Guidelines for some pancreatic neuroendocrine tumors (NETs) have shifted towards active surveillance given the indolent nature of this malignancy. We sought to assess the safety of delayed surgery on colorectal NETs as a surrogate for surveillance.

Resected, stage I, well-differentiated colorectal primary NETs included in the Surveillance, Epidemiology, and End Results Program from 2010 to 2020 were included. Demographics, interval from diagnosis to surgery, and disease-specific survival (DSS) were retrospectively analyzed. Clinical stage I patients in the National Cancer Database were then reviewed to assess the incidence of pathologic upstaging, as well as the impact of active surveillance on overall survival (OS).

Overall, 4275 patients met the inclusion criteria and 33 (0.8%) had disease-specific death; 61 (1.4%) patients had surgery > 6 months after diagnosis. Median DSS and overall follow-up were 34 and 68 months, respectively. Multivariable analysis demonstrated delayed surgery > 6 months (hazard ratio [HR] 4.82 [1.13-20.55], p = 0.033), male sex (HR 3.16 [1.43-7.03], p = 0.005), and age (HR 1.06 [1.03-1.10], p = < 0.001) were associated with increased risk, while having a rectal primary (HR 0.32 [0.15-0.68], p = 0.003) was protective; however, a > 6-month delay remained significant when analyzing rectal primaries alone (HR 4.5 [1-19.2], p = 0.044). Delay in surgery > 6 months was associated with a 14% (p = 0.0023) incidence of upstaging, while active surveillance was associated with decreased OS (HR 1.48 [1.02-2.13], p = 0.039) compared with upfront resection.

Prolonged delays in surgery > 6 months for colorectal NETs were associated with decreased DSS and a significant risk of upstaging, suggesting that surveillance may not be appropriate even for stage I disease.

Patients with gastric neuroendocrine neoplasms (GNENs) face elevated risks of second primary malignancies (SPMs), yet tools for personalized risk prediction are lacking. This study aimed to explore the risk factors associated with the development of SPMs in patients with GNENs and to establish a new competing-risk nomogram to predict the occurrence of SPMs.

We obtained clinical data for GNENs patients from the Surveillance, Epidemiology, and End Results (SEER) database covering the period from 2000 to 2015. Using Fine and Gray's proportional sub-distribution hazards model, potential risk factors for SPM development in GNENs' patients were identified. A competing-risk nomogram was then constructed to quantify the probability of SPMs' occurrence and was evaluated using the area under the receiver-operating characteristic (ROC) curves (AUC) and calibration curves.

Among the 5160 GNENs patients, 18.7% developed SPMs during a maximum follow-up period of approximately 131 months (median 82 months). Independent risk factors for SPMs included age, marital status, tumor size, histopathological grade, disease extent, and T staging. The nomogram based on these factors demonstrated relatively strong predictive accuracy.

This study identifies key risk factors for SPMs in GNENs patients and introduces a nomogram that effectively predicts SPM risk. This tool may help clinicians better assess patient risk and guide treatment decisions.

Complete resection is the only chance for cure in small intestine neuroendocrine neoplasms (SI-NEN). Previous ENETS guidelines proposed standards for the surgery of SI-NEN, which should be followed to provide long-term disease-free survival.

To analyze the results of reintervention for locoregional SI-NEN (stages I-III) after suboptimal initial resection.

Perioperative characteristics of all patients who underwent surgical reintervention after suboptimal initial resection (SIR) of locoregional SI-NEN were retrieved from a prospective database. Patient characteristics, initial and redo procedures, imaging before reintervention, pathological results of SIR, and after reintervention, including missed primary tumors and lymph node metastases, were retrospectively analyzed.

During a 15 years period, 21 of 93 (22%) patients had surgical reinterventions after SIR. In 20 of 21 (95%) cases, the initial resection was performed outside an ENETS center of excellence. Ten (48%) of those cases were emergency operations because of the bowel obstruction or bowel bleeding. Seven SIR (33%) cases were performed laparoscopically, and in another 5 (24%) cases, a complete endoscopic mucosa resection was performed. Imaging before reintervention visualized residual disease in 15 of 21 (71%) patients. Surgical reintervention included either lymphadenectomy alone (LAD, n = 3) or small bowel resection plus systematic LAD (n = 12) or right hemicolectomy/ileocecal resection with systematic LAD (n = 6), respectively. In 19 of 21 (90%) patients, a R0 resection could be achieved. One patient (5%) experienced postoperative clinically relevant complications. According to pathology, in 10 (48%) patients lymph node metastases, in 6 (29%) patients additional primary tumors, and in 5 (24%) patients, both lymph nodes metastases and primary tumors were left behind in the SIR. After mean follow-up of 52 months, 16 (76%) of 21 patients were free of disease, 4 (19%) patients were alive with disease, and 1 patient deceased of an unrelated cause.

The proposed standards to resect locoregional SI-NEN should be followed to avoid SIR, although the prognosis after adequate surgical reintervention is good.

Although the status of lymph node metastasis (LNM) is crucial in determining treatment strategy for duodenal neuroendocrine tumors (D-NETs), robust evidence for their potential LNM risk remains lacking. This systematic review aimed to summarize the prevalence and risk factors of LNM in D-NETs.

This systematic review of electronic databases identified eligible case-control and cohort studies for D-NET resected either endoscopically or surgically, published from 1990 to 2023. The primary outcome was the pooled prevalence of LNM in D-NETs. Secondary outcomes included the pooled prevalence of LNM according to tumor location and functionality, as well as identifying pathological risk factors for LNM. Meta-analysis was performed.

We identified 36 studies that involved 1,396 patients with D-NETs, including 326 with LNM. The pooled prevalence of LNM in D-NETs was 22.7% (95% confidence interval [CI] 17.3-29.2%). The prevalence was high in ampullary/peri-ampullary D-NETs and functional D-NETs (46.8 and 53.3%, respectively), whereas it was low in non-functional, non-ampullary D-NETs (NAD-NETs) (9.5%). Pathological risk factors for LNM in NAD-NETs included tumor size > 10 mm (odds ratio [OR] 7.31 [95% CI 3.28-16.31]), tumor invasion into the muscularis propria or deeper (OR 7.79 [3.65-16.61]), lymphovascular invasion (OR 5.67 [2.29-14.06]), and World Health Organization grading of G2 (OR 2.47 [1.03-5.92]).

