Nonfunctioning Pancreatic Neuroendocrine Tumors Research Articles

Identifying target ion channel-related genes to construct a diagnosis model for insulinoma.

Background: Insulinoma is the most common functional pancreatic neuroendocrine tumor (PNET) with abnormal insulin hypersecretion. The etiopathogenesis of insulinoma remains indefinable. Based on multiple bioinformatics methods and machine learning algorithms, this study proposed exploring the molecular mechanism from ion channel-related genes to establish a genetic diagnosis model for insulinoma. Methods: The mRNA expression profile dataset of GSE73338 was applied to the analysis, which contains 17 insulinoma samples, 63 nonfunctional PNET (NFPNET) samples, and four normal islet samples. Differently expressed ion channel-related genes (DEICRGs) enrichment analyses were performed. We utilized the protein-protein interaction (PPI) analysis and machine learning of LASSO and support vector machine-recursive feature elimination (SVM-RFE) to identify the target genes. Based on these target genes, a nomogram diagnostic model was constructed and verified by a receiver operating characteristic (ROC) curve. Moreover, immune infiltration analysis, single-gene gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) were executed. Finally, a drug-gene interaction network was constructed. Results: We identified 29 DEICRGs, and enrichment analyses indicated they were primarily enriched in ion transport, cellular ion homeostasis, pancreatic secretion, and lysosome. Moreover, the PPI network and machine learning recognized three target genes (MCOLN1, ATP6V0E1, and ATP4A). Based on these target genes, we constructed an efficiently predictable diagnosis model for identifying insulinomas with a nomogram and validated it with the ROC curve (AUC = 0.801, 95% CI 0.674-0.898). Then, single-gene GSEA analysis revealed that these target genes had a significantly positive correlation with insulin secretion and lysosome. In contrast, the TGF-beta signaling pathway was negatively associated with them. Furthermore, statistically significant discrepancies in immune infiltration were revealed. Conclusion: We identified three ion channel-related genes and constructed an efficiently predictable diagnosis model to offer a novel approach for diagnosing insulinoma.

Metabolic intervention by low carbohydrate diet suppresses the onset and progression of neuroendocrine tumors

Insulin signaling often plays a role in the regulation of cancer, including tumor initiation, progression, and response to treatment. In addition, the insulin-regulated PI3K-Akt-mTOR pathway plays an important role in the regulation of islet cell proliferation, and this pathway is hyperactivated in human non-functional pancreatic neuroendocrine tumors (PanNETs). We, therefore, investigated the effect of a very low carbohydrate diet (ketogenic diet) on a mouse model that develops non-functional PanNETs to ask how reduced PI3K-Akt-mTOR signaling might affect the development and progression of non-functional PanNET. We found that this dietary intervention resulted in lower PI3K-Akt-mTOR signaling in islet cells and a significant reduction in PanNET formation and progression. We also found that this treatment had a significant effect on the suppression of pituitary NET development. Furthermore, we found that non-functional PanNET patients with lower blood glucose levels tend to have a better prognosis than patients with higher blood glucose levels. This preclinical study shows that a dietary intervention that results in lower serum insulin levels leads to lower insulin signals within the neuroendocrine cells and has a striking suppressive effect on the development and progression of both pancreatic and pituitary NETs.

A Novel Observational Strategy for Nonfunctional Pancreatic Neuroendocrine Neoplasms With Texture Analysis: A Multicenter Retrospective Study.

