European Neuroendocrine Tumor Society Guidelines Research Articles

Systemic Therapy for Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PanNETs) account for approximately 2% of all pancreatic malignancies. Several systemic treatment options have been developed over the last four decades, ranging from cytotoxic chemotherapy and octreotide to newer targeted therapies like sunitinib, cabozantinib, and lenvatinib. Although surgery or liver-directed therapy remains cornerstone for management of metastatic PanNETs, however, they remain unfeasible in majority of cases. PanNETs behave differently than SI-NETs (small intestinal NET); the former is more aggressive and less responsive to somatostatin-based therapies. The optimal sequence of the systemic therapies for the advanced PanNETs depends mainly on the tumor burden, Ki-67 index, and the tempo of the disease. In the end, drawing from ENETS (European Neuroendocrine Tumor Society) and ESMO (European Society for Medical Oncology) guidelines, we propose a working algorithm for the management of advanced PanNETs, not amenable to surgery or liver-directed therapies.

A metastatic G2 neuroendocrine tumor smaller than 5 mm: A case report

BackgroundNeuroendocrine tumors (NETs) measuring <10 mm are widely thought to be at low risk of lymph node metastasis. Here we report a case of lymph node metastasis in a patient with a 4-mm NET that was classified as grade 2.Presentation of caseA 32-year-old woman was referred to our hospital after a positive fecal occult blood test. Colonoscopy revealed a 4-mm yellowish submucosal tumor, which was diagnosed as NET of the upper rectum and removed by endoscopic submucosal resection with ligation. Pathological examination of the specimen showed a 4-mm grade 2 NET with a Ki-67 labeling index of 4.4% without lymphatic or venous invasion. In accordance with the European Neuroendocrine Tumor Society guidelines, we performed robotic-assisted laparoscopic low anterior resection with lymph node dissection. Final pathological examination revealed invasion confined to the submucosal layer and metastasis to one lymph node (pT1aN1M0, Stage IIIB). There were no residual tumor cells in the scar after endoscopic submucosal resection with ligation.DiscussionShould G2 neuroendocrine tumors smaller than 5 mm be surgically resected?ConclusionsWe encountered a rare case of a small NET with lymph node metastasis that was treated by robotic-assisted laparoscopic low anterior resection with lymph node dissection. Additional surgery is an option to be considered for grade 2 NET even if it is small because of the possibility of lymph node metastasis.

Enhanced computed tomography features predict pancreatic neuroendocrine neoplasm with Ki-67 index less than 5%

BackgroundSeveral studies have suggested that patients with pancreatic neuroendocrine neoplasm (pNEN) with the Ki-67 index of < 5% are more likely to show better prognosis after clinical intervention. Moreover, the Ki-67 index at 5% has also been suggested as a potential threshold by the 2016 European Neuroendocrine Tumor Society guidelines. ObjectiveBased on preoperative enhanced computed tomography (CT), this study aimed to investigate imaging characteristics eligible to discriminate the ≤ 5% Ki-67 group from the > 5% Ki-67 group of patients with nonmetastatic pNEN. MethodsPatients with pathologically diagnosed pNEN and preoperative multiphase CT were enrolled. Their Ki-67 index was calculated and grouped according to the 5% cutoff value. The following CT imaging characteristics and some serum biomarkers were assessed between the two groups: the diameter, location, tumor margin, calcification, pancreatic atrophy, distal pancreatic duct dilation, vessel involvement, and enhancement pattern characteristics of both arterial phase (AP) and portal vein phase (PVP). ResultsA total of 142 patients with pNEN were enrolled in this study, comprising 104 in the low (Ki-67, 1%–5%) and 38 in the high index group (Ki-67, >5%). Alpha fetoprotein and cancer antigen 125 were significantly different between the two groups (P-values, 0.030 and 0.049, respectively). The diameter (P < 0.0001), margin (P = 0.003), distal main ductal dilation (P = 0.021), vessel involvement (P = 0.002), AP hypoenhancement (P < 0.0001), PVP hypoenhancement (P = 0.003), AP ratio (P = 0.0001), and PVP ratio (P = 0.0003) were significantly different between the low and high index groups. The area under the curve of the multivariate logistic regression model was 0.853. ConclusionNonmetastatic pNENs with larger diameter, ill-defined margin, distal main ductal dilation, and tumor hypoenhancement in AP in preoperative enhanced CT tend to have a Ki-67 index of > 5%.The results of this study provide an alternative method to clinicians to decide whether surgery is appropriate.

