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Appendiceal neuroendocrine neoplasms (ANEN) are mostly discovered coincidentally during appendicectomy and usually have a benign clinical course; thus, appendicectomy alone is considered curative. However, in some cases, a malignant potential is suspected, and therefore additional operations such as completion right hemicolectomy are considered. The existing European Neuroendocrine Tumour Society (ENETS) guidelines provide useful data about epidemiology and prognosis, as well as practical recommendations with regards to the risk factors for a more aggressive disease course and the indications for a secondary operation. However, these guidelines are based on heterogeneous and retrospective studies. Therefore, the evidence does not seem to be robust, and there are still unmet needs in terms of accurate epidemiology and overall prognosis, optimal diagnostic and follow-up strategy, as well as identified risk factors that would indicate a more aggressive surgical approach at the beginning and a more intense follow-up. In this review, we are adopting a critical approach of the ENETS guidelines and published series for ANEN, focusing on the above-noted “grey areas”.

Despite efforts from various endoscopy societies, reporting in the field of endoscopy remains extremely heterogeneous. Harmonisation of clinical practice in endoscopy has been highlighted by application of many clinical practice guidelines and standards pertaining to the endoscopic procedures and reporting are underlined. The aim of the proposed "standardised reporting" is to (1) facilitate recognition of gastrointestinal neuroendocrine neoplasms (NEN) on initial endoscopy, (2) to enable interdisciplinary decision making for treatment by a multidisciplinary team, (3) to provide a basis for a standardised endoscopic follow-up which allows detection of recurrence or progression reliably, (4) to make endoscopic reports on NEN comparable between different units, and (5) to allow research collaboration between NEN centres in terms of consistency of their endoscopic data. The ultimate goal is to improve disease management, patient outcome and reduce the diagnostic burden on the side of the patient by ensuring the highest possible diagnostic accuracy and validity of endoscopic exams and possibly interventions.

The authors regret that the world map presented in Figure 1 was incomplete. Please see the correct image for Fig 1 below. This has also been updated in the online article. [Figure presented] The authors would like to apologise for any inconvenience caused. © 2021 Elsevier Ltd

Purpose: Neuroendocrine neoplasms (NENs) differ in their biological behavior and growth potential in a way that can be predicted using histological classification and grading systems. A subset of pancreatic NENs (pNENs) may develop a more aggressive phenotype during the course of the disease, associated with an increase in the Ki-67 proliferation index (PI). The purpose of the study was to present the clinical characteristics of these patients. Methods: Using re-biopsy of growing lesions, we investigated the increase in Ki-67 PI sufficient to change initial grading (G). Results: Of 264 patients with well differentiated (WD) pNENs who showed progressive disease during follow-up, 15 (6%) exhibited an increase in Ki-67 PI at a median time 36.8 (9.3–255.8) months. All neoplasms had WD-morphology: five had G1 (Ki-67 median value 1%), nine G2 (median value 5%), one G3 (25%) grades. Upon change of Ki-67 PI, 3 patients had G2 (8%) and 12 G3 (57.5%) NENs, while all retained their WD-morphology. At last follow-up, eight patients were alive with a median overall survival (OS) of 52.5 (9.5–264.3) months. Μedian OS was shorter in patients who had a change in Ki-67 PI before 36 months compared to those who had a change of Ki-67 PI at a later stage (27.5 95%CI: 11.88–43.06 vs. 120.87 95%CI: 96.05–145.69; log-rank p = 0.018). Conclusions: During the course of their disease, 6% patients with progressive pNENs develop an increase in Ki-67 PI resulting in an increase in grading status while maintaining their morphology. This process is associated with worse OS when it occurs at an early stage. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Background/aims: Long-term outcomes are understudied in patients with well-differentiated appendiceal neuroendocrine neoplasms (WD-ANENs). We aimed to evaluate the validity of currently applied criteria for completion prophylactic right hemicolectomy (pRHC) and determine its association with patient outcomes, including health-related quality of life (HRQoL). Methods: Eligible patients from five European referral centers were divided between those who underwent appendectomy alone and those who underwent completion pRHC. HRQoL EORTC-QLC-C30 questionnaires and cross-sectional imaging data were prospectively collected. Age- and sex-matched healthy controls were recruited for HRQoL analysis’ validation. Results: We included 166 patients (119 women [71.2%]: mean age at baseline: 31 ± 16 years). Mean follow-up was 50.9 ± 54 months. Most patients (152 [92%]) had tumors ≤20 mm in size. Fifty-eight patients (34.9%) underwent pRHC that in final analysis was regarded as an overtreatment in 38/58 (65.5%). In multivariable analysis, tumor size >20 mm was the only independent predictor for lymph node (LN) involvement (p = 0.002). No mortality was reported, whereas 2-, 5- and 10-year recurrence-free survival in patients subjected to postoperative cross-sectional imaging (n = 136) was 98.5%, 97.8%, and 97.8%, respectively. Global HRQoL was not significantly impaired in patients with WD-ANEN compared with age- and sex-matched healthy individuals (median scores 0.83[0.08−1] vs 0.83[0.4−1], respectively; p = 0.929). Among patients with WD-ANEN impaired social functioning (p = 0.016), diarrhea (p = 0.003) and financial difficulties (0.024) were more frequently reported in the pRHC group. Conclusions: WD-ANEN is a low-malignant neoplasm with unconfirmed associated mortality, low recurrence rate, and overall preserved HRQoL. pRHC comes at a price of excessive surgery, functional HRQoL issues, and diarrhea. The value per se of a prophylactic surgical approach to patients with WD-ANENs

