD) was estimated using Kaplan-Meier analyses. Per-patient-per-month rates of healthcare resource utilization were compared using rate ratios from multivariable Poisson regression models. Multivariable linear regression models were used to compare mean monthly cost differences., Results: The median TTD was similar between the 2 matched cohorts (N = 543 each; long-acting octreotide = 19.2 months, lanreotide = 17.5 months, P = 0.58). Significantly fewer NET-related outpatient visits (rate ratio = 0.95, P = 0.005) and significantly lower total healthcare costs (mean monthly cost difference: all-cause = US -$3701, NET-related = US -$3752, Ps < 0.001) were observed in the long-acting octreotide cohort than lanreotide. Similar results were found in CS patients., Conclusions: Patients on first-line long-acting octreotide and lanreotide had similar TTD. Long-acting octreotide was associated with significantly lower total healthcare costs than lanreotide.

Background & Aims: Although multiple studies have reported an increasing incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) over the past decades, there are limited national data on recent trends. Using a population-based registry, we evaluated GEP-NET incidence trends in the United States population from 1975 through 2012, based on age, calendar year at diagnosis, and year of birth., Methods: GEP-NET cases from 1975 through 2012 were identified from the most recent version of the Surveillance, Epidemiology, and End Results registry using histologic and site codes. We calculated overall annual incidence, age-adjusted incidence (number of cases per 100,000), annual percent change (APC), and average APC by 5-year age intervals. We also evaluated the incidence rates by age, period, and birth year cohorts., Results: We identified 22,744 patients with GEP-NETs. In adults 25-39 years old, GEP-NET incidence rates decreased from the mid-1970s to the early 1980s, then increased until 2012. In adults ages 40 years and older or young adults ages 15-24 years, incidence rates generally increased continuously from 1975 through 2012. Adults ages 40-69 years had the most rapid increases in average APC (approximately 4%-6% per year). Overall incidence rates were highest in adults 70-84 years old. Since the inception of the Surveillance, Epidemiology, and End Results registry, GEP-NET incidence has increased in consecutive birth cohorts., Conclusion: The incidence of GEP-NET continues to increase-particularly in older adults. More recent generations have had higher GEP-NET incidence rates than more distant generations., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: In this study, we used the institutional pathological and clinical databases from The Mount Sinai Hospital to investigate the impact of mesenteric mass on clinical and staging features in small intestinal neuroendocrine tumors., Methods: Demographic, clinical, and staging data were collected. Tumor-node-metastasis stage was assigned according to the American Joint Committee on Cancer eighth edition staging manual. We used a χ-square test to evaluate the association between mesenteric mass and presenting symptoms, as well as the association between mesenteric mass and tumor characteristics, type of surgical resection, and use of somatostatin analogues., Results: Presence of mesenteric mass was strongly associated with highly symptomatic clinical presentation (P < 0.0001). Patients with a mesenteric mass were more likely to have more advanced tumor status (T3 and T4; P = 0.005). The presence of a mesenteric mass was also more strongly associated with metastatic disease (P = 0.002). Patients with a mesenteric mass were more likely to undergo extensive surgical resection (P < 0.0001) and be treated with somatostatin analogues (P < 0.003)., Conclusions: The data confirm our clinical observations that mesenteric involvement represents more extensive disease and is also associated with more aggressive treatment.

Objective: Neuroendocrine tumors (NETs) comprise 41.8% of small intestine malignancies. The NET nomogram is a 15-item prognostic tool that includes relevant factors for guiding management decisions. This is the first external validation of this tool among American patients at a tertiary treatment center., Methods: Patients who underwent surgical intervention from 2005 to 2017 were screened by retrospective chart review. Nomogram scores were calculated following the methods outlined by Modlin et al (Neuroendocrinology. 2010;92:143-157). Validation assessed the association between nomogram scores and survival using Wilcoxon test and Cox regression., Results: Among the 121 patients selected, the NET nomogram significantly predicted survival as a continuous variable (P < 0.01) and when dichotomized using 83 points to distinguish low-risk versus high-risk groups (P < 0.01). However, the nomogram was not universally applicable as even at our specialty center, variables such as chromogranin A and urinary 5-hydroxyindoleacetic acid are not routinely collected, whereas others, like tumor grade, do not reflect the most recently updated classifications., Conclusion: The NET nomogram accurately identified patients at low and high risk of death. However, revision to update prognosticators could improve its usefulness for predicting survival of small intestine NETs.