Quality of pathology reporting and adherence to guidelines in rectal neuroendocrine neoplasms: a Belgian national study

ABSTRACT The incidence of neuroendocrine neoplasms (NEN) in the rectum is rising since the introduction of colonoscopy screening programs. Guidelines, such as the European NeuroEndocrine Tumor Society (ENETS) algorithm, are mainly based on expert opinion. The goal of this nationwide study is to gain a better insight into the evolution in pathology reporting and adherence to the ENETS guidelines in Belgium. In Belgium, all NENs have to be reported to the Belgian Cancer Registry. We thoroughly reviewed all available pathology reports, coded as rectal NEN between 2004 and 2015, and reclassified according to World Health Organisation (WHO) classification 2019. To evaluate the adherence to the ENETS guidelines, population-based cancer registry data were linked with the medical procedures of the Belgian Health Insurance database. A total of 670 rectal NEN were retained and 16% of the cases needed reclassification. Annual incidence between 2004 and 2015 tripled from 0,20 to 0,61 per 100.000 inhabitants. Reporting of Ki67 proliferation index ameliorated most, while reporting of tumor size, lymphovascular and perineural invasion remained disappointing. Endoscopic ultrasound was performed in only 36.6% of the cases, while the mostly recommended mode of treatment (endoscopic/surgical/no resection) was followed in the majority of the cases. Incidence of rectal NEN in Belgium increased throughout the years and quality of pathology reporting improved especially after the WHO classification update in 2010. The growing awareness and knowledge among clinicians and pathologists in the community counters the need for centralization.

Glucagon-like Peptide-1 Receptor as Emerging Target: Will It Make It to the Clinic?

The glucagon-like peptide-1 receptor (GLP-1R) is an emerging target due to its high expression in benign insulinomas as well as in islet cell hypertrophia/hyperplasia (nesidioblastosis) and pancreatic β-cells. In 2008, occult insulinomas were localized for the first time in men using the metabolically stable radiolabeled glucagon-like peptide-1 (GLP-1) agonist [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 (111In-DTPA-exendin-4). Afterward, several radiopharmaceuticals for GLP-1R PET/CT imaging were synthesized and evaluated, for example, [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]-exendin-4 (68Ga-DOTA-exendin-4), [Cys40(MAL-NOTA-68Ga)NH2]-exendin-4 (68Ga-NOTA-exendin-4), and [Lys40(NODAGA-68Ga)NH2]-exendin-4 (68Ga-NODAGA-exendin-4). Several prospective comparison studies provided evidence that GLP-1R PET/CT is significantly more sensitive than contrast-enhanced MRI (ceMRI), contrast-enhanced CT (ceCT), GLP-1R SPECT/CT, somatostatin receptor PET/CT, and SPECT/CT in the detection of benign insulinomas, and insulinomas in the context of multiple endocrine neoplasia type 1. As a result, the European Neuroendocrine Tumor Society guidelines recommend GLP-1R imaging or selective intraarterial calcium stimulation and venous sampling (ASVS) in patients for whom there is a clinical suspicion of having an insulinoma but who have a negative ceMRI/ceCT or negative endoscopic ultrasound. Furthermore, there is growing evidence that GLP-1R PET/CT can visualize and localize adult nesidioblastosis. This is clinically relevant as the distinction between focal and diffuse nesidioblastosis is critical in directing a therapeutic strategy in these patients. Prospective studies have proven the clinical relevance of GLP-1R imaging as it is often the only imaging modality able to localize the insulinoma or nesidioblastosis. It is therefore likely that this noninvasive imaging modality will replace the invasive localization of insulinomas using ASVS. More experimental indications for GLP-1R imaging include the diagnosis of an insulinoma/nesidioblastosis in patients with postprandial hypoglycemia after bariatric bypass surgery and monitoring β-cells in patients with brittle type 1 diabetes after islet-cell transplantation. We believe that these indications and possibly future indications will bring GLP-1R imaging to the clinic.