Unmet medical needs are not infrequent in oncology, and these needs are usually of higher magnitude in rare cancers. The field of neuroendocrine neoplasms (NENs) has evolved rapidly during the last decade, and, currently, a new WHO classification is being implemented and several treatment options are available in the metastatic setting after the results of prospective phase III clinical trials. However, several questions are still unanswered, and decisions in our daily clinical practice should be made with limited evidence. In the 2016 meeting of the advisory board of the European Neuroendocrine Tumor Society (ENETS), the main unmet medical needs in the metastatic NENs setting were deeply discussed, and several proposals to try to solve them are presented in this article, including biomarkers, imaging, and therapy.

Objectives Vasoactive intestinal peptide-secreting tumors (VIPomas) are rare functioning neuroendocrine tumors often characterized by a difficult-to-control secretory syndrome and high potential to develop metastases. We hereby present the characteristics of 15 cases of VIPomas and provide a recent literature review. Methods This was a retrospective data analysis of 15 patients with VIPoma from 3 different centers and literature research through PubMed database during the last 10 years. Results Fifteen patients with VIPomas (9 with hepatic metastases at diagnosis) with watery diarrhea and raised VIP levels were studied. Ten patients (67%) had grade 2 tumors, 6 of 15 had localized disease and underwent potentially curative surgery, whereas the remaining 9 received multiple systemic therapies; 3 patients died during follow-up. The median overall survival was 71 months (range, 41-154 months). Patients who were treated with curative surgery (n = 7) had longer median overall survival compared with patients who were treated with other therapeutic modalities (44 vs 33 months). Conclusions The management of VIPomas is challenging requiring the application of multiple treatment modalities. Patients who underwent surgical treatment with curative intent appear to have higher survival rate. Central registration and larger prospective studies are required to evaluate the effect of currently employed therapies in these patients. © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Unmet medical needs are not infrequent in oncology, and these needs are usually of higher magnitude in rare cancers. The field of neuroendocrine neoplasms (NENs) has evolved rapidly during the last decade, and, currently, a new WHO classification is being implemented and several treatment options are available in the metastatic setting after the results of prospective phase III clinical trials. However, several questions are still unanswered, and decisions in our daily clinical practice should be made with limited evidence. In the 2016 meeting of the advisory board of the European Neuroendocrine Tumor Society (ENETS), the main unmet medical needs in the metastatic NENs setting were deeply discussed, and several proposals to try to solve them are presented in this article, including biomarkers, imaging, and therapy.