Approximately one-fourth of the patients with D-NETs had LNM. Endoscopic resection might be acceptable for non-functional NAD-NETs with diameters of 10 mm or less, but additional surgical resection with lymphadenectomy may be recommended for cases exhibiting pathological risk factors.

Gallbladder cancer (GBC) accounts for 1.7% of all cancer-related deaths. Neuroendocrine carcinoma of the gallbladder (GB-NEC) is a rare subtype of GBC that is more malignant than GBC. Small-cell neuroendocrine carcinoma of the gallbladder (GB-SCNEC) is a rare malignant tumor with a low incidence. To date, no universally accepted or satisfactory treatment exists. This case report details the clinical presentation, diagnostic process, and treatment strategy of a patient with GB-SCNEC. The analysis of this rare case is intended to provide clinicians with diagnostic and therapeutic insights for future research.

Pancreatic resections for pancreatic neuroendocrine tumors (pNET) may experience a higher complication rate than for pancreatic ductal adenocarcinoma (PDAC). This study aimed to determine the rate of the novel composite "Ideal Outcome" measure after resection for pNET, using PDAC as reference.

This observational cohort study included all consecutive patients after pancreatic resection for pNET and PDAC using the nationwide Dutch Pancreatic Cancer Audit (2014-2021). The primary outcome was Ideal Outcome; absence of postoperative mortality, postoperative pancreatic fistulas (POPF) grade B/C, other major complications, prolonged length of stay, reoperations and readmissions.

In total, 524 pNET and 2851 PDAC resections were included. The rate of Ideal Outcome was lower after resection for pNET (47.7% versus 55.7%; P<0.001) as compared to PDAC. This difference was driven by a lower rate of Ideal Outcome after pancreatoduodenectomy for pNET (37.7% versus 56.3%; P<0.001), with no difference after left pancreatectomy (54.5% versus 52.5%; P=0.598). Among the individual components of Ideal Outcome after pancreatoduodenectomy, the largest difference was a four times higher rate of POPF (32.1% versus 7.9%; P<0.001) after resection of pNET.

Patients undergoing pancreatoduodenectomy for pNET have a reduced Ideal Outcome rate compared to patients with PDAC, related to a fourfold increased risk of POPF. This highlights the value of pNET-specific patient counseling and the need for effective POPF mitigation strategies.

The term "carcinoid tumour" is no longer used and has given up its place to neuroendocrine neoplasms (NENs). Primary hepatic neuroendocrine neoplasms (PHNENs) are as rare as compromising 0.4% of all neuroendocrine neoplasms (NENs). Searching the central medical databases of PubMed/Medline, Web of Science, Scopus, Google Scholar, and the references of the articles, we have collected 10 cases of pediatric PHNENs of children. The inclusion criteria were full-text available literature in English and those under and equal to 19 years old. Diseases found during autopsy, carcinoma, and isolated gall bladder involvement also made the exclusion criteria. The mean age of the patients was 13.86 years, ranging from 8 to 19 years. Six female patients (55%) were in front of 5 males (45%). The right lobe was the most frequent site of involvement and surgery in four cases. Abdominal pain comprised the main symptom, and CT scans of most of them were common which helped in diagnosis. While a hepatic tumour is considered NEN, a detailed systemic evaluation of a primary tumour is mandatory to exclude metastatic HNEN. Secondary hepatic NENs are more common than primary ones. Surgical resection has had the most long-term success.

Small intestine neuroendocrine tumours (SI-NETs) are often diagnosed late with a UK median of 3 years and high misdiagnosis rates. Previous studies, largely based on patient surveys, offer little data on improving diagnosis. In 2017, the South Wales NET service underwent a nationally commissioned, systematic transformation, aiming to improve diagnosis through the development of a gastroenterology and surgical referral network, and education of these specialities. This study aims to assess the impact of the transformation on SI-NET diagnosis times and misdiagnosis rates using accurate hospital data, along with the diagnostic routes and investigations used for SI-NETs. We retrospectively analysed the hospital records of 224 patients diagnosed with SI-NETs referred to the South Wales NET service (110 pre-transformation and 114 post-transformation). Following the service transformation, there was a significant reduction in diagnosis times from a median of 12.5-5.2 months (p < .05), at an earlier stage (cases with metastases reduced from 77% to 62%), and reduced misdiagnosis rates from 40% to 25%. Colonoscopy, used to investigate the presenting gastrointestinal symptoms in 42% of patients prior to diagnosis, identified an abnormality in only 28%, compared with 97% with computed tomography (CT) scans. A gastroenterology and surgical referral network across hospitals may improve diagnosis in SI-NETs, leading to earlier detection and reducing misdiagnosis rates. Further exploration of GP interactions is needed. Caution is needed following negative colonoscopy in patients with persistent lower gastrointestinal symptoms as this could lead to missed SI-NET diagnosis if further abdominal imaging is not undertaken.

There is a general perception that the incidence of neuroendocrine neoplasms (NENs) has been increasing. Nevertheless, reports of actual population-based studies are scarce, and pertinent data from some geographical regions still need to be available. In this systematic literature review of population-based studies, we aimed to evaluate the available data to provide updated figures on the incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Guided by the PRISMA 2020 statement reporting items for systematic reviews, this study conducted a systematic search using Ovid in the bibliographic databases Embase, Medline, and Web of Science Core Collection. Only incidence-reporting studies were included. In total, 847 articles were identified, and through a strict evaluation process using predefined inclusion and exclusion criteria, we found 19 papers that reported the general incidence of GEP-NENs from all sites. In addition, we considered another 15 papers that focused on the epidemiologic aspects of single-organ studies. While the incidence rates of GEP-NEN vary across similar countries, the general incidence of GEP-NEN has been increasing worldwide in recent decades. The incidence of GEP-NENs has increased worldwide over the last two decades, and reliable figures from new regions add to this pattern. Nevertheless, variations in the classification, grading, and reporting of GEP-NENs in various studies make direct comparisons difficult.