Objective: This study aimed to describe the relative and excess risk of pancreatic neuroendocrine tumor (NET) at least 6 months after the first primary cancer (FPC) among the US population., Methods: Surveillance, Epidemiology, and End-Results Program data were analyzed for patients diagnosed as having FPC from 2000 to 2015 (n = 4,008,092). Standardized incidence ratios, excess risk, and average time to diagnosis of a second primary pancreatic NET were reported by FPC site, stratified by sex and receipt of radiotherapy and chemotherapy., Results: Risk of pancreatic NET was significantly higher after FPC at any site, any solid tumor (standardized incidence ratios, 1.3; 95% confidence interval, 1.2-1.5), pancreas, thymus, small intestine, liver, stomach, kidney, lung, and female breast. Excess incidence of pancreatic NET was highest among those with FPC (especially NET) of the pancreas, bladder, thymus, and female breast; those who received radiotherapy/chemotherapy for bladder, melanoma, and stomach cancers; and those who received chemotherapy for uterine, cervical, prostate, and other genital cancers. Time to diagnosis was shortest after pancreatic, liver, lung, and stomach cancer., Conclusions: Cancer survivors have increased risk and excess incidence of primary pancreatic NET compared with the population, particularly for certain primary sites. High-risk patients should receive regular follow-up screenings, counseling to reduce carcinogen exposure, and lifestyle interventions.

Our group observed the first case of synchronous gastric neuroendocrine tumor (NET) and duodenal gastrinoma with autoimmune chronic atrophic gastritis (CAG), in the absence of Helicobacter pylori infection. Demographic, clinical, endoscopic, and pathologic data were abstracted from the electronic medical record at Mount Sinai Hospital from 2013 to 2015. The patient's anonymity was carefully protected, and informed consent was obtained for publication of protected health information. A 53-year-old woman with hypertension presented to Mount Sinai Hospital in June 2013 for a second opinion for management of gastric and duodenal NETs. After evaluation by gastroenterology and surgery, repeat upper endoscopy with ultrasound and fine-needle aspiration revealed multiple diminutive type I gastric NETs and 2 duodenal NETs, against a background of autoimmune CAG, with biopsy pathology negative for H. pylori. She subsequently underwent a transduodenal resection of the duodenal NETs, confirming low-grade, gastrin-positive, stage T2 duodenal NET. On routine follow-up over the next 2 years, clinical, radiographic, and endoscopic surveillance revealed no recurrent or metastatic gastric or duodenal disease. This first report of synchronous duodenal gastrinoma and gastric NET in the setting of autoimmune CAG can broaden our understanding of gastric NET pathophysiology.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can be challenging to evaluate histologically. MicroRNAs (miRNAs) are small RNA molecules that often are excellent biomarkers due to their abundance, cell-type and disease stage specificity and stability. To evaluate miRNAs as adjunct tissue markers for classifying and grading well-differentiated GEP-NETs, we generated and compared miRNA expression profiles from four pathological types of GEP-NETs. Using quantitative barcoded small RNA sequencing and state-of-the-art sequence annotation, we generated comprehensive miRNA expression profiles from archived pancreatic, ileal, appendiceal and rectal NETs. Following data preprocessing, we randomly assigned sample profiles to discovery (80%) and validation (20%) sets prior to data mining using machine-learning techniques. High expression analyses indicated that miR-375 was the most abundant individual miRNA and miRNA cistron in all samples. Leveraging prior knowledge that GEP-NET behavior is influenced by embryonic derivation, we developed a dual-layer hierarchical classifier for differentiating GEP-NET types. In the first layer, our classifier discriminated midgut (ileum, appendix) from non-midgut (rectum, pancreas) NETs based on miR-615 and -92b expression. In the second layer, our classifier discriminated ileal from appendiceal NETs based on miR-125b, -192 and -149 expression, and rectal from pancreatic NETs based on miR-429 and -487b expression. Our classifier achieved overall accuracies of 98.5% and 94.4% in discovery and validation sets, respectively. We also found provisional evidence that low- and intermediate-grade pancreatic NETs can be discriminated based on miR-328 expression. GEP-NETs can be reliably classified and potentially graded using a limited panel of miRNA markers, complementing morphological and immunohistochemistry-based approaches to histologic evaluation.