Surgical resection is recommended for nonfunctional pancreatic neuroendocrine neoplasms (NF-pNENs). However, metastasis is rare in patients with small lesions with histological grade 1 (G1); thus, observation is an optional treatment approach for small NF-pNENs. Texture analysis (TA) is an imaging analysis mode for quantification of heterogeneity by extracting quantitative parameters from images. We retrospectively evaluated the utility of TA in predicting histological grade of resected NF-pNENs in a multicenter retrospective study. The utility of TA in preoperative prediction of grade were evaluated with 29 patients treated by pancreatectomy for NF-pNEN who underwent preoperative dynamic computed tomography scan between January 1, 2013 and December 31, 2020 at three hospitals affiliated with the Jikei University School of Medicine. TA was performed with dedicated software for medical imaging processing for determining histological tumor grade using dynamic computed tomography images. Histological tumor grades based on the 2017 World Health Organization Classification for Pancreatic Neuroendocrine Neoplasms were grade 1, 2 and 3 in 18, 10 and one patient, respectively. Preoperative grades by TA were 1 and 2/3 in 15 and 14 patients, respectively. The sensitivity, specificity and area under the curve for TA-oriented grade 1 lesions were 1.00, 0.889 and 0.965 (95% confidence interval=0.901-1.000), respectively. TA is useful for predicting grade 2/3 NF-pNEN and can provide a safe option for observation for patients with small grade 1 lesions.

Long-Term Outcomes of Tuberous Sclerosis Complex-Associated Non-functional Pancreatic Neuroendocrine Tumors: Should We Be More Conservative?

BackgroundHereditary syndromes such as tuberous sclerosis complex (TSC) account for 10% of pancreatic neuroendocrine tumors (PNETs). Surgical intervention is the current standard of care for sporadic PNETs (spPNETs) that are >2 cm in size. We compared the long-term outcomes of resected TSC-PNETs with patients with spPNETs.MethodsWe conducted a retrospective review of perioperative data and outcomes of TSC-PNETs compared with spPNETs. Inclusion criteria involved selecting patients whose tumors were no larger than 5.1 cm, the maximum size observed in the TSC-PNET group.ResultsOf the 347 patients resected for PNETs, 14 were TSC-PNETs and 241 were non-functional spPNETs. The median age for the whole cohort was 56 years (interquartile range [IQR] 21.0) and 47% were female. The median follow-up was 103.8 months (95% confidence interval [CI] 89.2–118.6). Specifically, 14 patients with TSC-PNETs and 194 patients with spPNETs were included. Compared with spPNETs, patients with TSC-PNETs were operated on at a younger age (24.0 vs. 57.5 years; p < 0.001), were more frequently multifocal (28.5% vs. 0.0%; p < 0.001), were more likely to undergo minimally invasive operations (78.6% vs. 24.3%; p < 0.001), and had more R1 resections (28.6% vs. 5.7%; p = 0.006). Local and distant tumor recurrence was only observed in the spPNET group. The 5-year mortality rates for the spPNET and TSC-PNET groups were 6.2% and 0.0%, respectively. No PNET-related deaths were observed among TSC-PNETs.ConclusionNone of the TSC-PNET patients recurred after a median follow-up of 78.0 months. The risk-benefit of aggressive pancreatic operations in TSC-PNET patients is still unclear and our findings suggest a conservative approach should be considered.

Dysglycemia in non-functioning pancreatic neuroendocrine tumors (NF-PNET): Further insights into an under recognized entity

ObjectivePancreatic neuroendocrine tumors (PNETs) are rare, but their incidence has risen significantly in recent years. Whereas diabetes mellitus (DM) is recognized in association with chronic pancreatitis and pancreatic cancer, it has not been well-characterized concerning non-functioning (NF)-PNETs.Study aim:to determine whether NF-PNETs are associated with DM/ Pre-DM and characterize the features of this putative association. MethodsRetrospective study to evaluate rate of Pre-DM /DM in subjects with NF-PNETs. ResultsStudy cohort of 129 patients with histologically confirmed NF-PNETs, ∼60% were men (M/F: 77/52). Abnormal glucose metabolism that preceded any treatment was seen in 70% of this cohort: overt DM in 34% and Pre-DM in 36% of the subjects. However, during follow-up, the overall prevalence rose to 80.6%, owing exclusively to newly diagnosed DM in subjects who received treatment.Patients with DM/Pre-DM were older (65 ± 11; 54 ± 14; p < 0.0001), the tumor was more commonly localized in the pancreatic body and tail (76.5% vs. 23.5% p = 0.03), while BMI (27 ± 6 vs. 28 ± 5 kg/m2), and tumor size (2.4 ± 2 vs. 2.9 ± 3.2 cm) were similar. The relative prevalence of DM in our cohort of NF-PNETs was 1.6 higher than that in the age and gender-adjusted general Israeli population (95 %CI: 1.197–2.212p = 0.03). ConclusionsWe found a high rate of impaired glucose metabolism, either DM or Pre-DM, in a large cohort of NF-PNETs. The high prevalence of diabetes/pre-diabetes was unrelated to obesity or tumor size. This observation should increase awareness of the presence of DM on presentation or during treatment of “NF”-PNETs.