Neuroendocrine tumors (NETs) are a diverse group of neoplasms whose prevalence is increasing globally, primarily due to advancements in diagnostic techniques. NETs arise from cells of the diffuse endocrine system and can occur in various locations, with the gastrointestinal tract being the most common. Their diverse clinical presentations, which range from asymptomatic to severe hormone-induced syndromes, pose significant diagnostic challenges. In emergency care, prompt recognition and management of complications such as bowel obstruction, ischemic events, hormonal crises, and metastases are critical. This review discusses the radiologic spectrum of NETs in emergent care, emphasizing the role of imaging in timely diagnosis and intervention.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are challenging to diagnose and manage. Because there is a critical need for a reliable biomarker, we previously developed the NETest, a liquid biopsy test that quantifies the expression of 51 neuroendocrine tumor (NET)-specific genes in blood using real-time PCR (NETest 1.0). In this study, we have leveraged our well-established laboratory approach (blood collection, RNA isolation, qPCR) with contemporary supervised machine learning methods and expanded training and testing sets to improve the discrimination and calibration of the NETest algorithm (NETest 2.0). qPCR measurements of RNA-stabilized blood-derived gene expression of 51 NET markers were used to train two supervised classifiers. The first classifier trained on 78 Controls and 162 NETs, distinguishing NETs from controls; the second, trained on 134 stable disease samples, 61 progressive disease samples, differentiated stable from progressive NET disease. In all cases, 80% of data was retained for model training, while remaining 20% were used for performance evaluation. The predictive performance of the AI system was assessed using sensitivity, specificity, and Area under Received Operating Characteristic curves (AUROC). The algorithm with the highest performance was retained for validation in two independent validation sets. Validation Cohort #I consisted of 277 patients and 186 healthy controls from the United States, Latin America, Europe, Africa and Asia, while Validation Cohort #II comprised 291 European patients from the Swiss NET Registry. A specificity cohort of 147 gastrointestinal, pancreatic and lung malignancies (non-NETs) was also evaluated. NETest 2.0 Algorithm #1 (Random Forest/gene expression normalized to ATG4B) achieved an AUROC of 0.91 for distinguishing NETs from controls (Validation Cohort #I), with a sensitivity of 95% and specificity of 81%. In Validation Cohort #II, 92% of NETs with image-positive disease were detected. The AUROC for differentiating NETs from other malignancies was 0.95; the sensitivity was 92% and specificity 90%. NETest 2.0 Algorithm #2 (Random Forest/gene expression normalized to ALG9) demonstrated an AUROC of 0.81 in Validation Cohort #I and 0.82 in Validation Cohort #II for differentiating stable from progressive disease, with specificities of 81% and 82%, respectively. Model performance was not affected by gender, ethnicity or age. Substantial improvements in performance for both algorithms were identified in head-to-head comparisons with NETest 1.0 (diagnostic: p = 1.73 × 10-9; prognostic: p = 1.02 × 10-10). NETest 2.0 exhibited improved diagnostic and prognostic capabilities over NETest 1.0. The assay also demonstrated improved sensitivity for differentiating NETs from other gastrointestinal, pancreatic and lung malignancies. The validation of this tool in geographically diverse cohorts highlights their potential for widespread clinical use.

The rate of distant metastasis in patients with pancreatic neuroendocrine tumors (PNETs) is 20%-50% at the time of initial diagnosis. However, whether tumor size can predict distant metastasis for PNETs remains unknown up to date.

We used Surveillance, Epidemiology, and End Results (SEER) population-based data to collect 6089 patients with PNETs from 2010 to 2019. The optimal cut-off point of tumor size to predict distant metastasis was calculated by Youden's index. Multivariate logistic regression analysis was used to figure out the association between tumor size and distant metastasis patterns.

The most common metastatic site was liver (27.2%), followed by bone (3.0%), lung (2.3%) and brain (0.4%). Based on an optimal cut-off value of tumor size (25.5 mm) for predicting distant metastasis determined by Youden's index, patients were categorized into groups of tumor size < 25.5 mm and ≥ 25.5 mm. Multivariate logistic regression analyses showed that, compared with < 25.5 mm, tumor size ≥ 25.5 mm was an independent risk predictor of overall distant metastasis [odds ratio (OR) = 4.491, 95% confidence interval (CI): 3.724-5.416, P < 0.001] and liver metastasis (OR = 4.686, 95% CI: 3.886-5.651, P < 0.001).

Tumor size ≥ 25.5 mm was significantly associated with more overall distant and liver metastases. Timely identification of distant metastasis for tumor size ≥ 25.5 mm may provide survival benefit for timely and precise treatment.

In the World Health Organization (WHO) 5th edition, prognosis of gastrointestinal (GI) well-differentiated neuroendocrine tumors (WDNET) depends on proliferation rate, commonly assessed by ki-67 immunohistochemical stain. In daily practice, the gold standard for WHO grade assessment by ki-67 staining, printing a photo of a tumor hotspot, counting the number of ki-67-positive cells out of 500 tumor cells, and calculating a percentage, is time-consuming and many cases are eyeballed. This study investigates the utility of a common tool, the manual cell counter used in hematology smear cell counting, for GI WDNET ki-67 counting. Of 59 resections, the number of cases with a WHO grade difference between gold standard print-and-count and the original report, eyeballing, and hematology counter method, was 23 (39 %), 14 (24 %) and 7 (12 %) cases, respectively. Of 37 biopsies, the number of cases with a WHO grade difference between gold standard print-and-count and the original report, eyeballing, and hematology counter method, was 10 (27 %), 12 (32 %) and 7 (19 %) cases, respectively. For resections, Chi square analysis comparing hematology counter method versus original report, where many cases were likely eyeballed, showed statistically significantly less cases with differing WHO grades from gold standard print-and-count for hematology counter-assessed cases (P = 0.0007), and the same Chi square analysis was marginally not significant (P = 0.09) for hematology counter versus eyeballing. Times taken to perform hematology counter method were statistically significantly lower than times taken for print-and-count. This study suggests the hematology cell counter could strike a reasonable balance between time and accuracy for WDNET resections.