There is no consensus on optimal follow-up for completely resected gastroenteropancreatic neuroendocrine tumors. Published guidelines for follow-up are complex and emphasize closer surveillance in the first 3 years after resection. Neuroendocrine tumors have a different pattern and timescale of recurrence, and thus require more practical and tailored follow-up. The Commonwealth Neuroendocrine Tumour Collaboration convened an international multidisciplinary expert panel, in collaboration with the North American Neuroendocrine Tumor Society, to create patient-centered follow-up recommendations for completely resected gastroenteropancreatic neuroendocrine tumors. This panel used the RAND/UCLA (University of California, Los Angeles) Appropriateness Method to generate recommendations. A large international survey was conducted outlining current the surveillance practice of neuroendocrine tumor practitioners and shortcomings of the current guidelines. A systematic review of available data to date was supplemented by recurrence data from 2 large patient series. The resultant guidelines suggest follow-up for at least 10 years for fully resected small-bowel and pancreatic neuroendocrine tumors and also identify clinical situations in which no follow-up is required. These recommendations stratify follow-up strategies based on evidence-based prognostic factors that allow for a more individualized patient-centered approach to this complex and heterogeneous malignant neoplasm.

We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.

Objectives: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare but have been increasing in incidence. Limited data on the long-term outcomes of patients with these tumors are available., Methods: In this study, we used population-based data from the National Cancer Institute to assess long-term disease-specific survival (DSS) of patients who have undergone surgery for nonmetastatic disease. All patients with NETs of the stomach, small intestine, colon, rectum, appendix, and pancreas diagnosed between 1988 and 2009 were identified from the Surveillance, Epidemiology and End Results registry. Staging was derived from Surveillance, Epidemiology and End Results data using the European Neuroendocrine Tumor Society guidelines. Cases with incomplete staging data were excluded, along with those with stage IV disease, or those who did not undergo surgical resection., Results: Kaplan-Meier analyses were constructed to determine DSS. Analyses were further stratified according to tumor site, stage at diagnosis, and tumor grade. Overall, 13,348 patients with GEP-NETs meeting the inclusion criteria were identified., Conclusions: There were excellent outcomes for most GEP-NET patients, with a 20-year DSS of greater than 75% across all sites and stages. Pancreatic tumors had the worst outcomes, but DSS remains greater than 50% at 20 years.

Objectives: This study aimed to determine the prognostic use of the extent of lymph node (LN) involvement in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) by analyzing population-based data., Methods: Patients in the Surveillance, Epidemiology, and End Results registry were identified with histologically confirmed, surgically resected GEP-NETs. We divided patients into 3 lymph node ratio (LNR) groups based on the ratio of positive LNs to total LNs examined: 0.2 or less, greater than 0.2 to 0.5, and greater than 0.5. Disease-specific survival was compared according to LNR group., Results: We identified 3133 patients with surgically resected GEP-NETs. Primary sites included the stomach (11% of the total), pancreas (30%), colon (32%), appendix (20%), and rectum (7%). Survival was worse in patients with LNRs of 0.2 or less (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.2-2.0), greater than 0.2 to 0.5 (HR, 2.0; 95% CI, 1.6-2.5), and greater than 0.5 (HR, 3.1; 95% CI, 2.5-3.9) compared with N0 patients. Ten-year disease-specific survival decreased as LNR increased from N0 (81%) to 0.2 or less (69%), greater than 0.2 to 0.5 (55%), and greater than 0.5 (50%). Results were consistent for patients with both low- and high-grade tumors from most primary sites., Conclusions: Degree of LN involvement is a prognostic factor at the most common GEP-NET sites. Higher LNR is associated with decreased survival.

Small bowel neuroendocrine tumors (SBNETs) have been increasing in frequency over the past decades, and are now the most common type of small bowel tumor. Consequently, general surgeons and surgical oncologists are seeing more patients with SBNETs in their practices than ever before. The management of these patients is often complex, owing to their secretion of hormones, frequent presentation with advanced disease, and difficulties with making the diagnosis of SBNETs. Despite these issues, even patients with advanced disease can have long-term survival. There are a number of scenarios which commonly arise in SBNET patients where it is difficult to determine the optimal management from the published data. To address these challenges for clinicians, a consensus conference was held assembling experts in the field to review and discuss the available literature and patterns of practice pertaining to specific management issues. This paper summarizes the important elements from these studies and the recommendations of the group for these questions regarding the management of SBNET patients.