Accurate non-invasive grading of nonfunctional pancreatic neuroendocrine tumors with a CT derived radiomics signature

PurposeThe purpose of this study was to develop a radiomics-signature using computed tomography (CT) data for the preoperative prediction of grade of nonfunctional pancreatic neuroendocrine tumors (NF-PNETs). Materials and methodsA retrospective study was performed on patients undergoing resection for NF-PNETs between 2010 and 2019. A total of 2436 radiomic features were extracted from arterial and venous phases of pancreas-protocol CT examinations. Radiomic features that were associated with final pathologic grade observed in the surgical specimens were subjected to joint mutual information maximization for hierarchical feature selection and the development of the radiomic-signature. Youden-index was used to identify optimal cutoff for determining tumor grade. A random forest prediction model was trained and validated internally. The performance of this tool in predicting tumor grade was compared to that of EUS-FNA sampling that was used as the standard of reference. ResultsA total of 270 patients were included and a fusion radiomic-signature based on 10 selected features was developed using the development cohort (n = 201). There were 149 men and 121 women with a mean age of 59.4 ± 12.3 (standard deviation) years (range: 23.3–85.0 years). Upon internal validation in a new set of 69 patients, a strong discrimination was observed with an area under the curve (AUC) of 0.80 (95% confidence interval [CI]: 0.71–0.90) with corresponding sensitivity and specificity of 87.5% (95% CI: 79.7–95.3) and 73.3% (95% CI: 62.9–83.8) respectively. Of the study population, 143 patients (52.9%) underwent EUS-FNA. Biopsies were non-diagnostic in 26 patients (18.2%) and could not be graded due to insufficient sample in 42 patients (29.4%). In the cohort of 75 patients (52.4%) in whom biopsies were graded the radiomic-signature demonstrated not different AUC as compared to EUS-FNA (AUC: 0.69 vs. 0.67; P = 0.723), however greater sensitivity (i.e., ability to accurately identify G2/3 lesion was observed (80.8% vs. 42.3%; P < 0.001). ConclusionNon-invasive assessment of tumor grade in patients with PNETs using the proposed radiomic-signature demonstrated high accuracy. Prospective validation and optimization could overcome the commonly experienced diagnostic uncertainty in the assessment of tumor grade in patients with PNETs and could facilitate clinical decision-making.

Consensus of clinical diagnosis and treatment for non-functional pancreatic neuroendocrine neoplasms with diameter &lt;2 cm

In clinical practice, pancreatic neuroendocrine neoplasms (pNENs) with a diameter smaller than 2 cm are commonly referred to as small pNENs. Due to their generally favorable biological characteristics, the diagnosis and treatment of small pNENs differ from other pNENs and are somewhat controversial. In response to this, the Chinese Pancreatic Surgery Association, Chinese Society of Surgery, Chinese Medical Association have developed a consensus on the diagnosis and treatment of small pNENs, which is based on evidence-based medicine and expert opinions. This consensus covers various topics, including concepts, disease assessment, treatment selection, follow-up, and other relevant aspects.