Background/Objectives: Extrapulmonary neuroendocrine carcinomas (EP-NECs) are rare, aggressive malignancies with no standardized treatment approach. Although platinum-based chemotherapy is considered the first-line therapy, overall survival (OS) and progression-free survival (PFS) remain limited. This study aims to evaluate the clinical and pathological characteristics of EP-NEC patients, their treatment responses, and survival outcomes. Methods: This retrospective observational study included 29 EP-NEC patients diagnosed and followed between 2015 and 2024. Clinical and demographic data, tumor localization, disease stage, administered treatments, and survival outcomes were analyzed. Kaplan-Meier survival analysis was used to assess OS and PFS, with subgroup comparisons performed via the log-rank test. Results: The most common primary tumor sites were the pancreas (21%), prostate (17%), and cervix (14%). At diagnosis, 55.2% of patients had metastatic disease. First-line platinum-based chemotherapy achieved an objective response rate of 82.1%, with a median PFS of 8.16 months and a median OS of 14.16 months. Surgical intervention significantly improved survival (p = 0.020), while a high Ki-67 proliferation index (>80%) was associated with worse PFS (p = 0.032). Other factors, including smoking status and liver-directed therapies, had no significant impact on survival. Conclusions: EP-NECs present with a poor prognosis despite platinum-based chemotherapy achieving high response rates. Surgical resection improves survival outcomes, whereas high Ki-67 expression is associated with a worse prognosis. These findings highlight the need for further research into novel therapeutic strategies for EP-NECs.

Imaging examinations exhibit a certain rate of missed detection for distant metastases of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). This study aims to develop and validate a risk prediction model for the distant metastases and prognosis of GEP-NENs. This study included patients diagnosed with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. External validation was performed with patients from the China-Japan Union Hospital of Jilin University. Univariate and multivariate logistic regression analyses were conducted on the selected data to identify independent risk factors for distant metastasis in GEP-NENs. A nomogram was subsequently developed using these variables to estimate the probability of distant metastasis in patients with GEP-NENs. Subsequently, patients with distant metastasis from GEP-NENs were selected for univariate and multivariate Cox regression analyses to identify prognostic risk factors. A nomogram was subsequently developed to predict overall survival (OS) in patients with GEP-NENs. Finally, the developed nomogram was validated using Receiver Operating Characteristic (ROC) curves, calibration curves, and Decision Curve Analysis (DCA). Kaplan-Meier analysis was employed to evaluate survival differences between high-risk and low-risk groups. A total of 11,207 patients with GEP-NENs were selected from the SEER database, and 152 patients from the China-Japan Union Hospital of Jilin University were utilized as an independent external validation cohort. Univariate and multivariate logistic regression analyses revealed that the primary tumor site, tumor grade, pathological type, tumor size, T stage, and N stage are independent predictors of distant metastasis in GEP-NENs. Additionally, among the 1732 patients with distant metastasis of GEP-NENs, univariate and multivariate Cox regression analyses identified N stage, tumor size, pathological type, primary site surgery, and tumor grade as independent prognostic factors. Based on the results of the regression analyses, a nomogram model was developed. Both internal and external validation results demonstrated that the nomogram models exhibited high predictive accuracy and significant clinical utility. In summary, we developed an effective predictive model to assess distant metastasis and prognosis in GEP-NENs. This model assists clinicians in evaluating the risk of distant metastasis and in assessing patient prognosis.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare malignancies deriving from the endocrine system in the gastrointestinal tract including the pancreas. Prognosis is greatly heterogenous due to its dependency on various factors, most importantly stage and differentiation. Several studies report an alarming rise in incidence in the past decade. Despite there being some therapeutical options, best therapy sequence still needs to be defined, particularly for unresectable and/or intermediate and high-grade NENs. Peptide receptor radionuclide therapy (PRRT) was approved in Europe and USA in 2017 and 2018, respectively. Studies with real-world systematic data on characteristics and treatment patterns of PRRT-receiving patients was non-existent at the time of this writing. In this retrospective study, we identified within the German NET-Registry 203 patients diagnosed with GEP-NEN having received PRRT from 1995 to 2023. We assessed general clinical patient characteristics, disease-specific characteristics, treatments and outcomes. To obtain a more up-to-date picture of treatment modalities and outcomes, a subgroup of the study population was allocated to the "therapy cohort," defined by patients with date of first diagnosis between 2010 and 2023 (open cohort). Mean age of the study population was 58 years (SD 12 years) with 51.7% being men. Most patients had a WHO performance score of 0 to 1 (41.4% and 50.5%, respectively). Most NEN cases were of small intestine/pancreatic origin (46.3% and 45.3%, respectively) and displayed well/moderate differentiation (55.3%). Ki-67 was generally within the 3% to 20% range (57.92%). Most patients presented with metastasis at diagnosis (73.9%). Somatostatin analogs (SSAs), chemotherapy and surgery were the most common non-PRRT therapy options (65.3%, 60.2%, and 50.0%, respectively). PRRT was most often applied as third- or second-line therapy (42.3% and 36.6%, respectively), usually after surgery and/or SSA treatment. As PRRT had been administered using different regimens, tumor response evaluation showed mixed responses. Given the low sample size and considerable amount of missing response data, no correlation analysis between PRRT sequencing and tumor response could be performed. Overall, the clinical characteristics and treatment patterns tend to follow trends observed in other studies or medical guidelines. Finally, this study presents real-world data that more accurately describes GEP-NEN disease in Germany and treatment modalities after PRRT's approval.

Gastrointestinal neuroendocrine tumors (GI-NETs) are slow-growing tumors with the potential for malignancy that originate from neuroendocrine cells. Therefore, early diagnosis and treatment of GI-NETs are necessary to prevent metastasis. The widespread use of colonoscopy, which allows early detection of rectal neuroendocrine tumors (rNETs) that are small enough to be treated endoscopically, has resulted in an increasing rate of endoscopic resection of rNETs. However, whether the long-term prognosis of endoscopically resected rNETs is favorable has not yet been determined. This study aimed to assess whether endoscopically resected rNETs affect the long-term prognosis of patients.

We retrospectively reviewed the medical records of 163 consecutive patients with rNETs who underwent endoscopic resection at 11 hospitals in Japan between 1999 and 2012. The primary analysis focused on 47 patients with 51 rNETs who underwent ≥ 10 years of follow-up. The secondary analysis focused on patients who underwent less than 10 years of follow-up.