Advanced small-bowel well-differentiated neuroendocrine tumours: An international survey of practice on 3rd-line treatment.

BACKGROUNDSomatostatin analogues are an established first-line therapy for well differentiated small bowel neuroendocrine tumours (Wd-SBNETs), while and peptide receptor radionuclide therapy (PRRT) is frequently used as a second-line therapy. Adequate treatment selection of third-line treatment remains challenging due to the limited prospective data currently available on the best therapeutic sequence. AIMTo understand current practice and rationale for decision-making by physicians in the 3rd-line setting by building an online survey. METHODSWeighted average (WA) of likelihood of usage between responders (1 very unlikely; 4 very likely) was used to reflect the relevance of factors explored.RESULTSReplies from representatives of 28 centers were received (5/8/2020-21/9/2020); medical oncologist (53.6%), gastroenterologist (17.9%); United Kingdom (21.4%), Spain (17.9%), Italy (14.3%). Majority from European Neuroendocrine Tumor Society (ENETS) Centres of Excellence (57.1%), who followed ENETS guidelines (82.1%). Generally speaking, 3rd-line treatment for Wd-SBNETs was: everolimus (EVE) (66.7%), PRRT (18.5%), liver embolization (LE) (7.4%) and interferon-alpha (IFN) (3.7%); chemotherapy (0%); decision was based on clinical trial data (59.3%), or personal experience (22.2%). EVE was most likely used if Ki-67 < 10% (WA 3.27/4) or age < 70 years (WA 3.23/4), in the 3rd-line setting (WA 3.23/4); regardless of presence/absence of carcinoid syndrome (CS), rate of progression or extent of disease. Chemotherapy was mainly utilised only if rapid progression (within 6 mo) (WA 3.35/4), Ki-67 10%-20% (WA 2.77/4), negative somatostatin receptor imaging (WA 2.65/4) or high tumour burden (WA 2.77/4); temozolomide or streptozocin was used with capecitabine or 5-fluorouracil (5-FU) (57.7%), FOLFOX (5-FU combined with oxaliplatin) (23.1%). LE was selected if presence of CS (WA 3.24/4) or Ki-67 < 10% (WA 2.8/4), after progression to other treatments (WA 2.8/4). IFN was rarely used (WA 1.3/4).CONCLUSIONEverolimus was the most frequently used therapeutic option in the third-line setting. The most important factors for decision-making included Ki-67, rate of progression, functionality and tumour burden; since this decision is based on multiple factors, it highlights the need for a multidisciplinary assessment.

Impact of margin status on outcomes after endoscopic resection of well-differentiated duodenal neuroendocrine tumors

Duodenal neuroendocrine tumors (DNETs) are known to have low metastatic potential and follow an indolent course. Although DNETs<1 cm in size are amenable to endoscopic resection, little is known about the long-term outcomes and recurrence rates of this approach. Sixty-three patients with DNETs from 3 centers were retrospectively studied from 2003 to 2018. We analyzed their resection modality (EMR, snare polypectomy, or forceps polypectomy), margin status, risk factors for recurrence, recurrence rate, and endoscopic surveillance patterns. Of the 63 patients who underwent endoscopic resection, 13 (20.6%) had recurrence. The presence of R1 margins was found to be a statistically significant risk factor for recurrence (P= .048). Mean surveillance time for all DNETs was 2.8 ± 2.6 years. Ninety-two percent of recurrences were detected within 3 years of resection. Our data suggest that the main predictor of recurrence in low-grade DNETs<1.0 cm is the presence of positive tumor margins at the initial endoscopic resection. More frequent, earlier surveillance after resection than that currently recommended by European Neuroendocrine Tumor Society guidelines may be warranted to promptly capture DNET recurrences. Additionally, no recurrences occurred in our cohort after 4 years of surveillance.