Purpose: Current staging criteria for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), while useful, have limitations. In this study, we used a population-based registry to evaluate the prognostic utility of the current staging systems and assess whether evidence-based modifications can improve survival predictions., Methods: We identified patients with confirmed GEP-NENs from the Surveillance, Epidemiology and End Results registry. We assigned tumour-node-metastasis status according to American Joint Committee on Cancer and European Neuroendocrine Tumor Society criteria. We derived a revised staging classification using Kaplan-Meier methods and Cox regression to assess disease-specific survival and compared the accuracy of potential models based on the Akaike Information Criterion (AIC) and Harrell's C-index. The revised classification was validated in an independent set., Results: We identified 10,268 patients with GEP-NENs. We found that multiple stages, as determined by current criteria, misclassified patients' prognosis. In particular, stage IIIB (T1-4N1) had overlapping survival with stage IIIA (T4N0). A revised system which reclassifies N1 disease into different stages based on T status (T1-2N1, T3N1 and T4N1) had an improved AIC (difference = 38) and C-index (0.86) compared to current staging. These revisions improved predictions in patients with both low and high-grade tumours from all primary sites. Results also were confirmed across all primary sites in the validation set., Conclusion: Current staging guidelines misclassify the prognosis of N1 patients. Our results suggest that a revised system could lead to better prognostication for GEP-NEN patients. Further validation followed by implementation of these revisions may improve treatment selection and design of clinical trials., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: To assess the value of apparent diffusion coefficient (ADC) measured with diffusion-weighted imaging (DWI) and enhancement ratios (ER) measured with contrast-enhanced T1-weighted imaging (CE-T1WI) for the characterization of histopathologic tumor grade of neuroendocrine tumor liver metastases (NETLM)., Materials and Methods: Twenty-two patients with pathology-proven NETLM and pretreatment 1.5 Tesla (T) and 3T MRI including DWI were included in this Institutional Review Board-approved retrospective study. ADC histogram parameters, including mean, minimum (min), skewness, and kurtosis as well as ER, were computed for all lesions. Tumor grading was based on the World Health Organization 2010 classification. Kruskal-Wallis and Mann-Whitney test were used to assess for differences in ADC and ER between different tumor grades. MRI parameters were correlated with pathologic findings using Spearman correlation test. Receiver operating characteristic analysis was performed to determine optimum thresholds for predicting tumor grade., Results: Forty-eight NETLM (mean size 3.5 cm) were analyzed with the following grade distribution: G1 (n = 25), G2 (n = 16), and G3 (n = 7). ADC-mean (×10 -3 mm 2 /s) of G3 tumors (0.87 ± 0.43) was significantly lower than that of G1 (1.47 ± 0.63) and G2 (1.27 ± 0.63; P = 0.042). A weak significant negative correlation was observed between ADC and tumor grade (ADC-mean: r = -0.33, P = 0.02; ADC-min: r = -0.37, P = 0.01) and Ki-67 (ADC-mean: r = -0.31, P = 0.03; ADC-min: r = -0.39, P = 0.007). AUROC, sensitivity and specificity of ADC-mean/ADC-min/ER (measured at the early arterial phase) for differentiation of G3 versus G1-G2 were 0.80/0.76/0.67, 100%/50%/70%, and 68.4%/84.2%/66.6%, respectively., Conclusion: ADC is a promising marker for characterization of histopathologic grade of NETLM. These results should be confirmed in a prospective study. J. Magn. Reson. Imaging 2016;44:1432-1441., (© 2016 International Society for Magnetic Resonance in Medicine.)

Objective: Small intestinal neuroendocrine tumors (SI-NETs) are often detected after they have become metastatic. Using a novel protein array, we identified pathways important in SI-NET metastasis development in surgically resected patients., Methods: Paired primary tumors and liver metastases from 25 patients undergoing surgical resection for metastatic SI-NETs were harvested. Extracted proteins were separated by sodium dodecyl sulfate gel and multiplex immunoblots were performed with 136 antibodies. Significant Analysis of Microarray was used to select for differentially expressed proteins. A tissue microarray was constructed from 27 archived specimens and stained by immunohistochemistry., Results: Comparing primary SI-NETs with matched normal small-bowel mucosa, 9 proteins were upregulated and cyclin E was downregulated. The SI-NET liver metastases demonstrated upregulation of P-ERK and p27 but downregulation of CDK2 and CDC25B. When comparing primary SI-NET with their paired liver metastases, cyclin E demonstrated a significant upregulation in the liver metastasis. Tissue microarray demonstrated higher p38 expression and lower Cdc 25b expression in SI-NETs versus liver metastases and confirmed higher expression of p27 in liver metastases versus normal liver., Conclusions: Few studies have compared protein expression in paired primary and metastatic SI-NETs. Our findings reveal changes in a limited number of proteins, suggesting that these may be targets for therapy.