The median follow-up period of patients included in the primary analysis was 12.3 years (range, 10-19.1 years). The median lesion size was 5 mm (range, 2-12). Three lesions were treated using conventional endoscopic mucosal resection (EMR). Twenty-nine lesions were treated using modified EMR. Nineteen lesions were treated using endoscopic submucosal dissection. The R1 resection rate and lymphovascular invasion rate were 15.7% and 25.5%, respectively. The curative resection (CR) rate and non-CR rate were 66.7% and 33.3%, respectively. Two patients with lesions treated with non-CR underwent radical surgery. None of the 47 patients experienced lesion recurrence during the 10-year follow-up period. Two patients whose lesions were treated with CR died of other diseases.

Death attributable to rNETs did not occur among patients who underwent at least 10 years of follow-up after endoscopic resection.

Gastroenteropancreatic neuroendocrine tumours (GEP-NETs), which may be hormone secreting (e.g., gastrinomas and insulinomas) or non-secreting (also known as non-functioning NETs) are associated with severe morbidity and have a median overall survival of 75-124 months. Studies have highlighted the importance of epigenetic mechanisms in GEP-NETs pathogenesis, with the most frequently mutated genes being the epigenetic regulators, MEN1, DAXX, and ATRX. However, the consequences of these aberrant epigenetic mechanisms are poorly understood. The calcium sensing receptor (CASR), a G protein coupled-receptor, is epigenetically silenced in cancers, and therefore we examined its role in GEP-NET subtypes. Using RNA-Scope and quantitative PCR analyses in two independent tumour cohorts from Europe (n = 18 patients) and the USA (n = 46 patients) we showed that CASR mRNA is almost completely absent in gastrinomas, insulinomas and non-functioning pancreatic NETs. Furthermore, immunohistochemical staining confirmed a significant reduction in CaSR protein expression in all GEP-NET subtypes, compared to normal islets. DNA methylationEPIC and ATAC-seq analyses in the pancreatic NET cell line QGP-1 showed the CaSR promoter was both hypermethylated and in a region of closed chromatin. Furthermore, transfection of wild type CaSR into QGP-1 cells decreased cell viability, in keeping with the CaSR having a role in cellular proliferation. In summary, our study reveals that CaSR expression is decreased in GEP-NETs and that this reduced expression is likely due to DNA methylation and chromatin changes. Moreover, we demonstrate that transfection of the CaSR into a PNET cell line reduces cell viability, thereby indicating that the CaSR acts as a tumour suppressor in this tumour type.

In recent years, advancements in omics technologies have significantly accelerated the identification of a broad spectrum of biomarkers based on DNA, RNA, microRNAs (miRNAs), and long non-coding RNAs, as well as proteins and metabolic and lipid alterations (Figure 1) [...].

Non-functional gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare tumors, and liver metastasis is the leading cause of death in patients with GEP-NENs. Due to the difficulty in conducting large cohort studies, no reliable tool currently exists to predict the risk of liver metastasis in these patients. This study aimed to develop and validate a nomogram model based on large cohort clinical data to accurately predict the risk of liver metastasis in patients with non-functional GEP-NENs.

A retrospective cohort study was conducted, encompassing 838 patients with non-functional GEP-NENs diagnosed between 2009 and 2023. Independent risk factors for liver metastasis were identified through univariate and multivariate logistic regression analyses. A nomogram was constructed based on significant predictors, including T stage, N stage, Ki-67 index, primary tumor site, and BMI. The model's performance was evaluated using the C-index, calibration curves, and decision curve analysis (DCA) for both training and validation cohorts.

The nomogram demonstrated excellent predictive performance, with C-index values of 0.839 and 0.823 for the training and validation sets, respectively. Risk stratification using the nomogram's total score effectively differentiated high-risk from low-risk patients. Kaplan-Meier survival analysis revealed significant survival differences between these groups (P < 0.0001). Moreover, the calibration curves indicated strong agreement between predicted and observed outcomes.

The developed nomogram is a reliable tool for predicting the risk of liver metastasis in non-functional GEP-NENs. It facilitates early identification of high-risk patients, thereby enabling personalized treatment and timely intervention. Future research should focus on multicenter validation and the integration of molecular markers to enhance the robustness and clinical applicability of the model.

Neuroendocrine neoplasms (NENs) of the colon and rectum are a heterogeneous group of epithelial neoplasms with neuroendocrine differentiation. They include well-differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinomas (NECs) and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Our aim was to calculate incidence, incidence trends and relative survival for colonic and rectal NETs, NECs, and MiNENs. We analyzed data covering the entire German population recorded between 2009 and 2021, calculating age-standardized incidence rates, annual percent changes, and the relative 5-year survival probability for the calendar period 2017-2021. Our comprehensive analyses included 12,602 NEN cases, with 59% located in the rectum. NECs, MiNENs and tumors with colonic location showed higher stages. We observed an increase in the incidence of NETs, particularly in patients aged <55 years, and in the incidence of MiNENs, and a constant incidence of NECs. The relative five-year survival was high for rectal NETs (95.9%, 95%-CI 94.6; 97.1) and colonic NETs (81.4%, 95%-CI 78.3; 84.5) and low for colonic NECs (20.5%, 95%-CI 17.6; 23.4) and rectal NECs (19.2%, 95%-CI 15.7; 22.6). The increase in the incidence of NETs might be partly due to colorectal cancer screening, improved diagnostics, and changes in classification of NETs. We attribute the increase in incidence of MiNENs to the recent introduction of this morphological category. Higher stages at diagnosis, a higher proportion of NECs and higher median age at diagnosis may contribute to the less favorable survival probabilities associated with colonic as opposed to rectal location.