Diagnostic Role and Therapeutic Perspectives of Endoscopic Ultrasound for Pancreatic Neuroendocrine Tumor

Pancreatic neuroendocrine tumors (PNETs) are rare tumors with malignant potential, but their incidence has appreciably increased over the last few decades. Diagnosis of PNETs is often difficult with conventional imaging methods. Cross-sectional imaging localizes less than 10% of PNETs less than 1 cm in diameter. Endoscopic ultrasound (EUS) has been shown to be superior to other imaging techniques in the preoperative localization and diagnosis of PNETs. The finding of a hyperenhanced lesion on contrastenhanced EUS was highly predictive of PNETs different from adenocarcinoma. Preoperative assessment of tumor differentiation and Ki-67 is an important prognostic factor for grading. Thus, EUS-guided fine needle biopsy may play a key role in the work-up of nonfunctioning PNETs, and attempts to measure Ki-67 on cytologic and histologic samples have been made. According to the European Neuroendocrine Tumor Society guidelines, there is no clear evidence of a survival benefit of surgery for nonfunctioning G1 PNETs &lt;2 cm in diameter. The benefits of curative surgery must be weighed against operative morbidity and mortality. Although surgical resection remains the mainstay for PNETs, EUS-guided ablation offers a relatively safe and effective treatment option in patients deemed unfit for, or who do not want to undergo, surgery. EUS-guided ablation provides an attractive therapeutic nonsurgical option for patients; however, further studies that better elucidate the long-term outcomes with standardization of technique will help define its role in the treatment of PNETs. The role of EUS in the diagnosis and treatment of PNETs is expected to make much progress in the future.

Comparison of Manual and Digital Assessment of KI-67 in Neuroendocrine Tumors

Abstract Introduction/Objective Proliferative activity is an essential prognostic and treatment indicator for neuroendocrine tumors (NET). Ki-67 proliferation index, if reported by unaided microscopic estimation on hot-spot locations could lead to variability and inconsistencies. This study aims to compare the Ki-67 assessment of NETs by visual estimation versus automated digital image analysis (Roche iCoreo/Virtuoso). Methods 212 patients with Ki-67-graded GI NETs (117 G1; 61 G2; 34 G3) from 2010 to 2019 were reassessed using digital image analysis quantification of hot spot areas of at least 500 cells (average 800 cells). Revised tumor grades were assigned according to the European Neuroendocrine Tumor Society guidelines and the 2010 World Health Organization classification and compared to initially reported grade. Results We found 75% concordance for G1, with 22% of cases upgraded to G2 and 3% of cases upgraded to G3. For G2, there was 70.5% agreement, with 13.1% of cases downgraded to G1 and 16.4% upgraded to G3. For G3, there was 100% agreement, (kappa=0.64, overall). Retrospective review of discordant G3 cases revealed cases with known metastasis, small fragments of tissue, or polyps. Scanning and scoring required approximately 10 minutes per case. Conclusion Our data shows the time/effort difference of visually estimating versus automated digital analysis may lead to significant classification errors in these tumors. Although digital analysis has limitations, including tumor heterogeneity, misidentification of tumor cells, and poor immunostaining which could require manual counting by a pathologist, this rigor should be reinforced and explicitly stated to increase accuracy and reproducibility of grading.

Surgery with Radical Intent: Is There an Indication for G3 Neuroendocrine Neoplasms?