Key Points Question Is cortical-sparing adrenalectomy associated with increased pheochromocytoma-specific morbidity and mortality for patients with bilateral pheochromocytomas compared with total adrenalectomy? Findings In this cohort study of 625 patients with bilateral pheochromocytomas, most had hereditary syndromes, but 36% initially presented with unilateral pheochromocytoma. Bilateral total adrenalectomy resulted in a high rate of adverse effects from glucocorticoid replacement therapy, whereas cortical-sparing surgery was not associated with a worse outcome. Meaning These findings suggest that cortical-sparing surgery may be the preferred approach for patients at risk for, or diagnosed with, bilateral pheochromocytomas, especially those harboring a germline mutation in one of the known predisposition genes., This cohort study compares outcomes associated with cortical-sparing adrenalectomy vs total adrenalectomy for patients with bilateral pheochromocytomas., Importance Large studies investigating long-term outcomes of patients with bilateral pheochromocytomas treated with either total or cortical-sparing adrenalectomies are needed to inform clinical management. Objective To determine the association of total vs cortical-sparing adrenalectomy with pheochromocytoma-specific mortality, the burden of primary adrenal insufficiency after bilateral adrenalectomy, and the risk of pheochromocytoma recurrence. Design, Setting, and Participants This cohort study used data from a multicenter consortium-based registry for 625 patients treated for bilateral pheochromocytomas between 1950 and 2018. Data were analyzed from September 1, 2018, to June 1, 2019. Exposures Total or cortical-sparing adrenalectomy. Main Outcomes and Measures Primary adrenal insufficiency, recurrent pheochromocytoma, and mortality. Results Of 625 patients (300 [48%] female) with a median (interquartile range [IQR]) age of 30 (22-40) years at diagnosis, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas and 224 (36%) were diagnosed with metachronous pheochromocytomas (median [IQR] interval to second adrenalectomy, 6 [1-13] years). In 505 of 526 tested patients (96%), germline mutations were detected in the genes RET (282 patients [54%]), VHL (184 patients [35%]), and other genes (39 patients [7%]). Of 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical sparing and were successful in 248 of 324 patients (76.5%). Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy. A third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing syndrome. Of 377 patients who became steroid dependent, 67 (18%) developed at least 1 adrenal crisis and 50 (13%) developed iatrogenic Cushing syndrome during median (IQR) follow-up of 8 (3-25) years. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median (IQR) of 8 (4-13) years, all of which were successfully treated with another surgery. Cortical-sparing surgery was not associated with survival. Overall survival was associated with comorbidities unrelated to pheochromocytoma: of 63 patients who died, only 3 (5%) died of metastatic pheochromocytoma. Conclusions and Relevance Patients undergoing cortical-sparing adrenalectomy did not demonstrate decreased survival, despite development of recurrent pheochromocytoma in 13%. Cortical-sparing adrenalectomy should be considered in all patients with hereditary pheochromocytoma.