Radiomics analysis from magnetic resonance imaging in predicting the grade of nonfunctioning pancreatic neuroendocrine tumors: a multicenter study

ObjectivesTo explore the potential of radiomics features to predict the histologic grade of nonfunctioning pancreatic neuroendocrine tumor (NF-PNET) patients using non-contrast sequence based on MRI.MethodsTwo hundred twenty-eight patients with NF-PNETs undergoing MRI at 5 centers were retrospectively analyzed. Data from center 1 (n = 115) constituted the training cohort, and data from centers 2–5 (n = 113) constituted the testing cohort. Radiomics features were extracted from T2-weighted images and the apparent diffusion coefficient. The least absolute shrinkage and selection operator was applied to select the most important features and to develop radiomics signatures. The area under receiver operating characteristic curve (AUC) was performed to assess models.ResultsTumor boundary, enhancement homogeneity, and vascular invasion were used to construct the radiological model to stratify NF-PNET patients into grade 1 and 2/3 groups, which yielded AUC of 0.884 and 0.684 in the training and testing groups. A radiomics model including 4 features was constructed, with an AUC of 0.941 and 0.871 in the training and testing cohorts. The fusion model combining the radiomics signature and radiological characteristics showed good performance in the training set (AUC = 0.956) and in the testing set (AUC = 0.864), respectively.ConclusionThe developed model that integrates radiomics features with radiological characteristics could be used as a non-invasive, dependable, and accurate tool for the preoperative prediction of grade in NF-PNETs.Clinical relevance statementOur study revealed that the fusion model based on a non-contrast MR sequence can be used to predict the histologic grade before operation. The radiomics model may be a new and effective biological marker in NF-PNETs.Key PointsThe diagnostic performance of the radiomics model and fusion model was better than that of the model based on clinical information and radiological features in predicting grade 1 and 2/3 of nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs).Good performance of the model in the four external testing cohorts indicated that the radiomics model and fusion model for predicting the grades of NF-PNETs were robust and reliable, indicating the two models could be used in the clinical setting and facilitate the surgeons’ decision on risk stratification.The radiomics features were selected from non-contrast T2-weighted images (T2WI) and diffusion-weighted imaging (DWI) sequence, which means that the administration of contrast agent was not needed in grading the NF-PNETs.

Observational study of surgical resection in small non-functional pancreatic neuroendocrine tumors: AS SEER-based study

The potential benefits of surgical resection for small non-functional pancreatic neuroendocrine tumors (NF-PNETs) in terms of survival remain uncertain. This study aimed to evaluate the impact of surgical treatment on patients with NF-PNETs. Using SEER data, we identified 1102 patients from 2004 to 2015 with well and moderately differentiated pancreatic neuroendocrine tumors (PNETs). The associations between continuous variables and receipt of surgery were assessed using Wilcoxon rank-sum tests. Kaplan–Meier survival curves for OS were compared using the log-rank test. We compared outcomes in patients who received surgical resection with those in patients who did not, using a univariable Cox model with inverse probability weighting according to the propensity score and propensity-score matching. Among the cohort of 1102 patients, a majority of 965 individuals (87%) underwent surgical intervention. Upon conducting univariate analysis, we observed that surgical treatment significantly prolonged patients' survival [HR = 0.41, 95% CI [0.26–0.65] P < 0.001]. However, the old [HR = 3.27, 95% CI (2.24–4.76), P 0.001], male gender [HR = 1.82, 95% CI (1.23–2.68), P = 0.003], and moderately well-differentiated factors [HR = 1.71, 95% CI (1.04–2.80), P = 0.034] were found to potentially decrease patients' survival time. In the multivariate analysis, male gender [HR = 1.73, 95% CI (1.15–2.61), P = 0.009] and the old factor [HR = 3.52, 95% CI (2.33–5.31), P < 0.001] emerged as influential predictors with higher hazard ratios. Notably, surgical treatment remained a significant factor associated with improved overall survival [HR = 0.53, 95% CI (0.33–0.84), P = 0.007]. Propensity-score matching and inverse probability weighting were employed as analytical techniques. The univariate analysis results showed favorable outcomes in the weight group [HR = 0.48, 95% CI (0.29–0.78), P = 0.003] and matched group [HR = 0.44, 95% CI (0.22–0.85), P = 0.015], respectively. Survival analysis further confirmed that surgical treatment contributed to increased overall survival (log rank, P < 0.05) in both the matching and weight groups. Patients diagnosed with small, non-functioning pancreatic neuroendocrine tumors who undergo surgical intervention exhibit improved overall survival (OS) outcomes. Therefore, surgery is strongly recommended for this patient population.