While platinum-based chemotherapy represents the standard treatment for advanced grade 3 (G3) neuroendocrine neoplasms (NENs) according to the European Neuroendocrine Tumor Society guidelines, the role of radical-intended surgery in these patients, as well as the use of adjuvant chemotherapy, are still controversial. The aim of the present work is to describe, in a retrospective series of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) G3, the overall survival (OS) rate and risk factors for death after radical surgery. Secondary aims are the description of median recurrence-free survival (RFS) and of the role of adjuvant chemotherapy. Multicenter analysis of a series of stage I-III GEP-NEN G3 patients receiving radical surgery (R0/R1) with/without adjuvant chemotherapy was performed. Sixty patients from eight neuroendocrine tumor (NET) referral centers, with median follow-up of 23months (5-187months) were evaluated. While 28.6% of cases had NET G3, 71.4% had neuroendocrine carcinoma G3 (NEC G3). The 2-year OS rate after radical surgery was 64.5%, with a statistically significant difference in terms of Ki67 threshold (cut-off 55%, P = 0.03) and tumor differentiation (NEC G3 vs. NET G3, P = 0.03). Median RFS after radical surgery was 14months, and 2-year RFS rate was 44.9%. Use of adjuvant chemotherapy provided no benefit in terms of either OS or RFS in this series. Surgery with radical intent might represent a valid option for GEP-NEN G3 patients with locoregional disease, especially with Ki67 value ≤ 55%.

1653 Large Cell Neuroendocrine Carcinoma of the Colon

INTRODUCTION: Neuroendocrine carcinomas heterogeneous group of tumors with variable clinical presentation and prognosis. Gastrointestinal neuroendocrine carcinomas are further divided into two types; small cell or large cell based on mitotic rate and or Ki-67 labeling by WHO or European Neuroendocrine Tumor Society guidelines. Large cell neuroendocrine carcinomas (LNEC) of primary colorectal origin are extremely rare and represent 0.25% of all colorectal cancers. LNEC are malignant and aggressive tumors which present in an advanced stage and median overall survival time is 4–16 months. LNEC can occur within the entire gastrointestinal tract and or biliary tract but are typically found within the colon, stomach and or rectum. Here, we report LNEC to highlight its clinical course and to expand clinician knowledge regarding this rare cancer. CASE DESCRIPTION/METHODS: 82-year-old male who initially presented to his primary care doctors office with 4-month history of 20-pound unintentional weight loss with associated vague left lower quadrant abdominal pain. Computed Tomography of the abdomen/pelvis revealed mass-like mucosal thickening measuring approximately 5.9 cm × 6.5 cm involving the distal transverse/proximal descending colon and with innumerable hypodense lesions throughout the liver consistent with diffuse metastatic disease. Colonoscopy revealed circumferential fungating partially obstructing large mass in the within the mid-transverse colon. Histopathologic report from the endoscopic biopsy showed positive staining for pancytokeratin and synaptophysin, which was consistent with a large cell neuroendocrine carcinoma. Patient was evaluated by oncology and has started receiving carboplatin and etoposide chemotherapy for palliative purposes. DISCUSSION: LNEC rare subtype of neuroendocrine carcinomas, which are aggressive and often present in an advanced stage. Early detection and identification is essential as this malignancy has different treatment implications when compared to adenocarcinoma. Interestingly, extrapulmonary neuroendocrine tumors resemble small cell lung cancer where carboplatin and etoposide have established utility due to high mitotic rate. This is the treatment option chosen for our patient. Further studies will need to be done to determine optimal treatment regimens for this rare disease.

Multimodality management, recurrence patterns, and long-term outcome of gastroenteropancreatic neuroendocrine neoplasms: Progress over 17years.