Objectives: The aim of this study was to investigate the treatment patterns and outcomes in two propensity score-matched cohorts of patients with neuroendocrine tumours (NETs) treated with first-line somatostatin analogue (SSA). Methods: Metastatic NET patients treated with first-line SSA (2009-2022) were retrospectively examined. First-line lanreotide vs. octreotide cohorts were matched 1:1 by propensity scores for demographics, tumour characteristics, and diagnosis year. Progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan-Meier analysis and the Cox proportional hazards model. Results: Among 441 patients, 310 were matched (155 in both the octreotide and lanreotide groups). First-line SSA was monotherapy (63.5%) or combination with other medications (36.5%). A total of 77% of second-line patients (188/244) maintained their initial SSA medication in combination with other therapies. Radioligand therapy with lanreotide (N = 72; 29.5%) or octreotide (N = 70; 28.7%) was the most common second-line treatment. First-line lanreotide and octreotide cohorts had similar median PFS (15.5; 95% CI: 13.6-19.1 vs. 14.0; 95% CI: 12.0-15.8 months), despite octreotide having a 36% higher likelihood of moving to the second line than lanreotide (95% CI: 1.05-1.76, p = 0.018). Multiple metastases (HR = 1.45; p = 0.004, 95% CI: 1.13-1.87) and Ki-67 > 20% (HR = 2.34; p < 0.001, 95% CI: 1.43-3.83) were significantly associated with the worst PFS. First-line lanreotide patients had a median OS of 10.4 years (95% CI: 7.5-NA) and octreotide 9.2 years (95% CI: 7.3-NA) (p = 0.537). Bone metastases increased death risk by 91% (p = 0.014; 95% CI: 1.14-3.20). Conclusions: SSA monotherapy is the main first-line treatment and most subsequent treatments include SSA with additional medications. Cohorts had similar PFS/OS, but octreotide demonstrated a 36% significantly higher likelihood of moving to the second-line treatment.

Objectives: While the treatment of non-small-cell lung carcinoma has improved rapidly, the treatment of pulmonary large-cell neuroendocrine carcinoma (LCNEC) remains underdeveloped. The use of immunohistochemistry allows for accurate risk stratification. With our study, we investigated the outcome of patients with pulmonary LCNEC and analyzed whether CK7 correlates with long-term survival. Methods: We retrospectively collected the monocentric data of patients which underwent anatomical resection for lung cancer between January 2012 and December 2020. Patients that did not show pulmonary LCNEC or adenocarcinoma, had a positive resection margin, or underwent neoadjuvant therapy were excluded. The long-term survival rate of the LCNEC and adenocarcinoma groups were compared before and after propensity score matching. Furthermore, we performed survival analyses for a subgroup of LCNEC distinguished by CK7 expression, followed by Cox regression analyses. Results: A total of 466 patients were integrated for further analysis. The mean age was 65.3 ± 9.6 years. There were no significant differences between both groups regarding age, gender, or comorbidities. In terms of the UICC stage, the groups were equally distributed. Mean survival in the LCNEC group was significantly worse than in the adenocarcinoma group (LCENC: 36.4 ± 7.5 months; adenocarcinoma: 80.7 ± 8.1 months; p-value = 0.001). The mean survival rate was 19.23 ± 4.8 months in the CK7 expression group and 57.01 ± 8.5 months in the group without expression, which reached statistical significance (p-value = 0.019). Conclusions: Our study suggests that pulmonary LCNEC has a significantly worse prognosis than pulmonary adenocarcinoma. CK7 expression seems to be correlated with a worse outcome for the long-term survival rate of patients suffering from highly malignant pulmonary LCNEC.

The parathyroid-hormone-related peptide has been shown in earlier studies to be secreted by pancreatic neuroendocrine tumors, although its secretion by gastroenteropancreatic neuroendocrine tumors is very rare. In contrast, a number of solid tumors, such as lung cancer and renal cell carcinoma, have frequently been shown to secrete parathyroid-hormone-related peptide.

We describe a case report of a 53-year-old Canadian white patient with refractory parathyroid-hormone-related-peptide-mediated hypercalcemia associated with metastatic pancreatic neuroendocrine tumors and review the available research. Our patient had severe hypercalcemia initially refractory to treatment. Computed tomography scan of the abdomen revealed a pancreatic lesion and multiple hepatic metastases. A liver biopsy confirmed metastatic pancreatic neuroendocrine tumor expressing parathyroid-hormone-related peptide. Circulating parathyroid-hormone-related peptide levels were at the upper limit of normal preoperatively and decreased sharply postoperatively following debulking of the tumor. Blood calcium levels eventually normalized on long-term administration of the somatostatin analog lanreotide in combination with denosumab.

We describe a case with parathyroid-hormone-related-peptide-mediated hypercalcemia in a pancreatic neuroendocrine tumor (parathyroid-hormone-related peptide tumor). Refractory hypercalcemia was likely the result of parathyroid-hormone-related peptide overproduction by the tumor and resolved following normalization of parathyroid-hormone-related peptide levels.

Our retrospective single-center study aims to evaluate the impact of structured reporting (SR) using a self-developed template on report quality compared to free-text reporting (FTR) in [18F]SiTATE Positron Emission Tomography/Computer Tomography (PET/CT) for the primary staging and therapy monitoring of patients diagnosed with neuroendocrine tumors (NET). In total 50 patients were included. FTRs and SRs were generated post-examination. All reports were evaluated by a radiologist and a surgeon through a questionnaire to determine their contribution to facilitating clinical decision-making and to assess their completeness, linguistic quality, and overall quality. SR significantly increased the capacity of facilitating therapy decision-making from 32% in FTR to 55% in SR (p < 0.001). Trust in the report was significantly higher in SR with a mean of 5.0 (SD = 0.5) vs. 4.7 (SD = 0.5) for FTR (p < 0.001). SR received significantly higher mean ratings regarding linguistic quality with 4.7 for SR vs. 4.4 for FTR (p = 0.004) and overall report quality with a mean of 4.9 for SR vs. 4.6 for FTR (p < 0.001). Concluding that SR enhances the overall quality of reports in [18F]SiTATE-PET/CTs for NET staging, serving as a tool to streamline clinical decision-making and enhance interdisciplinary communication in the future.

This study investigated the detection rate of colorectal neuroendocrine neoplasms (NENs) using large-scale colonoscopy data.

This cross-sectional analysis used large-scale data from a Japanese multicenter observational study of colonoscopies performed from 2010 to 2020.

Among 82,005 colonoscopy cases, colorectal NENs were identified in 71 (67 of which were neuroendocrine tumors), with a detection rate of 0.087% (95% confidence interval: 0.069-0.109). Most were small rectal lesions, with only 4 >10 mm in size and 3 located in the colon.