Islet cell tumors of the pancreas, also known as pancreatic neuroendocrine tumors, constitute less than 5% of pancreatic tumors, and 7% of all neuroendocrine tumors. Most are non-functional, and patients often present with metastatic disease. Functional tumors present with distinct clinical syndromes. Accurate staging is critical as surgery is both the cornerstone of treatment, and the only hope for cure. Medical management involves treating the manifestations of hormonal excess, and using somatastatin analogues when appropriate. Systemic chemotherapy, targeted molecular therapy, and peptide receptor radiotherapy may be used for refractory disease in lieu of or as an adjunct to surgery., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Aim: The incidence of gastric neuroendocrine tumors (NETs) has increased tenfold since the 1970s. Our aim was to describe the clinicopathologic profile, management, and outcomes of type I gastric NETs at The Mount Sinai Hospital., Methods: From existing databases of the Mount Sinai Division of Gastrointestinal Pathology and the Carcinoid Cancer Foundation, we identified 56 patients with type I gastric NETs seen at The Mount Sinai Hospital from 1993 to 2012. We generated a comprehensive dataset encompassing demographic, clinical, endoscopic, and pathologic factors. Survival information was determined from medical records and the Social Security Death Index. Tumor-node-metastasis staging was conducted, and tumors were graded based on mitotic counts and Ki67 index., Results: Median NET size was 3.0 mm; 55.8 % displayed multifocal disease. Stages I, II, III, and IV disease were observed in 83.8, 10.8, 5.4, and 0 %, respectively. Tumors were either low (69.7 %) or intermediate (30.3 %) grade. Furthermore, 3.6 % of patients developed gastric dysplasia, and 5.5 % had gastric adenocarcinoma. Patients underwent endoscopy every 15 months, while 28.6 % underwent polypectomy, 32.7 % somatostatin therapy, and 46.4 % surgical resection. 5- and 10-year disease-specific survival was 100 %., Conclusions: Most patients received annual endoscopic surveillance, with a minority undergoing surgical resection, though outcomes remained excellent independent of therapeutic approach. We identified a very low but real rate of loco-regional spread, despite the generally indolent behavior of type I gastric NETs. Several patients demonstrated concurrent dysplasia or adenocarcinoma, underscoring the efficacy of regular endoscopic management not only for gastric NETs, but also for dysplasia and adenocarcinoma.

Aim: To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors (PNETs) and provide consensus treatment recommendations., Methods: Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs, angiogenesis inhibitors, inhibitors of mammalian target of rapamycin and cytotoxic agents. At this time, there is little data to guide treatment selection and sequence. We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations. Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process. After studying the literature, a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale. Ratings were done both before and after an extended discussion of the evidence. Quantitative measurements of agreement were made and consensus statements developed from the second round ratings., Results: Specialties represented were medical and surgical oncology, interventional radiology, and gastroenterology. Panelists had practiced for a mean of 15.5 years (range: 6-33). Among 202 rated scenarios, disagreement decreased from 13.2% (26 scenarios) before the face-to-face discussion of evidence to 1% (2) after. In the final ratings, 46.5% (94 scenarios) were rated inappropriate, 21.8% (44) were uncertain, and 30.7% (62) were appropriate. Consensus statements from the scenarios included: (1) it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic; (2) it is appropriate to use everolimus, sunitinib, or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors; and (3) beyond first line, these same agents can be used. In patients with uncontrolled secretory symptoms, octreotide LAR doses can be titrated up to 60 mg every 4 wk or up to 40 mg every 3 or 4 wk., Conclusion: Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs.

Background/aims: Current staging guidelines for small intestinal neuroendocrine tumors (SI-NETs) differentiate between the presence (N1) and absence (N0) of lymph node (LN) metastases. However, the prognostic significance of the extent of LN involvement remains unknown. In this study, we used data from a population-based cancer registry to examine whether involvement of a higher number of LNs is associated with worse survival., Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with histologically confirmed, surgically resected SI-NETS diagnosed between 1988 and 2010. Patients were classified into three groups by the LN ratio (number of positive LNs/number of total LNs examined, LNR): ≤0.2, >0.2-0.5, and >0.5. We used the Kaplan-Meier method and Cox models to assess NET cancer-specific survival differences (up to 10 years from diagnosis) according to LNR status., Results: We identified 2,984 surgically resected patients with stage IIIb (N1, M0) SI-NETs with detailed LN data. More than half of the NETs were located in the ileum. A higher LNR was significantly associated with worse NET cancer-specific survival (p < 0.0001). Ten-year NET-specific survival was 85, 77, and 74% for patients in the ≤0.2, >0.2-0.5, and >0.5 LNR groups, respectively. In stratified analyses, higher LNR groups had worse survival only in early tumor (T1, T2) disease (p < 0.0001)., Conclusions: The extent of LN involvement provides independent prognostic information on patients with LN-positive SI-NETs. This information may be used to identify patients at high risk of recurrence and inform decisions about the use of adjuvant therapy., (© 2015 S. Karger AG, Basel.)