Many advances in the management of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) happened in the last two decades. This study highlights the progress in its management over 17years, outcomes, recurrence patterns, and follow up protocols. This retrospective analysis of prospectively maintained database at a single tertiary center included GEP-NEN patients from January 2001toAugust 2017. Management protocols were based on European Neuroendocrine Tumor Society guidelines. Recurrences were categorized as follows: localized nodal, regional, distant hepatic, or combined. Patients were divided into cohorts: cohort 1 (2001-2006), cohort 2 (2007-2011), and cohort 3 (2012-2017). Survival patterns were analyzed. One hundred andninety-two patients were included with 98 (51.04%) grade (G) 1, 64 (33.34%) G2, and 30 (15.63%) G3. One hundred andfour (54.16%) underwent curative surgery (58G1, 27 G2, and 19 G3). Overall follow up ranged from 3 to 276months; 39 were lost to follow up. Ninety-six patients had recurrences: 44 regional + distant and 40 liver-limited recurrences. One-, 3-, and 5-year survivals show significant differences among different treatment groups (p < 0.05). Significant increase in curative resections, chemotherapy utilization, and reduced recurrences were noted in cohort 3. Curative (R0) resection offered 1- and 3-year overall survival of 93.3% and 66.7% in cohort 1; 95.8% and 83.1% in cohort 2; and 100% and 92.9% in cohort 3. Curative resection is the most significant factor for improved survival. Debulking surgerical procedure have a role whereas upfront peptide receptor radionuclide therapy is questionable. Chemotherapy improves overall survival in inoperable/metastatic setting. Recurrence patterns indicate that a long-term follow up greater than 10years is necessary.

Management of Small Bowel Neuroendocrine Tumors.

Several important landmark trials have reshaped the landscape of non-surgical management of small bowel neuroendocrine tumors over the last few years, with the confirmation of the antitumor effect of somatostatin analogue therapy in PROMID and CLARINET trials as well as the advent of therapies with significant potential such as mammalian target of rapamycin inhibitor (mTor) everolimus (RADIANT trials) and peptide receptor radionuclide therapy (PRRT) with 177-Lutetium (NETTER-1 trial). This narrative summarizes the recommended management strategies of small bowel neuroendocrine tumors. We review the main evidence behind each recommendation as well as compare and contrast four major guidelines, namely the 2016 Canadian Consensus guidelines, the 2017 North American Neuroendocrine Tumor Society guidelines, the 2018 National Comprehensive Cancer Network guidelines, and the 2016 European Neuroendocrine Tumor Society guidelines. Different clinical situations will be addressed, from loco-regional therapy to metastatic unresectable disease. Carcinoid syndrome, which is mostly managed by somatostatin analogue therapy and the serotonin antagonist telotristat etiprate for refractory diarrhea, as well as neuroendocrine carcinoma will be reviewed. However, several questions remain unanswered, such as the optimal management of neuroendocrine carcinomas or the effect of combining and sequencing of the aforementioned modalities where more randomized controlled trials are needed.

Current Management and Predictive Factors of Lymph Node Metastasis of Appendix Neuroendocrine Tumors: A National Study from the French Group of Endocrine Tumors (GTE).

The primary endpoint was to analyze the predictive factors of lymph node involvement (LN+). Indications for additional right hemicolectomy (RHC) with lymph node (LN) resection after appendectomy for appendix neuroendocrine tumor (A-NET) remain controversial, especially for tumors between 1 and 2 cm in size. National study including all patients with nonmetastatic A-NET diagnosed after January, 2010 in France. In all, 403 patients were included. A-NETs were: within tip (67%), body (24%) or base (9%) of the appendix; tumor size was < 1 cm (62%), 1 to 2 cm (30%), or >2 cm (8%); grade 1 (91%); mesoappendix involvement 3 mm (5%); lymphovascular (15%) or perineural (24%) invasion; and positive resection margin (8%). According to the European NeuroEndocrine Tumor Society (ENETS) recommendations, 85 patients (21%) should have undergone RHC. The agreement between ENETS guidelines and the multidisciplinary tumor board for complementary RHC was 89%. In all, 100 (25%) patients underwent RHC with LN resection, 26 of whom had LN+. Tumor size (best cut-off at 1.95 cm), lymphovascular and perineural invasion, and pT classifications were associated with LN+. Among the 44 patients who underwent RHC for a tumor of 1 to 2 cm in size, 8 (18%) had LN+. No predictive factor of LN+ (base, resection margins, grade, mesoappendix, lymphovascular, perineural involvement) was found in this subgroup of patients. In the largest study using the latest pathological criteria for completion RHC in A-NET, a quarter of patients had residual tumor. Further studies are warranted to demonstrate the survival impact of RHC in this setting.