A predictive model for recurrence in non-functional pancreatic neuroendocrine tumors based on preoperative evaluation using endoscopic ultrasound-guided biopsy

Ye Won JEON, Woohyung LEE*, Yejong PARK, Bong Jun KWAK, Eunsung JUN, Ki Byung SONG, Dae Wook HWANG, Jae Hoon LEE, Song Cheol KIM. Ann Hepatobiliary Pancreat Surg 2023;27:S351. https://doi.org/10.14701/ahbps.2023S1.EP-84

Response to Commentary on '"Long-Term Outcomes of Parenchyma-Sparing and Oncologic Resections in Patients With Nonfunctional Pancreatic Neuroendocrine Tumors

Response to Commentary on '"Long-Term Outcomes of Parenchyma-Sparing and Oncologic Resections in Patients With Nonfunctional Pancreatic Neuroendocrine Tumors <3 cm in a Large Multicenter Cohort".

Metastatic insulinoma: exploration from clinicopathological signatures and genetic characteristics.

Insulinoma is a rare type of pancreatic neuroendocrine tumor with low incidence and low-malignant features. While very few insulinomas present with malignant behaviours, such as lymph node and liver metastasis, only a few studies have focused on this field owing to the limitation of samples. Existing evidence suggests that metastatic insulinoma largely derive from non-functional pancreatic neuroendocrine tumor. However, we found a portion of metastatic insulinomas may derive from non-metastatic insulinomas and explored their clinicopathological signatures and genetic characteristics. Four metastatic insulinoma patients with synchronous liver metastasis or lymph node metastasis at the Peking Union Medical College Hospital between October 2016 and December 2018 were enrolled, and whole exon and genome sequencing were performed on fresh frozen tissues and peripheral blood samples. Clinicopathological information and genomic sequencing results were collected and matched to explore the characteristics of the metastatic insulinomas. These four metastatic insulinoma patients underwent surgery or interventional therapy, and their blood glucose levels immediately increased and maintained within standard range after treatment. For these four patients, the proinsulin/insulin molar ratio <1 and primary tumors were all present as PDX1+, ARX-, and insulin+, which were similar to non-metastatic insulinomas. However, the liver metastasis showed PDX1+ and ARX+, insulin+. Meanwhile, genomic sequencing data showed no recurrently mutations and typical CNV patterns. However, one patient harboured the YY1 T372R mutation, a recurrently mutated gene in non-metastatic insulinomas. A portion of metastatic insulinomas were largely derived from non-metastatic insulinomas in hormone secretion and ARX/PDX1 expression patterns. Meanwhile, the accumulation of ARX expression may be involved in the progression of metastatic insulinomas.

Efficacy of endoscopic ultrasound-guided tissue acquisition for solid pancreatic lesions 20mm or less in diameter suspected as neuroendocrine tumors or requiring differentiation.