Molecular imaging modalities exploit aspects of neuroendocrine tumors (NET) pathophysiology for both diagnostic imaging and therapeutic purposes. The characteristic metabolic pathways of NET determine which tracers are useful for their visualization. In this review, we summarize the diagnostic value of all available molecular imaging studies, present data about their use in daily practice in NET centers globally, and finally make recommendations about the appropriate use of those modalities in specific clinical scenarios. Somatostatin receptor scintigraphy (SRS) continues to have a central role in the diagnostic workup of patients with NET, as it is also widely available. However, and despite the lack of prospective randomized studies, many NET experts predict that Gallium-68 ((68)Ga)-DOTA positron emission tomography (PET) techniques may replace SRS in the future, not only because of their technical advantages, but also because they are superior in patients with small-volume disease, in patients with skeletal metastases, and in those with occult primary tumors. Carbon-11 ((11)C)-5-hydroxy-L-tryptophan (5-HTP) PET and (18)F-dihydroxyphenylalanine ((18)F-DOPA) PET are new molecular imaging techniques of limited availability, and based on retrospective data, their sensitivities seem to be inferior to that of (68)Ga-DOTA PET. Glucagon-like-peptide-1 (GLP-1) receptor imaging seems promising for localization of the primary in benign insulinomas, but is currently available only in a few centers. Fluorine-18 ((18)F)-fluorodeoxyglucose ((18)F-FDG) PET was initially thought to be of limited value in NET, due to their usually slow-growing nature. However, according to subsequent data, (18)F-FDG PET is particularly helpful for visualizing the more aggressive NET, such as poorly differentiated neuroendocrine carcinomas, and well-differentiated tumors with Ki67 values >10%. According to limited data, (18)F-FDG-avid tumor lesions, even in slow-growing NET, may indicate a more aggressive disease course. When a secondary malignancy has already been established or is strongly suspected, combining molecular imaging techniques (e.g. (18)F-FDG PET and (68)Ga-DOTA PET) takes advantage of the diverse avidities of different tumor types to differentiate lesions of different origins. All the above-mentioned molecular imaging studies should always be reviewed and interpreted in a multidisciplinary (tumor board) meeting in combination with the conventional cross-sectional imaging, as the latter remains the imaging of choice for the evaluation of treatment response and disease follow-up., (© 2014 S. Karger AG, Basel)

Purpose: Small intestinal (SI) neuroendocrine tumors (NETs) have heterogeneous outcomes. The NET societies have recently proposed a TNM staging classification. In this study, we used population-based data to assess the validity of the staging system., Patients and Methods: We identified patients with SI-NETS diagnosed between 1988 and 2009 from the Surveillance, Epidemiology, and End Results registry. We used Kaplan-Meier analysis to assess disease-specific survival according to TNM status. Cox models were constructed to evaluate differences in prognosis after controlling for potential confounders., Results: We identified 6,792 patients with SI-NET. Although the current staging system was predictive of prognosis, there was overlap among some groups (stage I/IIA, P = .36; stage IIB/IIIB, P = .70). Additionally, stage IIIB patients had better survival than stage IIIA patients (P < .001). Adjusted analyses showed similar outcomes for T1 versus T2 disease (hazard ratio [HR], 1.02; 95% CI, 0.63 to 1.66). Patients with T3 (HR, 3.60; 95% CI, 2.28 to 5.69) and T4 (HR, 5.50; 95% CI, 3.42 to 8.86) tumors had significantly worse survival than patients with T1 disease. N1 involvement conferred worse survival in T1 (HR, 3.08; 95% CI, 1.75 to 5.44) and T2 disease (HR, 2.73; 95% CI, 1.84 to 4.07) but not in T3 (HR, 0.99; 95% CI, 0.76 to 1.30) or T4 (HR, 0.98; 95% CI, 0.71 to 1.35) disease. A revised classification showed no overlap in survival across groups., Conclusion: Progressively more advanced T status is associated with worse SI-NET prognosis. Regional lymph node involvement is a marker of worse survival only among patients with T1 or T2 status. These results suggest that revisions to the current staging classification may be helpful.