Purpose: To study the evolution and optimal management of metastatic bone disease (mBD) in patients with neuroendocrine neoplasms (NENs). Methods: Seventy-four patients were recruited from four NEN centers in this observational multicenter study. Results: Pancreas and small bowel were the most common primaries (30 and 27%, respectively). Almost all gastrointestinal (GI)-NENs were grades 1 and 2, whereas bronchopulmonary-thymic were atypical carcinoids. Thirty-two (43%) patients had synchronous metastatic bone disease (mBD) and three patients reported bone-specific symptoms; metachronous mBD developed at a median of 35 (range: 4–395) months. Thirty-six (86%) of patients with metachronous mBD had stage IV disease at diagnosis. Somatostatin receptor functional imaging and computed tomography were the modalities mostly used for mBD identification. Fifty-two patients received assessable bone-related therapy (bisphosphonates, denosumab, local radiotherapy, and radionuclide treatment). Improvement in mBD was seen in 5, stable disease in 22, and deterioration in 25 patients. The presence of synchronous mBD and the negative outcome of bone-related therapy negatively affected overall survival (OS). In the multivariate analysis, the stronger predictor of OS was the outcome of bone-related therapy (HR: 4.753; 95% CI: 1.589–14.213). Bisphosphonates therapy was the mostly used bone-specific treatment but its monthly administration did not affect OS. At last follow-up, 39 patients were alive with OS 50 (14–463) months. Conclusions: Early investigation for mBD offers a prognostic marker of patients with NENs, since synchronous mBD has a negative impact on survival. The outcome of bone-related therapy affects OS but the monthly administration of bisphosphonates did not show a benefit over less intense schemes. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Background: Capecitabine and temozolomide combination (CAPTEM) is associated with high response rates in patients with advanced neuroendocrine neoplasms (NENs). We evaluated the real-world activity and safety of CAPTEM from 3 NEN centers. Methods: Clinicopathological characteristics and outcomes of patients treated with CAPTEM for bulky or progressive disease (PD) were retrospectively analyzed. -Results: Seventy-nine patients with gastroenteropancreatic (grades 1-2 [n = 38], grade 3 [n = 24]) and lung/thymic (n = 17) NENs were included. Median treatment duration was 12.1 months (range 0.6-55.6). Overall, partial responses (PRs) occurred in 23 (29.1%), stable (SD) in 24 (30.4%), and PD in 28 (35.4%) patients. Median progression-free survival (PFS) and overall survival (OS) were 10.1 (6-14.2) and 102.9 months (43.3-162.5), respectively. On univariate analysis, NENs naive to chemotherapy and low Ki67 were associated with favorable responses (partial response [PR] + SD; p = 0.011 and 0.045), PFS (p < 0.0001 and 0.002) and OS (p = 0.005 and 0.001). Primary site (pancreas and lung/thymus) was also a significant prognostic factor for PFS (p < 0.0001) and OS (p < 0.0001). On multivariate analysis, gastrointestinal and unknown primary NENs (hazard ratio [HR] 0.3, 95% CI 0.1-0.8, p = 0.009 and p = 0.018) and prior surgery (HR 2.4, 95% CI 11-4.9, p = 0.021) were independent prognostic factors for PFS. Ki-67 was a poor predictor for favorable response in receiver operating characteristic analysis (area under the curve 0.678). Safety analysis of CAPTEM indicated rare events of serious (grades 3-4) toxicities (n = 4) and low discontinuation rates (n = 8) even in patients with prolonged administration (>12 months). Conclusions: CAPTEM treatment can be an effective and safe treatment even after prolonged administration for patients with NENs of various sites and Ki67 labeling index, associated with significant favorable responses and PFS. © 2019 S. Karger AG, Basel.

Recently, the European Neuroendocrine Tumor Society (ENETS) held working sessions composed of members of the advisory board and other neuroendocrine neoplasm (NEN) experts to attempt to identify unmet needs in NENs in different locations or with advanced/poorly differentiated NENs. This report briefly summarizes the main proposed areas of unmet needs in patients with functional and nonfunctional pancreatic NENs.