For non-functioning pancreatic neuroendocrine tumors (pNETs) ≤ 20mm, most guidelines consider follow-up observations as an option; however, the various treatment strategies are defined by size alone, even though the Ki-67 index is important for malignancy grading. Endoscopic ultrasound-guided tissue acquisition (EUS-TA) is the standard for the histopathological diagnosis of solid pancreatic lesions; however, recent results for small lesions remain unclear. Therefore, we examined the efficacy of EUS-TA for solid pancreatic lesions ≤ 20mm suspected as pNETs or requiring differentiation and the non-increase rate in tumor size in follow-up cases. We retrospectively analyzed data of 111 patients (median age = 58years) with lesions ≤ 20mm suspected as pNETs or requiring differentiation who underwent EUS-TA. All patients underwent specimen evaluation by rapid onsite evaluation (ROSE). EUS-TA led to a diagnosis of pNETs in 77 patients (69.4%) and tumors other than pNETs in 22 patients (19.8%). The histopathological diagnostic accuracy of EUS-TA was 89.2% (99/111) overall, 94.3% (50/53) for 10-20mm lesions, and 84.5% (49/58) for ≤ 10mm lesions, with no significant difference in diagnostic accuracy (p = 0.13). The Ki-67 index was measurable in all patients with a histopathological diagnosis of pNETs. Among 49 patients with a diagnosis of pNETs who were followed up, one patient (2.0%) showed tumor enlargement. EUS-TA for solid pancreatic lesions ≤ 20mm suspected as pNETs or requiring differentiation is safe and has adequate histopathological diagnostic accuracy, suggesting that follow-up observations of pNETs with a histological pathologic diagnosis are acceptable in the short term.

Endoscopic ultrasound fine-needle biopsy to assess DAXX/ATRX expression and alternative lengthening of telomeres status in non-functional pancreatic neuroendocrine tumors

Background/objectivesDeath domain-associated protein (DAXX) and/or α-thalassemia/mental retardation X-linked (ATRX) chromatin remodeling genes mutations and alternative lengthening of telomeres (ALT) activation are associated with more aggressive behavior of non-functional pancreatic neuroendocrine tumors (NF-PanNETs). We aimed to evaluate the reliability of such markers on endoscopic-ultrasound fine-needle biopsy (EUS-FNB) specimens. MethodsPatients who underwent EUS-FNB and subsequent surgical resection for PanNETs between January 2017 and December 2019 were retrospectively identified. Immunohistochemistry (IHC) to evaluate DAXX/ATRX expression and fluorescence in situ hybridization (FISH) for ALT status were performed. Primary outcome was the concordance rate of markers expression between EUS-FNB and surgical specimens. Secondary aims were association between markers and lesion aggressiveness, their diagnostic performance in predicting aggressiveness, and agreement of preoperative and post-surgical Ki67-based grading. ResultsForty-one NF-PanNETs (mean diameter 36.1 ± 26.5 mm) were included. Twenty-four showed features of lesion aggressiveness. Concordance of expressions of DAXX, ATRX, and ALT status between EUS-FNB and surgical specimens were 95.1% (κ = 0.828; p < 0.001), 92.7% (κ = 0.626; p < 0.001), and 100% (κ = 1; p < 0.001), respectively. DAXX/ATRX loss and ALT-positivity were significantly (p < 0.05) associated with metastatic lymphnodes and lymphovascular invasion. The combination of all tumor markers (DAXX/ATRX loss + ALT-positivity + grade 2) reached an accuracy of 73.2% (95%CI 57.1–85.8) in identifying aggressive lesions. Pre- and post-operative ki-67-based grading was concordant in 80.5% of cases (k = 0.573; p < 0.001). ConclusionDAXX/ATRX expression and ALT status can be accurately evaluated in a preoperative setting on EUS-FNB samples, potentially improving the identification of patients with increased risk and poorer prognosis.

Somatostatin Analogues or Active Surveillance in Sporadic and MEN1 associated Non-functioning Pancreatic Neuroendocrine Tumors

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Comparison of nomogram for Primary Nonfunctional Pancreatic Neuroendocrine Tumors based on the 7th vs 8th edition of the AJCC cancer staging manual.

Our study aimed to construct and validate prognostic nomograms for predicting survival for patients with Nonfunctional Pancreatic neuroendocrine tumor (NF-pNET). This retrospective study included 1824 patients diagnosed with NF-pNET in the Surveillance, Epidemiology and End Results database between 2004 and 2016. Randomization divided the patients into training (n = 1278) and validation (n = 546) cohorts. Prognostic factors were determined using Cox regression analyses, nomograms based on AJCC 7th and 8th staging system were constructed separately. The prediction models were validated using internal validation and external validation. Age, year of diagnosis, primary tumor site, grade, 7th or 8th TNM stage, surgery, tumor size were determined as prognostic indicator to construct two nomograms. Harrell's concordance index (C-index) of two nomograms exhibited a clinical predictive ability of 0.828 (95%CI, 0.808~0.849) vs 0.828 (95% CI, 0.808~0.849) in the internal verification. The c-index in the external validation was 0.812 (95%CI, 0.778~0.864) vs 0.814 (95% CI, 0.779~0.848). The predictive power of the two nomograms is comparable. Our nomogram may be a effective tool for predicting overall survival in patients with NF-pNET. The AJCC 8th-edition system provides discrimination similar to that of the 7th-edition system.