Neuroendocrine tumor of the appendix: Twelve years of results from a single institution.

The aim of this study was to investigate the incidence of appendiceal neuroendocrine tumors (NET) in an acute appendicitis cohort, as well as to investigate the behavioral form of the tumor. Our secondary aim was to investigate survival in patients with appendiceal NET. Between February 2006 and June 2018, 6518 appendectomies were performed for acute appendicitis in the department of surgery, University of Health Sciences, Okmeydanı Education and Research Hospital, İstanbul, Turkey. The medical records of these consecutive 6518 appendectomy patients were evaluated retrospectively. After the histopathological analysis, a total of 22 patients were identified as cases of appendiceal NET. These patients were included in the study. A retrospective analysis of data including gender, age, intraoperative surgical findings, duration of postoperative follow-up and survival, tumor localization, the diameter of the tumor, tumor grade, invasion, surgical margin, and stage of the tumor was performed. The incidence of appendiceal NET was 0.33%. Eleven patients were diagnosed as primary pathological stage pT1aN0M0 according to the European Neuroendocrine Tumor Society guidelines. One patient was diagnosed as primary pathological stage pT1bN0M0, and 10 patients were diagnosed as primary pathological stage pT2N0M0. The median tumor diameter was 7.6 mm. There was no patient with a tumor diameter greater than 20 mm. The incidence of appendiceal NET in our study is consistent with that stated in the literature. The results of our research suggest that further surgical procedures for NETs that occur coincidentally in patients of the AA cohort are often unnecessary. In addition, the study revealed that disease-free survival (100%) was good over a mean follow-up of 59.2 months.

2017 ENETS consensus guidelines: update for the standard of care of pancreatic neuroendocrine tumors

Neuroendocrine tumors(NET) is a rare tumor with high heterogeneity.Pancreatic NET is the most common type in China. European Neuroendocrine Tumor Society(ENETS) has launched the ENETS guidelines since 2006 and published the ENETS standard of care in 2009. With the newly targeted therapies and further research on NET, 2017 new edition of the ENETS standard of care has changed a lot in the diagnosis and treatment of NET. This article explains the update of pancreatic NET in the 2017 edition of the ENETS standard of care, and introduces pancreatic NET from pathology, imaging examination, surgery, systemic therapy, etc., and deepens the understanding of the diagnosis and treatment of pancreatic NET.

Long-term Outcomes of Gastroenteropancreatic Neuroendocrine Tumors.

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. 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. 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. 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.

Sporadic Small (≤20 mm) Nonfunctioning Pancreatic Neuroendocrine Neoplasm: is the Risk of Malignancy Negligible When Adopting a More Conservative Strategy? A Systematic Review and Meta-analysis

The management of small (≤20mm), nonfunctioning pancreatic neuroendocrine neoplasms (pNENs) remains under debate. The European Neuroendocrine Tumor Society guidelines advocate the possibility of a conservative approach. A systematic literature search was conducted to identify all studies comparing the risk of malignancy in small pNENs with respect to large ones (>20mm). Malignancy was defined based on the presence of nodal metastases. Distant metastases, tumor grading (G2-3), vascular microscopic invasion, stage III-IV, and overall and disease-free survival also were evaluated. The data were reported in two ways: using the risk difference (RD) and the likelihood of being helped or harmed (LHH). The search identified only 6 eligible studies with an overall population of 1697 resected pNENs: 382 (22.5%) small and 1315 (77.5%) large. The RD of lymph nodal metastases was -0.26 (95% confidence interval (CI): -0.31 to -0.22; P<0.001). The LHH was 0.34, suggesting that the risk of leaving a malignancy during follow-up due to the adoption of a conservative strategy was three times higher than the benefits. The risk difference of distant metastases, G3 lesions, G2-G3 lesions, stage III/IV, microscopic vascular invasion, death, and recurrence of the disease were lower in small NF-PNETs than large ones. The related LHH values suggested that a watch-and-wait policy never provided a benefit. Even if the malignancy rate in sporadic, small pancreatic neuroendocrine neoplasms was lower than in large ones, this difference did not justify a watch-and-wait policy.