The detection rate of colorectal NENs during colonoscopy is substantially higher than expected.

Rectal neuroendocrine tumors (NETs) are rare neoplasms that are usually asymptomatic and diagnosed incidentally. There are limited data on the presentation and management of high-grade poorly differentiated large friable rectal NETs. We report the first case of an 87-year-old male who presented with chronic diarrhea and subsequently had severe hematochezia complicated by hemorrhagic shock and cardiac arrest and was diagnosed with a 7-cm high-grade friable rectal NET. Our case sheds light on the need to consider NETs in cases of chronic diarrhea and on the importance of endoscopy-guided biopsy in the diagnosis and categorization, which can guide management.

Neuroendocrine tumors (NETs), although rare, are considered one of the most common gastrointestinal and bronchopulmonary pediatric neoplasms. We aimed to determine the incidence, tumor characteristics, management, and outcome of NETs and explore the role of genetic predisposition, focusing on low and intermediate grade tumors.

Using the Danish National Pathology Registry, we conducted a nationwide retrospective study including all Danish children aged ≤18 years diagnosed with a pathology-proven NET between 1995 and 2020.

We identified 220 patients, with a 1.89:1 female to male ratio. The yearly incidence was 6.84 per 1 million children, with no significant change in incidence throughout the observation period. NETs were located in the appendix (93.2%), the pulmonary system (4.5%), and pancreas (2.3%). One recurrence was noted in the pancreas in a genetically predisposed patient with multiple neuroendocrine neoplasia type 1 (MEN1), resulting in an overall recurrence rate of 0.5% (0% in appendiceal NETs; 0% in bronchopulmonary NETs; 20.0% in pancreatic NETs). No NET-related mortality was registered. Four patients had a known predisposing genetic condition, one appendiceal NET associated with neurofibromatosis type 1, and three pancreatic NETs associated with MEN1. Postsurgical surveillance regimes, choice of tumor markers, and imaging modality varied throughout the study period.

We confirmed a stable incidence of pediatric NETs during the study period. The overall recurrence rate was 0.5% and no NET-related mortality was observed. Known genetic predisposition was present in 1.8% of patients. Future guidelines should consider the apparent indolent nature and excellent prognosis of these tumors.

Patients with neuroendocrine tumor liver metastases (NETLMs) may develop carcinoid syndrome, carcinoid heart disease, or other symptoms from overproduction of hormones. Hepatic resection and cytoreduction is the most direct treatment of NETLMs in eligible patients, and cytoreduction improves symptoms, may reduce the sequelae of carcinoid syndrome, and extends survival. Parenchymal-sparing procedures, such as ablation and enucleation, should be considered during cytoreduction to maximize treatment of multifocal tumors while preserving healthy liver tissue. For patients with large hepatic tumor burdens, high-grade disease, or comorbidities precluding surgery, liver-directed and systemic therapies can be used to palliate symptoms and improve progression-free survival.

Liver metastasis impacts survival in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs); however, current guidelines lack consensus on post-resection surveillance and adjuvant therapy. A comprehensive risk stratification tool is needed to guide personalized management.

We aimed to develop and validate a predictive model for liver metastasis risk after surgical resection of GEP-NETs that incorporates pathological factors and adjuvant therapy.

Patients with GEP-NETs who underwent surgical resection with curative intent at three major Chinese hospitals (2010-2022) were identified. Univariable and multivariable Cox regression analysis identified independent risk factors of liver metastasis. The liver metastasis score (LMS) was developed using weighted risk factors and validated by tenfold cross-validation.

Among the 724 patients included in the analytic cohort, liver metastasis occurred in 66 patients (9.1%) at a median of 36 months; patients with liver metastasis had a worse 5-year overall survival (no liver metastasis 63.6% vs. liver metastasis 95.8%; p < 0.001). Independent predictors were Ki-67 index (hazard ratio [HR] 10.36 for Ki-67 3-20%, HR 18.30 for Ki-67 >20%, vs. <3%), vascular invasion (HR 5.03), lymph node metastases (HR 2.24), and lack of adjuvant therapy (HR 3.03). The LMS demonstrated excellent discrimination (C-index 0.888) and stratified patients into low, intermediate, and high-risk relative to 5-year risk of liver metastasis: 2.9%, 20.8%, and 49.7%, respectively (p < 0.001).

The novel LMS effectively predicted the risk of liver metastasis after surgical resection of GEP-NETs. This validated model can help guide personalized surveillance and adjuvant treatment strategies, potentially improving outcomes for high-risk patients.

Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from enterochromaffin cells that can arise from the gastrointestinal (GI) tract and pancreas. Surgical management is the cornerstone of treatment, with the optimal approach tailored by tumor grade, size, location, and presence of metastasis. This review discusses the current strategies for the surgical management of NETs of the gastroenteropancreatic tract.

A review of the available literature was conducted to evaluate surgical approaches to NETs. Consensus guidelines were incorporated to synthesize evidence-based recommendations.

For gastric NETs, surgical approach depends on Rindi Classification, WHO grade, and tumor size, with endoscopic approaches favored for smaller and low-grade lesions. Small bowel NETs can be multifocal and thus often require a surgical approach with careful evaluation of the entire intestine. Pancreatic NETs are categorized as functional or non-functional, with enucleation or formal resection strategies based on size, location, functional status, and risk of malignancy. Colorectal NETs are primarily treated with transanal localized or formal surgical resection, depending on lesion size and depth of invasion or presence of lymph node involvement. Appendiceal NETs are either treated with appendectomy or right hemicolectomy, depending on the size, location, and invasiveness of the lesions. For metastatic NETs, cytoreduction, liver transplantation, and targeted therapies offer symptom relief and possible survival benefits.

Surgical resection provides curative potential for localized NETs and symptom control in metastatic cases. Future research is essential to refine guidelines for intermediate-risk lesions and multifocal tumors, ensuring optimal outcomes for patients with gastroenteropancreatic NETs.

Colorectal neuroendocrine tumors with liver metastases (CRNELM) are associated with a poorer prognosis compared to their nonmetastatic counterparts. A comprehensive understanding of the tumor microenvironment (TME) heterogeneity between primary lesions (PL) and liver metastases (LM) could provide crucial insights for enhancing clinical management strategies for these patients.