Neuroendocrine tumors are a heterogeneous group of tumors originating in various anatomic locations. The management of this disease poses a significant challenge because of the heterogeneous clinical presentations and varying degrees of aggressiveness. The recent completion of several phase 3 trials, including those evaluating octreotide, sunitinib, and everolimus, demonstrate that rigorous evaluation of novel agents in this disease is possible and can lead to practice-changing outcomes. Nevertheless, there are many aspects to the treatment of neuroendocrine tumors that remain unclear and controversial. The North American Neuroendocrine Tumor Society published a set of consensus guidelines in 2010, which provided an overview for the treatment of patients with these malignancies. Here, we present a set of consensus tables intended to complement these guidelines and serve as a quick, accessible reference for the practicing physician.

Background: Rectal neuroendocrine tumors (NETs) are among the most common NETs. The aim was to validate European Neuroendocrine Tumor Society (ENETS)/North American Neuroendocrine Tumor Society (NANETS) staging and grading systems with regard to clinical outcomes., Methods: A comprehensive database was constructed from existing databases of the Mount Sinai Division of Gastrointestinal Pathology and the Carcinoid Cancer Foundation. Analysis was performed on 141 patients identified with rectal NETs seen at Mount Sinai Hospital between 1972 and 2011., Results: The median age was 52.7 years; 43% were males. Average tumor size was 0.88 cm. NETs <1 cm accounted for 75.6% of the tumors. Stage I, II, III and IV accounted for 79.4, 2.8, 5.0 and 12.8% of the tumors, respectively. G1 tumors accounted for 88.1%, G2 8.3% and G3 3.6%. Of G1 tumors, 94.6% were stage I and 5.4% were stage IV. The median survival time for all 141 patients was 6.8 years (range, 0.8-34.7 years). The overall 5-year survival rate was 84.4%. The 5-year survival rates for patients in stages I-IV were 92.7, 75.0, 42.9 and 33.2%, respectively. The 5-year survival rates for patients with G1-G3 tumors were 87.7, 47.6 and 33.3%, respectively. Univariate analysis of increased survival showed significance for lower stage, lower grade, smaller size, absence of symptoms and endoscopically treated tumors. Multivariate analysis showed that stage alone was statistically significant as the strongest predictor of survival., Conclusion: The results of our study validated ENETS/NANETS guidelines for staging and grading of rectal NETs in the US setting of a tertiary referral center. Staging according to ENETS/NANETS guidelines should be used in the treatment algorithm rather than size alone., (© 2013 S. Karger AG, Basel.)

Background: Pancreatic neuroendocrine tumors (PNETs) represent a group of diseases that pose diagnostic and therapeutic challenges due to their clinical and pathological heterogeneity as well as the limited number of patients available for clinical trials. Over the last couple of decades, a major progress in understanding tumor biology led to the discovery of new potential targets for the medical treatment of these tumors., Discussion: There are numerous novel targeted agents in various stages of preclinical and clinical development that offer considerable promise as monotherapy or combination therapy for PNETs. The question of whether traditional clinical research methods are appropriate for the development of novel, targeted anticancer agents has been the subject of many discussions. Major challenges include identifying a valid target, the most effective agent within a target class, the right subset of population to benefit from the drug, and the most appropriate setting to use the drug. As new agents emerge, oncologists are faced with making clinical decisions sometimes before having a high level of evidence. In this review, we attempt to address some of the management steps involved in treating patients with pancreatic neuroendocrine tumors, particularly well to moderately differentiated tumors. The purpose of this review is to offer a therapeutic sequence including surgery, liver-directed therapy, chemotherapy, and targeted therapy for this disease.