Background: Liver metastases are common in patients with neuroendocrine tumors (NETs), having a negative impact on disease prognosis. The options for selective therapy in patients with unresectable multiple liver metastases are limited to TACE (transarterial chemoembolization), TAE (transarterial embolization), or SIRT (selective internal radiation therapy). Aim: To explore the clinical outcome, survival and safety of these therapies in NETs patients. Methods: Retrospective case series of consecutive patients (mean age 56.6 years, 59% male) treated at two tertiary university medical centers from 2005 to 2015. Results: Fifty-seven patients with G1, G2, and low G3 NETs with liver metastases were investigated (pancreatic NET (pNET), 24; small bowel, 16; unknown origin (UKO), 9; rectal, 3; lung, 3; and gastric, 2). Fifty-three patients underwent TACE, three patients underwent TAE, and one patient underwent SIRT. Clinical improvement and tumor response were observed in 54/57 patients (95%), together with marked decreased in tumor markers. The median time to tumor progression following the first treatment was 14 ± 16 months. The median overall survival was 22 ± 18 months, more pronounced in the pNET, followed by small bowel and UKO subgroups. There was a trend for a better survival in patients with disease limited to the liver and in whom the primary tumor was resected. Conclusion: Hepatic intra-arterial therapies are well tolerated in the majority of patients with NETs and liver metastases and associated with both clinical improvement and tumor stabilization for prolonged periods. These therapies should be always considered, irrespective of the presence of extrahepatic metastasis. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Gastric carcinoids, formally named gastric neuroendocrine neoplasms (NENs), are derived from enterochromaffin-like cells of the stomach and are increasingly diagnosed. A majority are designated as type I (related to autoimmune gastritis) and type II (related to gastrinoma) neoplasms that develop secondary to gastrin hypersecretion. Types I and II gastric carcinoids are mostly small-sized (1–2 cm), multiple, low-malignancy potential lesions mainly confined to the gastric mucosa/submucosa. These lesions have an indolent course and low metastatic potential. In contrast, type III gastric carcinoids are single, larger-sized (>2 cm), non–gastrin-related lesions that infiltrate the muscular layers associated with local and distant metastases. © 2018 Elsevier Inc.

Neuroendocrine tumors of the small intestine are the most common causes of the carcinoid syndrome. Carcinoid heart disease occurs in more than half of the patients with the carcinoid syndrome. Patients with carcinoid heart disease who need to undergo surgery should also undergo preoperative evaluation by an expert cardiologist. Treatment with long-acting somatostatin analogs aims at controlling the excessive hormonal output and symptoms related to the carcinoid syndrome and at preventing a carcinoid crisis during interventions. Patients with a gastrinoma require pre- A nd postoperative treatment with high doses of proton pump inhibitors. Patients with a glucagonoma require somatostatin analog treatment and nutritional supplementation. Patients with a VIPoma also require somatostatin analog treatment and intravenous fluid and electrolyte therapy. Insulinoma patients generally require intravenous glucose infusion prior to operation. In patients with localized operable insulinoma, somatostatin analog infusion should only be considered after the effect of this therapy has been electively studied. © 2017 The Author(s).

The purpose of these guidelines is to assist physicians caring for patients with neuroendocrine neoplasia in considering eligibility criteria for peptide receptor radionuclide therapy (PRRT) and in defining the minimum requirements for PRRT. It is not these guidelines' aim to give recommendations on the use of specific radiolabelled somatostatin analogues for PRRT as different analogues are being used, and their availability is governed by varying international regulations. However, a recent randomized controlled trial, NETTER-1, has provided evidence that may establish 177Lu-DOTA-octreotate (LutaThera®) as the first widely approved agent. It also makes recommendations on what minimal patient, tumour, and treatment outcome characteristics should be reported for PRRT to facilitate robust comparisons between studies. © 2017 S. Karger AG, Basel.