May we challenge the ENETS guidelines in pancreatic neuroendocrine neoplasms? A quiz for French experts

IntroductionRecent guidelines have been published by a consensus of international experts (2016 ENETS (European NeuroEndocrine Tumor Society) guidelines). Nevertheless, in case of pancreatic neuroendocrine neoplasms (panNEN) the ENETS guidelines fail to propose a unique strategy in some situations, due to the lack of high-level of evidence and the absence of formal agreement between the experts drawing up the guidelines. Material and methodsA survey of 25 questions on panNEN was sent to 104 French experts challenging the guidelines. Questions focused on clinical situations in localized G-1/2 panNEN, localized G-3 panNEN, metastatic G-1/2 panNEN, and metastatic G-3 panNEN for which multiple options were proposed by the ENETS guidelines. ResultsFifty-seven experts (55%) have answered the survey. 18/25 questions obtained at least 50% similar responses, allowing a “consensus” or a “position statement”. Among the results, surgery of small panNEN is preferred to surveillance in young patients; the temozolomide–capecitabine combination is favored instead of streptozotocin-based chemotherapy for G-1/2 metastatic panNEN. ConclusionFrench experts are mostly in line with the European guidelines, but some differences do exist. Whilst waiting for prospective studies, this survey helps physicians to propose standardized procedures and identifies situations where a step forward has been enabled by French experts. This questionnaire paves the way for a simplified therapeutic algorithm of panNEN.

ENETS 2016 Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: An Update

The participants at the conference were asked to focus on the relevant literature published between 2011 and 2015. They met over two and a half days, in which data and new evidence were presented. The participants then retreated to break-out sessions according to their disciplines and were required to answer questions listed in a workbook created by the session chairs and the organizing committee. The workbook questions were tailored on the text of the initial guidelines framework [2, 4] , focusing on the new available evidence. All relevant areas were updated via a thorough literature review and the questions that the chairpersons considered appropriate to discuss the new evidence. All participants were encouraged to challenge the document. Recent data on new evidence and insights were intensely discussed in working-group sessions as well as during the plenary session. Notes were taken continuously, so that the final agreement on each question was noted and returned to each session chair for preparation of the consensus statements. The magnitude of the consensus for each answer was estimated to achieve unanimity. In addition to providing textual guidelines, delegates were requested to elaborate accurate but simple Several guidelines and standards of care on the management of neuroendocrine tumors (NETs) have been published by expert national and international groups in recent years [1–9] ; additional changes in how these patients are managed are evolving rapidly, and since the last European Neuroendocrine Tumor Society (ENETS) Guidelines in 2011/12 [8] , new important data have become available pertaining to novel diagnostic tools and therapies. On October 30th and 31st, 2014, the ENETS held an Advisory Board meeting in Vienna aiming at critically discussing and updating the ENETS Guidelines on the Diagnosis and Treatment of Neuroendocrine Tumors generated initially in 2005–2006 [2, 4] and revised in 2011 [8] . The consensus sessions covered the following neuroendocrine neoplasm-related topics by sites of origin or stage: gastroduodenal, midgut (including appendix), hindgut, functional pancreatic, non-functional pancreatic, and two final sessions that covered liver and other distant metastases from neuroendocrine neoplasms of any origin and a separate session devoted to neuroendocrine high-grade tumors and carcinomas. Published online: January 6, 2016