Objectives: Ascites secondary to neuroendocrine tumor metastases may arise from a variety of mechanisms. Our aim was to measure serum and ascitic chromogranin-A (CgA) to help determine whether ascites resulted from intraperitoneal/retroperitoneal disease burden or from other carcinoid complications such as congestive heart failure or portal hypertension., Methods: Patients with metastatic neuroendocrine tumors and ascites were identified. Chromogranin-A was obtained and measured from both serum and ascites. The causes of carcinoid ascites was categorized into 2 groups: high intraperitoneal or retroperitoneal disease burden (ie, peritoneal metastases and/or lymphatic obstruction; n = 12, group 1) or other organ-specific carcinoid complications such as CHF or portal hypertension (n = 12, group 2)., Results: An ascites CgA/serum CgA ratio greater than 1 was more likely to be found in group 1 (P = 0.01). This ratio produced 100% sensitivity and 75% specificity for ascites secondary to peritoneal metastases and/or lymphatic obstruction., Conclusions: An ascites CgA/serum CgA ratio greater than 1 produces excellent accuracy in predicting peritoneal metastases and/or retroperitoneal disease as the cause of ascites in the setting of metastatic carcinoid. This test may play a role in the earlier identification of those patients who may be well served by aggressive management.

Purpose of Review: Endoscopic ultrasound (EUS) is a valuable tool in the diagnosis and management of pancreatic neuroendocrine tumors. This review highlights advances over the last year in EUS in the evaluation of pancreatic neuroendocrine tumors., Recent Findings: We will focus on recent findings regarding the accuracy of EUS, EUS-guided fine needle aspiration (EUS-fine needle aspiration), emerging cytologic markers obtained from fine needle aspiration samples, and the role of EUS screening for patients with multiple endocrine neoplasia type 1 syndrome. Additionally, we will introduce potential therapeutic EUS interventions in the treatment of pancreatic neuroendocrine tumors., Summary: The present review highlights recent advances in the utility of EUS in the clinical management of pancreatic neuroendocrine tumors. Key studies from the last year demonstrate the important role of EUS in the diagnosis, prognosis, and treatment of pancreatic neuroendocrine tumors.

Small bowel neuroendocrine tumors (NETs) represent approximately one-third of NETs of the gastrointestinal tract, and their incidence is increasing. When determining if endoscopic resection is appropriate, endoscopic ultrasound is used to assess the lesion size and depth of invasion for duodenal NETs. A number of techniques, including endoscopic mucosal resection (EMR), bandassisted EMR (band-EMR), endoscopic submucosal dissection (ESD), and over-the-scope clip-assisted endoscopic full-thickness resection (EFTR), have been studied; however, the best technique for endoscopic resection remains unclear. The vast majority of currently available data are retrospective, and prospective studies with longer follow-up times are required. For jejunal and ileal NETs, endoscopic techniques such as video capsule endoscopy (VCE) and balloon enteroscopy (BE) assist in diagnosis. This includes localization of the primary NET in metastatic disease where initial workup has been negative, and the identification of multifocal disease, which may change management and prognostication. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine tumors (PNETs) are relatively rare; however, the incidence has increased over the last few decades. They are classified as functional or non-functional tumors according to the presence of associated clinical symptoms. The majority are nonfunctional tumors. For classification and staging, the World Health Organization 2010 classification system is the most commonly accepted. Chromogranin A is the most sensitive marker but has insufficient specificity. In general, PNETs are hypervascular tumors, and multiphasic contrast-enhanced computed tomography is considered the first choice for imaging study. Multiphasic magnetic resonance imaging can detect PNETs smaller than 2 cm and small liver metastasis compared with other modalities. Somatostatin receptor scintigraphy is often used in cases where functional PNETs are suspected. Positron emission tomography (PET) scan with 18F-fluorodeoxyglucose cannot visualize PNETs, but PET with 68-Ga DOTATATE can. Endoscopic ultrasonography can characterize smaller PNETs using contrast and confirm histology through fine needle aspiration or biopsy. In this article, we review the characteristics of grading systems and diagnostic modalities commonly used for PNETs. [ABSTRACT FROM AUTHOR]

Endoscopic ultrasound (EUS) is an advanced endoscopic technique currently used in the staging and diagnosis of many gastrointestinal neoplasms. The proximity of the echoendoscope to the gastrointestinal tract lends itself to a detailed view of the luminal pathology and the pancreas. This unique ability enables endoscopists to use EUS in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Diagnostic EUS allows previously unidentified NETs to be localized. EUS also determines tumor management by staging the GEP-NETS, enabling the clinicians to choose the appropriate endoscopic or surgical management. The ability to obtain a tissue diagnosis with EUS guidance enables disease confirmation. Finally, recent developments suggest that EUS may be used to deliver therapeutic agents for the treatment of NETs. This review will highlight the advances in our knowledge of EUS in the clinical management of these tumors. [ABSTRACT FROM AUTHOR]