We utilized single-cell RNA sequencing to analyze fresh tissue samples from CRNELM patients, aiming to elucidate the variations in TME between PL and LM. Complementary multidimensional validation was achieved through spatial transcriptomics, bulk RNA sequencing, and multiplex immunohistochemistry/immunofluorescence.

Our single-cell RNA sequencing analysis revealed that LM harboured a higher proportion of CD8 + T cells, CD4 + T cells, NK cells, NKT cells, and B cells exhibiting a stress-like phenotype compared to PL. RGS5 + pericytes may play a role in the stress-like phenotype observed in immune cells within LM. MCs in PL (PL_MCs) and LM (LM_MCs) exhibit distinct activation of tumor-associated signaling pathways. Notably, COLEC11 + matrix cancer-associated fibroblasts (COLEC11_mCAFs) were found to be significantly associated with LM_MCs. Cell communication analysis unveiled potential targetable receptor-ligand interactions between COLEC11_mCAFs and LM_MCs. Multidimensional validation confirmed the prominence of the characteristic stress-like phenotypes, including HSPA6_CD8_Tstr, HSPA6_NK, and COLEC11_mCAFs in LM. Moreover, a higher abundance of COLEC11_mCAFs correlated with poorer survival rates in the neuroendocrine tumor patient cohort.

Overall, our study provides the first single-cell analysis of the cellular and molecular differences between PL and LM in CRNELM patients. We identified distinct cell subsets and receptor-ligand interactions that may drive TME discrepancies and support metastatic tumor growth. These insights highlight potential therapeutic targets and inform strategies for better managing CRNELM patients.

Advanced lesions are often ignored in well-differentiated colorectal neuroendocrine neoplasms (NENs) smaller than 2 cm, and we aimed to develop an effective nomogram for these lesions.

We extracted data from the Surveillance, Epidemiology, and End Results (SEER) database and used a logistic regression model to identify independent risk factors for advanced disease. All these identified factors were included to construct the prediction model, and the receiver operating characteristic (ROC) curve, calibration plot and DCA curve were utilized to assess the predictive value. The data obtained from the National Cancer Center were utilized for external validation.

In total, 3223 patients were enrolled in the training set, including 2947 (91.4 %) with early disease and 276 (8.6 %) with advanced disease. The logistic analysis showed that age (odds ratio (OR) = 1.486, 95 % confidence interval (CI): 1.102-2.003, P = 0.009), tumor size (OR = 11.071, 95 % CI: 8.229-14.893, P < 0.001), tumor location (OR = 7.882, 95 % CI: 5.784-10.743, P < 0.001) and tumor grade (OR = 1.768, 95 % CI: 1.206-2.593, P = 0.004) were independent variables for advanced disease. All of them were included in the final prediction model. The area under the ROC curve (AUC) was 0.838 (95 % CI: 0.807-0.868). The calibration plot and Hosmer‒Lemeshow test (P = 0.108) indicated favorable consistency between the predicted probabilities and actual probabilities of advanced disease. The Brier score was 0.108, indicating acceptable overall performance. The DCA curve presented a significant clinical net benefit. In the validation set, both the ROC curve and calibration plot exhibited an acceptable discrimination ability (AUC = 0.807 (95 % CI 0.702-0.913) and calibration (Hosmer Lemeshow P = 0.997), respectively.

The prediction model had good value for identifying advanced disease from well-differentiated colorectal NENs smaller than 2 cm.

The molecular mechanisms underlying adrenal and thyroid neuroendocrine tumors, including their tumorigenesis, progression, and metastasis, involve unique pathways regulating cell cycle progression. To better understand these mechanisms and pathways, extensive in-depth research on cell cycle-related genes is necessary. This review aims to describe and interpret current single-cell RNA sequencing studies on neuroblastoma, medullary thyroid cancer, and pheochromocytoma tumors. Our review summarizes differentially expressed cell cycle-related genes with distinct functions, highlighting their potential as therapeutic targets and components of panels used to determine tumor type or aggressiveness. Although some insights have been gained, there is still limited information on these topics, and further research is required to explore the regulatory mechanisms of these tumors.

In recent years, the incidence of patients with colorectal neuroendocrine neoplasms (CRNENs) has been continuously increasing. When diagnosed, most patients have distant metastases. Liver metastasis (LM) is the most common type of distant metastasis, and the prognosis is poor once it occurs. However, there is still a lack of large studies on the risk and prognosis of LM in CRNENs. This study aims to identify factors related to LM and prognosis and to develop a predictive model accordingly.

In this study, the Surveillance, Epidemiology, and End Results (SEER) database was used to collect clinical data from patients with CRNENs. The logistic regression analyses were conducted to identify factors associated with LM in patients with CRNENs. The patients with LM formed the prognostic cohort, and Cox regression analyses were performed to evaluate prognostic factors in patients with liver metastasis of colorectal neuroendocrine neoplasms (LM-CRNENs). Predictive and prognostic nomogram models were constructed based on the multivariate logistic and Cox analysis results. Finally, the capabilities of the nomogram models were verified through model assessment metrics, including the receiver operating characteristic (ROC) curves, calibration curve, and decision curve analysis (DCA) curve.

This study ultimately encompassed a total of 10,260 patients with CRNENs. Among these patients, 501 cases developed LM. The result of multivariate logistic regression analyses indicated that histologic type, tumor grade, T stage, N stage, lung metastasis, bone metastasis, and tumor size were independent predictive factors for LM in patients with CRNENs (p < 0.05). Multivariate Cox regression analyses indicated that age, primary tumor site, histologic type, tumor grade, N stage, tumor size, chemotherapy, and surgery were independent prognostic factors (p < 0.05) for patients with LM-CRNENs. The predictive and prognostic nomogram models were established based on the independent factors of logistic and Cox analyses. The nomogram models can provide higher accuracy and efficacy in predicting the probability of LM in patients with CRNENs and the prognosis of patients with LM.

The factors associated with the occurrence of LM in CRNENs were identified. On the other hand, the relevant prognostic factors for patients with LM-CRNENs were also demonstrated. The nomogram models, based on independent factors, demonstrate greater efficiency and accuracy, promising to provide clinical interventions and decision-making support for patients.