The vast majority of gastrin-related gastrointestinal neuroendocrine neoplasms (GI-NENs) develop in the context of chronic atrophic gastritis (type 1), a condition closely related to autoimmune thyroid diseases. These neoplasms are defined as gastric NENs type 1 (GNEN1) and have recently been shown to constitute the commonest GI-NENs in a prospective study. GNEN1s are usually multiple and follow a relative indolent course, raising questions regarding the extent that such patients should be investigated and the appropriate therapeutic interventions needed. Recently, a number of consensus statements and guidelines have been published from various societies dealing with the diagnosis and management of GI-NENs. Endocrinologists are among the many different medical specialties involved in GNEN1s diagnosis and management. However, despite recent advances, few randomized trials are available, and thus existing evidence remains relatively weak compared to other malignancies. The purpose of this review is to provide recent evidence along with currently employed modalities addressing the diagnosis, management, long-term follow-up and potential comorbidities of GNEN1s. © 2014 John Wiley & Sons Ltd.

We evaluated the latest pathological criteria for completion right hemicolectomy (RHC) in patients with appendiceal neuroendocrine tumors (ANETs) with emphasis on the size of the primary tumor. Data of 28 consecutive patients who underwent RHC for ANETs in three tertiary hospitals were reviewed retrospectively to assess the indications for completion RHC. 10/28 patients were found to have residual disease (36%). In 8/28 patients (29%), the tumor diameter was

AIM: To describe disease characteristics and treatment modalities in a group of rare patients with metastatic gastric carcinoid type 1 (GCA1). METHODS: Information on clinical, biochemical, radiological, histopathological findings, the extent of the disease, as well as the use of different therapeutic modalities and the long-term outcome were recorded. Patients' data were assessed at presentation, and thereafter at 6 to 12 monthly intervals both clinically and biochemically, but also endoscopically and histopathologically. Patients were evaluated for the presence of specific symptoms; the presence of autoimmune disorders and the presence of other gastrointestinal malignancies in other family members were also recorded. The evaluation of response to treatment was defined using established WHO criteria. RESULTS: We studied twenty consecutive patients with a mean age of 55.1 years. The mean follow-up period was 83 mo. Twelve patients had regional lymph node metastases and 8 patients had liver metastases. The primary tumor mean diameter was 20.13 ± 10.83 mm (mean ± SD). The mean Ki-67 index was 6.8% ± 11.2%. All but one patient underwent endoscopic or surgical excision of the tumor. The disease was stable in all but 3 patients who had progressive liver disease. All patients remained alive during the follow-up period. CONCLUSION: Metastatic GCA1 carries a good overall prognosis, being related to a tumor size of ≥ 1 cm, an elevated Ki-67 index and high serum gastrin levels. © 2013 Baishideng Publishing Group Co., Limited. All rights reserved.

To study the clinical presentation, diagnostic approach, response to treatment, and the presence of other pathologies in patients with gastric carcinoid type 1 (GC 1) tumors. Retrospective analysis of 111 patients from four institutions and a mean follow-up of 76 months. The main indications for gastroscopy were upper gastrointestinal tract symptoms. The mean number of lesions, maximum tumoral diameter, and percentage of cells expressing Ki-67 labeling index were 3.6±3.8, 8±12.1 mm and 1.9±2.4% respectively. Serum gastrin and chromogranin A (CgA) levels were elevated in 100/101 and 85/90 patients respectively. Conventional imaging studies demonstrated pathology in 9/111 patients. Scintigraphy with radiolabeled octreotide was positive in 6/60 without revealing any additional lesions. From the 59 patients who had been followed-up without any intervention, five developed tumor progression. Thirty-two patients were treated with long-acting somatostatin analogs (SSAs), leading to a significant reduction of gastrin and CgA levels, number of visible tumors, and CgA immune-reactive tumor cells in 28, 19, 27, and 23 treated patients respectively. Antrectomy and/or gastrectomy were initially performed in 20 patients and a complete response was achieved in 13 patients. The most common comorbidities were vitamin B12 deficiency, thyroiditis, and parathyroid adenomas. Most GCs1 are grade 1 (82.7%) tumors presenting with stage I (73.9%) disease with no mortality after prolonged follow-up. Ocreoscan did not provide further information compared with conventional imaging techniques. Treatment with SSAs proved to be effective for the duration of administration.