Evaluation of Survival Following Surgical Resection for Small Nonfunctional Pancreatic Neuroendocrine Tumors

The number of patients with small nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs) is increasing. However, the role of surgery for small NF-PanNETs remains unclear. To evaluate the association between surgical resection for NF-PanNETs measuring 2 cm or smaller and survival. This cohort study used data from the National Cancer Database and included patients with NF-pancreatic neuroendocrine neoplasms who were diagnosed between January 1, 2004, and December 31, 2017. Patients with small NF-PanNETs were divided into 2 groups: group 1a (tumor size, ≤1 cm) and group 1b (tumor size, 1.1-2.0 cm). Patients without information on tumor size, overall survival, and surgical resection were excluded. Data analysis was performed in June 2022. Patients with vs without surgical resection. The primary outcome was overall survival of patients in group 1a or group 1b who underwent surgical resection compared with those who did not, which was evaluated using Kaplan-Meier estimates and multivariable Cox proportional hazards regression models. Interactions between preoperative factors and surgical resection were analyzed with a multivariable Cox proportional hazards regression model. Of the 10 504 patients with localized NF-PanNETs identified, 4641 were analyzed. These patients had a mean (SD) age of 60.5 (12.7) years and included 2338 males (50.4%). The median (IQR) follow-up time was 47.1 (28.2-71.6) months. In total, 1278 patients were in group 1a and 3363 patients were in group 1b. The surgical resection rates were 82.0% in group 1a and 87.0% in group 1b. After adjustment for preoperative factors, surgical resection was associated with longer survival for patients in group 1b (hazard ratio [HR], 0.58; 95% CI, 0.42-0.80; P < .001) but not for patients in group 1a (HR, 0.68; 95% CI, 0.41-1.11; P = .12). In group 1b, interaction analysis found that age of 64 years or younger, absence of comorbidities, treatment at academic institutions, and distal pancreatic tumors were factors associated with increased survival after surgical resection. Findings of this study support an association between surgical resection and increased survival in select patients with NF-PanNETs measuring 1.1 to 2.0 cm who were younger than 65 years, had no comorbidities, received treatment at academic institutions, and had tumors of the distal pancreas. Future investigations of surgical resection for small NF-PanNETs that include the Ki-67 index are warranted to validate these findings.

Surgical Management of Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PNETs) are relatively uncommon malignancies, characterized as either functional or nonfunctional secondary to their secretion of biologically active hormones. A wide range of clinical behavior can be seen, with the primary prognostic indicator being tumor grade as defined by the Ki67 proliferation index and mitotic index. Surgery is the primary treatment modality for PNETs. While functional PNETs should undergo resection for symptom control as well as potential curative intent, nonfunctional PNETs are increasingly managed nonoperatively. There is increasing data to suggest small, nonfunctional PNETs (less than 2 cm) are appropriate follow with nonoperative active surveillance. Evidence supports surgical management of metastatic disease if possible, and occasionally even surgical management of the primary tumor in the setting of widespread metastases. In this review, we highlight the evolving surgical management of local and metastatic PNETs.

The Surgical and Therapeutic Activities of Non-Functional Pancreatic Neuroendocrine Tumors at a High-Volume Institution.

This study aimed to summarize the surgical and therapeutic activities of non-functional pancreatic neuroendocrine tumors (NF-PanNETs) and perform survival analyses of a 15-year single-institutional cohort of NF-PanNETs. In total, 1001 patients with neuroendocrine neoplasms treated at Fudan University Shanghai Cancer Center were screened for inclusion, and 509 patients with NF-PanNETs from 2006 to 2020 were included. For time trend analyses, the 15-year study period was randomly divided into three periods. Survival analyses used the Kaplan-Meier method and Cox regression models. The total number of resected NF-PanNETs increased over the 15-year study period, from 5 resections in 2006 to 94 resections in 2020. A significant decrease in the tumor size was observed, from a mean of 4.0 cm to 3.3 cm, and to 3.0 cm in the most recent period (p = 0.006). Minimally invasive techniques gradually increased from 3.5% to 12.9%, and finally to 46.4% in the most recent period (p < 0.001). In non-metastatic and resected tumors, the tumor size (p < 0.001), positive lymph node (p < 0.001), adjuvant treatment (p = 0.048), and tumor grade (p < 0.001) were independent prognostic factors for recurrence-free survival (RFS). The microvascular invasion (p = 0.024) and tumor grade (p = 0.013) were independent prognostic factors for overall survival (OS). A malignant transformation from NET into neuroendocrine carcinoma was observed. An increasing number of NF-PanNETs resection and minimally invasive surgery was shown. In non-metastatic and resected tumors NF-PanNETs, tumor size, positive lymph node, adjuvant treatment, and tumor grade were independent predictors of RFS. Microvascular invasion and tumor grade were independent prognostic factors for OS.

Sporadic pancreatic neuroendocrine neoplasms: A retrospective clinicopathological and outcome analysis from a Latvian study group.

Although pancreatic neuroendocrine neoplasms (PNEN) are rare, there has been a constant increase in incidence. Furthermore, PNEN present unique clinical behaviors and long-term survival can be expected even in the presence of metastases as compared with ductal adenocarcinoma of the pancreas. Determining the best therapeutic approach and proper timing of therapy requires knowledge of reliable prognostic factors. Therefore, the aim of this study was to explore clinicopathological features, treatment, and survival outcomes of patients with PNEN based on Latvian gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) registry data. Patients with confirmed PNEN at Riga East Clinical University Hospital and Pauls Stradins Clinical University Hospital, between 2008 and 2020, were retrospectively analyzed. Data were collected and included in EUROCRINE, an open-label international endocrine surgical registry. In total, 105 patients were included. The median age at diagnosis was 64 years (IQR 53.0-70.0) for males and 61 years (IQR 52.5-69.0) for females. In 77.1% of patients, tumors were hormonally nonfunctional. Among those with functioning PNEN, 10.5% of patients presented with hypoglycemia and were diagnosed with insulinoma, 6.7% of patients presented with symptoms related to carcinoid syndrome; 30.5% of patients showed distant metastases at the time of diagnosis, and surgery was performed in 67.6% of patients. Notably, for five patients with nonfunctional PNEN <2 cm, a "watch and wait" approach was used; none of the patients developed metastatic disease. The median length of hospital stay was 8 days (IQR 5-13). Major postoperative complications were found in 7.0% of patients, and reoperation was conducted for 4.2% of patients, due to postpancreatectomy bleeding (2/71) and abdominal collection (1/71). The median follow-up period was 34 months (IQR 15.0-68.8). The OS at the last follow-up was 75.2% (79/105). The observed 1-, 5- and 10-year survival rates were 87.0, 71.2 and 58.0, respectively. Seven of the surgically treated patients had tumor recurrence. The median time of recurrence was 39 months (IQR 19.0-95.0). A univariable Cox proportional hazard analysis provided evidence that a nonfunctional tumor, a larger tumor size, the presence of distant metastases, a higher tumor grade, and the tumor stage were strong, negative predictors of OS. Our study represents the general trends of clinicopathological features and treatment of PNEN in Latvia. For PNEN patients, tumor functionality, size, distant metastases, grade, and stage may be useful to predict OS and must be confirmed in further studies. Furthermore, a "surveillance" strategy might be safe for selected patients with small asymptomatic PNEN.